Textbook of Female Sexual Function and Dysfunction Diagnosis and Treatment Textbook of Female Sexual Function and Dysfunction

Diagnosis and Treatment

Edited by

Irwin Goldstein, MD, IF Sexual Medicine Alvarado Hospital Department of Surgery University of California, San Diego San Diego Sexual Medicine San Diego, CA, USA Anita H. Clayton, MD, IF, FAPA, FASCP Department of Psychiatry and Neurobehavioral Sciences University of Virginia School of Medicine Charlottesville, VA, USA Andrew T. Goldstein, MD, FACOG, IF Department of Obstetrics and Gynaecology The George Washington University School of Medicine and Health Sciences Centers for Vulvovaginal Disorders Washington, DC, USA Noel N. Kim, PhD, IF Institute for Sexual Medicine San Diego, CA, USA Sheryl A. Kingsberg, PhD, IF Division of Behavioral Medicine Department of OB/GYN University Hospitals Cleveland Medical Center Departments of Reproductive Biology and Psychiatry Case Western Reserve University School of Medicine Cleveland, OH, USA This edition first published 2018 © 2018 by John Wiley & Sons Ltd

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Library of Congress Cataloging‐in‐Publication Data Names: Goldstein, Irwin, editor. | Clayton, Anita H., editor. | Goldstein, Andrew, M.D., editor. | Kim, Noel N., editor. | Kingsberg, Sheryl A., editor. Title: Textbook of female sexual function and dysfunction : diagnosis and treatment/edited by Irwin Goldstein, Anita H. Clayton, Andrew T. Goldstein, Noel N. Kim, Sheryl A. Kingsberg. Description: Hoboken, NJ : Wiley, 2018. | Includes bibliographical references and index. | Identifiers: LCCN 2017055314 (print) | LCCN 2017056729 (ebook) | ISBN 9781119266112 (pdf) | ISBN 9781119266150 (epub) | ISBN 9781119266136 (oBook) | ISBN 9781119266099 (cloth) Subjects: | MESH: Sexual Dysfunction, Physiological–diagnosis | Sexual Dysfunction, Physiological–therapy | Women | Sexuality–physiology Classification: LCC RC556 (ebook) | LCC RC556 (print) | NLM WP 610 | DDC 616.85/83–dc23 LC record available at https://lccn.loc.gov/2017055314 Cover Design: Wiley Cover Image: © Vectorig/Getty Images

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10 9 8 7 6 5 4 3 2 1 v

Contents

List of Contributors vii Foreword ix Preface xi

1 History of the International Society for the Study of Women’s Sexual Health (ISSWSH) 1 Sue W. Goldstein

2 Sexual Medicine Education and Training 7 Sharon J. Parish and Johannes Bitzer

Part I Hypoactive Sexual Desire Disorder 17

3 Nosology and Epidemiology of Hypoactive Sexual Desire Disorder 19 Leonard R. Derogatis

4 Central Nervous System Anatomy and Neurochemistry of Sexual Desire 25 James G. Pfaus and Sherri L. Jones

5 Psychological Management of Hypoactive Sexual Desire Disorder 53 Sheryl A. Kingsberg and Stanley E. Althof

6 Pathophysiology and Medical Management of Hypoactive Sexual Desire Disorder 59 Anita H. Clayton and Linda Vignozzi

Part II Arousal Disorders 101

7 Nosology and Epidemiology of Arousal Disorders in Women 103 Leonard R. Derogatis

8 Anatomy and Physiology of Arousal 107 Kwangsung Park and Noel N. Kim

9 Psychological Management of Arousal Disorders 127 Isbelia Segnini and Tuuli M. Kukkonen

10 Pathophysiology and Medical Management of Female Genital Arousal Disorder 145 Irwin Goldstein

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11 Pathophysiology and Medical Management of Persistent Genital Arousal Disorder 161 Barry R. Komisaruk and Irwin Goldstein

Part III Orgasm Disorders 173

12 Nosology and Epidemiology of Female Orgasm Disorder 175 Leonard R. Derogatis

13 Peripheral and Central Neural Bases of Orgasm 179 Emmanuele A. Jannini, Nan Wise, Eleni Frangos, and Barry R. Komisaruk

14 Psychological Management of Orgasm Disorders 197 Sara Nasserzadeh

15 Musculoskeletal Management of Orgasm Disorders 211 Karen Brandon

16 Pathophysiology and Medical Management of Female Orgasm Disorder 221 Irwin Goldstein and Barry R. Komisaruk

17 Pathophysiology and Medical Management of Female Orgasmic Illness Syndrome 239 Irwin Goldstein and Barry R. Komisaruk

Part IV Sexual Pain Disorders 245

18 Nosology and Epidemiology of Dyspareunia and Vulvodynia 247 Tami Serene Rowen and Andrew T. Goldstein

19 Anatomy and Physiology of Sexual Pain 257 Melissa A. Farmer

20 Psychological Management of Provoked Vestibulodynia 281 Caroline F. Pukall and Sophie Bergeron

21 Musculoskeletal Management of Pelvic and Sexual Pain Disorders 295 Sara K. Sauder, Fiona McMahon, and Amy Stein

22 Medical Management of Dyspareunia and Vulvovaginal Pain 319 Andrew T. Goldstein and Susan Kellogg Spadt

Part V Future 337

23 Future Developments and Research 339 James A. Simon

Index 349

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List of Contributors

Stanley E. Althof, PhD, IF Eleni Frangos, PhD Center for Marital and Sexual Health of Pain and Integrative Neuroscience Branch South Florida NCCIH–NIH West Palm Beach, FL, USA Bethesda, MD, USA

Sophie Bergeron, PhD Andrew T. Goldstein, MD, FACOG, IF Département de Psychologie Department of Obstetrics and Gynecology Université de Montréal The George Washington University School Montréal, QC, Canada of Medicine and Health Sciences Centers for Vulvovaginal Disorders Johannes Bitzer, MD, IF Washington, DC, USA University Hospital Basel Multidisciplinary Center for Sexual Medicine Irwin Goldstein, MD, IF Basel, Switzerland Sexual Medicine Alvarado Hospital Karen Brandon, DSc PT WCS, BCB‐PMD Department of Surgery Kaiser Permanente University of California, San Diego Fontana, CA, USA San Diego Sexual Medicine San Diego, CA, USA Anita H. Clayton, MD, IF, FAPA, FASCP Department of Psychiatry and Sue W. Goldstein, CSE, CCRC, IF Neurobehavioral Sciences San Diego Sexual Medicine University of Virginia School of Medicine San Diego, CA, USA Charlottesville, VA, USA Emmanuele A. Jannini, MD Leonard R. Derogatis, PhD Department of Systems Medicine Maryland Center for Sexual Health University of Rome Tor Vergata Towson, MD, USA Rome, Italy Melissa A. Farmer, PhD Department of Physiology Sherri L. Jones, PhD Feinberg School of Medicine Douglas Mental Health University Institute Northwestern University Department of Psychiatry, McGill University Chicago, IL, USA Montreal, QC, Canada

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Susan Kellogg Spadt, PhD, CRNP, IF, FCST, CSC James G. Pfaus, PhD, IF Center for Pelvic Medicine Center for Studies in Behavioral Bryn Mawr, PA, USA Neurobiology Department of Psychology, Concordia Noel N. Kim, PhD, IF University Institute for Sexual Medicine Montréal, QC, Canada San Diego, CA, USA

Sheryl A. Kingsberg, PhD, IF Caroline F. Pukall, PhD, CPsych Division of Behavioral Medicine Department of Psychology Department of OB/GYN Queen’s University University Hospitals Cleveland Medical Kingston, ON, Canada Center Departments of Reproductive Biology and Tami Serene Rowen, MD, MS, IF Psychiatry Department of Obstetrics, Gynecology and Case Western Reserve University School of Reproductive Sciences Medicine University of California, San Francisco Cleveland, OH, USA San Francisco, CA, USA

Barry R. Komisaruk, PhD Sara K. Sauder, PT, DPT Department of Psychology Austin, TX, USA Rutgers University Newark, NJ, USA Isbelia Segnini, MSc, CCRC, C‐AASECT Tuuli M. Kukkonen, PhD, CPsych Clinical El Cedral Department of Family Relations and Applied Caracas, Venezuela Nutrition University of Guelph James A. Simon, MD, CCD, NCMP, IF, FACOG Guelph, ON, Canada IntimMedicine Specialists™ Fiona McMahon, PT, DPT George Washington University School of Medicine Beyond Basics Physical Therapy, LLC Washington, DC, USA New York, NY, USA

Sara Nasserzadeh, PhD, DipPST Amy Stein, DPT, BCB‐PMD, IF Relationship & Sexual Health Consultants Beyond Basics Physical Therapy, LLC Palo Alto, CA, USA New York, NY, USA

Sharon J. Parish, MD, IF Linda Vignozzi, MD Department of Medicine in Sexual Medicine and Andrology Unit Clinical Psychiatry Department of Experimental and Clinical Department of Clinical Medicine Biomedical Sciences Weill Cornell Medical College University of Florence New York, NY, USA Florence, Italy Kwangsung Park, MD, PhD, IF Department of Urology Nan Wise, PhD Chonnam National University Medical Department of Psychology School Rutgers University Gwangju, Republic of Korea Newark, NJ, USA

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­Foreword

It is a unique honor and privilege for me to has grown in leaps and bounds since then, introduce readers to this outstanding new and this textbook provides impressive testi- volume on female sexual function and mony to the expanding knowledge base and ­dysfunction from the International Society clinical interests of the society. Since its incep- for the Study of Women’s Sexual Health tion, ISSWSH has benefited greatly from the (ISSWSH). The depth and breadth of cover- devotion and energy of its founding members age of this complex and rapidly evolving area and officers; with special credit due to Sue of women’s health is impressive, to say the and Irwin Goldstein, Sharon Parish, Sheryl least, and the inclusion of much new research Kingsberg, Anita Clayton, Stan Althof, Len and clinical data attests to the enormous Derogatis, Jim Simon, Noel Kim, Annamaria energy and dedication of growing numbers of Giraldi, and others. I would like to acknowl- researchers and clinicians dedicated to stud- edge also a special debt to my late friend and ies in female sexual health. This latest text- colleague, Sandra Leiblum, who served as the book is truly comprehensive in its coverage first president of ISSWSH. Her contributions of both physical and psychological sexual dis- are cited throughout this volume, and her orders, in addition to providing up‐to‐date, spirit and energy did much to inspire her basic science formulations of underlying ­colleagues, students and others to pursue mechanisms and processes; all from a con- clinical or research interests in women’s sex- sistent and coherent biopsychosocial per- uality. Sandy was also a dedicated educator spective. As a psychologist and former sex who taught human sexuality and women’s therapist, it is especially gratifying to see this sexual health to literally thousands of stu- biopsychosocial model applied increasingly dents and residents during her 40 year career across female sexual disorders and prob- at Rutgers. Her spirit lives on in these pages! lems, regardless of etiology or treatment Finally, a special word of appreciation is due approaches. The editors have done the field a to Sue Goldstein – associate editor of this great service in balancing these perspectives ­volume and much loved “mother hen” of the both within and across chapters. The text- society. No one has taken on more roles for book is unique also in the depth of scholar- the society, or worked as tirelessly as Sue in ship and extensive reference lists provided achieving the goals of ISSWSH. This volume with each of the chapters – what a resource is finally a testament to Sue’s enduring and for graduate students, residents and fellows! much appreciated contributions to the field. This new textbook is also a testament to the Thank you Sue on behalf of all! success of ISSWSH, which, in the 18 years since it was founded, has become the major Raymond C. Rosen, PhD professional society with a unique focus on Chief Scientist, New England Research female sexual health. Many of us recall the Institutes first meeting of the society in Boston in 2000, Former Professor of Psychiatry, Rutgers at which the initial mission statement was Medical School drafted and officers elected. The organization Co‐Director, Human Sexuality Program

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Preface

The International Society for the Study of expert clinical experience, ISSWSH is able to Women’s Sexual Health (ISSWSH) is an further its mission of communication, pro- international, multidisciplinary, academic, fessionalism and disseminating information. clinical and scientific organization dedicated The multidisciplinary field of women’s to providing opportunities for communica- ­sexual health has come a long way since the tion among scholars, researchers and practi- inaugural meeting of ISSWSH in 2000. For tioners about women’s sexual health; to almost two decades, ISSWSH has fostered support the highest standards of ethics and research in the study, nosology, diagnosis professionalism in research, education and and treatment of women with sexual health clinical practice of women’s sexual health; disorders. ISSWSH funds research projects and to provide the public with accurate infor- in women’s sexual health, especially impor- mation about women’s sexual health. tant in an era where government funds are ISSWSH strongly emphasizes and fer- lacking. ISSWSH supports numerous educa- vently supports the biopsychosocial manage- tional opportunities including annual meet- ment of women with sexual dysfunction. ings, educational courses, and publications With that encompassing mission and scien- from consensus‐based panels resulting in tific focus in mind, the ISSWSH Textbook of nomenclature, white paper and process of Female Sexual Function and Dysfunction: care documents. ISSWSH, an affiliate mem- Diagnosis and Treatment has been written ber society of the International Society for by ISSWSH members primarily to help Sexual Medicine (ISSM), has three official healthcare providers in the various disci- journals: The Journal of Sexual Medicine, plines involved in women’s sexual health, Sexual Medicine, and Sexual Medicine including sex therapy, pelvic floor physical Reviews. Using these and other journals that therapy and medical therapy, better manage publish in women’s sexual health, ISSWSH women with distressing sexual health issues. has helped grow scientific peer‐reviewed Since ISSWSH is the largest society com- publications in women’s sexual health, prised of specialists in women’s sexual health, expanding from 273 scientific peer‐reviewed the idea for an ISSWSH textbook to provide publications found in PubMed in 2000 (by the optimal scientific, multidisciplinary clini- using the key phrase “female sexual dysfunc- cal practice guidelines for use by providers tion”) to 772 in 2016 – almost tripling avail- was natural. With millions of women need- able literature, much of which has been ing help, ISSWSH members can provide authored by ISSWSH members. accurate data for the providers in the various This ISSWSH textbook is intended to pro- disciplines caring for women with sexual vide clinical practice guidelines for both health concerns. By writing a textbook on novice and expert practitioners treating female sexual dysfunction based on pub- women with sexual health concerns. In the lished laboratory and clinical research and ten years since the publication of the first xii Preface

multidisciplinary textbook in the field, Textbook of Female Sexual Function and Women’s Sexual Function and Dsyfunction, Dysfunction: Diagnosis and Treatment will our knowledge has expanded and medica- serve as a valuable tool to all those involved tions for treating various sexual dysfunc- in helping women maintain or restore their tions have been added in some countries to sexual health. the nonpharmacologic treatment strategies For ease of use, the text is divided into already available. As an official publication four basic sections: Hypoactive Sexual of the society, this material has been vetted Desire Disorder, Arousal Disorders, Orgasm by the editors on behalf of ISSWSH. Four Disorders, and Sexual Pain Disorders. of the editors (Clayton, I. Goldstein, A. Within each section there is content on the Goldstein, Kingsberg) have been presidents of nosology and epidemiology, anatomy and the society while the fifth (Kim) is president- physiology, and diagnosis and treatment elect. We have all given of our time freely from both ­psychologic and biologic points because of our passion for the field and our of view, including musculoskeletal manage- passion for ISSWSH, as has the associate ment where appropriate. editor, Sue W. Goldstein. In particular, Sue It is anticipated that ISSWSH will update spent countless hours as the central commu- this textbook as needed. The field of women’s nicator, tracker of progress, and editorial sexual medicine is rapidly evolving and associate, guiding this book from initial ISSWSH members have been influential in development to final publication. We would paving the way for expansion of knowledge also like to thank Gail Goldstein for her time in the field of female sexual dysfunction – this and efforts in helping to edit the pain textbook reflects current understanding. We section. hope that you agree and find the Textbook of It is imperative that clinicians understand Female Sexual Function and Dysfunction to the various conditions impacting sexual be an essential resource in caring for women desire, arousal, orgasm, and pain, how to and their sexual health. make a correct diagnosis, the therapeutic options available, and the science behind the Irwin Goldstein, MD, IF various treatments, in order to provide opti- Anita H. Clayton, MD, IF mal patient management and improve Andrew T. Goldstein, MD, IF patient quality of life. All women have the Noel N. Kim, PhD, IF right to health, including sexual health. The Sheryl A. Kingsberg, PhD, IF 1

1

History of the International Society for the Study of Women’s Sexual Health (ISSWSH) Sue W. Goldstein

Abstract

The International Society for the Study of Women’s Sexual Health (ISSWSH) emanated from a course assembling experts in different disciplines, becoming the model for the society. Seventeen years later the society remains multidisciplinary, with annual meetings featuring state of the art lectures, symposia on controversial topics, and abstracts judged on scientific merit. Educational efforts expanded from a half day precourse to a fall course and another in conjunction with the National Association of Nurse Practitioners in Women’s Health annually. Evidence‐based ­conferences have included consensus panels for nomenclature for desire, arousal, and orgasm; pain; genitourinary syndrome of menopause (GSM); clinical guidelines for identification of sexual health problems; and a process of care for the management of hypoactive sexual desire disorder. ISSWSH is now established as the leading organization for disseminating valuable information to providers, researchers and educators regarding management of distressing sexual dysfunction in women.

Keywords: ISSWSH; women’s sexual health; female sexual dysfunction; multidisciplinary; desire; arousal; orgasm; pain; GSM; nomenclature

The International Society for the Study of women, but Goldstein wanted to change that. Women’s Sexual Health (ISSWSH) is the Under the auspices of Boston University only professional organization dedicated to School of Medicine, he developed a course ­women’s sexual function and dysfunction. entitled New Perspectives in Female Sexual The society was founded less than two dec- Dysfunction, assembling experts in different ades ago. Therefore, the history of the society disciplines to share their information in an is directly linked to the history of the field. effort to piece together available knowledge. The approval of sildenafil in 1998 by This became the model on which the society ­regulatory agencies and a publication in the was developed three years later. New England Journal of Medicine [1] led The course was held in the Boston area in women to call urologist Irwin Goldstein to 1998, 1999 and 2000. The first year there demand a medication for their sexual health were over 200 registrants from around the problems. There was a paucity of information world. Associated with the 1998 course, the about the physiology of sexual function and American Foundation for Urologic Diseases the pathophysiology of sexual ­dysfunction in sponsored a consensus conference with 19

Textbook of Female Sexual Function and Dysfunction: Diagnosis and Treatment, First Edition. Edited by Irwin Goldstein, Anita H. Clayton, Andrew T. Goldstein, Noel N. Kim, and Sheryl A. Kingsberg. © 2018 John Wiley & Sons Ltd. Published 2018 by John Wiley & Sons Ltd. 2 Textbook of Female Sexual Function and Dysfunction

international experts, resulting in the devel- opment of nomenclature for use in women’s sexual dysfunction [2]. Prior to this time all nomenclature was based on the Diagnostic and Statistical Manual of Mental Disorders (DSM) of the American Psychiatric Association [3]. With the recognition of ­biologic components to sexual function, and the need to understand sexual dysfunc- tion in women, the course was lengthened and podium and poster sessions added. Attendance doubled in 1999 with many returning registrants. When queried about interest in initiating a society, the response was negative. The following year, however, the group had an overwhelmingly positive response and the Female Sexual Function Forum was born. The society was developed in a multidisci- plinary manner with by‐laws designating that each committee and the board of direc- tors be balanced in terms of gender, geogra- Figure 1.1 Sandra Leiblum, PhD, first president of phy, and discipline. All disciplines with an the International Society for the Study of Women’s interest in women’s sexual health would be Sexual Health, presiding over the business meeting. welcome in the society, with all active mem- (See plate section for color representation of the figure) bers having equal import, regardless of pro- fession, specialty or degree. Many members After a year as the Female Sexual Function of the inaugural board continue to be active Forum it was noted that the word “female” members, a testament to both the strength of could refer to animals, so, in 2001, the organi- and need for the organization. One of the zation was renamed the International Society first society benefits was the start of a mod- for the Study of Women’s Sexual Health. erated on‐line forum (ISSWSHNET) for dif- Alessandra Graziottin from Italy ascended to ficult cases that facilitated communication the presidency but the board remained stable among people from various locations, disci- to help the fledging society. Only active or plines, and perspectives. Having gone honorary members could serve on the board through multiple iterations, ISSWSHNET or as committee chairs, as affiliate members remains a benefit for society members. were associated with industry. The society The format of the first meeting set the tone struggled financially but survived through for future meetings, with state of the art the fierce passion of the board and the sup- ­lectures, symposia on controversial topics, port of its management company. and abstracts judged on scientific merit for Nearly 400 people attended the 2002 meet- podium or poster presentation. The hot topic ing in Vancouver – the first time this group through the first several annual meetings was met away from Boston. Held shortly after the the use of androgens in women, transitioning publication of the widely publicized Women’s later to oral contraceptives and sexual Health Initiative [4], the leadership responded ­dysfunction. The first business meeting and by adding a lunch seminar to disseminate election were held on 28 October 2000, accurate information and help dispel myths with Sandra Leiblum voted in as the first propagated by the press. Symposia were president (Figure 1.1). designed to span both the biological and History of the International Society for the Study of Women’s Sexual Health (ISSWSH) 3

­psychological realms in the basic science and to stay in the United States, as attendees and clinical arenas. While moving the 2003 meet- drug development programs were based in ing to Amsterdam was exciting, it put the the United States, allowing for growth of society at risk, with a decrease in attendance sponsorship opportunities. and increase in meeting costs. Under Cindy In 2011, the term of president (and conse- Meston’s leadership, a development commit- quently both president elect and past tee was established to seek industry support ­president) was changed from one to two to help underwrite the conference, as is com- years, allowing leadership to develop pro- mon among many other societies, with the jects and see them through fruition. With long term goal of financial stability. the approval by the Food and Drug Lorraine Dennerstein put her presidential Administration of medications for women stamp on the society by recruiting young with various sexual dysfunctions, industry researchers in an attempt to grow both the support grew and the society became fiscally society and the field. With the return to the sound. The ability to obtain unrestricted United States in 2004 the society collaborated educational grants meant the society could with the National Institutes of Health, fund educational projects outside of the cosponsoring the meeting “Vulvodynia and annual meeting. Under the leadership of Sexual Pain Disorders in Women” held the Andrew Goldstein a new nomenclature for day before the Atlanta ISSWSH meeting [5]. pain was developed in conjunction with For the first time, several pharmaceutical International Society for the Study of companies arranged their advisory board Vulvovaginal Disease and International meetings around the annual meeting, thus Pelvic Pain Society [6], and at a consensus supporting ISSWSH financially and giving meeting with the North American increased visibility to the young society. Menopause Society vulvovaginal atrophy A half‐day precourse on the “Practical was renamed as genitourinary syndrome of Management of Women’s Sexual Dysfunction” menopause or GSM [7], which is now the preceded the annual meeting, a response to accepted term. President Sharon Parish the increasing demand for instruction for assembled a nomenclature consensus con- both the novice and advanced health‐care ference to define disorders of desire, arousal, provider. The precourse enrollment that first and orgasm [8, 9], and coordinated a meeting year exceeded expectations with 160 attend- sponsored by ISSWSH to ensure these ees. The board responded by naming an edu- ­definitions would be considered as part of cation committee to develop a program of the new ICD‐11 coding [10]. Irwin Goldstein educational courses during the annual meet- supported the global development commit- ing, as well as a free‐standing three‐day tee, securing grants for projects, including a course to be held at another time of year. white paper on hypoactive sexual desire With these changes ISSWSH was begin- ­disorder [11], and a process of care for the ning to make its true mark on the field of management of women with generalized, medicine. In 2005, ISSWSH was under the acquired hypoactive sexual desire disorder leadership of its first male president, Stan [12]. For the first time, the society was finally Althof, and in 2006 the annual meeting able to set aside money in an investment moved from October to February, in an account in 2015 and to use its funds to offer attempt to find a dedicated time slot not grants to trainees and researchers early in ­conflicting with other societies, leaving the their careers, resulting in future presenta- October time available for the three‐day tions at ISSWSH annual meetings. ­educational “Fall Course”. The rotation of With ISSWSH dedicated solely to women’s east coast, west coast, Europe for annual sexual health, other organizations have meetings would continue for a few years turned to the society for education. ISSWSH (Table 1.1), until it made more financial sense has co‐sponsored a course with the National 4 Textbook of Female Sexual Function and Dysfunction

Table 1.1 Dates and locations of ISSWSH annual meetings and the presidents at that time.

Term President Meeting location

2000–2001 Sandra R. Leiblum, PhD Boston, MA (10/01) 2001–2002 Alessandra Graziottin, MD Vancouver, Canada (10/02) 2002–2003 Cindy M. Meston, PhD, IF Amsterdam, The Netherlands (10/03) 2003–2004 Lorraine Dennerstein, MBBS, PhD, DPM, IF Atlanta, GA (10/04) 2004–2005 Stanley E. Althof, PhD, IF Las Vegas, NV (10/05) 2005–2006 Anita H. Clayton, MD, IF, FAPA Lisbon, Portugal (03/06) 2006–2007 Anita H. Clayton, MD, IF, FAPA Lake Buena Vista, FL (02/07) 2007–2008 Annamaria Giraldi, MD, PhD, IF San Diego, CA (02/08) 2008–2009 Rosella E. Nappi, MD, PhD Florence, Italy (02/09) 2009–2010 Sheryl A. Kingsberg, PhD, IF St. Petersberg, FL (02/10) 2010–2011 Alan Altman, MD, IF Scottsdale, AZ (02/11) 2011–2012 Alan Altman, MD, IF Jerusalem, Israel (02/12) 2012–2013 Andrew T. Goldstein, MD, IF, FACOG New Orleans, LA (02/13) 2013–2014 Andrew T. Goldstein, MD, IF, FACOG San Diego, CA (02/14) 2014–2015 Sharon J. Parish, MD, IF, NCMP Austin, TX (02/15) 2015–2016 Sharon J. Parish, MD, IF, NCMP Charleston, SC (02/16) 2016–2017 Irwin Goldstein, MD, IF Atlanta, GA (02/17) 2017–2018 Irwin Goldstein, MD, IF San Diego, CA (02/18)

Association of Nurse Practitioners in including publication of clinical pearls and Women’s Health since 2014, providing assembling an official educational slide‐set, ­educational content. The society has both benefits for members. Online content taught CME courses at the International for both providers and patients has been and Society for Sexual Medicine, American will continue to be developed. Consensus College of Obstetrics and Gynecology, panels have convened to establish clinical and the International UroGynecology guidelines in different aspects of sexual Association, providing evidence‐based ­dysfunction in women. ISSWSH is now ­content to non‐ISSWSH members and established as a leading organization in spreading awareness of women’s sexual ­disseminating valuable information to function and dysfunction. ­providers, researchers, and educators in In recent years, the society has moved into order to improve management of distressing advocacy and has developed useful tools, sexual dysfunction in women.

­References

1 Goldstein I, Lue T, Padma‐Nathan H, et al. conference on female sexual dysfunction: Oral sildenafil in the treatment of erectile definitions and classifications. J Urol. dysfunction. New Engl J Med. 2000;163(3):888–893. 1998;338:1396–1404. 3 American Psychiatric Association. 2 Basson R, Berman J, Burnett A, et al. Report Diagnostic and Statistical Manual of Mental of the international consensus development Disorders IV, Text Revision (DSM‐IV‐TR). History of the International Society for the Study of Women’s Sexual Health (ISSWSH) 5

American Psychiatric Association, dysfunctions – Part I. J Sex Med. Washington, DC. 2003. 2016;13(12):1881–1887. 4 Rossouw J, Anderson GL, Prentice RL, et al. 9 Parish SJ, Goldstein, AT, Goldstein, SW, Risks and benefits of estrogen plus progestin et al. Toward a More Evidence‐Based in healthy postmenopausal women: principal Nosology and Nomenclature for Female results from the Women’s Health Initiative Sexual Dysfunctions – Part II. J Sex Med. randomized controlled trial. JAMA. 2016;13(12):1888–1906. 2002;288(3):321–333. 10 Reed GM, Drescher J, Krueger, RB, 5 Bachmann G, Rosen R, Pinn VW, et al. et al. Disorders related to sexuality Vulvodynia: a state‐of‐the‐art consensus on and gender identity in the ICD‐11: definitions, diagnosis and management. Revising the ICD‐10 classification based J Reprod Med. 2006;51(6):447–456. on current scientific evidence, best 6 Bornstein J, Goldstein AT, Stockdale CK, clinical practices, and human rights et al. 2015 ISSVD, ISSWSH, and IPPS considerations. World Psychiatry. Consensus Terminology and Classification 2016;15(3):295–321. of Persistent Vulvar Pain and Vulvodynia. 11 Goldstein I, Kim NN, Clayton AH, et al. J Sex Med. 2016;13(4):607–612. Hypoactive sexual desire disorder: 7 Portman D, Gass M, Kingsberg S, et al. International Society for the Study of Genitourinary syndrome of menopause: new Women’s Sexual Health (ISSWSH) Expert terminology for vulvovaginal atrophy from Consensus Panel Review. Mayo Clin Proc. the International Society for the Study of 2017;92(1):114–128. Women’s Sexual Health and the North 12 Clayton A, Goldstein I, Kim NN, et al. American Menopause Society. Menopause. The International Society for the Study 2014;21:1063–1068. of Women’s Sexual Health Process of 8 Derogatis L, Sand M, Balon R, et al. Toward Care for Management of Hypoactive a more evidence‐based nosology and Sexual Desire Disorder in Women. nomenclature for female sexual Mayo Clin Proc. 2018;93. 7

2

Sexual Medicine Education and Training Sharon J. Parish and Johannes Bitzer

Abstract

Sexual health care is part of general medical care and is needed throughout the life cycle of women. Education and training for clinicians is based on a biopsychosocial model of sexual health and should progress from undergraduate level through postgraduate and specialist training programs. The curriculum for each level must be competency based and include learning objectives; describe the knowledge, skills and attitudes; and include methods of monitoring the acquisition of new skills and knowledge. Undergraduate training must include general knowledge about the human sexual response, diagnostic categories and classifications, and skills to communicate about sexuality. Postgraduate and specialized training should provide a broader understanding of the biological, psychological, and social factors contributing to sexual dysfunction; the basis for ­comprehensive diagnosis; the ability to establish a therapeutic plan in collaboration with the patient; and the capacity to perform interventions or refer.

Keywords: sexual health education; female sexual dysfunction; sexuality communication skills; sexual medicine competencies

Sexual health care is part of general health care and is needed throughout the life span of women and men. Education and training for health‐care professionals are based on a biopsychosocial model of sexual health and should start at undergraduate level and be included in postgraduate and specialist training programs. The program of each level must include learning objectives; describe the knowledge, skills and attitudes from a competency perspective; and include methods of monitoring the learning process.

­Introduction medicine specialists. This array of needs implies that all physicians should receive Sexual problems and sexual dysfunctions basic education and training in sexual have a high prevalence worldwide. As sexual ­medicine and that a subgroup with interest health is part of general health, women and commitment in the field should receive ­consider health‐care professionals as the specialized postgraduate training [1]. “right persons” to help. The high prevalence Many institutions in different countries and high complexity of sexual health have tried to develop concepts about the ­problems create the need for services from learning objectives and competencies in both primary care clinicians and sexual ­sexual medicine for undergraduate, graduate

Textbook of Female Sexual Function and Dysfunction: Diagnosis and Treatment, First Edition. Edited by Irwin Goldstein, Anita H. Clayton, Andrew T. Goldstein, Noel N. Kim, and Sheryl A. Kingsberg. © 2018 John Wiley & Sons Ltd. Published 2018 by John Wiley & Sons Ltd. 8 Textbook of Female Sexual Function and Dysfunction

and postgraduate levels [2]. Based on the Knowledge includes: analyses of these programs and the literature ●● about patients’ needs, we propose a model of anatomy of sexual organs; ●● three levels of competence in female sexual basics of endocrine, central nervous dysfunction (FSD) that should be achieved ­system, neurological, and neuromuscular through education and training programs processes involved in central and periph- (Table 2.1) [3]. eral sexual response; ●● models of human sexual response; ●● contraception, sexually transmitted dis- Undergraduate (level 1) eases, safer sex practices.

Education and training for medical students Skills incorporate: is based on the transference of knowledge about human sexuality, prevalence of sexual ●● how to encourage patients to ask questions problems, and principles and skills related to about sexuality and talk about (disclose) communication about sexuality, including difficulties; strategies and techniques to help patients to ●● attitude toward discussing and managing disclose problems and difficulties in this sexual problems; ­intimate and vulnerable domain of life [4]. ●● openness towards the wide spectrum of The core framework for sexuality education sexual expression and sexual life styles; focuses on knowledge, skills, and attitudes ●● how to discuss and explain treatment [5, 6]. Attitudinal training primarily focuses plans, discuss benefits and risks. on the development of self‐awareness and the cultivation of nonjudgmental behavior Expert recommendations for enhancement and professionalism when interacting with of sexual health education in medical schools patients with sexuality concerns [6]. call for a multidimensional approach that

Table 2.1 Competencies for undergraduate, graduate and generalist physicians, and postgraduate specialists.

Competence level 2: Competence level 3: Competence level 1: graduate and generalist postgraduate undergraduate physicians specialists

Female sexual Know definition Diagnose based on standards Hormonal & drug dysfunctions Screen, diagnose Assess contributing factors treatment (low desire, arousal Know about Establish descriptive and Sensate focus dysfunction, contributing factors comprehensive diagnosis Couples therapy orgasmic and therapeutic (biopsychosocial model) Physiotherapy disorders, sexual options Elaborate treatment options pain disorders) Oncologic diseases Know impact and Establish a comprehensive Specialized surgical prevalence diagnosis including pre‐existing interventions Ask and screen factors, disease related factors, Mechanical and emotional, cognitive and intervention behavioral responses Hormonal intervention Develop treatment plan Physiotherapy Conservative treatment Metabolic and Know impact and Establish a comprehensive Modified sensate focus neurologic prevalence diagnosis including pre‐existing Mechanical diseases Ask and screen factors disease related factors, intervention and emotional, cognitive and Drug therapy behavioral response Physiotherapy Develop treatment plan Conservative treatment Sexual Medicine Education and Training 9 incorporates curricular reform and innova- The treatment plan may include education tion aimed at educational infrastructure [7]. and behavioral advice or more specialized Elements include developing a skills‐based interventions, such as hormonal and other curriculum, establishing multidisciplinary pharmacological treatment, surgery, physio- teams, integrating sexual health content therapy, and specialized psychotherapeutic across core curriculum courses and longitu- interventions. The latter competencies need dinally throughout medical school, creating special training (level 3) [9, 10]. mandatory blocks and electives, and includ- The International Consultation in Sexual ing assessment of sexual health knowledge in Medicine published a review of the current licensing examinations [7]. Ideally, at least state and future educational needs in one “champion” should be involved at each ­graduate and postgraduate sexual health institution to ensure that sexuality education education. The key points summarized that: is included and effectively integrated into the (i) sexual medicine has grown as a specialty entire curriculum [6]. in the recent decades; but regulatory aspects Sexuality education should be multidisci- of training, assessment, and certification are plinary and include psychiatry, gynecology, lagging behind scientific developments and urology, and primary care, and also may clinical knowledge; (ii) examples of curricula incorporate sex therapists, psychologists, and associated assessments may be related to ­epidemiologists, and sexologists. Sexual med- high quality sexual medicine care; (iii) com- icine content is optimally delivered through petency assessment has been applied to an array of interactive modalities that enable ­surgical training (primarily male), reflecting skills training and assessment. These include increased interest in simulation for skills didactics, panel discussions, small group training; (iv) although curriculum develop- case‐based seminars, role play, standardized ment has been primarily executed in patients, observed structured clinical exami- ­medical training, interest is emerging in nations with direct and immediate feedback, ­similar standards for training allied health community/peer education, and immersion/ ­professionals [2]. desensitization activities [5, 6]. Despite the emergence of some training A recent survey regarding lesbian, gay, opportunities employing varied methodolo- bisexual, and transgender‐related content in gies, objective measures of the impact of United States and Canadian allopathic and graduate and postgraduate physician training osteopathic medical schools reported that in sexual health on patient satisfaction and dedicated content hours to these topics was objective health outcomes are lacking [11]. small and that the perceived quality was ­variable. Suggested improvements included increased curricular time dedicated to les- ­Education and Training bian, gay, bisexual, and transgender‐related in Female Sexual Health Care health and disparities, instruction about the for Practicing Clinicians difference between behavior and identity, and faculty engagement to teach these topics [8]. To provide patients with competent sexual health care, professionals need to train and Graduate and Postgraduate develop knowledge, skills and attitudes (Level 2 and 3) related to the following key principles [12]: Graduate and generalist physicians, as well ●● Sexuality is an intimate part of the patient’s as medical specialists, should be able to under- identity, self‐esteem, shame, and vulnera- stand the sexual suffering of their patients and bilities. Therefore, talking about sexuality translate it into a descriptive and a compre- requires openness, empathy, a nonjudg- hensive diagnosis as the basis for a prelimi- mental approach, and a respectful attitude nary or more elaborate treatment plan. focusing on resources and not on deficits. 10 Textbook of Female Sexual Function and Dysfunction

●● Sexual problems and dysfunctions are biological and psychosocial factors con- ­usually the result of an interaction of tributing to the sexual problem, under- ­factors that are best identified using standing these factors as interactive. Based the biopsychosocial model. This means on a shared understanding between the that ­physicians have to be open to, clinician and patient, therapeutic options and interested in, different perspectives, should be reviewed together, individualiz- ­ranging from ­physiology/pathophysiology ing treatment according to the individual to psychology/psychopathology to social needs of the patient. psychology and sociology [13]. ●● Solutions to sexual problems and treat- Basic Structured Approach ment of dysfunctions may be a long‐term to a Patient Presenting process and, invariably, require the active with a Sexual Problem [14] collaboration of the patient or couple. This implies that clinicians frequently need to ●● Listen to the patient’s story (narrative) and include partners in the process, involve practice patient‐centered communication. patients in decision making, and adapt –– Utilize communications skills: active strategies that match the resources and ­listening, reflection, mirroring, sum- capacities of the patient [14]. marizing, responding to emotions, reframing. Incorporating these premises, we have ●● Ask differentiating questions. developed a semi‐structured approach to –– Enable differentiation of a sexual prob- patients with sexual problems and dysfunc- lem into primary versus secondary, tions that includes the elements that form ­situational versus global, abrupt begin- the core education and training for generalist ning versus slow process. physicians [4]. ●● Explore a typical sexual encounter or expe- rience (behavioral interactive sequence). Elements of a Structured –– “What happened last time when you Approach to a Patient with Sexual were sexually active?” Problems and Dysfunctions ●● Elaborate a descriptive diagnosis (using classification systems). The consultation in sexual medicine is –– Disorder/dysfunction according to ­characterized by the following elements: DSM‐5 [15], International Consultation ●● Patient‐centered: the patient with her on Sexual Medicine classification [16, needs, subjective suffering, questions, and International Society for the Study of priorities is at the center of the consulta- Women’s Sexual Health (ISSWSH) tion; she is empowered by knowledge and nomenclature [17], ICD‐10. insight. To achieve this, communication –– Use of questionnaires for screening and should include active listening, mirroring, diagnosis. summarizing, responding to emotions, ●● Explore conditioning and risk factors and providing information in a language ­contributing to the clinical problem. the patient can understand. The doctor– –M– edical (history, examination). patient relationship should be nonjudg- –– Individual psychological (sexual biogra- mental and based on respect, aimed at phy, major life events, lifecycle), sexual establishing a relationship of mutual trust learning. and confidence. –– Interactional: partner communication ●● Diagnosis and treatment are based on the and dynamics. biopsychosocial understanding of human –– Sociocultural: sexual norms and sexuality. The diagnostic workup in­ tegrates concepts. Sexual Medicine Education and Training 11

●● Elaborate a comprehensive explanatory (­oncologic, metabolic and neurological diagnosis as a working model to be shared ­disorders, etc.) [3]. with the patient. Algorithms and structured approaches –– Construct individualized nine‐field form the basis for education and training in table of conditioning factors (Table 2.2). female sexual disorders in general and in the ●● Develop a treatment plan. context of disease and treatment of disease. –– Use nine‐field table (Table 2.2) [18] Regarding the disease and therapy spe- results to address possible therapeutic cific factors, eight different levels through interventions. which a disease or a therapy can have an –– Practice shared decision making: impact on sexual function can be outlined ○○ discuss benefit/risk or advantages/ (Table 2.3) [3]. disadvantages of different options in relation to patient’s values and needs; ○○ make treatment decision transparent ­Education and Training and shared. in Female Sexual Health A useful instrument for training this Care for Sexual Medicine approach is the use of the graphic summary Specialists of the comprehensive explanatory diagnosis in the form of a modified nine‐field diagram Based on these schemas, sexual medicine (Table 2.2) [18]. The horizontal axis includes societies and institutions have developed edu- biomedical, psychological, and sociocultural cational and training programs defining factors; the vertical axis incorporates knowledge, skills, attitudes, and evaluation ­predisposing (distant, indirect), precipitating methods for defined sexual dysfunctions. (triggering), and maintaining (proximate These training programs are designed for spe- factors). cialists in sexual medicine. The European In addition, sexual health care for patients Society for Sexual Medicine (ESSM) and the with various medical conditions has to take International Society for the Study of into account disease and treatment specific Women’s Sexual Health have intensive factors that have an impact on the sexual courses that ­provide didactic, experiential, and function. For the most common conditions, hands‐on training in an interactive format. the algorithm shown in Figure 2.1 incor- The European Society for Sexual porates the specific medical condition Medicine designed such a curriculum that

Table 2.2 Modified nine‐field diagram [10] for the comprehensive explanatory diagnosis.

Biomedical Psychological Sociocultural

Chronic diseases Hormonal and drugs factors Intraindividual Interpersonal

Predisposing Distant Indirect Precipitating Factors Trigger Maintaining Proximate Direct 12 Textbook of Female Sexual Function and Dysfunction

Medical illness and sexuality

Pre-existing sexual difficulties and resources, body image, gender

Threat of the disease (stage etc.)

Disease and therapy specific factors with possible impact on sexual function

Body image Affective reaction Coping and resilience

Changes in sexual needs and couple dynamics

Individual clinical sexual dysfunction syndrome

Figure 2.1 Algorithm incorporating the specific medical condition. (See plate section for color representation of the figure)

Table 2.3 Disease and therapy specific factors Objectives for management of each disor- having an impact on female sexual function [3]. der include required knowledge, skills and attitudes. Danger The subjectively experienced threat Destruction Destruction of sexual organs ­Conclusion Disfigurement Visible changes of the body Disability: Loss of mobility, chronic pain Generalist physicians should be able to handicap address sexuality in the context of a medical and pain consultation, assess sexual health problems, Dysfunction Loss of neurovegetative and offer help or refer women to specialized col- neuromuscular function leagues. Undergraduate training must Dysregulation Hormonal and central include general knowledge about the human nervous disruptions sexual response as well as the diagnostic cat- Disease load Accompanying symptoms egories and classifications, and skills to com- (incontinence etc.) municate about sexuality. Postgraduate and Drugs Many secondary effects of specialized training should be competency drugs on sexual function based and provide: ●● a broader understanding of the biological, psychological and social factors contribut- includes detailed and proscriptive ing to sexual health and sexual dysfunction approaches to the spectrum of sexual prob- in general and in clinical conditions; lems and includes an array of educational ●● the basis for comprehensive diagnosis; and assessment methods. Core components ●● the capacity to establish a therapeutic plan of the ESSM curriculum are the assessment shared with the patient; and management of desire, arousal, and ●● the guidance to perform interventions orgasm ­disorders; assessment methods are according to individual competence or summarized in Tables 2.4, 2.5, and 2.6. refer to specialists. Sexual Medicine Education and Training 13

Table 2.4 Management of the patient with desire disorder [9, 19, 20].

Objective Assessment

Knowledge Anatomy Multiple choice Anatomy of the brain, enhancing and inhibiting pathways questions (MCQ) and networks Physiology of sexual desire Endocrine and neurotransmitter pathways and actions involved in the experience of desire Pathology Definitions in ISSWSH nomenclature and ICD‐10 Pathophysiological mechanisms of dysfunction (stimulating and inhibiting pathways) Risk and contributing factors Single best Biological, medical answer (SBA) ●● Diseases and drugs ●● Hormonal changes Psychological ●● Understanding the sexual biography (negative sexual learning, traumatic life events, vulnerability, sexual temperament) Relational ●● Partner conflicts about different needs, communication difficulties Sociocultural ●● Lack of sex education ●● Rigid sexual norms, role definitions Therapeutic options Sexual counseling Hormonal treatment Drug treatment (centrally acting) Body centered sex therapy Modified sensate focus Clinical Be able to: Extended matching skills ●● Perform a structured diagnostic interview including questions (EMQ) listening to the woman’s story, (narrative), summarizing, Objective and establishing a comprehensive diagnosis with structured clinical contributing elements and risk factors (nine‐field diagram) examination ●● Differentiate between primary and secondary dysfunction (OSCE) Perform a gynecologic examination with special focus on colposcopy of the vulva, examination of the vagina Develop a treatment plan together with the patient based on shared decision making Assess indication for medication treatment taking into account contraindications etc. Psychotherapy – cognitive behavioral therapy and mindfulness‐based therapy Systemic couple therapy Attitudes Empathic listening, encouraging to talk Role play Offer feedback opportunities, encourage questions Schedule follow up Be patient regarding change Table 2.5 Management of the patient with arousal disorder [9, 21].

Objective Assessment

Knowledge Anatomy MCQ Anatomy of the vulva, vagina and clitoris Differentiated knowledge about tissues, vascularization, hormonal receptors Physiology of sexual arousal Central and peripheral mechanisms of arousal including lubrication Pathology of arousal dysfunction Definitions of ISSWSH nomenclature and ICD 10 Pathophysiological mechanisms Risk and contributing factors SBA Biological, medical ●● Sex hormone deficiency ●● Diabetes/vascular factors ●● Smoking ●● Pelvic floor disorders ●● Lower urinary tract symptoms (LUTS) ●● Pelvic surgery ●● Neurological diseases ●● Drugs: antihormones, hormonal contraceptives, chemotherapy, antidepressants Psychological ●● Anxiety, depression ●● Lack of knowledge and experience (masturbation etc.) ●● Traumatic sexual biography (separation, violence, abuse) Relational ●● Conflict about needs and expectations ●● Lack of communication skills to negotiate about differences Sociocultural ●● Poverty/low income ●● Working conditions ●● Sexual norms Therapeutic options Sexual counseling Local and/or hormonal treatment Drug treatment (PDE‐5‐inhibitors) Body‐centered sex therapy Modified sensate focus Clinical Be able to perform a structured diagnostic interview including listening to EMQ, skills the woman‘s story, (narrative), summarizing, establishing a comprehensive OSCE diagnosis with contributing and risk factors (nine‐field diagram) Perform a gynecologic examination with special focus on colposcopy of the vulva, examination of the vagina Detect (exclude) vulvovaginal disease Develop a treatment plan together with the patient based on shared decision making Assess indication for medication taking into account contraindications Sensate focus, body centered psychotherapy, physiotherapy, masturbation exercises, systemic couple therapy Attitudes Empathic listening, encouraging to talk Role play Offer feedback opportunities, encourage questions Schedule follow‐up Be patient regarding change Sexual Medicine Education and Training 15

Table 2.6 Management of the patient with orgasmic disorder.

Objective Assessment

Knowledge Anatomy MCQ Anatomy of the brain, enhancing and inhibiting pathways and networks; anatomy and physiology of the vagina and the pelvic floor Physiology of orgasm Vascular and muscular response, woman’s experience Pathology Definitions of ISSWSH nomenclature and ICD 10 Pathophysiological mechanisms (excitatory and inhibitory pathways) Risk and contributing factors SBA Biological, Medical ●● Factors contributing to orgasm disorder ●● Antidepressant medication Psychological ●● Lack of education, experience ●● Partner conflict ●● Performance anxiety Relational ●● Inadequate stimulation Sociocultural ●● Lack of sex education ●● Rigid sexual norms Therapeutic options Sexual counseling Masturbation exercises Working with fantasies, sex toys Body centered psychotherapy Physiotherapy pelvic floor Clinical Be able to: EMQ, skills Perform a structured diagnostic interview including listening to the OSCE woman’s story, (narrative), summarizing, establishing a comprehensive diagnosis with contributing and risk factors (nine‐field diagram) Differentiate between primary and secondary Consider a gynecologic examination of the vulva, vagina if inadequate arousal is contributing or orgasmic dysfunction Develop a treatment plan together with the patient based on shared decision making Assess indication for medication treatment taking into account contraindications etc. Sensate focus, body‐centered psychotherapy, sex toys, physiotherapy masturbation exercises Systemic couple therapy Attitude Empathic listening, encouraging to talk Role play Offer feedback opportunities, encourage questions Schedule follow up Be patient regarding change 16 Textbook of Female Sexual Function and Dysfunction

­References medicine, 2009. J Sex Med. 2010;7:3305–3314. 12 1 Reisman Y, Eardley I, Porst H, the Bitzer J. Definition and diagnosis of Multidisciplinary Joint Committee on sexual problems. In Wylie KR (ed.) ABC Sexual Medicine (MJCSM). New of Sexual Health, 3rd edn. Chichester, UK: developments in education and training in John Wiley & Sons Ltd; 2015, pp.77–80. 13 sexual medicine. J Sex Med. Al‐Azzawi F, Bitzer J, Brandenburg U, et al. 2013;10:918–923. Therapeutic options for postmenopausal 2 Eardley I, Reisman Y, Goldstein S, et al. female sexual dysfunction. Climacteric. Existing and future educational needs in 2010;13:103–120. 14 graduate and postgraduate education. Bitzer J, Platano G, Tschudin S, Alder J. J Sex Med. 2017;14:475–485. Sexual counseling in elderly couples. J Sex 3 Bitzer J, Platano G, Tschudin S, Alder J. Med. 2008;5:2027–2043. 15 Sexual counseling for women in the American Psychological Association. context of physical diseases: a teaching Diagnostic and Statistical Manual of model for physicians. J Sex Med. Mental Disorders, Fifth Edition: DSM‐5. 2007;4:29–37. Arlington, VA: American Psychological 4 Brandenburg U, Bitzer J. The challenge of Association; 2013. 16 talking about sex: the importance of McCabe MP, Sharlip ID, Atalla E, et al. patient‐physician interaction. Maturitas. Definitions of sexual dysfunctions in 2009;63:124–127. women and men: A Consensus Statement 5 Shindel AW, Parish SJ. Sexuality education From the Fourth International in North American medical schools: Consultation on Sexual Medicine 2015. Current status and future directions. J Sex J Sex Med. 2016;13:135–143. 17 Med. 2013;10:3–18. Parish SJ, Goldstein AT, Goldstein SW, 6 Shindel AW. Sexuality education: a critical et al. Toward a more evidence‐based need. J Sex Med. 2015;12:1519–1521. nosology and nomenclature for female 7 Coleman E, Elders J, Satcher D, et al. sexual dysfunctions – Part II. J Sex Med. Summit on medical school education in 2016;13:1888–1906. 18 sexual health: report of an expert Bitzer J, Giraldi A, Pfaus J. A standardized consultation. J Sex Med. 2013;10: diagnostic interview for hypoactive sexual 924–938. desire disorder in women: standard 8 Obedin‐Maliver J, Goldsmith ES, operating procedure (SOP Part 2). J Sex Stewart L, et al. Lesbian, gay, bisexual, Med. 2013;10:50–57. 19 and transgender‐related content in Parish SJ, Hahn SR. Hypoactive sexual undergraduate medical education. JAMA, desire disorder: a review of epidemiology, 2011;306:971–977. biopsychology, diagnosis, and treatment. 9 Brotto LA, Bitzer J, Laan E, et al. Women’s Sex Med Rev. 2016;4:103–120. 20 sexual desire and arousal disorders. J Sex Goldstein I, Kim NN, Clayton AH, et al. Med. 2010; 7, 586–614. Hypoactive sexual desire disorder: 10 Bitzer J., Giraldi A, Pfaus J. Sexual desire International Society for the Study of and hypoactive sexual desire disorder in Women’s Sexual Health (ISSWSH) Expert women. Introduction and overview. Consensus Panel Review. Mayo Clin Proc. Standard operating procedure (SOP Part 1). 2017;92:114–128. doi: 10.1016/j. J Sex Med. 2013;10:36–49. mayocp.2016.09.018. 21 11 Parish SJ, Rubio‐Aurioles E. Education in Giraldi A, Rellini AH, Pfaus J, Laan E. sexual medicine: proceedings from the Female sexual arousal disorders. J Sex Med. international consultation in sexual 2013;10:58–73. 17

Part I

Hypoactive Sexual Desire Disorder

Chapter No.: 1 Title Name: p01.indd Comp. by: Date: 22 Mar 2018 Time: 11:29:04 AM Stage: WorkFlow: Page Number: 17 19

3

Nosology and Epidemiology of Hypoactive Sexual Desire Disorder Leonard R. Derogatis

Abstract

The chapter reviews the history and development of the diagnosis hypoactive sexual desire ­disorder (HSDD) and discusses its close ties to the evolution of the diagnostic system of the American Psychiatric Association (i.e. DSM‐I to DSM‐5). It reviews the principal criteria underly- ing the diagnosis and their underlying significance. The chapter also discusses the widespread ­dissatisfaction with the current DSM‐5 system and the development, in response, of the new ISSWSH diagnostic system for female sexual dysfunctions. Diagnostic standards for the HSDD diagnosis in the ISSWSH system are described and elucidated as an alternative to the DSM‐5 ­system. In addition, the chapter also provides a brief review of the current status of epidemiological research focused on the prevalence of HSDD as defined in contemporary nosological systems. Keywords: diagnosis; prevalence; nosology; nomenclature; FSD; HSDD

­Nosology first two iterations of the DSM were labeled as “Psychophysiological autonomic and vis- Historically, the diagnoses of female sexual ceral disorders” and were consistent with the dysfunctions (FSD), including hypoactive strong psychoanalytic influence holding sexual desire disorder (HSDD), have been sway at the time; etiology was attributed to made primarily based on clinical presentation repressed emotions. When Masters and and patient history rather than a formal Johnson [8] published their work in 1970, nosology grounded in etiology, pathogenesis, they did not identify nor emphasize disor- and clinical phenomenology. The evolution ders of sexual desire. However, Helen Singer of the diagnostic concept of HSDD is closely Kaplan [9] and Harold Lief [10] writing inde- tied to the development of the American pendently in 1977 questioned the omission Psychiatric Association’s Diagnostic (DSM) of this important dimension of sexual behav- system [1–7]. This is, in large measure, due to ior, which led to modifications in the Masters the belief of experts in the postwar twentieth and Johnson paradigm, and the inclusion of century medicine that female sexual dysfunc- a category for desire disorders (“Inhibited tions have a primarily psychological etiology. sexual desire”) in the DSM‐III [3]. The modern diagnostic category of HSDD Desire disorder was initially labeled has existed for approximately 30 years, begin- “Inhibited sexual desire” in the DSM‐III [3], ning with the DSM‐III [3]. Antecedent which was modified to “Sexual desire ­diagnostic categories for low desire in the ­disorder” in the DSM‐III‐R [4]. Finally, in the

Textbook of Female Sexual Function and Dysfunction: Diagnosis and Treatment, First Edition. Edited by Irwin Goldstein, Anita H. Clayton, Andrew T. Goldstein, Noel N. Kim, and Sheryl A. Kingsberg. © 2018 John Wiley & Sons Ltd. Published 2018 by John Wiley & Sons Ltd. 20 Textbook of Female Sexual Function and Dysfunction

DSM‐IV [5] the term “Hypoactive sexual The resulting dissatisfaction with the desire disorder” was introduced. The most DSM‐5 nomenclature is one of the principal recent iterations of the DSM definitions factors giving impetus to development of a of desire disorder are represented by new diagnostic system for female sexual dys- the text revised version of the DSM‐IV functions, established under the auspices of (i.e. DSM‐IV‐TR) [6] and the DSM‐5 [7]. two international expert panels, representing The DSM‐IV‐TR diagnosis requires the the ISSWSH Nomenclature Committee [13] dual criteria of (A), the symptomatic presen- and the International Consultation in tation associated with desire disorder, and Sexual Medicine [14]. In the new ISSWSH (B), “marked distress or interpersonal diffi- nomenclature, HSDD has been restored to culty”. The manifestation of the symptoms of an independent diagnostic category [11], as low sexual desire are further specified as has arousal disorder. ­having to be “persistent or recurrent”. Beyond In the ISSWSH nomenclature [11], the these criteria the condition must be specified diagnostic criteria for desire disorder have as occurring lifelong versus acquired and been extended and simplified, and the diag- ­situational in nature versus generalized. nostic label of HSDD has been restored, an The DSM‐5 definition of desire disorder important decision in light of the very large fundamentally requires three criteria be met: body of empirical evidence that has been Category (A) specifies the clinical phenome- established under this label. In the new nology of the condition, somewhat more ISSWSH nomenclature, HSDD presents with ­precisely than previous editions, and any of the following characteristics for a requires that defining clinical characteristics ­minimum period of at least six months: be present in a majority (e.g. 75%) of the ●● Lack of motivation for sexual activity encounters or episodes; a second (B) crite- characterized­ by: rion requires the condition to have been –– decreased or absent spontaneous desire ­present for at least six months; and third, the (i.e. sexual thoughts or fantasies); condition must cause “clinically significant –– decreased or absent responsive desire to distress in the individual”. In addition, the erotic cues or stimulation or inability to patient is requested to make a judgment as to maintain desire or interest through sex- the severity level of the condition, choosing ual activity. from “mild”, “moderate”, or “severe” as ●● Loss of desire to initiate or participate in descriptors. These added criteria help to sexual activity, including behavioral ­distinguish actual sexual dysfunctions from responses such as avoiding situations transient sexual difficulties and should help that could lead to sexual activity that is not to further homogenize diagnostic groupings secondary to sexual pain disorders. by reducing within‐groups variation. The most dramatic change in the DSM‐5 The manifest characteristic(s) must be involved eliminating HSDD as a distinct accompanied by clinically significant nosologic entity, replacing it with an amalga- ­personal distress that includes frustration, mation of the DSM‐IV HSDD and DSM‐IV grief, guilt, incompetence, loss, sadness or female sexual arousal disorder (FSAD) diagno- worry. In addition, the experience and impact ses. The resulting compounded diagnosis has of the symptoms of HSDD as a whole should been termed female sexual interest/arousal be rated by the affected person as mild, mod- disorder (FSIAD). This revised ­classification erate or severe. has proven to be highly controversial among Importantly, the new ISSWSH nosologic experts in the area of sexual medicine, as there system is highly compatible with the is little empirical support or confirmation for International Statistical Classification of the new diagnostic c­ategory and the logics Diseases and Related Health Problems, 11th upon which the ­compounded diagnosis are Revision (ICD‐11) [15], which will be soon based appear less than compelling [11, 12]. utilized worldwide. In ICD‐11, HSDD is also Nosology and Epidemiology of Hypoactive Sexual Desire Disorder 21 represented by an independent diagnostic sexually‐related personal distress has a much category, i.e. hypoactive sexual desire lower occurrence. Also, these two elements dysfunction. represent the core facets of contemporary definitions of HSDD, while earlier definitions focused more exclusively on the clinical ­Epidemiology details of low sexual desire. This distinction underlies the disjunction between contem- By far the large majority of our epidemiologi- porary epidemiological prevalence estimates cal studies in FSD are observational‐descrip- and prevalence rates from earlier research, tive in nature, with very few analytic trials where personal distress was not considered. being reported. This state of affairs is due, in Findings in earlier studies report much large measure, to the historical imprecision higher rates of dysfunction, primarily of the diagnostic systems used and the because the criterion of personal distress was ­relative absence of standardized and well‐ not included. For this reason, our brief review articulated methods [16]. Imprecise diagnos- of the prevalence of HSDD given here will tic definitions lead to inaccurate estimates of focus exclusively on those studies that used a occurrence rates and greatly impede the distress criterion in their HSDD definition. development of accurate rates for risk f­ actors. Probably the most comprehensive contem- As an example, Dunn [17] and her associates porary study of FSD prevalence was com- reviewed 28 studies of FSD and concluded, pleted by Shifren and her associates [19]. “…the heterogeneity of the studies ruled out Termed the PRESIDE study, they reported on the possibility of formally pooling the data” a large survey of over 50,000 households in (p. 418). They further felt that the variation the United States, with 31,581 respondents, in methodology was so great across the which probably represents the most complete ­studies that deriving a reliable pooled overall study to date on the prevalence of FSD in the estimate of prevalence for these disorders United States. Their results revealed 38.7% of was just not possible. Several years later, American women reported problems with Hayes [18] and his colleagues in their review low sexual desire, with the highest prevalence of prevalence studies concluded, “As meas- reported in the ≥65 year old group (74.8%) ures of sexual dysfunction and time frames and the lowest prevalence observed in the differ between studies, it is still not possible youngest age group (22.2%). The middle to determine reliable overall prevalence esti- group (45–64%) revealed a prevalence of mates of FSD” (p. 594). More recent studies 38.9% for problems of low sexual desire. have shown methodological improvements, However, since older women reported signifi- but variations in nomenclature have contin- cantly lower rates of personal distress than ued to impede progress. Until a scientifically the younger groups (12.6% vs. approximately valid and rigorously defined nosology is 25% in the two younger groups), the rates of achieved and adopted, our epidemiological diagnosed HSDD remained roughly equiva- estimates of prevalence for HSDD will con- lent, i.e. 10.08% overall. It has been theorized tinue to reflect wide variation. that the low rates of distress in older women, An important convention that should be even in the face of a higher prevalence of sex- employed when considering the epidemiol- ual difficulties, might be the result of changes ogy of HSDD is to distinguish those studies in partner status or the ­relatively diminished which require the presence of clinically importance of sex in long‐term relationships. ­significant personal distress to make the It is also distinctly possible that many older diagnosis from those in which the distress women viewed the lessening of sexual desire criterion is absent. This is a very critical dis- with age as a natural phenomenon, and not a tinction, since the occurrence of low sexual condition to be treated. desire among women is quite common; how- Probably the most closely comparable ever, low sexual desire in combination with recent study to PRESIDE is the Women’s 22 Textbook of Female Sexual Function and Dysfunction

International Study of Health and Sexuality A strong bidirectional cooccurrence (WISHeS) [20]. In this study, both low sexual between HSDD and clinical depression has desire and distress were measured in a sam- also been repeatedly observed, such that ple consisting of 1591 partnered women each is considered a significant risk factor from the USA and 1998 partnered women for the other condition. In a large meta‐anal- from Europe, aged 20–70 years. Much as was ysis, depressed patients had a 50–70% observed in PRESIDE, rates of low sexual increased risk of developing a sexual desire significantly increased across age ­dysfunction and patients with sexual dys- groups, while rates of personal distress function had 130–210% increased risk of decreased significantly with age. This disor- developing depression [22]. Similarly, the dinal interaction resulted in a finding French ELIXIR study [23] reported a preva- ­analogous to the PRESIDE study, that the lence rate of 65% for sexual dysfunction in prevalence of HSDD did not significantly their sample of depressed patients, and rates change with age. The overall prevalence for all sexual dysfunctions twice those found ­estimates ranged from a low of 7% for pre- in women free of these conditions. West [24] menopausal women in the 20–49 year old and her associates observed a rate of HSDD group, to a high of 16% for surgically meno- that was three times greater among pausal women, 20–49 years of age. depressed individuals in her cohort (20.6%) Conclusions were similar, to the effect that than the rate (6.9%) among the nonde- low sexual desire is a common problem pressed. Depression and HSDD are fre- among women across age groups, and even quently comorbid conditions, particularly in when the additional criterion of personal dis- light of the fact that loss of sexual desire may tress is added to certify an HSDD diagnosis, be a symptom of a major depressive episode. it remains a prevalent problem. In women and men with sexual dysfunction, There is also a fairly consistent pattern of the risk of developing depression was associated conditions reported with the increased 170–210% [22]. It is very difficult occurrence of HSDD. Women diagnosed to establish definitive directionality of effects with HSDD are significantly more likely to in this relationship, except via temporal dif- report being dissatisfied with their sex lives ferences in date of onset. In two cross‐sec- than women with normal desire and feel tional analyses, more than one‐third of more dissatisfied with their relationships. women with HSDD had comorbid depres- These women also tend to have more sion or treatment: 34% in the HSDD Registry chronic illnesses and poorer general health for Women [25] and 40% in the PRESIDE status. Effects between HSDD and these study [26]. conditions appear to be bidirectional for The data all point to the conclusion that the most part. In terms of specific health HSDD is a very prevalent problem among conditions, diabetes, ovary removal, uri- women, independent of age, with numerous nary tract problems, and breast cancer concomitant and comorbid conditions that appear to be more prevalent among women tend to complicate effective treatment with HSDD [21]. ­planning and problem resolution.

References

1 American Psychiatric Association. 2 American Psychiatric Association. DSM‐II: The Diagnostic and Statistical Manual of Diagnostic and Statistical Manual of Mental Mental Disorders. Washington, DC: Disorders, 2nd edn. Washington, DC: American Psychiatric Association; 1952. American Psychiatric Association; 1968. Nosology and Epidemiology of Hypoactive Sexual Desire Disorder 23

3 American Psychiatric Association. DSM‐ Fourth International Congress on Sexual III: Diagnostic and Statistical Manual of Medicine 2015. J Sex Med. 2016; Mental Disorders, 3rd edn. Washington, 13:135–143. DC: American Psychiatric 15 Reed GM, Drescher J, Krueger RB, et al. Association; 1980. Disorders related to sexuality and gender 4 American Psychiatric Association. identity in the ICD‐11: revising the ICD‐10 DSM‐III‐R: Diagnostic and Statistical classification based on current scientific Manual of Mental Disorders, 3rd edn evidence, best clinical practices, and revised. Washington, DC: American human rights considerations. World Psychiatric Association; 1987. Psychiatry, 2016; 15:205–221. 5 American Psychiatric Association. 16 Derogatis LR, Sand M, Balon R, et al. DSM‐IV: Diagnostic and Statistical Toward a more evidenced‐based nosology Manual of Mental Disorders, 4th edn. and nomenclature for female sexual Washington, DC: American Psychiatric dysfunctions – Part 1. J Sex Med. 2016; Association; 1994. 13:1881–1887. 6 American Psychiatric Association. DSM‐ 17 Dunn KM, Jordan K, Croft PR, et al. IV‐TR: Diagnostic and Statistical Manual Systematic review of sexual problems: of Mental Disorders. 4th edn revised. epidemiology and methodology. J Sex & Washington, DC: American Psychiatric Mar Ther. 2002; 28:399–420. Association; 2000. 18 Hayes RD, Bennett CM, Fairly CK, et al. 7 American Psychiatric Association. DSM‐5: What can prevalence studies tell us about Diagnostic and Statistical Manual of female sexual difficulty and dysfunction. Mental Disorders, 5th edn. Washington, J Sex Med. 2006; 3:589–595. DC: American Psychiatric Association; 19 Shifren JL, Monz BU, Russo PA, et al. 2013. Sexual problems and distress in United 8 Masters WH and Johnson, VE. Human States women: prevalence and correlates. Sexual Inadequacy. New York: Obstet Gynecol. 2008; 112(5):970–978. Bantam; 1970. 20 Dennerstein L, Koochaki P, Barton I, 9 Kaplan HS. The New Sex Therapy. New Graziottin A. Hypoactive sexual desire York: Brunner/Mazel; 1974. disorder in menopausal women: A survey 10 Lief HI. Inhibited sexual desire. Medical of Western European women. J Sex Med. Aspects of Human Sexuality, 1977;7: 94–95. 2006; 3:212–222. 11 Clayton AH, Derogatis LR, Rosen R, et al. 21 Derogatis LR, Burnett A. The epidemiology Does clinical research data support sexual of sexual dysfunctions. J Sex Med. 2008; desire and arousal disorders as distinct 5:289–300. diagnoses? J Sex Med. 2010;7(S3):143–144. 22 Atlantis E, Sullivan T. Bidirectional 12 Derogatis LR, Clayton AH, Rosen R, et al. association between depression and sexual Do multiple convergent measures of female dysfunction: A systematic review and meta‐ sexual dysfunction support sexual desire analysis. J Sex Med. 2012; 9(6):1497–1507. and arousal disorders as distinct diagnoses? 23 Bonierebale M, Lancon C, Tignol, J. J Sex Med. 2010;7(S3):142–143. The ELIXIR study: evaluation of sexual 13 Parish SJ, Goldstein AT, Goldstein SW, dysfunction in 4557 depressed patients in et al. Toward a more evidence‐based France. Curr Med Res Opin. 2003; nosology and nomenclature for female 19:114–124. sexual dysfunctions – Part II. J Sex Med. 24 West SL, D’Aloisio AA, Agans, RP, et al. 2016;13:1888–1906. Prevalence of low sexual desire and HSDD 14 McCabe MP, Sharlip ID, Atalla E, et al. in a nationally representative sample of US Definitions of sexual dysfunction in women women. Arch Intern Med. 2008. and men: a consensus statement from the 168:1441–1448. 24 Textbook of Female Sexual Function and Dysfunction

25 Clayton AH, Maserejian NN, Connor MK, 26 Johannes CB, Clayton AH, Odom DM, et al. Depression in premenopausal women et al. Distressing sexual problems in United with HSDD: baseline findings from the States women revisited: prevalence after HSDD Registry for Women. Psychosom accounting for depression. J Clin Med. 2012; 74(3):305–311. Psychiatry. 2009; 70(12):1698–1706. 25

4

Central Nervous System Anatomy and Neurochemistry of Sexual Desire James G. Pfaus and Sherri L. Jones

Abstract

Sexual desire comprises objective physiological, subjective psychological, and behavioral aspects, and can be defined as a presence of desire for, and fantasy about, sexual activity. In animals and humans, desire can be inferred by measuring behaviors such as willingness to work for sexual rein- forcers, or locomotor activity in anticipation of sexual activity. Inherent in all models of sexual behavior is the notion that the different components of sexual behavior require activation of differ- ent brain regions or networks for their coordination. That coordination requires tightly regulated feedback systems as well as molecular mechanisms that allow those systems to be amenable to steroid hormones and experience. In this chapter, we review central nervous system structures and the underlying neurochemistry involved in sexual excitation, inhibition, and disinhibition, drawn primarily from basic preclinical research in animals. We then discuss three potential treatments for female sexual desire or interest disorders that have undergone clinical trials.

Keywords: dopamine; HSDD; melanocortin; neuroanatomy; neurochemistry; ovarian hormones; sexual desire; testosterone; solicitations; serotonin

Sexual desire is in the brain. Sexual desire is driven by the expectation of sexual pleasure. Excitatory and inhibitory systems in the brain integrate internal and external stimuli to generate desire as a final endpoint.

­Introduction recommended for adoption into the ICD‐11 [2], in which desire for, and fantasy about, Sexual desire is a difficult concept to grasp, as engaging in sexual activity are chronically or it entails objective physiological, subjective recurrently deficient or absent. By converse psychological, and behavioral variables that logic, sexual desire would be the presence of reflect conscious recognition of its own state. desire for, and fantasy about, sexual activity. This implies a dynamic regulation of desire in The Diagnostic and Statistical Manual of the brain. No agreed‐upon definition of ­sexual Mental Disorders 5 (DSM‐5) of the American desire exists except that inferred from the Psychiatric Association kept hypoactive sex- ­definition of hypoactive sexual desire di­ sorder ual desire disorder but combined it for women by the International Society for the Study of with sexual arousal disorder into a new moni- Women’s Sexual Health (ISSWSH) [1], and ker called Female Sexual Interest and Arousal

Textbook of Female Sexual Function and Dysfunction: Diagnosis and Treatment, First Edition. Edited by Irwin Goldstein, Anita H. Clayton, Andrew T. Goldstein, Noel N. Kim, and Sheryl A. Kingsberg. © 2018 John Wiley & Sons Ltd. Published 2018 by John Wiley & Sons Ltd. 26 Textbook of Female Sexual Function and Dysfunction

Disorder [3], despite the fact that women can desire [7–10]. But from both a biological and present with predominantly low desire, pre- psychological perspective, this makes logical dominant arousal problems, or a combina- sense: animals must be able to respond to tion of the two [4]. Indeed, desire can be hormonal and neurochemical changes that viewed as distinct from arousal in animals signal their own sexual arousal and desire, and humans, with desire constituting a psy- and be able to interact with external sexual chological interest in sex and behaviors that incentives. Animals must be able to identify reflect such interest. Despite this separation external stimuli that predict where potential of arousal and desire, it is likely that desire is sex partners can be found, and subsequently informed or confirmed by the presence of seek them out, solicit, court, or otherwise autonomic or central arousal. In fact, many work to obtain them, distinguish sensory women and men regard sexual desire and cues and behavioral patterns of potential arousal as parts of one another, despite being partners from those that are not interested given distinct definitions [5]. Thus, desire as or receptive, and pursue desired sex partners it is expressed physically in conscious, goal‐ once sexual contact has been made. directed behavior, most closely resembles the terms “lust”, “libido”, and “horny” [1]. Desire can be inferred in both animals ­The Sexual Brain and humans by their willingness to work for sexual reinforcers, or in behavior that The brain organizes sexual stimulation into reflects the anticipation of sexual activity an overall interactive sense of sexual excita- [6]. In all species, sexual behavior is directed tion and inhibition that integrates societal, by a complex interplay between steroid psychological, and physiological factors ­hormone actions in the brain that give rise to (Figure 4.1). This is accomplished in evolu- sexual arousability, and experience with tionarily‐conserved sets of neurochemical ­sexual reward or pleasure that gives rise to pathways or “modules” that integrate endog- expectations of competent sexual activity, enous sex “drive” (e.g. gonadal hormone sta- including sexual arousal, desire, and ele- tus and energy metabolism) with autonomic ments of copulatory performance [7]. Sexual arousal in the hypothalamus, the intensity of experience allows animals to form instru- incentive sexual stimuli (unconditioned and mental and Pavlovian associations (i.e. asso- conditioned stimuli that activate or “prime” ciations formed between behaviors and attention and movement from distal to prox- devices such as levers or unrelated stimuli imal to interactive) in the hypothalamus and such as sound) that predict sexual outcomes limbic system, and the evaluation of sexual and, thereby, direct the strength of sexual context and executive function as it relates to response. Although the study of animal sexual excitation or inhibition overall [6]. ­sexual behavior by neuroendocrinologists In particular, cortical activation controls the has traditionally been concerned with mech- coding of information into “gestalts” (e.g. sets anisms of copulatory response related to of physical or interpersonal characteristics reproduction (e.g. lordosis in females and that individuals find conditionally attractive erections, mounts, intromissions, and ejacu- or unattractive; contexts that are suitable or lations in males), more recent use of condi- unsuitable for sexual activity; etc., following tioning and preference paradigms, and a from Pavlov [11]) and involves the activation focus on environmental circumstances and of the medial prefrontal cortex and the experience, has revealed sexual behaviors in descending inhibition of motor acts as part a variety of species that are driven by reward‐ of executive function. Within each are excita- related mechanisms in the brain that are tory and inhibitory neurochemical systems analogous or homologous to human sexual that control sexual response at any given Central Nervous System Anatomy and Neurochemistry of Sexual Desire 27

Dual control model

- Physiological and + Physiological and organic issues organic issues

- Psychosocial, cultural + Psychosocial, cultural and behavioral issues and behavioral issues

Sexual tipping point®

Inhibition Excitation

Variable and dynamic process

Figure 4.1 Sexual tipping point model of sexual excitation and inhibition. Cultural, psychological, and physiological factors conspire to tip the balance either toward excitation or inhibition. Sexually functional individuals maintain a degree of lability in the balance, and an ability to have it tipped toward either excitation or inhibition. Persons with hypoactive sexual desire disorder are likely to have the balance weighed down by inhibition. This can occur because of hypofunctional excitation, hyperfunction inhibition, or a combination of the two. After Perelman [67]. (See plate section for color representation of the figure) time. These systems are activated or sup- also participate in the ­generation of partner pressed by steroid hormones as well as by and mate preferences. The medial preoptic experience‐driven changes in gene expres- area is well suited as a central processor in the sion and neurochemical function [6]. It is linking of metabolic need, hormonal status, through these systems that priming stimuli and autonomic outflow, with the stimulation or drugs alter sexual response by changing of mesolimbic dopamine neurons in the the interpretation of stimuli and context. ­ventral tegmental area. The mesolimbic Attentional and emotional components are dopamine system projects to several impor- encoded largely in limbic structures, notably tant limbic and cortical structures, notably in the nucleus accumbens, septum, and amyg- the nucleus accumbens, corticomedial amyg- dala (Figure 4.2), that allow the animal to dala, lateral and medial septum, and medial focus on pleasure (or punishment) related prefrontal cortex, and is critical for all ani- stimuli in the environment. The hippocam- mals’ attention to incentive stimuli [14]; pus provides spatial maps of the external ­genitosensory, attentional, and emotional world and episodic memory for important systems are engaged at the same time follow- sexual encounters, and the paleocortex (e.g. ing the ­hormonal stimulation that occurs anterior cingulate gyrus) regulates autonomic around ovulation, linking reward‐related function along with anticipation of reward, incentive motivation to reproduction. decision making, and empathy [12, 13]. Along Finally, as mentioned above, although with limbic activation, hypothalamic struc- ­sexual responses can include thoughts and tures, notably the medial preoptic area and fantasies (at least in humans), they are ventromedial hypothalamus, activate sexual reflected in all animals as behavior. response in relation to hormonal status and Coordinated purposeful behavior comes metabolism, and in concert with regions, from the activity of both fine and gross motor such as the paraventricular nucleus and acts that are derived from the coordinated supraoptic nucleus, coordinate autonomic activation of motor cortex and the basal activation with elements of ­sexual desire ­ganglia, along with other motor structures in (e.g. solicitations, pursuit). Those structures the midbrain and the cerebellum. In addition 28 Textbook of Female Sexual Function and Dysfunction

Prefrontal cortex

Medial Striatum preoptic area Nucleus Caudate Putamen accumbens nucleus

Zona Ventral Dorsal incerta

Ventral pallidum l iata Mesocortical

Mesolimbic Amygdala

Hippocampus Nigrostr

VTA SN

Dopaminergic projections

Glutamatergic projections

GABAergic projections

Figure 4.2 A wiring diagram of sexual excitation and inhibition in the mammalian brain that reflects current understanding of neuroanatomical and neurochemical pathways. VTA: Ventral tegmental area; SN: substantia nigra. Modified from Kingsberg et al. [119]. (See plate section for color representation of the figure)

to coordinating body movements in space or endogenous hypogonadism (reviewed in and time, these structures crystallize motor Pfaus et al. [7]), it is not yet known whether memory, a function that is critical for motor sexual experience provides females with habit formation (the phenomenon whereby ­similar protection. motor acts at the beginning of behavioral learning are choppy and uncoordinated, but become virtually automated with ­Structure of Female Sexual ­practice). Although the formation of motor Behavior habits in males with extensive sexual ­experience protects sexual behavior against For all animals, sexual behavior occurs as a ­treatments or situations that might disrupt it, sequence or “cascade” of behavioral events. including novel environments, stress, genital Beach [15] recognized the heuristic value of ­anesthesia, brain lesions, and even castration separating sexual behavior into appetitive Central Nervous System Anatomy and Neurochemistry of Sexual Desire 29 and consummatory phases. Essentially, this ­different environments or appetitive cir- scheme followed from the work of early cumstances [7, 18]. As in animals, human twentieth century ethologists and experi- sexual desire and subjective sexual arousal mental psychologists [16, 17], who defined fit into an appetitive framework [7, 10, 19], appetitive (or “preparatory”) behaviors as whereas the more stereotyped patterns of those which bring an animal from distal to copulatory behavior fit into a consummatory proximal and into contact with goal objects framework. or incentives, like potential sex partners. Perhaps the most well‐known description In contrast, consummatory behaviors are of human sexual response is that of Masters performed once an animal is in direct con- and Johnson’s “EPOR” (Excitation, Plateau, tact with the incentive (i.e. to “consummate” Orgasm, Resolution) model (Figure 4.3) [20]. the goal). Consummatory sexual behaviors This model, derived from Moll’s original tend to be species specific, sexually differen- (1908) four‐stage model [21], flows in time as tiated, and stereotyped, whereas appetitive a cascade of behavioral and neurophysiologi- behaviors are more flexible. This also makes cal events, starting with sexual excitement sense, as survival often depends on behavio- (blood flow to the genitals and other ral f­lexibility, on an animal’s ability to learn a ­erogenous erectile tissues), then plateau variety of strategies to obtain goals in (parasympathetic maintenance of genital

Female Male

Orgasm Orgasm

Plateau Refractory Plateau Resolution period Resolution Refractory Resolution period Excitement Resolution Resolution 2 Excitement

123 3 1

Modified by Kaplan (1974) and Georgiadis et al. (2012)

Wanting Liking Learning Orgasm

Plateau Pleasure

Arousal Refraction Hedonic set-point Desire

Time Expectation Consummation Satiety

Figure 4.3 The “EPOR” (Excitation, Plateau, Orgasm, Resolution) model of Masters and Johnson, with modifications by Kaplan [21] and Georgiadis et al. [24] to fit more current models of arousal, desire, and incentive motivation. 30 Textbook of Female Sexual Function and Dysfunction

blood flow during sexual intercourse), culmi- active pursuits [25]. However, it is clear that nating in orgasm (a defining moment of women and some other primate females can euphoria, ecstasy, and pleasure in which have sexual intercourse anytime during the sympathetic systems move blood out of the ovulatory cycle. This can even occur without genitals), followed by resolution (also called a hormone priming in hypogonadal individuals refractory period during which inhibitory and, indeed, without prior desire or consent systems of the brain are activated to reduce [26]. Although sexually receptive behaviors the salience of external and somatosensory clearly exist in females of all species, they are sexual stimuli). The EPOR model describes far from passive when it comes to sex. Based at least three distinct patterns for women on observations of a variety of species, Beach that vary in the structure of the plateau, the [15] proposed that female‐initiated sexual intensity and number of orgasms, and the behaviors can be partitioned into a cascade of temporal offset of arousal during the resolu- essentially three temporal phases: attractivity tion phase, although it does not differentiate (behaviors like approach or scent marking the particular characteristics of the sexual that lure males to the females), proceptivity stimuli used to achieve orgasm (e.g., external (behaviors that precede receptive behaviors clitoral only, external and internal clitoral, and focus the male on pursuing the female), cervical, blended clitoral and cervical, extra- and receptivity (behaviors like lordosis and genital, etc.), nor was it based on an analysis lateral tail deflection in rats and hamsters, of actual genital blood flow. Subsequently, respectively, or sexual positions in humans Kaplan [22] added a phase of sexual desire, that allow vaginal penetration). More recently, consisting of fantasies and thoughts about Basson [25] (Figure 4.4) described how sexual activity, along with behavior aimed at “innate” sexual desire (potentially induced at obtaining sexual partners and/or sexual ovulation, for example by the combined ­gratification. The phases can also be action of estrogens and androgens in the described in terms of wanting (desire), liking hypothalamus and limbic system), activates (arousal, plateau and orgasm), and inhibition attention to incentive sexual stimuli, sexual (resolution) [23, 24]. arousal, and sexual receptive behaviors that, if Despite overarching theoretical models of positively reinforced, lead to a sensitization of human and animal sexual response that did attention and sexual arousal in the presence not posit sex differences in the basic response of salient and competent incentive sexual structure, female sexual behavior has, until cues. Her model is easily applicable to all spe- fairly recently, been considered “passive.” This cies and is similar to incentive models for is due, in part, to a general social ­construction ­sexual motivation produced by others [19, 27]. in Western society of female sexuality as Inherent in all models of sexual behavior is something that is “done to,” relative to more the notion that the components are separa- active male sexuality that “performs,” and to ble. This would require different brain the labeling of female sexual behavior in both regions or networks to control the compo- animals and humans as “receptive”, consisting nents, feedback systems that link them largely in animals of estrogen‐ and progestin‐ together, and molecular mechanisms that dependent behaviors that allow females to allow their activation to be altered by steroid accept male initiation (e.g. mounts) and be hormones and experience. open to vaginal penetration by engaging in Clearly, females and males engage in postural changes like lordosis, the character- mutual and complementary patterns of sex- istic arching of the back that raises the rump ual activity; however, it is the females that to allow penile intromission. Similarly, in initiate and control successful sexual interac- humans, hormone‐ and context‐dependent tion, including the initiation and temporal “responsive desire” has been viewed as allow- patterning of copulation. This occurs ing females to be responsive to a partner’s by a complex interaction of appetitive Central Nervous System Anatomy and Neurochemistry of Sexual Desire 31

Numerous Sexual incentives for receptiveness sex

Rewards: Innate sexual Sexual stimuli sexual and desire non-sexual (hormonally driven)

Sexual Responsive arousal desire (experientially driven)

Figure 4.4 Circular feedback model of sexual responsiveness by Basson. Note that experience with sexual reward in the model can increase the likelihood of response, whereas experience with sexual nonreward or punishment can diminish expectations of pleasure that reduce the functionality of the feedback system. From Basson [25].

precopulatory behaviors that attract and eral view that sexual behavior in women is solicit sex from males. These behaviors are “freed” from the dependence on steroid hor- taken to reflect both innate and “receptive” mones, women display a characteristic sexual desire, and may well be informed by or increase in self‐reported sexual desire and sum with sexual arousal. Once copulation arousal during ovulation (Figure 4.5) [30]. begins, females engage in receptive behaviors Across the ovarian cycle of women, steroid such as lordosis, pacing behaviors that con- hormone levels fluctuate in a cyclical man- trol the rate of sexual stimulation received ner. Circulating levels of estrogens, proges- during sexual interaction and copulation, tins, and androgens rise around the time of and defensive behaviors used either to pace ovulation, correlating with an increase in the copulatory contact if females cannot oth- sexual interest, activity and fantasies [19, 27, erwise do so, or to terminate the sexual inter- 30–34]. Removal of cyclic steroid hormone action [27–29]. These behaviors serve to release by long‐term administration of estro- optimize the rate and strength of sexual stim- gen‐containing oral contraceptives often ulation received by females, which, in turn, results in a decline in sexual desire, activity, initiates neuroendocrine reflexes associated and genital blood flow [31, 35–38]. It is with ­fertility and pregnancy. unclear whether the blunting of the cyclical induction of sexual activity and fantasies is directly due to the removal of the cyclicity of ­Sexual Behavior of Human the hormones acting on relevant tissues, or Females whether it is secondary to downstream effects of chronic administration of estro- Like other primates, the sexual behaviors of gens. Long‐term exposure to estrogens has women can be organized into specific pat- physiological effects that might disrupt sex- terns of sexual desire, arousal, orgasm, and ual behavior. For example, estrogens upregu- sexual inhibition, all of which are exquisitely late steroid hormone binding globulin sensitive to context, social learning, and real production by the liver, which are transport experience [25]. However, despite the gen- proteins that bind androgens with higher 32 Textbook of Female Sexual Function and Dysfunction

Human menstrual cycle Rat estrous cycle Ovulation Ovulation

Progesterone

Estradiol

Estradiol

Testosterone Progesterone

Testosterone Days 2 46810 12 14 16 18 20 22 24 26 28 Metestrus Diestrus Proestrus Estrus Follicular Luteal Menstrual Human sexual desire Macaque sexual desire 500

60 400 Solicitations

300 40

200 Approach

20 100 Mean frequency per male hour Mean frequency

Number of subjects reporting sexual desire Number of subjects reporting sexual 0 0

–1.5 –1.0 –0.5 0.5 1.0 1.5 2.0 1 2 3 4 5 6 7 8 9 11 10 13 12 –8 –7 –6 –5 –4 –3 –2 –1 Ovulation E2 peak Days relative to ovulation Days relative to estradiol peak

Figure 4.5 Top: Ovulatory cycles of humans (left) and rats (right). Bottom: Sexual desire in humans and rhesus macaques. Note how measures of desire peak around the time of ovulation. Secondary peaks have been reported around the time of menstruation in humans. From Pfaus et al. [27], after Wallen [26], Stanislaw and Rice [30].

affinity than estrogens [39–41]. As such, the particularly with replacement of estrogens in administration of an estrogen can lower cir- combination with testosterone [42, 45–53]. culating androgens such as testosterone. For women with chemically‐induced meno- Given the importance of androgens for pause (i.e. following chemotherapy or ­sexual desire in women, a reduction in circu- ­gonadotropin‐releasing hormone agonists), lating androgens by chronic use of oral con- those that experience chronic ovarian failure traceptives may be one reason why some report higher levels of sexual desire problems women experience a decrease in sexual desire than menstruating women with past chemo- on the pill. therapy treatment [54]. In postmenopausal A decline in sexual desire and activity also (55–70 year olds) breast‐cancer survivors, occurs following surgical, natural, and those treated with adjuvant hormone treat- ­chemically‐induced menopause. Surgically ments report lower levels of sexual arousal menopausal women, induced by bilateral and desire compared to age‐matched oophorectomy with or without hysterec- ­controls [55]. Moreover, those treated with tomy, experience a sudden and drastic aromatase inhibitors report lower sexual decline in sexual arousal and desire [42–44]. interest compared to five years earlier than These symptoms can be restored following do those treated with estrogen receptor adequate hormone replacement regimens, blockers or age‐matched controls. As such, Central Nervous System Anatomy and Neurochemistry of Sexual Desire 33 ample ­evidence suggests that fluctuating experience directing attention and behavior ovarian steroid hormone levels are impor- toward individuals and stimuli previously tant in normal sexual function in women, as associated with sexual reward. they are in other species. The copulatory patterns of women are also Despite a wealth of knowledge from animal fraught with problems of interpretation. studies, sexual desire in women is a matter of Although more stereotyped than appetitive great controversy. Although sexual arousal responses, consummatory patterns of copu- and desire can be defined by subjective lation in humans are, nonetheless, extremely reports, only arousal has been defined variable, even in cultures where certain posi- ­objectively (as increased genital blood flow). tions (e.g. missionary) are proscribed. Some There is not yet an objective measure of heterosexual positions (e.g. woman on top) desire, thereby forcing it to be inferred from can maximize her ability to get optimal exter- subjective self‐report or intuitively observed nal and internal clitoral stimulation, possibly ­behavior (e.g. flirtations). Desire appears along with direct stimulation of the cervix, to occur spontaneously in some women from the male. Other positions may embel- whereas in others it occurs in response to the lish other stimulus zones, and thus engage right male(s) or females(s) making the right different motor patterns to maximize the verbal and nonverbal gestures in the right stimulation achieved. And, of course, some contexts. As mentioned above, self‐reported women are extremely sensitive to external desire peaks during ovulation. This makes clitoral stimulation, and can only achieve antecedent hormonal conditions – effects of orgasm in that way, whereas others achieve estradiol, testosterone, and perhaps also pro- orgasms with blended internal and external gesterone, in the brain - likely motivational clitoral stimulation. Interestingly, there is no variables in its stimulation. Responsive human analogue to the lordosis reflex, desire, or the ability of the “right” stimuli to although lordosis‐like positions can be activate incentive motivational pathways in observed in women being mounted from the brain and excite attention and behaviors behind. A lordosis‐like arching of the back, that are indicative of desire, is also activated however, is not a hormone‐induced and/or by steroid hormones. As mentioned above, facilitated spinal reflex; those do not exist in desire is then expressed both as a spontane- humans, a fact that continues to limit the ous motivation and an attention toward human clinical application of the neuroendo- competent sexual stimuli [19, 27]. In both crine work done on lordosis in animals. cases, the emergent conscious awareness of Being “receptive” to vaginal penetration in sexual desire activates movement from distal women involves a conscious decision to to proximal to interactive, like the approach expose the vulva and open it to penetration. and solicitations of rats and macaques. Experience with orgasm or other types of Humans thus learn a baffling array of appeti- sexual pleasure and intimacy leads to tive responses that work differently in differ- ­expectancies of which positions “work”, thus ent cultures and contexts, or differently ­further constraining the sexual positions within a single culture at different epochs, and patterns of both women and men. and indeed differently with different people. And cultures constrain women’s responses, and indeed their own knowledge of their own ­Ovarian Hormones Set sexuality, to appropriate times and places. the Stage The brain must balance these excitatory and inhibitory influences to achieve an optimal As mentioned above, the cyclic actions of level for pleasure. And it must do this with estradiol, testosterone, and progesterone in hormonal influences weighing it toward females leads to changes in sexual response excitation, especially during ovulation, and and increases in sexual arousal and desire 34 Textbook of Female Sexual Function and Dysfunction

around the time of ovulation in all vertebrate level that allows any degree of finely‐grained species, including humans [30, 56], although neural or molecular analysis. Recent a smaller increase in arousal and desire advances in brain imaging and eye‐tracking has been reported around the time of technology have allowed cortical and subcor- ­menstruation [57]. Of the three steroids tical activation, and visual gaze, to be assessed released from the ovaries of mammalian in women viewing erotic visual stimuli, and females, testosterone is at its highest level some important paradigms have emerged to around the time of ovulation, whereas estra- correlate aspects of subjective sexual arousal, diol rises a few days earlier, peaking just desire, and orgasm to overall brain activation before ovulation (Figure 4.5). Progesterone patterns (Figure 4.6) [23]. Such data reveal a levels rise before, during, or after ovulation, great deal about the cognitive and limbic depending on the species. This hormonal control of different aspects of female sexual milieu during the periovulatory follicular behavior under different hormonally‐modu- phase alters the way in which visual sexual lated, pharmacological, or experiential con- stimuli are processed in women [58–61], ditions, and in ways that confirm data from which presumably leads to a shift in the females of other species. Nevertheless, these incentive value of the stimuli. Analogous paradigms lag behind the scope of neuroana- findings have been reported in other pri- tomical, neuropharmacological, histochemi- mates, for example in approaches and solici- cal, and molecular methods that can be used tations made around the time of the mid‐cycle with animal models. estradiol peak in rhesus macaques [62], and Most of the research done on the neurobi- in the appetitive and consummatory sexual ology of female sexual desire comes from behaviors that characterize the periovulatory rodent subfamilies, like rats, mice, hamsters, period of female rats [63]. Steroid hormones gerbils, voles, and musk shrews, lagomorphs drive sexual arousal and desire in response to like rabbits and myomorphs like guinea pigs, competent incentive stimuli. In turn, experi- less so from primates like rhesus and Japanese ence with sexual reward (and inhibition) macaques, and even less so from humans. modulates the strength and trajectory of Understanding the behavioral structure of responses to incentive sexual cues. This is each species’ appetitive and consummatory timed in most female mammals to the period phases is vitally important for a sophisticated around ovulation, thus stimulating females understanding of the neurobiological mech- to engage in the most rewarding behaviors anisms that control it. In many studies, the under the most reproductively‐relevant female’s receptive lordosis posture is taken as ­circumstances (see Pacing Behavior). This an index of her copulatory or “mating” contrasts with the relatively stable and behavior, rather than the full repertoire of ­continuous testicular androgen secretion in appetitive and consummatory sexual mammalian males (and its aromatization to responses. It is often the case in laboratory neural estradiol in different regions of the settings that females are tested in small brain) that maintains sexual arousability and chambers that do not allow them to approach responsiveness in a relatively continuous or escape the male or, in the case of females manner [64]. that pace the copulatory contact, allow them to regulate the timing and intensity of that ­How do We Study the Central contact. When appetitive responses are taken together with lordosis, it becomes Nervous System Regulation immediately apparent that there is extensive of Female Sexual Desire? conservation of the neurochemical mecha- nisms that control sexual behavior, which Although human sexual behavior is best generates homologies in the way that sexual studied in humans, it is often impossible to stimulation is perceived by the brain and do so with experimental precision or at a induces competent responses. Behavior is Central Nervous System Anatomy and Neurochemistry of Sexual Desire 35

Behavioral Motivation Consummation Satiety state wanting Liking inhibition Learning Genital responses

Pleasure

Excitement Plateau Orgasm Refraction

SRL Genital IPL S1 IPL dIPFC vIOT Ins ClausCvIOT Ins laus FO Ins FO Ins Temp FO Ins vIOT pole vITG

aMCC aMCC dMPFC pACC Pelvic M1 sACC pACC Brain vmPFC Cb HT networks HT HT HT vmPFC

Amy Med-temp AmyAMed-temp my Med-temp Amy Med-temp VS vmPFC vmPFC vmPFC HT HT HT HT VP VP

OFC OFCOFC

Encoding Sexual arousal Orgasm De-arousal Method brief VSS (photo) Long VSS (film) Penis stimulation Poststimulation odours

Figure 4.6 Patterns of brain activation in response to sexual stimulation as a function of the EPOR stages of sexual response. From Georgiadis et al. [23]. (See plate section for color representation of the figure)

the ultimate arbiter and can never be sup- ­Excitation, Inhibition, planted by the processes that underlie it. For example, release of the neurotransmitter and Disinhibition of Sexual dopamine in mesolimbic terminals like the Responses nucleus accumbens may be involved in all forms of appetitive motivation toward As mentioned previously, the notion of rewarding incentives like sex partners, but ­separate, but interactive, neural systems for just observing dopamine released there does behavioral excitation and inhibition goes not allow the viewer to conclude that what- back to the work of early neurophysiologists ever the animal was doing is positively like Sechenov, Sherrington, and Pavlov, and hedonic. Understanding the neurobiology of more modern psychologists like Gray, who animal sexual behavior also allows the con- applied the idea to the study of fear and sideration of models of sexual function and ­anxiety [65]. It has important implications for dysfunction that are directly applicable in sexual behavior because it posits that behav- the preclinical testing of drugs or other ior can commence either due to direct excita- treatments. tion or through a process of ­disinhibition. 36 Textbook of Female Sexual Function and Dysfunction

This concept was advanced further by ­sexual system of the brain [6]. These systems Bancroft and Janssen [66] and Perelman [67], essentially tip the sexual tipping point toward who presented dual control models of human excitation (Figure 4.8, left). At the hypotha- sexual response in which the net expression lamic level, genitosensory and olfactory of sexual behavior is based on the influence of information is integrated in both the medial excitatory and inhibitory neurochemical preoptic area and ventromedial hypothala- mechanisms in the brain and periphery, set mus, which have outputs to the paraven- around a “sexual tipping point” (Figures 4.1 tricular nucleus, supraoptic nucleus, and and 4.7). As in Gray’s theory, these models arcuate nucleus of the hypothalamus. In stress the adaptive nature of both excitatory turn, those regions control the release of and inhibitory processes. For example, the ­oxytocin, vasopressin both in brain and from adaptive nature of sexual excitement would the posterior pituitary, and the release of drive individuals to seek out sex partners for melanocortins, opioids, and adrenocortico- reproductive or reward purposes. The adap- tropin hormone from the anterior pituitary. tive nature of sexual inhibition would guard The medial preoptic area also sends lateral against situations that threaten the individual, efferents to the ventral tegmental area, which including chronically stressful life events. It stimulate dopamine neurons and dopamine would also be important to keep the optimal release in mesolimbic and mesocortical expression of behavior constrained to the ­terminals, such as the nucleus accumbens, “right time,” as in the case of females that dis- anterior cingulate cortex, lateral septum, play sexual behavior only during a periovula- corticomedial amygdala, and medial prefron- tory period, when they are most likely to tal cortex. Thus, the medial preoptic area is become pregnant. Bancroft and Janssen well situated to “drive” the dopamine‐­ viewed the propensity for sexual excitement mediated incentive motivational system in or inhibition as an individual tendency based the presence of salient unconditional and on the genetic makeup and/or behavioral conditional external sexual cues, and also to expectations of the individual: those whose register and perhaps link those cues to geni- propensity for central inhibition of sexual tosensory and autonomic input. In addition, response is too high have increased vulnera- noradrenergic inputs to the hypothalamus bility to sexual dysfunction, whereas those coming from the locus coeruleus are them- whose inhibitory propensity is too low would selves stimulated by the reticular activating be more likely to engage in hypersexual or system, which is stimulated by general auto- high risk sexual behavior. Indeed, the study of nomic and somatic inputs from the spinal sexual inhibition is also critical if we are to cord. For females, sensitivity to sexual arousal understand how certain events or drugs like is enhanced during ovulation, and thus excit- alcohol, cocaine, or amphetamine, may atory systems in the central nervous system induce sexual disinhibition and the propen- appear to require steroid hormone priming. sity to engage in risky sexual behaviors [68]. Estradiol regulates a variety of neurotrans- mitter and second messenger systems in Excitation brain areas involved in sexual behavior [69, 70] (reviewed in Pfaus et al. [63]). Excitation can be viewed from autonomic Estradiol priming induces the synthesis of arousal and genitosensory/erogenous stimu- α1B‐adrenergic receptors in the ventromedial lation as a “bottom‐up” phenomenon, in hypothalamus and augments the release of which individual sensory modules come dopamine in the striatum, nucleus accum- together at higher levels of processing. This bens, and medial preoptic area during copu- occurs in the thalamus, and also in each lation. Extracellular DOPAC, a dopamine domain of the hypothalamus, limbic system, metabolite, increases in the medial preoptic and cortex, that make up the excitatory area in the afternoon to the early evening of Excitation Inhibition (arousal, desire, interest) (reward/satiety, stress, or aversion)

Hormones Hormones Experience/expectation Experience/expectation (circulating levels/ (circulating levels/ (previous sexual encounters) (previous sexual encounters) actions in brain) actions in brain)

Arousability Arousability

Attention Attention

Sensory input from genitals Sensory input from incentives Sensory input from genitals Sensory input from incentives (perception of arousal) (olfactory/visual/auditory) (perception of arousal) (olfactory/visual/auditory)

Net behavioral output Net behavioral output (interest/solicitation/pursuit/copulation) (interest/solicitation/pursuit/copulation)

Figure 4.7 Neurochemical mechanisms of sexual excitation and inhibition. From Pfaus and Scepkowski [120]. (See plate section for color representation of the figure)

Chapter No.: 1 Title Name: Goldstein c04.indd Comp. by: MuthuVel Date: 22 Mar 2018 Time: 11:29:18 AM Stage: Proof WorkFlow:CSW Page Number: 37 38 Textbook of Female Sexual Function and Dysfunction

Excitation Inhibition – Inhibitory Excitatory ++Inhibitory Excitatory – Drugs or states Drugs or states Drugs or states Drugs or states that inhibit that activate that activate that inhibit DA 5-HT NE opioids ECBs OT DA MCs NE 5-HT opioids OT ECBs MCs

Figure 4.8 Neurochemical mechanisms of sexual excitation within a tipping point model. Left: sexual excitation. Right: Sexual inhibition. From Pfaus [6]. (See plate section for color representation of the figure)

proestrus, around the time that sexual behav- hypothalamus; and Lordosis). Although tes- ior is activated. Dopamine is also released tosterone is important in the expression of within the medial preoptic area in ovariecto- sexually appetitive behaviors in EB‐treated mized female rats treated with estradiol ben- rats [71], and its facilitative effects have been zoate and progesterone; however, this release well‐documented in male rat sexual behavior is not detected in females treated with estra- [72], the neurobiological mechanisms in diol benzoate alone. Hormone dependent females have not been explored. differences also occur with the application of dopamine agonists to the medial preoptic Inhibition area, such that in females primed with estra- diol benzoate alone, D2 receptor subtype Inhibitory synapses make up a large part of agonists facilitate sexual behavior, whereas in the central nervous system and local inhibi- estradiol benzoate + progesterone‐primed tory networks can hone a response by elimi- females D1 receptor subtype activation facil- nating competing responses that would itates sexual behavior. Tonic dopamine interfere with it (e.g. as happens in the visual release activates D2 receptors, whereas pha- system with lateral inhibition by amacrine sic dopamine release stimulates D1 recep- cells). Such inhibition can be observed when tors. Thus, priming with estradiol benzoate behavior comes in bouts or phases, and in a alone may tonically activate D2 receptors, sexual response cycle would be consonant whereas subsequent P administration may with the “R” phase, a period of postorgasmic stimulate phasic dopamine release within the refractoriness in which further sexual inter- medial preoptic area, and activate D1 recep- est is diminished. Local inhibition can also tors, to facilitate sexual behaviors. Estradiol play a role in the timing of behavior to make also stimulates the synthesis of melanocortin it occur only during optimal periods. Female type 4 receptors in the hypothalamus and desire and lordosis behavior in animals are synthesis of proopiomelanocortin in arcuate obvious examples. nucleus neurons, and stimulates the synthe- General behavioral inhibition, however, is sis of cholinergic receptors and enkephalin typically viewed as a “top‐down” phenome- within the ventromedial hypothalamus. non involving the cognitive process of Gamma‐aminobutyric acid and glutamate “­executive function” [73]. Animals always activation are also stimulated by estradiol in have to choose among different drives and these regions (see sections Solicitations; motivations (e.g. between feeding and Role of melanocortins; Glutamate in the ­copulation), and, indeed, between several ­ventrolateral portion of the ventromedial possibilities per motivational system, to Central Nervous System Anatomy and Neurochemistry of Sexual Desire 39 achieve an optimal outcome. The medial serotonin that induces satiety [6] (Figure 4.7, ­prefrontal cortex organizes this by creating right). The reward states induced by clitoral behavioral hierarchies based on expectan- stimulation, vaginocervical stimulation, or cies, planned actions, and calculations. The paced mating in rats appear to be independ- medial prefrontal cortex (and likely other ent of steroid hormone priming, although cortical areas) therefore, must inhibit a com- the priming is necessary to activate the excit- plex and ongoing interplay of motor tenden- atory systems that bring about the behavior cies to arrive at planned and sustained in the first place [7, 74]. At present it is not actions. People or rats with disrupted pre- known where such inhibition actually takes frontal function, either due to lesions or neu- place. Indeed, the mPOA and VMH have rochemical imbalance, have great difficulty receptors for all three transmitter systems, focusing attention on tasks, are unable to indeed for all three opioid systems. Activation inhibit competing responses, and experience of delta opioid receptors in the mPOA inhibit retroactive and proactive interference [73]. lordosis [75], whereas activation of mu opi- With regard to sexual behavior, such top‐ oid receptors in the VMH inhibits lordosis down inhibition can be activated as “moral- [76]. Inhibition also comes in the form of ity” and would be based on a cultural value estrous termination [77]. system that imposes “right” and “wrong” on certain behaviors, such that some that feel Disinhibition good are “right” and can be experienced without guilt, whereas others are “wrong” As noted above, certain prosexual drugs can and carry the weight of guilt and/or rule of disinhibit sexual response, but only in indi- law against them. This type of inhibition viduals with sexual inhibition (reviewed in gives rise to the classic “approach–a­ voidance” Pfaus et al. [68]). Male rats trained not to conflict, where the expectation of reward copulate with sexually nonreceptive females drives the desire, but the inhibition imposed will attempt copulation with them under the by the real or perceived aversive conse- influence of alcohol, amphetamine, cocaine, quences of engaging in sexual activity blunts and methamphetamine. Alcohol and cocaine the initiation of behavior. Such inhibition stimulate appetitive behaviors in females may well lie at the root of the inhibited sexual primed with estradiol alone. Intermittent response experienced by women who are not amphetamine or methamphetamine admin- taught to express their sexual desires without istration sensitizes sexual approaches and some form of guilt. Such inhibition would solicitations in female rats and increases likely be reinforced if women experienced neuronal activation in the medial amygdala sexual nonreward during copulation, and and ventromedial hypothalamus following such reinforced inhibition would likely over- copulation. However, methamphetamine lay itself on desire components to suppress treatment also makes female rats less selec- them directly. Some women may be more tive in preference for particular males. susceptible to this type of inhibition than Disinhibition may also occur as a function others. Accordingly, the “prosexual” nature of hormone priming. Systems that normally of drugs such as alcohol, cocaine, and meth- maintain inhibition over female sexual amphetamine, may be a function of their behavior during nonovulatory periods likely ability to disinhibit such suppressed sexual must be inhibited to allow the behavior to response [68]. occur. This appears to be the case for some Refractory inhibition that comes after systems in the ventromedial hypothalamus orgasm involves the activation of at least that help to time the behavior and that help three neurochemical systems: opioids that to bring about estrous termination (see induce pleasure, euphoria, and ecstasy; Glutamate in the ventrolateral portion of endocannabinoids that induce sedation; and the ventromedial hypothalamus). Thus, the 40 Textbook of Female Sexual Function and Dysfunction

brain is set up with modules that gather and towards a sexually active male and make interpret sensory input and generate compe- approach responses in anticipation of sexual tent motor outputs at optimal times. This stimulation and reward. allows reward systems to be activated when females engage in the right behaviors at the right times, and allows such behavior to ­Solicitations ­optimize the reproductive outcomes. The fact that paced copulation is both rewarding The pioneering work of Wallen et al. [62], to females and results in stronger copulatory McClintock [29], and Erskine [28] refined stimulation from males, leading to a greater Beach’s [15] general category of “proceptive” chance of successful impregnation, is a good behaviors in female macaques and rats into example of the intricate timing systems that species‐specific descriptions of sexual blend the two. Far more is known about the approach, solicitation, and pacing. In rats, neural and neurochemical control of lordosis solicitations could be defined as full (head- than appetitive sexual approach, solicitation, wise orientation to the male followed by a or pacing behaviors. These are outlined in runaway) or partial (hops and darts, and the next sections. ­perhaps also ear‐wiggles) depending on how close in proximity the female was to the male and whether she had room to run away. ­Sexual Approach Behaviors Pacing could be operationalized as any behavior that imposed temporal control over Mesolimbic dopamine is involved in the sen- the rate of mounts, intromissions, and ejacu- sitization and crystallization of incentive lations. Female mounting of sexually sluggish response [14], especially within terminals in or naïve males was considered by Beach to be the nucleus accumbens. Microdialysis stud- a “super‐solicitation behavior” that would ies have shown that dopamine in the nucleus allow females to “show” the male what they accumbens increases during copulation in wanted (reviewed in Pfaus et al. [63]). ovariectomized female rats or hamsters Lesion studies show distinct effects on primed fully with estradiol benzoate and appetitive and consummatory behaviors. ­progesterone. In rats the increase is approxi- Excitotoxic lesions of the medial preoptic mately 150% of baseline when females are area abolished both full and partial solicita- presented with a gonadally intact, sexually tions, but enhanced lordosis in sexually‐ vigorous male rat behind a screen, and experienced ovariectomized rats primed increases to approximately 180% when the with estradiol benzoate and progesterone screen is removed and copulation ensues [80]. Lesions of the medial prefrontal cor- [78]. The temporal resolution of microdialy- tex also inhibited the temporal patterning sis (e.g. 10‐min samples), however, does not of full solicitations [81], In contrast, lesions permit specific behaviors to be correlated of the lateral septum or ventral tegmental with the rise in dopamine, especially during area did not alter the frequency of hops copulation. However, the degree of release is and darts. However, lesions of the medial positively correlated with the number of preoptic area, ventromedial hypothalamus, attempts made by the female to nose‐poke or medial amygdala, abolished the mount- through the wire‐mesh divider. dopamine ing of sexually sluggish males in ovariect- release increases more in the NAc and dorsal omized rats primed with estradiol striatum in hormonally‐primed females that ­benzoate + progesterone, whereas crystal- must make an operant response to gain line implants of estradiol to the ventrome- access to males compared to females that do dial hypothalamus, but not the medial not [79], suggesting that mesolimbic and stri- preoptic area or medial amygdala, induced atal dopamine release helps orient the female the behavior in ovariectomized rats. Central Nervous System Anatomy and Neurochemistry of Sexual Desire 41

Role of Incertohypothalamic ­neurons terminate in the medial preoptic Dopamine area and secrete α‐melanocyte stimulating hormone. Two melanocortin receptors exist As with lesions of the medial preoptic area, in the brain, MC3 and MC4, of which the systemic administration of dopamine antag- ­latter is found in the medial preoptic area. onists such as haloperidol abolish solicita- Bremelanotide is a synthetic analogue of tions but augment lordosis [82, 83]. This α‐MSH and is the active metabolite effect does not appear to be mediated by of ­melanotan‐II. Systemic administration ­mesolimbic dopamine, as 6‐hydroxydopa- of bremelanotide stimulates solicitations mine lesions of ventral tegmental area dopa- ­selectively in female rats primed with mine neurons projecting to the nucleus ­estradiol benzoate or estradiol benzo- accumbens did not alter solicitations in small ate + progesterone [94]. The precursor, chambers [84]. However, dopamine in the ­melanotan‐II, produces a weaker effect [95], medial preoptic area plays a key role in the although five consecutive days of melano- stimulation of solicitations, with D2 receptor tan‐II administration produces an effect activation facilitating solicitations in ovariec- ­similar to bremelanotide in magnitude. The tomized rats treated with estradiol benzoate enhancement of solicitations by bremelano- alone, and D1 receptor activation facilitating tide is duplicated by infusions to the lateral solicitations in ovariectomized rats treated ventricles or medial preoptic area, but with estradiol benzoate and progesterone not the ventromedial hypothalamus [9]. [85, 86]. Dopamine projections to the medial Systemic bremelanotide also stimulates preoptic area originate in the zona incerta dopamine release in the medial preoptic and dopamine turnover in the zona incerta area, but not nucleus accumbens or dorsal increases with estradiol administration [87]. striatum of ovariectomized rats treated with Extracellular DOPAC, a dopamine metabo- estradiol benzoate and progesterone. Finally, lite, increases in the medial preoptic area in the ­stimulation of solicitations by systemic the afternoon to the early evening of proes- bremelanotide can be reversed by a infu- trus, around the time that sexual behavior is sions of a selective MC4 antagonist (HS019) activated, and dopamine is also released to the medial preoptic area, but not ventro- within the medial preoptic area in ovariecto- medial hypothalamus [9]. It can also be mized rats treated with estradiol benzoate reversed by infusions of the D1 antagonist and progesterone, but not in rats treated with SCH‐23390 to the mPOA [9], suggesting estradiol benzoate alone [88–91]. Infusions that incertohypothalamic. Dopaminergic of SCH‐23390, a D1 antagonist, to the medial terminals in the medial preoptic area con- preoptic area of ovariectomized rats primed tain MC4 receptors that drive dopamine with estradiol benzoate + progesterone signifi- release, which, in turn, stimulates solicita- cantly reduced solicitations selectively [86]. tions by acting on D1 receptors in this brain region. Thus, the in­ tegration between mel- Role of Melanocortins anocortin and ­dopamine systems in the medial preoptic area is a critical component Melanocortins like α‐melanocyte stimulat- in the regulation of solicitations. ing hormone are derived from proopi- omelanocortin, a precursor peptide made Glutamate in the Ventrolateral largely in the arcuate nucleus, from which is Portion of the Ventromedial also derived the opioid β‐endorphin and Hypothalamus adrenocorticotropic hormone [92]. α‐ Melanocyte stimulating hormone synthesis Full and partial solicitations are also under the is stimulated by estradiol [93] within arcuate control of the ventromedial hypothalamus. nucleus ne­urons. Projections of those In a series of studies, Georgescu et al. [96, 97] 42 Textbook of Female Sexual Function and Dysfunction

investigated the inhibitory role of glutamate ­Pacing Behavior neurons in the ventrolateral VMH on the ­sexual behavior of female rats. Both full and The ability of female rats to pace the copula- partial solicitations were inhibited dramati- tory contact is critical for the timing of cally by infusions of glutamate, and also by ­intromissions. This timing leads to distrib- infusions of the selective ionotrophic recep- uted stimulation of the external glans clitoris, tor agonists AMPA and kainate to sexually internal clitoris/G‐spot, and cervix, stimula- experienced ovariectomized rats primed with tion that female rats find rewarding [88, estradiol benzoate and progesterone acutely, 90, 91], and that facilitates pregnancy or the or repeatedly primed with estradiol benzoate induction of pseudopregnancy and sets the alone and receiving AMPA infusions in place reward state necessary for the induction of of copulation [98]. Conversely, infusions of partner preference [101, 102]. Female rats the dual AMPA/kainate receptor antagonists pace at a faster rate early in the copulatory CNQX and DNQX to the ventrolateral interaction, but with successive ejaculations ­ventromedial hypothalamus of sexually the number of level changes per mount in ­experienced OVX rats primed with EB alone bilevel chambers increases dramatically, increased full and partial solicitations [97]. thereby increasing male interintromission intervals. In unilevel pacing chambers, the Differential Effect of Opioid latency to return to the male’s side after Receptors mounts, intromissions, and ejaculations shows a progressive increase in time, which Pfaus and Pfaff [99] reported that infusion of increases with successive ejaculatory series. the delta opioid agonist DPDPE, but not the Low, steady rates of pacing are induced in kappa opioid agonist U50‐488 h, or the mu ovariectomized rats by estradiol benzoate opioid agonist DAMGO, to the lateral ventri- and progesterone, whereas ovariectomized cles of sexually experienced ovariectomized rats administered estradiol benzoate alone rats primed with estradiol benzoate alone or show higher rates of pacing and rejection estradiol benzoate and a low dose of proges- responses. Fully primed female rats tested in terone (to induce moderate lordosis and low small chambers that offer no escape from the solicitations) increased solicitations in bilevel male also display rejection responses (e.g., chambers significantly over control infusions. rearing and boxing postures [103]) at a higher It is not known at present where in the brain rate than females tested in chambers where this facilitation of solicitations may occur. they can escape. It would appear that females Taken together, these data suggest that the use rejection responses to pace the copula- connections between the ventromedial tory contact if they cannot do so otherwise. hypothalamus and medial preoptic area are However, in those conditions, copulation critical in the regulation of solicitations rela- does not induce a reward state sufficient to tive to lordosis. This is evident from the fact induce conditioned place preference or con- that medial preoptic area lesions suppress ditioned partner preferences, and does not solicitations but augment lordosis, and is an facilitate pregnancy or pseudopregnancy. example of the kind of mutually‐exclusive Very little work has been done examining behavioral patterns discussed by Konorski the neural control of pacing. However, [100]. Females cannot hold a lordosis posture ­bilateral radiofrequency lesions of the lateral while making a forward‐directed solicitation septum, but not the medial preoptic area, and vice versa. Mutually interactive inhibi- disrupted the pattern of female exits from the tory subsystems in the two regions likely male side of a three‐hole unilevel pacing regulate the timing of solicitations and chamber [104]. In general, females with lat- lordosis. eral septal lesions did not leave the male side Central Nervous System Anatomy and Neurochemistry of Sexual Desire 43 after mounts and took significantly more the rump that, in turn, allows the male’s penis time than sham‐lesioned females to leave the to penetrate the vagina. It also exposes the male side after intromissions or ejaculations. external clitoral glans to stimulation from the This suggests that activation of the lateral male’s pelvis as he thrusts from behind. More septum by copulatory stimulation is an is known about lordosis than any other important component of the regulation of behaviorally relevant spinal reflex with pacing. It is not known whether such lesions supraspinal control, except perhaps the con- would facilitate or inhibit the development of trol of penile erection [108] and the condi- place or partner preferences. Guarraci et al. tioned eye‐blink response [109, 110]. We [105] found that cell body lesions of the may consider the propensity for female rats medial preoptic area, but not medial amyg- to show lordosis, in a context where they dala or bed nucleus of the stria terminalis, have the choice to approach and withdraw increased the intromission and ejaculation from the male, as an analogy to Basson’s contact‐return latencies of females in pacing ­concept of “sexual receptiveness,” a form of chambers, and increased the number of responsive desire that indicates a willingness withdrawals from the male’s side following to engage in sexual behavior with a partner. intromisisons, suggesting that medial preop- The seminal work of Pfaff [111, 112] tic area activation is critically involved in merged electrophysiology with anatomy and keeping females with males, consistent with pharmacology and behavioral neuroendocri- its role in solicitations. Interestingly, clitoral nology with molecular biology to determine anesthesia induced by lidocaine injections the modular supraspinal components of the also increased the number of exits and lordosis reflex and its control by ovarian returns displayed by ovariectomized, estra- ­hormones acting on specific receptors in the diol benzoate and progesterone‐primed rats brain (Figure 4.7). The action of steroids on in a four‐hole unilevel pacing chamber, those receptors alters the brain’s neurochem- decreased the amount of time spent with istry though both direct and indirect genomic males, and increased the ejaculation return actions, which, in turn, activate excitatory latency [106]. This indicates that clitoral sexual systems and inhibit inhibitory sexual stimulation maintains low rates of pacing, systems. This activation/disinhibition alters which increase if the stimulation is blunted. the reaction of the female to incentive sexual As noted above, polysynaptic clitoral affer- stimuli, which leads her to being attracted to ents project to the medial preoptic area and competent sexual cues. It engages approach clitoral stimulation activates Fos in medial behaviors and solicitation of sex from the regions of the medial preoptic area of female male and, upon simple palpation of the flanks rats. It is not yet known whether the reward and perineum, the female no longer reacts induced by clitoral stimulation is eliminated with violent intense rejection but rather with by medial preoptic area lesions, although ear wiggles and sexual receptivity. Thus, the such lesions clearly disrupt conditioned behavioral reflex is linked by the mechanics place preference induced by vaginocervical of gene transcription and translation in criti- stimulation [107]. cal hypothalamic circuits to the timing of ovulation so that the two can co‐occur. Coordinating physiological responses with ­Lordosis behavior requires timing. Hormone priming essentially sets up a timing system for lordo- Lordosis is a hormonally modulated spinal sis onset and offset. Although some of the reflex that characterizes sexual “receptivity” neurochemical systems involved in onset are in females of most mammalian species part of the excitatory system, others are (Figure 4.6). The arching of the back raises ­actually inhibitory and keep lordosis from 44 Textbook of Female Sexual Function and Dysfunction

occurring too soon. Likewise, activation of activate lordosis. This action then constrains the excitatory neurochemical systems keeps lordosis to the periovulatory period. the potential for lordosis on long after the Local actions of both mu and delta opioids, female has taken herself out of the mating and glutamate, appear to keep lordosis game. In general, the hypothalamic targets of ­constrained until such time as those systems estradiol include neurosecretory neurons, are either inhibited directly or the action of such as gonadotropin‐releasing hormone excitatory neurochemical systems over- and dopamine neurons, that affect both comes the inhibitory tone. Serotonin is the ­pituitary secretion and sexual behavior, and most intensely studied transmitter in this local circuitry neurons, such as proopi- category and, as might be expected, projec- omelanocortin, gamma‐aminobutyric acid, tions from the raphe to the ventromedial and glutamate. hypothalamus inhibit female sexual behavior, as do projections to the prefrontal cortex that Activation of Excitatory Systems induce top‐down inhibition. Treatment of ovariectomized rats with behaviorally Estradiol and progesterone activate gene ­effective doses of estradiol plus progesterone expression for a number of neurochemical significantly reduces the turnover of seroto- systems in the hypothalamus, most notably in nin in the ventromedial hypothalamus in a the medial preoptic area and ventromedial manner that correlates with changes in hypothalamus, which stimulate lordosis. ­lordosis behavior. Decreased serotonin This includes an upregulation of specific in parallel with increased sexual behavior is ­neurotransmitter receptors by estradiol also seen across the estrous cycle. This inhib- (e.g. progestin receptors, oxytocin receptors, itory effect of serotonin on female sexual adrenergic α1 receptors, muscarinic receptors, behavior is associated with an inhibitory melaocortin 3 and 4 receptors, and delta effect on ventromedial hypothalamus neu- ­opioid ­receptors, gonadotropin‐releasing hor- ronal activity, although the affected cell types mone receptors, GABA‐A receptors, and D1 have not been described. The serotonin dopamine receptors – reviewed in Pfaus et al. receptor subtype 2C has been localized to [63]). This changes how the circuit between the ventromedial hypothalamus. Acute sys- the two regions operates. Enzymes are also temic treatment with the selective serotonin upregulated in this system, including nitric reuptake inhibitor fluoxetine disrupts estrous oxide synthase, prostaglandin‐D synthase, cyclicity and reduces lordosis and the amount and dopamine β‐hydroxylase (that metabo- of time ovariectomized rats primed with lizes dopamine to noradrenaline), leading to estradiol benzoate and progesterone spend an upregulation of the end products. Nitric with males. oxide, in particular, is a critical and ubiquitous In summary, neurobiological studies in player in neurotransmitter release, so its rodent models show that lesions to specific upregulation is important in helping to set the regions can have distinct effects on compo- stage for the upregulated neurochemical sys- nents of sexual response. The connections tems to play a functional role in the generation between the ventromedial hypothalamus and of the behavior. Pharmacological studies help medial preoptic area appear to be critical to to confirm the role played by these neuro- this dissociation, and numerous neuropep- chemical substrates. tide and neurotransmitter systems can be acting to excite, inhibit, or disinhibit at any Inhibition of Inhibitory Systems one time. Just as the initiation of female sex- ual desire can be complex, disordered sexual Tonic inhibitory systems exist for lordosis in desire likely requires targeting of multiple the medial preoptic area and ventromedial neurobiological mechanisms in an individu- hypothalamus that must be overridden to alized approach. Central Nervous System Anatomy and Neurochemistry of Sexual Desire 45

­Relevance of Animals the nucleus accumbens. Acute flibanserin to Humans also decreased serotonin levels in all areas. However, chronic flibanserin increased An important example of how basic preclini- dopamine and norepinephrine significantly cal research in animals translates into clinical in the medial prefrontal cortex, but did treatments comes from the study of the neu- not alter serotonin, glutamate, or gamma‐­ rochemistry of sexual desire. At least three aminobutyric acid relative to chronically potential treatments for disorders of sexual injected controls. Likewise, acute bremelano- desire or interest in women have undergone tide increased solicitations selectively in clinical trials (Figure 4.9), including the ­preclinical models using ovariectomized rats primed with low doses of estradiol benzoate, ­serotonergic mixed 5‐HT1A agonist/5‐HT2A antagonist flibanserin (approved by the Food or low estradiol benzoate and progesterone, and Drug Administration in the United and increased dopamine release selectively States as Addyi®), the melanocortin agonist in the medial preoptic area. Finally, acute bremelanotide, and a combined pill contain- treatment of ovariectomized rats primed ing testosterone and a phosphodiesterase 5 with low estradiol benzoate with testoster- inhibitor called Lybrido®. Chronic flibanserin one and a phosphodiesterase 5 inhibitor increased solicitations and reduced rejection increased solicitations and hops and darts. responses in ovariectomized rats primed All three drugs have shown significant with estradiol benzoate or estradiol benzoate ­efficacy in increasing self‐reported sexual and progesterone [113]. Microdialysis sam- desire in pre‐ and postmenopausal women ples from the medial prefrontal cortex, diagnosed with hypoactive desire disorder nucleus accumbens, and medial preoptic [9, 114–118]. The ability of these three drugs area showed that acute flibanserin increased to stimulate ­solicitations in a rat model of basal levels of norepinephrine in all areas, hypoactive sexual desire predicts their func- along with dopamine in the medial prefron- tional application in women with hypoactive tal cortex and medial preoptic area, but not sexual desire and interest. This suggests

Treatments for HSDD

Figure 4.9 Treatments for sexual desire disorders and their potential mechanisms of action in the brain. From Pfaus [121]. (See plate section for color representation of the figure) 46 Textbook of Female Sexual Function and Dysfunction

strongly that the neurochemical systems tional work on the neural and hormonal sys- underlying appetitive sexual behaviors that tems that mediate sexual responses in women reflect sexual desire are conserved between can be derived from basic and preclinical at least rats and humans, and that transla- research in other species.

References

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5

Psychological Management of Hypoactive Sexual Desire Disorder Sheryl A. Kingsberg and Stanley E. Althof

Abstract

Hypoactive sexual desire disorder (HSDD) is best understood using a biopsychosocial model to capture the interaction of physiologic, psychologic and sociocultural influences. This model also enables a comprehensive approach to treatment that is rooted in the psychological, interpersonal, cultural and biological domains. The decision regarding which modality is appropriate is individu- alized and based upon the specifics of any patient’s presenting problem. Psychotherapy focuses primarily on the psychological and sociocultural factors contributing to distressing low desire and seeks to ameliorate some of the impact of HSDD on the woman and her relationship. Sex therapy generally consists of psychoeducation, couple exercises including sensate focus, and individual and group psychotherapeutic approaches including cognitive behavioral therapy and mindfulness cog- nitive behavioral therapy.

Keywords: hypoactive sexual desire disorder (HSDD); psychotherapy; sex therapy; biopsychosocial

Desire is best understood as being under the influence of biological, psychological and interpersonal factors. Regardless of the precipitating causes of hypoactive sexual desire disorder, biologic, psychologic, and interpersonal changes will occur over time, thus impacting the woman’s sexual desire and the couple’s sexual equilibrium. Combining medical and psychotherapeutic interventions is the natural extension of the biopsychosocial model.

­Introduction changes will occur over time, thus impacting the woman’s sexual desire and the couple’s The biopsychosocial model (Figure 5.1), sexual equilibrium. which has been used broadly in medicine and Some of the influences in the biological psychiatry for decades, captures the ever sphere may include: the woman taking an changing influences of biological, psycho- antidepressant that negatively affects her logical, and cultural societal concerns [1]. It libido and orgasmic ability, neurotransmitter is a dynamic rather than static model that imbalance such as that experienced with captures a snapshot of the woman at only one major depression, or the hormonal changes point in time. Regardless of the precipitating associated with menopause. Undesirable causes of hypoactive sexual desire disorder, impacts from the psychological and interper- biological, psychological, and interpersonal sonal sphere may include a history of sexual

Textbook of Female Sexual Function and Dysfunction: Diagnosis and Treatment, First Edition. Edited by Irwin Goldstein, Anita H. Clayton, Andrew T. Goldstein, Noel N. Kim, and Sheryl A. Kingsberg. © 2018 John Wiley & Sons Ltd. Published 2018 by John Wiley & Sons Ltd. 54 Textbook of Female Sexual Function and Dysfunction

Depression, anxiety, gender Illness, medication, surgery, Biology Psychology conflict, sexual or physical neurobiology, vascular and abuse, alcohol or drug hormonal conditions abuse

Upbringing, cultural Quality of current and past and religious concerns, Sociocultural Interpersonal relationships, partner contextual issues such as performance and technique, privacy, different shifts STDs

Figure 5.1 Biopsychosocial model of sexual response. (See plate section for color representation of the figure)

or physical abuse that makes feeling sexual ­hypoactive sexual desire disorder. These may desire unsafe, symptoms of depression, the include body image issues, childhood genital partner’s infidelity, ghosts of previously dis- surgeries, attachment concerns, restrictive tressing relationships, the partner’s sexual upbringing, troubled family relationships, dysfunction, psychiatric or substance abuse inadequate sexual information, and trau- problems, or the threat of abandonment. matic early s­exual experiences. Precipitating Cultural concerns may include religious factors are ones that trigger the onset of ­prohibitions or teachings that sex is dirty hypoactive sexual desire disorder and may and should not be enjoyable. Given the mul- include a new medication, surgery, discovery titude of potential etiologic factors impact- of infidelity, struggles with infertility, trauma, ing desire, the use of a more comprehensive psychological impact of an illness or its treat- global assessment of sexual issues may pro- ment (e.g. mastectomy) and/or relationship vide a more accurate understanding of what distress. Maintaining factors, which rein- initiates and maintains hypoactive sexual force the persistence of the symptom, include desire disorder. ­performance anxiety, guilt, psychiatric disor- Additionally, the biopsychosocial model der, relationship discord, loss of attraction enables a comprehensive approach to between partners, fear of intimacy, impaired ­treatment rooted in the psychological, inter- self‐image, restricted foreplay, sexual myths, personal, cultural and biological domains and poor communication. Finally, contextual [2, 3]. The model also explains the failure of factors may include the current stresses treatments for biological problems that from attempting to conceive, fatigue from ignore relevant psychological contributions full time employment, child rearing, and and psychological treatments that disregard ­caring for the home. the biomedical factors. The biopsychosocial model follows a In addition to the biopsychosocial model, ­logical progression examining all relevant another organizing principle of evaluation is biomedical and psychological aspects that the division of etiological variables into may account for the condition of hypoactive ­predisposing, precipitating, maintaining, sexual desire disorder and other related and contextual factors [2, 3]. Predisposing ­sexual problems, such as arousal disorder, factors may make the woman susceptible to anorgasmia, and pain. Such an evaluation is a Psychological Management of Hypoactive Sexual Desire Disorder 55 collaborative endeavor between the clinician nondemand sensual touching exercises [5, 6]. and patient that offers the patient the In a couple‐based approach, the objectives ­advantage of shared decision making. The of sensate focus therapy are to reduce clinical synthesis derived from this process ­avoidance of sensual touching or sexual activ- serves as a pragmatic road map for treating ity and related anxiety, improve sexual com- all of the biopsychosocial variables identified munication between partners, and improve that precipitate or maintain the symptom of intimacy by re‐introducing sexual activity in a hypoactive sexual desire disorder. gradual way. Exercises might begin with non- The focus here is on the psychological, genital touching, and assuming successful interpersonal and cultural/contextual contri- achievement of each successive series of butions to hypoactive sexual desire disorder, ­exercises, move to genital touching, and as other chapters will present the biological ­ultimately intercourse [7]. in greater detail. Modern sex therapy is an extension of Masters and Johnson’s work that uses ­specific techniques to address problems of sexual ­Psychotherapy/Sex Therapy desire, arousal, orgasm, and pain. Generally, sex therapy is a short‐term (approximately for Hypoactive Sexual three months) treatment conducted in an Desire Disorder individual, couples, or group setting [8]. The decision regarding which modality is appro- Historically, women with sexual dysfunc- priate is based upon the specifics of any tions were treated using psychoanalytic patient’s presenting problem. Sex therapy methods. Other than anecdotal case reports, generally consists of psychoeducation, cou- no large scale, systematic trials or data were ple exercises including sensate focus, and available. Psychoanalysts initially viewed counseling. women’s sexual desire as “pale imitations of Cognitive behavioral therapy approaches the more robust sexual drive in men.” [4]. gained prominence in the early 1980s. In the 1960s and 1970s, Masters and Cognitive behavioral therapy focuses on Johnson revolutionized the treatment of sex- identifying and altering behaviors (e.g. avoid- ual problems by working with couples to ance of sexual activity) and cognitions overcome the psychological and behavioral (e.g. unrealistic expectations) that contribute obstacles that may impede natural function to low sexual desire in women [9, 10]. Because [5, 6]. They developed a highly structured cognitive distraction during sexual activity is two‐week treatment model employing male prevalent among women with hypoactive and female cotherapy teams. The multiple sexual desire disorder, the application of cog- facets of their treatment included physical nitive challenging strategies (i.e. identifying, examination, history taking, individual and challenging, and replacing irrational thoughts) couples’ psychotherapy, and prescription of is a mainstay of cognitive behavioral sex ther- behavioral tasks, such as sensate focus. Based apy. Education is also an important compo- on their clinical judgment, Masters and nent of cognitive behavioral therapy and can Johnson reported both an end of treatment help the woman/couple understand how outcome and a five‐year follow‐up outcome. adequate erotic stimulation and physical They reported astounding success rates of stimulation contribute to their sexual desire 72–98% for female sexual dysfunctions and and arousal. only a 5% relapse rate after five years. Mindfulness techniques were incorpo- A core component of Masters and Johnson’s rated into a cognitive behavioral framework work and sex therapy in general is the pre- by Brotto et al. [11, 12]. Mindfulness is scription of sensate focus, a graded series of derived from Buddhist meditation practices 56 Textbook of Female Sexual Function and Dysfunction

and focuses on being present and nonjudg- ­Integrating Psychotherapy mental awareness of bodily sensations or in Multimodal Treatments perceptions. Mindfulness cognitive behavio- for Hypoactive Sexual ral therapy can be especially helpful for Desire Disorder women who have a disconnect between gen- ital and subj­ ective arousal (a positive mental ­engagement/focus in response to a sexual Combining medical and psychotherapeutic stimulus) [13]. interventions is the natural extension of the biopsychosocial model. In men with erectile dysfunction and premature ejaculation, com- bination therapy harnesses the power of both ­Psychotherapy/Sex Therapy treatments to quickly reverse symptoms, Outcomes enhance efficacy, increase treatment and relational satisfaction, and decrease patient The majority of the psychotherapy outcome discontinuation [8, 17–21]. studies are notoriously flawed, with few using To date, there are no studies on combina- control groups or validated outcome meas- tion therapy for female sexual dysfunction. ures. Outcome studies demonstrate sex ther- However, combining current pharmacologic apy to be moderately effective at improving treatments with psychosocial interventions is sexual desire, especially when compliance likely to enhance the positive effects of phar- with the recommended exercises is high. macotherapy. It also offers support to women Overall the noncontrolled efficacy rates for with the distressing problem of hypoactive the treatments in these studies range between sexual desire disorder and may confer posi- 52 and 74% [14]. A 2013 systematic analysis tive benefit to their relationship as well. found an effect size of 1.03 on the outcome of symptom severity and of 0.86 for sexual satis- faction, suggesting a high level of efficacy [15]. ­Conclusion For women with low relationship satisfac- tion, improving sexual function alone may A biopsychosocial model informs both etiol- not be sufficient to alleviate their sexual dis- ogy and treatment. However, it should also tress. Therefore, focusing on improving the be noted that one size does not fit all. Some intimate relationship would be an impor- women will benefit more from psychothera- tant first step for a woman with low sexual peutic options, some from pharmacologic desire and concomitant low relationship options, and some from an integrated multi- quality. However, couple/marital therapy modal approach. A thorough evaluation of alone, without adjunct sex therapy, may not underlying psychological, interpersonal, and be sufficient to improve women’s sexual cultural causes may lead to the most optimal desire [16]. approach.

­References

1 Althof S, Leiblum S, Chevret‐Meason, et al. operating procedure (SOP Part 1). J Sex Psychological and interpersonal dimensions Med. 2013;10:36–49. of sexual function or dysfunction. J Sex Med. 3 Bitzer J, Giraldi A, Pfaus J. A standardized 2005;26:793–800. diagnostic interview for hypoactive sexual 2 Bitzer J, Giraldi A, Pfaus J. Sexual desire and desire disorder in women: standard hypoactive sexual desire disorder in women. operating procedure (SOP Part 2). J Sex Introduction and overview. Standard Med. 2013;10:50–57. Psychological Management of Hypoactive Sexual Desire Disorder 57

4 Lief H, Friedman R. History of psychologic 14 Kingsberg S, Althof S, Simon J, et al. treatments. In: Goldstein I, Meston C, Female sexual dysfunction‐medical and Davis S, and Traish A (eds) Women’s Sexual psychological treatments. J Sex Med. Function and Dysfunction. London: Taylor 2017;14(12):1463–1491. and Francis; 2006, pp. 427–433. 15 Günzler C, Berner MM. Efficacy of 5 Masters WH, Johnson VE. Human Sexual psychosocial interventions in men and Response. Boston, MA: Little, Brown & women withsexual dysfunctions – a Company; 1966. systematic review of controlled clinical 6 Masters WH, Johnson VE. Human Sexual trials. J Sex Med. 2012;9:3108–3125. Inadequacy. Boston, MA: Little, Brown & 16 McCabe M. Editorial comment on Company; 1970. “Psychological treatment trials for 7 Kaplan H. The New Sex Therapy. New hypoactive sexual desire disorder: A sexual York: Bruner Mazel; 1974. medicine critique and perspective.” J Sex 8 Althof S. Sex therapy and combined Med. 2015;12:2459–2460. (sex and medical) therapy. J Sex Med. 17 Althof S. New roles for mental health 2011;8:1827–1828. clinicians in the treatment of erectile 9 Carvalho J, Nobre P. Sexual desire in dysfunction. J Sex Educ Ther. women: an integrative approach regarding 1998;23:229–231. psychological, medical, and relationship 18 Althof S. Sex therapy in the age of dimensions. J Sex Med. 2010;7:1807–1815. pharmacotherapy. Annu Rev Sex Res. 10 Nobre P. Determinants of sexual desire 2006:116–132. problems in women: Testing a cognitive‐ 19 Comio L, Massenio P, La Rocca R, et al. emotional model. J Sex Marital Ther. The combination of dapoxetine and 2009;35:360–77. behavioral treatment provides better 11 Brotto LA. Evidence‐based treatments for results than dapoxetine alone in the low sexual desire in women. Front management of patients with lifelong Neuroendocrinol. 2017;45:11–17. premature ejaculation. J Sex Med. 12 Brotto LA, Basson R. Group mindfulness‐ 2015;12:1609–1615. based therapy significantly improves sexual 20 Perelman M. Combination therapy: desire in women. Behav Res Ther. Integration of sex therapy and 2014;57:43–54. pharmacotherapy. In: Balon R and Taylor 13 Brotto LA, Chivers ML, Millman RD, Segraves R (eds) Handbook of Sexual Albert A. Mindfulness‐based sex therapy Dysfunction. New York: Marcel Dekker; improves genital‐subjective arousal 2005, pp. 13–41. concordance in women with sexual desire/ 21 Perelman M. A new combination treatment arousal difficulties. Arch Sex Behav. for premature ejaculation: A sex therapist’s 2016;45:907–921. perspective. J Sex Med. 2011;3:1004–1012. 59

6

Pathophysiology and Medical Management of Hypoactive Sexual Desire Disorder Anita H. Clayton and Linda Vignozzi

Abstract

Human sexual behavior is stimulated by numerous hormonal, cerebral (neurotransmitter) and social factors. Therefore, several physical and medical factors as well as some medications have been associated with low sexual desire. Validated questionnaires such as the Decreased Sexual Desire Screener (DSDS) are extremely useful tools to establish the diagnosis of hypoactive sexual desire disorder and to identify potential causes or exacerbating factors for reduced desire. Therefore, the first line intervention for women with reduced sexual desire is to address any modi­ fiable risk factor, following the process of care. Other important medical treatment options consist of either the use of central nervous system (CNS) agents or hormonal therapy. Indeed, sex hor­ mones such as androgens have been recognized as important determinants of female sexual func­ tion, therefore representing an important therapeutic strategy to positively modulate sexual desire.

Keywords: female sexual desire; hormones; neurotransmitters; hypoactive sexual desire disorder; HSDD; hypoandrogenism; depression; SSRI; antidepressants; testosterone; flibanserin

Sex hormones, in particular testosterone, are important determinants of female sexual desire. Other hormones (i.e. thyroid hormones, prolactin) have been reported to modulate sexual desire. Psychiatric conditions (depression) are frequently comorbid with hypoactive sexual desire disorder with a bidirectional risk relationship; some medical conditions, such as metabolic/endocrine and neurological disorders have been reported to modulate sexual desire An evidence‐based flowchart for management of hypoactive sexual desire disorder includes:

●● diagnosis (using validated questionnaire or interview); ●● evaluation for the presence of organic diseases that may be contributing to acquired, generalized hypoactive sexual desire disorder; ●● modification of any medical, sexual, psychological, and social factors that may potentially cause or worsen hypoactive sexual desire disorder (intervention includes psychotherapy); ●● treatment (use of central nervous system agents or hormonal therapy).

­Neurobiological Endocrinology mitter), and social factors. In particular, in females relevant changes in behavior occur Sex Steroid Hormones not only across the reproductive life but have also been hypothesized to occur across In the human species, instinctive behaviors, the menstrual cycle; the famous Duke of such as sexual behavior, are stimulated by Mantua’s aria from Giuseppe Verdi’s opera numerous hormonal, cerebral (neurotrans­ Rigoletto (“La donna è mobile, qual piuma al

Textbook of Female Sexual Function and Dysfunction: Diagnosis and Treatment, First Edition. Edited by Irwin Goldstein, Anita H. Clayton, Andrew T. Goldstein, Noel N. Kim, and Sheryl A. Kingsberg. © 2018 John Wiley & Sons Ltd. Published 2018 by John Wiley & Sons Ltd. 60 Textbook of Female Sexual Function and Dysfunction

vento, muta d’accento, e di pensiero”, “Woman strual cycle; (ii) their variations in response is flighty like a feather in the wind, she changes to other hormones or neurotransmitters; (iii) in voice and in thought”; 1851), depicts as one their secondary variations in response to illustration the provocative concept that psychological modifications, which may be women’s behavior may be c­ onsidered mobile individual, interindividual within the couple, (“inconstant”) and rapidly changing over and psychosocial. time. From a more scientific perspective, a wide amount of research has recently Steroid Biosynthesis addressed the potentially adaptive changes and Metabolism in human female mating (including sexual behaviors) across the menstrual cycle [1–7]. A simplified scheme of steroid biosynthesis Fluctuations in female sex steroids across is shown in Figure 6.1. The three main classes the reproductive cycle seem to orchestrate of steroid hormones are glucocorticoids, these shifts in sexual behavior. However, add­ mineralocorticoids, both synthesized by the ing layers to this complexity, three kinds of adrenal cortex, and sex steroids (progesto­ difficulty accompany any attempt to ascer­ gens, androgens, and estrogens), synthesized tain the precise function of hormones in the by the adrenal cortex and the gonads. sexual behavior of women: (i) their changes Cholesterol is the major substrate of the at the individual level according to develop­ biosynthesis of steroids, representing the ment (puberty, menopause) and the men­ basic molecular structure of all steroid

Cholesterol

ACTH 1 MINERALOCORTICOIDS hCG - LH PROGESTAGENS

2 11-deoxy- Corticosterone Aldosterone Pregnenolone Progesterone corticosterone

3 3 GLUCOCORTICOIDS

17 hydroxy- 17 hydroxy- α 2 α 11-deoxy- Cortisone pregnenolone progesterone cortisol Cortisol

44 ANDROGENS ESTROGENS

Dehydro- 2 8 9 epiandrosterone Androstenedione Estrone 16-Hydroxyestone Estriol

5 5 5

2 8 Androstenediol Testosterone 17β-estradiol

6 Dihydrotestosterone

7

5αandrostanediol

Figure 6.1 Biosynthesis of steroid hormones. The enzymes involved in androgen and estrogen biosynthesis or metabolism are indicated by numbers. 1 = 20,22‐desmolase; 2 = 3β‐hydroxysteroid dehydrogenase‐isomerase; 3 = 17α‐hydroxylase; 4 = 17,20‐desmolase; 5 = 17β‐hydroxysteroid dehydrogenase; 6 = 5α‐reductase; 7 = 3β‐ ketoreductase; 8 = aromatase; 9 = 16α‐hydroxylase. Pathophysiology and Medical Management of Hypoactive Sexual Desire Disorder 61

­hormones. Cholesterol can be synthesized precursors of estrogens. Estrone and 17β‐ by steroidogenic cells but is mainly up taken estradiol are derived from ∆4‐androstenedi­ from circulating lipoproteins. Micellar one and testosterone, respectively, through lipoproteins are complex macromolecules the loss of the C19‐carbon residue and constituted by a central fraction, made by desaturation or aromatization of the ­A‐ring. ­triglycerides and cholesterol esters, sur­ These steps involve aromatase, a complex rounded by a hydrophilic layer of phos­ microsomal enzyme. Estriol, the weakest pholipids, free cholesterol, and multiple natural estrogen, is mainly a metabolic proteins (apolipoproteins). The lipoproteins product of estrone and estradiol. are c­lassified according to their hydrated density into five major classes: chylomi­ Plasma Transport of Sex Steroids crons, very low density, intermediate ­density, low density­ , and high density Unconjugated steroid hormones are rela­ ­lipoproteins. Low density lipoprotein‐­ tively insoluble in aqueous solutions and, cholesterol is currently thought to bind to thus, circulate in blood bound to plasma pro­ the membrane receptors on the steroido­ teins, mainly to albumin and to specific bind­ genic cells and to be internalized. Its protein ing proteins. Albumin binds all unconjugated content is degraded and cholesterol content steroids with very high capacity but low transferred to intracellular compartments, affinity. Specific binding proteins that bind from where it is transported back to the steroids with high affinity but lower capacity liver as high density lipoprotein. Cholesterol are also involved: androgens and, to a lesser is cleaved to form pregnenolone, which is extent, estrogens are specifically bound by converted to the biologically active proges­ sex hormone binding globulin. The plasma terone. Subsequent hydroxylation of pro­ concentrations of sex hormone binding glob­ gesterone at three different positions (C21, ulin are increased by estrogens and an excess C11, C18) leads to the formation of aldos­ of thyroid hormones, and decreased by terone, the most potent mineralocorticoid. androgens, synthetic progestins (derivatives Pregnenolone and progesterone are both of the 19‐nor‐testosterone precursor), and hydroxylated at the C17 position to form insulin. Sex hormone binding globulin the relative 17α‐hydroxyl‐derivatives, which decreases throughout puberty, more in males are the key precursors for the biosynthesis than in females. As a result, a sex difference is of either cortisol or androgens. Androgens, observed in adulthood, mean sex hormone dehydroepiandrosterone and ∆4‐andros­ binding globulin levels being about three tenedione, a moderately active androgen, times higher in men (14.7 ± 4.4 µg/l) than in are reduced to testosterone, the most potent women (5.3 ± 1.5 µg/l). In contrast, sex hor­ secreted androgen. Hence dehydroepian­ mone binding globulin markedly increases drosterone, a steroid with weak androgenic during pregnancy (about 10‐fold). Only a activity, is actually the precursor for the small percentage of the circulating sex ster­ most potent androgens. Androgens are oids is present in the “free” (unbound) form. metabolized at several sites. When testos­ In the blood of adult women (follicular terone enters a cell, it is converted to a more phase), only 1% of testosterone is free, 66% is potent steroid, which exerts its action in bound to sex hormone binding globulin, 30% autocrine/paracrine manner or on cells of bound to albumin, and the rest to other other tissues. Testosterone is metabolized plasma proteins. These proportions are to dihydrotestosterone, and then to 5α‐ respectively, 0.5%, 78%, 20%, and 1.5% for androstane‐3α, 17β‐diol (5α‐androstane­ dihydrotestosterone, and 2%, 37%, 60% and diol), with androgenic activity 2.5 and 1.5 1% for estradiol. Vermeulen has shown that times greater than testosterone, respectively. the rate of testosterone metabolism corre­ The ∆4‐androgens are also the essential lates with its free plus albumin‐bound fraction. 62 Textbook of Female Sexual Function and Dysfunction

An automatic calculator to evaluate free All cellular structures of the ovary produce ­testosterone level is available at http://www. steroids but in different amounts according to issam.ch/freetesto.htm [8]. the secreting cells and/or the menstrual cycle phases. The interstitial cells have the principal Secretion and Production of Sex function to synthesize and secrete androgens, Steroids such as ∆4‐androstenedione and testosterone. In contrast, progesterone is mainly produced Steroids are not stored in the synthesizing by luteinized granulosa cells. Aromatization cell, therefore if not used as substrate for a of ∆4‐androstenedione to estrone and of tes­ specific step in steroidogenesis, steroids are tosterone to estradiol takes place in the follicle secreted and released in the blood stream. and corpus luteum but is mainly the task of Steroid secreting glands are the main source granulosa cells. During the menstrual cycle, of steroids. However, peripheral conversions developing follicles produce estrogens that between androgens and from androgens to dominate the ­follicular phase, the corpus estrogens do occur in several tissues (liver, luteum produces progesterone and estrogens brain, skin, fat, and target cells). The blood in the luteal phase, and interstitial stroma cells production rate of a hormone is the sum of produce androgens. the quantity secreted and the amount formed The adrenal glands produce a significant by peripheral conversion. Table 6.1 lists the amount of progestogens and androgens. production rate of sex steroids. Adrenal androgens are mainly synthesized in the zona reticularis of the adrenal cortex. Origin of Sex Steroids The relative contribution of the adrenal to the plasma pool of ∆4‐androstenedione The ovary and the adrenal glands are the two varies between 30 and 45% according to the main organs producing sex steroids. Their phase of the menstrual cycle. In contrast, relative contribution varies for each hor­ dehydroepiandrosterone, the most abun­ mone, according to the phase of the menstrual dant androgen secreted, is mainly of adre­ cycle (Table 6.1). The menstrual cycle is nal origin (Table 6.1). Secretion of ­usually divided into three periods: follicular, estrogens, mainly estrone, normally occurs ovulatory, and luteal phases. in small amounts in the zona reticularis; in

Table 6.1 Blood production rate and relative contribution (%) of glandular secretions and peripheral conversion to blood production of sex steroids in young adult women.

Production Hormone rate (mg/24 h) % from adrenals % from ovary % from conversion

Progesterone (follicular) 0.8–2.5 50–70 10–25 20–55 (luteal) 15–50 5 90 1 (pregnant) 230–310 (mostly from (mostly from (mostly from placental origin) placental origin) placental origin) Testosterone 0.25–0.3 15–20 25–30 50–60 ∆4‐androstenedione 2–5 30–45 45–60 10 DHEA 7–15 60–70 10–25 15 Estrone 0.6–0.8 1–2 60–70 30–40 17β‐estradiol 0.01–0.1 0 85–90 10–15

DHEA = dehydroepiandrosterone Pathophysiology and Medical Management of Hypoactive Sexual Desire Disorder 63 contrast, adrenal glands do not secrete prior to ovulation, estradiol levels drop and estradiol at any stage of life. plasma progesterone begins to rise. Follicular In children, ovarian secretions are insig­ rupture occurs 16–24 hours after the lutein­ nificant or nonexistent. In contrast, the adre­ izing hormone peak. The most important nal contribution to all sex hormones is feature of the luteal phase is the marked prominent. From about seven years of age, increase in progesterone levels, which reach adrenal production of dehydroepiandroster­ their maximum about eight days after the one rises abruptly and progressively, in paral­ luteinizing hormone peak. In the absence of lel to the relative development and ovulation, sex hormone levels resemble those enlargement of the zona reticularis within observed in the early follicular phase. In the adrenal cortex. This process continues postmenopausal women, sex steroids are at throughout puberty. This change in the pat­ significantly lower levels. Mean (±SD) values tern of adrenal secretion (referred to as observed at different periods of reproductive “adrenarche”) precedes by 2–3 years the life are listed in Table 6.2. onset of puberty. In postmenopausal women, the main source of estrogens is extra‐gonadal, Regulation of the Hypothalamus– such as fat, liver and specific nuclei in the Pituitary–Ovary Axis hypothalamus. In this period of life, the adrenals are the major source of ∆4‐andros­ Schematically, steroid secretion by the tenedione; its conversion into estrone ovary is regulated by two polypeptides hor­ accounts for virtually all the estrone pro­ mones, luteinizing hormone and follicle‐ duced. The postmenopausal ovary continues stimulating hormone, which are produced to produce androgens (testosterone and by the gonadotropic cells of the anterior ∆4‐androstenedione). pituitary gland. From a neurobiological perspective, the gonadotropin releasing Sex Hormone Levels hormone secretory system anatomically develops relatively early in life, when activa­ In normally menstruating women, the grad­ tion of the gonadotropin releasing hormone ual or day‐to‐day changes in the plasma levels secretory system may be important for mas­ of sex steroids reflect the changing secretory culinization of the brain and attainment of activities of the various ovarian cells. A typi­ subsequent sexual behavior. In female pri­ cal profile is illustrated in Figure 6.2. mates, these early periods of gonadotropin During the first half of the follicular phase releasing hormone secretion seem to occur (early follicular phase), the ovarian secretion at low levels throughout the juvenile period of estrogens, androgens, and progestins is [9]. Therefore, the synthetic capacity of relatively stable. The second half of the folli­ gonadotropin releasing hormone is present cular phase (late follicular phase), beginning even before puberty in that gonadotropin about 7–8 days before the preovulatory lute­ releasing hormone expression reaches adult inizing hormone surge, is characterized by a levels. After the first year of postnatal life, rise in estrogen levels. Estradiol rises slowly the hypothalamic–pituitary–gonadal axis is at first and then reaches a maximum several quiescent until reactivation occurs to hours before the luteinizing hormone mid‐ prompt pubertal onset. Puberty onset is a cycle peak. The estrone level rises in parallel, function of the central control of gonado­ but less. Increases in plasma levels of ∆4‐ tropin releasing hormone secretion, reflect­ androstenedione and testosterone precede ing the integration of multiple internal and the mid‐cycle luteinizing hormone surge by external cues acting upon a genetically several days, reaching their maximum on the determined process. A plethora of different day of the luteinizing hormone peak. Shortly pathways involving neuropeptides and sys­ before the luteinizing hormone peak and temically produced steroids can directly 64 Textbook of Female Sexual Function and Dysfunction

60

40

LH LH (mU/mL) FSH (mU/mL) 20 20 FSH 15

400

200 Estradiol Estradiol (pg/mL) Estradiol Estrone

150

gesterone 10 gesterone (ng/dL) 17-OH P 5 (ng/mL) Pro

-OH Pro 50 P 17

200 30 T

150 (ng/dL) (ng/dL) Testosterone 10 A

100 ∆4-androstenedione

36.8

36.5

Basal body 36.2 MM temperature (°C) temperature –180–4–8–12 +12+8+4 days

Early Late

Follicular phase Luteal phase

Figure 6.2 Hormonal fluctuations during menstrual cycle. Body temperature change is also shown. Pathophysiology and Medical Management of Hypoactive Sexual Desire Disorder 65

Table 6.2 Blood levels of the main sex steroids at different periods of reproductive life.

Follicular phase Mid‐luteal Pregnancy Hormone Early Late phase Postmenopausal 3rd trimester

Progesterone (ng/dl) 56 ± 10 56 ± 10 1350 ± 490 25 ± 8 12 361 ± 3394 Testosterone (ng/dl) 22 ± 5 37 ± 9 35 ± 6 25 ± 12 67 ± 46 ∆4‐androstenedione (ng/dl) 77 ± 28 220 ± 45 149 ± 43 75 ± 20 166 ± 111 DHEA (ng/dl) 515 ± 107 515 ± 107 515 ± 107 220 ± 80 363 ± 233 Estrone (pg/ml) 49 ± 8 75 ± 220 84 ± 8 29 ± 15 541 ± 278 17β‐estradiol (pg/ml) 68 ± 14 180 ± 500 123 ± 11 12 ± 4 16 640 ± 2375

DHEA = dehydroepiandrosterone modulate gonadotropin releasing hormone medial basal area, where gonadotropin release. Kisspeptin‐1 and its receptor is one releasing hormone is secreted into the hypo­ of the major regulatory system of gonado­ thalamic–hypophyseal portal system. The tropin releasing hormone neurons [10, 11]. pulsatile gonadotropin releasing hormone Genetic studies demonstrated that disabling release is an inherent function of gonadotro­ mutations and targeted deletions of the G‐ pin releasing hormone neurons, acting protein‐coupled receptor of kisspeptin‐1 directly on the pituitary gonadotrope cells to (previously called GPR54) in humans and maintain gonadotropins (luteinizing hor­ mice resulted in sexual infantilism and mone and follicle‐stimulating hormone) hypogonadotropic hypogonadism [12, 13]. secretion. During puberty, the amplitude of Kisspeptin neurons in the hypothalamic luteinizing hormone and follicle‐stimulating arcuate nucleus act on gonadotropin releas­ hormone release increases progressively and ing hormone nerve terminals in the median stimulates the ovaries to produce the gonadal eminence and regulate basal pulsatile gon­ sex steroids (testosterone and estradiol). The adotropin releasing hormone/luteinizing reactivation of gonadotropin releasing hor­ hormone release [14, 15]. Kisspeptin‐1 is mone release up to the first signs of physical highly expressed in cells residing in the maturation is referred to as “gonadarche”. As anteroventral periventricular nucleus, the stated above, an independent endocrine medial amygdala, and the arcuate nucleus. ­process of maturation of the adrenal glands, Interestingly, similar to other neurons pre­ known as “adrenarche”, contributes to sex sent in the arcuate nucleus, kisspeptin‐1 steroid secretion that occurs during puberty. neurons are dependent on energy status Adrenal androgens, including dehydroepi­ and are able to respond to metabolic cues androsterone, dehydroepiandrosterone sul­ [16–18]. fate, and androstenedione progressively Interindividual variability in the timing of increase after birth and continue during puberty indicates that the onset of puberty is adolescence and into young adulthood [19]. not only a function of chronological age. A multitude of information about metabolic Factors Modulating Secretion fuels, energy stores and somatic develop­ of Gonadotropin Releasing ment and social environment impact upon Hormone and Gonadotropins the gonadotropin releasing hormone secre­ tory network. Gonadotropin releasing hor­ Gonadotropin releasing hormone release mone is synthesized by a limited group of into the portal blood is characterized by 2000 neurons of the anterior hypothalamus intermittent pulses superimposed on a lower projecting dorsally in the hypothalamic level of continuous secretion. Gonadotropin 66 Textbook of Female Sexual Function and Dysfunction

releasing hormone pulse characteristics are Other stimuli influencing gonadotropin major determinants of gonadotropin pulsa­ releasing hormone release are: tile secretion, which varies both in amplitude and frequency according to the phase of the Opioid peptides: β‐endorphin and enkepha­ menstrual cycle. Luteinizing hormone pulses lins inhibit the release of luteinizing occur every 1–2 hours in the early follicular ­hormone and to a lesser extent that of fol­ phase with increasing amplitude until preo­ licle‐stimulating hormone. On the other vulation. In the preovulatory period there is hand, naloxone (an opiate receptor antag­ an increase in both amplitude and frequency. onist) increases luteinizing hormone During the luteal phase, there is a remarkable ­levels; this effect was positively correlated reduction in luteinizing hormone pulsatility with the previous endogenous levels of to once every four hours, while the amplitude estradiol. Indeed, β‐endorphin levels in is about twice as high as in the follicular hypophyseal portal blood are reduced phase. The frequency of gonadotropin releas­ after ovariectomy and restored by estro­ ing hormone secretion is determined by the gen supplementation [22]. Therefore, it firing rate of the neurons, while the ampli­ seems that estrogens may have a positive tude is determined by stimuli acting either at feedback on the release of opioid peptides. the cell body or at the nerve terminals. Sex Neurotransmitters: various monoamin­ steroids acting on kisspeptin‐1 system in the ergic brain neurotransmitters control arcuate nucleus exert negative feedback. gonadotropin releasing hormone neu­ Indeed, while gonadotropin releasing hor­ ronal activity and, thus, the amplitude of mone neurons do not express estrogen gonadotropin releasing hormone secre­ receptor alpha, a high percentage of kisspep­ tion. Noradrenaline has a facilitatory tin‐expressing cells express steroid receptors. action on the gonadotropin releasing hor­ Therefore, kisspeptin‐1 neurons are consid­ mone neurons. Dopamine is considered ered as the main steroid‐sensitive neurons an inhibitor of gonadotropin releasing mediating the feedback effects of sex steroids hormone secretion and its action is on gonadotropin releasing hormone secre­ enhanced by estrogens. Direct serotonin tion. However, estrogens also stimulate kiss­ input from serotonin neurons located in peptin‐1 signalling in the anteroventral raphe nuclei to preoptic gonadotropin periventricular nucleus of the hypothalamus, releasing hormone neurons has been thus stimulating gonadotropin releasing hor­ demonstrated in rodents. Treatment of mone release. Estradiol robustly stimulates immortalized mouse gonadotropin releas­ the expression of kisspeptin‐1 in the anter­ ing hormone neurons with a nonselective oventral periventricular nucleus of the female serotonin receptor agonist causes a tran­ rat and mouse [20, 21]. These and other sient increase in gonadotropin releasing observations led to the hypothesis that kiss­ hormone release followed by reduction of peptin neurons in the anteroventral periven­ pulsatile gonadotropin releasing hormone tricular nucleus mediate the positive secretion [23]. feedback effect of estradiol. These differen­ Prolactin: this hormone exerts short‐ tial effects exerted in the arcuate nucleus and loop feedback on the release of gon­ anteroperiventricular nucleus are the neuro­ adotropins. Prolactin acts as a biological basis of the negative and positive neuro­transmitter and may influence the feedback, respectively, of estrogens on gon­ turnover of ­catecholamines in the brain. adotropins during the menstrual cycle. It could also reduce luteinizing hormone/ Therefore, circulating concentrations of follicle‐stimulating hormone levels by estrogens define the levels of kisspeptin‐1 raising of hypothalamic dopamine and, in mRNA expression in the female brain in a high concentration, reduce the pulsatile site‐specific manner. release [24]. Pathophysiology and Medical Management of Hypoactive Sexual Desire Disorder 67

Effects of Sex Hormones Variation ­behavioral development that occur during on Brain, Sexual Function puberty. Indeed, puberty is not only loosely and Behavior anchored to marked internal and external Early Development physical changes and secondary sexual char­ acteristics and fertility, but also to the pro­ A wealth of evidence indicates that andro­ found changes in drives, motivations, gens play a critical role in organizing gender psychology, and social life. The attainment of identity, sexual orientation, and other behav­ complex social and behavioral capacities ioral traits in humans, specifically through mold the perceptions, motivations, and binding to androgen receptors in the brain behavioral repertoire necessary for repro­ [25]. In contrast, animal models in rodents ductive success. Steroid hor­ mones are key demonstrated that androgens aromatization determinants in the development and organ­ into estrogens and binding of estrogen to ization of brain during the adolescent transi­ estrogen receptors is necessary for brain tion from childhood to adulthood, when masculinization [26, 27]. This interspecies sociosexual maturity is attained. The specific discrepancy is most probably due to the fact behaviors that are organized by gonadal hor­ that alpha‐fetoprotein binds estrogen and mones are gender‐dimorphic. However, prevents it from entering and masculinizing research on the role of ovarian hormones in the brain in rodents [26, 27], but not in the organization of female sociosexual humans, where it shows a very low affinity behaviors lags far behind that in males. for estrogen [28]. If masculinization of the The complex interplay of luteinizing hor­ brain was also estrogen‐mediated in humans mone, follicle‐stimulating hormone, and ste­ as in rodents, then unbound estrogens would roidal hormones is hypothesized to facilitate cross the blood–brain barrier and masculin­ sexual behavior in adolescence, emerging ize the human female brain. In addition, perceptual sensitivity for facial cues related women with complete androgen insensitivity to sexual interest, and the development of syndrome, despite producing normal‐to‐ adult mating preferences [35]. Adolescence is high male levels of testosterone [29], show characterized by an emerging “receptivity” female gender identity [30], sexual attraction (interest in sexual objects), which does not to men [31], and feminine brain architecture necessarily equate with “proceptivity” (the and behavior [32]. Additionally, human urge to seek and initiate sexual activity) [36]. males with aromatase deficiency typically Hormonal changes of puberty have been sug­ present as normal males, despite the absence gested to induce sexual dimorphism in neu­ of aromatization in the brain or elsewhere roanatomical development across [33]. This suggests that androgens and a adolescence [37, 38]. Interestingly, the amyg­ functional androgen receptor are actually dala and hippocampus are the brain struc­ necessary for masculinizing the human brain tures where a high density of estradiol and and behavior. In a case‐control double‐blind androgen receptors are found [35]. Therefore, study involving data from the US/Denmark these two brain regions are expected to be Prenatal Development Project, prenatal selectively influenced by sex hormones dur­ exposure to progesterone was associated ing adolescence.[35]. Goddings and col­ with higher rates of bisexuality, regardless of leagues found pubertal related amygdala sex [34]. In contrast, estrogen receptor stim­ growth for both sexes [39]. Indeed, pubertal ulation seems to exert a limited role. sex hormones testosterone and estradiol, independent of age, drive sex differences in Puberty gray matter, white matter, amygdala and cau­ The next crucial life history transition is date volumes across adolescence. Changes in puberty. Both gonadarche and adrenarche testosterone levels are associated with the are relevant contributors to brain and development of total white matter, right 68 Textbook of Female Sexual Function and Dysfunction

amygdala, and bilateral caudate volumes in ness, and without heavy regulatory influence boys, whereas estradiol was related to the from frontal regions [47]. Therefore, the abil­ development of total white matter, right ity of testosterone and estradiol to trigger amygdala, and total gray matter volume in amygdala development and activation is a girls. Therefore, individuals with higher paramount feature in the understanding of estradiol levels displayed increases in amygdala how sex steroids may modulate appetitive volumes across adolescence. Interestingly, in sexual motivation within and outside aware­ animal models, a similar gender dimorphism ness. The mesolimbic dopamine system is was found in the amygdala in male rats com­ probably the best known neurobiological pared to females during puberty [40]. pathway able to enhance “wanting,” and to Estrogen has been found to increase den­ process romantic love. Several neurobiologi­ dritic spine density in the medial amygdala in cal studies conclude that love is character­ female rats. Animal [41] and human [42] ized by significantly increased activation of models have also demonstrated estradiol to specific brain regions such as the ventral teg­ reduce myelination during puberty in mental area, medial insula, anterior cingulate females. In summary, these results indicate cortex, hippocampus, nucleus accumbens, that estradiol and testosterone may drive caudate nucleus, and hypothalamus, which sexually dimorphic changes in the amygdala also mediate reward, motivation, and emo­ during pubertal development in both human tion regulation [48]. and animal models. This plasticity in brain volumes, driven by Adulthood sex hormones, may have important implica­ There is compelling experimental evidence tions for gender‐related differences in behav­ that brain structural alteration does occur ior and mental health. It has been also in adulthood. A recent study demon­ hypothesized that these changes seen across strated that women’s brains might modify puberty in brain volumes of total white mat­ slightly every month, in synchronization ter, cortex, and amygdala may account for with menstrual cycles. Thirty women under­ different affective processing in girls and went magnetic resonance imaging and levels boys. However, further research is necessary of estrogen in the blood were measured. Both to definitively elucidate the actions of sex grey and white matter in the brain increased hormones on microstructural development as estrogen levels rose, causing the hip­ during adolescence. Indeed, the amygdala pocampus to increase in volume, which, in tightly connects with cortical regions to reg­ turn, may affect women’s behavior [49]. This ulate emotion and can respond to cues of important study is the first to link subtle hor­ motivational significance (both fears and monal variations during the menstrual cycle desires), even when occur outside awareness. to a rapid, remarkable microstructural Even though the amygdala is well known for change in the hippocampus (within days). its rapid response to signals for danger [43], These data are consistent with evidence from it has been recently demonstrated to respond other studies reporting the influence of the also to rapid “unseen” sexual as well as drug menstrual cycle on the human brain [50, 51]. stimuli, thus indicating its importance in the At the time of ovulation, gray matter volume processing of signals for reward [44, 45]. significantly increases by about 1.8% [52]. Interestingly, a decrease in amygdala respon­ Studies comparing regional brain variations siveness to arousing stimuli has been in women during different phases of the described in women with postpartum menstrual cycle reported larger gray matter decrease in sexual interest [46]. This brain’s volumes in the right fusiform/parahip­ rapid response to sexual reward cues may pocampal gyrus during the early follicular stem from the brain’s capacity to initiate sex­ phase, i.e. between onset of menstruation to ual desire in an instant, also outside aware­ five days before ovulation [53], as well as Pathophysiology and Medical Management of Hypoactive Sexual Desire Disorder 69 increased gray matter volume in the right identified as one of the brain regions linked anterior hippocampus and decreased gray to behavioral inhibition and self‐related matter in the right dorsal basal ganglia (glo­ anticipation of a sexual action [65]. Women bus pallidus/putamen) in the high‐estrogen, taking oral contraceptives also show less late‐follicular phase, i.e. days 10–12 after activity in several prefrontal regions and fail onset of menses [50]. Perturbations in adult to show the attenuation of activity in the hippocampal neurogenesis plays an impor­ amygdala observed in naturally cycling tant role in the pathophysiology of various women [66]. Overall there is growing evi­ disease states, including depression [54, 55]. dence that several brain areas, including the In summary, brain structure in adulthood is amygdala and hippocampus, are influenced dramatically plastic and influenced by hor­ by sex hormones, but future investigations monal fluctuations [54, 56, 57]. Progressive are needed to identify the amygdala and hip­ age‐related brain atrophy was observed in pocampus dependent behaviors influenced postmenopausal women and in women by sex hormones. receiving antiestrogens [58, 59], thus sug­ gesting a neuroprotective role for estrogens Role of Estrogens and Progesterone [60]. A recent study evaluated the time Both estrogen and progesterone activate course of regional brain activity induced by classical genomic receptors as well as non­ visual sexual stimulation in premenopausal classical membrane‐associated receptors. and menopausal women, and assessed the The classical nuclear estrogen receptors effect of menopause on the brain areas asso­ (ERα and ERβ) [57, 60] and progesterone ciated with sexual arousal in menopausal receptors [67] are highly expressed in brain women using functional magnetic resonance areas involved in emotion and cognition, imaging [61]. The brain areas with signifi­ such as the amygdala and hippocampus. cantly higher activation in premenopausal However, sex steroids can bind to multiple women versus menopausal women included neuronal receptors, including serotonin, the thalamus, amygdala, and anterior cingu­ dopamine, and GABAA receptors [68, 69]. In late cortex. This reduced brain activity of the addition to genomic actions, both estrogen thalamus, amygdala, and anterior cingulate and progesterone exert acute effects on syn­ cortex in menopausal women might be the aptic physiology through the activation of neurobiological correlate of a menopause‐ multiple intracellular pathways to down­ related decrease in sexual arousal [61]. stream membrane receptors [70]. The G Structural and functional investigations have protein‐coupled estrogen receptor (GPER1, also revealed significant changes within the also known as GPR30) has been identified as brain in women using hormonal contracep­ one of the main estrogen‐sensitive receptors tives. A significant increase in gray matter responsible for the rapid nongenomic volume in the pre‐ and postcentral gyri, para­ actions of estrogen. G protein‐coupled hippocampal gyrus, fusiform gyrus, and the estrogen receptor is highly expressed at the superior, middle and inferior temporal gyri level of the synapse and rapidly regulates was observed in women taking hormonal hippocampal dendritic morphology and contraceptives [53]. In particular, the precen­ synaptic plasticity. Therefore, some the neu­ tral gyrus is a brain area with a high density roprotective actions of estrogens might be of estrogen receptors [62] and has greater linked to G protein‐coupled estrogen recep­ relative volume in women than in men [63]. tor activation [70]. In men, activation of the precentral gyrus has A woman’s lifespan is characterized by rele­ already been related to measures of penile vant periods of hormonal change, beginning turgidity under erotic vs. nonerotic visual with rising estrogen levels during puberty, stimulation [64]. Together with the cingulate high estrogen levels during pregnancy, and cortex, precentral gyrus activation has been rapid falls postpartum, declining levels during 70 Textbook of Female Sexual Function and Dysfunction

peri‐menopause, and extremely low levels in logical functions, sexual behavior and the postmenopause [71]. Intriguingly, these stress response, are tightly modulated by sex major transitions in sex hormone levels seem steroid hormones. Estrogen has been to be associated with a parallel incidence of reported to heterogeneously modulate sero­ mood disorder. [72]. In addition to these tonin function via the regulation of neuro­ major shifts in hormonal levels, mild changes transmitter synthesis, degradation and in endogenous sex hormones, as occur dur­ binding to receptors [72]. In particular, acute ing the monthly cycle, have also been associ­ estrogen administration has been reported to ated with changes in mood [73] and sexual have opposite effects on the serotonin sys­ behavior [74]. In the pathology of premen­ tem as compared to a more chronic treat­ strual dysphoric disorder [74], an imbalance ment‐regimen. Therefore, the effect of of the normal functioning of the serotonergic estrogen on serotonin cannot be exclusively and dopaminergic system has been hypothe­ classified as stimulatory or inhibitory. sized. As previously reported, typically four Also, progesterone has been reported to main pathways are described for the dopa­ regulate serotonergic neurotransmission [72, minergic system that are deeply involved in 81]. Chronic progesterone treatment seems sexual desire (Chapter 4). Conflicting find­ to decrease 5‐HT1A receptor expression in ings of estrogen effects on dopaminergic rats [82]. Progesterone is rapidly metabolized neurotransmission have been documented in the brain to 5α‐pregnandione or 5β‐preg­ [72]; however, most of the studies report an nandione through a 5α‐ or 5β‐reductase, overall facilitating effect on dopaminergic respectively. Both pregnandiones can be neurotransmission [75–78]. An estrogenic reduced further in ring A, resulting in the priming seems also to be necessary for pro­ formation of 3α‐ or 3β‐pregnanolones. These gesterone‐modulating effects on dopaminer­ reduced forms of progestins stimulate gic transmission [79]. However, further ­lordosis (sexual receptivity in female rats) studies are needed before translating these when injected into the ventromedial hypo­ preclinical findings to the human brain, thalamic nucleus and preoptic area in rodents behavior, and potential pathology. Nevertheless, [83]. Interestingly, in brain areas involved in recent studies support an interaction progesterone regulation of female sexual between estrogen and dopamine on cogni­ behavior, such as the hypothalamus and pre­ tive domains, such as decision making [77], optic area progesterone receptors, are upreg­ fear extinction [78], and memory bias [80]. In ulated by estrogens [83]. Facilitation of particular, estradiol is hypothesized to direct lordosis has been demonstrated in ovariecto­ decision making toward more accessible, mized estrogen primed rats after implanta­ even if smaller, rewards [77], and to mediate tion of 5α‐, 3β‐pregnenolone in the medial memory bias through the interaction with preoptic area. Intrahypothalamic total pro­ dopamine in the dorsal striatum [80]. An gesterone levels show a good correlation interaction between estrogen and dopamine with the capacity of progesterone to stimu­ in prefrontal cortex function has also been late lordosis in rats [83]. suggested to play an important role during a Interestingly, both estrogen and progester­ working memory task [76]. The serotonin one have been demonstrated to influence system plays a multitude of roles, most selective serotonin reuptake inhibitor treat­ importantly balancing mood. Serotonergic ment response [84]. In particular, estrogen neurons are highly expressed in the dorsal blocks serotonin clearance, thus resulting in and medial raphe nuclei of the midbrain with enhancement of serotonin function. This ascending fibers projecting to the frontal effect appears to be a consequence of estro­ cortex, striatum, thalamus, amygdala, hypo­ gen receptor‐β and/or G protein‐coupled thalamus, and hippocampus. In particular, estrogen receptor stimulation. In humans, a two important serotonin‐mediated physio­ recent study found an association between Pathophysiology and Medical Management of Hypoactive Sexual Desire Disorder 71 antidepressant efficacy and polymorphism of to amphetamine challenge [98]. Such effects the serotonin transporter gene in premeno­ were blunted by dopaminergic antagonists pausal women only, but not in postmenopau­ [99], suggesting that dopaminergic pathways sal women [85]. These findings suggest that mediate the behavioral outcomes induced by hormonal status is crucial for antidepressant androgens. As stated previously, sexual efficacy, postmenopausal women gaining less desire and female‐initiated sexual behavior benefit from antidepressant treatments com­ change across the menstrual cycle, with a pared to women of reproductive age [86, 87]. peak during the fertile phase [100–102]. Such In conclusion, the interaction between variation across the cycle is not observed in ovarian hormone levels, age and genotype women using oral contraceptives [101], appear to modulate serotonin function in which suppress ovulatory fluctuations of all females. Interestingly, basic and clinical stud­ sex steroids. In fact, not only estradiol but ies over the past three decades have consist­ also testosterone peak near ovulation ently demonstrated that the serotonergic (Table 6.2) [71]; thus, testosterone is another system is intimately involved in the patho­ good candidate for the cyclic shift in sexual genesis of depression [88, 89]. Changes in desire. The evidence that androgens are serotonin neurotransmission have been important modulators of women’s sexual repeatedly associated with the therapeutic function stems mainly from studies of testos­ response to antidepressant and mood stabi­ terone therapy given to postmenopausal lizing medication. Almost all currently women with hypoactive sexual desire disor­ employed treatments for depression, includ­ der (see later paragraph on “Treatment”). ing the tricyclic antidepressants, the selective Some pioneering studies first suggested that serotonin reuptake inhibitors, the monoam­ testosterone positively regulates sexual desire ine oxidase inhibitors, and lithium, exert not only in men but also in women. For their antidepressant effects through a direct example [103], low estradiol and testosterone or indirect increase in serotonergic neuro­ levels during lactation were associated with transmission. Thus, the side effects of almost low libido. Similarly, in a small observational all these drugs include a reduction of sexual study [104], antiandrogen therapy was found desire [90]. to negatively affect libido in women. In a rep­ resentative sample of 1021 Australian women Role of Androgens (ages 18–75), low androgens levels increased It has been proposed that androgens have the risk of low sexual desire, arousal, and important effects in modulating sexual desire responsiveness [105]. In particular, in young in women. The vaginal response to erotic women (<44 years old), low sexual desire, stimuli is increased in women with high tes­ sexual arousal, or sexual responsiveness was tosterone levels [91]. Additionally, a signifi­ significantly associated with a low dehydroe­ cant incidence of masturbatory activity piandrosterone sulfate value [105]. Most corresponds with the midcycle peak of recently, the association between androgens androgens [92]. Other data highlight the and sexual desire was investigated in 560 potential excitatory role of androgens on the healthy Danish women 19–65 years old. Free reward system in humans [93, 94]. Several testosterone and androstenedione were sig­ studies in adult rodents have demonstrated nificantly linked with sexual desire both in that testosterone administration induced women 19–24 years old and in women 25–44 conditioned place preference in rodents [95– years old [106]. In the Study of Women’s 97]. In another animal model, administration Health Across the Nation, testosterone and of a cocktail consisting of testosterone cypi­ dehydroepiandrosterone sulfate were both onate, nandrolone decanoate, and boldenone positively associated with masturbation fre­ undecylenate, increased the rate of self‐ quency and desire across the menopausal administration and enhanced the sensitivity transition [107]. 72 Textbook of Female Sexual Function and Dysfunction

In addition, oophorectomy, with a rele­ weeks, the two treatment groups reached vant reduction of not only estrogens but similar serum testosterone levels and a also androgens produced by the ovaries, is ­similar significant increase in sexual function associated with decreased sexual desire and from baseline [112]. This study clearly frequency of sexual fantasies [108]. ­suggested that the effect of testosterone on Androgen treatment increased the intensity sexual function is not mediated by aromatiza­ of sexual desire in oophorectomized women tion to estrogens in adequately estrogenized who were randomized to receive one of postmenopausal women. three different sex steroid replacement regi­ With ageing, the mean circulating lev­ mens: estrogen–androgen combined, an els of total and free testosterone decrease estrogen‐alone drug, an androgen‐alone progressively from the early reproductive drug, or a placebo [108]. Accordingly, com­ years [113]; adrenal production of bined supplementation with estradiol and the androgen precursors, androstenedione androgen in oophorectomized women pro­ and dehydroepiandrosterone, also decreases moted sexual desire, sexual arousal, and linearly with ageS [113, 114]. Therefore, increased numbers of fantasies vs. estradiol an overall age‐related decrease in testoster­ alone [109]. In addition, in a double‐blind, one is observed. Several pathophysiologic placebo‐controlled trial involving 533 conditions are considered as common oophorectomized women (ages 20 to over causes of low testosterone in women 65) with concurrent hypoactive sexual (Box 6.1). desire disorder, testosterone treatment sig­ In conclusion, androgens are important nificantly ameliorated both sexual desire determinants of female sexual function. Low and satisfying sexual activity [110]. The levels of total and free testosterone, ∆4 effects of exogenous estradiol vs estradiol androstenedione, and dehydroepiandroster­ plus testosterone were studied in six surgi­ one sulfate are linked to lower sexual desire. cally menopausal women and five premeno­ However, there is no threshold for any of pausal women using functional magnetic these androgens that can be used to diagnose resonance imaging patterns of brain activa­ women with low sexual function or candidates tion in response to a sexual stimulus. Six for testosterone therapy. weeks of estradiol was associated with global increases in the brain for erotic and neutral stimuli. Estradiol plus testosterone Box 6.1 Conditions associated to low was associated with higher activation in the testosterone in women.

limbic system, which reached a level similar ●● Aging to that observed in premenopausal women ●● Panhypopituitarism [111]. These data suggest a positive effect of ●● Hyperprolactinemia testosterone on sexual desire in women ●● Hypothalamic amenorrhea (i.e. anorexia with reduced or absent ovarian androgen nervosa) production. ●● Primary ovarian insufficiency (all causes): However, the role of sex steroids on libido, bilateral oophorectomy; chemotherapy or and in particular whether the effect of testos­ radiation to pelvis or chemical ovarian terone is mediated by aromatization to _ suppression (e.g. gonadotropin releasing estradiol, has been recently elucidated. A hormone analogs) randomized controlled trial was conducted ●● Adrenal insufficiency in 76 postmenopausal women using trans­ ●● Antiandrogen therapy (e.g. spironolactone, dermal estradiol plus a 0.5% transdermal tes­ cyproterone acetate) tosterone gel 400 ml/d who were randomly ●● Oral estrogen assigned to the aromatase inhibitor letrozole ●● Glucocorticoid therapy 2.5 mg/d or placebo for 16 weeks [112]. At 16 Pathophysiology and Medical Management of Hypoactive Sexual Desire Disorder 73

Role of Kisspeptin in Female Role of Oxytocin in Female Sexual Desire Sexual Desire Kisspeptin is a crucial reproductive hormone Oxytocin is a small neuropeptide synthe­ that potently activates the reproductive axis, sized in the supraoptic and paraventricular acting in the hypothalamus to stimulate down­ nucleus of the hypothalamus and secreted stream secretion of reproductive hormones into the systemic circulation by nerve termi­ [14, 115]. However, the expression of kisspep­ nals in the posterior pituitary gland. Oxytocin tin‐1 and its cognate receptor (KISS1R) is not is critically involved in female reproduction, limited to the hypothalamus. As stated before, facilitating pair bonding and affiliative kisspeptin‐1 neurons are also present in limbic behaviors in vertebrates from toads to brain structures in rodents and humans, humans [117]. The functions of oxytocin in including the medial amygdala. However, the uterine contractility and the breastfeeding role of kisspeptin‐1 in these areas is far from are also well known. Oxytocin is released clear. The limbic system has established roles simultaneously by the brain of mother and in emotional and reproductive behavior and is her infant during suckling. It appears that considered the anatomical framework uniting oxytocin is essential for the onset of normal sex, emotion, and reproduction in humans (for maternal behavior, as well as for the building more details see Chapter 4). A recent rand­ of the mother/infant bond in all the animal omized, double‐blinded, cross‐over, placebo‐ species studied such far. However, oxytocin controlled study demonstrated that intravenous has also been implicated as having an impor­ infusion of kisspeptin‐1 (1 nmol/kg/h) in 29 tant role in sexual responsiveness, arousal, healthy young men enhanced activity in key and orgasm. Both sexual partners secrete limbic and paralimbic structures when view­ oxytocin simultaneously during sexual inter­ ing sexual images [116]. These structures course. This parallel release of oxytocin rein­ included the anterior and posterior cingulate forces the sexual arousal of both partners and as well as the left amygdala. Interestingly, sex­ is associated with affiliative, nonaggressive ual aversion decreased as a function of kiss­ behavior, favoring the formation of pair peptin‐1’s enhancement of several structures bonding. The role of oxytocin in female sex­ of the sexual‐processing network (including ual function and, especially, in desire is com­ the cingulate, putamen, and globus pallidus), plex and not completely elucidated. However, suggesting a role for kisspeptin‐1 in sexual dis­ animal studies provide a wealth of informa­ inhibition [116]. Moreover, kisspeptin‐1 stim­ tion about the biological function of oxytocin ulated key structures of the mesolimbic reward [117]. In rat studies, oxytocin administration and fronto‐striatal‐amygdala‐midbrain sys­ has been found to increase lordosis (sexual tems (including the hippocampus, amygdala, receptivity in female rats), with the effect and cingulate) more in subjects with lower appearing dependent on sex steroids. baseline sexual desire and reward trait [116]. In However, oxytocin knockouts display normal addition, kisspeptin also enhanced the mating behavior but do not experience bond­ response to bonding images activating regions ing [117, 118]. Estradiol increases the expres­ similar to those activated with sexual images sion of oxytocin and its receptors in the (i.e. the amygdala and the anterior and poste­ ventromedial hypothalamus of the rat [119], rior cingulate), with additional activation of and a group of oxytocin receptor positive the thalamus and globus pallidus. Collectively, cells has been identified in the medial pre­ these data suggest that kisspeptin enhances frontal cortex of female mice. In a small study limbic responses to sexual and bonding stim­ enrolling 30 healthy premenopausal women, uli; the activation of these sexual arousal struc­ serum oxytocin levels were reduced in the tures correlates with increased reward luteal phase and were correlated with lower measures as well as with reduced sexual aver­ scores on the lubrication scale of the Female sion [116]. Sexual Function Index [120]. 74 Textbook of Female Sexual Function and Dysfunction

Role of Prolactin in Female mones in the mature mammalian brain has Sexual Desire been recently recognized [123]. In particular, Prolactin is a hormone secreted by lacto­ in human cortical brain tissue thyroid hor­ trophs in the anterior pituitary. It enhances mones are present in high (nanomolar) con­ the turnover of dopamine in brain areas centrations. In peripheral tissues, where involved in the regulation of sexual behavior thyroxine is converted to triiodothyronine, (i.e. nigrostriatal and mesolimbic tracts). In thyroxine concentrations usually far exceed particular, in the tuberoinfundibular tract levels of triiodothyronine, the thyroid hor­ chronic increases of prolactin levels (hyper­ mone with the highest biological activity. In prolactinemia) induced dopamine release, contrast, in the brain thyroxine and triiodo­ thus leading to suppression of gonadotro­ thyronine concentrations are in an equimo­ pin‐releasing hormone with subsequent lar range [124]. Their relative receptors are ­hypogonadotropic hypogonadism. Central also prevalent in the mature brain. Indeed, hypogonadism may be the main underlying nuclear receptors for triiodothyronine, the mechanism of hyperprolactinemia‐associ­ thyroid hormone with the highest biological ated low sexual desire. However, a direct activity, are widely distributed in adult rat effect of increased prolactin on sexual desire brain, with the highest density in the amyg­ has been also hypothesized. In fact, prolactin dala and hippocampus. Thyroid hormones receptors were found in the diencephalic appear to play an important role in regulat­ incerto‐hypothalamic dopaminergic system, ing central noradrenergic function and it has which is tightly connected with the medial been suggested that thyroid dysfunction may preoptic area, the most important area for be linked with abnormalities in central the control of motivational and consumma­ noradrenergic neurotransmission. An inter­ tory aspects of sexual behavior [121]. In con­ action of thyroid hormones with serotonin trast to other areas, in the incerto‐hypothalamic neurotransmission has been also docu­ dopaminergic system, prolactin did not mented [125]. Some evidence in humans release dopamine, suggesting a direct, inhibi­ with thyroid dysfunction suggests that hypo­ tory role of prolactin on sexual motivation. thyroid status is associated with a reduced An extensive list of causes of hyperprol­ serotonin responsiveness. Furthermore, this actinemia has been reported elsewhere [122]. appears to be reversible with thyroid replace­ ment therapy [126, 127]. However, given the Role of Thyroid Hormones in Female small number of studies in humans, and a Sexual Desire limited sample size, definitive conclusions In primary hypothyroidism, elevated hypo­ cannot be established. In contrast, results thalamic thyrotropin releasing hormone from studies in animals yielded stronger evi­ stimulates prolactin secretion, with subse­ dence that thyroid status has a relevant quent high prolactin levels. Although hypo­ impact on serotonergic neurotransmission in thyroidism is usually considered a possible the adult brain [128]. Thyroid hormone may cause of hyperprolactinemia, it is accompa­ enhance cortical serotonergic neurotrans­ nied by normal serum prolactin levels in the mission via two distinct mechanisms: (i) by majority of patients (roughly 60%). Therefore, disinhibiting cortical and hippocampal sero­ additional mechanisms for decreased sexual tonin release through a reduction of the 5‐ desire in hypothyroidism should be taken HT1A autoreceptors sensitivity in the raphe into account. Hypothyroidism is often asso­ area; and (ii) by increasing cortical serotonin ciated with depressive disorders, although neurotransmission through an increase of the mechanism for this is unclear. Thyroid cortical 5‐HT2 receptor sensitivity [125, 128]. hormones are critically involved in the devel­ Hyperthyroidism has been also associated opment of the central nervous system. with reduced desire. Thyroid hormones However, an important role of thyroid hor­ influence androgen activity by altering the Pathophysiology and Medical Management of Hypoactive Sexual Desire Disorder 75 production of sex hormone‐binding globulin ­Pathophysiology by hepatocytes [129]. It has been hypothe­ sized that these responses are mediated Several physical and medical factors as well directly by thyroid hormone receptors acting as some medications have been associated at the level of the human sex hormone bind­ with low sexual desire (Box 6.2). ing globulin gene. Thyroid hormones exert their effects at the gene level via thyroid hor­ Box 6.2 Conditions and medications mone receptors, which generally bind as a associated with low sexual desire. heterodimer with the retinoid X receptor to thyroid hormone response elements within ●● Surgically induced menopause and other target gene promoters. However, a typical conditions associated to low androgen thyroid hormone response element has not levels been documented within the human sex hor­ ●● Hyperprolactinemia mone binding globulin promoter region ●● Thyroid disorders [130]. It has been suggested that the thyroid ●● Diabetes mellitus/Obesity/Metabolic hormone‐induced increase in sex hormone syndrome binding globulin gene expression is mediated ●● Depression indirectly through the release of hepatocyte ●● Low urinary tract symptoms nuclear factor‐4α [130]. Therefore, a change ●● Neurological diseases in the metabolic state of the liver after thy­ ●● Medications (antidepressant, antipsy- roxine treatment could in turn influence chotic, oral contraceptives, antiandrogens) hepatocyte nuclear factor‐4α expression, leading to increased sex hormone binding globulin expression. Suppression of the thy­ Surgically Induced Menopause roxine‐induced hepatocyte nuclear factor‐4α and Other Conditions Associated levels in hapathocytes completely blocked with Low Androgen Levels the thyroxine‐induced increase in sex hor­ mone binding globulin promoter region Women who have undergone oophorectomy activity [131]. In conclusion, a decreased free have been reported to have a higher risk of testosterone concentration due to a marked developing adverse health consequences, increase in sex hormone binding globulin such as shorter life expectancy, with a 13% might be the underlying mechanism for increase in all‐cause mortality, coronary hypoactive sexual desire disorder in hyper­ heart disease (23%), lung cancer (29%), and thyroid women. colorectal cancer (49%) [134]. It has been established that surgical menopause may Role of Metabolic Disease lead to distressing and abrupt symptoms, Both obesity and metabolic syndrome have especially sexual dysfunction, compared with been recently associated with increased vas­ women who undergo natural menopause cular resistance in the clitoris and impaired [135, 136], with surgical menopause roughly sexual arousal, suggesting that these cardio‐ doubling the risk of having low sexual desire metabolic risk factors may have a greater than natural menopause [137]. Sexual desire direct negative impact at the genital level scores are highly correlated with sexual than at a central one [132, 133]. However, arousal, orgasm, and sexual pleasure, dem­ these metabolic diseases have also been asso­ onstrating that low sexual desire is frequently ciated with reduced sexual desire. Therefore, associated with impaired functioning in a reduced libido in patients affected by dia­ other aspects of the sexual response. As betes mellitus or metabolic syndrome may described before, the ovary is one of the main be, at least in part, related to reduced sexual sources of androgens in women. Most studies arousal during intercourse. indicate that surgical menopause is associated 76 Textbook of Female Sexual Function and Dysfunction

with lower total and free testosterone levels to bone loss, cognitive impairment, and a than natural menopause [138–143]. Therefore, high prevalence of mood and anxiety disor­ the reduction in androgen levels due to ova­ ders, including major depressive disorder riectomy is the most plausible cause of [152]. More importantly, a clear association increased risk for hypoactive sexual desire between sexual problems, including low sex­ disorder in surgical menopause. Compared ual desire, and eating disorder psychopathol­ with the naturally postmenopausal ovary, ogy has been identified [153]. which continues low‐level secretion of testos­ Hypopituitarism often consists of hypog­ terone, surgically induced menopause is onadotropic hypogonadism and/or sec­ associated with an abrupt cessation of steroid ondary adrenal insufficiency, thereby production [142]. This sudden and complete impairing the two major sources (ovary loss of all ovarian steroids is also associated and adrenal gland) of androgen produc­ with more severe menopausal symptoms tion. Reduced concentrations of total (hot flashes, vaginal dryness, dyspareunia, ­testosterone, free testosterone, and andros­ and mood changes) as compared to naturally tenedione have been demonstrated in menopause [142]. However, women who had women presenting with hypopituitarism surgical menopause and took hormone ther­ [154]. In women with adrenal insufficiency apy experienced significantly less severe (either secondary or primary), but not in symptoms, but hormone replacement ther­ women with hypogonadism, a relevant apy did not completely counteract vaginal reduction of dehydroepidandrosterone sul­ dryness, pain with intercourse, and loss of fate is also described. interest in sex [142]. According to a Cochrane review, hormone replacement therapy had a Hyperprolactinemia small‐to‐moderate benefit when treating As stated before hyperprolactinemia is asso­ sexual dysfunction in perimenopausal and ciated with hypogonadotropic hypog­ postmenopausal women [144]. Additionally, onadism, reduced ovarian production of sex women who undergo surgical menopause steroids, and low sexual desire [155–157]. In show poorer psychosocial outcomes than a small study of 63 women with morphologi­ those who undergo natural menopause [145], cally verified hypothalamic‐pituitary disor­ with younger women experiencing more ders and hyperprolactinemia, decreased depressive symptoms and lower psychosocial sexual desire was present in more than 30% functioning than older women undergoing of cases [156]. the same procedure [146]. Apart from surgical menopause, some Hypothyroidism/Hyperthyroidism other clinical conditions have been recog­ nized to be associated with a reduction in There is a paucity of data regarding thyroid androgens levels and with reduction of sex­ disorders and female sexuality. However, ual desire (Box 6.1) [147]. A reduced level of hypothyroidism in women is another testosterone was reported in women with endocrine condition previously associated premature ovarian insufficiency as compared with decreased libido. Three case‐control to age‐matched healthy counterparts [148– studies reported decreased sexual desire 150]. In particular, in subjects with Turner either in women with overt [158–160] or syndrome, reduced circulating levels of sev­ subclinical [158, 161] hypothyroidism. On eral androgens (testosterone and ∆4‐andros­ the other hand, hyperthyroidism has also tenedione) are roughly 40% lower than in been associated with reduced sexual desire age‐controls and are also associated with [160, 162], most probably linked to an reduced sexual desire [151]. increase of sex hormone binding globulin Anorexia nervosa, is a psychiatric disorder levels with a parallel reduction in free complicated by severe hypogonadism le­ ading testosterone. Pathophysiology and Medical Management of Hypoactive Sexual Desire Disorder 77

Diabetes Mellitus metabolic syndrome [169]. The number of metabolic syndrome criteria was strongly Female sexual dysfunction and urinary associated with reduced sexual activity and incontinence have been indicated as two of reduced sexual desire and satisfaction, sug­ the major problems, negatively affecting gesting a cumulative association of cardio­ quality of life among women with diabetes vascular risk factors with sexuality. Among [163, 164]. A recent meta‐analysis demon­ metabolic syndrome components, elevated strated that having any type of diabetes triglyceride levels were the most tightly asso­ almost doubled the risk of sexual dysfunction ciated with low sexual desire [169]. Three [164]. Several of the studies in type 1 and 2 other smaller case‐control studies did not diabetes specifically reported a reduction of find any significant association between met­ libido. In particular, in the long‐term abolic syndrome and sexual desire domain Epidemiology of Diabetes Interventions and [170–172]. Therefore, available evidence Complications study, 57% of women with suggests that metabolic syndrome might be type 1 diabetes suffered from decreased sex­ associated with hypoactive sexual desire dis­ ual desire [165]. However, female sexual dys­ order, but further studies are needed. function associated with diabetes mellitus is likely to be multifactorial, with peripheral macrovascular/microvascular and neuro­ Obesity genic complications proposed [132, 133]. In In population‐based studies, sexual desire particular, decreased capillary engorgement was found to decrease as a function of obesity in response to erotic stimuli was found using and increasing body mass index [173, 174]. vaginal photoplethysmography in women However, this evidence was not confirmed in with diabetes as compared with healthy con­ three clinical samples of women seeking or trol subjects without diabetes [166]. A small undergoing weight loss treatment [175–177]. study enrolling 30 women with diabetes and These prior studies supporting an association 20 control subjects, demonstrated that between body mass index and sexual dys­ reduced (vibratory) sensation at multiple function observed lower sexual functioning genital and extragenital sites was associated at higher levels of body mass index. In one with diabetes mellitus [167]. Diabetes has sample [178], more than half of women seek­ been reported to greatly impact vaginal ing bariatric surgery reported reduced sexual physiology, being associated with alterations desire. It is important to note that women of the vaginal lamina propria vascular net­ seeking weight loss surgery showed a signifi­ work, nitrergic signaling, and androgen cantly greater impairment in sexual function­ receptor expression [168]. In conclusion, dia­ ing than obese women who do not [175]. betic end‐organ complications may play a Women seeking surgery for weight loss may role in decreasing women’s sexual arousal, thus experience more severe physiological or with a subsequent reduction of sexual desire. psychological distress that accounts for dif­ ferences in sexual function. An intimate rela­ Metabolic Syndrome tionship between binge eating and sexual functioning has been also described in obese Data for metabolic syndrome and hypoactive subjects [177]. The perceived lack of control sexual desire disorder are conflicting. Among over eating, which determines a sense of 376 postmenopausal, community‐dwelling shame [179], was thus hypothesized to women from the Rancho Bernardo Study worsen sexual functioning. Alternatively, the (aged ≥40 years, mean baseline age = 73 years), reduced satisfaction in sexual life may lead to women with metabolic syndrome showed lifestyle changes, with increased calorie significantly lower sexual activity and lower intake [180]. Observational studies have con­ sexual desire compared with women without sistently demonstrated a trend towards an 78 Textbook of Female Sexual Function and Dysfunction

improvement of sexual desire after weight dysfunctions in women include [189]: loss [181, 182]. More importantly, it was (i) overactive bladder, currently defined as a reported that change in reported sexual desire syndrome characterized by urinary urgency, was associated with deviation from each associated with increased daytime frequency woman’s individual body mass index trajec­ and nocturia; (ii) urgency urinary inconti­ tory. In particular, greater‐than‐expected nence, defined as a loss of urine associated weight gain seems to be responsible for con­ with urgency to void; (iii) stress urinary current decrease in desire, whilst an increase incontinence, which is the involuntary leak­ in desire occurred in patients showing age of urine during maneuvers involving sud­ greater‐than‐expected weight loss. Weight den increased intra‐abdominal pressure; and loss after intensive lifestyle intervention was (iv) mixed urinary incontinence, with con­ not significantly associated with resolution of current stress urinary incontinence and female sexual dysfunction [183]. In contrast, a urgency urinary incontinence. In general, complete resolution of female sexual dys­ lower urinary tract symptoms negatively function for a majority of patients six months affect quality of life and are commonly asso­ postbariatric surgery has been reported [181]. ciated with female sexual dysfunction [190, Improved body image, increased self‐esteem, 191]. Women with urinary incontinence and/ and perceived sexual attractiveness may be or lower ­urinary tract symptoms were more the most important determinant factors lead­ likely to suffer from sexual dysfunction [190], ing to improved sexual desire following inter­ mainly sexual pain disorder (44%) and hypo­ vention for weight loss [178, 181]. active sexual desire (34%) than the general female population. Similarly, other studies Depression reported that stress urinary incontinence and low urinary tract symptoms might nega­ As reported in the previous chapters, depres­ tively affect sexual desire [192]. The patho­ sion is an important risk factor for low sexual genic mechanisms underlying this association desire. In particular, in the Hypoactive Sexual are unclear. A contribution of serotonin on Desire Disorder Registry Study, about 30% of lower urinary tract function has been recog­ women with acquired, generalized hypoactive nized. A wide variety of serotonin receptor sexual desire disorder presented concurrent subtypes are present in bladder urothelium, symptoms or diagnosis of depression [184]. smooth muscle, autonomic excitatory nerve Adding a layer of complexity, most antidepres­ terminals, and central pathways controlling sants are associated with decreased desire the micturition reflex [193–195]. Serotonin [185, 186]; therefore, use of antidepressant has both physiological and pathological medication may actually substitute one causa­ functions in the lower urinary tract. Recently, tive factor of hypoactive sexual desire disorder serum serotonin has shown an independent for another. During the assessment phase, negative correlation with lower urinary tract every patient with low sexual desire should symptoms and with urinary incontinence. In thus be screened for depression, as depression the current National Institute for Health and and decreased sexual desire have demon­ Care Excellence guidelines, duloxetine, a ser­ strated a strong bidirectional association [187]. otonin‐noradrenaline reuptake inhibitor, has been recommended as treatment for women Urinary Tract Symptoms with lower urinary tract symptoms who are not surgical candidates or those who prefer Urinary tract symptoms in women are drugs to surgery [196]. Moreover, it may be extremely common. According to the litera­ that women with urinary incontinence avoid ture, 11–73% of women suffer from some sexual intimacy because of fear of involun­ urinary tract symptoms throughout their tary leakage of urine during intercourse or lifespan [188]. The most distressing urinary orgasm. Pathophysiology and Medical Management of Hypoactive Sexual Desire Disorder 79

Neurological Diseases was found to be one of the most important pre­ dictors of a woman’s subjective response to Various chronic neurological diseases show a sexual stimuli. Similarly, antidepressant medi­ negative influence on sexual desire in women. cations may also lower desire. Antiandrogen Examples include multiple sclerosis [197] drugs are usually used in women with hir­ and spinal cord injury [198]. Based on the sutism [204]. Spironolactone and cyproterone available data, we conclude that some neuro­ acetate, the antiandrogens most commonly logical diseases appear to be associated with used in the treatment of hirsutism, possess decreased sexual desire, but data are limited. intrinsic hormonal activity and interfere with steroidogenesis. Cyproterone acetate also Medications shows significant antigonadotropic effects. Side effects of these drugs include frequent Among medications, special attention should menstrual irregularity. Other antiandrogen be paid to antidepressant treatments (as dis­ drugs, such as flutamide and finasteride, can be cussed before), antipsychotics, and other drugs also used in women with hirsutism. Flutamide increasing prolactin levels [199]. In addition, a is a nonsteroidal compound with pure antian­ focused medical history should also ascertain drogen activity that acts to block the androgen the use of combined oral contraceptives [200], receptor site. However, some data suggest that as well as antiandrogen drugs. The estrogen/ flutamide might also reduce the synthesis of progestin combination contraceptive pills androgens and/or increase their metabolism to inhibit the mid‐cycle peak of gonadotropin inactive molecules. Liver toxicity is a rare but releasing hormone from the hypothalamus, potentially severe side effect of flutamide. thus suppressing pituitary luteinizing hormone Finasteride is a very potent inhibitor of the type and follicle‐stimulating hormone, and inhibit­ 2 isoenzyme of 5α‐reductase, the enzyme ing ovulation [201]. Women taking oral contra­ responsible for conversion of testosterone to ceptives do not ovulate, do not experience the active metabolite dihydrotestosterone physiological fluctuations in sex hormones [204]. As increased 5α‐reductase activity is (estradiol, progesterone, and testosterone), and considered a pathogenic mechanism of hir­ therefore, do not experience cyclic peaks in sutism, selective enzyme inhibition has been sexual behaviors [200]. These hormones are proposed as a rational medical approach to this not completely suppressed by oral contracep­ condition as well. tives and the levels of endogenous sex steroids Some antidepressants, such as selective in the peripheral blood are maintained at level serotonergic reuptake inhibitors, are well similar to that detected in the early follicular known to induce sexual side effects. As phase of the menstrual cycle [201]. However, stated, selective serotonin reuptake inhibi­ even though all types of oral contraceptives tors may inhibit gonadotropin releasing decrease levels of total and free testosterone, ­hormone, thus reducing testosterone levels. the greatest effect on the increase of sex hor­ Recently the US Food and Drug mone binding globulin is seen with higher ethi­ Administration stated that antidepressant‐ nyl estradiol dose and with a third or fourth related sexual dysfunction is an important generation progestins [202]. This relevant hor­ entity that should be adequately assessed monal reduction might be responsible for during clinical trials with the use of available lower levels of sexual desire reported in some instruments and described in product labels. oral contraceptive users [200]. A recent pla­ cebo‐controlled, double‐blind, randomized Substances of Abuse trial demonstrated that desire was significantly reduced by levonorgestrel‐containing oral con­ Numerous substances of abuse, including traceptives in comparison to placebo [203]. alcohol, tobacco, and opioids, are correlated Interestingly, duration of oral contraceptive use with sexual dysfunction in women. Endogenous 80 Textbook of Female Sexual Function and Dysfunction

opioids exert an important action on the phys­ (no previous history of normal functioning) iological sexual functioning through effects at or acquired (prior normal functioning) and specific opioid receptors and control of the according to whether it occurs only in lim­ release of gonadotropin releasing hormone ited circumstances (situational) or in all sex­ and, thus, follicle‐stimulating hormone and ual experiences (generalized). The DSM‐5 luteinizing hormone, with subsequent devel­ merged desire and arousal into the single opment of hypogonadotropic hypogonadism. diagnosis, female sexual interest‐arousal dis­ Opioids use also exerts a negative influence on order, but this new clinical entity has not adrenal androgen. Studies show that long‐term been validated nor studied in any clinical use of alcohol leads to inhibition of the hypo­ trial. In conclusion, for the purpose of this thalamic‐pituitary‐gonadal axis and reduces chapter, we use the DSM‐IV definition of the release of gonadotropins from the pitui­ hypoactive sexual desire disorder. tary. Therefore, in both opioid and alcohol abusers, a reduction of androgen levels and Screening Tools libido have been observed [205]. The Decreased Sexual Desire Screener [207] is a validated self‐administered questionnaire that that can help clinicians in establishing the ­Diagnosis presence and severity of hypoactive sexual desire disorder (Box 6.3). The Decreased Low or decreased sexual desire that causes Sexual Desire Screener is an extremely useful personal distress is the core feature of hypo­ tool to be also used by clinicians without active sexual desire disorder as defined by expertise in sexual medicine. The first four the Diagnostic and Statistical Manual, Fourth yes/no questions make an accurate diagnosis Edition, Revised (DSM‐IV‐TR) [206]. of an acquired, distressing, reduction in sex­ Hypoactive sexual desire disorder is a rela­ ual desire. The fifth question lists potential tively common but often undiagnosed condi­ causes or exacerbating factors for reduced tion. As for other sexual dysfunctions, desire. Patients who do not endorse all of the hypoactive sexual desire disorder may be first four questions are unlikely to have hypo­ defined according to the duration as lifelong active sexual desire disorder.

Box 6.3 Decreased Sexual Desire Screener.

1) In the past, was your level of sexual desire or interest good and satisfying to you? YES NO 2) Has there been a decrease in your level of sexual desire or interest? YES NO 3) Are you bothered by your decreased level of sexual desire or interest? YES NO 4) Would you like your level of sexual desire or interest to increase? YES NO 5) Please circle all the factors that you feel may be contributing to your current decrease in sexual desire or interest: A) An operation, depression, injuries, or other medical condition YES NO B) Medications, drugs, or alcohol you are currently taking YES NO C) Pregnancy, recent childbirth, menopausal symptoms YES NO D) Other sexual issues you may have (pain, decreased arousal, orgasm) YES NO E) Your partner’s sexual problems YES NO F) Dissatisfaction with your relationship or partner YES NO G) Stress or fatigue YES NO Pathophysiology and Medical Management of Hypoactive Sexual Desire Disorder 81

Other screening tools for female sexual There are no specific investigations to dysfunction may be used, even though they confirm or exclude acquired, generalized are more dimensional and less specific to hypoactive sexual desire disorder, and reduced sexual desire. The Female Sexual ­additional laboratory (e.g., thyroid stimulat­ Function Index is a well‐validated, 19‐item ing hormone, prolactin), or imaging investi­ self‐report instrument that evaluates differ­ gations are only occasionally required based ent dimensions of sexual function, includ­ upon the patient’s medical history and ing desire, arousal, lubrication, orgasm, examination. In particular, if hyperprol­ satisfaction, and pain. It is useful to reliably actinemia is suspected, a prolactin blood differentiate between sexually dysfunc­ test will be done. The initial determination tional and healthy women (with a cut‐off of prolactin can be performed at any time of score <26.5 indicating sexual dysfunction) the day but it should absolutely avoid exces­ and to measure treatment efficacy (www. sive venipuncture stress [199]. A single fsfiquestionnaire.com) [208]. The Female determination is usually sufficient to estab­ Sexual Distressed Scale – Revised version lish the diagnosis, but when in doubt 2–3 [209] is a validated questionnaire consisting samples separated by at least 15–20 minutes of 13 items scoring distress, dissatisfaction, should be drawn after obtaining venous and other negative feelings related to sexual access. Normal values of prolactin in women dysfunctions, including low desire. are generally lower than 25 µg/l. A prolactin In general, patients with sexual dysfunc­ level greater than 250 µg/l usually indicates tions expect clinicians to inquire about their the presence of a prolactinoma, whereas general health. During assessment, the prolactin level greater than 500 µg/l is diag­ medical history should be focused to ascer­ nostic of a macroprolactinoma [199]. tain the presence or suspicion of organic However, it should be underscored that diseases that may be contributing to selected drugs, including antipsychotic acquired, generalized hypoactive sexual medications and metoclopramide, may desire disorder. A list of medical conditions cause prolactin levels increase above associated with hypoactive sexual desire 200 µg/l. In addition, in patients with disorder has been described previously asymptomatic hyperprolactinemia (without (Box 6.2). In particular, depression should galactorrhoea, menstrual irregularity, infer­ be carefully evaluated. Depressive illness tility), assessment for macroprolactin is can be easily identified with some questions mandatory. The term macroprolactinemia evaluating the presence of depressed mood indicates the situation in which a prepon­ or anhedonia during the previous two weeks derance of the circulating prolactin consists or the current use of antidepressant medi­ of the larger molecules (such as a dimer, “big cations. However, according to the recent prolactin,” and a much larger polymeric US Preventive Services Task Force form, “big‐big prolactin”) [199]. Larger pro­ Recommendation Statement, an accurate lactin forms (macroprolactin) are charac­ depression screening instrument is the terized by a lower/absent bioactivity, and Patient Health Questionnaire [210]. Although thus macroprolactinemia should be sus­ a general physical examination of patients pected when typical symptoms of hyperpro­ who experience hypoactive sexual desire lactinemia are absent. Polyethylene glycol disorder is often unremarkable and it has a precipitation is an inexpensive way to evalu­ low diagnostic yield, a focused physical ate the presence of macroprolactin in the examination, including a pelvic examina­ serum [199]. tion, may facilitate important reassurance As mentioned before, both hypothyroid­ for the patient that she is anatomically ism and hyperthyroidism have been associ­ ­normal or identify genital arousal or pain ated with reduced sexual desire. Therefore, disorders. if a disorder of thyroid function is sus­ 82 Textbook of Female Sexual Function and Dysfunction

pected, a blood thyroid‐stimulating hor­ ­Therapeutic Strategies mone will be measured. Diagnosis of for Hypoactive Sexual Desire hypothyroidism is based on symptoms Disorder [211] and the results of a blood thyroid stimulating hormone level. Hypothyroidism Modification of neuroendocrine commonly manifests as a slowing in physi­ factors contributing to low cal and mental activity but may be asymp­ sexual desire tomatic. An elevated thyroid stimulating hormone requires measurement of the level Following the ISSWSH process of care, [213] of the thyroid hormone thyroxine. A low when the presence of acquired, generalized level of thyroxine and high level of thyroid hypoactive sexual desire disorder is diagnosed, stimulating hormone indicate overt hypo­ it is particularly crucial to take a focused medi­ thyroidism. Normal blood levels of triiodo­ cal, sexual, psychological, and social and drug thyronine and thyroxine but a higher than history to identify any factors that may be normal level of thyroid stimulating potentially reversible. Indeed, etiology of hypo­ ­hormone is a condition called subclinical active sexual desire disorder is often complex hypothyroidism, which usually is without and multivariate, and several pathophysiologi­ outward signs or symptoms. In contrast, cal factors (see the section “Pathophysiology”) hyperthyroidism is a condition in which the may cause hypoactive sexual desire disorder by thyroid gland produces a high level of thy­ either decreasing sexually excitatory processes roid hormones and thyroid stimulating or increasing inhibitory ones. Therefore, the hormone is usually suppressed. Commonly first line intervention for women with hypoac­ reported symptoms of hyperthyroidism are tive ­sexual desire disorder is to remove any palpitations, fatigue, tremor, anxiety, sleep modifiable risk factor that has been identified disturbance, weight loss, heat intolerance, during the assessment phase. and sweating. Frequent physical findings are tachycardia, tremor of the extremities, Treatment of Hyperprolactinemia and weight loss. In conclusion, thyroid Therapeutic strategy for hyperprolactinemia stimulating hormone should be measured must be driven by the underlying etiology when a woman with hypoactive sexual [199]. In symptomatic patients with suspected desire disorder also presents clinical suspi­ drug‐induced hyperprolactinemia, discon­ cion of hypothyroidism [211] or hyperthy­ tinuation of the medication for 4–5 drug half‐ roidism [212]. lives or substitution of an alternative drug, Although several studies indicate that followed by re‐measurement of serum prol­ androgen levels are positively associated with actin is recommended. If the drug cannot be sexual interest and arousal in women (see discontinued and the onset of the hyperprol­ previously), there is no cut‐off level for any actinemia is not temporally coincident with androgen that distinguishes women with/ drug initiation, a pituitary magnetic resonance without normal sexual function. Hence, image should be obtained to exclude the pres­ measurement of androgens is not recom­ ence of pituitary or hypothalamic mass. In mended to diagnose low sexual desire or any contrast, in patients with asymptomatic other female sexual dysfunction. Testosterone medication‐induced hyperprolactinemia, a and sex hormone binding globulin levels are treatment with dopamine agonists is not rec­ only required if considering testosterone ommended, but the use of estrogen in patients therapy. However, since several conditions with long‐term hypogonadism is suggested. (Box 6.1) have been associated with reduced In symptomatic hyperprolactinemia due to testosterone level, their presence should be prolactinoma, treatment with dopamine ago­ carefully evaluated during the assessment nists is currently the gold standard therapy to phase. lower prolactin levels, decrease tumor size, Pathophysiology and Medical Management of Hypoactive Sexual Desire Disorder 83 and restore gonadal function [199]. Among insufficiency, either primary or secondary. In dopamine agonists, cabergoline is the treat­ women presenting with adrenal insufficiency, ment of choice because it has higher efficacy four months of treatment with dehydroepi­ in normalizing prolactin levels and restoring androsterone (50 mg/d) resulted in an normal sexual function, as well as a higher increased frequency of sexual thoughts, frequency of pituitary tumor shrinkage. interest, and satisfaction, as well as improved Cabergoline generally only needs to be well‐being and decreased depression and administered either once or twice per week anxiety [215]. In contrast, many other subse­ due to its extremely long half‐life (weekly quent studies did not confirm these results. dose of 0.5–2.0 mg) [199]. In contrast, asymp­ In 2009, a meta‐analysis demonstrated that tomatic patients due to microprolactinomas dehydroepiandrosterone therapy in adrenal should not be treated with dopamine ago­ insufficiency showed a low‐to‐moderate nists. Pituitary surgery, usually by the transs­ improvement in health‐related quality of life phenoidal approach, is generally reserved for and depressive symptoms, but it had no prolactinoma resistant to maximal tolerable effects on sexual well‐being [216]. Accordingly, doses of dopamine agonists. In 70–90% of a recent guideline of the Endocrine Society patients with hypoactive sexual desire disor­ recommends against the routine prescrip­ der, dopamine agonists lower prolactin levels tion of dehydroepiandrosterone for the treat­ to normalize both hypoactive sexual desire ment of women with low androgen levels due and gonadal function. to hypopituitarism, adrenal insufficiency, surgical menopause, pharmacological gluco­ Treatment of Hypothyroidism/ corticoid administration, or other conditions Hyperthyroidism associated with low androgen levels, because there are limited data supporting clinical Standard treatment for hypothyroidism improvement with therapy [217]. Thus, avail­ involves daily use of the synthetic thyroid able evidence does not support the use of hormone levothyroxin. [211]. This oral medi­ dehydroepiandrosterone in women with or cation restores adequate hormone levels, without adrenal insufficiency. Data on other reversing the signs and symptoms of hypo­ low testosterone conditions like Turner syn­ thyroidism. In contrast, several treatments drome, anorexia nervosa, and hypopituita­ for hyperthyroidism exist. The treatment rism are inadequate to support the use of choice is driven by patient’s age, physical con­ testosterone. dition, underlying cause, and the severity of the hyperthyroidism. First‐line treatment Treatment of Depression or usually involves antithyroid medications, Antidepressant‐Induced Low including propylthiouracil and methimazol, Sexual Desire which gradually reduce symptoms of hyper­ Bupropion has selectivity for inhibition of thyroidism. Symptoms usually begin to the dopamine and norepinephrine reuptake improve in 6–12 weeks but treatment with transporters. It alleviates sexual symptoms antithyroid medications typically continues caused by other antidepressant medication, at least a year and often longer [214]. However, hence providing a potential off‐label it is actually not known whether restoring a approach in the treatment of hypoactive euthyroid state can improve low sexual desire ­sexual desire disorder. A recent placebo‐­ in hypothyroid or hyperthyroid patients. controlled functional magnetic resonance imaging study on healthy subjects receiving Treatment of Conditions Related paroxetine or bupropion demonstrated that to Low Testosterone Level brain regions related to the processing of As stated previously, another condition asso­ emotional and autonomic components of erotic ciated with low androgens levels is adrenal stimulation showed reduced responsiveness 84 Textbook of Female Sexual Function and Dysfunction

under paroxetine but not with bupropion antagonist at 5‐HT1D, 5‐HT3, and 5‐HT7 [218]. A recent systematic review and meta‐ receptors, agonist at 5‐HT1A receptors, and analysis on the effectiveness of bupropion as partial agonist at 5‐HT1B receptors. This an antidepressant identified 51 studies, combined effect increases extracellular con­ dividing into four categories: bupropion as centrations of serotonin, dopamine, and monotherapy for depression; bupropion pre­ noradrenaline [225], and might be responsi­ scribed with another antidepressant; bupro­ ble for the less frequent sexual side effects. In pion in “other” populations (e.g. bipolar a recent randomized, double‐blind trial, depression, elderly populations); and the treatment‐emergent sexual dysfunctions evaluation of the side effects of bupropion. were not significantly different between vor­ More methodologically robust trials demon­ tioxetine (15–20 mg/d) and placebo‐treated strated the superiority of bupropion over pla­ groups [226]. Similar results were demon­ cebo, and most head‐to‐head trials showed strated in double‐blind, placebo‐controlled an equivalent efficacy with other antidepres­ trial with vortioxetine (10–15 mg/d) in sants. Moreover, most of the studies on the depressed patients [226]. Finally, vortioxetine co‐administration of bupropion with another has been recently found to improve escitalo­ antidepressant showed an additional effect pram‐associated sexual dysfunction in [219]. Therefore, it is recommended as an patients with well‐treated major depressive alternative antidepressant treatment without disorder [227]. adverse effects concerning sexual arousal Vilazodone, a selective serotonin reuptake and libido. inhibitor with partial agonist activity at the Some other newer antidepressants have 5‐HT1A receptor, approved for the treatment also been associated with less sexual dys­ of major depressive disorder, has few sexual function. Agomelatine, a stable analog of side effects [228]. Three studies showed that melatonin, is a melatonin receptor agonist treatment with vilazodone 40 mg/d was asso­ and a 5‐HT2C receptor antagonist. A recent ciated with improved sexual function from meta‐analysis demonstrated that agomela­ baseline and limited adverse impact on sex­ tine is an effective antidepressant with simi­ ual function relative to placebo [228]. In a lar efficacy to standard antidepressants [220]. recent phase IV study [229], the efficacy, However, it shows similar rates of sexual dys­ safety, and tolerability of vilazodone (20 and function compared with placebo and lower 40 mg/d) versus placebo were evaluated in rates compared with serotoninergic antide­ patients with major depressive disorder; cit­ pressants [221]. alopram was used as an active control. Across Desvenlafaxine, the major metabolite of treatment groups, baseline sexual function venlafaxine, has recently been associated improved in women and men, major depres­ with greater orgasmic dysfunction in healthy sive disorder responders, and patients with men, but not in a group of healthy women. baseline sexual dysfunction [229]. There were no differences in other sexual Finally, management strategies for antide­ areas (libido and arousal) in comparison with pressant‐related sexual dysfunction include a placebo [222]. An additional randomized progressive reduction of dosage, drug substi­ controlled trial in a depressed population tution, holiday weekends and the use of anti­ treated with desvenlafaxine 50–100 mg/d or dotes [230]. Controlled and open‐label placebo, sexual function was comparable studies demonstrated the efficacy of bupro­ between desvenlafaxine and placebo [223]. pion to reverse antidepressant‐associated Vortioxetine, a new multimodal‐serotonin sexual dysfunction [231]. antidepressant, displays robust procognitive Sexual dysfunction is a frequent long‐term properties in addition to antidepressant side effect of treatment with antipsychotics effects [224]. In addition to its blockade of [232]. A decrease in dopamine activity and serotonin transporter reuptake, it is an D2‐receptor blockade removes the inhibitory Pathophysiology and Medical Management of Hypoactive Sexual Desire Disorder 85 effect of dopamine on prolactin secretion, distress indicated by the Female Sexual thus inducing hyperprolactinemia, which Distress Scale – Revised Item 13, compared might be the main potential determining fac­ to placebo. The most commonly reported tor of antipsychotic‐associated loss of libido adverse effects of flibanserin treatment were [232]. Several antipsychotics induce hyper­ drowsiness (11.8%), vertigo (10.5%), and prolactinemia, such as haloperidol, risperi­ fatigue (10.3%) [234–236], which are gener­ done, paliperidone, and amisulpride, and are ally mild and transient. Bedtime dosing more likely to be associated with low libido. ­mitigates these adverse effects. In contrast, Additionally, a meta‐analysis [233] demon­ these risks increase when the drug is taken strated that significant differences exist during the daytime, with concomitant use of across different antipsychotics with quetia­ cytochrome P‐450 3A4 inhibitors (i.e. some pine, ziprasidone, perphenazine, and ari­ antiretroviral drugs, antihypertensive drugs, piprazole being less or not related to sexual antibiotics, and fluconazole, which increases dysfunction (16–27%), while olanzapine, ris­ systemic exposure to flibanserin by a factor peridone, haloperidol, and clozapine were of 4.5–7), and with significant alcohol use. associated with higher sexual dysfunction This last interaction is based on the results of rates (40–60%). alcohol‐challenge study showing an increase in sedation, syncope, and hypotension in the Treatments for Hypoactive Sexual treatment group, although alcohol was not Desire Disorder restricted in the three major pivotal trials, and increases in these adverse effects were Apart from psychological interventions not found. As a result, the FDA required a ­discussed in the previous chapter, important boxed warning and an alcohol contraindica­ treatment options for women with hypoactive tion, and a postapproval risk evaluation man­ sexual desire disorder consist of either the use agement strategy that requires health‐care of central nervous system agents or hormonal prescribers and pharmacies to become certi­ therapy, following the process of care [213]. fied to prescribe or dispense the medication. The first of three FDA‐required postmarket­ Central Nervous System Agents ing alcohol studies included 96 healthy pre­ Flibanserin, the only Food and Drug menopausal women who were randomized Administration (FDA) approved drug for to 1 of 12 sequence groups for seven treat­ acquired (at least to the time of writing this ments: flibanserin 100 mg or placebo with chapter), generalized hypoactive sexual ethanol 0.6 g/kg, 0.4 g/kg, or 0.2 g/kg or fli­ desire disorder in premenopausal women, is banserin 100 mg only. Dizziness with fliban­ a serotonin 1A receptor agonist and a seroto­ serin plus alcohol was 39.8%, 34.1%, and nin 2A receptor antagonist thought to 27.4% respectively, and 31.3% with fliban­ increase dopamine and norepinephrine and serin alone. There was no effect of ethanol decrease serotonin activity in the brain. The concentration on orthostatic blood pressure, effectiveness of the 100 mg bedtime dose of vertigo, hypotension, or somnolence, and no flibanserin was evaluated in three 24‐week syncope was observed [237]. randomized, double‐blind, placebo‐­ Other central nervous system active controlled trials involving over 3500 premen­ agents, approved for indications other than opausal women (mean age 36 years) with hypoactive sexual desire disorder, are used acquired, generalized hypoactive sexual off‐label for the treatment of hypoactive sex­ desire disorder. In these three pivital phase 3 ual desire disorder. Bupropion, approved studies (Violet, Daisy, Begonia) [234–236], as an antidepressant, has demonstrated flibanserin increased satisfying sexual events improvement in sexual desire in premeno­ and sexual desire as measured by the Female pausal women with hypoactive sexual desire Sexual Function Index, with a reduction in disorder at doses of 300–400 mg/d [238]. 86 Textbook of Female Sexual Function and Dysfunction

Finally, in case reports and one small open descending order were application site reac­ label trial, trazodone, a heterocyclic antide­ tions, acne, breast pain, headache, and hir­ pressant with 5‐HT1A agonist, 5‐HT2A and sutism. Other than blood testosterone levels, α1‐adrenergic receptor antagonist proper­ laboratory findings (liver function tests, ties, has been reported to increase sexual hematology, lipid profiles, clotting measures, desire in postmenopausal, nondepressed and carbohydrate metabolism) remained women with sleep and sexual complaints essentially unchanged from baseline and did [239–241]. not differ among treatment groups. The Food and Drug Administration withheld Hormonal Management of Hypoactive approval of the 300 µg/d testosterone patch Sexual Desire Disorder (Off‐Label based on concerns about long‐term negative in United States) effects that were not demonstrated in clinical As previously discussed, although low levels use in the European Union. In fact, in a 12‐ of androgens, including total and free testos­ month randomized controlled trial of a terone, androstenedione, and dehydroepian­ transdermal testosterone product (150 or drosterone sulfate, have been associated with 300 mg/d) or placebo in 814 naturally and low sexual desire [107, 242, 243] (no cutoff surgically menopausal women not taking level of these serum hormones has been estrogen supplementation, 300 µg/d trans­ established to identify women with hypoac­ dermal testosterone increased and sustained tive sexual desire disorder). Moreover, evi­ the number of satisfactory sexual events and dence does not support the routine use of was safely administered [248]. Data regard­ systemic testosterone or other androgens ing the safety of testosterone in long‐term (for example dehydroepiandrosterone) in studies (up to four years’ duration) raised no women suffering from conditions associated concerns [249]. with low androgen levels (Box 6.1) [216, 244]. When serum levels of testosterone are Accordingly, a recent meta‐analysis showed maintained within the normal range for pre­ that systemic dehydroepiandrosterone treat­ menopausal women with a variety of sexual ment was not effective in improving libido complaints, short‐term safety data are reas­ and sexual function in postmenopausal suring [217, 248–251]. Presence of hirsutism, women with normal adrenal function [244]. androgenic alopecia, and/or acne are contra­ In contrast, compelling evidence consist­ dictions to testosterone therapy. No increased ently demonstrates that high physiologic breast cancer risk has been observed for cur­ doses of testosterone therapy improve desire, rent or past users [252–254] of parenteral arousal, vaginal blood flow, orgasm fre­ testosterone therapy. quency, and sexual satisfaction in surgically According to the recent Endocrine Society and naturally menopausal women either Guideline, a 3–6‐month trial of testosterone alone or in combination with menopausal treatment is suggested in postmenopausal estrogen therapy [110, 245–247]. In 24‐week women suffering from hypoactive sexual phase 3 clinical trials in naturally and surgi­ desire disorder [217]. However, testosterone cally postmenopausal women with hypoac­ formulations for women are not globally tive sexual desire disorder, the 300 µg/d available, so the use of testosterone prepara­ testosterone patch was found to significantly tions formulated for men or those formu­ improve sexual desire as measured by the lated by pharmacies can easily lead to Profile of Female Sexual Function and fre­ supraphysiological concentrations and viri­ quency of satisfying sexual events versus pla­ lization (acne, hirsutism, voice deepening, cebo. Level of sexually‐related distress using clitoromegaly, and androgenic alopecia) the Personal Distress Scale also decreased [217]. Therefore, if testosterone therapy is but did not differ significantly from placebo. prescribed, measurement of testosterone The most common adverse events in levels is recommended at baseline and every Pathophysiology and Medical Management of Hypoactive Sexual Desire Disorder 87 six months thereafter to identify supraphys­ moderate benefit, but when pain was consid­ iologic levels. ered tibolone showed no effect to a small Tibolone, a selective estrogen receptor benefit [144], not unexpected with improve­ modulator, appears to exert weak estrogen, ments in vaginal atrophy with a selective progestogen and/or androgen activities estrogen receptor modulator. Therefore, [255]. One of the major metabolites of tibo­ tibolone does not appear to have an inde­ lone is weakly androgenic and tibolone low­ pendent effect on sexual desire. ers sex hormone binding globulin, resulting in an increase in endogenous free testoster­ one, so it has been proposed as a potential ­Conclusions off‐label treatment for hypoactive sexual desire disorder. A recent meta‐analysis Neuroendocrine function associated with showed that, in symptomatic or early post­ excitation and inhibition of sexual desire menopausal women, tibolone appeared to should be fully evaluated and modifiable fac­ have no effect to a small benefit on overall tors addressed. Specific treatments may sexual function versus the control. Other improve sexual desire in women with hypo­ subpopulation analyses have suggested a active sexual desire disorder.

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J Clin Endocrinol Metab. 2009;94(10): vortioxetine in the treatment of major 3676–3681. depressive disorder. Neuropsychiatr Dis 217 Wierman M, Arlt, W, Basson, R, et al. Treat. 2014;10:1297–1307. Androgen therapy in women: a 226 Mahableshwarkar A, Jacobsen PL, reappraisal: an endocrine society clinical Serenko M, et al. A randomized, double‐ practice guideline. J Clin Endocrinol blind, placebo‐controlled study of the Metab. 2014;99:2489–3510. efficacy and safety of 2 doses of 218 Abler B, Seeringer A, Hartmann A, et al. vortioxetine in adults with major Neural correlates of antidepressant‐ depressive disorder. J Clin Psychiatry. related sexual dysfunction: a placebo‐ 2015;76:583–591. controlled fMRI study on healthy males 227 Jacobsen P, Mahableshwarkar AR, Chen Y, under subchronic paroxetine and et al. Effect of vortioxetine vs. bupropion. Neuropsychopharmacology. escitalopram on sexual functioning in 2011;36:1837–1847. adults with well‐treated major depressive 219 Patel K, Allen S, Haque MN, et al. disorder experiencing SSRI‐induced Bupropion: a systematic review and sexual dysfunction. J Sex Med. meta‐analysis of effectiveness as an 2015;12(10):2036–2048. antidepressant. Ther Adv 228 Clayton A, Kennedy SH, Edwards JB, et al. Psychopharmacol. 2016;6(2):99–144. The effect of vilazodone on sexual 220 Taylor D, Sparshatt A, Varma S, function during the treatment of major Olofinjana O. Antidepressant efficacy of depressive disorder. J Sex Med. agomelatine: meta‐analysis of published 2013;10(10):2465–2476. and unpublished studies. Br Med J. 229 Clayton A, Gommoll C, Chen D, et al. 2014;348:g1888–1907. Sexual dysfunction during treatment of 221 Montejo A, Majadas S, Rizvi SJ, Kennedy major depressive disorder with SH. The effects of agomelatine on sexual vilazodone, citalopram, or placebo: function in depressed patients and healthy results from a phase IV clinical trial. Int volunteers. Hum Psychopharmacol. Clin Psychopharmacol. 2011;26(8):537–542. 2015;30(4):216–223. 222 Clayton A, Reddy S, Focht K, et al. An 230 Keks N, Hope J, Culhane C. Management evaluation of sexual functioning in of antidepressant‐induced sexual employed outpatients with major dysfunction. Australas Psychiatry. depressive disorder treated with 2014;22:525–528. desvenlafaxine 50 mg or placebo. J Sex 231 Zisook S, Rush AJ, Haight BR, et al. Use of Med. 2013;10:768–776. bupropion in combination with serotonin 223 Clayton A, Hwang E, Kornstein SG, et al. reuptake inhibitors. Biol Psychiatry. Effects of 50 and 100 mg desvenlafaxine 2006;59:203–210. versus placebo on sexual function in 232 González‐Blanco L, Greenhalgh AM, patients with major depressive disorder: a Garcia‐Rizo C, et al. Prolactin meta‐analysis. Int Clin Psychopharmacol. concentrations in antipsychotic‐naïve 2015;30(6):307–315. patients with schizophrenia and related 224 Sanchez C, Asin KE, Artigas F. disorders: A meta‐analysis. Schizophr Res. Vortioxetine, a novel antidepressant with 2016;174(1–3):156–160. multimodal activity: Review of preclinical 233 Serretti A, Chiesa A. A meta‐analysis of and clinical data. Pharmacol Ther. sexual dysfunction in psychiatric patients 2015;145:43–57. taking antipsychotics. Int Clin 225 Alvarez E, Perez V, Artigas F. Psychopharmacol. 2011;26(3): Pharmacology and clinical potential of 130–140. Pathophysiology and Medical Management of Hypoactive Sexual Desire Disorder 99

234 Derogatis L, Komer L, Katz M, et al. 2014/12/06. doi: 10.1111/jsm.12774. Treatment of hypoactive sexual desire PubMed PMID: 25475395. disorder in premenopausal women: 244 Elraiyah T, Sonbol, MB, Wang, Z, et al. efficacy of flibanserin in the VIOLET Clinical review: The benefits and harms of Study. J Sex Med. 2012;9(4):1074–1085. systemic dehydroepiandrosterone 235 Thorp J, Simon J, Dattani D, et al. (DHEA) in postmenopausal women with Treatment of hypoactive sexual desire normal adrenal function: a systematic disorder in premenopausal women: review and meta‐analysis. J Clin efficacy of flibanserin in the DAISY study. Endocrinol Metab. 2014; J Sex Med. 2012;9(3):793–804. 99(10):3536–3542. 236 Katz M, DeRogatis, LR, Ackerman, R, 245 Simon J, Braunstein G, Nachtigall L, et al. et al. Efficacy of flibanserin in women Testosterone patch increases sexual with hypoactive sexual desire disorder: activity and desire in surgically results from the BEGONIA trial. J Sex menopausal women with hypoactive Med. 2013;10:1807–1815. sexual desire disorder. J Clin Endocrinol 237 Sicard E, Raimondo D, Vittitow J, et al. Metab. 2005;90(9):5226–5233. Effect of alcohol administered with 246 Braunstein G, Sundwall DA, Katz M, et al. flibanserin on dizziness, syncope, Safety and efficacy of a testosterone patch and hypotension in healthy for the treatment of hypoactive sexual premenopausal women. 23rd Congress desire disorder in surgically menopausal of the World Association for Sexual women. Arch Intern Med. Health; Prague, 2017. 2005;165:1582–1589. 238 Segraves R, Clayton, A, Croft, H, et al. 247 Shifren J, Davis S, Moreau M, et al. Bupropion sustained release for the Testosterone patch for the treatment of treatment of hypoactive sexual desire hypoactive sexual desire disorder in disorder in premenopausal women. J Clin naturally menopausal women: Results Psychopharmacol. 2004;24:339–342. from the INTIMATE NM1 Study. 239 Eraslan D, Ertekin E, Ertekin BA, Oztürk Menopause. 2006;13(5):770–779. O. Treatment of insomnia with hypnotics 248 Davis S, Moreau, M, Kroll, R, et al. resulting in improved sexual functioning Testosterone for low libido in menopausal in post‐menopausal women. Psychiatr women not taking estrogen therapy. N Danub. 2014;26(4):353–357. Eng J Med. 2008;359:2005–2017. 240 Medina C. Clitoral priapism: a rare 249 Nachtigall L, Casson P, Lucas J, et al. condition presenting as a cause of vulvar Safety and tolerabililty of testosterone pain. Obstet Gynecol. patch therapy for up to 4 years in 2002;100:1089–1091. surgically menopausal women receiving 241 Michael A, O’Donnell EA. Fluoxetine‐ oral or transdermal oestrogen. Gynecol induced sexual dysfunction reversed by Endocrinol. 2011;27(1):39–48. trazodone. Can J Psychiatry. 250 Davis S, Hirschberg, AL, Wagner, LK, 2000;45:847–848. et al. The effect of transdermal 242 Davis S, Davison SL, Donath S, Bell RJ. testosterone on mammographic density in Circulating androgen levels and self‐ postmenopausal women not receiving reported sexual function in women. systemic estrogen therapy. J Clin JAMA. 2005;294:91–96. Endocrinol Metab. 2009;94:4907–4913. 243 Wahlin‐Jacobsen S, Pedersen AT, 251 Davis S. Cardiovascular and cancer safety Kristensen E, et al. Is there a correlation of testosterone in women. Curr Opin between androgens and sexual desire in Endocrinol Diabetes Obe. women? J Sex Med. 2014. Epub 2011;18:198–203. 100 Textbook of Female Sexual Function and Dysfunction

252 Dimitrakakis C, Jones, R, Liu, A, et al. 254 Glaser RL, Dimitrakakis C. Reduced Breast cancer incidence in breast cancer incidence in women treated postmenopausal women using with subcutaneous testosterone, or testosterone in addition to usual testosterone with anastrozole: A hormone therapy. Menopause. prospective, observational study. 2004;11(5):531–535. Maturitas. 2013;76:342–349. 253 Davis S, Wolfe R, Farrugia H, et al. The 255 Modelska K, Cummings S. Tibolone for incidence of invasive breast cancer among postmenopausal women: systematic women prescribed testosterone for low review of randomized trials. J Clin libido. J Sex Med. 2009;6:1850–1856. Endocrinol Metab. 2002;87(1):16–23. 101

Part II

Arousal Disorders

Chapter No.: 1 Title Name: p02.indd Comp. by: Date: 22 Mar 2018 Time: 11:29:47 AM Stage: WorkFlow: Page Number: 101 103

7

Nosology and Epidemiology of Arousal Disorders in Women Leonard R. Derogatis

Abstract

This chapter reviews the history and development of the diagnosis female sexual arousal disorder (FSAD) and discusses its close ties to the evolution of the diagnostic system of the American Psychiatric Association (i.e. DSM‐I to DSM‐5). It reviews the principal criteria underlying the diagnosis and their underlying significance. The chapter also discusses the widespread dissatisfaction with the current DSM‐5 system, and the development, in response, of the new ISSWSH diagnostic ­system for female sexual dysfunctions. Diagnostic standards for the FSAD diagnosis in the ISSWSH sys- tem are described and elucidated as an alternative to the DSM‐5 system. In addition, the chapter provides a brief review of the current status of epidemiological research focused on the prevalence of FSAD as defined in contemporary nosological systems.

Keywords: diagnosis; prevalence; nosology; nomenclature; FSD; FSAD

­Nosology DSM‐III [2], a superordinate category of “psychosexual disorders” was introduced, of As with other categories of female sexual dys- which “Inhibited sexual excitement” was one function, the formal nosologic definition of constituent category. Inhibited sexual excite- arousal disorders in women has evolved over ment was defined as: “Recurrent and persis- time with the progression of the Diagnostic tent inhibition of sexual excitement during and Statistical Manual of Mental Disorders sexual activity”. The principal manifestation (DSM) diagnostic system. Female sexual was, “…complete failure to attain or maintain arousal disorder (FSAD) began in a relatively the lubrication‐swelling response of sexual undifferentiated state as one of a number of excitement until the completion of the sexual categories of “psychophysiological autonomic act” (p. 156). This characterization focused and visceral disorders” termed “psychophysi- exclusively on genital response and charac- ological genitourinary reactions” [1]. The sec- terizes the first clear representation of ond iteration of the DSM as it relates to arousal dysfunction in the woman. female sexual arousal disorder maintained With the DSM‐III‐R [3], published seven this undifferentiated delineation, “psycho- years later, the label of the superordinate cat- physiological genitourinary reactions” [1]. egory was modified to simply “sexual dys- It was not until the DSM‐III [2] in 1980 functions”, and the label of “female sexual that significant nosological changes appeared arousal disorder” was first introduced. In this in female sexual arousal disorder. In the edition, the woman could manifest the

Textbook of Female Sexual Function and Dysfunction: Diagnosis and Treatment, First Edition. Edited by Irwin Goldstein, Anita H. Clayton, Andrew T. Goldstein, Noel N. Kim, and Sheryl A. Kingsberg. © 2018 John Wiley & Sons Ltd. Published 2018 by John Wiley & Sons Ltd. 104 Textbook of Female Sexual Function and Dysfunction

­condition in one of two ways: either, “persis- ­dissatisfaction with the DSM‐5 nomencla- tent or recurrent complete or partial failure ture for female sexual dysfunction has to attain or maintain the lubrication‐swelling ­ultimately served as a strong influence in response of sexual excitement until comple- bringing about the development of the new tion of the sexual activity”, or “persistent or more rigorous and scientific ISSWSH recurrent lack of a subjective sense of sexual ­nosology [8] for female sexual dysfunction. excitement and pleasure during sexual As has been outlined in detail [8], there ­activity” (p. 165). Thus, a cognitive‐subjec- have been numerous previous attempts to tive component was introduced for women define female sexual arousal disorder, some that was also present in the male definition of focused solely on genital physiology, others arousal disorder. In addition, the generic concentrating on the subjective emotional specifiers of “lifelong versus acquired” and response, and still others featuring a com- “generalized versus situational” were intro- bined genital and subjective/emotional duced in the DSM‐III‐R. response. Each definition carries with it both In the DSM‐IV [4], the definition of female strengths and weaknesses, which are too sexual arousal disorder again returned to an numerous to examine here. exclusively physical genital portrayal. It was The new ISSWSH nosology defines female described as: “a persistent or recurrent ina- genital arousal disorder (FGAD) as follows: bility to attain or maintain until completion “Female genital arousal disorder is defined as of the sexual activity, an adequate lubrica- the inability to develop or maintain an ade- tion‐swelling response of sexual excitement” quate genital response, including vulvovagi- (p. 500). In addition, a second criterion, the nal lubrication, engorgement of the genitalia, required presence of “manifest personal dis- and sensitivity of the genitals associated with tress” was added at this time. The specifiers, the sexual activity for a minimum of six lifelong/acquired and generalized/situational months” (p. 8) [8]. Subcategories are identi- were characterized as specifying subtypes in fied as (i) related to vascular injury or this edition. ­dysfunction and/or (ii) neurological injury or The DSM‐5 [5] does not represent arousal dysfunction. Clinically significant personal disorder as a distinct diagnostic entity, but distress remains a required feature of the rather merges it with hypoactive sexual presentation, and previous traditional speci- desire disorder, to create the combined diag- fiers from the DSM‐IV and DSM‐5 remain as nostic entity female sexual interest/arousal aspects of the new definition as well. disorder (FSIAD). The diagnosis requires An exclusionary caution is appended to the that the patient manifest at least three of six diagnosis of female genital arousal disorder possible diagnostic characteristics for a mini- involving the conditions of vulvovaginal mum period of at least six months, and that atrophy, vulvovaginal infection, inflamma- these symptoms be accompanied by manifest tory disorders of the vulva or vagina, vestibu- personal distress. In addition, the level of lodynia and clitorodynia. Any of these severity of the condition must be specified by conditions would preclude a specific diagno- characterizing it as “mild”, “moderate” or sis of female genital arousal disorder. “severe”. A strength of the diagnostic category of The introduction of the diagnosis of female female genital arousal disorder is that meas- sexual interest/arousal disorder in the DSM‐5 urement of the vascular and neural status of has been met with a substantial measure of the patient may be achieved by much more concern by experts in the area of sexual med- precise objective instruments that provide icine [6, 7]. Difficulties with the merged diag- highly reliable ratio scale measurement as nostic indication have been reviewed in other compared to questionnaire‐based assess- sections of this book (Chapter 3). However, ments. Evaluations of the complex subjective‐ to focus on a more positive perspective, emotional status of the patient are avoided in Nosology and Epidemiology of Arousal Disorders in Women 105 this definition, thereby avoiding a controver- ual arousal disorder was the PRESIDE study sial component of prior female sexual arousal conducted by Shifren [9] and her colleagues, disorder definitions. Although there should who surveyed over 31,000 respondents from be no problem in implementing these assess- over 50,000 US households. In PRESIDE, the ments in clinical trials and research protocols, unadjusted prevalence of the problem of low it is true that the instruments required for sexual arousal, regardless of the presence of these measurements are not typically found in distress, was 26.1%. The overall prevalence of the practitioner’s office. However, a careful low arousal with distress was 5.4%, with the history and clinical examination will enable a intermediate age subgroup (45–64 years) diagnosis to be made in most instances. having the highest prevalence of 7.5%, and the youngest age group having the lowest prevalence of 3.3%. The oldest age group ­Epidemiology (≥65) had a prevalence of 6.0%. Hayes [10] and colleagues published a The epidemiology of female sexual arousal review in 2006 of female sexual difficulties in disorder suffers from the same limitations as which they attempted to integrate informa- other diagnostic categories of female sexual tion on duration of the difficulty into their dysfunction: imprecise nomenclature, equiv- analysis. Only 11 out of 1248 studies met ocal diagnostic criteria, and nonstandardized their inclusion criteria and only two of them study designs or outcomes measurement. In included a distress criterion. Based on this addition, as with other categories of female data, 31% of the women experienced sexual sexual dysfunction, there is the introduction arousal difficulties with distress and 28% of the disjunctive personal distress criterion experienced difficulties with a duration of that separates prevalence rates into those ≥6 months. The authors indicated that while estimated with a distress criterion as part of rates of the specific types of sexual difficul- the diagnostic definition and those where the ties varied widely, a consistent pattern distress criterion is omitted. The distress cri- emerged across the studies with prevalence terion has become a pivotal element of con- rates decreasing from desire > orgasm > arous- temporary approaches to female sexual al > pain. dysfunction nomenclature, distinguishing Obviously, it is too soon to have any data between true cases of persistent dysfunction available on the prevalence rates of the new versus transient sexual difficulty. Thus, only diagnostic categories in the ISSWSH nosol- epidemiological studies that include the dis- ogy; however, because of the articulation of tress criterion are discussed here. much more rigorous criterion and use of As was the case with hypoactive sexual explicit specifiers, it is anticipated that preva- desire disorder, the most comprehensive lence data will be more precise and reliable recent study of the prevalence of female sex- than historical estimates have been in the past.

­References

1 American Psychiatric Association. The 3 American Psychiatric Association. DSM‐III‐R: Diagnostic and Statistical Manual of Mental Diagnostic and Statistical Manual of Mental Disorders. Washington, DC: American Disorders. 3rd edn Revised. Washington, DC: Psychiatric Association; 1952. American Psychiatric Association; 1987. 2 American Psychiatric Association. DSM‐III: 4 American Psychiatric Association. DSM‐IV: Diagnostic and Statistical Manual of Mental Diagnostic and Statistical Manual of Mental Disorders. 3rd edn. Washington, DC: Disorders. 4th Ed. Washington, DC: American Psychiatric Association; 1980. American Psychiatric Association; 1994. 106 Textbook of Female Sexual Function and Dysfunction

5 American Psychiatric Association. DSM‐5: 8 Parish SJ, Goldstein AT, Goldstein SW, Diagnostic and Statistical Manual of Mental et al. Toward a more evidence‐based Disorders. 5th edn. Washington, DC: nosology and nomenclature for female American Psychiatric Association; 2013. sexual dysfunctions – Part II. J. Sex. Med. 6 Clayton AH, Derogatis LR, Rosen R, et al. 2016;13:1888–1906. Does clinical research data support sexual 9 Shifren JL, Monz BU, Russo PA, et al. desire and arousal disorders as distinct Sexual problems and distress in United diagnoses? J Sex Med. 2010;7(S3):143–144. States women: prevalence and correlates. 7 Derogatis LR, Clayton AH, Rosen R, et al. Obstet Gynecol. 2008;112(5):970–978. Do multiple convergent measures of female 10 Hayes RD, Bennett CM, Fairly CK, et al. sexual dysfunction support sexual desire and What can prevalence studies tell us about arousal disorders as distinct diagnoses? J Sex female sexual difficulty and dysfunction. Med. 2010;7(S3):142–143. J. Sex. Med. 2006;3:589–595. 107

8

Anatomy and Physiology of Arousal Kwangsung Park and Noel N. Kim

Abstract

Sexual arousal is a physiological response to internal and external stimuli and is mediated by both central and peripheral nervous systems. This chapter focuses specifically on genital arousal, which is characterized by changes in sensation, tissue contractility, vasocongestion, and lubrication. The physiological events of the sexual arousal response in women are related to the structural integrity of genital tissues and the function of vascular, neural, and hormonal systems. The strongest evi- dence, thus far, indicates that the adrenergic and nitric oxide signaling systems play important roles in acutely regulating genital blood flow but sex steroid hormones are also critical for maintaining genital tissue health. The additive, synergistic or antagonistic interactions of cellular processes will ultimately determine the overall physiological responses manifested as blood flow, lubrication or tissue contractility.

Keywords: sexual arousal; genital engorgement; parasympathetic; nonadrenergic noncholinergic; nitric oxide; vasoactive intestinal polypeptide; vaginal lubrication; aquaporin; androgen; estrogen

Sexual arousal is a physiological response to internal and external stimuli and is mediated by both central and peripheral nervous systems. Genital arousal is characterized by changes in sensation, tissue contractility, vasocongestion, and lubrication. Neural, endocrine, and vascular factors affect specific and distinct cellular components within genital tissues to maintain their function.

­Introduction physiological changes in the genitals include vulvovaginal lubrication (vaginal fluids and Sexual arousal comprises both genital and secretions of paraurethral and Bartholin’s extragenital responses that anticipate sexual glands), genital engorgement, and increased activity and continue up to the point of sensitivity of the genitalia. Extragenital orgasm [1–4]. These responses result from changes include erection of the nipples, flush- the processing of internal stimuli (e.g., dreams, ing of the skin, and increases in heart rate, fantasies, memories, love, intimacy needs, blood pressure, and respiration rate. libido) and external stimuli (e.g., auditory, While subjective arousal has been assessed visual, olfactory, tactile), leading to increased in clinical studies apart from the physical activity in the central and peripheral nervous responses of genital arousal, recent expert systems (Figure 8.1) [5, 6]. Characteristic opinion has raised the possibility that subjective

Textbook of Female Sexual Function and Dysfunction: Diagnosis and Treatment, First Edition. Edited by Irwin Goldstein, Anita H. Clayton, Andrew T. Goldstein, Noel N. Kim, and Sheryl A. Kingsberg. © 2018 John Wiley & Sons Ltd. Published 2018 by John Wiley & Sons Ltd. 108 Textbook of Female Sexual Function and Dysfunction

Internal Perception of a External stimuli SEXUAL stimuli STIMULUS Dreams, fantasies, Olfactory, tactile, memories, love, gustative, physical drive PSYCHOPLASTICITY auditive, visual NEUROPLASTICITY Modulated by Sexual hormones

AUTONOMIC EMOTIONAL MOTOR COGNITIVE System AFFECTIVE System System System

GENITAL, BEHAVIORAL AND CLINICAL CORRELATES

Figure 8.1 Physiology of sexual desire/interest and central arousal. (Adapted from [6].) (See plate section for color representation of the figure)

arousal can be more consistently understood structural integrity of genital tissues and the as a manifestation of sexual desire [7; also see ­function of vascular, neural, and hormonal Chapter 4, Desire: CNS Anatomy and systems [16, 17]. Thus, relevant anatomy will Neurochemistry of Sexual Desire]. This per- be integrated into discussions of mechanism. spective arises from several lines of evidence that suggest that women often conflate their experience of sexual arousal and desire [8] ­Hemodynamic and, generally, have less cognitive awareness of their own genital arousal that is an auto- Considerations for Genital nomic response and can occur in the absence Sexual Arousal of subjective arousal [9–11]. In part, this dis- cordance may be a function of decreased The genital arousal response is manifested by proprioception of internal genital organs in increased blood flow to the genital tissues, women, as evidenced by the observation that which results in clitoral engorgement and subjective sexual arousal is more strongly accompanying vulvar swelling [18–20]. With correlated with vulvar blood flow than vagi- sexual stimulation, increased blood flow to nal vasocongestion [12]. Further, men (who the clitoral cavernosal and labial arteries have full visual and sensory feedback from results in increased clitoral intracavernosal their genitals) have a higher degree of con- pressure, protrusion of the glans clitoris, and cordance between subjective sexual arousal engorgement of the labia minora [21, 22]. The and genital arousal when compared to clitoris is an important organ for female sex- women [13–15]. However, other mechanistic ual arousal and the contemporary under- explanations cannot be ruled out and the standing of clitoral anatomy is the functional nature of subjective sexual arousal remains entity of the clitoral complex, composed of under active investigation. the distal vagina, urethra, and clitoris [18]. This chapter focuses exclusively on the This functional grouping of tissues has also mechanisms regulating genital sexual arousal. been termed the “clitoral urethral complex” The physiologic events of the sexual arousal [23] or “clitourethrovaginal complex” [24]. response in women are related to the These associated structures have c­ommon Anatomy and Physiology of Arousal 109

Lamina Epithelium Propria Muscularis Adventitia (Inner circular, outer longitudinal) Vaginal contractility & tone

Mucification Neurotransmitter content & distribution Keratinization

Permeability Blood vessel growth & reactivity

Blood flow

Lubrication Artery

Vaginal lumen

Nerve

Figure 8.2 Interaction between cellular constituents of the vagina and the physiological processes mediated by them. (Adapted from [17].) vasculature and innervation and move in The vagina consists of distinct layers of unity during sexual activity [19, 24]. ­tissue defined by the epithelium, lamina Magnetic resonance imaging technology propria, muscularis, and the adventitia has enabled better access to understanding (Figure 8.2). The vagina also has an extensive the female sexual response. Dynamic mag- vascular network, primarily within the lam- netic resonance imaging scans of pelvis and ina propria (submucosal) layer and vaginal genitals showed a change in engorgement engorgement is critical for the production of that occurred within three minutes of audio- lubricating fluids during sexual arousal visual sexual stimulation and reached a peak (Figure 8.2) [27]. Vascular corrosion cast level at about nine minutes [25, 26]. The clit- studies in rats have demonstrated that the oral volume can be increased by 50–300% subepithelial region of the vagina contains a when engorged [25]. Engorgement of the dense and rich network of capillaries that clitoris is achieved with minimal corporal perfuse the epithelium and larger venous veno‐occlusion. This is consistent with the sinuses that can functionally imbue the function of the clitoris, which is primarily a vagina with erectile tissue‐like qualities [28]. sensory organ that engorges during sexual Noninvasive anatomical study of the vaginal activity. Only in the pathologic state of clito- microvessel architecture showed that the ral priapism is there significant corporal vaginal microcirculation consisted of homog- veno‐occlusion. enously distributed hairpin‐shaped capillary 110 Textbook of Female Sexual Function and Dysfunction

loops [29]. In the nonaroused state, this tissue and intravaginal injection of α‐adrenergic microcirculation of the vagina exhibits a receptor antagonists causes a marked phenomenon called vasomotion (detected as increase in the amplitude and duration of the pseudorandomly distributed low and high engorgement response with and without pel- amplitude signals by photoplethysmography) vic nerve stimulation [39, 48–50]. In clinical that decreases when vaginal blood flow studies, the α1‐adrenergic receptor antagonist increases during sexual stimulation [30]. phentolamine has been reported to improve While this serves as a sensitive measure of vaginal lubrication in postmenopausal sexual arousal in research studies, the clinical women with female sexual arousal disorder significance of this phenomenon remains to [51] while the α2‐adrenergic receptor agonist be determined. clonidine impaired both vaginal engorge- ment and subjective sexual response when administered to healthy volunteers [52]. ­Neural Regulation of Sexual Interestingly, mild systemic activation of Arousal the sympathetic system (15–30 minutes pos- texercise) can also facilitate the genital arousal Increased activation of the autonomic nerv- response in women [53]. While exercise‐ ous system stimulates parasympathetic out- induced sympathetic activation by itself does flow from the sacral nerves (S2, S3, S4) to not cause increased vaginal engorgement, allow genital engorgement and vaginal lubri- moderate sympathetic activation followed by cation. Stimulation of sympathetic activity visual sexual stimulation enhances vaginal causes increases in heart rate and blood pres- blood volume and vasocongestion to a greater sure, as well as activation of striated muscle extent than visual sexual stimulation alone that participates in sexual activity. Within [54]. In healthy women, it is likely that erotic female genital tissues, multiple studies have stimulation specifically results in relaxation demonstrated the presence of adrenergic, of smooth muscle within the genital organs, cholinergic and nonadrenergic noncholiner- even in the face of increased systemic sympa- gic (NANC) neurotransmitters (neuropep- thetic output. Elevated systemic blood pressure tide Y, vasoactive intestinal polypeptide, and positive chronotropic/inotropic effects peptide histidine methionine, nitric oxide, on the heart, secondary to moderate sympa- calcitonin gene‐related peptide, substance P) thetic activation, would facilitate genital [31–47]. While the roles of each of these neu- engorgement by increasing the pressure gra- rotransmitters remains incompletely charac- dient between the larger resistance arteries terized, the strongest evidence, thus far, and the local genital circulation. indicates that the adrenergic and nitric oxide signaling systems play important roles in reg- Nitrergic Regulation of Genital ulating genital blood flow. Arousal

Adrenergic Regulation of Genital Studies have demonstrated the presence of Arousal neuronal and endothelial nitric oxide syn- thase (NOS) in clitoral and vaginal tissues, as In the basal, nonstimulated state, norepi- well as functional changes to blood flow after nephrine from sympathetic nerve terminals administration of drugs that interfere with constricts vascular and nonvascular smooth nitric oxide synthesis/signaling or nitric muscle to maintain low genital blood flow oxide‐liberating compounds [33, 40, 48, and a high degree of tone to the vaginal wall. 55–61]. In human vaginal tissue, immunore- In vitro and in vivo animal studies have dem- activity for phosphodiesterase type 5 was onstrated the presence of functional α1‐ and localized in the endothelium and smooth α2‐adrenergic receptors in vaginal and clitoral muscle of blood vessels [57]. Anatomy and Physiology of Arousal 111

In addition, vaginal and clitoral smooth Neuropeptide Y has been detected at rela- muscle cells in culture have been shown to tively high concentrations in human, rabbit, express phosphodiesterase type 5 [62, 63]. and rat vagina [34, 38, 74–76]. Due to its Clinical studies have shown that in healthy ­primary localization within nerve fibers near women, the phosphodiesterase type 5 inhib- blood vessels, it has been postulated that itor sildenafil significantly improved arousal, neuropeptide Y regulates blood flow in the orgasm, and enjoyment when compared vagina. In isolated tissue studies, neuropep- with placebo [64–67]. However, other tide Y was shown to constrict small arteries ­clinical studies have shown no improvement from human cervix and have an additive in women’s sexual function [68, 69]. Thus, effect to norepinephrine [74], suggesting that while the physiological significance of the neuropeptide Y has vasoconstrictor activity nitric oxide‐cyclic GMP system is well estab- and may have a similar function in the vagina. lished, the clinical efficacy of phosphodies- While substance P and calcitonin gene‐ terase type 5 inhibitors in treating female related peptide are known to be involved pri- sexual dysfunction may depend upon appro- marily in sensory pathways, these peptide priate screening and identification of neurotransmitters have been shown to medi- patients most likely to benefit from such ate vasodilation in specific vascular beds of therapy. the brain and ovaries [77, 78]. Their roles in modulating the sexual arousal response Regulation of Genital Arousal by remain to be elucidated. other Nonadrenergic Noncholinergic (NANC) Afferent Pathways Influencing Neurotransmitters Genital Arousal

With regard to other nonadrenergic non- Sensory input from the genitals can initiate cholinergic neurotransmitters, several and/or propagate the arousal response. reports have suggested that exogenous Different genital tissues and organs have dif- ­vasoactive intestinal polypeptide can relax ferent sensitivities to varying stimuli. These clitoral and vaginal smooth muscle and include mechanosensitivity (pressure stimu- increase blood flow [44, 46, 50, 70–72]. lus), chemosensitivity (irritant stimulus), However, there has been no conclusive and thermosensitivity (cool or warm stimu- experimental evidence for the functional lus). Mechanical and chemical stimulation involvement of endogenous vasoactive of the cervix is associated with intense and intestinal polypeptide due to the lack of “touch” sensations mediated by the vagus, specific and selective antagonists for vaso- hypogastric (T11‐L3), and pelvic (L6‐S1) active intestinal polypeptide receptors. nerves [79, 80]. Mechanical and chemical Peptide histidine methionine is a vasoactive stimulation of the vagina elicits gentle to intestinal polypeptide precursor and is intense sensations of distension, which are colocalized in nerve fibers with vasoactive mediated by the pelvic nerve [79, 80]. Touch intestinal polypeptide in the female repro- and thermal stimulation of the clitoris (skin ductive tract. In the vagina, peptide histi- sensitivity) are mediated by the pudendal dine methionine is present in higher nerve (L6) [79, 80]. The pudendal nerve also concentrations than vasoactive intestinal carries sensory information to the spinal polypeptide and can cause relaxation of the cord from the vulva and striated pelvic and nonvascular smooth muscle by acting perineal muscles [79, 80]. through the same receptors as vasoactive Nerve transection and tracer studies in intestinal polypeptide [44, 73]. Peptide histidine animal models have provided valuable methionine has also been reported to information regarding both the neuroanat- increase vaginal blood flow in women [45]. omy and neurophysiology of the genital 112 Textbook of Female Sexual Function and Dysfunction

organs and the sexual response. Afferent Possible Mechanisms of Vaginal fibers from the clitoris travel in the puden- Transudation dal nerve. The conduction velocity of myeli- As discussed previously, vaginal vasoconges- nated clitoral afferent fibers is slightly tion enhances the production of lubricating slower than skin afferent pathways (about fluid. This fluid primarily consists of plasma 10–15 m/s) [81]. In comparison, conduction transudate that is produced as follows: (i) the velocities of nerves from the vagina and capillaries of microcirculation become uterus are significantly slower (2 m/s), cor- dilated, resulting in increased hydrostatic responding to the conduction velocity of C‐ pressure; (ii) plasma transudate (ultrafiltrate) fibers [81]. The receptive fields of vaginal is forced into the interstitial space around the afferent fibers are smallest at the orifice and blood vessels; and (iii) the transudate passes progressively increase in size up the vaginal through the vaginal epithelium onto the canal to the vagino‐cervical junction [82]. mucosa of the vagina [93]. This translates to poorer localization of sen- As summarized in Figure 8.3, three sepa- sation internally. In relative terms, the ante- rate mechanisms have been proposed to rior vaginal wall has denser innervation explain transvaginal epithelial permeability. than the posterior wall and the distal vagina Firstly, the ionic transcellular transport has denser innervation than the proximal mechanism accounts for plasma transudate vagina (relative to the cervix) [82]. The being filtered from the submucosal capillaries vagus nerve is important for analgesia and by actively transferring Na+ from the capillary pupil dilation and may be activated by vag- lumen to the interstitial fluid with water ino‐cervical stimulation. Women with spi- absorption following osmotic drag [94]. nal cord injury can experience orgasm with Secondly, transcellular fluid transport may vagino‐cervical stimulation through the also occur through aquaporin (AQP) water vagal pathways but it remains unclear channels. Aquaporins are water channel pro- whether the vagus serves as a supplemental teins that are expressed in many fluid‐con- sensory pathway or whether it may only be taining tissues such as kidney tubules and activated after spinal cord injury [83–86]. glandular epithelia, including the human vaginal epithelium and subepithelial capillar- ies [95–97]. A subset of aquaporins called ­Regulation of Vaginal aquaglyceroporins have also been identified Lubrication in the human vaginal epithelium and can transport glycerol and some solutes, as well The vagina has a potential space covered by a as water [95, 96, 98]. In animal studies, spe- film of fluid, which is usually insufficient to cific aquaporin proteins translocate from the allow painless penile penetration and cytoplasm to the plasma membrane after thrusting [87]. Comfortable or pleasurable pelvic nerve stimulation [99], suggesting that sexual intercourse requires vaginal lubrica- aquaporins are dynamically regulated to tion, which is part of the sexual arousal increase membrane permeability to water response and reflects a women’s sexual health upon sexual stimulation. [88, 89]. Vaginal fluid is derived from several Thirdly, plasma transudate may move sources, including vaginal transudate and through the epithelial paracellular (intercel- fluids from the upper reproductive tract, lular) space and is controlled by the resist- such as cervical mucus and endometrial and ance of the epithelial tight junction (RTJ) and tubal fluids [90]. The chemical composition the epithelial lateral intercellular space (RLIS) of vaginal fluid is represented by a mixture of [100–102]. This paracellular permeability is ions (Na+, K+, Cl− and Ca2+), glycerol, lactic regulated by estrogen through the expres- acid, acetic acid, and glycogen [90–92]. sion of intracellular structural proteins and Anatomy and Physiology of Arousal 113

Lumen + K Paracellular Transcellular

RTJ RTJ, RLIS AQPs R LIS Na+, K+ K+

Na+ Basement membrane Capillary blood

Figure 8.3 Mechanisms of transvaginal epithelial permeability. (See plate section for color representation of the figure)

­extracellular tight junction proteins [100, ­chloride efflux, resulting in increased surface 103]. This estrogen response occurs more ­liquid and hydration of secretions. rapidly in vaginal epithelial cells from pre- menopausal women compared to those from ­Modulation of Female postmenopausal women [100]. Genital Arousal by Sex Purinergic Receptors and Vaginal Steroid Hormones Moisture Sex steroid hormones may regulate distinct Purinergic receptor ligands have been stud- cellular components of the vagina ied for their effects on the physiology of vari- (Figure 8.4). Each of these cellular interac- ous systems throughout the body [104]. tions influences specific physiological events Gorodeski et al. first reported P2Y receptor such as growth and function of neurons, responses in human endocervical cells in blood vessels, smooth muscle, and epithelial vitro and have presented evidence of P2Y2 cells. Preclinical and clinical studies suggest receptor gene expression in these cells [105, that estrogens modulate genital hemody- 106]. In animal studies, P2Y2 receptor mRNA namics and are critical for maintaining struc- was localized to endocervical and cervical tural and functional integrity of vaginal gland, epithelium, and stratified squamous tissues [109–112]. Estrogen deprivation may epithelium of the vagina and topical applica- lead to decreased pelvic blood flow, resulting tion of P2Y2 receptor agonists increased vag- in diminished vaginal lubrication, clitoral inal moisture in ovariectomized animals to fibrosis, thinning of the vaginal wall, and levels that were comparable to or signifi- decreased vaginal submucosal vasculature cantly higher than control animals [107]. [113, 114]. In addition, estrogen deficiency Studies of cervical mucus quantity and com- leads to involution and atrophy of the genital position in response to fluctuating hormone organs, adversely affecting cervical, endocer- levels in women has shown that certain vical, and glandular mucin production. In mucin subtypes are upregulated during ovu- contrast, estrogen replacement in postmeno- lation [108]. Stimulation of the P2Y2 receptor pausal women increases pelvic blood flow, activates phospholipase C, which results in re‐establishing vaginal structural integrity increased inositol trisphosphate levels and and lubrication. release of calcium from the endoplasmic Androgens are not only essential for the reticulum. This stimulates cellular functions development of reproductive function in such as increased mucin secretion and women and hormonal homeostasis but also 114 Textbook of Female Sexual Function and Dysfunction

Sex steroid hormone Soluble Activated receptor hormone-receptor complex

? Stimulation/Inhibition Ion channel of gene transcription activation Genomic Putative ? membrane modulation of DNA receptor cell function Nongenomic Steroid hormone receptor modulation of number, affinity or signalling cell function

Changes in cellular function caused by sex steroid hormones may result in changes to:

Epithelial cells: Nonvascular smooth muscle: 1) Mucification Blood vessels: 1) Growth/atrophy 2) Keratinization 1) Growth/atrophy 2) Response to neurotransmitters 3) Permeability 2) Vaso-reactivity

Neurons: Lubrication and 1) Distribution pattern blood flow 2) Synthesis and/or release of neurotransmitters

Figure 8.4 Proposed mechanisms of sex steroid hormone action in regulating vaginal function. Binding of steroid hormones to specific receptors (intracellular or membrane bound) leads to genomic and nongenomic activation of cellular processes. These include regulation of steroid receptor synthesis, activation of ion channels, increased DNA synthesis, regulation of growth factors, and neurotransmitter synthesis. The cascade of events triggered by sex steroid hormone binding brings about changes in vaginal tissue structure and function that modulate the vaginal arousal response to sexual stimulation. (Reprinted from [17].)

represent the immediate precursors for the and mucification, neurotransmitter biosyn- biosynthesis of estrogens [115]. Although thesis and function, smooth muscle contrac- clinical studies have indicated that andro- tility, and expression of sex steroid receptors gens modulate sexual arousal responses in genital tissue is discussed in greater detail [116–126], the precise mechanisms by which in the following subsections. androgens facilitate such responses is not fully characterized. In addition, progesterone Effect of Sex Steroid Hormones is an important signaling molecule in periph- on Genital Tissue Structure eral nerves, where it promotes myelin sheath formation by activating expression of specific In addition to the long established effects of hormone sensitive genes [127]. However, the estrogen on vaginal epithelium [128], ova- role of progesterone on peripheral vaginal riectomy can also reduce the volume of arousal remains poorly understood. the vaginal muscularis layer with a consider- The role of steroid hormones in modulat- able increase in connective tissue between ing tissue structure, blood flow, lubrication muscle bundles [129]. Other studies in rats Anatomy and Physiology of Arousal 115 and rabbits have also consistently noted (NOS) in endothelial cells, oocytes, heart, decreased smooth muscle content and kidney, skeletal muscle, esophagus, and cer- increased connective tissue in both the vagina ebellum [134–137]. In a similar fashion, sex and clitoris after ovariectomy [130, 131]. steroid hormones may modulate genital Estradiol supplementation in ovariectomized blood flow through the regulation of nitric animals can restore smooth muscle content oxide synthase (NOS). Yet, ovariectomy in the vaginal wall and decrease interstitial increases enzymatic activity and protein fibrosis but under histological examination, ­levels of NOS in the vagina and clitoris [130, the tissue can be qualitatively different in 131, 138] while estrogen supplementation appearance from control animals [129]. given for various periods of time (3–14 days), Testosterone treatment may also restore beginning two weeks after ovariectomy, muscularis fiber bundles but to a lesser reversed these changes [130, 131, 138, 139]. extent than estradiol [129]. A combination of It has been postulated that the upregulation estradiol and testosterone or a combination of NOS may be a compensatory mechanism of estradiol and progesterone was necessary to mitigate the adverse changes occurring to restore vaginal muscularis fiber bundles in throughout the vaginal wall, but it is unknown ovariectomized animals to an appearance if these changes are transient or stable and it that was similar to control intact animals remains unclear if this occurs in women after [129]. Thus, while the vaginal epithelium is surgical or natural menopause. Further, primarily responsive to estrogen, these find- ­specific changes in the endothelium of the ings suggest that estrogens, androgens, and vaginal submucosal vasculature have not progestins have additive effects in submucosal been examined with regard to NOS activity structures of the vaginal wall that cannot be and expression. replicated by any individual hormone. NOS expression in the proximal (upper) vagina may be more sensitive to estrogen Effect of Sex Steroid Hormones than the distal (lower) vagina, potentially on Genital Blood Flow and Vaginal reflecting the different embryonic origins of Lubrication upper vagina that arises from the Müllerian duct, whereas the lower vagina is derived In animal studies, hormone depletion by from the urogenital sinus [140]. Interestingly, ovariectomy resulted in a significant reduc- estrogen downregulated NOS activity in the tion in vaginal blood flow in response to pel- rabbit lower urinary tract (bladder and ure- vic nerve stimulation when compared to thra) but not in upper urinary tract (kidney) controls [58, 110, 132]. Estradiol or estradiol [141]. Thus, estrogen may exert similar regu- plus testosterone treatment of ovariectomized lation over NOS in genital and lower urinary animals restored genital blood flow responses tissues. Similar to estrogen, progesterone to pelvic nerve‐stimulation. Treatment of also increases NOS activity in rat and rabbit ovariectomized animals with testosterone vagina [142, 143] but androgens (testoster- alone did not result in increased genital one, dihydrotestosterone, delta‐5‐androstene- blood flow in the rabbit [58] but was effective diol) do not reverse the upregulation of NOS in increasing blood flow in the rat [133]. in the vagina after ovariectomy [138]. These observations suggest that estrogens In addition to modulating NOS, sex steroid and androgens regulate the vascular compo- hormones may also modulate blood flow by nents of genital tissues, but these effects may regulating the activity of vasoactive intestinal be species specific. polypeptide in the vagina [131, 138, 139, In the vasculature, estrogen is known to 141–145]. For example, the binding affinity generally be beneficial in maintaining of vasoactive intestinal polypeptide to tissues endothelial function and has been demon- of the genital tract was greatest in ovariecto- strated to upregulate nitric oxide synthase mized rabbits treated with estrogen and 116 Textbook of Female Sexual Function and Dysfunction

progesterone [144]. Furthermore, adminis- ­neurotransmitter function. In addition, vaginal tration of vasoactive intestinal polypeptide to tissue from testosterone‐treated animals postmenopausal women receiving no hor- developed significantly greater contractile mone replacement failed to increase vaginal force to exogenous noradrenaline. These blood flow, whereas those receiving hormone observations suggest that testosterone may be replacement exhibited increases in blood an important regulator of vaginal nonvascular flow that were comparable to premenopausal smooth muscle contractility. Contrasted with women [145]. the positive effects of estrogen and progester- Genital atrophy and diminished genital one on vasoactive intestinal polypeptide‐ blood flow, secondary to declining estrogen induced blood flow in the vagina (previous (as occurs during peri‐ and postmenopause), section), different hormones clearly have very negatively affects vaginal lubrication in specific and localized effects (e.g., the vascula- women [146, 147]. These clinical observa- ture within the lamina propria versus the tions are further supported by laboratory smooth muscle in the muscularis layer). studies. In estrogen‐deprived animals, pro- Adrenergic nerves of the female genital duction of vaginal transudate was markedly tract are also sensitive to changes in the hor- decreased compared to controls and was monal milieu. In animal studies, treatment restored by estrogen treatment [148]. Vaginal with estrogen alone or a mixture of estradiol mucin production has been reported to be and progesterone increased the norepineph- stimulated by low doses of estrogen but rine content of adrenergic nerves in the reduced by high doses of estrogen [149–151]. vagina [155–157]. In contrast to the effects of Androgens have also been shown to increase estrogen on adrenergic neurotransmitter vaginal mucification in the rat [152, 153]. content, the density of overall innervation has Treatment of ovariectomized rats with topi- been observed to increase in the rat vagina cal dehydroepiandrosterone, which can be subsequent to ovariectomy and decrease after converted within tissues to more active estrogen administration [158]. These changes androgens and estrogens, resulted in com- consisted of adrenergic, cholinergic, and plete reversal of vaginal atrophy and stimu- ­calcitonin gene‐related peptide‐containing lated proliferation and mucification of the nerves, which can mediate vasoconstriction vaginal epithelium [154]. and nociception. It was suggested that similar changes may explain the sensitivity and Effects of Androgens hyperalgesia of the vagina in postmenopausal and Estrogens on Vaginal women. In other studies using rats, testoster- Innervation and Smooth Muscle one significantly increased the density of Contractility adrenergic nerve fibers and this effect was attenuated when estradiol was co‐administered Genital sexual arousal induces changes in the with testosterone [129]. These observations tissue properties of the vaginal canal that are in suggest differential regulation of both motor part regulated by the tone of the smooth mus- and sensory nerves in the vagina by sex cle within the muscularis layer. Ovariectomy steroid hormones. reduces relaxation of vaginal smooth muscle to electric field stimulation (neurogenic response) Effects of Androgens and to exogenous vasoactive intestinal poly- and Estrogens on Androgen peptide in organ bath studies [50]. While and Estrogen Receptors estrogen supplementation was ineffective, androgen treatment enhanced relaxation to While the effects of steroid hormones on the electrical stimulation and restored vasoactive regulation of estrogen and progesterone intestinal polypeptide‐induced relaxation, receptors in reproductive organs have been suggesting that androgens may modulate extensively investigated [159, 160], there are Anatomy and Physiology of Arousal 117 limited studies on the regulation of expres- phenomena have also been observed in clini- sion of sex steroid hormone receptors in the cal studies. Messenger RNA for the estrogen vagina [161]. In ovariectomized rats, estro- receptor‐α isoform increases in the vagina of gen receptor (ER) protein and specific bind- postmenopausal women and decreases after ing of estradiol to estrogen receptor was systemic hormone replacement therapy, but increased in the vagina after four weeks, not with local intravaginal administration of whereas estradiol replacement (at physiolog- low dose estradiol [164]. Also, when com- ical concentrations) decreased estrogen pared to pre‐ or postmenopausal women, receptor [132]. Given the critical role of the androgen receptor protein levels increased in estrogen receptor in maintaining vaginal tis- the vagina of women treated with long‐term, sue structure and function, this may repre- high dose testosterone prior to undergoing sent a compensatory upregulation of receptor transgender surgery [165]. in response to low systemic estrogen. Importantly, a subphysiological dose of estra- diol did not prevent the upregulation of ­Summary and Conclusions estrogen receptor in ovariectomized rats and this low dose of estradiol restored vaginal Genital arousal is dependent upon the proper blood flow responses to levels that were simi- function of neural, endocrine, and vascular lar to control animals [132]. This suggests systems. The content and distribution of that a critical level of estrogen is required in nerve fibers, blood vessels, nonvascular the vagina to impact estrogen receptor levels smooth muscle, extracellular matrix, and the and that low dose estradiol may exert benefi- health of the epithelium can impact upon cial effects on vaginal tissue structure and normal vaginal responses (engorgement and function in the postmenopausal state. These lubrication) during sexual arousal. The addi- findings are consistent with the efficacy of tive, synergistic or antagonistic interactions intravaginal low dose estrogen for vaginal of cellular processes will ultimately deter- atrophy in postmenopausal women [162, mine the overall physiological responses 163]. In contrast, androgen receptors in the manifested as blood flow, lubrication or vagina are downregulated after ovariectomy ­tissue contractility. Thus, pathological and testosterone treatment of ovariecto- changes in any of the processes discussed in mized rats prevented this downregulation this chapter may lead to alterations in neuro- [133]. Estrogen receptor in the vagina transmitter function, tissue composition/ remained elevated in ovariectomized rats structure, and smooth muscle contractility, irrespective of testosterone treatment. with concomitant decreases in vaginal blood Thus, the estrogen receptor undergoes flow, lubrication, and sensation, resulting in reciprocal regulation by estrogen in the diminished vaginal arousal. A detailed dis- vagina, whereas the androgen receptor is cussion of arousal disorder is provided in a positively regulated by testosterone. Similar separate chapter.

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9

Psychological Management of Arousal Disorders Isbelia Segnini and Tuuli M. Kukkonen

Abstract

There are a number of psychosocial, relational, and contextual factors that impact female sexual arousal. Although there are no studies that establish causality, numerous significant correlational relationships exist and it follows that addressing these variables in evaluation and psychological treatment can help improve sexual functioning in women. For example, treatment of a female patient whose dysfunction stems from changes related to aging should have a different focus than that of a survivor of abuse. This chapter offers an exploration of the factors that affect sexual desire and arousal disorders in women, as well as tools available for diagnosis and treatment of sexual dysfunction.

Keywords: sexual desire; sexual arousal; arousal disorder; psychological treatment; psychological factors that impact sexual arousal; effects of partner dysfunction in women; relationship effects of erectile dysfunction; cognitive behavioral sexual therapy; treatment of sexual dysfunction; female sexual arousal

Psychosocial, emotional, and partner factors that impact female sexual arousal. Tools for assessment and diagnosis of dysfunction. Comparison of common treatments of dysfunction.

­Introduction Female sexual arousal was first measured by gynecologist William Masters and sexolo- During a woman’s lifetime, the female sexual gist Virginia Johnson who conducted labora- response is greatly influenced by both bio- tory observations of sexual behaviors, logical issues including hormonal, neuro- including masturbation and intercourse [1]. logic, and vascular factors, and by They identified psychological and physiolog- sociocultural factors. It follows then, that ical aspects of sexual behavior, describing female sexuality depends on multiple ele- four main phases of the sexual response: ments, including those that govern couple excitement, plateau, orgasm, and resolution. relationships. As many of these variables as One relevant finding was that, in women, an possible should be taken into account when emotional component is of paramount evaluating a patient with a sexual health importance. In other words, according to disorder. Masters and Johnson, women must be

Textbook of Female Sexual Function and Dysfunction: Diagnosis and Treatment, First Edition. Edited by Irwin Goldstein, Anita H. Clayton, Andrew T. Goldstein, Noel N. Kim, and Sheryl A. Kingsberg. © 2018 John Wiley & Sons Ltd. Published 2018 by John Wiley & Sons Ltd. 128 Textbook of Female Sexual Function and Dysfunction

­emotionally involved in order to enter the the Kaplan model remain valuable in under- first phase (excitement) [1]. standing sexual responses in women. In two In the 1970s, sex therapist Helen Singer separate studies, that included 133 nurses in Kaplan developed a three‐phase model of the the United States and 429 women in human sexual response: desire, excitement, Denmark, about two‐thirds of the women in and orgasm [2]. The innovation of this cogni- either population did not endorse the Basson tive‐physiological model was the inclusion of model, favoring the Masters and Johnson or desire as the first stage. The incorporation of the Kaplan models [5, 6]. Further, in these desire as a part of the sexual response pro- nonclinical study samples, women who vided the foundation for research in sexual endorsed the Basson model tended to have function and dysfunction over almost 40 lower scores on the Female Sexual Function years. In 2013, the DSM‐5 united the desire Index (FSFI) [5, 6]. and excitement stages for the purposes of To conclude, sexual arousal in women diagnosis of dysfunction, which gave rise to involves multiple variables and stimuli, which the present controversy on the topic [3]. provoke a physical and/or emotional response, Both Masters and Johnson’s and Kaplan’s leading to (further) sexual interactions models considered that arousal can begin between a woman and her partner. with emotional and/or physical stimulation Additionally, female sexual function and dys- [1, 2]. This phase can last any length of time, function can impact a woman’s self‐esteem, from a few minutes to several hours. On the well‐being, and relationships. It is important other hand, Basson described a new model to stress the role of biological, psychological, of the human sexual response cycle [4]. She developmental and contextual elements, per- affirmed that, in women, there are reasons sonal history, couple interaction, and partners’ beyond plain sexual hunger to engage in possible sexual dysfunction both in evaluation sexual actions with a partner, such as to and treatment of possible dysfunction [7, 8]. increase emotional closeness, attachment, and commitment. The cycle can be ­Etiology: Psychological described as follows: (i) a woman begins in a neutral stage; (ii) she could wish an intimate Factors that Impact Sexual contact or she could be responsive to a part- Arousal ner’s proposition; (iii) this self‐initiation or responsiveness enables an immediate bio- The relationship between various psycho- logical and/or psychological response, logical factors and female sexual arousal has which functions as a stimulus for sexual been well established, albeit through correla- arousal [4]. tional and self‐report studies. In particular, The mental aspect of sexual arousal may be research examining negative moods, anxiety as important as the attention to genital vaso- and stress has demonstrated significant links congestion and other physical sexual to sexual dysfunction [9]. Less frequently responses [4]. The awareness of desire and studied has been the association between physical arousal induces a feedback loop that positive mood and sexual arousal. Laboratory potentially increases the level of excitement. induced positive moods have significantly This leads to emotional and/or physical satis- increased subsequent self‐reported sexual faction, which could, in turn, augment the arousal to sexual stimuli, and pre‐existing couple’s level of emotional intimacy. Thus, positive affect has also been shown to predict the Basson model incorporates positive or increased sexual arousal in a laboratory set- negative experiences within the cycle to have ting [10–13]. an emotional impact on future encounters Additionally, a daily diary study in a sample [4]. Nevertheless, it is important to empha- of women found a bidirectional relationship size that the Masters and Johnson model and between mood and sexual activity, with Psychological Management of Arousal Disorders 129 positive mood predicting next day sexual schemas and poor body image have been activity and sexual activity predicting next linked to lower sexual satisfaction and higher day lower levels of stress and negative mood levels of sexual dysfunction [12, 30–34]. In a [14]. Although the studies looking at general recent study examining 88 women between positive affect were conducted on women the ages of 18 and 25 years, Quinn‐Nilas and without sexual arousal difficulties, it is con- colleagues found that poorer ratings on vari- ceivable that examining and encouraging ous body image scales significantly predicted positive affect in women with arousal diffi- lower levels of sexual arousal as measured by culties might be worthwhile. the FSFI. Specifically, body dissatisfaction and negative feelings about one’s appearance Depression were predictive of decreased ratings of sexual arousal. Further, they found that body image Various studies have examined the link concerns specific to sexual encounters were between self‐reported sexual functioning and the strongest predictor of arousal difficulties. depression and have found a significant rela- tionship across different life stages. Higher Environmental Stressors levels of depression are associated with poorer sexual functioning in college‐aged Environmental or external stressors, such as adults, pregnant, and postpartum women, as financial worries and work‐related deadlines, well as women in middle age and later stages are also associated with higher levels of sex- of life [15–21]. Moreover, a nationally repre- ual dysfunction [35–40]. For example, in a sentative sample of over 31 000 respondents recent factor analysis on daily stressors in a in the United States found that approximately sample of 246 participants, researchers found 40% of women with sexual arousal disorders that financial stressors and stresses related to had comorbid depression and the link low socioeconomic status were significantly between depression and sexual functioning is related to lower scores of sexual functioning maintained even when controlling for ant‐ in women [36]. depressant medication use [22–24]. Culture and Religion Anxiety Furthermore, culture and attitudes towards In addition to depression, women’s self‐ sexuality can interact to predict sexual dys- reported sexual functioning is also related to function. For example, in a study of East anxiety disorders [25, 26]. Specifically, women Asian and Euro‐Canadian women, sexual with anxiety disorders report significantly conservatism was a significant predictor of worse sexual functioning than those without sexual dysfunction in the East Asian sample anxiety disorders [27]. It is important to note, of women but not the Euro‐Canadian sample however, that moderate levels of anxiety in [41]. Religiosity can also impact sexual dys- nonclinical populations have been shown to function, with one study of 223 women dem- facilitate sexual arousal and interest [10, 17, onstrating that higher religious adherence 28, 29]. The degree of anxiety, therefore, and was a significant risk factor for female sexual not just its presence, is likely relevant in the dysfunction [42]. Additionally, higher levels assessment of sexual arousal difficulties. of sexual guilt and religiosity were signifi- cantly associated with lower levels of sexual Body Image desire in both Euro‐Canadian and East Asian women [43], and higher levels of sexual guilt A number of other variables have been linked in general have also been found to be signifi- to poorer sexual functioning in women. cantly related to lower levels of sexual arousal Internal perceptions such as negative self‐ [44–46]. 130 Textbook of Female Sexual Function and Dysfunction

Although the large majority of studies exam- ing “how men can have sex almost every day ining factors that affect sexual functioning are and/or want sex after having an argument.” In conducted on women who identify as hetero- general, women prioritize levels of affection sexual, a comprehensive review of the litera- and intimacy rather than the frequency of ture suggests that many of the same variables coitus in their sexual encounters. are also important to the sexual functioning of At the beginning of a relationship, new women who have sex with women [47]. Factors stimuli, context, and the process of getting to such as age, religion, cultural recognition, rela- know each other incentivize frequent sexual tionship duration, sexual satisfaction, psycho- contact for a couple. Over time, a lack of logical well‐being, and relationship satisfaction behavioral variation reduces intensity of are similar to those found in heterosexual ­feelings and less time is spent promoting inti- women. Additionally, there are a number of macy, thus patient complaints are related to factors that might be unique to lesbian cou- the routine, shorter precoitus time and lower ples, such as internalized homonegativity, quality of sexual play [49]. Marital satisfac- degree of being “out”, power, and social sup- tion and duration of the relationship can thus port, that could indirectly impact the experi- profoundly affect a woman’s capacity to feel ence of sexual dysfunction [48]. and express arousal.

Relational Factors that Impact Childhood Sexual Abuse Sexual Arousal Female sexual function and dysfunction are Sexual dysfunction in men and women may greatly affected in different ways by the expe- be diagnosed and treated in isolation but it is rience of sexual abuse. Multiple factors have more effectively addressed within the con- to be accounted for when dealing with this text in which it was acquired. Relationally‐ type of occurrence: age, frequency and inten- motivated sexual dysfunction in women sity of contact, the sociocultural context, could be a function of relationship commit- body image, body‐related esteem, mood, ment and duration, sexual abuse as a child or physical damage, relationship with the of a sexual dysfunction suffered by her part- abuser, the appearance of violence, and kind ner, which can affect her emotional state dur- of treatment received, if any. There are ing sexual arousal and/or interactions. In immediate, intermediate, and long‐term general, negative expectations related to sex- consequences to emotional and physical sex- ual life can have a direct effect on how women ual health, which can be rooted in any of the will respond to sexual stimuli [48]. previously listed factors. For example, guilt associated with childhood sexual abuse is an Relationship Commitment immediate psychological outcome; lowered and Duration body esteem may be considered an interme- diate consequence, which leads to the ongo- Marital gratification has an important role in ing result of depression and sexual aversion sexual satisfaction and vice versa, especially in or rejection. women. For example, if her partner has been Clinical experience shows that depression unfaithful, a woman could feel angry or is a common consequence of sexual abuse. In depressed, which may reduce sexual desire and a 2016 study, it was found that significantly arousal. Another potential reaction is low self‐ more symptoms of depression were reported esteem, body image, and self‐confidence, in those women with a history of childhood resulting in similarly decreased levels of arousal. sexual abuse [50]. Additionally, lower body In clinical practice, women sometimes talk esteem was associated with sexual inhibition about communication differences between and decreased sexual excitement. Both clini- the sexes. They express difficulty understand- cal practice and research have found that Psychological Management of Arousal Disorders 131 cognitive and affective factors, such as guilt partner’s erection rather than her own related to childhood sexual abuse, may result sexual feelings or needs. Lastly, a woman in a fear of or aversion to sexuality [11]. whose partner experiences erectile dys- function may come to reject sexual propositions entirely out of her belief ­The Effects of Partner that “nothing would happen and/or Dysfunction in Women both of us will be frustrated,” thus sexual contact becomes “an ordeal to be Any sexual impairment present in an indi- endured” [52]. –– Long‐term relationship effects of erec- vidual can affect both members of the cou- tile dysfunction are largely negative. ple. In that sense, clinicians should work as a The stress experienced by the female multidisciplinary team in order to have the partner results in magnification of the breadth of experience to provide an accurate impact of the condition on the male diagnosis, as well as efficacious treatment to partner. The male partner, in this case, the patient and her partner. In this section, may also decrease the frequency of selected male sexual impairments and their propositions in response to the woman’s effects on female sexual and emotional health apathy or disgust. This outcome places are discussed, including: erectile dysfunc- the relationship under ongoing strain. tion, premature ejaculation, delayed or ●● Premature ejaculation: sexual function as absent ejaculation, and Peyronie’s Disease. well as satisfaction is affected by prema- Each of these has a physical and emotional ture ejaculation. This condition places effect on the male half of the pair, but also on stress and a feeling of personal distress on the female by impacting her self‐esteem, the man, which contributes to a deteriora- emotional perception of sexual intercourse, tion of intimacy. and, ultimately, her response to future sexual –– Immediate psychological effects for the stimulation whether or not she remains with woman include sexual dissatisfaction, the same partner. the feeling that something is missing ●● Erectile dysfunction: the arousal phase in from the relationship, frustration that men is manifested principally by the erec- her wishes and needs are not met [52]. tion of the penis. Any chronic impairment –– In the long term, one or both partners can result in stress to the man, reducing his may intentionally reduce the time and self‐confidence, and straining the couple’s scope of pre‐intercourse activities, pro- relationship [51]. voking chronic difficulties in arousal –– Immediate psychological effects for the and excitement of the woman, and woman include worry that she is not affecting her ability to reach orgasm attractive enough for her partner to during coitus. This can result in a female become completely aroused, that he is sexual dysfunction, such as hypoactive no longer in love with her, that he has sexual desire disorder or anorgasmia. found another (more attractive or adven- –– Long‐term relationship effects of pre- turous) partner, or that he has been/ mature ejaculation are mostly negative. become homosexual. “…She may feel Psychological stress of the man and lonely, emotionally abandoned…” [52]. woman may decrease overall relation- –– Long‐term psychological effects for the ship satisfaction. woman may include a decrease in ●● Delayed or absent ejaculation: a delay or arousal, as she feels that coitus will be absent ejaculation is the least understood impossible or intercourse will only last and least studied male dysfunction [53]. In for a short time. She may focus all of her clinical practice, women express that attention during sexual activities on her “something is happening with her partner’s 132 Textbook of Female Sexual Function and Dysfunction

feeling toward her, because he has delayed or confusion regarding future sexual or no ejaculation”. This kind of condition interactions. can cause interpersonal problems and in –– Immediate psychological effects on the some cases presents a barrier to fertility. female partner of a man suffering from There may also be physical side effects Peyronie’s disease are typically con- for the woman – patients complain that cerned with penetration impairment. the “time it takes for their partner inside As a consequence, there can be less con- the vagina makes it dry and sometimes the nection and intimacy, low satisfaction, skin gets irritated, provoking pain even and sexual relationship withdrawal. when lubricant is used.” –– In the long term, the female partner of a –– For the woman, immediate negative man with Peyronie’s disease may experi- psychological effects are related to the ence diminished sexual function, mood, pain caused during intercourse. Women and satisfaction. who orgasm multiple times during –– Surprisingly, overall relationship satis- intercourse or who need a longer time faction of couples was not significantly to become aroused are less likely to affected by Peyronie’s disease. complain or suffer when their male partner experiences delayed or absent ejaculation. ­Health and Lifespan –– Long term, the pain of intercourse may Considerations motivate the woman to refuse a sexual proposition until her vaginal tissue has At any given stage in life, there may be chal- recovered or longer. –– The relationship effects of delayed or lenges that impact sexual arousal as seen absent ejaculation generally depend from the various factors discussed previ- on whether pain is experienced and its ously. Individual, relational, and sociocul- severity. As stated earlier, some tural variables can all impact a woman’s women have complementary sexual sexual response and must be considered needs or desires that may reward this regardless of life stage in the assessment of condition. sexual dysfunction. Additionally, there are certain health issues and lifespan considera- ●● Peyronie’s disease: several research stud- ies have focused on the effect of Peyronie’s tions that have a higher risk for sexual ­dysfunction that may impact the type of disease on the female partner in a rela- treatment that is undertaken. tionship. However, studies have found that the physical interference on sexual activity imposed by Peyronie’s disease Pregnancy affects not only the diagnosed male but also his female partner [54, 55]. Female Pregnancy has consistently been linked to partners of men who received treatment poorer sexual functioning in women [56–58]. for their penile curvature demonstrated One prospective study of 63 women demon- improvement on all domains of the female strated decreased sexual functioning, as sexual function index, as well as reporting measured on the female sexual function global improvement in their sex lives and index, as pregnancy progressed and func- their relationships [55]. There may be a tioning continued to be poorer than at base- feeling of helplessness related to partner line six months postpartum. Other self‐report frustration and/or sadness connected to studies have demonstrated that women in intimacy [16]. It is important that both their third trimester had poorer sexual func- partners discuss the condition in an open tioning than those in their first and second manner, which can reduce feelings of fear trimesters [58, 59]. Additionally, research Psychological Management of Arousal Disorders 133 examining postpartum sexual functioning with age [66]. Additionally, across all age demonstrated that nearly two‐thirds of study groups, women were less likely than men to respondents experienced sexual dysfunction be engaging in sexual activity and, for those within the first year postpartum and, of who were, approximately half indicated that those, approximately half complained of they had a sexual dysfunction that they found ­sexual arousal difficulties [60]. Moreover, bothersome. A review of population‐based voluntary and medically necessary termina- studies found significant declines in sexual tion of pregnancy resulted in significantly functioning associated specifically with the poorer sexual functioning for women, with menopausal transition, with rates of reported women undergoing voluntary termination dysfunction doubling from early to late men- being worse off [61]. Although mode of deliv- opause [67]. More recently, another commu- ery (vaginal versus cesarean section) has not nity‐based study of 3302 women aged 42–52 been found to significantly impact female years found modest associations between sexual functioning overall, vaginal delivery is reported sexual arousal and follicle stimulat- associated with significantly decreased ing hormone in this age group, suggesting scores on the sexual arousal domain of the that hormonal changes specific to meno- female sexual function index [62, 63]. pause, and not just age, can contribute to arousal difficulties [68]. Infertility Diabetes In addition to pregnancy, women struggling with infertility are at higher risk for sexual There are numerous studies that suggest dysfunction than those without infertility poorer sexual functioning in women with [64, 65]. One case control study of 119 diabetes (both types 1 and 2) as compared to women with infertility and 99 healthy con- healthy controls [69, 70]; however, a recent trols found that 40% of women with infertil- meta‐analysis suggests that other factors, ity met the criteria for sexual dysfunction on such as levels of depression, body mass index the female sexual function index, as com- and age are important variables that could be pared to 25% of the control group. Their partially accounting for this relationship [71]. scores on the sexual arousal and desire domains Pontiroli and colleagues included 26 studies were significantly lower. Furthermore, the in their meta‐analysis with over 3000 dia- women with infertility retrospectively indi- betic women and found that although there cated that their level of sexual functioning was an increased risk for female sexual dys- prior to their diagnosis was similar to that of function in women with diabetes as com- healthy controls [65]. More recent research pared to controls, this risk was restricted to suggests that a lack of sexual interest or premenopausal women. Furthermore, body desire is the most common complaint for mass index was the only independent varia- women undergoing in vitro fertilization [66]. ble to be associated with female sexual func- tion scores, suggesting that when assessing Aging and Menopause female sexual dysfunction in women with diabetes, these other variables play an impor- Aging and going through the menopausal tant role. transition are significantly related to increased incidence of sexual arousal diffi- Metabolic Syndrome culties. The National Social Life, Health and Aging Project, which examined a probability There are studies that have found a link sample of over 3000 individuals from the between poor sexual functioning and meta- ages of 57–85 years, found that the incidence bolic syndrome in women [72–75]. A study of sexual dysfunction increases significantly examining postmenopausal women found 134 Textbook of Female Sexual Function and Dysfunction

that those with metabolic syndrome had and sexual histories are the predominant significantly higher rates of female sexual methods used to collect subjective data con- dysfunction with worse scores on all domains cerning patients’ sexual health, while a vari- of the female sexual function index as com- ety of assessment tools exist to collect more pared to women without metabolic syn- objective data. drome [76]. Other studies, however, have not found this association. For example, in Sexual History women with polycystic ovarian syndrome, body weight was not related to sexual func- Although there are no standardized clinical tioning; rather, polycystic ovarian syndrome interviews to assess sexual response, guide- itself was associated with significantly poorer lines for structuring the assessment typically sexual arousal on the female sexual function recommend a biopsychosocial approach, index as compared to women without poly- whereby the clinician will obtain diagnosti- cystic ovarian syndrome [77]. Additionally, cally relevant information in various domains studies comparing sexually active obese pre- [89–91]. menopausal women with healthy controls This assessment should include informa- found no significant differences in the vari- tion on the nature of the problem, the extent ous domains of the female sexual function and the context in which it occurs, as well as index [78, 79]. a history of the presenting issue. Getting a sense of perceived impairment across every Cancer activity in which the problem is present can be useful to highlight whether there are vari- Sexual arousal difficulties are common in ations or exceptions to the problem (e.g. Are women with various cancers, although most the difficulties with sexual arousal consistent research has focused on breast and gyneco- in partnered versus unpartnered activities? logical cancers [80]. In general, estimates of Are there some activities that seem less female sexual arousal disorder range from 25 affected by the problem?). Understanding to 50%, depending on the type of cancer [81– the history of the difficulty allows for the 84]. These difficulties with sexual arousal have determination of a timeline (e.g. Has this dif- been shown to persist long after treatment is ficulty always been present or has it devel- terminated [85–87]. A recent study of 2178 oped over time? Were there periods in the adult female survivors of childhood cancer patient’s life where this problem was not pre- and 408 siblings found that the cancer survi- sent?) The degree of impairment across vari- vors had significantly lower sexual function- ous domains of the patient’s life is key to ing, including poorer sexual arousal, as determining how intrusive this difficulty has measured on the sexual functioning question- become (e.g. Is the patient experiencing naire, than their siblings, even after control- interruptions to work, social, and other non- ling for various demographic variables [88]. sexual areas of functioning as a result of the arousal difficulties?). Additionally, it is essen- tial that clinicians get a sense of the degree of ­Assessment of Sexual distress within the individual as it relates to Response the problem, as well as the motivation to seek treatment at this particular time. As discussed previously, there are many fac- A more general sexual history should tors to be considered in order to accurately include background and current information assess human sexual health. They may be on the various relational and psychosocial subjective (quality of sexual encounters) or variables mentioned throughout this chapter objective (frequency of defined sexual expe- (Table 9.1). Understanding relationship his- riences). Patient psychological interviews tory, current relationship strengths and Psychological Management of Arousal Disorders 135

Table 9.1 Sexual history.

Current sexual arousal issues Sexual activities in which the problem does and does not occur (e.g. various partnered activities, masturbation, etc) History of the current problem Degree of perceived impairment Level of distress Any situations or factors that have improved sexual functioning Any previous treatments and degree of success Motivation for treatment Biological factors Age Medical conditions, surgeries, medical treatments Lifestyle Psychosocial factors Depression Anxiety Environmental stressors Attitudes towards sexuality Body image Culture, religion Previous trauma Relational Factors Relationship commitment and duration Partner support Partner dysfunction Couple communication struggles, and partner dysfunction will help der, none have published studies supporting determine the course of treatment. Any con- their long‐term use. Topical lubricants, vita- current health (physical or psychological) min E, mineral oils, and creams can serve to conditions need to be taken into considera- augment lubrication during sexual activity. tion, as well as medications that might be While they do not enhance vasocongestion or interfering with arousal (see Chapter 10 for address underlying causes of female sexual additional information). Finally, psychosocial arousal disorder, these treatments are rela- variables, cultural and religious background, tively low risk and tolerated by patients across as well as more general information on social the lifespan and across different medical con- location, can help determine extraneous var- ditions. One study examining a botanical iables that might influence treatment. massage oil (Zestra) found that its use did lead While a wide variety of assessment instru- to increased self‐reported sexual arousal in ments exist to evaluate female sexuality, sex both women with and without female sexual response, desire, and other elements of sexual arousal disorder, although no physical meas- health, none are concerned primarily nor ures of arousal were obtained [92]. Assessing exclusively with female arousal. Table 9.2 shows patients for any allergies, skin sensitivities or more information about arousal‐dedicated medical contraindications is important prior items found in five well‐known assessments. to suggesting such treatments. Another alternative to topical agents are suction devices used to increase blood flow ­Nonpharmacological to the genital area. The use of an EROS ther- Treatments apy device (NuGyn, Saint Paul, MN) has demonstrated improvement in female sexual Although there are a number of different function index scores [93, 94] and, more lubricants and creams that have been recently, a proof of concept study on Fiera employed to treat female sexual arousal disor- (Aytu Women’s Health LLC, Englewood, CO) 136 Textbook of Female Sexual Function and Dysfunction

Table 9.2 Common female sexual health assessment instruments and arousal‐related items.

Assessment instrument Items that relate to female arousal

Brief Index of Sexual functioning (BISF‐W) [106] 5,13,14 Sexual Functions Questionnaire (SFQ) [107] 7,8,9,10,11,12,13,14 Female Arousal and Desire Inventory (SADI) [108] N/A* Sexual Interest and Desire Inventory (SIDI) [109] 11,12 Female Sexual Functions Index (FSFI) [110] 3,4,5,6

*The items are not numbered and all may apply to measurement of female arousal function and dysfunction.

has produced positive results in premenopau- Patients presenting any sexual dysfunction sal women [95]. Finally, lifestyle improvements, are typically requested to temporarily discon- such as the addition of exercise routines, can tinue sexual relations in order to redirect also improve sexual functioning in patients attention from the issue. Instead, it is sug- with comorbid medical ­conditions [96, 97]. gested that patients spend time cultivating intimate, nonsexual encounters to increase harmony and affective physical contact. It is ­Psychological Treatment also recommended, in some cases, to watch and read erotic materials and use sexual toys In clinical practice, a basic principle for any to stimulate sexual consideration. kind of psychological treatment is to estab- Female arousal disorder is often associated lish a trusting, empathetic, and respectful with emotional distress related to sexual anx- relationship with the patient. In treatment of iety, poor couple interaction, sexual aversion, sexual dysfunctions, it should also be com- and/or pain before and/or during sexual mon practice to individualize each patient contact. and his/her partner to identify etiology and reach a more accurate diagnosis from a Cognitive Behavioral Therapy multidimensional model. Any sexual dysfunction produces psycho- The foundation of cognitive behavioral logical distress and relationship difficulties therapy is rooted in the role of cognitive that can stimulate performance problems factors in the way people react, feel, and and anxiety [98]. In order to prevent these behave. Thoughts, beliefs, ideas, and cog- negative outcomes, patients and their part- nitive schema are developed during the ners may require a baseline sexual education learning years and persist throughout our primer and the safety to express their needs lives. When these elements are negative, and expectations. On the other hand, it is they constitute automatic thoughts, images, important to be aware that intimacy and a and feelings that interfere with sexual pleas- loving connection are essential elements in ure in both men and women. The objective order to allow men and women to reach a of cognitive behavioral therapy is to iden- functional, satisfactory, and (sexually) active tify the cognitive schema or beliefs for bet- relationship. Thus, the interrelation between ter understanding of the psychological a dysfunctional or unsatisfactory relation- processes. This implies: approach and revi- ship and sexual difficulties can be sion of thoughts, identification and elimina- unclear – at times, the relationship status is tion of undesirable behaviors, and their the cause, and sometimes it is the conse- substitution for desirable ones and positive quence [21]. communication. Through this technique, Psychological Management of Arousal Disorders 137 patients change their attitudes in a positive Couples’ and Individual Therapy manner toward sex, making their sexual Treatment of sexual dysfunction can be lives more pleasurable and focusing on the approached with varying etiologies – organic, quality of their sexual relationships instead psychological, or a combination of the two. of other factors such as intercourse fre- Sex therapy is an important tool in the psy- quency [99]. The main tool in cognitive chological treatment of arousal‐related prob- behavioral sexual therapy is maieutics – use lems. Through this technique, clinicians of the Socratic method to question the evaluate underlying factors and triggers to a patient, challenging her ideas, schema, and patient’s arousal‐related sexual dysfunction. beliefs, with the final goal of modifying the However, as noted previously, arousal and cognitions in order to cause changes in her other sexual dysfunctions affect both mem- behavior [100]. bers of a couple and, thus, treatment may be Mindfulness Therapy appropriate for a single patient and/or for a patient and her partner. While patients may Associated with ancient practices such as elect to attend sessions alone or with a part- meditation, mindfulness has been used to ner before even beginning therapy, clinicians treat chronic pain, stress, depression, and may also recommend that a patient coming other ailments. It can be combined with in alone bring her partner or vice versa. cognitive behavioral therapy (discussed in When Kaplan wrote The New Sex Therapy, the previous section), cognitive coaching, she designed a set of exercises for the treat- and other methods to achieve promising ment of sexual dysfunctions based on results [101]. Recent research has examined Masters and Johnson’s indications for sex the integration of mindfulness as part of the therapy [1, 104]. In couples’ therapy, the first treatment of sexual dysfunction in women recommendation is to stop sexual contact following gynecological cancer [102], sex- between partners in order to redirect mutual ual distress, and a history of sexual abuse. attention away from the dysfunction. During In the last decade, mindfulness has also this stage, the couple is also given mutual been incorporated into psychological massage exercises with no genital touching, ­treatments for desire/arousal disorders in which are meant to encourage focus on their women. bodies’ sensations, increase good communi- The objective of mindfulness therapy is cation of sexual needs, and to allow the awareness and acceptance of sensations, patients to give and receive pleasure without emotions, and thoughts, focusing one’s com- the expectation that “something has to hap- plete attention on the present. A 2011 study pen.” Ultimately, the goal is to help the patient by Silverstein et al. [103] affirms that the and her partner feel comfortable with one practice and mastery of this technique should another. carry benefits for overall patient well‐being, When the first goals are reached, the next but also allows the patient to recognize and couples’ exercise includes genital contact experience all physical interoceptive and sex- without any evaluation of the physical ual signals during sexual encounters. This response. In successive sessions, the physical study confirmed that mindfulness training contact includes coitus with no expectation allows women to develop their ability to of experiencing an orgasm. The objective focus, reduce depression and anxiety, and is to have the patients concentrate on sen- improve their self‐image and general satis- sations, then share them with their partner. faction. As a consequence, women can attain The final step is for the couple to have a consonance between physical and emotional ­complete sexual encounter, starting with sex- responses, thus ameliorating female sexual ual play. This exercise may incorporate any arousal disorders. of those previously completed. The main 138 Textbook of Female Sexual Function and Dysfunction

objective is that both members of the couple problem only. In these cases, it is still rec- feel comfortable and fulfilled throughout the ommended that the therapist engage the experience. partner. Successful efforts may offer In contrast, individuals’ sex therapy begins the partner the opportunity to describe with exploration of the patient’s sexual his- the patient’s symptoms, then leading tory, then sexual education (as needed) and a them to discuss their own reactions and program of exercises to be completed at impressions. home, in private. The goal of individual ther- Potential treatments for arousal dysfunc- apy is for the patient to resolve her sexual tion in women must incorporate a wide conflicts through self‐knowledge of her body, variety of contextual elements. For exam- sexual needs, and personal growth. Progress ple, the effects of dysfunction and those of will allow her to express and communicate intense relationship dissatisfaction are so her sexual excitement and needs to her part- similar that they can easily be mistaken for ner. Individual sex therapy is carried out each other. However, the treatment options through a customized treatment plan, which available, including combinations of cogni- is designed in the first few sessions, while her tive behavioral therapy, mindfulness ther- background, sexual history, and complaints apy, and traditional sex therapy, allow are introduced and explored. Weekly therapy clinicians to tailor therapeutic plans to their sessions are recommended for the first few patients’ needs. In general, it is important months. to recognize that dysfunction may be diag- The home exercises center around famil- nosed in a woman or her partner but that iarizing the patient with her anatomy and the most likely case is that both members of the way that she experiences sensations the pair suffer emotional and/or physical [105]. When she is comfortable with her effects of the diagnosis. genitals, it is recommended that she touch them, with and without lubricant (in order to redirect attention from the amount of ­Conclusions natural wetting). Female patients are directed to finish their exploration with or In summary, there are a number of psycho- without an orgasm. social, relational, and contextual factors While couples’ therapy removes undesira- that impact female sexual arousal. Although ble sexual experiences and then reacquaints there are no studies that establish causality, the patient and her partner sexually through numerous significant correlational rela- structured mutual experiences, individuals’ tionships exist and it follows that address- therapy focuses on empowering self‐knowl- ing these variables in therapy can help edge with education and does not recom- improve sexual functioning in women. mend abstinence. In general, patients Therapists must consider the factors dis- presenting with sexual dysfunction are rec- cussed in this chapter in conjunction with ommended to begin with individual sex ther- medical conditions and any physiological apy (which may or may not include findings (Chapter 10). Ultimately, a com- psychotherapy). Following that, if the patient prehensive biopsychosocial assessment has a partner, it becomes important to incor- and treatment plan will provide women porate them into the therapeutic plan, as with the most holistic approach to amelio- described above. rating their sexual arousal difficulties. There may be cases when a woman’s Thus, diagnosis and treatment by a multi- partner refuses to attend therapy because disciplinary team could be the best way to the dysfunction is perceived as ‘her’ deal with a woman’s sexual dysfunction. Psychological Management of Arousal Disorders 139

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10

Pathophysiology and Medical Management of Female Genital Arousal Disorder Irwin Goldstein

Abstract

Female genital arousal disorder is considered to be the inability to develop or maintain adequate genital responses, including vulvovaginal lubrication, engorgement of the genitalia, and sensiti­ vity of the genitalia, associated with sexual activity and causes distress for a minimum of six months. Sexual arousal of genital tissues occurs, in part, secondary to the central nervous system processing of both physical and emotional stimuli before and during sexual activity. This enhanced neurologic activity in the sympathetic and parasympathetic autonomic nervous ­systems results in multiple central and peripheral physiological changes. Female cognitive arousal disorder is defined as difficulty or inability to attain or maintain adequate mental excite­ ment associated with sexual activity as manifested by problems with feeling turned on, engaged, and/or mentally sexually aroused for a minimum of six months. Treatments include psychologic strategies, vaginal lubricants, and/or vaginal moisturizers, devices, local and systemic ­vasodilation agents, local and systemic hormones, systemic agonists to central nervous system excitatory neu­ rochemicals and central nervous system antagonists to inhibitory neurochemicals, and ­neurologic interventions. Keywords: genital arousal; cognitive arousal; sympathetic hypogastric nerve; parasympathetic pelvic nerve; vaginal lubrication; clitoral engorgement; cardiovascular health; genitourinary syn- drome of menopause; testosterone; estradiol; local and systemic vasodilation agents

Peripheral genital arousal responses are associated with tumescence of the labia minora, vaginal introitus, glans clitoris, corpora cavernosa of the clitoral shaft and crura, periurethral glans including the urethral meatus, anterior vaginal wall structures including the periurethral region and prostatic tissue, and Halban’s fascia. Risk factors include cardiovascular and neurologic disorders. Biological‐based treatment strategies include vaginal lubricants and/or moisturizers, devices, vasodilation agents, hormone agents, systemic agonists or antagonists to central nervous system excitatory or inhibitory neurochemicals, neurological interventions.

Textbook of Female Sexual Function and Dysfunction: Diagnosis and Treatment, First Edition. Edited by Irwin Goldstein, Anita H. Clayton, Andrew T. Goldstein, Noel N. Kim, and Sheryl A. Kingsberg. © 2018 John Wiley & Sons Ltd. Published 2018 by John Wiley & Sons Ltd. 146 Textbook of Female Sexual Function and Dysfunction

­Physiology of Female increased sensitivity of the genitalia to Genital Arousal Responses touch [3, 4, 6]. The increase in lubricating secretions in the Sexual arousal of genital tissues in women vestibule and vagina include a combination of occurs, in part, secondary to the central mucin released from androgen dependent nervous system processing of both physical minor vestibular glands and major vestibular and emotional stimuli before and during sex­ Bartholin glands, and the prostate in the ual activity. This enhanced neurological periurethral region of the anterior vaginal activity in the sympathetic (hypogastric) and wall. Within the vagina, increased arterial parasympathetic (pelvic) autonomic nervous blood flow results in a transudate of plasma systems results in multiple central and that passes through water channels in the vag­ peripheral physiological changes [1–4]. inal mucosa [3, 4, 6, 7]. Concerning central changes, increased During sexual arousal in women, the pelvic sympathetic hypogastric efferent activity floor muscles initially relax but as sexual increases a woman’s focus, wakefulness, and arousal increase and orgasm approaches, concentration. Sympathetic activation is asso­ sympathetic hypogastric motor stimulation ciated with increases in heart rate, respiratory results in eventual rhythmic contraction of rate, and blood pressure. At the height of sex­ the pelvic floor muscles during orgasm [3, 4]. ual arousal in women, just prior to orgasmic In addition, there are nongenital changes release, these physiological parameters may noted during sexual arousal in women. reach values as high as 120 beats/min for heart Extragenital arousal includes erection of the rate, 40/min for respiratory rate, and 180/120 nipples, sensitivity of the skin of the ear mmHg for blood pressure [5]. lobes, fingers, wrists, thighs, buttocks, and Concerning peripheral changes, the flushing of the facial skin [3, 4]. increased parasympathetic nervous system Several different methodologies have been efferent activity leads primarily to vasodila­ used to objectively measure the genital tion of baseline arteriolar resistance within changes during sexual arousal in women, genital tissues, resulting in increased blood including heated oxygen electrode, infrared inflow to genital and some nongenital tis­ thermography, impedance plethysmography, sues. Classic, well‐documented peripheral vaginal photoplethysmography, color duplex genital responses that are associated with Doppler ultrasonography, and magnetic res­ sexual arousal in women depend, in part, onance imaging (MRI) [3, 4]. on the integrity of the hypogastric‐cavern­ osal arterial bed that perfuses the genital tissues to cause tumescence of: (i) the labia ­Subjective Component minora, (ii) the vaginal introitus, (iii) the of Female Sexual Arousal glans clitoris and the corpora cavernosa of the clitoral shaft and clitoral crura, (iv) the Sexual arousal in women may also include a periurethral glans including the tissue of central subjective awareness of the genital the urethral meatus, (v) the anterior vaginal and extragenital changes. The presence or wall structures including the periurethral absence of genital sexual arousal may be region and prostatic tissue, and (vi) Halban’s either congruent or incongruent with the fascia [3, 4, 6, 7]. perceived subjective awareness of arousal. Other sexual arousal physiological For example, genital arousal has been docu­ changes in women include vaginal lubrica­ mented to occur in situations without any tion, smooth muscle relaxation of the vagi­ subjective enjoyment, such as in cases of sex­ nal wall leading to lengthening and widening ual assault. In the context of sexual assault, of the vaginal lumen, increased temperature subjective sexual arousal is not present, yet of the engorged tumescent genitals that can evidence of peripheral genital arousal may be be identified by thermography [8], and present [9, 10]. The literature that supports Pathophysiology and Medical Management of Female Genital Arousal Disorder 147 the existence of female sexual arousal being sexual pain disorders. In 2013, the DSM‐5, considered as both genital and subjective released by the American Psychiatric subtypes is limited. Some investigations con­ Association, combined the diagnoses of the sider that vasocongestion and vaginal lubri­ DSM‐IV‐TR definitions of female sexual cation are perhaps evolutionary mechanisms, arousal disorder (FSAD) with hypoactive sex­ in part, to prevent vaginal injury during sex­ ual desire disorder [14, 15]. There are insuffi­ ual activity, including unwanted sexual activ­ cient scientific data to consider that female ities [11, 12]. genital arousal disorder and hypoactive sexual desire disorder are a single female sexual dys­ function entity. The ISSWSH Consensus defi­ ­Nomenclature – Female nition of hypoactive sexual desire disorder Sexual Arousal Disorder highlights the differences and the interrela­ (FSAD) tions between hypoactive sexual desire disor­ der and female genital arousal disorder [13]. The International Society for the Study of Women’s Sexual Health (ISSWSH) has developed new expert consensus definitions ­Risk Factors for Women of female sexual arousal disorders. Female with FGAD genital arousal disorder (FGAD) is consid­ ered to be the inability to develop or main­ Risk factors for female genital arousal disor­ tain adequate genital responses, including der are categorized primarily as psychologi­ vulvovaginal lubrication, engorgement of cal, cardiovascular, neurological, and other the genitalia, and sensitivity of the genitalia, such as anatomical changes that may occur associated with sexual activity and causes after pelvic radiation and/or surgery [13]. distress for a minimum of six months. If the Concerning cardiovascular integrity, the woman’s ­difficulty with genital arousal is relationship between cardiovascular health due to insufficient stimulation, then female and female genital arousal disorder was genital arousal disorder should not be diag­ examined in the summary of the third nosed. Subcategories of female genital Princeton Consensus conference [16]. This arousal ­disorder are related to: (a) vascular consensus document provides a review of the injury or dysfunction and/or (b) neurologi­ literature that shows that cardiovascular cal injury or dysfunction. Vulvovaginal conditions, such as hypertension, hyperlipi­ infection/inflammation, vestibulodynia, demia, metabolic syndrome, obesity, diabe­ and/or clitorodynia should be excluded tes, and coronary artery disease, increase the before the diagnosis of female genital risk of female genital arousal disorder. arousal disorder is made. This disorder is Metabolic syndrome is a multifactorial disor­ most often acquired and generalized, der that includes concomitant impaired glu­ although there are unusual cases of lifelong cose tolerance/diabetes, central obesity, high female genital arousal ­disorder [13]. Female triglycerides, low levels of high‐density lipo­ cognitive arousal disorder (FCAD) is protein, and hypertension. This group of risk defined as difficulty or inability to attain or factors increases the relative risk for develop­ maintain adequate mental excitement asso­ ing coronary artery disease, diabetes, stroke, ciated with sexual activity as manifested by and other health problems. problems with feeling turned on, engaged, Concerning neurologic integrity, disorders and/or mentally sexually aroused for a mini­ that can adversely affect the central nervous mum of six months. system and peripheral nervous system, such Female genital arousal disorder is separate as diabetes and multiple sclerosis, may also and distinct from other female sexual dys­ affect female sexual arousal. Pudendal neu­ functions, such as hypoactive sexual desire ropathy from multiple causes, such as disorder (HSDD), orgasm dysfunction, and/or childbirth or bicycling, can result in female 148 Textbook of Female Sexual Function and Dysfunction

genital arousal disorder [17]. Radiculopathy decline in total and free testosterone level of the sacral spinal nerve roots from sacral with age, as dehydroepiandrosterone sulfate spinal pathology (Tarlov cyst) or lumbar spi­ serves as a prehormone for about half of nal pathology (annular tear, facet cyst, disc ovarian testosterone production [23–26]. impingement, and spinal stenosis) can cause Hormonal changes may play a pathophysi­ female genital arousal disorder [18]. ological role in younger women concerning Research findings suggest that excitation of inadequate sexual arousal based on inade­ the sympathetic hypogastric nervous system quate blood flow to the sexually responsive activation via exercise and sympathetic‐activat­ organs. Estrogen influences vascular function ing medications may facilitate the early stages via genomic and nongenomic mechanisms. of female sexual arousal, while drugs that cause Estrogen has direct effects on genital anatomy, inhibition of the sympathetic hypogastric nerv­ enhancing peripheral blood flow and improv­ ous system, may inhibit female sexual arousal ing vaginal lubrication. Testosterone also and contribute to the symptoms of female geni­ appears to be important for vasomotor effects, tal arousal disorder [19, 20]. enhancing vaginal blood flow and lubrication Anatomical changes associated with pelvic from effects that may be due to direct andro­ irradiation and/or pelvic surgery may cause gen actions or in part be due to estradiol bio­ damage to both small blood vessels and nerve synthesis from testosterone in the vascular endings and may result in female genital bed. Research indicates that vaginal tissue arousal disorder. Radiation therapy to the cer­ may express a specific nuclear receptor for the vix can induce vaginal fibrotic anatomical androgen, Δ5‐androstenediol [27]. changes that lead to female genital arousal dis­ As long as women continue to regularly order. Pelvic surgeries, including radical hys­ ovulate, estrogen and progesterone levels are terectomy with or without irradiation, total maintained until the time of perimenopause. abdominal hysterectomy, and pelvic organ However, factors that interfere with cyclical prolapse surgery have been reported as caus­ sex steroid production, such as weight loss ing female genital arousal disorder [21, 22]. and anorexia nervosa, in which estrogen and progesterone levels may fall, will interfere with sex steroid levels. Androgen levels do ­Endocrine Changes decline with age from the young reproduc­ and Endocrine Risk Factors tive years; therefore, aging contributes to a in Women with Female decline in androgens [25, 26]. Hyperprolactinemia can result in hypog­ Genital Arousal Disorder onadotrophic hypogonadism and loss of libido, and distress. Adrenal insufficiency is Estradiol and progesterone levels fall during associated with reductions in dehydroepian­ perimenopause and menopause when ovula­ drosterone sulfate and free and total testos­ tion eventually ceases. In contrast, total and terone. Similarly, glucocorticosteroid excess, free testosterone levels fall from the third to either endogenous or exogenous, leads to the fifth decade in premenopausal women. adrenal suppression and androgen insuffi­ such that women in their 40s have about half ciency and, thus, may indirectly inhibit sex­ the circulating levels of women in their 20s. ual function [26]. Furthermore, in the late reproductive years Traditionally, hormonal action has been there is failure of the mid‐cycle rise in free understood as endocrine and paracrine. testosterone that characterizes the menstrual Labrie described intracrinology as the forma­ cycle in young ovulating women. The levels tion of active hormones that exert their action of dehydroepiandrosterone sulfate and dehy­ in the same cells in which synthesis took place droepiandrosterone also fall with increasing without release into the pericellular compart­ age. This may contribute significantly to the ment. Tissue sensitivity to androgens will Pathophysiology and Medical Management of Female Genital Arousal Disorder 149 vary according to the amount and activity of similar to symptoms of genitourinary syn­ the enzymes 5α‐reductase and aromatase drome of menopause (GSM or vulvovaginal that may vary considerably between individu­ atrophy). Ideally, adequate management of als. Tissue responses may also vary, with sub­ systemic and local genital sex steroid hor­ tle differences in individual receptors. Thus, mones, such as estradiol and testosterone, in even with highly sensitive assays for sex ster­ women with genitourinary syndrome of oids the measurement of any sex steroids will menopause may result in symptom resolu­ provide only an indication of deficiency or tion [32]. excess, but not an absolute measure of tissue The diagnosis of female genital arousal dis­ exposure or tissue sensitivity and responsive­ order is made primarily by history and physi­ ness, and the clinical features will be the cal examination. Even after adequate mainstay of diagnosis [28]. stimulation, women with female genital Because of its high affinity for sex hormone arousal disorder are distressed or bothered binding globulin, under normal physiological by such complaints as lack of: swelling of the conditions in women only 1–2% of total cir­ labia and/or clitoral tumescence, vaginal culating testosterone is free or biologically lubrication, and/or increased sensitivity in available. Elevations in estradiol, as occur genital tissues. Physical examination, espe­ during pregnancy, hyperthyroidism, and cially using vulvoscopy, can be used to rule liver disease, cause a marked increase in sex out the exclusionary conditions listed above, hormone binding globulin levels, whereas such as vulvovaginal infection/inflammation, hypothyroidism, obesity, and hyperinsuline­ vestibulodynia, and/or clitorodynia. mia are associated with decreased sex hor­ Laboratory testing that can be used to help mone binding globulin levels. In addition, establish a neurologic and/or vascular basis oral administration of steroid hormones can for female genital arousal disorder includes: alter sex hormone binding globulin levels quantitative sensory testing (biothesiometric, whereas parenteral administration of these hot and cold perception testing) [18], sacral compounds, such as topical or intravaginal, dermatome testing in the prone position over typically has a much weaker influence on sex the gluteal, thigh, and calf regions (Sacral 1–4) hormone binding globulin [29]. using biothesiometry [18], bulbocavernosus Standard doses of oral nonbiologically reflex latency testing [18], pelvic floor electro­ identical estrogen as used in the oral contra­ myography, vaginal blood flow as measured ceptive pill will increase sex hormone bind­ by color duplex Doppler ultrasonography ing globulin to values as much as 3–10 times [33], vaginal blood flow using vaginal pulse the normal sex hormone binding globulin amplitude during photoplethysmography value. Use of the oral contraceptive pill [34], vascular resistance using impedance ple­ results in additional hormonal changes, such thysmography, infrared thermography [8, 35], as suppressed ovarian function, suppressed and heated vaginal electrode. The drawback of estradiol and progesterone levels, suppressed all these objective tests of neurologic and vas­ ovarian testosterone production, and low cular integrity in women is the limited data on pituitary gonadotrophins [30, 31]. what values constitute absent FGAD and what values are consistent with female genital ­Diagnosis of Women With arousal disorder. In particular, for vaginal ple­ Female Genital Arousal thysmography the correlation between vagi­ nal blood flow measures and verbal reports of Disorder arousal is poor. Diagnostic questionnaires such as the Symptoms of female genital arousal disorder female sexual function inventory (FSFI) have in menopausal women in the vulva, clitoris, not been validated in this new female genital vestibule, urethral meatus, and vagina are arousal disorder diagnosis/domain [36]. 150 Textbook of Female Sexual Function and Dysfunction

Women presenting with sexual arousal ­Treatment of Women concerns should have routinely measured with Female Genital hormone blood tests. For example, thyroid Arousal Disorder stimulating hormone is indicated to assess for hypothyroidism or hyperthyroidism. Psychological strategies Measurement of estradiol and follicle stim­ ulating hormone is indicated especially to Concerning women with female genital diagnose premature ovarian failure in arousal disorder who have accompanying amenorrheic women. Prolactin should be psychological concerns, psychological man­ measured in the setting of oligomenorrhea, agement options, such as formal psychother­ amenorrhea and/or galactorrhea. Free or apy including sensate focus therapy, cognitive bioavailable testosterone measures are the behavior therapy, and/or mindfulness ther­ most reliable indicators of tissue testoster­ apy, can be considered as part of a broader one exposure. Testosterone levels reach a biopsychosocial approach. Such strategies nadir during the early follicular phase, with typically focus on adjusting feelings, atti­ small but less significant variation across tudes, actions, sentiments, and relationship the rest of the cycle. Thus, blood should be communication/behaviors that may be inter­ drawn after day 8 of the cycle, and prefer­ related to the female genital arousal disorder ably before day 20 [37]. state. Alternatively, more conservative The gold standard methodology for approaches to lessen anxiety and improve ­measurement of free testosterone is consid­ symptoms if female genital arousal disorder ered by many investigators to be equilib­ may include yoga, massage therapy, and acu­ rium dialysis. The Sodergard equation can puncture [39–41]. be reliably used to calculate free testoster­ one if total testosterone, albumin and, sex Vaginal Lubricants and/or Vaginal hormone binding globulin are known. Moisturizer Strategies Measurement of free testosterone by ­analogue assays are unreliable and should For women with female genital arousal disor­ not be used in clinical practice. The free der, one treatment strategy is to try vaginal androgen index [nmol/l total testoster­ lubricants and/or vaginal moisturizers. one100/nmol/l sex hormone binding glob­ Arousal disorder complaints in women with ulin] has been used as a surrogate for free female genital arousal disorder typically testosterone, but it is unreliable when sex include vaginal dryness, itching, irritation, hormone binding globulin levels are low. and/or dysuria and are especially common in The measurement of sex hormone binding women with genitourinary symptoms of globulin is relatively simple to perform menopause (GSM) [32]. In women with with good reproducibility. Dehydr­oe­ female genital arousal disorder, the vulva, piandrosterone is usually measured in the vestibule, and vagina may be quite sensitive sulfated form, dehydroepiandrosterone sul­ to touch or to pressure application, such that fate, because the half‐life is much longer, the patient may have varying difficulties with resulting in more stable levels. Dehydroe­ any sexual contact or even with sitting, walk­ piandrosterone sulfate does not vary in ing, or running. Specifically, vaginal inter­ concentration within the various phases of course or penetration including gynecologic the menstrual cycle. There are published speculum examination in a woman with normal, age‐related decline curves for female genital arousal disorder may become dehydroepiandrosterone sulfate. If low lev­ bothersome and uncomfortable. els are found, a morning cortisol level Menopausal symptoms, especially vaginal should be drawn to rule out adrenal insuf­ dryness, itching, irritation, and dysuria, have ficiency [38]. traditionally been managed by a regimen of Pathophysiology and Medical Management of Female Genital Arousal Disorder 151 hormone replacement therapy. Hormone cants clinically last longer than water‐based replacement therapy is, however, contraindi­ vaginal lubricants. Silicone lubricants should cated with a history of breast cancer or a his­ not be used in conjunction with silicone tory of venous thromboembolic disease. In vibrator or mechanical devices. Petroleum‐ place of traditional hormone replacement based vaginal lubricants, such as petroleum therapy, there are several nonhormonal jelly or oil‐based vaginal lubricants, may treatment strategies for the woman with damage latex condoms. It is suggested to female genital arousal disorder, such as non­ avoid specific vaginal lubricants with per­ hormonal moisturizers and lubricants, that fumes or flavors, or with actions advertised can help with distressing symptoms of as causing warmth or tingling, since these decreased arousal [42–44]. If use of moistur­ have little data concerning safety. It is further izers and lubricants does not provide suffi­ suggested to avoid specific vaginal lubricants cient symptom relief, patients may then that have ingredients such as parabens, or consider other nonhormonal strategies, such propylene glycol, or glycerin, as these may CO2 fractional lasers [45, 46], or even the use promote yeast infections. The simpler the list of local hormonal strategies that are not of ingredients in a vaginal lubricant, the more associated with clinically relevant increases it is preferred. Examples of water‐based vagi­ in systemic hormone blood levels, such as nal lubricants intended for vaginal use local, low‐dose estradiol (0.03%) and low include Good Clean Love and Slippery Stuff dose testosterone (0.1%) applied daily directly Paraben Free. Examples of silicone‐based to the vestibule and vagina. vaginal lubricants intended for vaginal use Concerning the use of vaginal moisturizers include Uberlube and Sliquid. Other options as treatment of female genital arousal disor­ for vaginal lubricants intended for vaginal der, these are applied directly to the vaginal use include natural oils such as mineral oil, epithelium multiple times per week as a reg­ olive oil, emu oil, and coconut oil, but these ular practice, independent of sexual activity. can degrade the material in condoms [42–44, Vitamin E oil is an example of a vaginal mois­ 48, 49]. turizer; Luvena is another example of a vagi­ nal moisturizer that is free of parabens and Device Strategies glycerin [47]; these latter agents may increase the risk of vaginal Candida infections. Concerning the use of vibrator or nonvibrat­ Vaginal moisturizers appear to act by trap­ ing mechanical devices as treatment of ping moisture, hydrating vaginal tissues, and female genital arousal disorder, these have lowering vaginal pH levels. A lower vaginal been shown to augment bothersome periph­ pH level is more effective at controlling bac­ eral arousal symptoms. Vibrator and/or non­ terial growth. Regular use of a vaginal mois­ vibrating mechanical devices provide a vital turizer may be sufficient to reduce nonhormonal, nonpharmacological treat­ bothersome symptoms of decreased arousal, ment option and, thus, allow women with especially vaginal dryness, itching, and irrita­ female genital arousal disorder to avoid drugs tion, and enable vaginal intercourse/penetra­ as a first‐line strategy. tion [42–44]. Herbenick et al. found that the more than Concerning the use of vaginal lubricants as half of women used vibrator or mechanical treatment of female genital arousal disorder, devices during sex activity [50, 51]. Vibrator these are applied as needed to the vaginal devices generate vibration stimuli, via a series introitus to reduce friction and relieve symp­ of pulses of electromagnetic waves of variable toms of dryness and irritation during the amplitude and frequency, to the peripheral sexual event. Vaginal lubricants may be dorsal, perineal, and/or external hemorrhoi­ either liquid or gel, and may be either water dal nerves, branches of the pudendal nerve based or silicone based. Silicone‐based lubri­ that pass afferent sensory information to 152 Textbook of Female Sexual Function and Dysfunction

sacral roots S2, 3, 4. A‐beta fibers, are the can also be facilitated by use of mechanical largest fibers within the peripheral nerves vacuum clitoral engorgement devices. Such that mediate touch, mild pressure, sensation vacuum clitoral engorgement devices pro­ of joint position, and vibration. vide negative pressure suction to the glans Vibrators come in a variety of shapes and clitoris, acting to enhance clitoral blood sizes, for internal use (typically phallic shaped) inflow and achieve a non‐neurogenic or external use (often with a loop attachment mechanical clitoral engorgement. There are for use as a finger toy or mechanical ring). The several devices that combine both various rabbit vibrator comprises of a penetration levels of vibratory stimulation to the clitoris, shaft with an attached vibrating clitoral stimu­ with vacuum engorgement to the clitoris, lator. Vibrator wands, such as the Hitachi and achieve an enhanced clitoral engorge­ Magic Wand, are large powerful vibrators that ment. We recently investigated the degree of generally plug into an electrical outlet [52]. engorgement of the external genitalia, as There are no safety regulations for the measured by thermography, to a mechanical manufacture of vibrator or nonvibrating device (Fiera) that combined vibration and devices, as these are sold as novelties and do vacuum suction functions, and found a sta­ not require manufactures to adhere to regu­ tistically significant increase in temperature lations reporting the chemicals and materials in the labia, vestibule, and clitoris from base­ used in the device. For example, a high level line values. Of the participants, 92% endorsed of phthalates, chemical plasticizers that help the development of genital arousal [8]. create the malleable and soft effect, and banned in children’s toys, can be often be Local and Systemic Vasodilation found in vibrator or nonvibrating devices. Agents Brands that use silicone as their main mate­ rial, like LELO and We‐Vibe, have no phtha­ There are no current government‐approved lates. The patient with female genital arousal topically applied or systemic arousal drugs disorder should always check the ingredients for treatment of female genital arousal disor­ in a device and avoid devices that contain der. All pharmacologic agents, local or sys­ PVC, vinyl and/or jelly rubber, and/or if the temic, used to induce vasodilation in women device has a rubber or chemical like odor. with female genital arousal disorder are con­ These vibrator devices have been shown to sidered off‐label. increase blood flow to genital tissues and Concerning the use of local vasodilating increase temperature in these genital tissues. pharmacologic agents as treatment of female These vibrator devices also decrease the genital arousal disorder, the drug most widely bothersome peripheral symptoms of low studied in women’s genital tissues has been arousal in women with female genital arousal prostaglandin E1, a vasodilator that produces disorder [50–52]. a rise in intracellular cyclic adenosine A dildo is a nonvibrating device that is used monophosphate (cAMP) and activation of for sexual stimulation of the vagina and/or protein kinase A. Prostaglandin E1, unlike anus. Dildos are generally made of silicone orally administered phosphodiesterase type but can be made of other body safe materials, 5 inhibitors, increases blood flow without the such as Titanium or clear medical grade requirement for accompanying sexual borosilicate hard glass, that is nontoxic, able arousal. Genital smooth muscle relaxation is to withstand high physical forces without induced by increased protein kinase A activ­ structural compromise, nonporous, and can ity, so that in women with FGAD, application even be put in the dishwasher, making them of prostaglandin E1 can be predicted to result easy to clean [53]. in local genital vasodilation and enhanced Clitoral engorgement, which plays a vital vestibular and vaginal lubrication [35]. function in sexual arousal in many women, Alprostadil, a synthetic form of PGE1, has Pathophysiology and Medical Management of Female Genital Arousal Disorder 153 been approved in men to treat erectile dys­ type 5 inhibitors has, however, yielded incon­ function using intracavernosal and intraure­ sistent results. One study found a significant thral delivery systems, but alprostadil has improvement in arousal sensation and lubri­ never been shown to be effective in men as cation in women who received the oral phos­ treatment for erectile dysfunction when used phodiesterase type 5 inhibitor sildenafil locally on penile skin. versus placebo, whereas a large randomized Several studies have examined the use of double‐blinded study of subjects with female alprostadil in the treatment of female genital genital arousal disorder found no significant arousal disorder. Becher et al. studied topical responses in patients given the active silde­ alprostadil on the clitoris using duplex nafil drug. Daily tadalafil, another oral phos­ Doppler sonography [54]. We evaluated phodiesterase type 5 inhibitor, studied in a using thermography as an assessment of gen­ small group of premenopausal women with ital blood flow the effect of topical alprostadil type 1 diabetes with arousal difficulty, on the external genitalia compared with an showed subjective sexual improvement ver­ over‐the‐counter (OTC) marketed lubricant. sus placebo. Vardenafil, another oral phos­ Compared to placebo, there was a statisti­ phodiesterase type 5 inhibitor along with cally significant increase in temperature systemic testosterone caused an improve­ recorded in three different genital ment in genital responses, as measured by regions – the vulva, vestibule, and clito­ vaginal photoplethysmography, in women ris – in women not subjected to visual sexual with female genital arousal disorder. Oral stimulation. These differences occurred at phosphodiesterase type 5 inhibitors are asso­ different time points, with the most rapid ciated with systemic side effects that deter difference occurring in the vulva. The treatment continuation, such as headache, increases in genital temperature and arousal flushing, nausea, rhinitis, and visual distur­ occurred with no reported systemic or local bances [56–60]. adverse events. On‐demand subcutaneously delivered The prime advantage of topical vasodilator bremelanotide, a centrally acting melanocor­ vasodilation products is that these are not tin receptor agonist, was used in the treat­ systemically delivered and, thus, would not ment of women with female genital arousal be expected to be associated with the usual disorder and hypoactive sexual desire disor­ unwanted systemic side effects of orally der and demonstrated significantly greater administered vasodilator treatments, such as improvement in multiple outcome variables phosphodiesterase type 5 inhibitors. In clini­ versus placebo. This agent has reported side cal trials examining the safety of alprostadil effects of nausea, flushing, somnolence, and in women with female genital arousal disor­ increases in blood pressure [61]. der, adverse events were classified as mild and were usually transient. These included Local and Systemic Hormone local, topical reactions, such as vaginal itch­ Agents ing and burning, which were likely related to the delivery base compound and not the Concerning the use of local estrogen hor­ active drug. Another advantage of topical monal agents as treatment of dryness and vasodilatory agents is quick absorption yield­ ­discomfort, typically associated with genito­ ing fast onset of action [35, 54, 55]. urinary syndrome of menopause, these have Concerning the use of systemic vasodilat­ been widely used and have received govern­ ing pharmacologic agents as treatment of ment approval especially for treatment of female genital arousal disorder, the drug class menopausal symptoms. Local estrogen most widely studied in women has been ­hormonal agents should be considered if phosphodiesterase type 5 inhibitors. Use of nonhormonal agents such as moisturizers peripherally acting oral phosphodiesterase and lubricants have not shown efficacy, and 154 Textbook of Female Sexual Function and Dysfunction

especially if other vulvar, vestibular, and vagi­ estradiol as treatment of genital discomfort nal pathologic conditions have been ruled or pain, these agents have been reported as out, such as infection, dermatologic condi­ most useful when applied to the vestibule, tions, vestibulodynia, or high tone pelvic the site of endodermal embryology that is floor disorders. Local vaginal estrogen ther­ anatomically located between Hart’s line and apy may then be considered a reasonable the hymen. Vestibular tissue has numerous option and involves placing low‐dose estro­ androgen receptors and plays an important gen directly inside the vagina, to facilitate role in release of mucous from minor and regrowth of vaginal epithelial lining, reduc­ major vestibular glands during sexual ing the number of para‐basal cells, increasing arousal. There are no FDA‐approved testos­ the number of glycogenated epithelial cells, terone products considered safe and effective and decreasing the vaginal pH, thus promot­ for women with female genital arousal disor­ ing hormonal‐based angiogenesis in the lam­ der. All local testosterone products are con­ ina propria layer of the vagina and facilitating sidered off‐label. A typical dose to be applied vaginal lubrication opportunity during sex­ to the vestibule daily is testosterone 0.1% and ual arousal [62–64]. estradiol 0.03%, in a hypoallergenic base, in a There are several widely used, FDA‐ pea‐sized amount [65]. approved, local estrogen hormonal agent Concerning the use of systemic estrogen treatment options for patients with dryness hormonal agents as treatment of dryness and associated with genitourinary syndrome discomfort, typically associated with genito­ menopause. Vaginal estrogen creams with urinary syndrome of menopause, there are either biological identical estradiol (Estrace), many FDA‐approved delivery systems, or conjugated equine estrogen (Premarin) including oral pills, patches, gels, vaginal are typically applied intravaginally daily for rings, and intramuscular injections. For several weeks and then several times a week women with a uterus, those who have not after that. Intravaginal estradiol rings can be had a hysterectomy, concomitant use of pro­ used including Estring, a soft silicone ring gesterone will act to protect the endometrial that slowly releases estradiol into the local lining of unopposed stimulation. The ideal vaginal environment and needs to be replaced goal of estradiol therapy is a value of approxi­ every three months. Intravaginal estradiol mately 35–50 pg/ml, the usual upper value of tablets (Vagifem) 10 mcg are small pills normal for many reference laboratories in placed via a preloaded applicator, inside the menopause and values consistent with vagina daily for several weeks, and then sub­ 8–10% of peak estradiol values in the repro­ sequently several times a week. Systemic ductive years. Follow‐up blood tests for estradiol blood test values are not relevantly estradiol should considered initially at three‐ increased with local cream, ring or pill‐based month intervals and then as needed, such as delivery system, especially after the vaginal every 6–12 months if stable. Side effects of epithelium has regrown. Women who choose estradiol treatment include breast pain, nip­ to use local vaginal estrogen therapy do not ple discharge, and uterine bleeding. Usually, need to use concomitant progestogen to pro­ the dose of estradiol is decreased if side tect the uterus, as local estrogen does not effects occur. Other side effects that need to seem to increase the risk of endometrial can­ be discussed include breast cancer and cer. Research on the safety of vaginal estro­ thromboembolic disease. If systemic estra­ gen in women with breast cancer is ongoing; diol treatment results in improvement of studies, however, suggest that the amount of arousal function in women with female geni­ estrogen released is not likely to increase the tal arousal disorder, the patient should con­ risk of breast cancer recurrence [62–64]. sider staying on estradiol therapy for 6–12 Concerning the use of local testosterone months and taking a drug holiday from the hormonal agents in combination with local treatment to see if the treatment is still Pathophysiology and Medical Management of Female Genital Arousal Disorder 155 required. In most cases, estradiol therapy is needs to thoroughly counseled regarding needed to maintain the arousal function contraception and risk of adverse effects on a improvement in women with female genital fetus. Ongoing monitoring should include arousal disorder [66–68]. assessment for signs of androgen excess, reg­ In 2013, the FDA approved ospemifene, ular breast and pelvic examination, monitor­ a selective estrogen receptior modulator ing of serum testosterone levels and in the (SERM) as a safe and effective treatment for presence of abnormal bleeding, endometrial moderate to severe dyspareunia in meno­ biopsy [73, 74]. pause [69, 70]. An ideal goal of testosterone therapy is a Concerning the use of systemic testoster­ calculated free testosterone value of 0.6–0.8 one hormonal agents as treatment of female ng/dl. Follow‐up blood tests for total testos­ genital arousal disorder, discussion should terone, sex hormone binding globulin, and ensue as to the carefully monitored use of dihydrotestoserone should initially be made biologically‐identical testosterone. There are at three‐month intervals and then as needed, no FDA‐approved testosterone products for such as every 6–12 months if stable. The women, so the choices include off‐label use of three choices of testosterone therapy include: FDA‐approved testosterone products for daily topical products typically applied to the men dosed at approximately one‐tenth of the back of the calf; weekly intramuscular injec­ intended male dose or off‐label use of com­ tions of testosterone, typically into the vastus pounded testosterone products. Testosterone lateralus; and 4–6 monthly testosterone pel­ values diminish with age and testosterone lets. A 75 mg testosterone pellet product is may yet prove to be a useful therapy for female FDA‐approved for men. Side effects of tes­ genital arousal disorder, especially in late pre­ tosterone treatment typically are cosmetic menopausal women. Data addressing sys­ and include increased facial hair, thinning of temic testosterone treatment of female genital scalp hair, acne, and oily facial skin. Usually, arousal disorder in premenopausal women the dose of testosterone is decreased if side have relied primarily on observational data, effects occur. If testosterone treatment and in vitro and in vivo animal models, with results in improvement of arousal function, few published randomized placebo‐con­ the patient should consider staying on testos­ trolled trials. Thus, at this time the use of tes­ terone treatment for 6–12 months and taking tosterone therapy in premenopausal women a drug holiday from the treatment to see if with female genital arousal disorder remains the treatment is still required. In most cases, controversial, as large multi‐institutional pla­ testosterone therapy is needed to maintain cebo‐controlled evidence for efficacy and the arousal function improvement [73, 74]. safety in this population is limited at present [25, 71–73]. Systemic Agonists to Central Potential adverse effects of testosterone Nervous System (CNS) Excitatory therapy need to be considered, including hir­ Neurochemicals and Central sutism and acne, balding, voice deepening, Nervous System (CNS) Antagonists and cliteromegaly. Other symptoms associ­ to Inhibitory Neurochemicals ated with exogenous androgen excess may include menstrual disturbances and poly­ All pharmacological strategies for female cythemia. There is no evidence that paren­ ­genital arousal disorder management are teral testosterone therapy has adverse ­considered off‐label. Hypothetical off‐label cardiovascular effects. There is no evidence pharmacologicl strategies are based on using that exogenous testosterone increases the pharmacologic agents that are agonists to the risk of endometrial cancer or endometriosis. excitatory neurochemicals of the central nerv­ Any woman with female genital arousal dis­ ous system and are antagonists to the inhibi­ order treated with testosterone therapy tory neurochemicals in critical nuclei [75]. 156 Textbook of Female Sexual Function and Dysfunction

In female genital arousal disorder manage­ increased. To prescribe flibanserin, the ment, it is hypothesized that increasing cen­ health‐care provider needs to be certified in tral nervous system sexual excitatory the risk evaluation and mitigation strategy processes with agonists of dopamine, oxy­ (REMS) program. Efficacy for libido improve­ tocin, and/or norepinephrine, or decreasing ment may not develop for up to 8–12 weeks; central nervous system sexual inhibitory it is anticipated it is similar for the arousal processes with antagonists of opioid and/or function improvement. serotonin would improve the genital arousal function in women with female genital arousal disorder. ­Neurologic Interventions Off‐label pharmaceutical agonist agents potentially for female genital arousal disor­ Concerning women with female genital der that may act on excitatory neurotrans­ arousal disorder from suspected reduced mitters in critical nuclei and the doses we sensory information, some women state: “I recommend initially to women include: cannot feel my vagina, I cannot feel my clito­ bupropion 75 mg/d in the morning; cabergo­ ris, and I cannot feel my labia when they are line 0.5 mg each Monday and each Thursday; being touched”. Such women may have a ropinirole 0.25 mg one to three times a day; hypofunctioning sacral spinal nerve root oxytocin lozenges 250 U sublingually – one (SSNR) radiculopathy within the cauda hour prior to sexual activity; and/or amphet­ equina from various sacral and lumbar amine, dextroamphetamine mixed salts, 2.5– pathologies. Under such circumstances, neu­ 10 mg taken 30 minutes prior to sexual rogenital testing may help establish the loss activity, but if taken after 2:00 p.m., difficulty of neurological integrity, abnormalities may with sleep should be considered [5]. be visualized on sacral and lumbar spine Off‐label pharmaceutical antagonist agents MRIs, and targeted epidural steroid injec­ potentially for female genital arousal disor­ tions show diminished female genital arousal der that may act on inhibitory neurotrans­ disorder symptoms. It is hypothesized that mitters in critical nuclei and the doses we female genital arousal disorder may occur as recommend initially include: buspirone 10 a manifestation of mechanical irritation of mg BID, and/or naltexone 50 mg/d [75]. the genital sensory and possibly autonomic Off‐label pharmaceutical agonist and nerve roots, which could result in hypofunc­ antagonist agents potentially for female geni­ tion of sacral spinal nerve roots. Our hypoth­ tal arousal disorder that may act on both esis is based, in part, on subsequent surgical excitatory and inhibitory neurotransmitters reduction of the intervertebral discs, or sur­ in critical nuclei include the use of fliban­ gical treatment of Tarlov cysts, that success­ serin at a dose of 100mg/night. Flibanserin is fully alleviates the symptoms. Mechanical a nonhormonal, centrally acting, postsynap­ impingement of intervertebral discs on the tic serotonin 1A receptor agonist and a sero­ cauda equina seems to be an etiological fac­ tonin 2A receptor antagonist; it is classified tor in certain cases of female genital arousal as a multifunctional serotonin agonist and disorder [18]. antagonist. Flibanserin use results in a decrease in serotonin activity and an increase in dopamine and norepinephrine activity. ­Conclusions While flibanserin is currently an FDA‐ approved treatment for generalized acquired This chapter on female sexual arousal disor­ hypoactive sexual desire disorder in premen­ ders first reviewed the physiology of female opausal women, studies have reported that genital arousal responses and concluded that all domains in the female sexual function the peripheral genital arousal occurs second­ index, including arousal function, are ary to the central nervous system processing Pathophysiology and Medical Management of Female Genital Arousal Disorder 157 of both physical and emotional stimuli before of six months. Subcategories of female geni­ and during sexual activity. Eventually sexual tal arousal disorder are related to: (i) vascular arousal occurs because of enhanced and pro­ injury or dysfunction, and/or (ii) neurologi­ gressive neurologic activity in the sympa­ cal injury or dysfunction. Female cognitive thetic (hypogastric) and parasympathetic arousal disorder is defined as difficulty or (pelvic) autonomic nervous systems that inability to attain or maintain adequate men­ results in multiple central and peripheral tal excitement associated with sexual activity physiological changes. Based on the current as manifested by problems with feeling ISSWSH nomenclature, female genital turned on, engaged, and/or mentally sexually arousal disorder is considered to be the ina­ aroused for a minimum of six months. The bility to develop or maintain adequate genital risk factors for women with female genital responses, including vulvovaginal lubrica­ arousal disorder include psychological, car­ tion, engorgement of the genitalia, and sensi­ diovascular, neurological, and other factors tivity of the genitalia, associated with sexual such as anatomic changes that may occur activity, and causes distress, for a minimum after pelvic radiation and/or surgery.

­References

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11

Pathophysiology and Medical Management of Persistent Genital Arousal Disorder Barry R. Komisaruk and Irwin Goldstein

Abstract

Persistent genital arousal disorder (PGAD), first described in 2001, is characterized by persistent or recurrent, unwanted or intrusive, distressing feelings of genital arousal or being in the verge of orgasm not associated with concomitant sexual interest, thoughts or fantasies. Prevalence ranges from about 0.5 to 6.7%. Patients with PGAD often exhibit catastrophizing behavior from the ­unremitting genital arousal, sometimes resorting to suicide. Treatment strategies focus on either disease modification designed to resolve underlying pathology causing abnormal sensory informa- tion passing to the brain, or symptomatic treatments designed to increase inhibition of abnormal information. A common cause of PGAD is sacral spinal nerve radiculopathy, from Tarlov cysts, herniated intervertebral discs or stenosis‐induced chronic Cauda Equina Syndrome. It is hypoth- esized that PGAD might result from hyperactivity of sacral nerve roots. Surgical reduction of the intervertebral discs, or treatment of Tarlov cysts successfully alleviated the PGAD symptoms, ­supporting this hypothesis. Keywords: persistent genital arousal disorder (PGAD); unwanted feelings of clitoral engorgement; emotional lability; suicidality; compromised orgasm; overactive bladder; psychological stress; brain neurochemical imbalance; radiculitis of sacral spinal nerve root; Tarlov cyst

Persistent genital arousal disorder is associated with despair, emotional lability, and/or suicidality. Risk factors include abnormal psychological states, imbalance in brain excitatory and inhibitory neurochemicals; pelvic floor dysfunction; abnormal venous or arterial vascular issues; peripheral neuropathies, genital infections, genital dermatological conditions; radiculopathies of the sacral spinal nerve roots. Treatments are either “disease modification treatment strategies” designed to resolve underlying pathology passing abnormal information to the brain or “symptomatic strategies” designed to increase central neurochemical inhibition reducing symptoms

­Introduction approximately 0.5 to 6.7% [2]. In a study of 1634 female college students, the prevalence Persistent genital arousal disorder was of persistent genital arousal disorder was first described in 2001 [1] but remains 1.5% [3]. Thus, ­hundreds of thousands of an under‐researched sexual medicine women in the United States are predicted to ­condition. The prevalence rate for persis- have this di­ sorder. Persistent genital arousal tent genital arousal disorder ranges from disorder is a symptom‐based condition

Textbook of Female Sexual Function and Dysfunction: Diagnosis and Treatment, First Edition. Edited by Irwin Goldstein, Anita H. Clayton, Andrew T. Goldstein, Noel N. Kim, and Sheryl A. Kingsberg. © 2018 John Wiley & Sons Ltd. Published 2018 by John Wiley & Sons Ltd. 162 Textbook of Female Sexual Function and Dysfunction

­characterized by unwanted and intrusive improved such that contemporary treatment feelings of ­peripheral sexual arousal that are strategies now more frequently result in the not usually associated with objective evi- cure of the condition. Consistent with dence of peripheral sexual arousal [4]. There the perspective of multiple and independent is a broad spectrum of patient complaints etiologies for persistent genital arousal associated with persistent genital arousal ­disorder, a wide range of psychological and ­disorder. Symptoms may last minutes to physical treatments have been investigated hours or days and may be intermittent or with variable success rates, as reported in persistent. Sometimes the symptoms remit case studies, including: psychological ther- after orgasm(s). Sometimes nothing is asso- apy for persistent genital arousal disorder ciated with symptom relief. Several online associated with mood concerns [10], pelvic questionnaire‐based survey studies have floor physical therapy for high‐tone pelvic confirmed the negative impact of persistent floor dysfunction [14], discontinuing certain genital arousal disorder on psychological and medications such as trazodone [16], hor- sexual health [2, 5]. Patients with persistent mone treatment for genitourinary syndrome genital arousal disorder often exhibit cata- of menopause (GSM), pudendal nerve blocks strophizing behavior from the unwanted and or trigger point injections or nerve entrap- unremitting genital arousal [4], even resorting ment surgery for pudendal neuropathy to suicide in several documented cases [6]. [22, 23], electroconvulsive therapy or tran- There are no known animal models of scranial magnetic stimulation [15, 24, 25], ­persistent genital arousal disorder and much spine surgery such as resection of Tarlov of the knowledge concerning pathophysiol- cysts [26], endoscopic lumbar discectomy ogy, diagnosis, and treatments of persistent that resolves radiculitis of the sacral genital arousal disorder in the peer‐reviewed ­spinal nerve root [27], embolization of a pel- literature is in the form of case studies [7–19]. vic ­arterial‐venous malformation or of pelvic Consequently, researchers and clinicians varicose veins for pelvic congestion syn- have a limited understanding of the condi- drome [28], dorsal slit surgery and removal tion and its medical management. Multiple of keratin pearls for clitorodynia [29], etiologies of persistent genital arousal disor- and vestibulectomy for neuro‐proliferative der have been proposed and, as with many ­vestibulodynia [30]. other sexual dysfunctions, it is likely that there are multiple pathophysiological causes that can result in the symptoms typically ­International Society consistent with the condition. for the Study of Women’s Since 2001, multiple management strate- Sexual Health (ISSWSH) gies for persistent genital arousal disorder Consensus Conference have been attempted but the condition has traditionally defied usual psychological and Nomenclature – Persistent biological strategies for management of sex- Genital Arousal Disorder ual dysfunctions. As a result, the focus of management has been on reducing the dis- As in the consensus reached by the ISSWSH tressing bothersome and intrusive symptoms Consensus Nomenclature Conference, per- through the judicious use of oral medication sistent genital arousal disorder is character- that induces an increase in brain neurochem- ized by persistent or recurrent, unwanted or ical inhibition and/or a reduction in brain intrusive, distressing feelings of genital neurochemical excitation [12, 17, 20, 21]. arousal or being in the verge of orgasm (geni- Despite continuing challenges, management tal dysesthesia) not associated with concomi- of persistent genital arousal disorder has tant sexual interest, thoughts or fantasies [4]. Pathophysiology and Medical Management of Persistent Genital Arousal Disorder 163

Persistent genital arousal disorder may be ingestion of certain medications such as associated with: trazodone, or abrupt discontinuation of medications such as selective serotonin ●● limited resolution, no resolution, or reuptake inhibitors [12, 16, 19, 33]; aggravation of symptoms by sexual activ- ●● increased sexual excitatory processes in ity with or without aversive and/or com- the central nervous system that involve promised orgasm in terms of impaired dopamine, oxytocin, melanocortin, and orgasm frequency, intensity, timing, and/ norepinephrine, as well as decreased or pleasure; ­sexual inhibitory processes in the central ●● aggravation of genital symptoms by certain nervous system that involve opioids, endo- circumstances (sitting, car driving, listen- cannabinoids, and serotonin [34]; ing to music, general anxiety, stress or ●● pelvic floor dysfunction, specifically high‐ nervousness; tone pelvic floor dysfunction [14]; ●● despair, emotional lability, catastrophiza- ●● abnormal venous or arterial vascular issues tion and/or suicidality; emanating from large pelvic varices associ- ●● inconsistent evidence of genital arousal on ated with pelvic congestion syndrome [28] physical examination during symptoms or from large pelvic arterio‐venous malfor- (lubrication, swelling of clitoris or labia). mations sending unrelenting arterial When persistent genital arousal disorder inflow to the clitoris [35]; occurs concomitantly with complaints of ●● abnormal sensory information (neuropa- overactive bladder and/or restless leg syn- thy) from peripheral genital nerves drome, it may be considered restless genital (­dorsal, perineal, inferior hemorrhoidal, syndrome [48]. pudendal, pelvic) associated with various peripheral pathologies such as: vestibulo- dynia, ­clitorodynia or genitourinary syn- ­Risk Factors and Clinical drome of menopause; injury to or Etiology of Persistent irritation of the pudendal nerves that Genital Arousal Disorder transmit pain and other sensations; abnormal response of ­tissues to Candida infection or allergy; ­dermatologic condi- Persistent genital arousal disorder is likely a tions such as lichen sclerosus or lichen symptom‐based condition in which multiple planus; vulvar granuloma fissuratum; pathophysiologies can result in the symp- pathology of the peri‐urethral glans; toms typically associated with the disorder and bladder or rectal prolapse or rectal [4]. Persistent genital arousal disorder may diverticulum [14, 22, 23, 29, 30]; be associated with: ●● abnormal sensory information (radiculop- ●● psychosocial issues resulting in stress, athy) passing from sacral spinal nerve roots worry, anxiety and/or panic [31]; examples within the cauda equina from various in which psychosocial issues may result in sacral and/or lumbar pathologies such as increased persistent genital arousal disor- Tarlov cysts [26, 36], disc impingement der symptoms include: personal losses, from annular tear, facet cyst, and/or spinal unresolved marital conflict, traumatic stenosis; abnormal sensory information relationship experiences, mood disorders, from S2, S3 and S4 may then synapse in fatigue, emotional concerns, past trauma the conus medullaris and then ascend to and abuse history, cultural and religious the brain; exclusions; ●● abnormal sensation originating from cen- ●● psychiatric disorders including anxiety, panic tral spinal cord pathology above the cauda and/or depressive disorders [10, 25, 32], equina that affects genital afferent activity. 164 Textbook of Female Sexual Function and Dysfunction

Note that “sexual dysfunction” and “altered As a result of this innervation pattern, irri- sensation of the genitals” are major character- tation of, or damage to, the cauda equina by istics of the “cauda equina syndrome” [37–39]. physical herniation/compression by one or The cauda equina consists of the sensory and more intervertebral discs (most commonly at motor nerve roots of the sacral and lumbar L5–S1 or L4–L5) or other pathology such as dermatomes. The sacral dermatomes are inflammation, edema, displaced vertebra innervated by the pudendal and pelvic nerves, (spondylolisthesis), or a constellation of one which convey sensation from the clitoris, or more of the following symptoms may vagina, perineum and anal sphincter, and occur (Figure 11.1): altered genital sensation, homologous genital components in men, dyspareunia, reduced genital arousal, abnor- which enter the sacrum at levels S2–S4. These mal genital arousal (persistent genital arousal nerves enter the sacrum, pass superiorly as disorder), less intense orgasm, anorgasmia, individual nerve roots of the cauda equina decreased or absent penile/vaginal sensation, and first synapse in the sacral division of the incontinence during intercourse, absent or spinal cord proper (i.e. in the “conus medul- reduced bulbocavernosus reflex, numbness, laris”), which is typically located at vertebral perineal (“saddle”) burning sensation, sen- level Thoracic 12, just below the lowest rib sory deficit or anesthesia, other lumbosacral [40, 41, 42]. The cauda equina also contains root sensory deficits, lower extremity weak- lower lumbar nerve roots, which convey sen- ness, sensory deficit below the knee, leg sation from the feet, legs, and buttocks. reflex change, bladder or bowel incontinence Efferent sacral and lumbar nerve roots com- or retention), altered urinary sensation, prise part of the cauda equina, providing the low back pain, and/or sciatica. parasympathetic and somatic motor innerva- It is important to note that the pathology tion of the genital region and lower limbs. consistent with persistent genital arousal

Pre-accident condition Pre-operative condition

Cauda equina L4-5 healthy L4 disc L5-S1 disc Vertebral herniation body impinging the cauda equina L5 Intervertebral disc

S1 Sagittal view of the S2 lumbar spine

Figure 11.1 Schematic representation of a herniated intervertebral disc at L5‐S1 impinging on, and irritating, the nerve roots of the cauda equina. If the radiculitis affects the sacral spinal nerve roots (SSNR) various neurogenic sexual dysfunctions, such as persistent genital arousal disorder (PGAD), may be experienced. Several cures of men and women with PGAD secondary to radiculitis of the SSNR have been realized with minimally‐invasive out‐patient lumbar spine surgery. (See plate section for color representation of the figure) Pathophysiology and Medical Management of Persistent Genital Arousal Disorder 165

­disorder includes hyperstimulated sensory anesthesia nerve block to the specific sus- and/or motor function. Minimal mechanical pected location (trigger point injection) irritation can have significant stimulatory may result in reduction of the persistent effect on sensory nerves, as seen in the case genital arousal disorder symptoms; of inducing a chronic pain and allodynia ●● medication‐related pathophysiologies: a model in rats by placing a ligature of surgical full history of medication use; thread loosely around the sciatic nerve. Thus, ●● abnormal sensory information passing it seems plausible that even minimal mechan- from peripheral genital nerves associated ical impingement by a herniated interverte- with various peripheral pathologies: physi- bral disc against the nerve fibers of the cauda cal examination, including diagnostic pro- equina could generate inflammation and/or cedures such as vulvoscopy, cotton swab edema and, thereby, stimulate genital (Q‐tip) testing, and vaginal wet mount and ­awareness, hypersensitivity, and even hyper‐ smear testing should be performed to reflexivity, such as can occur in persistent assess for such pathologies as lichen genital arousal disorder [43–48]. planus, lichen sclerosus, vulvar granuloma fissuratum and desquamative inflamma- tory vaginitis; ­Diagnosis of Women ●● endocrine disorders, such as elevated thy- with Persistent Genital roid hormone: diagnostic blood testing Arousal Disorder may be performed to obtain baseline and then posttreatment values; these include: Women with persistent genital arousal thyroid stimulating hormone (TSH), free ­disorder should undergo a thorough biopsy- triiodothyronine (free T3), total triiodo- chosocial history and physical examination, thyronine (total T3), free thyroxine (free and laboratory tests. Diagnostic efforts T4), and total thyroxine (total T4); ●● should be made to identify if there are any vascular pathophysiologies, such as pelvic reversible causes of persistent genital arousal varices or pelvic arterio‐venous malforma- disorder. In this case, modification of any tions: physical examination may reveal reversible causes would be recommended lower extremities with vulvar varicose prior to focus on the initiation of sympto- veins; pelvic ultrasound studies, CT or matic therapeutic interventions for persis- MRI examinations of the pelvis, and venog- tent genital arousal disorder. It should be raphy or selective arteriography may be noted that, for various reasons, some women considered. with persistent genital arousal do not wish treatment and prefer to leave the persistent Nerve blocks with steroids and local anes- genital arousal condition untreated. thetics to specific suspected locations may Potential diagnostic strategies for persis- aid in the diagnosis of neuropathy of the dor- tent genital arousal disorder symptoms, sal nerve, perineal nerve, inferior hemorrhoi- depending on the types of concerns, are: dal nerve, or pudendal nerve if the injections result in marked reduction of the persistent ●● psychological: psychological assessment; genital arousal disorder symptoms. Similarly, ●● psychiatric: referral to a psychiatrist or diagnostic nerve blocks may also be used to other mental health professional for appro- confirm vestibulodynia (hormone‐mediated, priate psychiatric assessment; neuro‐proliferative) or urethral meatal ●● pelvic floor pathophysiologies: pelvic floor pathology (prolapse). Specifically for women physical therapy assessment; for women with suspected hormone‐mediated vestibu- with persistent genital arousal disorder lodynia or genito‐urinary syndrome of men- who may be considered to have high‐tone opause (vulvovaginal atrophy), diagnostic pelvic floor dysfunction, a diagnostic local hormonal assessment should be considered 166 Textbook of Female Sexual Function and Dysfunction

by measuring serum values of testosterone, inhibition of the abnormal inf­ ormation. sex hormone binding globulin, calculated This latter strategy can be used to free testosterone, estradiol, progesterone, ­therapeutically intervene in patients with luteinizing hormone, follicle stimulating hor- ­persistent ­genital arousal disorder toward mone, prolactin, and thyroid stimulating keeping the condition tolerable. hormone. Diagnostic neuro‐genital tests (e.g. quanti- tative sensory testing, sacral dermatome Disease Modification Treatment ­testing, bulbocavernosus reflex latency test- Strategies for Persistent Genital ing, urodynamic testing) may be useful in Arousal Disorder diagnosing abnormal sensory information Potential therapeutic strategies for address- (radiculopathy) passing from central sacral ing conditions that may be causing or con- spinal nerve roots within the cauda equina tributing to symptoms of persistent genital from various sacral and lumbar pathologies. arousal disorder are outlined here. Diagnostic MRI studies of the sacral and lumbar spine areas should further be consid- ●● Psychological concerns: treatment strate- ered. If a suspicious lesion is noted on MRI, a gies, such as formal psychotherapy, includ- diagnostic epidural local steroid/anesthesia ing sensate focus therapy, cognitive injection to the specific lesion that resulted behavioral therapy, and/or mindfulness in marked reduction of the persistent genital therapy, typically focus on modifying arousal disorder symptoms would provide ­feelings, attitudes, actions, sentiments, and evidence that the symptoms result from the relationship communication/­behaviors that lesion. If it is suspected that persistent geni- may be causally related to the persistent tal arousal disorder symptoms may be due to genital arousal disorder condition [10]. abnormal sensory information (radiculopa- More conservative strategies to reduce anx- thy) passing from central sacral spinal nerve iety may include yoga and acupuncture. roots above the cauda equina, a reduction in ●● Psychiatric therapy: judicious use of symptoms after a targeted diagnostic epi- ­psychiatric medications may help the per- dural injection of analgesic or anesthetic sistent genital arousal disorder condition would provide evidence of pathology of the [12, 21]. These include such medications nerve roots in the cauda equina (e.g. impinge- as: antidepressants, which address such ment by protruding intervertebral discs). different complaints as depression, dysthy- mia, anxiety disorders, eating disorders, and borderline personality disorder; antip- ­Treatment of Women sychotics, which address such psychotic complaints as schizophrenia and psychotic with Persistent Genital symptoms arising in the setting of other Arousal Disorder conditions such as mood disorders; anxio- lytics, which address anxiety disorders; There are two types of treatment for women depressants, which are used as hypnotics with persistent genital arousal disorder. Firstly, and sedatives; and mood stabilizers, which disease modification treatment strategies are address bipolar disorder and schizoaffec- designed to resolve the underlying pathology tive disorder. or pathologies causing the abnormal sensory ●● Pelvic floor pathophysiologies: pelvic floor information eventually passing to the brain. physical therapy should be performed Alternatively, when no curative strategies are especially for women with high‐tone pelvic identified or are feasible, symptomatic treat- floor dysfunction [14]. Adjunctive use of ment strategies are considered to increase trigger point injections, vaginal or rectal Pathophysiology and Medical Management of Persistent Genital Arousal Disorder 167

diazepam or baclofen, and/or intramuscu- ●● Vulvar granuloma fissuratum: consider lar onabotulinum toxin A may result in therapeutic reconstructive posterior vesti- reduction of the persistent genital arousal bulectomy with vaginal advancement flap. disorder symptoms. ●● High‐tone pelvic floor dysfunction: con- ●● Medication‐related pathophysiologies (e.g. sider therapeutic pelvic floor physical ther- trazodone): consider identifying strategies apy strategies with or without local skeletal to eliminate the suspected medication [16]. muscle relaxants or onabotulinum toxin ●● Endocrine pathophysiologies: for condi- A injections. tions such as hyperthyroidism, therapeutic ●● Abnormal sensory information passing methimazole should be considered. from suspected central nervous system ●● Vascular pathophysiologies: for pelvic pathology above the cauda equina: ­consider varices or pelvic arterio‐venous malforma- neurosurgery strategies or electroconvul- tions, therapeutic embolization strategies sive therapy. by a vascular interventionalist should be ●● Abnormal sensory information (radicu- considered [28, 35]. lopathy) passing from sacral spinal nerve ●● Abnormal sensory information passing roots within the cauda equina from various from peripheral genital nerves associated sacral and lumbar pathologies: consider with various peripheral pathologies: con- minimally invasive endoscopic and naviga- sider therapeutic strategies related to the tional spine surgery [26]. diagnosis. ●● Clitorodynia: consider therapeutic release In clinical experience, sacral spinal nerve of clitoral adhesions or dorsal slit surgery radiculopathy is being increasingly appreci- with removal of keratin pearls [30]. ated as a common cause of persistent genital ●● Neuropathy of the dorsal, perineal, inferior arousal disorder. More specifically, radicu- hemorrhoidal nerves and/or pudendal lopathy may result from Tarlov cysts and/or nerves: consider therapeutic local anesthe- herniated intervertebral discs or stenosis‐ sia combined with steroid blocks to the induced chronic cauda equina syndrome. specific suspected location, therapeutic It is hypothesized that persistent genital strategies such as transcutaneous electrical arousal disorder may occur as a manifesta- nerve stimulation (TENS) or neuromodu- tion of mechanical irritation of the genital lation through inferential stimulation sensory (and possibly autonomic) nerve (InterStim™, Medtronic) of the sacral roots, which could stimulate hyperactivity of nerves or specific targeting of the puden- sacral nerve roots. Our hypothesis is based dal nerves [22, 49, 50]. in part on the attenuation of symptoms upon ●● Hormonally‐mediated vestibulodynia: administration of epidural anesthesia within consider therapeutic hormonal interven- the spinal canal at the site of genital sensory tion such as systemic testosterone and/or nerve roots that are affected (e.g. impinge- local administration of testosterone/­ ment by intervertebral discs), as determined estradiol cream to the vestibule. by MRI findings. Our hypothesis is also ●● Neuro‐proliferative vestibulodynia: con- based on our experience of attenuation of sider therapeutic complete vestibulectomy symptoms by morphine‐induced analgesia with vaginal advancement flap. produced by intrathecal (i.e. direct subdural) ●● Vestibulodynia related to suspected injection at the conus medullaris (site of the ­dermatologic conditions such as lichen first synapse of the genital sensory nerve sclerosus or lichen planus: consider roots). Further support of our hypothesis is ­therapeutic use of ultrapotent steroids. provided by the attenuation of symptoms ●● Prolapse of the urethral meatus: therapeu- by subsequent surgical reduction of the tic reconstructive urethral prolapse repair. intervertebral discs, or surgical treatment of 168 Textbook of Female Sexual Function and Dysfunction

Tarlov cysts, which ­successfully alleviated the condition manageable and tolerable. the persistent genital arousal disorder To achieve increased inhibition of abnormal symptoms. sensory information, pharmacologic agents Thus, we believe that persistent genital that decrease neurotransmission should be arousal disorder is a form of genital radicu- considered. These agents may include tricyclic lopathy due to stimulatory irritation of the antidepressants, calcium channel blocking genital sensory nerve roots. We suggest agents, and anticonvulsants. Also, pharmaco- that persistent genital arousal disorder be logic agents that decrease dopamine action, included as a subtype of the chronic form of such as vareniclene tartrate [17], or that cauda equina syndrome on the basis that potentiate the action of serotonin, should be mechanical impingement of intervertebral considered. These agents may include selec- discs on the cauda equina seems to be a clear tive serotonin reuptake inhibitors and/or etiological factor in certain cases of persis- ­serotonin and norepinephrine reuptake tent genital arousal disorder. Furthermore, inhibitors. Opioid agonist pharmacologic “sacral spinal nerve radiculopathy” would agents should also be considered. We recently seem to be a more general and inclusive reported that zolpidem, a nonbenzodiazepine ­terminology to characterize both Tarlov indirect gamma‐aminobutyric acidA recep- cyst‐induced persistent genital arousal tor agonist that potentiates GABA release by ­disorder and cauda equina irritation‐induced modifying the benzodiazepine binding site, persistent genital arousal disorder. This per- can be effective in reducing persistent genital spective is consistent with reports that surgi- arousal disorder symptoms [20]. cal removal of the clitoris or uterus as a presumptive treatment for persistent genital arousal disorder did not result in relief of the ­Conclusion disorder, and that this was incorrectly per- ceived as persistent arousal originating in the Persistent genital arousal disorder is an “phantom” organ [50]. Evidently, the phe- uncommon sexual pathology that has nomenon would be better explained, in those been recognized for the first time in the cases, by recognition that the pathology was ISSWSH Nomenclature for Female Sexual “upstream”, affecting the sensory nerves Dysfunctions. Persistent genital arousal dis- proximal to the genitals per se, and only per- order may be caused by numerous underly- ceived by the patient as originating in the ing pathological conditions, which may be genitals. The present clinical experience unraveled by multiple diagnostic procedures. ­provides an hypothesis that for effective Therapies include disease modification strat- curative treatment of persistent genital egies directed at curing the persistent genital arousal disorder, “sacral spinal nerve radicu- arousal disorder condition and symptomatic lopathy” should be considered as a specific therapies to reduce the persistent genital neuropathic etiology [36–41, 43–48]. arousal disorder symptoms so that the condi- tion is manageable and tolerable. In several Symptomatic Treatment Strategies cases where persistent genital arousal for Persistent Genital Arousal ­disorder may have been caused by sacral spi- Disorder nal nerve radiculopathy, minimally‐invasive spine surgery may be helpful. While more Symptomatic therapeutic strategies for per- research is needed in this area, detailed and sistent genital arousal disorder are based on systematic diagnostic investigation by a dedi- pharmacologic agents that can increase cated health‐care provider can greatly inform ­inhibition of the response to the abnormal therapeutic approaches to assist patients in sensory activity. This option can be used to alleviating symptoms or even curing this therapeutically intervene toward keeping debilitating condition. Pathophysiology and Medical Management of Persistent Genital Arousal Disorder 169

­References

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Part III

Orgasm Disorders

Chapter No.: 1 Title Name: p03.indd Comp. by: Date: 22 Mar 2018 Time: 11:30:26 AM Stage: WorkFlow: Page Number: 173 175

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Nosology and Epidemiology of Female Orgasm Disorder Leonard R. Derogatis

Abstract

This chapter reviews the history and development of the diagnosis female orgasmic disorder (FOD) and discusses its close ties to the evolution of the diagnostic system of the American Psychiatric Association (i.e. DSM‐I to DSM‐5). It reviews the principal criteria underlying the diagnosis and their underlying significance. The chapter also discusses the widespread dissatisfaction with the current DSM‐5 system and the development, in response, of the new ISSWSH diagnostic system for female sexual dysfunctions. Diagnostic standards for the FOD diagnosis in the ISSWSH system are described and elucidated as an alternative to the DSM‐5 system. In addition, the chapter also provides a brief review of the current status of epidemiological research focused on the prevalence of FOD as defined in contemporary nosological systems.

Keywords: diagnosis; prevalence; nosology; nomenclature; FSD; FOD

­Nosology There was little change to this section of the DSM until the publication of the innova- In the first half of the twentieth century, a tive DSM‐III [3] in 1980 when female sexual broad spectrum of orgasmic disorders were dysfunctions were categorized under the loosely categorized under the term “frigidity”, heading of “Sexual Dysfunctions” and prob- most centrally defined as the inability of lems with orgasm were labeled “Inhibited a woman to achieve vaginal orgasm [1]. Female Orgasm”. The core definition focused Although numerous possible causes were on the delay or absence of an orgasmic advanced, the condition was perceived pri- response following a “normal sexual excite- marily as a psychological problem. Consistent ment phase”. The central focus on “delay or with the thinking of the times, when the first absence of orgasm after a normal sexual edition of the Diagnostic and Statistical excitement phase” continued through the Manual of Mental Disorders (DSM) [2] was DSM‐III‐Revised and DSM‐IV [4], with the published in 1952, problems with orgasm addition of the distress criterion as a pivotal (specified as “frigidity”) were included requirement for diagnosis in the DSM‐IV. under a category of “Psychophysiological In the DSM‐5 [5], the requirements of key Autonomic and Visceral Disorders” cata- symptoms being present in the majority logued under a broader category of (≥75%) of sexual encounters was introduced, “Disorders of Psychogenic Origin”. as was a ≥6 month duration criterion.

Textbook of Female Sexual Function and Dysfunction: Diagnosis and Treatment, First Edition. Edited by Irwin Goldstein, Anita H. Clayton, Andrew T. Goldstein, Noel N. Kim, and Sheryl A. Kingsberg. © 2018 John Wiley & Sons Ltd. Published 2018 by John Wiley & Sons Ltd. 176 Textbook of Female Sexual Function and Dysfunction

The distress criterion (i.e. the condition ­Epidemiology causing “clinically significant distress”) was retained as a standard feature of the diagno- The epidemiology of female orgasmic dis- sis. In the DSM‐5, “marked reduced intensity orders, like the other categories of female of orgasmic sensations” was added to the list ­sexual dysfunction, suffers from numerous of possible symptoms of orgasmic dysfunc- problems and shortcomings. Firstly, the tion. The general admonition to insure that failure of studies to include a distress symptoms were not due to another DSM or ­criterion until recently represents a major medical disorder or exclusively due to the problem that has resulted in a large body of physiological effects of another substance or prevalence data no longer relevant to medication was retained in the DSM‐5. ­contemporary nomenclatures. Secondly, The Nomenclature Committee of the the restricted historical definitions of International Society for the Study of orgasmic disorder, which focused heavily Women’s Sexual Health (ISSWSH), based on “the delay or absence of an orgasmic on its collective clinical deliberations and response after sufficient stimulation” as a research review, concluded that while the central criterion, have led to a constricted above criteria for female orgasmic disorder and limited definition of orgasmic disorder were appropriate and valid, additional fea- to support prevalence data. Nonetheless, tures of the orgasm experience (disturbances there are a small group of studies that have in orgasmic pleasure and orgasmic timing) achieved a certain level of acceptable rigor qualified as sufficient to meet the require- and the prevalence rates from these studies ments as dysfunctions. The omission of are provided here. decreased or absent pleasure and the inabil- Investigators in the PRESIDE study [7] ity to control timing of orgasm in previous also collected data on female orgasmic definitions of female orgasmic disorder was ­disorder. Importantly, the PRESIDE study felt to be a significant oversight and one that also included a distress criterion. The unad- should be rectified in a new nomenclature justed prevalence of problems with orgasm system [6]. in the PRESIDE sample was 20.5%. When In the ISSWSH nomenclature, female the ­distress criterion was added, the rate orgasmic disorder is defined as “…a persis- fell to 4.7%. When data were analyzed by tent or recurrent, distressing compromise of age group, rates were higher for the older orgasmic frequency, intensity, timing and/or groups, at 5.7% and 5.8% for women aged pleasure associated with sexual activity for a 45–64 years and ≥65 years, respectively, and minimum of 6 months” [6]. Specific criteria lower (3.4%) for women aged 18–44 years. defining female orgasmic disorder are: Unlike the data for hypoactive sexual desire and s­exual arousal disorders, there was a ●● frequency: orgasm occurs with decreased frequency or is absent (anorgasmia); direct relationship between distressing orgasmic problems and age. A higher rate ●● intensity: orgasm occurs with decreased intensity (muted orgasm); of female orgasmic disorder was associated with surgical menop­ ause, current depres- ●● timing: orgasm occurs too early (prema- ture orgasm) or too late (delayed orgasm) sion, anxiety problems, arthritis and than is desired by the woman; ­urinary incontinence. Interestingly, heart disease and diabetes were not significantly ●● pleasure: orgasm occurs with absent or diminished pleasure (anhedonic orgasm). related to any of the sexual problems in the study. The traditional specifiers of lifelong/ Hayes and his associates published a com- acquired and generalized/situational are prehensive review of prevalence studies of retained in the ISSWSH definition. female sexual dysfunctions in 2006 [8]. They Nosology and Epidemiology of Female Orgasm Disorder 177 reviewed 1248 separate studies but found that In 2001, Simon and Carey published a only 11 studies met their criteria for inclusion. review of the previous decade of prevalence Of those, only two employed a distress crite- research on sexual dysfunctions [10]. They rion, and the proportions of distressed women reported that 51 studies had been published in those studies with orgasm problems ranged in the previous decade as compared to 47 widely from 21 to 67%. Orgasm difficulty studies published in the 50 years preceding had an unadjusted overall rate of 35% across that time, suggesting a significant increase in studies. the volume of research in the field. However, Graziottin reported on data from 2467 research in the field was highly unstandard- women from four European countries who ized during this period. Different nomencla- participated in the WISHeS study, which also tures were used, diverse operational included data on the presence of psychologi- definitions were employed, distinct preva- cal distress along with orgasmic difficulty [9]. lence periods (6 months versus 1 year, versus While the main focus was on hypoactive sex- lifetime) were involved, and distress criteria ual desire disorder, rates of orgasmic diffi- were rarely used, all of which led to extremely culty were reported to be almost equivalent uneven methodology in study designs. It is across samples from the four countries anticipated that the recent development of a involved: France, 20%; Italy, 18%; Germany, rigorous new nomenclature for female sexual 21%; United Kingdom, 18%. These rates are dysfunctions by ISSWSH will ensure a more highly consistent considering the cultural positive assessment of the status of the field a distinctions across these populations. decade from now.

­References

1 Angel, K. The history of ‘Female Sexual 6 Parish SJ, Goldstein AT, Goldstein SW, Dysfunction’ as a mental disorder in the 20th et al. Toward a more evidence‐based century. Curr Opin Psychiatry. nosology and nomenclature for female 2010;23:536–541. sexual dysfunctions – Part II. J Sex Med. 2 American Psychiatric Association. 2016;13:1888–1906. The Diagnostic and Statistical Manual of 7 Shifren JL, Monz BU, Russo PA, et al. Mental Disorders. Washington, DC: Sexual problems and distress in United American Psychiatric Association; 1952. States women: prevalence and correlates. 3 American Psychiatric Association. DSM‐III: Obstet Gynecol. 2008;112(5):970–978. Diagnostic and Statistical Manual of Mental 8 Hayes RD, Bennett CM, Fairly, CK, et al. Disorders, 3rd edn. Washington, DC: What can prevalence studies tell us about American Psychiatric Association; 1980. female sexual difficulty and dysfunction. 4 American Psychiatric Association. DSM‐IV: J Sex Med. 2006;3:589–595. Diagnostic and Statistical Manual of Mental 9 Graziottin A. Prevalence and evaluation of Disorders, 4th edn. Washington, DC: sexual health problems. J Sex Med. American Psychiatric Association; 1994. 2007;4:211–219. 5 American Psychiatric Association. DSM‐5: 10 Simon J, Carey JP. Prevalence of sexual Diagnostic and Statistical Manual of Mental dysfunctions: Results from a decade of Disorders, 5th edn. Washington, DC: research. Arch Sex. Behav. American Psychiatric Association; 2013. 2001;30:177–219. 179

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Peripheral and Central Neural Bases of Orgasm Emmanuele A. Jannini, Nan Wise, Eleni Frangos, and Barry R. Komisaruk

Abstract

The clitoris and the clito‐urethro‐vaginal complex are responsive to ovarian hormones and are the main peripheral structures that, with significant individual differences, provide the genital peripheral afferent component of female sexual pleasure. In the central nervous system during orgasm, essentially all of the major brain systems are activated, including the brainstem, limbic system, cerebellum, and cortex. In a symphony of integration, these peripheral and central systems mediate the sensory, cognitive, autonomic, and motor events of orgasm.

Keywords: autonomic; brain; cervix; clitoris; clito‐urethro‐vaginal complex; G spot; limbic; neurotransmitters; orgasm; vagina

The hormone‐dependent clitoris and the clito‐urethro‐vaginal complex are the main peripheral structures triggering, in an exquisitely individual manner, the genital part of female sexual pleasure. Centrally, women’s orgasm entails activation of essentially all the major brain systems, including brainstem, limbic system, cerebellum and cortex. These central and peripheral systems mediate the sensory, autonomic, and motor events of orgasm.

­Functional Anatomy versus orgasm elicited without direct stimula- tion of the external clitoris, respectively) and Adult female genital tissues are hormone from orgasm elicited by stimulation of other dependent in their histology, gross anatomy anatomical structures (uterus, nipple, brain, and functionality. This partly can account for etc.) [2]. The stimulated clitoris is the primary the considerable individual variability of the anatomical source of clitoral orgasm, while female genitalia (e.g. clitoris and periurethral the penetrated vagina is the source of female erectile tissue), which corresponds to evident sexual pleasure in a woman without distress inter‐ and intra‐individual variability in female and, probably in a lower number of women, of sexual response. Female sexual pleasure is vaginally‐activated orgasm. a broader term than female orgasm. The absence of a full orgasm in a woman without Histology of the Clitoris distress does not always prevent the pleasure of sexual activity [1]. Furthermore, we will The clitoris shares with the penis, in their ­distinguish clitoral orgasm from vaginally‐ embryonic derivation, certain macro‐­ activated orgasm (i.e. orgasm elicited with anatomical aspects and histologic structure.

Textbook of Female Sexual Function and Dysfunction: Diagnosis and Treatment, First Edition. Edited by Irwin Goldstein, Anita H. Clayton, Andrew T. Goldstein, Noel N. Kim, and Sheryl A. Kingsberg. © 2018 John Wiley & Sons Ltd. Published 2018 by John Wiley & Sons Ltd. 180 Textbook of Female Sexual Function and Dysfunction

However, it is reductive, both conceptually between the anterior and posterior walls; (iii) and ontogenetically, to consider it as an the histological changes due to hormonal embryological hypo‐developed penis. and life cycle. The microscopic anatomy consists of The vagina in reproductive life is lined by a ­cavernous tissue encircled by a thin fibrous stratified squamous epithelium organized capsule surrounded by large nerve trunks. into rugal folds that enable vaginal distensa- This cavernous tissue consists of trabecular bility (compliance) without the risk of smooth muscle and connective tissue, which ­laceration. Beneath the epithelium there is a encase the cavernous sinusoidal spaces. The dense, thin layer of elastic fibers and then the ultrastructure of the female erectile tissue robust fibromuscular layer. The fibrous cap- within the clitoris is comparable to that of the sule external to this muscular coat is rich in penis, but with some important differences [3]. elastic fibers and large venous plexuses. The nerve network distribution pattern has The vaginal wall contains an innermost been studied, using the neuro‐marker S‐100 layer, the tunica mucosa, and an intermediate and neuron specific enolase‐immunoreactiv- layer, the tunica adventitia. ity, demonstrating that tissue organization in The immunohistochemical analysis of the the corpora cavernosa of the clitoris is essen- vaginal wall (Table 13.1) shows the presence tially similar to that of the penis, except for of the nitric oxide–cyclic GMP–type 5 phos- the absence of the subalbugineal layer inter- phodiesterase (NO‐cGMP‐PDE5) biochemi- posed between the tunica albuginea and the cal machinery and a series of several other erectile tissue [4]. This has functional impli- substances also involved in female arousal cations, suggesting that the clitoral erection and pleasure. Immunohistochemical studies physiology differs from that of the penis. have demonstrated the presence of a large The histology of the clitoris is not constant; number of nerve fibers stained for NO syn- with increasing age there is a decrease in clit- thase (NOS) in the environment of smooth oral cavernous smooth muscle fibers with a muscle tissue and below the Malpighian relative increase of cavernous connective tis- ­vaginal epithelium. The different isoforms of sue, as measured by histomorphometry [5]. NOS also have a complex pattern of distribu- Clitoral corpora cavernosa are well stained tion in the human vagina: the constitutive by antibodies against steroid hormone recep- enzyme isoforms (neuronal and endothelial) tors; the biochemical physiology of erection are expressed in the nerve fiber layer, in the will be described in the next section on vagi- vascular endothelium, and in the smooth nal histology [6]. Although it is well known muscle fibers of the cavernous erectile tissue that the clitoris is responsive to androgens, as of the vaginal wall, and in the Malpighian demonstrated by clitoromegaly in female epithelium of the mucosa. The Malpighian virilization [7], surprisingly, well‐mapped epithelium also expresses the inducible distribution and characterization of sex hor- ­isoform, iNOS. The colocalization of NOS mone receptors in the clitoris is currently isoforms and PDE5 in the context of the lacking. Table 13.1 shows the substances ­cavernous structures of the anterior vaginal found in the genitalia of animals and women, wall is related to the production and catabo- based on immunohistochemistry. lism of cGMP produced locally during sexual stimulation [21]. Histology of the Vagina Gross Anatomy of the Clitoris To understand the role of the vagina in female orgasm and female sexual pleasure, three The clitoris is an erectile organ located basic concepts should be considered: (i) the medial and inferior to the pubic arch and morphological variability in individuals; (ii) symphysis [39], which, due to its multifac- the presence of some structural differences eted structure, has been named the “clitoral Peripheral and Central Neural Bases of Orgasm 181

Table 13.1 Histological findings in clitoris and vagina [8].

Factor Tissue Animal Function/Localization Reference

NOS Clitoris Human Neurotransmission, blood flow 9, 10, 11, Vagina Rabbit control and capillary permeability 12, 13 Mouse Pig Cow nNOS Clitoris Human Nerve fibers supplying smooth 14, 15, 16, Vagina Rat muscle, perivascular nerve 17, 18 Rabbit plexuses, lamina propria eNOS Clitoris Human Vascular endothelium, 3, 14, 15, Vagina Rat perivascular smooth muscle. 19 Rabbit 17, 18 iNOS Vagina Human Production of NO under certain 15 conditions PDE5 Clitoris Human Breakdown of cGMP. Decrease of 15, 20, 21, Vagina Rabbit sexual arousal 22, 23 Skene’s gland CGRP Vagina Human Neurotransmission, blood flow 9, 11, Clitoris Pig control and capillary 24, 25 permeability, involved in sensation SP Clitoris Human Neurotransmission, blood flow 10, 11, 24 Vagina Pig control and capillary permeability Cow NPY Clitoris Human Neurotransmission, blood flow 9, 11, 24, Vagina Pig control and capillary permeability 26 Oxytocin Clitoris Rat efferent neuronal control 27 Vagina Estrogen Distal vagina Rabbit Down‐regulation of NOS 28 receptors Androgen Proximal Rabbit Facilitation of vaginal smooth 28 receptors Vagina muscle relaxation TGF□1 Vagina Diabetic Fibrosis 29 rat VIP Clitoris Human Smooth muscle relaxation, 9, 10, 11, Vagina Cat neurotransmission, blood flow 24, 30, 31, Rat control and capillary permeability 32, 33 Guinea pig Goat Hen Pig PSA Skene’s gland Human Prostatic marker 34, 35 PAP Skene’s gland Human Prostatic marker 35, 36 UP1 Skene’s gland Human Protection of uroepithelium? 37 Chromogranin Skene’s gland Human Marker of neurosecretion 15, 38 Pig 182 Textbook of Female Sexual Function and Dysfunction

complex” [40] (see Tables 13.2 and 13.3 of the clitoris. The tunica albuginea is a dense for innervation and vascularization, respec- connective tissue sheath covering the body of tively). In the clitoris, several structures are the clitoris [42]. identified. The external clitoris consists of Some anatomical aspects have been related the glans (the visible portions of the clitoral to clitoral function. While the os penis is complex), prepuce (the skin likened to penile widely represented in mammals, with the foreskin), and frenulum (a posterior fold). unique exception of humans and rabbit [43], The internal clitoris, containing most of the the occurrence of the os clitoridis is variable. erectile tissue, consists of the body (paired Mice, but not rats, have a small os clitoridis corpora, diverging to form the crura), the corresponding to the intramembranous bulbs (comparable to the corpus spongiosum part of the proximal element of the os penis. of the penis) [41], and the crura (surrounding Neonatal treatment with androgens, but not the urethra and attaching to the ischiopubic estrogens, stimulates the growth of the os rami). The corpora and the bulbs communi- clitoridis [44]. At birth, clitoral size may be cate through the venous plexus of Kobelt. The related to ethnicity [45, 46]. The following suspensory ligaments secure the clitoris to average values have been reported: 5.9 mm in the labia, the mons pubis, and the pubic newborns of Jewish origin and 6.6 mm in ­symphysis, which prevents the straightening Bedouin babies [47], which is almost twice

Table 13.2 Innervation of female sexual organs.

Nerve Role Innervated region

Dorsal nerve of the clitoris Somatic innervation Clitoris complex (from the pudendal nerve) Cavernous nerves (from the Supply the erectile tissue arteries Corpora cavernosa of inferior hypogastric plexus) through visceral fibers the clitoris Vaginal plexus Visceral innervation Vagina Pelvic splanchnic nerves Visceral innervation Vagina Pudendal nerve Visceral innervation Lower third of the vagina

Table 13.3 Vascularization of female sexual organs.

Vessel Role Vascularized region

Dorsal clitoral arteries, perineal Arterial supply Erectile tissue of glans and body arteries, and deep arteries External pudendal Arterial supply Prepuce Dorsal vein Venous drainage to the Clitoris vesical venous plexus Kobelt Plexus Venous drainage Communication between bulbs and corpora cavernosa of citoris Vaginal arteries and their Arterial supply Vagina anastomoses with branches of the uterine, inferior vesical and internal pudendal arteries Internal pudendal artery Arterial supply Vaginal walls Peripheral and Central Neural Bases of Orgasm 183 that of the 3.27 mm in white and the 3.66 mm to the pubococcygeal muscle and fixed to the measured in black neonates [48]. There are perineal membrane, with individual varia- reports of a negative correlation between tion. The posterior wall is separated from the birth weight and clitoral length [49] but not rectum by the rectovaginal septum and from with gestational age [50]. Women with the anus by the perineal fibromuscular ­anorgasmia were reported to have a smaller tissue. clitoral glans and clitoral components far- The vagina, and in particular the anterior ther from the vaginal lumen than women vaginal wall, is richly innervated. with normal orgasmic function [51]. Microdissection reveals that the distal ante- The anogenital distance is also related to rior vaginal wall is significantly thicker than female orgasm and female sexual pleasure. the proximal anterior vaginal wall and that It is considered a biomarker for the prenatal this region is the most densely innervated hormonal environment, in particular to the area, suggesting regional differences in the exposure to androgens. Perineum length ability to trigger the erotic stimuli [56]. was reported, on average, to be half that of The female prostate (prostata foemina), males [52]. The anogenital distance measure- previously termed Skene glands or periure- ment immediately after birth has been thral glands, surrounds the urethra within ­suggested as a noninvasive method to assess the anterior vaginal wall, with a microscopic uterine exposure to sexual hormones [53]. structure similar to its male counterpart, A greater anogenital distance was associated albeit with some important differences that with higher testosterone levels in women underlie functional diversity. The glandular [54]. Another anatomical aspect that may component of the female prostate consists account for the variation in ability to experi- predominantly of ductal structures that open ence orgasm is the distance between the independently into the lumen of the urethra, glans clitoris and the urethra. With a distance while the acinar secretory component is rela- less than 2.5 cm, vaginally‐activated orgasm tively less well developed. The female pros- may more easily occur [55]. tate is considered the main source of prostate‐specific antigen present in the fluid Gross Anatomy of the Vagina emitted from the urethra (the “female ejacu- late”) resulting from direct stimulation of the The vagina, too often considered primarily anterior vaginal wall [57]. The stromal com- as just a part of the birth canal, is more ponent that surrounds the glands is much appropriately defined as the female organ of more developed in the female prostate than copulation. It consists of a tubular fibromus- in the male, and is formed by a fibromuscular cular structure that extends in the direction connective tissue rich in nerve and blood posterosuperior from the vestibule between vessel terminations. the labia minora to the cervix, at a right angle to the long axis of the uterus (see Tables 13.2 Functional Changes During and 13.3 for innervation and vascularization, Arousal and Orgasm respectively). The vagina can be considered to consist of a posterior wall and an anterior Modern imaging techniques allow visualiza- wall, in continuity with each other, with an tion of the dynamic interactions of the female H‐shape when seen in cross‐section in the genitals during sexual self‐stimulation and relaxed state. penetration [58–60]. Although the search for The vagina is attached laterally to the the “mythical” G‐spot was unsuccessful in ­pelvic sidewalls and caudally to the uterus, finding a unique structure, it had the merit to thus, further permitting distensability and have highlighted the dramatic role for female adaptation to changes in pressure. The con- orgasm and female sexual pleasure of the nective tissue of the vaginal walls is attached vagina in general, and anterior vaginal wall in 184 Textbook of Female Sexual Function and Dysfunction

particular, and to provide the anatomical to subject, even possibly changing within the basis for vaginally‐activated orgasm [61, 62]. same subject in relation to the different The anatomical relationships and the phases of life. Understanding the anatomy dynamic interaction among clitoris, urethra, and the physiology of the clito‐urethro‐­ and anterior vaginal wall, as evidenced vaginal complex will help to prevent damage through ultrasound imaging during coitus, to the neural, muscular and vascular compo- made evident the need of an improvement in nents during surgical procedures of this the nomenclature. essential body component. The term clito‐urethro‐vaginal complex was coined to identify a multifaceted ­Brain Activity and Correlates ­morpho‐functional area (Figure 13.1), which, when properly stimulated during penetra- of Orgasm tion, can induce vaginally‐activated orgasm in some women [2, 63]. Vaginally‐activated While there are many brain imaging studies orgasm involves the pumping effect on the of sexual arousal [64–74], those of orgasm are Kobelt plexus, while the root of the clitoris is fewer and more variable. During orgasm in particularly stretched by the penis and com- women, the brain regions reported to be acti- pressed against the anterior vaginal wall, vated include the amygdala and hippocampus the pubic symphysis and the urethra with [64, 66, 75–77], hypothalamus [64, 65, 72, 73], the surrounding exocrine glands and erectile the dopaminergic system from ventral teg- tissue. The anatomical structures that mentum [78] to nucleus accumbens [76, 77], ­participate in the clito‐urethro‐vaginal com- anterior cingulate [76–79], frontal cortices plex formation are exquisitely hormone‐­ [76, 77], and the cerebellum [76–79]. As yet sensitive and, hence, different from subject unresolved is a discrepancy in the literature

Clitoral glans

Urethral opening Corpus cavernosum Bulb of vestibule

Vaginal opening Crus of clitoris Anterior vaginal wall

Prostata foeminina ducts

Figure 13.1 Anatomy of the CUV complex. Schematic representation of the external and internal clitoris and the vaginal opening. The insert, an anterior vaginal wall obtained from a cadaver [15, 21], represent the intimate relationships between all the different anatomical structures involved in the female sexual pleasure. (See plate section for color representation of the figure) Peripheral and Central Neural Bases of Orgasm 185 as to whether the frontal and temporal by genital self‐stimulation [79, 84, 87, 88]. ­cortical regions become activated (based on This could be a basis for anecdotal reports fMRI) during orgasm [76, 80] or deactivated that nipple stimulation may elicit orgasm (based on PET) [81, 82]. The overall similari- [89]. Evidently, a complex brain system ties in brain activity during orgasm between becomes activated incrementally, leading up men and women are greater than the differ- to an orgasmic crescendo that involves wide- ences, with some exceptions in the amygdala, spread brain activation, and then “cooling temporal lobe, lower brainstem [78, 83] and down” as shown in Figures 13.2 and 13.3. during the post‐orgasm refractory period [84]. Brain Activity Related to Orgasm Genital Sensation and Projections to the Brain To characterize the change from high arousal just prior to orgasm in comparison with Orgasm reported as being elicited by stimu- orgasm per se, we electronically subtracted lation of the clitoris, vagina, and/or cervix the activity during the 10 seconds just prior has been described as having different quali- to the onset of orgasm (indicated by the ties. Clitoral orgasm has been characterized women pressing a button at the onset of as more localized than vaginally‐activated orgasm) from the 10‐s activity during orgasm, which has been described as deeper orgasm. The differentially activated brain and more whole‐body, while cervical orgasm regions were amygdala, hippocampus, has been described in more abstract terms nucleus accumbens, hypothalamus, septum, (e.g. a “shower of stars” or “images of univer- anterior cingulate and insular cortices, and sal spaciousness”). Combining the genital lower brainstem regions including ventral stimulation sites was described as “mixed” tegmental area, periaqueductal gray, and orgasms [61, 85]. In a study of 128 women, dorsal raphe (Figure 13.4). 95% of the women claimed that clitoral stim- ulation contributed to their orgasm, while Role of Different Brain 65% said vaginal stimulation, and 35% said Components in Orgasm cervical [86]. By selective self‐stimulation of the clitoris, The nucleus accumbens and the ventral teg- vagina or cervix, different, but overlapping, mental area were both activated at orgasm. regions of the genital sensory cortex (i.e. the The ventral tegmental area is a major paracentral lobule) were activated, most source of the neurons of the mesolimbic sys- likely corresponding to the differential but tem, which project to the nucleus accumbens overlapping innervation by pudendal, pelvic, where they release dopamine. Dopaminergic and hypogastric nerves, respectively [79]. antagonists can attenuate, and dopaminergic On the basis that stimulation of each of these agonists promote, sexual response and genital components can elicit orgasm and orgasm [61]. In rats, dopamine was released the observation that a larger brain region is during mating behavior [90]. activated by the combination of stimulation One of the salient features of orgasm in of these genital components, representing a women is a marked elevation of the pain larger population of genitally‐activated neu- threshold [91]. We observed an activation of rons, this implies that combined stimulation the periaqueductal gray and the dorsal raphe of these genital components could generate during orgasm. These two brain regions orgasms that are more intense, sensually play a significant role in the descending complex, and pleasurable than if stimulated brainstem‐spinal cord pain‐attenuating by more limited genital components. Nipple ­system [92] in which serotonin produced by self‐stimulation also activated the paracentral the raphe neurons activates the “pain gate” lobule, overlapping with the regions activated control mechanism in the spinal cord. 186 Textbook of Female Sexual Function and Dysfunction

IH CO UM TC OX CM

Figure 13.2 Descriptive “tapestry” representation of brain activity in response to clitoral self‐stimulation leading up to, during, and after orgasm in each of six women. Each woman’s tapestry consists of 80 columns, each column representing a Brodmann area. Each row represents a successive two‐second sample of functional MRI activity, starting at the top. The relative magnitude of brain activity in each region at each time period is represented as brightness. The shorter vertical bars to the right of each tapestry represents the onset and duration of orgasm; the longer bars represent the onset and duration of clitoral self‐stimulation. Note the maximum activation in widespread brain regions during orgasm, in contrast to the variable patterns of regional brain activity leading up to, and after, orgasm. These descriptive data and those in the subsequent figures comprise part of the doctoral dissertation of Dr Nan Wise at Rutgers University. Dr Eleni Frangos collaborated in portions of the research. (See plate section for color representation of the figure)

This descending system was shown to be is also probably involved in the emotional activated by vaginal stimulation in rats [93]. [100] correlates of orgasm. The anterior cingulate and insular cortices Penfield showed that electrical stimulation activated at orgasm have also been shown to of the hippocampus elicited dreamlike be activated by painful stimuli [94–96]. There imagery [101]. Perhaps the activation of the is a curious similarity between the facial gri- hippocampus at orgasm plays a significant maces of women and men during orgasm role in fantasy generation during orgasm. and pain – labeled on a website as the face of How may nucleus accumbens, cingulate cor- “sweet agony”, perhaps related to evidence tex, insular cortex, amygdala, hippocampus, that the afferent spinal cord pathway for pain and paraventricular nucleus of the hypothala- and orgasm apparently both use the spi- mus (PVN) contribute to the characteristics of nothalamic pathway [97, 98]. orgasm? The PVN neurons produce oxytocin The amygdala and posterior hypothalamus and become activated during orgasm, releas- are activated at orgasm (Figure 13.4). These ing oxytocin into the bloodstream from two regions may be involved in the sympa- the posterior pituitary gland [102, 103]. In thetic autonomic division that induces the response to this oxytocin, the uterus contracts increased heart rate and blood pressure vigorously, generating sensations that women characteristic of orgasm [99]. The amygdala claim intensify the pleasure of orgasm [61]. Peripheral and Central Neural Bases of Orgasm 187

post insl pfc ant cing nacc amyg hpc SII post cing pcl pc vta

Mid stim > Early stim

Orgasm > Mid stim

Orgasm > Early recovery

Early recovery > Late recovery

Figure 13.3 Preliminary group fMRI data (N = 10) providing evidence that maximum overall activation in widespread regions of the brain was observed at orgasm. Multiple brain “sections” are shown, representing the regions identified by the labels above them. The data were generated by subtracting one 10‐second epoch from another. Thus, activity during the first 10 s of stimulation (“Early stim”) was subtracted from the 10‐s activity midway between the start of stimulation and the start of orgasm (“Mid stim”). The activity at mid‐stim was subtracted from the 10‐s epoch starting when the women pressed a button indicating initiation of orgasm. The subsequent postorgasm responses were comparably subtracted as indicated (“recovery” refers to the phase after the women pressed the button to indicate the end of their orgasm). Abbreviations: amyg: amygdala; ant cing: anterior cingulate cortex; hpc: hippocampus; nacc: nucleus accumbens; pc: parietal cortex; pcl: paracentral lobule; pfc: prefrontal cortex; post cing: posterior cingulate cortex; post insl: posterior insula; SII: Supplementary sensory cortex (operculum); vta: ventral tegmental area. (See plate section for color representation of the figure)

The PVN also plays an essential role in oxytocin serves both as a hormone in orgasm ejaculation. In rats, these neurons are stimu- in women and men and as a neurotransmitter lated by dopamine (at D4 receptors) [104], in ejaculation in males [108]. some of which project to the posterior The nucleus accumbens is activated at ­pituitary and bifurcate. The other oxytocin‐ orgasm in women [76] (Figure 13.4) and containing axons project down through the receives a significant dopaminergic input spinal cord and synapse on neurons at the from neurons in the ventral tegmental area. lumbar to sacral levels that control erection The ventral tegmental area is also activated and ejaculation [105], with oxytocin acting as during orgasm in men [78]. Thus, this dopa- a sympathetic division preganglionic stimu- minergic system is evidently activated during latory neurotransmitter [106, 107]. Thus, orgasm in women and men. Pharmacological 188 Textbook of Female Sexual Function and Dysfunction

N Accumbens Septum Ant hypothalamus Amygdala

Hippocampus Post hypothalamus Operculum (S2) Post cingulate ctx

Post insula Periaqueductal gray Paracentral lobule Post parietal ctx

Figure 13.4 Preliminary group data providing evidence of regional activation pattern “going over” into orgasm. The group activity in each region during the 10 seconds immediately prior to the button press was subtracted from the 10 seconds immediately after the button press, by which the women indicated the start of their orgasm. Brain areas activated at criterion of z = 1.65 are labeled by a square; those at a criterion of z = 1.55 are labeled by a circle. Brain areas from the brain stem analysis are labeled by an asterisk and are activated at a criterion of z = 1.0. While the latter two z criteria are lower than customary, the data are shown in order to represent activity in brainstem regions represented by very few voxels, which might otherwise be subject to a type 2 error. (See plate section for color representation of the figure)

studies provide evidence that dopaminergic lum plays not only a motoric, but also a sig- blockade attenuates orgasmic intensity, and nificant perceptual/cognitive‐hedonic, role dopaminergic stimulation intensifies it [61]. in orgasm. The nucleus accumbens is activated during The cingulate cortex, which is strongly acti- cocaine or nicotine‐induced euphoric “rush” vated at orgasm, likely plays a dual role of [75, 109], which share characteristics of stimulating the output of the sympathetic orgasm [110]. division of the autonomic system and The cerebellum becomes activated at ­generating the intense feelings of orgasm. orgasm in women and men [76, 78, 82, 83]. At orgasm in women, the heart rate, blood Increased muscle tension, which can reach pressure, pupil diameter, and pain thresholds peak levels at orgasm [111], is regulated by each approximately double in magnitude the cerebellum via proprioception and the [99], all of which indicate a net intense activa- gamma efferent system [112]. Since muscle tion of sympathetic output. The observations tension contributes to the sensory pleasure that the cingulate cortex also responds to “… of orgasm [110], it is likely that the cerebel- pleasant touch, taste and olfactory stimuli Peripheral and Central Neural Bases of Orgasm 189

Corollary Animal Studies suggests that this region is not only involved in the processing of affectively negative Consistent with the brain regions that are ­stimuli such as pain and aversive taste” [113], activated during orgasm in humans, studies but rather more generally to intense emotion‐ in the laboratory rat report activation of provoking feelings [114, 115]. many of the same‐named brain components The insular cortex, which is also reliably in response to genital stimulation. Thus, and strongly activated during orgasm, medi- based on the indicator c‐fos, activation was ates visceral feelings, especially pleasure and reported in the amygdala [123–128] and par- pain [116, 117]. Activation of both the amyg- aventricular nucleus of the hypothalamus dala and the hippocampus occurs during [124]. Furthermore, dopamine is released in orgasm (Figure 13.4). Consistent with this the nucleus accumbens [90]. More precise finding is that both the amygdala and the understanding of the anatomy and functional hippocampus are susceptible to temporal neurophysiology of orgasm should facilitate lobe or psychomotor epilepsy [118], which in improving current therapeutic strategies may generate orgasmic feelings, and pre‐­ and in developing novel treatments for seizure “orgasmic aura” [119–122]. ­orgasmic dysfunction.

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14

Psychological Management of Orgasm Disorders Sara Nasserzadeh

Abstract

Psychological factors involve in facilitating or hindering the experience of orgasm are still under study. This chapter discusses orgasm as an element in the human sexual response cycle as we understand to date. It provides a summary of the most common predisposing, precipitating, and maintaining factors known to be underlying orgasmic disorders. It then discusses various models, ideas, and techniques that were proposed by clinicians and researches to assess, manage or treat these problems including the Holistic Assessment and Therapies Model (HAT). Definition and expression of orgasm related problems and their clinical implications are discussed.

Keywords: orgasm; psychological; orgasmic; sexual response; social; cultural; language; holistic; assessment; treatment; diagnosis; disorder

The linear model of sexual response has evolved over the years to a more circular model which is much more aligned with what an individual might experience. Psychosocial and psychological factors can predispose a person to orgasmic dysfunction, precipitate an episode of concerning experience, or contribute to the perpetuation of the condition. Definition and expression of orgasm related problems vary across cultures, which could have clinical implications.

­Introduction ­Orgasm

This chapter focuses on optimizing clinical This simple word could be a reminder of success with women presenting with orgasm pleasure or pain, grief or gain for many disorders where underlying psychological women and couples. Orgasms have been factors are at play. It will provide an overview defined and redefined throughout history. of some of the psychosocial and psychologi- The word itself derives from the ancient cal factors that could predispose a woman to Greek orgasmos, which means, “to swell as orgasm dysfunction, precipitate an episode with moisture, be excited or eager” (Oxford of dysfunction, or contribute to the perpetu- Dictionary). One of the most quoted ation of the orgasm condition. ­definitions today belongs to John Money and

Textbook of Female Sexual Function and Dysfunction: Diagnosis and Treatment, First Edition. Edited by Irwin Goldstein, Anita H. Clayton, Andrew T. Goldstein, Noel N. Kim, and Sheryl A. Kingsberg. © 2018 John Wiley & Sons Ltd. Published 2018 by John Wiley & Sons Ltd. 198 Textbook of Female Sexual Function and Dysfunction

colleagues (1991) “The zenith of sexuoerotic are described as more intense, but located experience that men and women character- in the outer region of the vagina. They ize subjectively as voluptuous rapture or ­further report that deep orgasms with ecstasy. It occurs simultaneously in the brain/ internal sensation were linked to male part- mind and pelvic genitalia. …” [1]. ners who were perceived to be considerate, This conceptualization of orgasm as a dominant, with a noticeably attractive measure of the success of any sex‐related smell, and providing firm penetration [3]. behavior or activity also stems, in part, from However, it is also important to note that the significance sexual pleasure has within a some ­hypothesized reproductively specific cultural context. Is sexuality seen as ­significant characteristics, such as being an integral part of overall health and well‐ muscular, masculine, and aggressive, were being or is it linked to a certain stage of life not differentially associated with women such as puberty or marriage? [2]. Is sexual experiencing deep orgasms. According to pleasure seen as part of every healthy sexual Gallup and colleagues, orgasm frequency relationship or is it considered as a luxury? Is was highly correlated with orgasm intensity orgasm an entity that only one of the ­partners but intensity was found to be a better pre- is permitted, expected to have or believed to dictor of sexual satisfaction than orgasm experience? Who, within a culture, is expected frequency [4]. In the same research, fre- to receive sexual pleasure? Is sexual pleasure quency of orgasms for heterosexual female seen as a component of overall health or a college students was found to be dependent luxury men enjoy, or something that is given on three factors: partner’s family income, to certain people by certain others? his self‐­confidence, and how attractive he We could dedicate a whole book to was. Orgasm intensity, on the other hand, ­definitions of orgasm, as it is such an was found to depend on how attracted ­individualistic and subjective experience. women felt toward their male partners, the Barry Komisaruk at Rutgers University number of times they had sex per week, and explains: “It is like asking someone to ratings of sexual satisfaction. Gallup and describe how something tastes!” To have a colleagues also found that women who had baseline, though, this chapter defines started having sex at a younger age reported orgasms as a buildup of pleasurable sensa- being more satisfied with their sex lives in tions and excitement to a peak intensity that general. Men’s sense of humor was also releases tension and creates a feeling of satis- reported to enhance orgasm frequency in faction and relaxation [2]. the 54 women who were included [4]. In criticizing evolutionary explanations of female orgasms (i.e. the idea that female ­Orgasms and the Sexual orgasms had a purpose for the sake of repro- Response Cycle duction), Elizabeth Lloyd in The Case of the Female Orgasm takes on questions of how There is still much debate around whether data on female sexuality and orgasms were female orgasm is necessary, unnecessary, obtained and debunks explanations that she fictional, a luxury, how it should feel and believes to be inadequate [5]. For the sake of how frequently. In a study of heterosexual providing context for this chapter, it is worth- couples King and Belsky from University of while to consider an overview of the evolu- East London, report that women experi- tion of sexual response models since the ence two types of orgasms which they call linear model was introduced by Masters and Surface and Deep orgasms. According to Johnson in 1966 [6]. In the linear model of King and colleagues, Deep orgasms are sexual response, both men and women associated with internal feelings like float- thought to undergo four stages, beginning ing and internal pulsing. Surface orgasms with excitement/arousal and proceeding to Psychological Management of Orgasm Disorders 199

Orgasm

Plateau Resolution

Resolution Resolution

Excitement B

A C

ABC

Figure 14.1 Female sexual response model developed by Masters and Johnson, 1966 [6].

Figure 14.2 Circular model of female Surrender sexual response developed by Whipple Sensations and Brash‐McGreer, 1997 [8].

Ref

lection Orgasm

Plateau Resolution Seduction

Desire Excitement

plateau, orgasm, and resolution (Figure 14.1). similar sexual responses, which then could Helen Kaplan added the concept of desire to lead to unnecessary pathologization of nor- the model and presented the model in three mal behavior in women [6, 7]. Whipple and phases: desire, arousal, and orgasm [7]. While Brash‐McGreer then argued that many this model was more generally applicable, as women do not move progressively and the science of sexology and empirical cases of sequentially through the phases as described psychosexual therapy accumulated, the [8]. This gave birth to the circular model of model needed some further revisions to fit sexual response. This new model was based the evolving understanding around women’s on David Reed’s Erotic Stimulus Pathway sexual response. (published for the first time by William Both Masters and Johnson, as well as Stayton in 1998) [9], which comprises four Kaplan, assumed that men and women have stages (Figure 14.2): seduction (encompassing 200 Textbook of Female Sexual Function and Dysfunction

desire), sensations (excitement and plateau), an important piece of information we could surrender (orgasm), and reflection (resolu- share with clients who feel the pressure of tion). The main insight of this model was that experiencing a certain outcome from their women may not experience all of the phases sexual engagement. As it is ­presented in introduced in previous models. For example, Figure 14.3, this model incorporates the they may move from sexual arousal to orgasm importance of emotional intimacy, sexual and satisfaction without experiencing sexual stimuli, and relationship satisfaction. It further desire or they can e­ xperience desire, arousal, acknowledges that female sexual functioning and satisfaction but not orgasm. The pleasant can proceed in a complex and circuitous man- and satisfying sexual experiences may have a ner, and is dramatically and significantly reinforcing effect on a woman, leading to the affected by numerous psychosocial issues (e.g. seduction phase of the next sexual experi- satisfaction with the relationship, self‐image, ence. If, during reflection, the sexual experi- previous negative sexual experiences). ence did not provide pleasure and satisfaction, the woman may not have a desire to repeat the experience, based on the reward‐seeking ­Orgasms within tendency of the brain. The circle is a pleasure the Cultural Framework oriented, not a goal oriented model, where any activity can lead to pleasure and there is Does one have an orgasm, or experience one? not a goal of orgasm. Is an orgasm like an object, something one This thinking was then further developed by can own, give and take? Or is it an experi- Dr. Rosemary Basson within the context of the ence, a journey, something that is subjec- responsive nature of women’s sexual desire tively felt and described rather than being [10]. According to Basson, women have many witnessed or confirmed by others? Should it reasons to engage in sexual activity other than be treated differently when it comes to exist- sexual drive. The Basson model clarifies that ence in solitude or amongst partners? the goal of sexual activity for women is not Defining issues around pleasure and orgasm necessarily orgasm but rather personal outside of the clinical diagnostic definitions ­satisfaction, which can manifest as physical will rely heavily on culture, gender roles, and satisfaction (could be orgasm) and/or emo- the public’s level of awareness and knowledge tional satisfaction (a feeling of intimacy and around sexuality, sexual health, and the func- connection with a partner) [10]. This could be tioning of the human body. When assessing a

Emotional Seeking out and Figure 14.3 Nonlinear model of intimacy being receptive to female sexual response developed by Basson, 2000 [10]. Emotional and physical satisfaction

Spontaneous Sexual sexual drive stimuli

Arousal and sexual desire

Sexual arousal Biological physiological Psychological Management of Orgasm Disorders 201 woman, it is important to consider how sexual women had experienced penile‐vaginal inter- acts are perceived within that person’s culture. course, out of which 25% of men and 50% of Who is expected to receive pleasure and who women reported pretending orgasm [12]. is expected/deserves to give it? Traditional This might not seem a problem at face value; cultures do not see all types of pleasure, sexual however, some of these students might go on experience, and sexual expressions through to shape long‐term relationships in which at the same lens as more egalitarian and goal‐ some point they do not wish to “fake” their focused cultures. orgasms anymore, which could cause their Today, in our current sociopsychological partners to develop a sense of betrayal, context, sexual desire, sexual fulfillment, humiliation, and distrust. The fact that there love, and happiness are seen as closely is a way to “imitate” or “fake” an orgasm tells related. Pleasure and orgasms are considered us a lot about an unspoken normative con- to be critical parts of adult sexuality and, as struct that exists around what orgasms such, are necessary to maintaining a healthy should look like. On the other hand, strug- lifestyle and healthy romantic/sexual rela- gling individuals might be in search of reas- tionship [11]. Simply put, orgasms are seen surance to become certain that what they or as being a part of healthy adult sexuality, their partners feel is, in fact, orgasm. which is, in turn, part of a healthy adult In another study which looked at linguistic ­lifestyle. Therefore, the Basson model, which representation and definition of orgasm does not present orgasm as a necessary phase across 27 languages, Chiang and Chiang cat- in sexual response for women, may be a relief egorized orgasm into three groups: orgasm for women but is not always as acceptable or as a physiological response, orgasm as a psy- appealing to some male partners, as they chological state, and orgasm as an ideal goal expect reactions and gratifications for their [11]. The terminology in Bengali (anonndo loved ones similar to what they experience. kora, “enjoy oneself”), French (Je jouis, “I In fact, the experience of orgasm for many enjoy”), Persian (Farsi) (lezat bordan, couples seems to be so central to their idea of “Enjoying”), and Portuguese (Brazilian) (Eu sexuality that it is often used as a measurement estou gozando, “I’m enjoying”) can be trans- of the success of any given sexual activity, of lated and understood as the English concept the compatibility of partners, and of the pleas- of “I’m enjoying”. It has been mentioned that ure experienced [4]. This mostly stems from orgasm consists of related concepts such as the way in which sexuality is ­conceptualized in (feeling of) satisfaction and (feeling of) pleas- the western world. When sexuality is equated ure. In French (la petite mort), an orgasm to, or synonymous with, sexual activity it directly translates to something that refers to becomes measurable like any other individual the altered state of consciousness and the achievements. It is seen as a physical response feeling experienced during orgasm of not (mainly erection, lubrication) followed by the having control over the body [13–15]. individual’s ability to experience orgasms as a Taking a closer look at the ways in which result of that performance. Compatibility, orgasms were defined across cultures, a additionally is measured more so from an evo- ­significant deal of crossover between the psy- lutionary ­perspective, focusing on reproduc- chical state and feelings became apparent. tion and success of reproduction, as outlined In Bengali, as in Persian (Farsi), “satisfaction by Gallup and colleagues [4]. is happening” and in Vietnamese “extreme This is to the extent that the whole issue of pleasure” all denote a certain type of feeling pretending or faking orgasm has become a [11]. The way orgasms were ­articulated point of conversation and research on its within the linguistic analysis, 16 languages own. Muehlenhard and Shippe reported that had adapted a version of or a meaning similar in a study with 180 male and 101 female col- to “I’m coming,” three languages used endings lege students, 85% of the men and 68% of the “I’m ending”. Wilkins and Hill note that the 202 Textbook of Female Sexual Function and Dysfunction

motion verbs “come” and “go” vary from cul- first must be acknowledged as a “prob- ture to culture as to “whom the deictic center lem” – something that is not within the range can be shifted, how far the deictic center can of normal. But what is normal will depend in grow to include other places/­peoples, and large part on the context within which the what ­metaphorical extensions are possible” “problem” is embedded. Thus, the overall cul- [16]. Location, direction of movement, the ture and, more specifically, the sexual culture number of speakers involved, and the context in which we are immersed can sometimes determine whether going or coming is used contribute to the existence or prevalence of a when linguistically conceptualizing orgasms. certain disorder, as culture affects human “When the ‘reaching’ of an orgasm is being psychology, values, attitudes, and behaviors. conceptualized as ‘coming’, it may be implying Today, in the West, many people experience that orgasm is a process of reaching a certain significant pressure not only to perform sexu- destination” [11]. Out of all the orgasm termi- ally but to “dangle from the chandeliers”. nologies collected, linguistic expressions with Women’s partners are expected to “give”, the meaning “I’m discharging” have the most and women are expected to “have”, earth‐shat- gender‐specific usages out of all the other cat- tering orgasmic experiences. This pressure, egories. Specifically, for Mandarin Chinese, along with many others, remains as a shadow of Indonesian, and Turkish, the terminology expectation that haunts many women who may used for orgasm in males are “I’m shooting”, struggle to experience something (an orgasm) “about to shoot”, and “discharge”, respectively. that they are taught to believe should be effort- In these linguistic expressions, it seems that less. Both men and women are expected to the focus is on the physiological response of have satisfying sex lives (while their idea of it is an ejaculation during a male orgasmic experi- very much tainted) and if they do not then they ence [15, 17, 18]. In Vietnamese, both genders begin to look for the “problem”. can use “to (get) out” to announce an orgasm. At the opposite end of the spectrum, All of the linguistic expressions used in these ­consider a more traditional culture where languages appear to be indicating that an women’s sexuality is equated with reproduc- orgasm is a physiological experience of dis- tion and wifely duty. Orgasms are perceived charging fluid or releasing tension out of the as something meant for men to enjoy; not for body depending on the gender specific expe- women. In this case, the lack of female riences of a male or female orgasm. In other orgasms will not be addressed as issues, since words, it is predominantly conceptualized as it is simply the way things are in their natural a physical response. state. Sexual pain disorders can also be The overview just provided should form viewed in a similar light, especially in cul- our basic tools for assessment, the way we tures where pain is taught to be an expected word our history‐taking questions, and the outcome of sexual intercourse for women. way we formulate and present our treatment Pain, in such cases, will less likely be per- plans to the clients. This will also help with ceived as something that is problematic since our understanding regarding the client’s it is considered normal and even expected. presentation of their issue area of emphasis and concern. Clinical Context

According to the fifth edition of the Diagnostic ­Orgasm Dysfunctions and Statistical Manual for Mental Disorders (DSM‐5), female orgasm disorder is character- Cultural Context ized by a significant change in orgasm, such as delay, reduction of intensity, or cessation, that For any physical or psychological condition to has been present for at least six months and be perceived as an issue worthy of attention, it that causes significant distress for the woman Psychological Management of Orgasm Disorders 203

[19]. Although no single cause has been identi- The presence of distress is one of the main fied, female orgasm disorder has been associ- criterion that differentiates a clinically sig- ated with relational problems, stress, nificant orgasm disorder from other com- depression, anxiety, the use of medication, and plaints. Kluck and colleagues found that the existence of chronic underlying medical while high standards directed toward sexual conditions. (Ironically, orgasms are also known partners caused few problems sexually, an to reduce physiological and psychological individual’s perception that her partner stress.) For some women, the condition is life‐ expects her to be the “perfect sexual partner” long and has persisted since the first sexual had a much more serious and at times delete- encounter, which makes it a primary disorder. rious effect on individuals [21]. It could For others, the problematic change in orgasm almost be the equivalent of performance might occur after a period of satisfying sexual anxiety in a male who presents with ejacula- activity and enjoyment and, as such, it is con- tory or erectile difficulty due to the height- sidered to be a secondary disorder. In some ened pressure they perceive from their cases, the disturbance may only happen with partners or themselves to perform in an ideal some sexual activities or partners but not per- way. The fact that we use the language of sist in other situations (situational versus life‐ “achieving or reaching orgasm” should be long disorder). In other cases, the condition reconsidered since, for many women, an persists in all sexual encounters. orgasm is not the chief end. As discussed in a When it comes to orgasm disorders, previous publication, “experiencing orgasm” women are overrepresented as compared to may be more appropriate [2]. men, which adds to our responsibility to In a clinical setting, it becomes important assess this condition in an accurate and to study and analyze not only the ways in timely manner. Male orgasm disorder was which orgasms are experienced but also how changed to delayed ejaculation in DSM‐5, they are thought about, expressed, and dis- which arguably has its pros and cons and is cussed. The way an individual conceptualizes beyond the scope of this chapter [19]. “orgasm” plays a critical role in understand- However, it is wise to keep the partner’s sex- ing the sociocultural nuances around his or ual profile and problems in mind when her perceptions, attitudes, and values sur- assessing a female client. Laan and colleagues rounding sexuality, sexual well‐being, and found that more than half of married women sexual health. The language used to describe report arousal or orgasm problems. Of these, what an orgasm is to the client gives critical more than three quarters reported they were insight into what meaning is loaded on to otherwise satisfied with their sexual relation- “orgasm” as a word, idea, and ideal. An ships [20]. Hopefully, the long‐standing myth orgasm is only one part of the entire human that if you fix the relationships, your sexual sexual experience, and only one of a number problem will be gone, can be dispelled right of ways in which an individual might experi- here and now, and for good. Also, referring to ence sexuality and pleasure throughout the Basson’s model and her argument that life course. orgasm is not necessarily what women are after in any given sexual encounter, we, as cli- Clinical Considerations nicians, have to be conscious of not using these statistics to frame a problem that is not The clinical suggestions provided in this seen as such by clients. chapter are based on the Holistic Assessment Not all women experiencing difficulty with and Therapies (HAT) model for the assess- orgasms would come in to our offices with ment, diagnosis, and management/treatment similar concerns or expectations. Some of sexual dysfunctions [22]. HAT encourages women experience high levels of distress, practitioners to work holistically and as while others are only mildly bothered [19]. a part of a team to conduct a thorough 204 Textbook of Female Sexual Function and Dysfunction

­investigation of the client’s sexual concern by Common Beliefs/Myths that taking the overall well‐being and context of Perpetuate Orgasm Dysfunction the life of the client into account. It also In addition to examining an individual’s socio- stands for the various “hats” that a practi- cultural beliefs, biases, thoughts, and feelings tioner wears during the whole process of around sexuality, it is also important to address working with clients through the five stages any points of misinformation that could be of the clinical journey. This takes the previ- perpetuating the client’s distress. For example, ously suggested bio‐psycho‐social model [23, some common misconceptions include: 24] and adds five practical dimensions to it: addressing, assessment, diagnosis, manage- ●● women fear that if they experience orgasm ment/treatment, and follow‐up [22]. while pregnant – or even if they have sex- A significant aspect of addressing sexuality‐ ual encounter while pregnant – it could related issues or sexual dysfunctions with harm the baby; ­clients is the healing power that is offered by ●● if a woman does not have an orgasm dur- being able to express what previously may not ing intercourse she will not get pregnant; have been expressible due to relational, cul- ●● if a woman does not experience orgasms tural or interpersonal barriers. Keeping the through vaginal intercourse, there must be PLISSIT Model [Permission (P), Limited something wrong with her; information (LI), Specific Suggestions (SS), ●● if a woman is unable to experience an and Intensive Therapy (IT)] in mind [25], even orgasm with a partner but has no problem in cases when the clinicians expertise may not experiencing one through masturbation, it be psychosexual therapy, giving permission to will mean that her partner is not a compat- the client to talk about his or her sexuality, ible one; sexual experiences (or lack thereof), worries, ●● if a woman has an orgasm it will be embar- needs, fears, and desires can be a significant rassing because she will lose control; stepping stone toward healing. In cases like ●● intersex individuals have less capability to this, the assessment is part of the treatment. experience orgasm and sexual pleasure; After (or if needed) in parallel to these ●● lesbian women are attracted to women stages, the author would like to suggest an because they have never experienced “real added element to the original PLISSIT model pleasure” with a man; [Referral (R)], to encourage the clinicians to ●● asexual people are told that if they had ever make a referral to an appropriate colleague if experienced an orgasm then they would that is necessary. This practice is not thought have changed their minds. about by some and frowned upon by others who equate making referrals to firing a client Finally, one of the most common beliefs or giving up. [22]. about female orgasms is that they are given There are other factors that will impact to women by their partners. This perception the assessment, management and, in general, can go both ways in further creating compli- the outcome of our work with a client. cations around what it means to experience Psychosexual therapists do not have the same orgasm. On one hand women may feel as if privileges as a medical professional who can they are not in control of their pleasure, since examine the client physically; therefore, the orgasms are given and, therefore, passively importance of a thorough history taking received. On the other hand, if a woman does questionnaire is paramount. For example, not experience orgasm while with a partner, there are genital practices by various cultural her perception of her partner may shift nega- groups that could impact their experience tively. Also, it may create feelings of dissatis- and expressions of orgasm, lack of awareness faction and anxiety in their partners, as they about them could hinder or even mislead our may feel they are unable to pleasure their treatment process [26, 27]. female partners. Psychological Management of Orgasm Disorders 205

Box 14.1 First point of contact. offer an overall picture of the woman’s sexual life and will provide the opportunity to dis- ●● Sex therapists cuss various aspects in more detail. It is ●● Sex coaches important to make note of any significant ●● Physical therapists transitions that have occurred in the wom- ●● Medical professionals and surgeons an’s life. Has there been a chronic or life‐ ●● Spiritual guides threatening medical condition such as ●● Body workers surgery, cancer, a heart attack or a spinal cord ●● Somatic coaches injury? What are the individual’s concerns ●● Psychoanalysts about re‐engaging in sex? Is sexuality seen as ●● Surrogates. a quality of life issue and, therefore, less important than other, life‐or‐death con- cerns? It is important to look at body image The help‐seeking behavior of the client and issues, particularly around surgeries. the first point of contact for each individual Another line of questioning regarding might be different (Box 14.1), depending on transitions refers to recent changes in the their exposure to resources, their informa- family structure. For some women, after tion and knowledge regarding their condi- childbirth they feel guilty experiencing pleas- tion, as well as what is available to them ure for themselves, or they feel that sexuality personally and socially, including insurance is somehow less appropriate after one has coverage. Also, the purpose of seeking help become a mother [32]. There could also be for various individuals might differ. For the issues related to painful intercourse [33]. majority, it might be to see if they are normal, Alternatively, have there been any recent why they are experiencing (or not) what they additions to the family in terms of elderly do, how to compensate for their shortcoming parents who now require care? in their relationship or how to fix themselves It is important for therapists to have the and the issue. For others, it might be to basic knowledge to rule out medical, physio- receive a label and put themselves and their logical, pharmacological, and physical partners at ease or even make a legal case for comorbidities. For example, for women divorce. All of these will inform the client’s whose sexual dysfunction developed during decision on where to seek help. For example, or after menopause, hormonal treatment is in countries such as Turkey and Iran that often useful in conjunction with behavioral ­recognize sexual dysfunction as grounds for treatments. Just having such basic knowl- divorce, diagnosis has a completely different edge, the therapist could make a suggestion purpose and outcome. Sexual incompatibil- to the client to go for an assessment by her ity between spouses is one of the most fre- obstetrician/gynecologist to determine if it is quently cited grounds for divorce in these safe for her to go on hormone therapy [34]. countries [28, 29]. In our Western goal‐oriented, egalitarian culture it is important to pay attention to the language that women use. When someone ­Assessment expresses distress, is it her own distress or her partner’s distress? At least theoretically, a When assessing for orgasm disorder it is rec- woman who no longer wishes to have sex ommended to start by establishing a baseline with her partner might not be experiencing by administering the female sexual function “clinically significant distress” though her index (FSFI) [30]. The female sexual distress partner might be. scale (FSDS) is subsequently used to deter- Understanding the client’s expectations mine the level of impact that the current con- around sex and sexuality is another area for dition has on the individual [31]. This would assessment. Perhaps she thought she was 206 Textbook of Female Sexual Function and Dysfunction

­satisfied but now her friends think her vaginal intercourse, the report was that at a orgasm should be more intense and she is certain point the woman was experiencing missing out. Given the media’s fixation on some contractions that were similar to sex and sexuality, many individuals and orgasm contractions but the feeling was not ­couples might need to manage their expecta- reported by the woman as orgasm “like how tions of what is desirable and even possible it feels with clitoral stimulation”. This might for them. be an interesting area for further research to Of course, as mentioned above, through- see if there is any nerve block, dissociation of out the assessment the clinician must pay sensation or mental block that prevents cer- close attention to the language the client tain women from feeling the pleasure of uses. Experiencing fears may play a signifi- orgasm while their body reportedly has gone cant role in orgasm dysfunction (Box 14.2). through the physical expressions of it. She might have an underlying fear of being Another possibility is that if the clitoral considered loose or overexperienced if she orgasm has been experienced by these shows that she is enjoying sexual acts or women long before they experienced pene- experiencing orgasm. If she fears she will lose trative sex then the primary feeling they control and be embarrassed she might alto- associate with orgasm might be the one they gether ignore or prevent any act that may know from this experience. They might not lead to an orgasm. She could be worried recognize the sensation created via intravagi- about the mess that lubrication or emission nal stimulation as it is not as intense as they may create or, alternatively, she could be are used to experiencing (described as Deep worried about not “ejaculating”, which is and Surface orgasm [3]). increasingly expected from women by ­partners who are influenced by commercial videos and pornography (personal clinical ­Diagnosis observations). I personally have seen women who were Taking into account the previous discus- caught by the myth of “when you have an sion on the importance of cultural and clin- orgasm you will know” and, therefore, were ical context, and after thorough assessment, worried that they might have never experi- the diagnosis phase (see DSM‐5 definition enced orgasm (especially through intravagi- in the Clinical Context section) is inevitable nal stimulation). When I give them and their for some clients. To some, this might come partners stimulatory exercises, I ask the part- as a relief, while to others, it might add to ners to insert a finger or two inside the vagi- the burden [35]. Box 14.3 summarizes the nal canal while stimulating the clitoris and common pros and cons that are partially report any contractions after. In six cases reported by King and Nazareth [36]. that presented with anorgasmia with penile‐­

Box 14.2 Fears experienced. ­Management/Treatment

●● Fear of losing control ●● Fear of not ejaculating Several psychological treatment options are ●● Fear of being embarrassed available to address the complex components ●● Fear of being considered loose of female orgasm disorder. Couples therapy ●● Fear of being considered overexperienced is reported to be an effective intervention ●● Fear of lubricating too much and creating for couples whose relationship issues are a mess. contributing factors to the orgasm disorder [20]. Pereira and colleagues suggest that Psychological Management of Orgasm Disorders 207

Box 14.3 Pros and cons of giving For example, if the couple does not disclose a diagnosis. their self‐stimulation habits in front of each other for any given reason, it would not be Pros wise to bring this up in a conjoint session.

●● She is not alone The CBT approaches usually are short and ●● There is an explanation do not go beyond 12–14 weeks. During these ●● There is the possibility of a treatment self‐exploration and stimulation trainings, ●● Opportunity for education as a part of the clients are gradually exposed to genital stim- treatment process ulation and may incorporate role play, sexual ●● Opening communication between the fantasy, and vibrators to facilitate orgasm. couple. There are a number of workshops and train- ings that might be recommended to the cli- Cons ents depending on the ease of the clinician in making these referrals, the code of ethics and ●● High expectations from the medical conduct within the licensure body of the treatment place of practice, and the willingness of the ●● Medicalization client to take part in such workshops. Meston ●● Labeling and colleagues suggest that CBT that focuses ●● Polarizing the sexual relationship. on promoting changes in attitudes and ­sexually relevant thoughts, decreasing ­anxiety, and increasing orgasm ability and ­during couples therapy, the woman and her satisfaction could be beneficial for clients partner have an opportunity to improve on presented with orgasm dysfunctions [38, 39]. their communication skills, listening, reflec- Laan, Rellini, and Barnes report that “direct tion, emotional expression, and conflict reso- masturbation training” can take place in lution [37]. In cases where the woman is individual therapy, when sexual inexperience treated individually, cooperation from the or discomfort is present [20]. It is reported sexual partner is recommended and encour- that this technique is extremely effective, aged. It is important for this inclusion to hap- resulting in 90% of women becoming orgas- pen in a delicate manner and in consideration mic during treatment. For women whose of the client’s and the couple’s cultural con- sexual dysfunction stems from inability to text. This is particularly important around focus or remain “in the moment” during sex- issues of gender roles and also around what is ual activity, yoga practice and mindfulness permissible or allowed in terms of sexual training were reported to be effective inter- encounters (e.g. certain kinds of touching, ventions [40]. In general, Barker shares that the inclusion of assisted devices and toys, existential therapy could move the couple’s and certain positions). When distressing and thinking beyond orgasm and, with this eas- conflicting thoughts and emotions are pre- ing of pressure, their overall sexual encoun- sent in a women diagnosed with female ters would be more pleasurable [41]. orgasm disorder, cognitive behavioral ther- In a recent article, Safron introduced “the apy (CBT) can effectively address these con- rhythmic entrainment” model wherein sexual cerns to reduce symptoms [20]. stimulation induces entrainment of coupling In cases where sexual inexperience or dis- mechanical and neuronal oscillatory systems, comfort is involved, self‐stimulation training thus creating synchronized functional net- is recommended. Again considering the cul- works within which multiple positive feed- tural background and the context of the cou- back processes intersect synergistically to ple, the therapist might want to consider contribute to sexual experience [42]. Safron giving these trainings in individual sessions. explains that: These processes generate states 208 Textbook of Female Sexual Function and Dysfunction

of deepening s­ensory absorption and trance, that they feel estranged by their bodies or feel potentially culminating in orgasm if critical anger as if their bodies have failed them. thresholds are surpassed. The centrality of Therefore, there is a psychological block to rhythmic stimulation (and its modulation by experiencing pleasure [44]. These clients salience) for surpassing these thresholds sug- need to be instructed to give themselves time gests ways in which differential orgasmic and try not to pressure themselves or push responding between individuals (or with dif- away their partners out of fear of disappoint- ferent partners) may serve as a mechanism ing the partner if the client doesn’t experience for ensuring adaptive mate choice. Being orgasm. They can be encouraged to find aware of all these techniques will help add to enjoyment in reconnecting with their bodies the therapist’s toolbox. and their partner’s and gradually widen their Education and a bibliography could be an experience of pleasure. Giving reassurance, impactful part of addressing any sexual issue. along with accurate medical and s­cientific What we learn from media and popular information to the woman and her partner of ­culture about orgasms sometimes assists in any gender, will go a long way. making the subject less of a taboo; however, at times it also creates or strengthens myths about anatomy, functioning, pleasure, and ­Follow‐Up and Referral orgasms. In cases where sexuality education is not commonplace (either not accessible or Due to the multidimensional nature of any not permitted), the sources of these myths, sexual dysfunction, including orgasm disor- whether media or porn, also become the ders, it is extremely important to have an source of sexuality education. effective, accessible, and expert network for Lack of literacy in sexual health, anatomy referral and support. Not only for the client and sexual function is common. Even inter- but also for the clinicians. Within the com- course is challenging for some couples, let munity of mental health practitioners, by alone experiencing pleasure. Relationship large, it is frowned upon to refer a client to stress also was found to be highly associated another provider (before they form their with female sexual dy­ sfunction [43]. These detachment with the therapist), which some- factors are further complicated by the cou- times has its merit. However, due to lack of ples’ lack of information regarding sexual comprehensive education and training of organs, their function, and ingrained mis- practitioners within the field of psychosexual conceptions regarding what the outcome of therapy, at times, it seems that keeping the any sexual encounter should be [22]. clients in one’s care would be an ethical Educating clients about their sexuality in dilemma of its own [45]. Thankfully, this is a general will go a long way toward dispelling bit less stigmatized when working with pro- myths and this is true specifically after a life‐ fessionals across disciplines. The importance altering event, such as being diagnosed with of having a referral network and knowing cancer and going through treatments, having how to refer and when is pivotal. a child, miscarriage, starting menopause, hav- ing a heart attack, or having experienced or living with severe injuries. Each of these events may have individual as well as rela- ­Acknowledgements tional consequences. For example, the woman who has survived a heart attack, or her part- The author would like to thank Rayka Kumru ner, might fear that she will be too excited by for her dedicated assistance with research, orgasm and, therefore, more prone to another and formatting of the content provided in heart attack. Some cancer survivors report this chapter. Psychological Management of Orgasm Disorders 209

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1 Money J, Wainwright G, Hingsburger D. 13 Bancroft, J. Human Sexuality and its The Breathless Orgasm, 1st edn. Buffalo, Problems, 1st edn. London: Churchill NY: Prometheus Books; 1991. Livingstone; 1989. 2 Komisaruk BR, Whipple B, Nasserzadeh S, 14 Davidson JM. (1980). The psychobiology of Beyer‐Flores C. Orgasm Answer Guide, 1st sexual experience. In Davidson JM, edn. Baltimore, MA: Johns Hopkins Davidson R J (eds) The Psychobiology of University Press; 2009. Consciousness. New York: Plenum Press; 3 King R, Belsky J. A Typological approach to 1980, pp. 271–332. testing the evolutionary functions of 15 Mah K, Binik YM. The nature of human human female orgasm. Arch Sex Behav. orgasm: a critical review of major trends. 2012;41(5): 1145–1160. Clin Psychol Rev. 2001;21(6) 823–856. 4 Gallup GG, Ampel BC. Wedberg N, 16 Wilkins DP, Hill D. (1995). When “go” means Pogosjan A. (2014). Do orgasms give “come”: Questioning the basicness of basic women feedback about mate choice? Evol motion verbs. Cogn Linguist. 1995;6:209–259 Psychol. 2014;12(5):958–978. 17 Newman HF, Reiss H, Northup JD. Physical 5 Lloyd EA. The Case Of The Female basis of emission, ejaculation and orgasm Orgasm, 1st edn. Cambridge, MA: Harvard in the male. Urology. 1982;19:341–350 University Press; 2005. 18 Tuckwell HC. A neurophysiological theory 6 Masters WH, Johnson VE. Human Sexual of a reproductive process. Int J Neurosci. Response, 1st edn. New York: Bantam 1989;44:143–148. Books; 1966. 19 American Psychiatric Association. 7 Kaplan HS. Disorders of Sexual Desire Diagnostic and Statistical Manual of and Other New Concepts and Techniques Mental Disorders, 1st edn. Washington, in Sex Therapy. New York: Simon and DC: American Psychiatric Publishing, 2013. Schuster; 1979. 20 Laan E, Rellini AH, Barnes T. (2013), 8 Whipple B, Brash‐McGreer K. Standard Operating Procedures for Female Management of female sexual dysfunction. Orgasmic Disorder: Consensus of the In: Sipski ML, Alexander CJ (eds) Sexual International Society for Sexual Medicine. Function in People with Disability and J Sex Med. 2013;10:74–82. Chronic Illness. A Health Professional’s 21 Kluck AS, Zhuzha K, Hughes K. Sexual Guide. Gaithersburg, MD: Aspen perfectionism in women: not as simple as Publishers, Inc.; 1997, pp 509–534. adaptive or maladaptive. Arch Sex Behav. 9 Stayton WR. A theology of sexual pleasure. 2016;45(8):2015–2027. Am Baptist Q. 1989;8(2):1–15. 22 Nasserzadeh S. Practical recommendation 10 Stehle B. Incurably Romantic. Philadelphia, to work with couples presenting with PA: Temple University Press; 1985. unconsummated marriages in any Basson R. Human sex‐response cycles. healthcare setting. Middle Eastern Society J Sex Marital Ther. 2001;27(1):33–43. for Sexual Medicine. 2014;6. 11 Chiang AY, Chiang W‐Y.(2016) Behold, 23 Rosen RC, Barsky J. Normal sexual I am coming soon! A study on the response in women. Obstet Gynecol Clin conceptualization of sexual orgasm in North Am. 2006;33(4):515–526. 27 languages. Metaphor and Symbol. 24 Althof SE, Leiblum SR, Chevret‐Measson M, 2016;31(3):131–147. et al. Original research—psychology: 12 Muehlenhard CL, Shippee SK. Men’s and psychological and interpersonal women’s reports of pretending orgasm. dimensions of sexual function and J Sex Res. 2010;47(6):552–567. dysfunction. J Sex Med. 2005;2(6):793–800. 210 Textbook of Female Sexual Function and Dysfunction

25 Annon JS. The PLISSIT model: a proposed recommendations on sexual dysfunctions conceptual scheme for the behavioral in women. J Sex Med. 2010;7:314–326. treatment of sexual problems. J Sex Educ 35 Shifren JL, Monz BU, Russo PA, Segreti A, Ther. 1976;2(1):1–15. Johannes CB. Sexual problems and distress 26 Nasserzadeh S. Ethnic and cultural aspects in United States women: prevalence and of sexuality. In: Wylie K (ed) ABC of Sexual correlates. Obstet Gynecol. 2008; Health, 3rd edn. Chichester, UK: Wiley 112(5):970–978. Blackwell; 2015, pp. 101–103. 36 King M, Holt V, Nazareth I. Women’s views 27 Nasserzadeh S. Genital practices around the of their sexual difficulties: agreement and world and implications for policy and disagreement with clinical diagnoses. Arch practice. Plenary address, World Congress of Sex Behav. 2007;36(2):281–288. Sexology, Prague, Czech Republic, May 2017. 37 Pereira VM, Arias‐Carrión O, Machado S, 28 Barikani A, Ebrahim SM, Navid M. The et al. Sex therapy for female sexual cause of divorce among men and women dysfunction. Int Arch Med. 2013;6(1):37. referred to marriage and legal office in 38 Meston CM. Hull E, Levin RJ, Sipski M. Qazvin, Iran. Glob J Health Sci. Disorders of orgasm in women. J Sex Med. 2012;4(5):184–191. 2004;1(1):66–68. 29 Aker S, Böke Ö. The effect of education on 39 Meston CM, Levin RJ, Sipski ML, et al. the sexual beliefs of family physicians. Int J Women’s orgasm. Annu Rev Sex Res. Sex Health. 2016;28(1): 111–116. 2004;15:173–257. 30 Rosen R, Brown C, Heiman J, et al. The 40 Brotto LA, Barker M. Mindfulness in Female Sexual Function Index (FSFI): a Sexual and Relationship Therapy, 1st edn. multidimensional self‐report instrument London: Routledge: 2014. for the assessment of female sexual 41 Barker M. Existential sex therapy. Sex function. J Sex Marit Ther. Relation Ther. 2001;26(1):33–47. 2000;26:191–208 42 Safron A. What is orgasm? A model of 31 Derogatis LR, Rosen R, Leiblum S, et al. sexual trance and climax via rhythmic The Female Sexual Distress Scale (FSDS): entrainment. Socioaffect Neurosci Psychol. Initial Validation Of A Standardized Scale 2016;6:3163. For Assessment Of Sexually Related 43 McCabe MP, Connaughton C. Sexual Personal Distress In Women”. J Sex Marit dysfunction and relationship stress: how Ther. 2002;28(4):317–330. does this association vary for men and 32 Kenny JA. Sexuality in pregnant and women? Curr Opin Psychol. breastfeeding women. Arch Sex Behav. 2017;13:81–84. 1973;2:215–229. 44 Lindwall L, Bergbom I. The altered body 33 Leeman LM, Rogers RG. Sex after after breast cancer surgery. Int J Qual Stud childbirth: postpartum sexual function. Health Well‐being. 2009;4(4):280–287. Obstet Gynecol. 2012;119(3):647–655. 45 Nasserzadeh S. Sex therapy: a marginalized 34 Basson R, Wierman ME, van Lankveld J, specialization. Arch Sex Behav. 2009;38(6): and Brotto L. Summary of the 1037–1038. 211

15

Musculoskeletal Management of Orgasm Disorders Karen Brandon

Abstract

Understanding the role of contractile and noncontractile tissue in different phases of the sexual response cycle is a key to determining impairment in the myofascial and musculoskeletal systems in orgasm disorder. The continuum from attenuating arousal and peak sexual tension, and spasms occurring afterwards, lends to multiple points of dysfunction. Diagnosis starts with history and physical examination including overall observation and focused examination of the genitalia. The clinician should request a pelvic floor volitional contraction, relaxation and elongation, and observe the correctness, timing, and excursion of the muscle unit. Other assessments include elec- tromyography and 4D transperineal ultrasound. Orgasmic disorder can be the result of overactivity or underactivity of the pelvic floor muscles, or noncontractile connective tissue restriction. Treatments include myofascial, musculoskeletal, and neuromotor interventions. Clinicians should screen for alterations in musculoskeletal structures after surgery or parity that cause change in sexual function related to orgasm.

Keywords: hypertonus; hypotonus; musculoskeletal; myofascial; pelvic floor; orgasm; ischiocaver- nosus muscle; bulbospongiosus muscle; rehabilitation; physical therapy

Orgasmic disorder may result from dysfunctional (hypertonic or hypotonic) muscles intimately associated with genital organs or within the surrounding pelvic floor, as well as noncontractile elements like the viscerofascia. Diagnostic efforts should assess connective tissue and muscular units of the pelvic floor, as well as the related skeletal elements of the trunk, pelvic girdle, and hips to identify any pain or issues with muscle mobility, stability, and strength. Identifying incidents/events (e.g. surgery or local trauma) that would change the myofascial structures or chemical/hormonal changes or stressors/neural changes that might cause changes in orgasmic function are critical to formulating successful treatment or management strategies.

­Introduction musculoskeletal systems in sexual dysfunc- tion. In orgasm, which has been believed to be Understanding the role of contractile and an automated (fixed) response cycle to par- noncontractile tissue in different phases of the ticular stimuli, pathology models have been sexual response cycle is key to determining if challenged by new research in functional there is an impairment in the myofascial and ­neuroimaging of the mechanisms of orgasm

Textbook of Female Sexual Function and Dysfunction: Diagnosis and Treatment, First Edition. Edited by Irwin Goldstein, Anita H. Clayton, Andrew T. Goldstein, Noel N. Kim, and Sheryl A. Kingsberg. © 2018 John Wiley & Sons Ltd. Published 2018 by John Wiley & Sons Ltd. 212 Textbook of Female Sexual Function and Dysfunction

[1–3]. The significance of a healthy, function- Conditions that affect physiologic achieve- ing myofascial and musculoskeletal system as ment and maintenance of arousal may a responder and attenuator to the arousal ­overlap with orgasmic potential in the mus- experienced as the woman approaches orgasm culoskeletal domain. The ischiocavernosus is often overlooked in clinical practice. This and bulbospongiosus muscles are primarily chapter focuses on describing assessment of responsible for maintaining pressure on the these systems and interventions for address- dorsal vein of the clitoris but the role this has ing relative dysfunctions. in the physiology of clitoral engorgement is unclear. The clitoral hood must be mobile enough to allow for the examination of the ­Diagnosis glans clitoris and to ensure there are no underlying clitoral adhesions. Clitoral adhe- Excluding pain, the conditions that may sions may permit the presence of keratin involve a mechanical dysfunction of the struc- pearls and balanitis that may interfere and tural tissues (end organ or peripheral) could cause discomfort and hypersensitivity with include female orgasmic disorder as defined orgasm. The levator ani muscles reduce the by the ISSWSH Nomenclature Consensus vasocongestion by rhythmic contractions [8]. panel [4]. This definition includes conditions In addition, noncontractile elements like the that adversely affect orgasm after normal sex- viscerofascia surrounding the lower third of ual excitement, such as clitoral phimosis, scar/ the vaginal canal and the vestibule and vulva contraction, connective tissue restriction or must have mobility free of restrictions. pelvic floor muscular underactivity, overactiv- Arguably the continuum between the attenu- ity, or incoordination of pelvic floor muscles. ating arousal, peak sexual tension, and The basis for female orgasm has been spasms occurring afterwards [5] lends itself extensively studied [5–7]. From a neuromo- to multiple points of dysfunction that must tor perspective, a thorough description of the be clarified with clinical assessment. The clonic nature of the reflexive response has subcategories previously described by earlier been linked to the need for sufficient arousal. versions of classification models include a The increasing vasocongestion in the pelvic breakdown of the symptoms and signs [10]. muscles triggers the muscle spindle stretch reflex and, therefore, overcomes the gamma bias to produce a rhythmic contraction. ­Evaluation of These contractions serve to reduce the pres- Musculoskeletal Function sure that the excess fluid is creating and these contractions continue until the spindle bias History taking afferents determine the resistance is back to baseline [8]. This brief description does A comprehensive history should be taken to not exclude the influence of higher neural determine if there are any red‐flags that centers and recognizes that an orgasm is a would explain changes in sexual function multisystem expression, but this description that need immediate medical management attempts to explain the mechanisms of the (i.e. signs and symptoms of cancer, new neu- local contractile tissue. rological symptoms, or acute pain/blood Pathophysiologic factors of the local geni- loss). Secondly, a detailed medical history tal structures, therefore, would include would identify comorbidities that may any restriction that prevents arterial filling, impact orgasmic sexual function, including a vasoconstriction maintenance, trigger of the list of current medications and surgical afferent response at the clitoris, and muscles ­procedures. Screening for other conditions that will not respond to slight stretch or do that impact the musculoskeletal system is not coordinate well to contract [9]. imperative as changes in bowel, bladder [11], Musculoskeletal Management of Orgasm Disorders 213 and lower quarter mobility through lumbar spine, pelvic girdle, and hips could highlight impairments in the pelvic musculature. It is important to ask for current or historic neu- ral signs including numbness, weakness, or any alteration that may warrant further neu- rological assessment of the cauda equina. After a detailed history is taken, the clini- cian asks for further clarification of the onset of the orgasmic dysfunction and includes overview of a brief sexual history to screen for other sexual domain dysfunction. Sexual function questionnaires, such as the Female Sexual Function Index (FSFI) items 11–13 [12], the Female Sexual Function Questionnaire (SFQ‐28) items 22‐24 [13], and the Changes in Sexual Functioning Questionnaire (CSFQ‐FC) items 11–14 [14], cover orgasm conditions. A previous reported baseline for orgasm function is established (if possible) and conditions under which the problem occurs (i.e. specific partner, self‐ Figure 15.1 Testing pelvic girdle for stimulation with or without tools/toys, under incoordination – Stork test/Trendelenberg test. stressful ­circumstance) are noted. Special attention is also paid to changes in orgasmic function after incidents that would change the myofascial structures via surgery or local trauma and those that would affect tissue directly (chemical/hormonal changes) or indi- rectly (stressors/neural changes). If pain is identified, preventing orgasm, or during or afterwards, reclassification of condition is made to address multifactorial pain etiology.

Physical Examination

After history is taken, gross observation is used for screening functional mobility for trunk, pelvic girdle (Figure 15.1), and the hip. Coordination of trunk and extremity muscles to meet demand of required postures and positions is tested against gravity and resist- ance, inclusive of desired sexual positions. (Figures 15.2 and 15.3). Restrictions in breathing pattern and availability of lum- bopelvic‐hip movement should be assessed (Figure 15.4), as well as palpation of the ­rectus abdominus and evaluation of length Figure 15.2 Testing functional positions of sexual and strength (Figure 15.5). Any abnormal activity – quadriped with pelvic tilting. 214 Textbook of Female Sexual Function and Dysfunction

Figure 15.3 Functional testing for sexual Figure 15.5 Abdominal strength positions – “happy baby” pose. testing – Sarhmann progression.

findings, such as lack of range of motion, strength, or impaired control, should be fur- ther assessed and special tests included to assign a musculoskeletal impairment diagno- sis and determine if it has a relationship to the presenting complaint. Once complete explanation of the anatomy and purpose of the examination is completed and consent for genital examination is obtained from the patient, the physical thera- pist continues to ensure patient control [15] and participation with the examination with ongoing but brief narrative of examination, “checking in” while observing nonverbal communication, and taking breaks at appro- priate times to summarize the findings. Initially the genitalia are observed as a screening before proceeding with an internal examination. The physical therapist notes the presence of discharge, swelling, rash, fis- sures or erythema. Labia majora are observed as well as separating them to look at the labia Figure 15.4 Coordination of pelvic girdle for sexual minora, vestibule, and clitoral hood. As the function – bridge with breathing. clinician describes what they are assessing, Musculoskeletal Management of Orgasm Disorders 215 they can ask the patient to pull back the clito- hymenal ring, which is evaluated for extensi- ral hood or indicate they will do so to evalu- bility. Next, the superficial layer of muscle ate the clitoral glans and mobility of the hood can again be palpated between the index fin- if there is underlying clitoral adhesions. It is ger inserted and the thumb externally for important to visualize the corona of the tenderness and myofascial restriction and glans; failure to visualize the corona may sig- screening for Bartholin’s gland tenderness. nal the presence of clitoral adhesions. Clitoral Internal assessment of the ischiocavernosus glans is observed for color and size; the size by the internal finger can be completed. should be approximately the size of end Moving to deeper palpation the puborectalis, of the cotton swab. If indicated, a vestibule pubococcygeus, and iliococcygeus can be Q‐tip test can be performed, as well as a light examined next for tenderness, tension, and touch sensation test for S2‐S4 dermatomes. stiffness. When a contraction and relaxation The purpose of this information is to identify is requested, further quality and quantifica- any red flags regarding integrity of the tissue tion of pelvic floor muscle strength (such as and the neural innervation. If all of these the modified Oxford grading scale), length, areas have been documented as screened and coordination can be assigned. Palpation recently by a physician, physician’s assistant of obturator internus, ischiococcygeus, and or nurse practitioner, then there is no need to piriformis muscles for the same functions subject the patient to in‐depth testing, unless can be completed and should be compared there has been a change in status or signifi- bilaterally. Any referred pain on palpation cant time since initial assessment. Those should be noted. As indicated, palpation of trained to use a vulvoscope (colposcope) are viscera including urethra, base of the bladder, able to more clearly observe abnormalities in cervix, base of the uterus, and rectum can the vulvar, vestibular, and vaginal tissues; rule out involvement of these structures if however, most physical therapy offices do nontender and having normal mobility [17]. not have this equipment and still have to refer the patient back to the physician, physi- Other Assessments of the cian’s assistant or nurse practitioner for care Pelvic Floor of conditions not of musculoskeletal origin. Next, the clinician requests a pelvic floor Electromyography of the pelvic floor is often volitional contraction, relaxation, and elon- used to establish pelvic floor recruitment gation and observes the correctness, timing, patterns and identify hyperactivity or and excursion of the muscle unit. Involving ­hypoactivity [18, 19]. Although there is lim- the patient with use of a mirror can aid in ited reliability when measuring amplitude execution of the request, as well as under- [20, 21], the information gained using sur- standing the muscle function and feedback face electromyography to measure resting of effort. Verbal cues can be modified to state (tonic), responsiveness for volitional achieve the desired demonstration. Following contraction, endurance, and return back to this, the clinician describes the superficial baseline (phasic) can contribute to the total- layer of pelvic floor muscles and bilaterally ity of understanding the muscle function palpates the bulbospongiosus, superficial [22]. It should not be used as determinant of transverse perineal muscles, and perineal muscle force. Further information can be body for tenderness and identifies presence gathered regarding the force measurement of any myofascial restriction [16]. using intravaginal dynamometry [23], while The clinician then explains the next step pelvic floor muscle resting tone and force of the examination, which is internal, and can be measured with perineometry and asks permission to start that component. manometry [24]. One gloved lubricated finger is carefully Use of 4D transperineal ultrasound can introduced into the vaginal introitus to the demonstrate both morphological differences 216 Textbook of Female Sexual Function and Dysfunction

from normal in resting states [25] by measur- can also be a contributor to persistent sensa- ing the levator plate angle; it can also tions of genital arousal in the absence of ­demonstrate dynamic displacement of the ­sexual desire or stimulation, also known as urethrovesicular junction and anorectal persistent genital arousal disorder (PGAD), angle relating to the pelvic floor excursion due to the inability to relieve venous outflow capability [26]. These adjunctive tools of obstructed by pelvic muscle overactivity [29]. assessment are included to describe pelvic Persistent genital arousal disorder can exist floor function more comprehensively, con- with and without pain; its etiologies include tributing to defining the “state of operation” peripheral and central factors (Chapter 11). of the muscle unit. Their use in concert with Patients can also present with underactiv- signs, symptoms, and standard physical ity of deep pelvic floor muscles, demon- examination may give a more comprehensive strated by low tone on palpation, poor picture of their function in vivo. compression or elevation on dynamometry, perineo/manometry or small displacement on ultrasound. Although studies exist that ­Categories of Myofascial have evaluated the association between pel- vic floor muscle weakness and sexual dys- and Musculoskeletal function [30], specific improvement in Dysfunction orgasm is not defined and has not been directly studied. For the older studies that After completing the examination, the clini- evaluated pelvic floor muscle and orgasm, cian determines the relationships between controversy exists regarding pelvic muscle symptoms and findings. It is important that strengthening and reported orgasm function the physical therapist clarifies if female [31]. More evidence is emerging that shows a orgasmic disorder diagnosis is multimodal relationship between a strong pelvic floor and if musculoskeletal impairments may and improved quality and intensity of orgasm contribute a percentage to the dysfunction [32], possibly due to increased stretch and but may not explain the entire condition. pressure receptors, but no study has demon- While there are many definitions for muscle strated change from anorgasmia to orgasmic function and updates are perpetual, the by increasing muscle strength alone. ­current terminology in pelvic floor muscle Ultimately, the lack of homogeneity in the function and dysfunction standardized by research as to the baseline of pelvic floor the International Continence Society will muscle function, the symptom report/patient be used [27]. desired goal, and the outcome pertaining to Overactivity of pelvic floor muscles is specifically female orgasmic disorder allows ­demonstrated with concurrent findings of only for speculation as to the relationships tenderness on palpation, impaired volitional between pelvic floor muscle underactivity relaxation or elongation, possible elevated and reduction of orgasm dysfunction and resting activity, muscle stiffness upon palpa- requires individualization of interventions. tion, or shortened contraction excursion. A final area to classify is noncontractile con- It can exist in the superficial pelvic muscle nective tissue restriction – any restriction that layers or the deep levator ani group. is demonstrated as immobility of the labia, ves- Overactivity can lead to pain but can also tibule, clitoral hood [33], hymenal ring, vaginal exist without pain and demonstrate dysfunc- introital mucosa or perineal body that limits tion with an inability to achieve orgasm that is adequate access and use of the perineal struc- hypothesized to be due to shortened muscle tures for sexual stimulus. This can occur as a length not allowing local tissue perfusion and result of hormonal def­ iciencies, dermato- potential compression of clitoral, perineal or pathologies, vaginal delivery trauma, surgical rectal branches of the pudendal nerve [28]. It procedures, perineal injuries, or part of genital Musculoskeletal Management of Orgasm Disorders 217 cutting practices. Health of the tissues must can also include use of perineal small soft factor in their ability to stretch and also pro- ­tissue balls or internal vaginal dilators/­ duce an adequate amount of tensioning. This accommodators to stretch larger areas of condition can pertain to superficial scars as ­tissue in the absence of pain. well as deep scars, such as with urogynecologi- cal procedures. Musculoskeletal Interventions

To the extent that the pelvic floor muscles ­Overview of Treatment are attached to the bony pelvis, there is Options always room for static or dynamic structural imbalances along the entire kinetic chain from the foot to the head. While the body In recent years, increasing attention has been adapts significantly to many alterations in paid to addressing the patient as a whole length tension relationships, at times it may from a biopsychosocial perspective. The role be assessed that the joint position or availa- as clinicians is to contribute to a whole per- ble arthrokinematics are not optimized for son view of the condition and in our practice efficient function. After a fall onto one’s hip scopes address the component of dysfunc- or a macrosomic vaginal delivery, it is possi- tion found with specific skill and training. ble that a structural dysfunction is contribut- The interventions in physical therapy are ing to pelvic floor muscle dysfunction. If so, wholly provided to aid the body in restorative address the arthokinematic limitation with processes in areas where it has lost mobility, joint mobilization in any of the effective stability, and strength. These can be consid- forms and then ensure that the new range is ered myofascial, musculoskeletal or neuro- used and supported well with the muscular motor in their approach. Within each area, structures. It is also important to recognize there is a common goal but different tech- that physical patterns occur through the niques are available. It is also important to whole body once an orgasm is triggered and treat patients individually and remember musculoskeletal impairments can prohibit they can have comorbidities that require them, alter them or even make them painful. sequential organization of interventions. Neuromotor Interventions Myofascial Interventions All targeted exercise that involves volitional Soft tissue mobilization can be termed to be or responsive contraction requires neuromo- a manual therapy that affects the skin, fascia tor training. It includes contractions towards and muscle to increase extensibility. It can be strength and coordination as well as reduc- applied directly or indirectly to achieve a ing tone and relaxation. In addition, there is reduction in previously tested painful palpa- the potential for peripheral input to effect a tion, range of motion or lack of flexibility. In central change. Pelvic muscle exercise can be patients with restrictions in their connective practiced to increase correctness, speed, tissue that limits mobility of tissues of the stamina, endurance of contraction or to perineum, the clinician can manually mobi- release or elongate the muscle. All exercises lize the tissue away from (direct) or towards should focus on functional positions and (indirect) the restriction. They can deter- demands. Because sexual function has vari- mine what structures and depth they want to ety, multiple demands of the trunk, hips, and evaluate and treat. Noncontractile structures pelvic floor muscle require a variety of motor adjacent to the muscles, such as viscero‐­ patterns. It should also include an awareness fascial and neuro‐fascial connections, of training for actively relaxing the pelvic can be targeted. Mechanical interventions floor. 218 Textbook of Female Sexual Function and Dysfunction

­Outcomes/Follow‐Up surgery or parity that cause change in sexual function related to arousal or orgasm. Giving There are few studies on physical therapy patients counsel on possible changes to sexual interventions specific to improving sexual function, whether transient, adaptable or per- dysfunction with orgasm [34–36]. There are manent, is important to affirming that the more that studied evaluating the benefits of patient’s sexuality is an important part of their physical therapy, specifically for overactive quality of life and that every effort is made to pelvic floor in sexual pain disorders address what can be improved medically. that showed good efficacy [29, 37–39]. Nevertheless, it is important that an assess- ment of the pelvic floor muscle and the ­Conclusion related musculoskeletal system be completed to properly direct care of the individual Assessment of the structures involved in impairments in an effort to address the entire orgasm must include an evaluation of the clinical picture. More research that includes connective tissue and muscular units of the musculoskeletal and myofascial impairments pelvic floor to rule out musculoskeletal con- found in those classified with female orgas- tributions to dysfunction. Further assess- mic disorders would help clarify impairment ment of the trunk, pelvic girdle, and hips can based treatments that could then be studied demonstrate barriers to freedom of move- with randomized, controlled trials. ment or adequate coordination of pelvic floor muscle for the purpose of participating in the orgasmic response. Specific interven- ­Screening/prevention tions targeting restoration of mobility or strength can be valuable in patients who have It is recommended that clinicians carry out female orgasmic dysfunction after local screening and early intervention to address trauma, skeletal changes or connective tissue alterations in musculoskeletal structures after restrictions.

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10 Basson R, Leiblum S, Brotto L, et al. strength using four different techniques. Revised definitions of women’s sexual Int Urogynecol J Pelvic Floor Dysfunct. dysfunction. J Sex Med. 2004;1(1):40–48. 2001;12(1):27–30. 11 Pauls RN, Rogers RG, Parekh M, et al. 22 Pullman SL, Goodin DS, Marquinez AI, Sexual function in women with anal et al. Clinical utility of surface EMG: report incontinence using a new instrument: of the therapeutics and technology the PISQ‐IR. Int Urogynecol J. assessment subcommittee of the American 2015;26(5):657–663. Academy of Neurology. Neurology. 12 Rosen R, Brown C, Heiman J, et al. The 2000;55(2):171–177. Female Sexual Function Index (FSFI): a 23 Miller JM, Ashton‐Miller JA, Perruchini D, multidimensional self‐report instrument DeLancey JO. Test‐retest reliability of an for the assessment of female sexual instrumented speculum for measuring function. J Sex Marital Ther. vaginal closure force. Neurourol Urodyn. 2000;26(2):191–208. 2007;26(6):858–863. 13 Quirk F, Haughie S, Symonds T. The use of 24 Naess I, Bo, K. Can a pelvic floor muscle the sexual function questionnaire as a contraction reduce vaginal resting screening tool for women with sexual presssure and resting EMG activity? dysfunction. J Sex Med. 2005;2(4):469–477. Neurourol Urodyn. 2013;32(8). 14 Keller A, McGarvey EL, Clayton AH. 25 Morin M, Bergeron S, Khalife S, et al. Reliability and construct validity of the Morphometry of the pelvic floor muscles Changes in Sexual Functioning in women with and without provoked Questionnaire short‐form (CSFQ‐14). J Sex vestibulodynia using 4D ultrasound. J Sex Marital Ther. 2006;32(1):43–52. Med. 2014;11(3):776–785. 15 Rosenbaum TY. Pelvic floor involvement in 26 Braekken IH, Majida M, Engh ME, Bo K. male and female sexual dysfunction and Test‐retest reliability of pelvic floor muscle the role of pelvic floor rehabilitation in contraction measured by 4D ultrasound. treatment: a literature review. J Sex Med. Neurourol Urodyn. 2009;28(1):68–73. 2007;4(1):4–13. 27 Messelink B, Benson T, Berghmans B, et al. 16 Sarton J. Assessment of the pelvic floor Standardization of terminology of pelvic muscles in women with sexual pain. J Sex floor muscle function and dysfunction: Med. 2010;7(11):3526–3529. report from the pelvic floor clinical 17 Hartmann D, Sarton J. Chronic pelvic floor assessment group of the International dysfunction. Best Pract Res Clin Obstet Continence Society. Neurourol Urodyn. Gynaecol. 2014;28(7):977–990. 2005;24(4):374–380. 18 Podnar S, Mrkaic M, Vodusek DB. 28 Both S, van Lunsen R, Weijenborg P, Standardization of anal sphincter Laan E. A new device for simultaneous electromyography: quantification of measurement of pelvic floor muscle continuous activity during relaxation. activity and vaginal blood flow: a test in a Neurourol Urodyn. 2002;21(6):540–545. nonclinical sample. J Sex Med. 19 Capson AC, Nashed J, McLean L. The role 2012;9(11):2888–2902. of lumbopelvic posture in pelvic floor 29 Laan E, van Lunsen RHW. Overactive pelvic muscle activation in continent women. floor: sexual functioning. In: Padoa A, J Electromyogr Kinesiol. 2011;21(1):166–177. Rosenbaum TY (eds) The Overactive Pelvic 20 Auchincloss CC, McLean L. The reliability Floor. New York: Springer; 2016, pp. 17–29. of surface EMG recorded from the pelvic 30 Lara LA, Montenegro ML, Franco MM, floor muscles. J Neurosci Methods. et al. Is the sexual satisfaction of 2009;182(1):85–96. postmenopausal women enhanced by 21 Peschers UM, Gingelmaier A, Jundt K, physical exercise and pelvic floor muscle et al. Evaluation of pelvic floor muscle training? J Sex Med. 2012;9(1):218–223. 220 Textbook of Female Sexual Function and Dysfunction

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16

Pathophysiology and Medical Management of Female Orgasm Disorder Irwin Goldstein and Barry R. Komisaruk

Abstract

Female orgasm disorder, the second most reported sexual problem among women, is characterized by a persistent or recurrent distressing compromise of orgasm frequency, intensity, timing, and/or pleasure. Multiple diagnostic procedures may be used to help resolve the various aspects of the underlying female orgasm disorder. Risk factors include psychosocial issues, psychiatric disorders, certain medications, central nervous system neurotransmitter imbalances associated with pelvic floor dysfunction, high‐ or low‐tone pelvic floor dysfunction, male partner sexual dysfunctions, genital medical conditions, or endocrine, neurologic or vascular disorders or debilitating disease. There has been limited research on the physiology of orgasm in women and the pathophysiologies, diagnoses, and treatments of the multiple female orgasm disorders. Therapeutic strategies include treatment considered disease modification aimed to cure the female orgasm disorder condition or symptomatic treatment aimed to reduce the female orgasm disorder symptoms so that the orgasm function is improved. More research is needed.

Keywords: female orgasm disorder; orgasm; sympathetic efferent activity to pelvic organs; intense pleasure/well‐being/contentment; brain neurotransmitter imbalance; anorgasmia; delayed orgasm; orgasm anhedonia; pleasure dissociative orgasm dysfunction; radiculopathy of the sacral spinal nerve root

Female orgasm disorder is characterized by a persistent or recurrent distressing compromise of orgasm frequency, intensity, timing, and/or pleasure, associated with sexual activity for a minimum of six months. Multiple diagnostic procedures may be used to help resolve the various underlying female orgasm disorder biopsychosocial pathophysiologies. Therapies may be considered disease modification to either cure the female orgasm disorder condition or to reduce the female orgasm disorder symptoms.

­Introduction ­Genital Responses Prior to, During and Immediately Female orgasm disorder is the second most after Orgasm in Women reported sexual problem for women [1, 2]. There has been limited research on the phys- The drive to experience orgasm occurs, in iology of orgasm in women and the patho- part, because orgasm achieves several physiologies, diagnoses, and treatments of ­objectives. Firstly, orgasm is associated with the multiple female orgasm disorders. memorable events that are often expressed as

Textbook of Female Sexual Function and Dysfunction: Diagnosis and Treatment, First Edition. Edited by Irwin Goldstein, Anita H. Clayton, Andrew T. Goldstein, Noel N. Kim, and Sheryl A. Kingsberg. © 2018 John Wiley & Sons Ltd. Published 2018 by John Wiley & Sons Ltd. 222 Textbook of Female Sexual Function and Dysfunction

ecstasy, euphoria, and extreme pleasure and during, and after orgasm. There is no current act to motivate the individual to want to consensus as to what regions of the brain are experience orgasm again in the future and, specifically activated or inactivated during thereby, encourage reproduction. Secondly, orgasm in women [7, 8]. One group claims orgasm is associated with increased areas that are inactivated include the temporal ­sympathetic efferent activity to the pelvic and prefrontal areas. The brain region associ- organs that acts to undo physiologic pelvic ated with increased orgasm‐related activation vasocongestion associated with the peak of included the left anterior vermis and deep cer- sexual arousal in various genital and pelvic ebellar nuclei [9]. Another group [10] reported structures including the clitoris, labia, increased functional magnetic resonance ­urethral glands, vagina, uterus, and pelvic imaging activity in the nucleus accumbens, ­ligaments [3–6]. the paraventricular nucleus of the hypothala- An operational definition of orgasm in mus, the hippocampus, amygdala, insula, women may be considered as: “… a variable anterior cingulate cortex, cerebellum, para- transient peak sensation of intense pleasure central lobule of the sensory cortex, and pre- creating an altered state of consciousness, frontal cortex. Unfortunately, comparisons of usually with an initiation accompanied by these studies are difficult because of various involuntary, rhythmic contractions of the factors, including dissimilarity in the arousal pelvic striated circumvaginal musculature, stimulation used, difference in maneuvers often with concomitant vaginal, uterine and used to limit head movement artifacts, the anal contractions, and myotonia that resolves diverse basal levels used for subtraction from the sexually induced vasocongestion (some- arousal images to obtain the specific levels times only partially) and myotonia, generally associated with sexual arousal, and the lack of with an induction of well‐being and content- agreement for what comprises significant ment” [6]. In general, the most apparent activation above basal levels. physical sign of orgasm is the sense of Immediately after orgasm, there are rapid ­vaginal and/or pelvic striated muscle rhyth- reductions in heart rate, blood pressure and mic contractions [3–6]. respiration. There are changes in the genita- There have been inadequate investigations lia, including detumescence or decongestion characterizing physiologic changes that occur and return of basal labial hue. The height- in women just prior to, during, and immedi- ened arousal‐induced vaginal lubrication ately after orgasm. At the peak of female sex- ends and the excess fluids are reabsorbed ual arousal just before orgasm, maximal heart osmotically returning the vaginal eputhelium rate, blood pressure, and respiration values to basal or “just moist” conditions [3, 4]. are detected. Furthermore, progressive sexual Blood levels of hormones such as epineph- arousal physiological changes of engorge- rine, vasoactive intestinal peptide, oxytocin, ment, tumescence and vasocongestion are vasopressin, and prolactin have been meas- observed in the genitalia [3, 4]. ured before, during, and after orgasm in During orgasm, repeated pelvic muscle women. Prolactin and oxytocin are increased contractions of varying intensity and dura- during orgasm [3, 4]. tion are noted. In some women, these are intense, repetitive and can last for several seconds, while in others, contractions are ­ISSWSH Consensus weaker, less intense, and contract only for a limited duration. Sensitivity to pain is also Conference Nomenclature – reduced at orgasm [3, 4]. Female Orgasm Disorder Brain imaging by functional magnetic ­resonance imaging or positron emission In the DSM IV, female orgasm disorder was tomography have characterized regions considered: a female sexual disorder, associ- ­activated or inhibited or unchanged before, ated with negative personal consequences, Pathophysiology and Medical Management of Female Orgasm Disorder 223 that was not better accounted for by a gen- health‐care providers also manage women eral medical or psychiatric condition and not distressed with compromises in orgasm due exclusively to the direct physiologic ­timing, such as orgasms that occur sponta- effects of a substance or medication, in which neously or too early (premature orgasm). women had “persistent or recurrent delay in, Biopsychosocial sexual medicine health‐ or absence of orgasm after a normal sexual care providers manage women distressed excitement phase” [11]. In the DSM‐5, female with aversive peripheral and/or central orgasm disorder was considered: a female symptoms that occur prior to, during or sexual disorder that persisted a minimum of ­following orgasm (female orgasmic illness six months and was not better explained by a syndrome). Additionally, biopsychosocial nonsexual mental disorder or consequence sexual medicine health‐care providers man- of severe relationship distress or other sig- age women distressed with symptoms of nificant stressors and not due to effects of ­persistent genital arousal not associated substance/medication or other medical con- with concomitant sexual interest (persistent ditions, with the presence of the following genital arousal disorder, genital dysesthesia), “on all or almost all (75–100%) occasions of where orgasm may be aversive and/or sexual activity: (i) marked delay in, marked compromised. infrequency of, or absence of orgasm and A broader, more diverse view of orgasm (ii) marked reduced intensity of orgasmic disorder in women would include female sensations” [12]. In summary, as it relates to orgasmic disorders, where the primary specific patient complaints about female orgasm complaint is a compromise of orgasm disorder, combining the two most orgasm frequency, intensity, timing, and/or recent DSM system classifications, female pleasure. Alternatively, the primary orgasm orgasm disorder has been defined by com- complaint may be aversive symptoms that promises in orgasm quality relating to: (i) occur prior to, during, or following the absence of orgasm, (ii) delay in orgasm, (iii) orgasm (female orgasm illness syndrome) infrequency of orgasm or (iv) reduced inten- and are not related, per se, to a compromise sity of orgasm, after adequate sexual stimula- of orgasm quality. tion and arousal, causing personal distress. The prevalence of the DSM‐based female Sexual medicine health‐care providers, orgasmic disorder, which is characterized by however, manage women who complain of orgasm concerns plus distress, is 4.7% [1]. far more broad, diverse, and differing orgas- There are no prevalence data on the current mic complaints than that represented in the broader ISSWSH definition of orgasm disor- DSM system. The past or current DSM defi- ders. There are no prevalence data on female nitions for women with orgasm disorders orgasm illness syndrome actually fail to characterize and include the This chapter addresses female orgasm various other kinds of bothersome and dis- disorder. Separate chapters address female tressing female orgasmic disorders seen, orgasm illness syndrome (Chapter 17) observed, and managed by biopsychosocial and persistent genital arousal disorder sexual health‐care providers of women with (Chapter 11). sexual dysfunction. A more inclusive, user‐ friendly, sexual medicine health‐care ­provider‐oriented classification of women ­Female Orgasm Disorders with distressing orgasm is required. For example, biopsychosocial sexual medicine (ISSWSH Consensus health‐care providers manage women dis- Conference Nomenclature) tressed with compromises in orgasm pleasure, such as reduced or absent pleasure (anhe- Female orgasm disorder is characterized by a donic orgasm, or pleasure dissociative orgasm persistent or recurrent, distressing compro- ­disorder). Biopsychosocial sexual medicine mise of orgasm frequency, intensity, timing, 224 Textbook of Female Sexual Function and Dysfunction

and/or pleasure, associated with sexual psychiatric disorders including anxiety and/ ­activity for a minimum of six months [13]. or depression [14–16]. Female orgasm disorder may also exist, in ●● Frequency: orgasm occurs with reduced part, associated with use of certain medica- frequency (diminished frequency of tions, such as selective serotonin reuptake orgasm) or is absent (anorgasmia). inhibitors typically used for treatment of ●● Intensity: orgasm occurs with reduced depression. Serotonin, a central nervous sys- intensity (muted orgasm). tem sexual response inhibitor, is elevated ●● Timing: orgasm occurs either too late with the use of selective serotonin reuptake (delayed orgasm) or too early (spontane- inhibitors, such that the medication inhibits ous or premature orgasm) than desired by orgasm capability. Other drug classes that the woman. negatively affect orgasm include antipsy- ●● Pleasure: orgasm occurs with absent or chotics, antihypertensives, benzodiazepines, reduced pleasure (anhedonic orgasm, histamine 2 receptor antagonists, and pleasure dissociative orgasm disorder). ­anticonvulsants [17–19]. Female orgasm disorder may be classified Female orgasm disorder may exist, in part, as “lifelong” if the condition is present from various factors. throughout the person’s life or “acquired” if the condition develops later in life. Female ●● Brain central nervous system neurotrans- orgasm disorder may be classified as “gener- mitter imbalances in excitatory and inhibi- alized” if the condition is present at all times tory critical nuclei [20]. or “situational” if the condition is present ●● Associated with pelvic floor dysfunction, only in certain situations. both high‐tone and low‐tone pelvic floor dysfunction [21, 22]. ●● Male partner sexual dysfunctions, such as erectile dysfunction or premature ejacula- ­Risk Factors for Women with tion, or female partner sexual dysfunc- Female Orgasm Disorder tions, such as low sexual interest or sexual pain disorder. The inadequate sexual Multiple biopsychosocial pathophysiologies arousal that may occur in these cases of female orgasm disorder can result in the ­represent examples where partner issues symptoms typically associated with female may result in insufficient central nervous orgasm disorder. system sexual excitatory processes or Female orgasm disorder may exist, in increased central nervous system sexual part, from psychosocial issues. Spectatoring inhibitory processes [23, 24]. (obsessive self‐observation during sex), unre- ●● Endocrine disorders, such as low testoster- solved marital conflict, religious guilt, fear of one, low estradiol states including meno- pregnancy, ineffective sexual communica- pause and genitourinary syndrome of tion, traumatic relationship experiences, menopause, prolactinoma, or hypothy- mood disorders, fatigue, emotional concerns, roidism [25–27]. past trauma and abuse history, cultural and ●● Genital medical conditions that are dis- religious prohibitions, and feeling excess tracting, such as: genital dermatologic pressure to have a sexual experience, all conditions such as lichen plannus, ­represent examples in which psychosocial lichen sclerosus, or from vestibulodynia issues may result in insufficient central nerv- conditions such as hormonally‐mediated ous system sexual excitatory processes or vestibulodynia, neuro‐proliferative vestib- increased central nervous system sexual ulodynia, vulvar granuloma fissuratum, inhibitory processes. Female orgasm disor- and/or desquamative inflammatory der may also exist, in part, associated with ­vaginitis [28, 29]. Pathophysiology and Medical Management of Female Orgasm Disorder 225

●● Neurologic disorders [30–32]: these may ents of the hypogastric nerve regulate blood be subclassified as peripheral nervous sys- flow and, thereby, control vaginal lubrica- tem disorders (neuropathy of the dorsal tion, women with complete spinal cord injury nerve, perineal nerve, inferior hemorrhoi- below thoracic T12 can experience psycho- dal nerve, pelvic or pudendal nerve) or genic vaginal lubrication, but women with central nervous system disorders (trau- complete spinal cord injury above thoracic matic head injury, spinal cord injury, phan- T10 cannot. However, women with complete tom orgasms, epilepsy, Parkinson’s Disease, spinal cord injury above thoracic T10 have multiple sclerosis, radiculopathy of the intact pudendal nerve afferents and hypogas- sacral spinal nerve roots. tric nerve efferents, so they can experience reflexive, although not psychogenic, vaginal Neurologic Disorders lubrication. Genital afferent activity is conveyed within Traumatic Brain Injury the spinal cord to the brain via the spinotha- The variable and multiple regions of brain lamic tract. If this pathway is interrupted, damage resulting from traumatic brain injury clitoral stimulation‐induced orgasm is may induce female orgasm disorder, along blocked. However, women with complete with other sexual dysfunction symptoms spinal cord injury above thoracic T10 may such as decreased or increased libido, loss of retain cervical and vaginal sensibility and genital sensation, and reduced lubrication. experience orgasms from that stimulation via The sexual dysfunction produced by the the vagus nerves [37]. Functional magnetic traumatic brain injury may be direct, on resonance imaging brain scanning provided physiologic control [e.g. orgasm), or indirect evidence that the brain region to which the (e.g. emotional reactions to one’s self‐esteem, vagus nerves project (i.e. the nucleus of body image, or sexual identity) [33–35]. the solitary tract in the medulla oblongata of the brainstem) is activated by cervical or Spinal Cord Injury vaginal self‐stimulation in women with com- Depending on the location and “complete- plete spinal cord injury above thoracic T10. ness” of the spinal cord injury and the spe- Furthermore, three of the five women with cific genital response, the effects of spinal complete spinal cord injury experienced cord injury on sexual response vary because orgasm from the vaginal or cervical self‐ the afferent and efferent genital nerves con- stimulation, which resulted in widespread nect to the spinal cord at different levels of activation throughout the brain. Thus, there the spinal cord. The pudendal nerves, which is evidence of two separate genital‐orgasmic convey clitoral sensation, enter the spinal neural pathways in women: the main, spi- cord at sacral levels S2–S4, so “complete” nothalamic, pathway within the spinal cord ­spinal cord injury at that level or above, and the “auxiliary” vagus nerve pathway, blocks the ability to perceive clitoral stimula- which bypasses the spinal cord and projects tion. The hypogastric nerves, which convey directly to the brain, capable of activating cervical and uterine sensation, enter the spi- orgasm [37]. nal cord much higher (i.e. at thoracic levels In cases of pregnant women with complete T10–T12, bypassing the lumbar and sacral spinal cord injury who have intact hypogas- levels). Consequently, pregnant women who tric nerve input to the spinal cord because have complete spinal cord injury below their complete spinal cord injury is below ­thoracic level T12 can feel their uterus con- T12, those women can “feel their uterine tracting and their fetus moving, because contractions and fetal movements normally” the hypogastric nerve afferents enter above [38]. There are assertions in the literature the level of the injury and their access to the that vaginal and anal sensation is lost after brain remains intact [36]. Because the effer- complete spinal cord injury at S4 and above 226 Textbook of Female Sexual Function and Dysfunction

[39], that there is “total loss of sensitivity of orgasm imagery in dreams almost as vividly the internal organs in patients with complete as though it were the real thing. … [This transection of the spinal cord above T‐10”, ­finding] offers conclusive evidence that cog- and that genital sensations are lost and nitional eroticism can be a variable of sex orgasm is not possible after complete spinal entirely independent of genitopelvic sensa- cord injury at T10 or above [40]. But contrary tion and action. The brain, in other words, to these assertions, Cole stated, “However can work independently of the genitalia in difficult it may be to understand, spinal the generation of erotic experience, just as injured women report orgasms in spite of the genitalia of paraplegics can work reflexly complete denervation of all pelvic structures” and independently of the brain. … The occur- [41]. Cole’s assertion is supported by more rence of orgasm imagery in the sleep dreams recent reports of orgasm in “complete quad- of paraplegics may be regarded as a special riplegic” women [42], women with complete example of phantom imagery. It is of interest spinal cord injury between C4 and T9. that this phantom experience was restricted Women with spinal cord injury or complete to sleep. Awake or asleep, there were no spinal cord injury above T10 reported feel- other reported examples, from any of the ing spontaneous menstrual discomfort or patients, of phantom sensation or imagery cramps, further evidence of the existence of a attributable to the genitalia” [44]. spinal cord bypass pathway (i.e. the vagus Money described the case of a woman, nerves) [37]. 32 years of age, who was injured in a fall three years earlier that produced a fracture “Phantom” Orgasms dislocation at C6 and C7. The injury left Patients with complete spinal cord injury and her incontinent and completely paralyzed no genital sensation have reported “phan- from the waist down, except for minimal tom” orgasms in their dreams, indicating the toe movements that disappeared following critical role of the brain in orgasm, independ- rhizotomy. She described that when she ent of the genitals. Patients with an intact had a “sexy dream” she always “reached a spinal cord and with an amputated foot climax” [44]. reported that in response to genital stimula- tion (which, in the sensory cortex, is repre- Epilepsy sented adjacent to the foot [43] they felt Epilepsy is reported to exert potent and orgasms extending into their phantom foot. ­variable effects on sexuality; patients with Money presented the concept of “phantom epilepsy may experience states of hypo‐ or orgasm” in characterizing patients with spi- hypersexuality, and their seizures may feel nal cord injury and no genital sensation who as if they are genital orgasms or “nongenital experienced orgasm in their sleep [44]. In orgasms”. The seizure‐related orgasms may this case, at least in some patients, the “phan- be described as “unwelcome” or pleasurable tom” is the orgasm experienced as genital. Of [45]; in the latter case, a woman refused 14 patients who had spinal cord injury antiepileptic medication or brain surgery, between C5 and L1, all had experienced claiming that she enjoyed her orgasmic orgasm before injury. Eight of the patients auras and did not want to have them elimi- reported experiencing sexual intercourse in nated [46]. In the case of a 57‐year‐old their dreams and five of these patients woman with a tumor in the left anterior reported orgasm imagery in dreams after medial temporal lobe, she had a two‐month their injuries. In Money’s words, these history of daily seizures that she described patients with paraplegia, “had no genitopel- as a sudden pleasure‐provoking feeling “like vic gratification (none ejaculated after their an orgasm”. Antitumor medication regressed injury]. It is therefore all the more remarka- the tumor and the seizures subsided. There ble a phenomenon that some of them had are numerous reports of men and women Pathophysiology and Medical Management of Female Orgasm Disorder 227 experiencing orgasmic feelings just prior to Multiple Sclerosis the onset of an epileptic seizure, termed an Multiple sclerosis in women is character- “orgasmic aura” [45–48]. The most common ized by genital sensory dysfunction, loss brain region from which these orgasmic of libido, decreased vaginal lubrication, auras originate, based on electroencephalo- increased spasticity during sexual activity, graphic recordings, is the right temporal loss of orgasmic capacity [54], and bladder lobe of the forebrain, which contains the and bowel dysfunction [55, 56]. Orgasmic hippocampus and the amygdala. The aura dysfunction in women with multiple sclero- may have a spontaneous onset or may be sis was reported to evolve independently of triggered by some specific stimulus, e.g. disease duration and physical disability. brushing the teeth. There are reports of Abnormality of genital sensation in women ­epileptic seizures that originate in the genital‐ with multiple sclerosis is likely related to projection zone (paracentral lobule) of absent or decreased cortical evoked the sensory cortex. In those cases the indi- responses to electrical stimulation of the viduals report that they experience genital pudendal nerve, which innervates the clito- sensation that develops into an orgasm, and ris [57, 58]. Lesions of the pons [59] are the orgasm feels as if it were generated by involved in cases of anorgasmia [60]. Lesions genital stimulation [48]. However, some of the left temporal periventricular and orgasmic auras are not necessarily experi- right visual association areas were also enced as originating in the genitals, and are reported to be associated with decreased described as “nongenital” orgasms [49]. In a orgasmic function [61]. However, lesions of study of 29 patients with temporal lobe epi- the frontotemporal cortex or midbrain were lepsy, 20 were characterized by “global correlated with higher female sexual func- hyposexuality”, experiencing orgasms less tion index scores, indicating a disinhibiting than once per year or never. After these effect of these brain regions on orgasmic patients received temporal lobectomy, their function [62]. seizures ceased, and they became “chroni- cally hypersexual” [50]. Radiculopathy of the Sacral Spinal Nerve Roots Parkinson’s Disease The pudendal and pelvic nerves involved in Although not universally observed [51], sig- orgasm convey sensation from the clitoris, nificant deleterious effects on sexuality and vagina, prostate, vulva, vestibule, perineum, orgasm have been reported in patients with and anal sphincter and enter the sacrum at Parkinson’s disease. In a study of patients levels Sacral 2‐4. Upon entering the sacrum, with Parkinson’s disease, 7/10 women these nerves pass superiorly as individual reported that, since their diagnosis, they had nerve root components of the cauda equina. reduced sexual interest and orgasm fre- The cauda equina also consists of sensory quency, and 4/10 were unable to experience and motor nerve roots from the lower lum- orgasm. The spouses noted a decrease in bar dermatomes, which convey sensation their affected partner’s sexual interest in the from the feet, legs, and buttocks. The sacral majority of the cases [52]. On the basis of the nerve roots first synapse in the sacral divi- extensive evidence of the role of dopamine sion of the spinal cord proper at the conus in sexual response and orgasm [53], it is medullaris, typically located at vertebral level likely that the loss in sexual response and Thoracic 12 just below the lowest rib. Efferent orgasm in Parkinson’s disease – as well as sacral and lumbar nerve roots comprise part the loss of motor function – is closely related of the cauda equina, providing the parasym- to the deterioration of the dopaminergic pathetic (but not sympathetic) and somatic neuron system, which is characteristic of innervation of the genitalia and somatic this disease. motor innervation of the lower limbs [63]. 228 Textbook of Female Sexual Function and Dysfunction

As a result of this innervation pattern, elevated fasting plasma glucose, high serum when there is irritation of, or damage to, the triglycerides, and low levels of high‐density cauda equina by physical herniation/com- lipoprotein [66]. Based on a study of 376 post- pression by one or more intervertebral discs, menopausal women (mean age 73) to whom most commonly at Lumbar 5‐Sacral 1 or the female sexual function index was admin- Lumbar 4‐5, a constellation of one or more of istered, the women who fulfilled the criteria the following symptoms may occur: altered for a diagnosis of metabolic syndrome showed (increased or decreased) genital sensation a significant correlation with low sexual activ- including paresthesias and persistent genital ity and desire, arousal, orgasm, and satisfac- arousal disorder, less intense orgasm, anor- tion. Furthermore, low sexual activity was gasmia, and lumbar root sensorimotor defi- correlated with angina, heart attack, and cits, such as lower extremity weakness, ­coronary bypass surgery [65]. sensory deficit below the knee, leg reflex In an earlier study of women with diabetes, change, low back pain, and/or sciatica [63]. 35% of 125 had lost the ability to experience Female orgasm disorder may also exist, in orgasm after the onset of their disorder, part, associated with vascular disorders whereas only 6% of a comparison group of including hypertension, metabolic syn- 100 nondiabetic women were anorgasmic drome, and diabetes. In a meta‐analysis of 24 (and had never experienced orgasm). There studies relating cardiovascular disease to was no association between the diabetes‐ sexuality in women, the authors concluded related anorgasmia and age, diabetes dura- that cardiovascular disease detrimentally tion, or severity of neuropathy [67]. In a affected all the measured domains of sexual subsequent study, women with type 1 diabe- function (i.e. desire, arousal, vaginal lubrica- tes (insulin‐dependent) showed an overall tion, orgasm, sexual satisfaction, and pain). 40% incidence of sexual disorders (including Hypertensive women were found to have decreased capacity to experience orgasms, more difficulty in experiencing lubrication decreased vaginal lubrication, and decreased and orgasm than the healthy comparison sexual desire), whereas the age‐matched group [64]. A study of the effect of heart comparison group showed only a 7% inci- attack on sexuality compared one hundred dence of any kind of sexual disorder [68]. women hospitalized for myocardial infarc- In the diabetic group compared with the tion with an age‐matched sample of one hun- comparison group, there were additional dred women hospitalized for other reasons. indicators of peripheral neuropathy, i.e. All of the women underwent a 57‐item inter- higher vibration perception thresholds meas- view about their sex lives, including specifi- ured at the clitoris and hands, incontinence, cally whether they lacked sexual intercourse and reduced foot perspiration. due to a partner’s illness or erectile dysfunc- Female orgasmic disorder may also exist, tion, lacked enjoyment of sexual intercourse, in part, associated with debilitating dis- or were emotionally distressed about being eases (e.g. cancer, degenerative diseases). A unable to experience orgasm during inter- study assessed sexual well‐being (using the course. The authors reported a significant sexual relationships and activities question- correlation between positive responses on naire) in 3708 women at least 50 years old the above specific questions and the women’s who were either cancer survivors or can- history of myocardial infarction [65]. cer‐free. Compared with the cancer‐free Metabolic syndrome, which is associated women, the cancer survivors reported with the risk of developing cardiovascular greater difficulty in experiencing orgasm disease and type 2 (insulin‐resistant) diabe- (61 versus 28%), becoming aroused (55 ver- tes, consists of three or more of the following sus 32%), and were more concerned about conditions: abdominal obesity, hypertension, their orgasmic experience (18 versus 7%) Pathophysiology and Medical Management of Female Orgasm Disorder 229 and their sexual desire (15 versus 7%). The (trigger point injection) may result in authors did not propose a mechanism to reduction of the female orgasmic disorder account for these differences [69]. symptoms. For women with female orgas- mic disorder who may be considered to have low‐tone pelvic floor dysfunction, ­Diagnosis of Women with strategies that would increase muscle Female Orgasm Disorder tone may result in reduction of the female orgasmic disorder symptoms [21, 22]. ●● Distracting and bothersome genital medi- Women with bothersome and distressing cal conditions that may be associated with female orgasmic disorder should undergo a discomfort and cause female orgasm thorough biopsychosocial history and physi- ­disorder: physical examination, including cal examination, and laboratory tests. diagnostic procedures such as vulvoscopy, Diagnostic efforts should be made to identify cotton swab (Q‐tip) testing, and vaginal if there are any reversible causes of female wet mount and smear testing, should be orgasmic disorder. In this case, modification performed to assess for such pathologies of any reversible causes would be recom- as: lichen plannus, lichen sclerosus, vulvar mended prior to focus on the initiation of granuloma fissuratum, and desquamative symptomatic therapeutic interventions for inflammatory vaginitis [28, 29]. female orgasmic disorder. ●● Endocrine disorders in part causing female Multiple pathophysiologies of female orgasm disorder, such as low testosterone, orgasmic disorder have been proposed that low estradiol, low thyroid and elevated can result in the symptoms typically associ- prolactin hormones: diagnostic blood test- ated with female orgasmic disorder. ing can be performed to obtain baseline ●● Psychological problems in part causing and then post‐treatment values. These female orgasmic disorder: psychosocial endocrinopathy states may be classically assessment should be performed [14–16]. noted in the genitourinary syndrome of ●● Medication‐related pathophysiologies, in menopause or in reproductive age women part, causing female orgasmic disorder: a on hormonal birth control. The diagnostic full history of medication use should be blood tests include: total testosterone, sex performed. Certain medications negatively hormone binding globulin, dihydrotestos- affect orgasm, such as selective serotonin terone, luteinizing hormone, follicle reuptake inhibitors, antipsychotics, anti- ­stimulating hormone, prolactin, thyroid hypertensives, benzodiazepines, histamine stimulating hormone, estradiol and pro- 2 receptor antagonists, and anticonvul- gesterone. Calculated free testosterone sants [17–19]. can be performed using the law of mass ●● Partner‐related pathophysiologies, in part, action calculator and the values of total causing female orgasmic disorder: partner testosterone and sex hormone binding sexual dysfunction assessment should be globulin [70–72]. performed. ●● Neurologic pathophysiologies in part ●● Pelvic floor pathophysiologies, in part, ­causing female orgasm disorder: diagnos- causing female orgasmic disorder: pelvic tic testing can be performed to help lo­ calize floor physical therapy assessment should the sites of neurologic impairment. be performed. For women with female Diagnostic neuro‐genital tests may be orgasmic disorder who may be considered ­considered, such as quantitative sensory to have high‐tone pelvic floor dysfunc- testing, sacral dermatome testing, bulbo- tion, a diagnostic local anesthesia nerve cavernosus reflex latency testing, and block to the specific suspected location ­urodynamic testing [63]. Diagnostic 230 Textbook of Female Sexual Function and Dysfunction

­magnetic resonance ­imaging studies of the considered to lower the high tone state. sacral and lumbar spine areas should fur- Adjunctive use of trigger point injections, ther be considered. If a suspicious lesion is vaginal or rectal diazepam or baclofen, and/ noted on magnetic resonance imaging, a or intramuscular onabotulinum toxin A may diagnostic epidural local steroid injection result in improvement of the female orgasm to the specific lesion that resulted in disorder symptoms. For women with low‐ marked reduction of the female orgasm tone pelvic floor dysfunction, traditional disorder symptoms and enhanced genital physical therapy strategies may be considered sensitivity would provide evidence that the to raise the low tone state [77–81]. female orgasm disorder symptoms resulted For women with female orgasm disorder from the spinal lesion. who have underlying medication‐related ●● Vascular pathophysiologies in part causing pathophysiologies, such as use of agents female orgasm disorder, such as cardiovas- known to reduce orgasm function, including cular disease or metabolic syndrome: duplex selective serotonin reuptake inhibitors, Doppler ultrasonography or clitoral/vulvar antipsychotics, antihypertensives, benzodi- thermography may be considered [73]. azepines, histamine 2 receptor antagonists, and anticonvulsants: identifying strategies to eliminate these agents, if possible, or to ­Treatment of Women with switch to agents with less orgasm interfering Female Orgasm Disorder properties, should be considered [17–19]. For women with female orgasm disorder There are two types of treatment for women who have underlying endocrine pathophysi- with female orgasm disorder. Firstly, disease ologies, such as low testosterone, low estra- modification treatment strategies are designed diol, low thyroid and elevated prolactin to cure the female orgasm disorder and resolve hormones: various treatment strategies may the underlying pathophysiology(ies). be considered. For women with female orgasm disorder and low testosterone, dis- Female Orgasm Disorder Disease cussion should ensue as to the carefully Modification Treatment Strategies ­monitored use of biologically‐identical tes- tosterone. There are no FDA‐approved tes- For women with female orgasm disorder who tosterone products for women, so the choices have underlying psychological concerns: psy- include off‐label use of FDA‐approved tes- chological treatment strategies, such as for- tosterone products for men dosed at approx- mal psychotherapy including sensate focus imately one‐tenth of the intended male dose therapy, cognitive behavior therapy, and/or or off‐label use of compounded testosterone mindfulness therapy, typically focusing on products. An ideal goal of testosterone ther- modifying feelings, attitudes, actions, senti- apy is a calculated free testosterone values of ments, and relationship communication/ 0.6–0.8 ng/dl. Follow‐up blood tests for total behaviors that may be causatively related to testosterone, sex hormone binding globulin, the female orgasm disorder condition. More and dihydrotestosterone should initially be conservative strategies to reduce anxiety may made at three‐month intervals and then as include yoga and acupuncture [74–76]. needed, such as every 6–12 months if stable. For women with female orgasm disorder The three choices of testosterone therapy who have underlying pelvic floor pathophysi- include: daily topical products typically ologies, in part, causing persistent genital applied to the back of the calf, weekly intra- arousal disorder: pelvic floor physical therapy muscular injections of testosterone typically strategies should be performed. For women into the vastus lateralus, and 4–6‐monthly with high‐tone pelvic floor dy­ sfunction, testosterone pellets. A 75 mg testosterone ­traditional physical therapy strategies may be pellet product is FDA‐approved for men. Pathophysiology and Medical Management of Female Orgasm Disorder 231

Side effects of testosterone treatment typi- of biologically‐identical thyroid hormone. cally are cosmetic and include increased There are FDA‐approved thyroid hormone facial hair, thinning of scalp hair, acne, and products. The ideal goal of thyroid therapy is oily facial skin. Usually the dose of testoster- a thyroiod stimulating hormone value of one is decreased if side effects occur. If tes- 1–2 μU/ml. The typical starting daily dose of tosterone treatment results in improvement thyroid hormone is 25 µg/d. Follow‐up blood of orgasm function, the patient should con- tests for thyroid stimulating hormone, free sider staying on testosterone treatment for triiodothyronine, total triiodothyronine, free 6–12 months and taking a drug holiday from thyroxine, and total thyroxine should initially the treatment to see if the treatment is still be made at three‐month intervals and then as required. In most cases, testosterone therapy needed, such as every 6–12 months if stable. is needed to maintain the orgasm function Side effects of thyroid treatment typically improvement [71, 72]. are: headache, insomnia, nervousness, irrita- For women with female orgasm disorder bility, fever, hot flushes, sweating, pounding and low estradiol, typically women in meno- heartbeats or fluttering in the chest region. pause: discussion should ensue as to the Usually the dose of thyroid hormone is carefully monitored use of biologically‐­ decreased if side effects occur. If thyroid hor- identical estradiol. There are many FDA‐ mone treatment results in improvement of approved estradiol products for women in orgasm function, the patient should consider menopause, including oral pills, patches, staying on thyroid hormone treatment for gels, vaginal rings, and intramuscular injec- 6–12 months and taking a drug holiday from tions. For women with a uterus, those who the treatment to see if the treatment is still have not had a hysterectomy, concomitant required. In most cases, thyroid hormone use of progesterone will act to protect the therapy is needed to maintain the orgasm endometrial lining of unopposed stimula- function improvement [25, 82, 83]. tion. The ideal goal of estradiol therapy is a For women with female orgasm disorder value of approximately 35–50 pg/ml, the and increased prolactin hormone levels: dis- usual upper value of normal for many refer- cussion should ensue as to obtaining mag- ence laboratories in menopause and values netic resonance imaging of the pituitary with consistent with 8–10% of peak estradiol val- gadolinium. In most cases, a microadenoma ues in the reproductive years. Follow‐up will be identified and medical management blood tests for estradiol should initially be with cabergoline will follow. In rare cases of made at three‐month intervals and then as local mass lesion symptom – producing needed, such as every 6–12 months if stable. ­macroadenomas, neurosurgical referral is Side effects of estradiol treatment include: indicated. In most cases, medical manage- breast cancer, thromboembolic disease, breast ment will involve use of carefully‐monitored pain, nipple discharge, uterine bleeding. FDA‐approved cabergoline. The ideal goal of Usually the dose of estradiol is decreased if cabergoline therapy is a normal prolactin side effects occur. If estradiol treatment value of 4–23 ng/ml. The typical starting results in improvement of orgasm function, dose of cabergoline is 0.5 mg twice a week on the patient should consider staying on estra- Monday and Thursday. Follow‐up blood diol therapy for 6–12 months and taking a tests for prolactin should initially be made at drug holiday from the treatment to see if the three‐month intervals and then as needed, treatment is still required. In most cases, such as every 6–12 months if stable. estradiol therapy is needed to maintain the Side effects of cabergoline treatment orgasm function improvement [71, 72]. ­typically are: feeling short of breath on exer- For women with female orgasm disorder tion, chest discomfort, dry cough, feeling and low thyroid hormone: discussion should weak or tired, loss of appetite, rapid weight ensue as to the carefully monitored use loss, and lower back pain. Usually the dose of 232 Textbook of Female Sexual Function and Dysfunction

cabergoline is decreased if side effects occur. ­radiculopathy in general, and Tarlov cysts If treatment with cabergoline, which is a and/or herniated intervertebral disc or dopamine receptor stimulant (and prolactin ­stenosis‐induced chronic cauda equina secretion inhibitor), results in improvement ­syndrome in particular, may cause female of orgasm function, the patient should orgasm disorder. It is hypothesized that ­consider staying on cabergoline treatment female orgasm disorder may occur as a mani- for 6–12 months. A follow‐up pituitary festation of mechanical irritation of the geni- ­magnetic resonance imaging is indicated. tal sensory (and possibly autonomic) nerve Taking a drug holiday from the cabergoline roots, which could result in hypofunction of may be attempted to see if the treatment is sacral nerve roots. Our hypothesis is based in still required. In most cases, cabergoline part on our recent findings that administra- therapy is needed to maintain the lowered tion of epidural steroids at the site of the prolactin levels and for orgasm function ­genital nerve roots, and subsequent surgical improvement [84, 85]. reduction of the intervertebral discs, or sur- Concerning distracting and bothersome gical treatment of Tarlov cysts, successfully genital medical conditions that may be asso- alleviated the female orgasm disorder symp- ciated with discomfort and cause female toms. This hypothesis supports the concept orgasm disorder: management should be that the female orgasm disorder hypofunc- offered based on the underlying pathophysi- tion is a form of genital radiculopathy due to ology. Treatment of the genital dermatologic hypofunction of the genital sensory nerve conditions, including lichen plannus and roots. It is suggested that female orgasm dis- lichen sclerosus, typically involve initial use order be included as a subtype of the chronic of daily ultra‐potent steroids, such as form of cauda equina syndrome, on the basis ­clobetasol propionate 0.05% ointment. The that mechanical impingement of interverte- condition of vulvar granuloma fissuratum is bral discs on the cauda equina seems to be a often cured by posterior vestibulectomy with clear etiological factor in certain cases of vaginal advancement flap reconstruction. female orgasm disorder [63]. The condition of desquamative inflamma- tory vaginitis, a sterile form of vaginitis, can Female Orgasm Disorder be caused by an irritant or allergic reaction to Symptomatic Treatment Strategies chemicals or be caused by a lack of estrogen. The characteristic sign of desquamative Symptomatic therapeutic strategies for inflammatory vaginitis is a copious yellowish female orgasm disorder are based on phar- discharge that dries like glue. Sheets of white macologic agents used to rebalance brain blood cells and parabasal cells are seen central nervous system excitatory and inhibi- on smear. Typical treatment requires tory neurotransmitter imbalances. In female using 2 g each night for one month of a orgasm disorder management, it is hypothe- ­compound – hydrocortisone 10%; estradiol sized that increasing central nervous system 0.02%; and clindamycin 2% in a vaginal cream sexual excitatory processes with agonists of base (VersaBase). Diflucan 150 mg once per dopamine, oxytocin, and/or norepinephrine, week is also used [86, 87]. or decreasing central nervous system sexual Concerning women with female orgasm inhibitory processes with antagonists of opi- disorder from suspected reduced sensory oid and/or serotonin, would improve orgasm information (radiculopathy) passing from function. As there are no FDA‐approved hypofunctioning sacral spinal nerve roots agents to safely or effectively treat female within the cauda equina from various sacral orgasm disorder, all such pharmaceutical and lumbar pathologies: minimally invasive therapies are off‐label. endoscopic and navigational spine surgery Off‐label pharmaceutical agonist agents may be considered. Sacral spine nerve potentially for female orgasm disorder that Pathophysiology and Medical Management of Female Orgasm Disorder 233 may act on excitatory neurotransmitters, and To prescribe flibanserin, the health‐care the doses one of the authors recommends ­provider needs to be certified in the risk eval- initially to women with female orgasm disor- uation and mitigation strategy program. der, include: bupropion 75 mg/d in the AM; Efficacy for libido improvement may not cabergoline 0.5 mg q Monday and q Thursday; develop for up to 8–12 weeks, and it may be ropinirole 0.25 mg qdaily – TID; oxytocin similar for the orgasm function improve- lozenges 250 U sublingually – one hour prior ment. The most common adverse events to sexual activity; and/or amphetamine, dex- reported, in terms of placebo‐corrected rates troamphetamine mixed salts, 2.5–10 mg of occurrence, included mild‐to‐moderate taken 30 minutes prior to sexual activity, but severity dizziness (9.2%), somnolence (8.3%), if taken after 2:00 p.m. difficulty with sleep nausea (6.5%), and fatigue (3.7%). These side should be considered. effects are not uncommon with central nerv- Off‐label pharmaceutical antagonist agents ous system active medications that influence potentially for female orgasm disorder that serotonin [88–93]. may act on inhibitory neurotransmitters, and the doses one of the authors recommends initially to women with female orgasm disor- ­Conclusions der, include: buspirone 10 mg twice a day, and/or naltexone 50 mg/d. Female orgasm disorder is a relatively com- Off‐label pharmaceutical agonist and mon sexual medicine condition. The antagonist agents potentially for female ISSWSH Nomenclature for Female Sexual orgasm disorder that may act on both excita- Dysfunctions has broadened the definition tory and inhibitory neurotransmitters include such that female orgasm disorder is charac- use of flibanserin at a dose of 100 mg/night. terized by a persistent or recurrent, distress- Flibanserin is a nonhormonal, centrally act- ing compromise of orgasm frequency, ing, postsynaptic serotonin 1A receptor ago- intensity, timing, and/or pleasure, associated nist and a serotonin 2A receptor antagonist, with sexual activity for a minimum of six and is classified as a multifunctional seroto- months. Multiple diagnostic procedures may nin agonist and antagonist. Flibanserin use be used to help resolve the various underly- results in a decrease in serotonin activity and ing female orgasm disorder biopsychosocial an increase in dopamine and norepinephrine pathophysiologies. Therapies may be consid- activity, based on laboratory animal studies. ered disease modification aimed to cure the While flibanserin is currently an FDA‐ female orgasm disorder condition. Therapies approved treatment for generalized acquired may be considered symptomatic, aimed to hypoactive sexual desire disorder in premen- reduce the female orgasm disorder symp- opausal women, studies have reported that all toms, so that the orgasm function is domains in the female sexual function index, improved. More research is needed in female including orgasm function, are increased. orgasm disorder.

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myofascial pelvic pain. Investig Clin Urol. 85 Rastrelli G, Corona G, Maggi M. The role 2017;58(2):134–139. of prolactin in andrology: what is new? Rev 78 Adelowo A, Hacker MR, Shapiro A, et al. Endocr Metab Disord. 2015;16(3):233–248. Botulinum toxin type A (BOTOX) for 86 Mitchell L, King M, Brillhart H, Goldstein refractory myofascial pelvic pain. Female A. Cervical ectropion may be a cause of Pelvic Med Reconstr Surg. desquamative inflammatory vaginitis. Sex 2013;19(5):288–292. Med. 2017;5(3):e212–e214. 79 Crisp C, Vaccaro CM, Estanol MV, et al. 87 Burrows L, Shaw HA, Goldstein AT. The Intra‐vaginal diazepam for high‐tone pelvic vulvar dermatoses. J Sex Med. floor dysfunction: a randomized placebo‐ 2008;5(2):276–283. controlled trial. Int Urogynecol J. 88 Goldstein I, Kim NN, Clayton AH, et al. 2013;24(11):1915–1923. Hypoactive sexual desire disorder: 80 Carrico D, Peters KM. Vaginal diazepam International Society for the Study of use with urogenital pain/pelvic floor Women’s Sexual Health (ISSWSH) Expert dysfunction: serum diazepam levels and Consensus Panel Review. Mayo Clin Proc. efficacy data. Urol Nurs. 2017;92(1):114–128. 2011;31(5):279–284. 89 Portman D, Brown L, Yuan J, et al. 81 Rogalski M, Kellogg‐Spadt S, Hoffmann Flibanserin in postmenopausal women AR, et al. Retrospective chart review of with hypoactive sexual desire disorder: vaginal diazepam suppository use in high‐ results of the PLUMERIA study. J Sex Med. tone pelvic floor dysfunction. Int 2017;14(6):834–942. Urogynecol J. 2010;21(7):895–899. 90 Gao Z, Yang D, Yu L, Cui Y. Efficacy and 82 Oppo A, Franceschi E, Atzeni F, et al. safety of flibanserin in women with Effects of hyperthyroidism, hypoactive sexual desire disorder: a hypothyroidism, and thyroid autoimmunity systematic review and meta‐analysis. J Sex on female sexual function. J Endocrinol Med. 2015;12(11):2095–2104. Invest. 2011;34(6):449–453. 91 Katz M, DeRogatis LR, Ackerman R, et al. 83 Atis G, Dalkilinc A, Altuntas Y, et al. Sexual Efficacy of flibanserin in women with dysfunction in women with clinical hypoactive sexual desire disorder: results hypothyroidism and subclinical from the BEGONIA trial. J Sex Med. hypothyroidism. J Sex Med. 2013;10:1807–1815. 2010;7:2583–2590. 92 Jayne C, Simon JA, Taylor LV, et al. 84 Worsley R, Santoro, N, Miller, KK, et al. Open‐label extension study of flibanserin Hormones and female sexual in women with hypoactive sexual desire dysfunction: beyond estrogens and disorder. J Sex Med. 2012;9(12):3180–3188. androgens – Findings from the 93 Parish S, Hahn SR. Hypoactive sexual Fourth International Consultation on desire disorder: a review of epidemiology, Sexual Medicine. J Sex Med. biopsychology, diagnosis, and treatment. 2016;13:283–290. Sex Med Rev. 2016;4(2):103–120. 239

17

Pathophysiology and Medical Management of Female Orgasmic Illness Syndrome Irwin Goldstein and Barry R. Komisaruk

Abstract

Female orgasmic illness syndrome refers to those rare aversive symptoms that have been reported to occur prior to, during, or following orgasm, arbitrarily divided into central or peripheral aversive symptoms. Central aversive symptoms may include disorientation, confusion, impaired judgment, decreased verbal memory, anxiety/agitation/akathisia, insomnia, laughter, dysphoria/crying/ depression, fatigue, seizures, muscle weakness/paralysis, and/or headache. Peripheral aversive symptoms may include diarrhea, constipation, muscle ache, sneezing, abdominal pain, diaphoresis, chills, hot flashes, pruritus, facial/ear/foot pain, and genital pain. Symptoms may last for minutes, hours, or days post-orgasm and varies widely within individuals. More research is needed.

Keywords: orgasm illness syndrome (OIS); central aversive symptoms associated with orgasm; peripheral aversive symptoms associated with orgasm; confusion associated with orgasm; crying associ- ated with orgasm; depression associated with orgasm; headache associated with orgasm; abdominal pain associated with orgasm; genital pain associated with orgasm; sneezing associated with orgasm

Symptoms may last for minutes, hours, or days post-orgasm, and can vary widely in individuals. Central aversive symptoms include disorientation, confusion, impaired judgment, decreased verbal memory, anxiety/agitation/akathisia, insomnia, laughter, dysphoria/crying/depression, fatigue, seizures, muscle weakness/paralysis, and/or headache. Peripheral aversive symptoms include diarrhea, constipation, muscle ache, sneezing, abdominal pain, diaphoresis, chills, hot flashes, pruritus, facial/ear/foot pain, and genital pain.

­Introduction ­ISSWSH Consensus Nomenclature – Female Female orgasmic illness syndrome refers to Orgasmic Illness Syndrome those rare aversive symptoms that have been reported to occur prior to, during, or follow- Female orgasmic illness syndrome is not ing orgasm [1]. Such symptoms may be arbi- mentioned in either the DSM IV [2] or the trarily divided into either central aversive DSM‐5 [3]. Sexual medicine health‐care pro- symptoms or peripheral aversive symptoms. viders do manage women who complain of

Textbook of Female Sexual Function and Dysfunction: Diagnosis and Treatment, First Edition. Edited by Irwin Goldstein, Anita H. Clayton, Andrew T. Goldstein, Noel N. Kim, and Sheryl A. Kingsberg. © 2018 John Wiley & Sons Ltd. Published 2018 by John Wiley & Sons Ltd. 240 Textbook of Female Sexual Function and Dysfunction

varying bothersome and distressing orgas- even several hours after orgasm [4–10]. Use mic complaints, and, although rare, it is not of anti‐epileptics has been reported to reduce helpful to such patients who seek help and these orgasm‐induced seizures. The orgasm‐ counsel that such orgasmic phenomena are induced seizure focus has often been found not represented in a nomenclature system within the temporal lobe [4, 5, 7, 10] but [1]. Thus, a more comprehensive, biopsycho- numerous other locations such as paracen- social sexual medicine health‐care provider‐ tral lobule [6], cerebral hemisphere [8], oriented classification of women with ­superior postcentral gyrus [10], or parietal distressing orgasm symptoms, such as those parasagittal regions [3] have been identified. denoted as female orgasmic illness syndrome Various brain pathologies have been reported, was required in women whose primary com- such as post‐traumatic brain injury [6], or plaint is aversive symptoms that occur prior even secondary to an astrocytoma [5]. to, during, or following the orgasm. The ISSWSH Nomenclature Consensus Headache (Coital Cephalalgia) Conference considered female orgasmic ­illness syndrome to be consistent with Concerning women with female orgasmic ill- peripheral and/or central aversive symptoms ness syndrome and sexual headaches – coital that occur prior to, during, or following cephalalgia – there is more peer reviewed orgasm [1]. Central aversive symptoms may published literature on this symptom of include disorientation, confusion, impaired female orgasmic illness syndrome than any judgment, decreased verbal memory, anxi- other [11–13]. These sexual headaches are ety/agitation/akathisia, insomnia, laughter, rare and mostly benign. They typically begin dysphoria (post-coital dysphoria)/crying/ as a dull headache in the head and neck and depression (post-coital tristesse), fatigue, sei- are bilateral in two thirds of cases. They zures (orgasmic epilepsy), muscle weakness/ increase with sexual excitement and become paralysis (cataplexy), and/or headache (coital intense at orgasm [11–13]. The pathophysi- cephalalgia). Peripheral aversive symptoms ology is likely related to the adrenalin release may include diarrhea, constipation, muscle associated with orgasm, intense sexual ache, sneezing, abdominal pain, diaphoresis, excitement, and contraction of facial and chills, hot flashes, pruritus, facial/ear/foot neck muscles. [14]. For some patients, the pain, and genital pain (dysorgasmia). Such female orgasmic illness syndrome headaches orgasm‐associated symptoms may last for may be related to the elevated blood pressure minutes, hours, or days post-orgasm and that occurs during orgasm. The pain has a vary widely in individuals variable duration and variable intensity, last- In this chapter, some of the many examples ing from one minute up to 72 hours [11–13]. of female orgasmic illness syndrome are If the painful headache is, however, sudden examined. It is clear that more research is and severe, this may warrant evaluation by need to safely and efficaciously manage these magnetic resonance angiography to rule out patients. intracranial pathology [15]. It is estimated that female orgasmic illness syndrome head- aches occur in approximately 1% of the pop- ­Central Aversive Symptoms ulation [13]. Concerning women with female orgasmic illness syndrome and sexual head- Seizures (Orgasmolepsy) aches, conservative treatment may consist of beta‐blockers and/or antimigraine medica- Concerning women with female orgasmic tion [13, 16]. In patients who do not improve ­illness syndrome and the occurrence of sei- on these medications, indomethacin or a cal- zures with orgasm, multiple cases have been cium channel antagonist such as verapamil reported occurring at the time of orgasm or can be tried [11, 13]. We have found that Pathophysiology and Medical Management of Female Orgasmic Illness Syndrome 241 anticonvulsants such as topirimate can be after consensual sexual activity, that can successful in some cases that are otherwise include tearfulness and sadness, and that can resistant to treatment. last up to an hour [26–28]. This has been reported to occur in approximately one‐third Sneezing of women [27]. It is unclear at this time how to best safely and effectively manage The association between sneezing and sexual such patients. excitement or even sexual ideation has been know for more than 100 years [17]. Concerning the association of sneezing and/ ­Peripheral Aversive or rhinorrhea with orgasm, reports have Symptoms hypothesized that activation of one auto- nomic regulated function (orgasm) may Genital Pain (Dysorgasmia) ­activate a different autonomic‐regulated function (sneezing) [18–20] and that sneez- Concerning women with female orgasmic ill- ing is an orgasm of the respiratory system ness syndrome and bothersome distracting [21]. Concerning treatment of orgasm‐ genital pain with orgasm (dysorgasmia), after induced sneezing, various strategies have ruling out other causes of dyspareunia, been employed, some with minimal efficacy, reports claim low dose tricyclic antidepres- such as antihistamines, nasal decongestants, sant amitriptyline (50 mg) can be helpful and nasal anesthetics [18–20]. [29]. We have seen female orgasmic illness syndrome and dysorgasmia related to radicu- Muscle Weakness/Paralysis litis of the sacral spinal nerve roots from both (Cataplexy) sacral and lumbar spine pathology where the afferent sensory pelvic nerve is inflamed and Concerning women with female orgasmic ill- is responsible for the dysorgasmia. For such ness syndrome and muscle weakness/paraly- patients, it is recommended to undergo sis (cataplexy), symptoms of post-orgasmic neuro‐genital testing with quantitative sen- loss of total muscle control for less than a sory testing, sacral dermatome testing, and minute have been reported as far back as bulbocavernosus reflex latency testing [30]. approximately 100 years [22–25]. It is unclear If abnormal, magnetic resonance imaging of at this time how to best safely and effectively the sacral and lumbar spine should be con- manage such patients but it may be that use of sidered. If pathology is noted, a focal epidural amphetamine, dextroamphetamine mixed steroid and local anesthesia nerve block is salts, 2.5–10 mg taken 30 minutes prior to likely to reveal diminution of distracting sexual activity may help these patients as the ­genital pain wth orgasm (dysorgasmia) pharmacologically mediated heightened adr- symptoms, in which case minimally invasive energic activity may counteract the cataplexic endoscopic and navigational spine surgery symptoms [23–25]. More research is needed. could be considered [30].

Dysphoria (Postcoital Dysphoria)/ Facial/Ear/Foot Pain Crying/Depression (Postcoital Tristesse) Facial/ear/foot pain in women in relation to orgasm is reported in the literature [31–33]. Concerning women with female orgasmic ill- For women with female orgasmic illness syn- ness syndrome and the post-coital negative drome and foot pain, this may be explained aspects of dysphoria (postcoital dysphoria)/ by the homuncular somatosensory cortical crying/depression (post-coital tristesse), this representation, in which the representation has been described in secure relationships, of the clitoris and genitals lies inferior to that 242 Textbook of Female Sexual Function and Dysfunction

of the feet and toes [34, 35]. Foot pain with ­Conclusions orgasm may even occur after a below‐the‐ knee amputation [36]. An epidural nerve It is evident that women may report unusual block localized to sacral dorsal root ganglia central and/or peripheral symptoms associ- can temporarily stop the foot pain with ated with orgasm. In this chapter, some orgasm [32]. For women with female orgas- ­information and direction for the clinician mic illness syndrome and face or ear pain encountering such a patient is provided. with orgasm, one report showed that symp- Most of the data are derived from case toms can last up to 15 minutes and successful reports. More research is needed in female treatment involved a sympathomimetic agent orgasmic illness syndrome, as it is clear that to counteract the reduced post-orgasmic the central and peripheral (neuro)physiology ­sympathetic nervous system activity [33]. of orgasm is complex.

­References

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Part IV

Sexual Pain Disorders

Chapter No.: 1 Title Name: p04.indd Comp. by: Date: 22 Mar 2018 Time: 11:31:32 AM Stage: WorkFlow: Page Number: 245 247

18

Nosology and Epidemiology of Dyspareunia and Vulvodynia Tami Serene Rowen and Andrew T. Goldstein

Abstract

Sexual pain is common can involve a wide array of disorders of the vulva, vagina, cervix, uterus, adnexa, pelvic floor muscles, and nerves that innervate these structures. The three most frequently used terms to describe sexual pain in women are: vulvodynia, dyspareunia, and vaginismus. There has been an evolution in terminology of sexual pain that allows for a better understanding of the source of the pain. Vulvodynia specifically can be associated with inflammation, hormonal changes, neurological, musculoskeletal, embryologic, genetic as well as psychosocial factors. The outcomes can lead to severe impact on a woman’s quality of life.

Keywords: vulvodynia; vestibulodynia; vaginismus; dyspareunia; genito‐pelvic pain disorder; ­sexual pain; inflammation; hormonal changes; quality of life

Sexual pain can involve the vulva, vestibule, pelvis muscles as well as internal organs and has both a physiological and psychological basis. Sexual pain has been described for centuries: the nosology has changed significantly. Contemporary terminology takes into account the many factors contributing to this condition. Sexual pain is highly prevalent and carries a significant cost to society.

­Background In addition, an understanding of the epide- miology of these disorders is essential in Sexual pain is common and can have severe order to properly screen and counsel patients. negative effects on women and their part- ners. Sexual pain can involve a wide array of disorders of the vulva, vagina, cervix, uterus, ­Nosology adnexa, pelvic floor muscles, and the nerves that innervate these structures. In order to The three most frequently used terms to fully understand sexual pain and urogenital describe sexual pain in women are: vulvo- pain, a thorough examination of the histori- dynia, dyspareunia, and vaginismus. The cal and current terminology is very useful. term “vulvodynia” (chronic vulvar pain) is

Textbook of Female Sexual Function and Dysfunction: Diagnosis and Treatment, First Edition. Edited by Irwin Goldstein, Anita H. Clayton, Andrew T. Goldstein, Noel N. Kim, and Sheryl A. Kingsberg. © 2018 John Wiley & Sons Ltd. Published 2018 by John Wiley & Sons Ltd. 248 Textbook of Female Sexual Function and Dysfunction

derived from the combination of the words the vestibule and with associated vestibular “vulva” (the external genitalia in females) findings [12]. Friedrich went on to become a and Odyne, the Greek goddess of pain. founding member of the International Society Descriptions of vulvodynia can be found in for the Study of Vulvovaginal Disease ancient texts such as the Ramesseum Papyrus (ISSVD), which has since become the preemi- and in the writings of Soranus of Ephesus [1]. nent society in terms of research, advocacy, The term “dyspareunia” (i.e. pain during and nosology related to vulvodynia. The intercourse) was first used by Robert Barnes ISSVD was formed in 1970 and had its first in 1878 in his treatise “A Clinical History of Congress in 1971 [13]. In 1975, the ISSVD the Medical and Surgical Disease of Women” described generalized vulvodynia (GVD), [2]. Lastly, the term vaginismus (an involun- also known as “essential” or “dysesthetic” vul- tary contraction of the musculature of the vodynia, as “burning vulva syndrome” at its vagina that interferes with intercourse) was world congress [1]. Eight years later, the coined by J Marion Sims in 1862 [3]. The first ISSVD adopted the first standard definition scientific examination of vulvodynia was of GVD as chronic vulvar discomfort, charac- began in the late nineteenth century by terized by the patient’s complaint of burning Thomas [4], who described this condition as and sometimes stinging, irritating, or raw an “excessive sensibility of the nerves supply- ­sensations [1, 14]. ing the mucous membrane of some portion As more providers showed an interest in of the vulva, sometimes confined to the vulvodynia, the focus narrowed onto the dif- ­vestibule… [and] other times to one labium ferent subtypes of this condition, describing minus.” In addition, the Scottish gynecologist vestibular pain as distinct from generalized Alexander Skene, for whom the periurethral vulvar pain and pain that is not solely related glands are named, reported “a supersensi- to sexual activity [15, 16]. In 1992, a thorough tiveness of the vulva. When, however, the review on vulvodynia incorporated the role examining finger comes in contact with the of dermatoses, infection, inflammation, and hyperaesthetic part, the patient complains of neuralgia [17]. In 1999, the ISSVD replaced pain, which is sometimes so great as to cause vestibulitis with “vestibulodynia”, acknowl- her to cry out” [5]. edging that the condition is not solely related By the mid‐twentieth century, Dickinson to inflammation [10]. Later, the ISSVD documented that in a majority of women expanded on the term of vulvodynia to clas- ­suffering from dyspareunia the source of sify it based on whether or not there was a pain could be localized to the hymen, ure- stimulus, calling it “provoked” or “unpro- thra, and fourchette [6]. Additional research voked” as well as “localized or generalized”. documented the role of inflammation in The term provoked vestibulodynia (PVD) ­vulvodynia [7–10]. To reflect the importance refers to provoked pain that is localized to of the role of inflammation on vulvar pain, the vulvar vestibule, whereas generalized various authors coined the terms “focal vuvoldynia refers to unprovoked, diffuse vul- ­vulvitis”, “vestibular adenitis”, “focal vestibuli- var pain affecting the entire vulvar region. tis vulvae”, and later “vulva vestibulitis The 2003, ISSVD terminology formed the syndrome”­ [1]. foundation of vulvodynia research for the In the 1980s, Freidrich and Woodruff pub- next decade. Many of these studies explored lished a detailed description of the vulvar ves- possible causative factors for vulvodynia, tibule, addressing anatomic features that are such as hormonal, inflammatory, neuropro- most associated with pain [11]. Friedrich also liferative, musculoskeletal, and genetic. published an early account of 28 women with Other studies have focused on treatment symptoms of vulvodynia, which he called vul- options. Lastly, additional studies introduced var vestibulitis syndrome (VVS). He defined new modifying descriptors, such as primary/ the diagnosis as pain on touch, localized to secondary and intermittent/persistent. Nosology and Epidemiology of Dyspareunia and Vulvodynia 249

Box 18.1 2015 Consensus terminology and classification of persistent vulvar pain and vulvodynia. A) Vulvar pain caused by a specific disorder* B) Vulvodynia – vulvar pain of at least three i) Infectious (e.g. recurrent candidiasis, months’ duration, without clear iden­ tifiable herpes) cause, which may have potential associ- ii) Inflammatory (e.g. lichen sclerosus, ated factors. lichen planus, immunobullous disorders) The following are the descriptors: iii) Neoplastic (e.g. Paget disease, squa- ●● Localized (e.g. vestibulodynia, clitorodynia) mous cell carcinoma) or generalized or mixed (localized and iv) Neurologic (e.g. postherpetic neural- generalized) gia, nerve compression, or injury, ●● Provoked (e.g. insertional, contact) or neuroma) ­spontaneous or mixed (provoked and v) Trauma (e.g. female genital cutting, spontaneous) obstetrical) ●● Onset (primary or secondary) vi) Iatrogenic (e.g. postoperative, chemo- ●● Temporal pattern (intermittent, persistent, therapy, radiation) constant, immediate, delayed) vii) Hormonal deficiencies (e.g. genitouri- nary syndrome of menopause [vulvovag- *Women may have both a specific disorder (e.g. lichen inal atrophy], lactational amenorrhea) sclerosus) and vulvodynia

Because of the substantial advances in the two defines the descriptors of vulvodynia. understanding of vulvodynia made over These descriptors help to describe the loca- the last dozen years, in 2015 the ISSVD, tion of the pain as well as the temporal pat- the International Society for the Study of tern of the pain. This section reflects the Women’s Sexual Health (ISSWSH), the findings that pain characteristics typically International Pelvic Pain Society (IPPS), and used to define persistent pain conditions may representatives from the American Congress be more useful for classifying vulvodynia of Obstetricians and Gynecologists (ACOG) subtypes than specifiers based on hypothe- and the National Vulvodynia Association sized etiology. Examples, therefore, might (NVA) convened a consensus congress to include “primary provoked vestibulodynia” revise the vulvar pain and vulvodynia nomen- or “secondary spontaneous intermittent clature. The final terminology was accepted clitorodynia”. by all three societies during July and August However, the greatest difference between 2015 (Box 18.1) [18]. the 2015 terminology and the 2003 terminol- The terminology is divided into two sec- ogy is the addition of “potential associated tions. The first part is called “vulvar pain factors” (Box 18.2). This addition represents caused by a specific disorder”. This part con- a paradigm shift in the approach to vulvo- tains vulvar pain conditions for which a cause dynia, resulting from research that has shown can be clearly identified (e.g. pain due to her- that several factors may be associated with pes genitalis, lichen sclerosus, genital cut- the development and maintenance of the ting, etc.). The second section is the new condition, rendering vulvodynia likely the definition of vulvodynia: vulvar pain of at result of a multifactorial process. Given that least three months duration, without clear these associated factors may be leading the identifiable cause, which may have potential ­direction of future basic science studies and associated factors. A special section of part treatment trials, it is worth examining them: 250 Textbook of Female Sexual Function and Dysfunction

Box 18.2 2015 Consensus terminology and classification of persistent vulvar pain and vulvodynia – potential associated factors.

Appendix: potential factors associated with ●● Neurologic mechanisms vulvodynia ●● Central (spine, brain; level of evidence 2) ●● Peripheral: neuroproliferation (level of ●● Comorbidities and other pain syndromes ­evidence 2) (e.g. painful bladder syndrome, fibromyalgia, ●● Psychosocial factors (e.g. mood, interper- irritable bowel syndrome, temporomandib- sonal, coping, role, sexual function; level of ular disorder; level of evidence 2) evidence 2) ●● Genetics (level of evidence 2) ●● Structural defects (e.g. perineal descent; ●● Hormonal factors (e.g. pharmacologically level of evidence 3) induced; level of evidence 2) ●● Inflammation (level of evidence 2) ●● Musculoskeletal (e.g. pelvic muscle ­overactivity, myofascial, biomechanical; level of evidence 2)

­Genetic Factors oophorectomy and hysterectomy (without oophorectomy) and commonly prescribed Several studies suggest that some women medications, such as combined hormonal have a genetic predisposition to developing contraception, which include combined this condition via at least three (potentially oral contraceptive pills [23]. Combined overlapping), mechanisms: genetic polymor- hormonal contraception use leads to a phisms that increase the risk of candidiasis reduction in serum estradiol and free tes- or other infections, genetic changes that tosterone by decreasing ovarian production allow prolonged or exaggerated ­inflammatory of estrogen and total testosterone and by responses, and increased susceptibility to inducing the liver to produce increased lev- hormonal changes associated with oral els of sex hormone binding globulin. In ­contraceptive pills [19–22]. addition, some combined hormonal contra- ceptives contain synthetic progestogins that act as testosterone antagonists at the ­Hormonal Factors androgen receptor. It has been shown that combined hormonal contraceptives cause The tissues of the vulva and vagina are both histopathologic changes in the vestibular responsive and dependent on sex steroids mucosa, thereby increasing vulnerability to (hormones) for proper health and function. mechanical strain and decreasing mechani- There are many causes of decreased sex cal pain thresholds [24]. steroids, both natural and iatrogenic, that Given their effects on sex steroids, it is per- can lead to dyspareunia. The most common haps not surprising that studies have shown cause of decreased sex steroids in women is that combined hormonal contraceptives are menopause. Other natural causes include associated with symptoms consistent with anovulation secondary to: lactation, ano- provoked vestibulodynia. Bazin and col- rexia, hypothalamic amenorrhea, excessive leagues showed, in a case‐controlled study, physical activity or physiological stress, and that women who used combined hormonal hyperprolactinemia. Iatrogenic causes of contraceptives prior to the age of 17 had a decreased circulating sex steroids include relative risk of 11 of developing vulvodynia Nosology and Epidemiology of Dyspareunia and Vulvodynia 251

[25]. In addition, Burrows and Goldstein vestibule. Hypertonicity of deeper muscles described a case series of 50 consecutive (e.g. ileococcygeus, obturator internus) can women who developed vestibulodynia while lead to vaginal or deep thrusting dyspareunia on oral contraceptive pills, and who were [33]. In addition, overactivity of the bulbo- successfully treated with topical estradiol cavernosus and ischiocavernosus is associ- and testosterone [26]. ated with clitorodynia [34].

­Inflammation ­Neurologic Mechanisms – Central Although both women with vestibulodynia and healthy women have inflammatory cells Several controlled studies have demonstrated in the vestibular mucosa, the relative abun- that women with vulvodynia have evidence of dance and organization of these cells may central sensitization. Pukall et al. were the first differ between women with and without to examine women with vulvodynia using vestibulodynia. A recent paper demon- functional magnetic resonance ­imaging [35]. strated that women with vestibulodynia The results of this study indicated that have higher densities of B lymphocytes and women with vestibulodynia exhibited evi- mature mucosal IgA‐plasma cells. In addi- dence of augmented neural activity in tion, both B and T lymphocytes were response to painful vestibular stimulation in arranged into germinal centers in women areas involved in pain modulation, such as with vestibulodynia, but not in controls the somatosensory, insular, and anterior cin- [27]. Furthermore, other authors have found gulate regions – areas that are commonly an increase in mast cell density in the activated in patients with other pain condi- mucosa of women with vestibulodynia [28]. tions. In addition, nonpainful pressure led to Many studies also show increased pro‐ significant activation levels in insular, frontal, inflammatory cytokines, neurokines, and and somatosensory regions in women with chemokines in biopsies of women with vul- vestibulodynia. These results suggest that vodynia [29, 30]. In addition, heightened women with vulvodynia have an increased systemic inflammatory response has been perception of nonpainful and painful stimu- demonstrated by researchers using a topical lation to the vestibule. cutaneous challenge with yeast in vulvo- dynia cases compared to controls [31]. ­Peripheral – Neuro‐ Proliferation ­Musculoskeletal Researchers have found that women with The discomfort of vulvodynia can also be provoked vestibulodynia have up to 10 associated with pelvic floor muscle overac- times the density of c‐afferent nociceptors tivity. Prolonged holding patterns can result nerve endings in their vestibular mucosa in decreased tissue oxygenation, muscle than normal women [36, 37]. In addition, overactivity, shortening of sarcomeres, and Bornstein et al. found increased numbers of the development of myofascial trigger points mast cells in vestibular tissue of women [32]. Hypertonicity (overactivity) of the mus- with vulvodynia [28]. Persistently activated cles that insert at the posterior vestibule – the mast cells release nerve growth factor and pubococcygeus, puborectalis, and superficial heparinase that allow newly sprouted nerve transverse perineum – can lead to allodynia endings to invade the superficial mucosa of (as seen in vestibulodynia) in the posterior vestibule [38]. 252 Textbook of Female Sexual Function and Dysfunction

­Psychosocial Factors toxin injections. Conversely, a woman with a history of endometriosis who gradually Population‐based studies have shown that develops severe vestibulodynia after using anxiety, depression, childhood victimization, combined hormone contraceptives might be and post‐traumatic stress are risk factors for better treated by stopping the combined hor- the development of vulvodynia [39]. Women mone contraceptives and using topical hor- with vulvodynia were four times more likely monal therapy to the vestibule. A more among women to have a history of a prior thorough discussion of specific treatments mood or anxiety disorder as compared to can be found in the next chapters of this women without vulvodynia. Psychological textbook. factors associated with greater pain intensity or sexual dysfunction in women with vulvo- dynia include pain catastrophizing, fear of ­Additional Nosology pain, hypervigilance to pain, lower pain self‐ efficacy, negative attributions about the pain, It is important to note that other profes- avoidance, anxiety, and depression [40]. sional societies have also tried to address terminology related to dyspareunia. For example, The International Association for ­Embryological/Congenital the Study of Pain includes a section on “Pain Factors of Vaginismus or Dyspareunia” [43]. These classifications were updated in 2011 to included generalized and provoked vulvar The cooccurrence of vulvodynia with inter- pain syndrome [43], reflecting the growing stitial cystitis/painful bladder syndrome understanding that vulvar pain presents in a may be related to a congenital disorder of variety of ways. Vulvodynia is included in urogenital sinus‐derived endothelium [41]. the International Classification of Disease Additional evidence to support this hypoth- (ICD‐10) and includes modifiers of “other” esis is that women with primary vestibulo- and unspecified” [44]. dynia exhibit umbilical hypersensitivity more The American Psychological Association’s often than women with secondary vestibulo- (APA) previous edition of the Diagnostic dynia and nonaffected women, suggesting and Statistical Manual, 4th edition (DSM‐ that some cases of primary vestibulodynia IV) has two separate “Sexual Pain Disorders” may be associated with a congenital neuronal that were included in the section on sexual hyperplasia in tissue derived from the primi- dysfunctions, which it labeled on sexual tive urogenital sinus [42]. dysfunc“vaginismus” [45]. The most recent edition combined these two into a single ­category of Genito‐Pelvic Pain/Penetration ­Associated Disorder (GPPPD) [46]. This change Factors – Conclusion occurred for several reasons [18, 47–49]. Firstly, the defining feature required for It is likely that one or more of these associ- diagnosis of vaginismus in previous genera- ated factors may be clinically prominent, and tions of the DSM was the presence of vaginal may help in choosing further evaluation muscle spasm. Research, however, has failed methods and treatments. For example, in the to prove the presence of muscle spasm as a patient with significant pelvic floor overac- valid or reliable diagnostic criteria. Secondly, tivity, treatment may consist of pelvic floor diagnosis based solely on vaginal spasm does physical therapy, possibly in combination not address the elements of fear of penetra- with muscle relaxants (such as diazepam tion, anxiety, and pain, which are integral suppositories) and or intralevator botulinum components of this condition. Lastly, several Nosology and Epidemiology of Dyspareunia and Vulvodynia 253 studies have shown that clinicians have a includes hospital and insurance payments, very difficult time distinguishing between leave from work, and transportation costs dyspareunia, vestibulodynia, and vaginis- among others. In a nonprobability study mus, thus the similarities outweigh the using a conservative estimate of vulvodynia differences. prevalence, the authors estimated the annual cost of vulvodynia to be US$ 31–72 billion [55]. This study also demonstrated the very ­Prevalence real impact on quality of life experienced by women with vulvodynia, which has been well Prevalence studies of vulvodynia have indi- described in the literature [56–59]. Ponte cated that it is prevalent, with lifetime went even further in demonstrating that ­estimates ranging from 8 to 28%, in repro- women with vulvodynia have worse quality ductive‐aged women in the general popula- of life scores that similar women with other tion [50–52]. In a study comparing two skin and vulvar conditions [57]. separate geographical regions with differ- ing access to health care there was still ­similar prevalence of about 8% [52]. Further, ­Conclusion these authors show that prevalence is dif- ferent with regards to race, where nonwhite The history of modern medicine’s under- Hispanic women had an odds ratio of 1.4 standing of vulvodynia reflects the slow pro- for vulvodynia. Further research showed gress that is being made in addressing that daily pain is worse in black women women’s sexual health concerns. We now compared to white women and that they understand that there are many etiologies of describe their pain differently as well [53]. sexual pain, and pain confined to the vulva When looking at just dyspareunia, however, encompasses multiple systems, including nationally representative data in the United neurological, musculoskeletal, hormonal, States suggest the prevalence is closer dermatological, and inflammatory. The to 30% [54]. importance of a thorough and accurate nosology allows providers and patients to understand both the causes and manifesta- ­Impact tions of vulvar pain in addition to directing them towards treatment options. Vulvodynia Research looking into the economic impact is highly prevalent during a woman’s lifetime of vulvodynia has shown significant cost on and as we train more providers to recognize an individual and population level. During a its multifaceted nature, we are better able to six‐month period of treatment, the individ- offer solutions to this common and distress- ual costs were US$ 8862.40 per patient. This ing condition.

­References

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19

Anatomy and Physiology of Sexual Pain Melissa A. Farmer

Abstract

Efficient clinical assessment, diagnosis, and treatment of women with sexual pain requires a com- prehensive knowledge of the physiological systems underlying acute and chronic nociception. Whereas acute episodes of sexual pain are mediated by end‐organ pathology, persistent sexual pain must be conceptualized in terms of ongoing peripheral, spinal, and brain mechanisms that can lead to dramatic functional changes in nociception and enhanced pain perception. This state‐of‐the‐art review draws from rigorous rodent and human research to explore potential mechanisms underlying the symptom configurations associated with sexual pain. A strong understanding of these mechanisms is essential for the assessment and strategic treatment of women who present with unremitting sexual pain.

Keywords: sexual pain; physiology; anatomy; pelvic; nociception; mechanisms; sensitization; referred pain; chronic

The initiation and maintenance of chronic pain reflects a combination of peripheral, spinal, and brain mechanisms. Pain assessments based on symptom configurations, rather than existing diagnostic categories, are useful in deciphering mechanisms of referred pain. Visceral nociceptors are poised to hijack cutaneous nociceptive circuits through spinally‐mediated cross‐talk.

­Introduction pain perception is not solely dependent on nociceptive input. Pain and nociception are indispensable Just as a woman’s subjective experience of ­contributors to female sexual function. desire and arousal are central to the study of Nociception refers to the physiological pro- female sexual function, pain perception also cesses that mediate detection of environ- guides our understanding of pain physiology. mental threats and the relay of this This chapter reviews the mechanisms of the information through the peripheral and cen- acute and chronic pain physiology of genito‐ tral nervous systems. In contrast, pain is the pelvic pain. Acute genito‐pelvic pain arises cortically mediated subjective experience from trauma, inflammation, or infection and that can emerge when nociceptive signals usually resolves as tissue heals. Given that are integrated into the neural networks chronic pain persists beyond the normal underlying consciousness. Therefore, nocic- healing period, by definition the mechanisms eption may not lead to pain perception, and underlying chronic pain maintenance are

Textbook of Female Sexual Function and Dysfunction: Diagnosis and Treatment, First Edition. Edited by Irwin Goldstein, Anita H. Clayton, Andrew T. Goldstein, Noel N. Kim, and Sheryl A. Kingsberg. © 2018 John Wiley & Sons Ltd. Published 2018 by John Wiley & Sons Ltd. 258 Textbook of Female Sexual Function and Dysfunction

independent of acute tissue pathology. of 5–30 m/s), terminate in superficial lamina Therefore, the assessment and treatment of I and deep lamina V of the dorsal horn, and genito‐pelvic pain requires an understanding lead to the immediate perception of sharp of the “rules” of nociception in the periphery, pain. In contrast, unmyelinated C fibers spine, and brain and how these rules are vio- transmit mechanical, thermal, and/or chemi- lated in chronic pain states across time. cal nociceptive information more slowly (at rates of 0.5–2 m/s) and terminate in laminae I and IIouter of the dorsal horn, yielding a ­Nociceptor Structure gradual pain perception of dull or burning and Function pain. More fine‐grained nociception is achieved with specialized receptor proteins Across species, the close correspondence and ion ­channels located on nerve endings. between sensory neuron firing properties These receptors and channels mediate (i) the and magnitude of pain perception indicates transduction, or conversion, of a sensory that general properties of neuronal function stimulus into an electrical signal and (ii) the can be deduced from subjective pain percep- encoding, or one‐to‐one correspondence, of tion [1, 2]. Nociceptors are free nerve end- electrical signals to stimulus attributes that ings that detect noxious or potentially the brain can interpret (e.g. modality, loca- harmful mechanical, thermal, chemical, and tion, threshold, intensity, timing). For electrical stimuli that are usually perceived as instance, increased stimulus intensity is painful. Their cell bodies are located in the encoded by an increased rate of neuronal fir- dorsal root ganglion, with one peripheral ing, and the timing of neuronal firing encodes process extending to the target tissue and stimulus duration. Collectively, the interface one process terminating in the ipsilateral between a sensory stimulus and these func- dorsal horn of the spinal cord. All nocicep- tional properties of nociceptors contribute to tors release the excitatory neurotransmitter complex sensory perceptions, such as pain. glutamate and can be distinguished accord- Detection of mechanical stimulation is ing to five structural and functional criteria central to sexual arousal because sexual that facilitate encoding of a broad variety of activity involves skin‐on‐skin contact, sensory stimuli: (i) nerve diameter (which including manual, oral, and/or genital stimu- determines conduction velocity and response lation of oneself and/or one’s partner. Gentle latency) and the presence of myelination, (ii) mechanical pressure is encoded by Aβ mech- stimulus modality (i.e. mechanical, thermal, anoreceptors (including Merkel cells, and/or chemical input), (iii) functional Pacinian, Ruffini, and Meissner’s corpuscles) response characteristics (rate of neuronal fir- that terminate in laminae IIinner, III, and IV of ing, threshold of activation, adaptation pro- the dorsal horn, and by a non‐nociceptive file), (iv) receptor expression modulating population of C fibers that mediates pleasant these response properties, and (v) functional touch, mild heat analgesia, and potentially properties unique to somatic or visceral erotic touch [5, 6]. Recently described Piezo nociceptors [3, 4]. These criteria are not receptors encode more nuanced gradations absolute, as new subpopulations of nocicep- of mechanical pressure and stretch, includ- tors will inevitably be identified in the com- ing stretch in urothelial cells (piezo1) and ing decades. Nociceptive signals are intraluminal pressure and fullness (piezo2) transmitted by Aδ and C nerve fibers that [7]. In particular, piezo2 will play an impor- detect either a single sensory modality (uni- tant role in our future understanding of genito‐ modal) or two or more sensory modalities pelvic pain thresholds. Piezo2 expression (polymodal) (Table 19.1). Large, myelinated mediates reduced pain thresholds (mechani- Aδ fibers rapidly conduct mechanical, ther- cal allodynia), is required for Merkel cell mal, and/or cold nociceptive signals (at rates mechanosensitivity, and leads to activation of Anatomy and Physiology of Sexual Pain 259

Table 19.1 Structure and function of peripheral sensory afferent neurons mediating genito‐pelvic sensation and pain.

Neuron Cutaneous Fiber diameter Conduction structure nerve Muscle nerve (µm) velocity (ms)

Myelinated Large diameter Aα I 13–20 80–120 Small diameter Aβ II 6–12 35–75 Smallest diameter Aδ III 1–5 6–25 Unimodal Mechanical nociceptors Unimodal Thermal nociceptors Polymodal Mechano‐heat nociceptors Unmyelinated C IV 0.2–1.5 0.5–2 *Also warm temperature Unimodal Thermal nociceptors and itch Unimodal Mechano‐heat nociceptors Polymodal Mechano‐heat/chemical/cold nociceptors Quickly adapting → sensitive to heat and mechanical stimulus under basal conditions Slowly adapting → exhibits temperature‐dependent sensitization, reduced heat detection threshold, greater heat hyperalgesia

Aβ nerve fibers, which can acquire nociceptor lation of P2X3, leading to P2X3 overexpression characteristics in certain pathological states [10, 11]. This hypothesis is indirectly sup- discussed later in this chapter [8]. ported by data in postmenopausal women Most noxious stimuli also involve some and rodents showing that ­tissue depletion of degree of mechanical stimulation. The transi- estrogen is associated with mechanical allo- tion from nonpainful to painful mechanical dynia [12, 13]. Similarly, vulvar punch biopsies pressure (i.e. pain threshold) is encoded by from women with provoked vestibulodynia the P2X3 subclass of purinoreceptors. P2X3 exhibit dramatic reductions in estrogen activation provokes the rapid release and receptor‐α expression [14]. P2X3 participates detection of adenosine triphosphate to gener- in the amplification of persistent pain signals ate a rapid and time‐limited inflammatory at the peripheral and spinal levels. For response [9]. P2X3 expression is inhibited by instance, increased bladder urothelial P2X3 estrogen receptor‐α binding on C‐fiber noci- expression in women with interstitial cystitis/ ceptors (mediated by signaling pathways bladder pain syndrome may implicate the dependent on cyclic adenosine monophos- presence of altered lumbosacral P2X3 phate, protein kinase A, and extracellular response properties observed in rodent mod- ­signal‐regulated protein kinases 1 and 2 els of bladder inflammation [15, 16]. These ­interactions), which strongly suggests that data also raise the possibility that aversive estrogen–P2X3 interactions modulate nocic- feelings of fullness and mechanical allodynia eptive signaling via immune mechanisms. reported by women with persistent genital Reduced mechanical pain thresholds may arousal disorder could, in part, reflect a basal reflect inadequate estrogen receptor‐α regu- state of P2X3 disinhibition [17]. 260 Textbook of Female Sexual Function and Dysfunction

P2X3 frequently colocalizes with the cap- or extended treatment with agonists (e.g. saicin receptor (i.e. the transient receptor topical capsaicin) to induce depolarization potential cation channel subfamily V mem- blockade, and/or estrogen receptor‐α ber 1 receptor, previously the vanilloid 1 ­agonists may prove fruitful in managing pain. receptor), which is a cation channel receptor The actions of receptors may differ located on polymodal C fiber nociceptors in between basal, inflammatory, and neuro- skin and, especially, visceral organs. Under pathic states. For instance, acute inflamma- normal physiological conditions, the capsai- tion is characterized by thermal hyperalgesia cin receptor activates with noxious thermal that is dependent on capsaicin receptor (>43 °C), chemical, and acidic stimuli expression and mechanical hyperalgesia that (pH < 5) and facilitates the perception of relies on expression of transient receptor burning heat pain [18]. Women with pro- potential ankyrin 1 [18]. Blockade of tran- voked vestibulodynia exhibit increased cap- sient receptor potential ankyrin 1 normalizes saicin receptor expression in subepidermal mechanical sensitivity without affecting vulvar nerves, which implicates a greater inflammation or capsaicin receptor expres- capacity to detect noxious vulvar stimula- sion. Receptors that express transient recep- tion [19]. Capsaicin receptor expression in tor potential cation channel subfamily V keratinocytes may also contribute to nocic- member 4 encode innocuous warmth in eptive signaling [20]. Capsaicin receptors basal conditions and mediate inflammation‐ exhibit a range of unique functions that can induced visceral mechanical sensitivity. contribute to symptom variability in genito‐ Notably, these three receptors, in variable pelvic pain. Under acidic conditions capsai- combinations, are expressed by most abomino‐ cin receptors activate at room temperature pelvic visceral afferents. (20–25 °C), which would allow these recep- tors in acidic vulvar tissue (pH 3.8–4.5) to transmit burning heat sensations in the ­Hormonal Regulation absence of high temperatures. Sustained activation of these receptors with topical Estrogen is implicated in sensation and capsaicin promotes a calcium‐dependent nociception at the peripheral, spinal, and decrease in channel activity that prevents supraspinal levels. In the brain, estrogen pro- nerve firing for an extended period [21]. motes endogenous opioid analgesia and spi- This desensitization mechanism may explain nal inhibition of pain, yet it also facilitates the treatment of vulvar pain with topical hippocampal capsaicin receptor‐mediated capsaicin, and brief trials combining capsai- pain hypersensitivity. [23–25]. Spinal estrogenic cin and lidocaine (for comfort) can be used regulation of μ‐ and/or κ‐opioid heterodimer to assess the degree of peripheral nerve con- expression is critical for a female‐specific tributions to vulvar pain [22]. Capsaicin neural pathway for opioid analgesia [26–28]. receptors can sensitize the activity of neigh- Estrogen receptors are present in lumbosa- boring receptors, like P2X3, and provide a cral dorsal root ganglia and on peripheral ter- feasible mechanism for mechanical pres- minals of putative nociceptors, with estrogen sure‐induced sensations of burning pain. receptor‐α expressed in the vulva, vagina, Note that this phenomenon does not require uterus, bladder, and ovaries, and estrogen nerve injury – it represents a phenotypic receptor‐β intensely expressed in the ovaries shift in how sensory input is detected [21]. [29, 30]. Both receptors are distributed Collectively, these data suggest that nocicep- throughout the vaginal epithelium, labia tors encoding both mechanical and heat minora epidermis, and vaginal smooth mus- pain are functionally poised to play major cle [31]. In the periphery, rapid 17β‐estradiol roles in genito‐pelvic pain. Use of P2X3 signaling of membrane‐bound estrogen antagonists, capsaicin receptor antagonists receptors ‐α and ‐β plays a key role in regulating Anatomy and Physiology of Sexual Pain 261 mechanical nociception [9]. For example, ceptives reduces sex steroid hormones and P2X3‐dependent painful bladder distension is may lead to insufficient estrogen receptor‐α inhibited by estrogen receptor‐α binding, and binding of P2X3 receptors, yielding lower ovariectomy increases bladder P2X3 receptor pressure and/or distension pain thresholds. expression by 300% [32, 33]. The respective Notably, vulvar vestibule expression of roles of estrogen receptors ‐α and ‐β remain estrogen receptor‐β, the receptor subtype poorly understood and their functions vary associated with increased nociceptive action, based on site(s) of action (peripheral or cen- is upregulated in women taking oral contra- tral), levels of bioavailable sex steroid hor- ceptives, a population that exhibits lower mones in local tissue and in free circulation, mechanical pain thresholds than naturally presence of inflammation or disease, states of cycling women [45–47]. Pain hypersensitiv- hormone depletion (e.g. oophorectomy, men- ity could develop with long‐term alterations opause, lactational amenorrhea, etc.), and in estrogen and/or progesterone levels by physiological adaptations resulting from promoting de novo nerve sprouting and long‐term supplementation (e.g. oral contra- hyperinnervation [48–50]. However, oral ceptive use). contraceptive use alone may not be sufficient It is feasible that nociceptor signaling to enhance the risk of developing chronic could qualitatively differ across the cycle as vulvar pain. A subgroup of women with low hormones fluctuate. During pre‐ovulatory basal androgen receptor transcriptional periods of high circulating estrogen, function and low free testosterone levels may enhanced structural integrity of tissue and have a greater risk for developing provoked estrogenic inhibition of P2X3 may allow vestibulodynia [51, 52]. These data reinforce genital tissue to withstand the physically that acute and adaptive effects of sex steroid rigorous act of intercourse. In contrast, hormones on nociception are mechanisti- depletion of female gonadal hormones in cally distinct and clinically relevant. rodents induces mechanical and thermal pain hypersensitivity that parallels a three- fold increase of P2X3 receptor expression in ­Somatic and Visceral Pain the dorsal root ganglion [13, 34, 35]. Restoration of sexual function with combi- Nociceptors exhibit unique functional prop- nation oral/topical estrogen treatment in erties based on the tissue type in which they hormonally deficient women may, there- are embedded (Figure 19.1). “Somatic” noci- fore, reflect improved physical integrity of ceptors innervate skin, muscle, and bone and the vaginal epithelium and normalized contribute to pain perception that closely mechanical pain thresholds [36–39]. Given correlates with stimulus intensity, duration, the pivotal role of estrogen in bladder and and location, and it has distinctive qualities uterine visceral nociception, it likely plays (“sharp”, “pinching”, etc.). Tissue depth can an important role in referred and comorbid impact the spatial perception of somatic pelvic pain [40, 41]. pain: for instance, deep muscle pain may be The long‐term consequences of oral con- perceived across the length of the muscle. In traceptive use on genito‐pelvic pain remain contrast, “visceral” pain caused by hollow poorly understood. On the one hand, estro­gen‐ organ distension and traction is perceived dependent conditions like endometriosis along the midline of the body as diffuse dis- can benefit from oral contraceptive and comfort that may lag seconds or minutes ­aromatase inhibitor use [42]. In contrast, behind noxious stimulation. Visceral sensa- extended use of oral contraceptives, espe- tions include nausea, bladder and stomach cially low‐estrogen formulations, may confer filling, distension (vaginal, rectal, intestinal, greater risk for developing provoked vestibu- esophageal), menstrual cramps, and bloat- lodynia [43, 44]. Chronic use of oral contra- ing, but many visceral experiences lack an 262 Textbook of Female Sexual Function and Dysfunction

Somatic nociceptors Figure 19.1 A circle graph depicts pain referral patterns between 14 Visceral nociceptors anatomically‐distinct body locations that exhibit spinal “cross‐talk.” Depicted Lower abdomen Lower abdomen body regions are innervated by either Uterus somatic nociceptors (left, in blue) or Suprapubic visceral nociceptors (right, in red). The lines connecting body locations Bladder represent either (a) viscero–visceral Low back (organ to organ) interactions, indicated in with grey dashed lines, or (b) viscero–somatic (organ to muscle/skin) Cervix interactions, indicated with solid red Pelvic floor lines. Methods of data collection include muscles electrophysiology, animal behavior with Urethra symptom comodulation, and Perineum quantitative sensory testing techniques in women. Note that additional pain Vagina referral patterns between structures on Upper this circle graph almost certainly exist, thighs Colon Vulvar but are not supported by current vestibule research.

adequate vocabulary (e.g. the sensations genital quantitative sensory testing research associated with catheter insertion, venous that uses somatic tissue (e.g. volar forearm) cannulation, or having food lodged in one’s as a “control” for lower genital tract sensitiv- throat). The body must be able to tolerate ity may be comparing fundamentally differ- some physiological discomfort associated ent types of pain [56]. The significant with normal functions (e.g. with bowel or anatomical variability in vulvovaginal shape bladder distension). The viscera are, there- and size may also facilitate visceral pain fore, exclusively innervated with both high through simple mechanical traction. Genital threshold nociceptors that transmit innocu- sensitivity testing should always be validated ous and noxious input and with intensity‐ against clinical pain reports because differ- encoding nociceptors, which allows visceral ent tissues may exhibit variable degrees of pain to emerge only with prolonged and/or hypersensitivity [57]. intense noxious stimulation [53]. Moreover, high threshold nociceptors can create a time delay between visceral stimulation and its ­Referred Pain subjective perception (refer to Table 19.2). The lower third of the female genital tract, Referred pain is one of the least appreciated including the vulva, urethra, and proximal mechanisms underlying genito‐pelvic pain vagina, receives a combination of both and other comorbid pain syndromes. Symptom patterns and mechanisms underlying different types of pain. and mechanisms underlying different patterns Symptom somatic and visceral innervation [54]. As a Referred pain is a regular feature of visceral result, conditions like provoked vestibulo- pain and can also account for many seem- dynia may be characterized by complex noci- ingly enigmatic pain symptoms [58]. Three

Table 19.2 ceptive signaling. Dynamic modeling has major hypotheses should be considered revealed that vulvar pain perception closely when a woman reports pain in a specific corresponds with the quality and time course location: (i) her pain is caused by tissue of vulvar punctate pressure, whereas the pathology in target tissue, (ii) pain is referred delayed onset of distension‐induced vulvo- from another site exhibiting tissue pathology, vaginal pain is consistent with visceral trans- and/or (iii) pain is cortically mediated as a duction [55]. These findings imply that sensory memory. In practice, genito‐pelvic Table 19.2 Symptom patterns and mechanisms underlying different types of pain.

Mechanisms

Types of Pain Adaptive function(s) Acute triggers Pain maintenance Symptoms

No ciceptive Somatic Detection of noxious stimuli at Requires continued presence of Transient pain (seconds to minutes) Signals potential for tissue skin, muscle and bone noxious stimulus injury Vi sceral Intense or prolonged organ Requires continued presence of Transient pain (seconds to hours) distension or pressure noxious stimulus Inflammatory Pro‐inflammatory cascades in Peripheral nerve sensitization, Tissue hypersensitivity (days – weeks), Eliminates cause of injury response to tissue injury, repeated inflammatory insults (e.g. edema, redness, itch and repairs tissue detection of pathogens, radiation infections); occult inflammation (e.g. mast cell proliferation) Fu nctional Sexual activity, dietary triggers, Increased excitability of nociceptors Pain with intercourse, bladder filling or Limits physical activity severe or recurrent infections, and/or dorsal horn interneurons, voiding, digestion, defecation, secondary and promotes fear nervous system priming by early referred pain and/or organ pelvic floor muscle dysfunction learning of illness‐related adverse events cross‐sensitization pain cues Neu ropathic Presumed nerve injury or nerve May include increased excitability of Gain of function (spontaneous burning or No adaptive function compression nociceptors and/or dorsal horn electric shock‐like pain, dysesthesia) and/ neurons or loss of function (numbness, tingling, “pins and needles”)

Chapter No.: 1 Title Name: c19.indd Comp. by: Date: 22 Mar 2018 Time: 11:31:55 AM Stage: WorkFlow: Page Number: 263 264 Textbook of Female Sexual Function and Dysfunction

pain rarely fits neatly into existing diagnostic urogenital sinus, including vulvar vestibule, categories, which is not surprising given that bladder, urethra, umbilicus, and prostate); vulvodynia, bladder pain syndrome/intersti- however, pain referral regularly deviates tial cystitis, dysmenorrhea, pelvic girdle pain, from such patterns. Clinical signs of pain and debatably (painful) endometriosis are referral from viscera to somatic tissue include diagnoses of exclusion. Therefore, pain cutaneous and deep muscle hyperalgesia assessments based on symptom configura- (but not altered detection thresholds), which tions, rather than existing diagnostic catego- emerges over minutes to hours and may out- ries, are useful in deciphering mechanisms of last the original visceral pain [63]. Referred referred pain. visceral pain can generate one or more Somatic afferent fibers account for 90% of regions of referral to somatic tissue (e.g. nerves that terminate in the spinal cord, referred uterine pain that is experienced in while the remaining 7–10% are visceral affer- the lower back), or it can manifest as a radiat- ent fibers that may synapse at, above, or ing, burning, aching, prickling, and/or elec- below their originating dermatome (or even trical shock‐like pain that moves throughout on the contralateral side of the spinal cord) the pelvic cradle, which is reminiscent of [54, 59]. Visceral nociceptors synapse onto neuropathic pain features [64, 65]. Therefore, dorsal horn interneurons in laminae I, II, and referred pain is an umbrella term that can V that also receive somatic terminations, and indicate: (i) pain referred from a v­isceral the resulting nociceptive signals – regardless structure to muscle, with no muscle hyperal- of their tissues of origin – are then transmit- gesia; (ii) pain referred from a visceral struc- ted along specialized ventro‐lateral funiculus ture to muscle, resulting in muscle projections to the brain. With intense nox- hyperalgesia; and (iii) expansion of referred ious stimulation, the visceral–somatic con- hyperalgesia following intense and/or per- vergence of nociceptors onto common sistent nociceptive input and/or presence of interneurons allows neural discharges from ­co‐occurring visceral pain conditions. one afferent to influence the electrical activ- Accordingly, more frequent visceral pain ity of another and to sensitize their shared ­episodes are associated with greater pain interneuron [54]. Visceral nociceptors are, threshold reductions at sites of pain referral therefore, poised to hijack cutaneous nocic- [64]. Similarly, presence of comorbid chronic eptive circuits. visceral pain conditions may promote This neuronal “cross‐talk” establishes three increased intensity and greater spatial spread types of functional interactions between the of referred hyperalgesia [66]. participating afferent fibers, including viscero– Referred deep muscle hyperalgesia in the visceral (organ to organ), viscero–somatic pelvic floor musculature may contribute to (organ to muscle/skin), or somato–visceral diffuse pain sensations, given that muscle (muscle/skin to organ) interactions pain can be perceived along the length of the (Figure 19.2). Rodent data have confirmed muscle. [67]. It is hypothesized that this the functional convergence of abdominal and hyperalgesia results from a viscero–muscular pelvic visceral organs in 13–60% of lumbosa- reflex that induces painful muscle contrac- cral dorsal horn neurons, with variation tions that can ultimately become maintained observed between spinal segments [60]. independent of the original visceral input. Importantly, referred pain can manifest in Muscle hyperalgesia referred from the viscera neighboring dermatomes due to the broad can, in turn, cause secondary referred pain arborization of visceral afferents onto multi- across multiple dermatomes and promote a ple spinal cord segments [61, 62]. Classic broad spectrum of extra‐pelvic pain symp- accounts of visceral pain focused on referral toms that are not due to sensitization, per se. between body sites with common embryo- It is plausible that localized muscle pain, or logical origins (e.g. tissue derived from the “trigger points” are the product of visceral Anatomy and Physiology of Sexual Pain 265

(a) Visceral pain referred to somatic and visceral tissue

Uterus Lower back Bladder (visceral) (somatic) (visceral)

(b) Somatic/visceral pain referred to visceral tissue Vulvar Pelvic floor muscles Bladder (Somatic/visceral) (somatic) (visceral)

Figure 19.2 Hypothetical referred pelvic pain patterns supported by the clinical literature that are suggestive of spinal cross‐talk between visceral and somatic nociceptors. (a) Based on the clinical co‐occurrence of uterine cramps and low back pain, this schematic depicts visceral pain originating in the uterus (far left) as a potential cause of somatic pain referred to muscles in the lower back (viscero–somatic referred pain, middle). Alternatively, uterine pain could also refer to a visceral structure like the bladder (viscero–visceral referred pain, far right) to create more diffuse pelvic pain. (b) Given the co‐occurrence of pelvic floor muscle dysfunction/pain and chronic vulvar pain, this schematic depicts somatic–visceral pain originating at the vulvar vestibule (far left, due to dual innervation of the lower one‐third of the female reproductive tract) as a potential cause of somatic pain referred to pelvic floor muscles (somato–/viscero–somatic referred pain, middle). In contrast, vulvar pain referral to the bladder has been described and is supported by high clinical comorbidity between chronic vulvar and bladder pain (somato–/viscero–visceral referred pain, far right). Both clinical presentations (a) and (b) would likely include both localized and diffuse pelvic pain. Note that referred pain is a normal feature of visceral pain and the interactions shown here are not “pathological” if the referred pain resolves in a timely manner. pain referral, rather than primary dysfunc- influence pain generated at either site [69]. tions. Care should be taken to parse referred Accordingly, the successful treatment of pain muscle pain from reactive muscle tension, originating in one visceral organ can partially which is a natural defensive response to pain, alleviate pain symptoms associated with and from the muscle tension and pain that other organs sharing overlapping innerva- emerge as the body attempts to compensate tion [69]. Pain referral is ultimately depend- for functional deficits caused by genito‐pelvic ent on continued nociceptive input and its pain. Pelvic floor physical therapists have the spinal mediation; as a result, anesthetic ideal education and training to help disentan- blocks at the site of pain referral provide only gle the causes and consequences of referred partial relief [70, 71]. genito‐pelvic pain within a larger biopsycho- social framework [68]. Spinally mediated cross‐talk can intensify ­Vascular Pain or strategically alleviate pain symptoms. Viscero–visceral hyperalgesia caused by The discrepancy between pain perception cross‐organ sensitization in animals and and degree of arterio‐venous pathology is a humans confirms that referral can mutually classic feature of visceral pain [54]. In general, 266 Textbook of Female Sexual Function and Dysfunction

vascular pain arises either from inadequate The lower genital tract (vagina and vulva) or excessive blood flow to a body region. exhibits ongoing low‐grade inflammation, Circulation is impaired when tissue, muscles, presumably as a defense against pathogens and tendons are deprived of oxygen or con- introduced with invasive sexual contact or stricted by edema leading to elevated inter- migrated from nearby body sites (e.g. anorec- nal venous pressure. Visceral vasculature can tal bacteria) [74–76]. The degree of inflam- also be compressed by surrounding muscle mation can vary based on a woman’s vaginal and fascia, depending on regional differences and bladder flora (which changes across the in pelvic floor muscle architecture. For exam- menstrual cycle), presence of injury (e.g. vagi- ple, shorter coccygeus muscle fibers can gen- nal fissures), tissue‐specific inflammatory erate greater force than longer pubovisceral profiles (e.g. upper versus lower genital tract), muscle fibers [67]. The generated biome- exposure to new immune threats (e.g. sexu- chanical forces result in stretch, compres- ally transmitted infections), priming by past sion, shear, or injury of vasculature that immune threats, host resilience to new contribute to pelvic pain through local immune threats, genetic polymorphisms that inflammation and/or direct nerve compres- bias the inflammatory response, and interac- sion. The resilience of vasculature is compro- tions between these factors [56, 77–79]. mised by estrogen‐mediated signaling Therefore, inflammation results from, medi- cascades that promote vasodilation, compro- ates, and fine‐tunes nociception to enhance mise vascular smooth muscle contraction, the sensitivity and specificity of nociceptive alter vascular remodeling, and weaken signaling. The presence of inflammation may venous walls. reflect immune responses to current as well Acute venous dilation is rarely painful, yet as past immune threats. As a result, inflam- chronic venous reflux is considered a diag- mation per se may be a poor indicator of nostic indicator of pelvic congestion syn- underlying pain pathology. Given the com- drome, a symptom complex characterized by plexity of this process, the dynamics of aching, burning pain with muscle exertion inflammation are discussed in relation to the (e.g. claudication) that radiates from the but- pathogen–host interactions that may facili- tocks to feet, as well as neuropathic symp- tate emergence of the most common cause of toms like numbness, paresthesia. Pelvic dyspareunia, provoked vestibulodynia. congestion syndrome is characterized by The standard clinical assumption is that venous insufficiency, as corroborated by vestibulodynia pain arises from vulvar ves- ­evidence of pelvic, abdominal, and thigh var- tibular inflammation that is secondary to icose veins. However, pelvic venous dilation repeated exposure to biological or synthetic and compromised venous integrity are also inflammagens (e.g. recurrent yeast infec- present in many healthy women who do not tions), neuroproliferation, and hormonal have these symptoms [72]. Again, this is not antagonists (not mutually exclusive). surprising given that superficial and deep Regarding the first hypothesis, nonautoim- venous reflux are not correlated with pain mune inflammation reflects an interaction perception. between stimulus severity (e.g. a pathogen’s virulence, pathogen load, frequency of repeated exposures, etc.) and host resilience ­Inflammation (e.g. genetic and developmental influences, microbial abundance/richness, immune sup- As a normal feature of female reproductive pression, etc.). Although the detection of physiology, inflammation is not an inherently pathogenic viruses, yeast, and bacteria by pathological process. Menstruation is thought epithelial toll‐like receptors immediately to be initiated by progesterone withdrawal‐ triggers a nonspecific “innate” immune induced pro‐inflammatory responses [73]. cascade [80], each of these pathogens in Anatomy and Physiology of Sexual Pain 267

­isolation may contribute to clinically relevant by tissues of common embryological origin pain: repeated yeast exposures cause persis- (urethra, bladder, umbilicus) [87, 88]. These tent vulvar pain, postviral neuropathic pain shared immunological abnormalities may, can last years beyond primary infections, and therefore, predispose women with vulvar pain bacteria may modulate nociception [81–83]. to develop comorbid bladder and/or urethral Some of these microorganisms have even pain, a diagnostic overlap that is consistently evolved unique adaptations to evade domi- observed in the literature [89]. Moreover, nant immune responses in human hosts [84]. women with provoked vestibulodynia are 2.5 Therefore, inflammation per se may account times as likely to exhibit loss‐of‐function mel- for a limited degree of pain pathophysiology anocortin‐1 receptor polymorphisms that observed in women with genito‐pelvic pain. may interfere with the downregulation of pro- Recent evidence has revealed one innate inflammatory cytokines and adhesion mole- immune pathway that may play a major role cules generated by the nuclear factor‐κB in the initiation and maintenance of pro- pathway [90, 91]. This polymorphism may voked vestibulodynia in women with histo- impact a broad range of pain mechanisms ries of recurrent vulvovaginal candidiasis. An because the melanocortin‐1 receptor medi- experimental mouse model of chronic vulvar ates κ‐opioid analgesia in women, modulates pain following recurrent Candida albicans μ‐opioid analgesia, and pain thresholds in infections provided causal evidence that pro- women [92–95]. Indeed, most of the genetic longed yeast exposure can initiate persistent polymorphisms identified in genito‐pelvic pain and vulvar hyperinnervation [82]. The pain populations appear to impact inflamma- role of yeast exposure in the maintenance of tory cascades, host–pathogen interactions, provoked vestibulodynia is supported by the and pain sensitivity [88]. differential cytokine expression induced by The body cannot afford to sustain a bio- yeast‐exposed fibroblasts isolated from vesti- logically expensive response like inflamma- bule versus nonvestibule punch biopsies in tion indefinitely because these resources women with and without the condition [75]. must be available to defend against new In both groups, vestibule fibroblasts expressed threats. Inflammation promotes physiologi- more interleukin‐6 and prostaglandin than cal adaptations that maintain efficient nocic- nonvestibule fibroblasts. This cytokine eptive signaling as chronic pain persists, and expression is mitigated by blocking Dectin‐1 these adaptive solutions will change over gene expression and is almost abolished with time. Sensory neurons are the only afferents inhibition of nuclear factor‐κB phosphoryla- that can regenerate in mammals, and de novo tion [85]. Estrogen receptor‐α binding nerve sprouting is a well‐documented conse- directly inhibits nuclear factor‐κB pathways, quence of chronic pain pathology observed which suggests a critical role of estrogen in with frank tissue injury, skin scratching, regulating nociception and related immune infection, and even radiation in rodent mod- reactivity [86]. Note that yeast‐induced noci- els [82, 96, 97]. Indeed, women with pro- ception can sensitize nociceptive pathways voked vestibulodynia exhibit increased that are ultimately independent of the pres- density of vulvar calcitonin gene‐related pep- ence or absence of yeast, and such mecha- tide expressing C fiber nociceptors and area nisms are difficult to study in vitro. vulvar vestibular nerve fibers, compared to These studies highlight the importance of healthy controls [98, 99]. Therefore, vulvar anatomical and genetic factors in provoked neuroproliferation may in some cases evolve vestibulodynia, a pain condition that is as a long‐term consequence of inflammation. ­frequently comorbid with pelvic, abdominal, A pervasive bias continues to influence the and temporomandibular pain. The unique field’s understanding of inflammation and is immune profile of the vulvar vestibule, a based on the expectation that chronic inflam- ­urogenital sinus‐derived tissue, may be shared mation will resemble the acute inflammatory 268 Textbook of Female Sexual Function and Dysfunction

state. Instead, one of the most common find- Repeated noxious stimulation can enhance ings across pelvic pain populations is evi- the firing properties of C fiber nociceptors in dence of increased mast cell count and/or a process called peripheral sensitization [65, mast cell degranulation [100–103]. 104]. Peripheral sensitization is defined by the following five functional changes in noci- ­Peripheral and Central ceptors: (i) reduced activation thresholds due to changes in membrane potentials, (ii) Sensitization enhanced magnitude of signaling, (iii) gen- eration of spontaneous signaling with no The term “sensitization” is not in itself mech- stimulus (i.e. ectopic discharges), (iv) anistically useful because amplified nocicep- enhanced magnitude of signaling with tive signaling can be sustained by the repeated stimulation (wind‐up), and (v) nociceptor that detects noxious input, and/ recruitment of “silent nociceptors”, which are or the spinal cord interneurons that relay previously non‐nociceptive Aβ afferents that these signals, and/or the brain that interprets switch phenotypes to become nociceptors and learns from these signals. However, this [105]. Inflammation is the most common concept can be used to better interpret con- cause of peripheral sensitization and it is a figurations of pain symptoms (Figure 19.3). normal physiological process from which our

Primary hyperalgesia Secondary hyperalgesia (a) Vulvar vestibule Labia majora

(b) Uterus Peri-uterine tissue

Figure 19.3 Spatial characteristics of primary and secondary hyperalgesia (enhanced pain sensitivity) that would be expected with injury/inflammation at the (a) vulvar vestibule or (b) uterus. Primary hyperalgesia occurs at the site of injury as a natural consequence of peripheral nociceptor sensitization. These nociceptors may trigger spinal cord central sensitization of dorsal horn interneurons, which generates a region of secondary hyperalgesia that surrounds the region of primary hyperalgesia (injury/inflammatory site) that is only hypersensitive to noxious mechanical stimulation. This phenomenon can account for mechanical hyperalgesia in vulvar tissue surrounding the vulvar vestibule in women with provoked vestibulodynia (a). A parallel (and hypothetical) example is provided for primary hyperalgesia originating with uterine injury/ inflammation (b). In this example, secondary hyperalgesia in surrounding uterine tissue may not be perceived as a distinct pain because both sites of visceral hyperalgesia produce similar diffuse sensations of pain. Note that central sensitization is a normal (albeit time‐limited) consequence of strong inflammatory pain and the interactions shown here are not “pathological” if the secondary hyperalgesia resolves in a timely manner and the primary hyperalgesia dissipates soon thereafter. Anatomy and Physiology of Sexual Pain 269 bodies usually recover. It can generate clini- identifiable lesion or disease of the soma- cal symptoms like mechanical and heat allo- tosensory system, and (v) the hypothetical dynia and hyperalgesia at the site of injury, diagnoses of “central sensitivity” or “central without the independent participation of spi- sensitivity syndrome” [64, 65]. Similarly, nal cord interneurons. symptoms like allodynia and hyperalgesia Central sensitization is a powerful idea, as present with peripheral as well as central it provides a physiological mechanism for sensitization, and their relationship to other sustained pain in the absence of the precipi- pain symptoms must be considered to deci- tating stimulus. Prolonged activation of pher their underlying mechanisms [107]. peripheral nociceptors can trigger enhanced Central sensitization shares key features activity of spinal cord cephalad projecting with but is not synonymous with neuropathic neurons in proportion to intensity, repeti- pain. Although central sensitization is con- tion, and duration of the nociceptive input sidered a key pathological process used to [106]. Symptoms consistent with central sen- define the initiation of neuropathic pain, sitization include touch but not thermal neuropathy encompasses a broader range of hypersensitivity around the perimeter of the symptoms including spontaneous (unpro- primary injury. This may include increased voked) fluctuations of burning or electrical punctate pain sensitivity (hyperalgesia) shock‐like pain. Neuropathic pain may mediated by A δ fibers, pain with moving include regional numbness or “pins and nee- tactile pressure (dynamic tactile allodynia) dles” sensations that indicate a loss of func- mediated by “silent nociceptors” (Aβ fibers), tion; central sensitization exclusively reflects and pain sensations that persist long after gain of function. Importantly, the mainte- vulvar or bladder stimulation has ceased nance of central sensitization, but not neuro- [65]. Thermal hyperalgesia is rarely observed. pathic pain, is dependent on continued When central sensitization and referred pain provocation of peripheral nociceptors. co‐occur, secondary hyperalgesia may take a However, it is possible for these processes to different form: silent nociceptors can medi- coexist in a woman with chronic genito‐pel- ate new regions of cutaneous or deep muscle vic pain. To date, the presence of central sen- hypersensitivity [64]. However, the most dis- sitization in many types of genito‐pelvic pain tinctive signature feature of central sensitiza- has not been supported by evidence due to tion is the temporal dissociation between confusion regarding its definition, variability removal of the noxious stimulus and contin- between diagnoses, and methodological lim- ued spinal interneuron firing that underlies itations [63, 108]. pain after‐sensations. This can be contrasted It is tempting to invoke central sensitiza- with the period of quiescence that separates tion as a catch‐all mechanism for unex- the removal of a visceral stimulus and pro- plained clinical pelvic and nonpelvic pain. longed visceral pain. Mechanisms underlying However, the mere presence of pain hyper- central sensitization of visceral nociceptive sensitivity is not evidence of this phenome- signals remain poorly understood and may non [107]. It is a functional change unique to not follow the same “rules” as sensitization of spinal cord interneurons that requires very somatic nociceptive signals. specific conditions (moderate, repetitive Note that central sensitization may coexist noxious stimulation) to be maintained and with, but is not the same as, the following: (i) rekindled; otherwise it will extinguish [109]. peripheral sensitization, (ii) “wind‐up”, which To date, no study has demonstrated a parallel refers to the summation of excitatory input phenomenon in cortical neurons, and there- by a subset of hyperexcitable dorsal horn fore no empirical data supports the claims interneurons (without stimulus‐response that maladaptive pain behaviors, catastro- temporal dissociation), (iii) referred pain, (iv) phization, or other psychological “amplifica- neuropathic pain, which is caused by an tions” of pain are symptomatic of central 270 Textbook of Female Sexual Function and Dysfunction

sensitization. Similarly, the extrapolation of sory cortices, prefrontal cortex, thalamus, central sensitization to explain complex brainstem, and other regions, and individual symptom patterns found in comorbid pain regions mediated distinct aspects of pain conditions is purely hypothetical at this point location, sensation, affect, intensity, and [65]. Worst case, the misuse of the term will higher cognitive processing [116–119]. More promote the haphazard mixing and match- recently, this interpretation has been ques- ing of heterogeneous chronic pain conditions tioned because the activation of brain regions in the absence of empirical or clinical data. originally associated with acute nociceptive The spinal relay of nociceptive information processing are not specific to noxious stimu- to the brain is influenced by cortically‐­ lation and show limited overlap with neural controlled descending pain modulation, “signatures” of chronic pain. Recent meta‐ which can be experimentally evaluated analyses and large‐scale studies have found using conditioned pain modulation para- that acute pain sensitivity has minimal prog- digms. Conditioned pain modulation is sta- nostic value across chronic pain populations ble in healthy and chronic pain populations [120, 121]. Instead, more recent evidence and may provide prognostic value; however, suggests that mesocorticolimbic, rather than it has not been assessed in relation to clinical sensory encoding regions, mediate the tran- symptom change [110–112]. Two of three sition to and maintenance of pain chronicity studies failed to identify abnormal spinal [122]. For instance, a longitudinal brain inhibition in vestibulodynia, as evidenced by imaging study determined that the neural intact diffuse noxious inhibitory control via representation of spontaneous fluctuations conditioned pain modulation [113–115]. of subacute low back pain shift from nocice- Indeed, symptoms like temporal summation ptive to limbic regions as patients transi- suggests that spinally mediated facilitation tioned to chronicity [123]. These findings (or gain) plays a more dominant role than highlight the distinction between pain sensa- descending inhibition. Conditioned pain tion and the long‐term suffering it causes, modulation studies in other populations given that both should ideally be targeted in await replication. pain management efforts. Realistically, the transition from acute to chronic pain reflects three broad classes of ­The Brain mechanisms, including peripheral, spinal, and brain processes. The initiation and main- Ultimately, pain perception is a cortically‐ tenance of chronic pain reflects a combina- mediated phenomenon. Therefore, all content tion of these components that must evolve discussed to this point – from the initial detec- over time: spinal central sensitization will tion of sensory stimuli to the dynamic spinal eventually extinguish without additional relay of this information – culminates in a noci- peripheral input, and it is not known whether ceptive signal that can be attended to, ignored, additional insults (e.g. recurrent infections, or even distorted by brain circuits. Although a pain flares) are sufficient to indefinitely sus- thorough treatment of this topic cannot be tain central sensitization [109, 124]. Likewise, achieved here, a brief review of the current initial formation of a strong emotional mem- state of pain neuroimaging is presented. ory related to pain is naturally reinforced It was previously believed that the brain with continued exposure to the detrimental regions that mediate pain perception must impact of chronic pain on mood, daily func- represent a specialized neural network. This tion, sexual relationships, and identity. assumption was supported by many studies One of the most intriguing findings from demonstrating that acute pain perception the field of pain neuroimaging is that the correlates with functional activation of the degree of brain functional and structural insula, anterior cingulate cortex, somatosen- reorganization can reflect clinically meaningful Anatomy and Physiology of Sexual Pain 271 pain properties, such as subjective pain systems. Theoretically, more variability in intensity, duration, and even emotional pain perception – especially in response to dimensions of pain. Whereas moment‐to‐ environmental perturbation – may be indica- moment changes in perception are reflected tive of a peripheral‐dominant pain. In con- in brain functional properties, the longer‐ trast, unprovoked pain with low variability is term consequences associated with chronic more consistent with centrally‐mediated pain, such as symptom severity, correlate pain, potentially with intermittent peripheral with neocortical gray matter (neuronal) den- nerve contributions. Importantly, genito‐ sity/volume and white matter (axonal) pelvic pain symptoms may reflect a combina- microstructure. This suggests that networks tion of peripheral and central factors, thereby can manifest short‐ and long‐term neuro- implying that concurrent treatment approaches plasticity by (i) adapting to brain state targeting peripheral and central abnormali- changes in order to optimize the representa- ties may yield the greatest gains. The hypoth- tion of information, as well as (ii) evolving esis that early and chronic genito‐pelvic are over time based on reinforced functional maintained by distinct factors suggests the connections, which may in turn promote existence of (at least) two subtypes: the sub- structural changes [125]. clinical/early onset phenotype and the A final comment on the physiological sub- chronic phenotype. To date, the majority of strates of pain perception: despite the clinical genito‐pelvic pain research has been con- reliance on numerical rating scales, pain per- ducted on the chronic phenotype based on ception does not operate on an absolute scale. etiological assumptions that preferentially Pain is evaluated relative to the state that reflect the early phenotype. immediately preceded its onset and relative to Visceral pain deserves special consideration predicted outcomes based on past experience here because it is not purely sensory in [126]. A critical principle revealed by investi- nature: it reflects (i) the diffuse sensations by gations of neural encoding of nociceptive which visceral nociception is currently input is that the experience of pain begins defined; (ii) negative emotion; and (iii) with pain anticipation. The dynamic nature of increased sympathetic nervous system pain perception – including peripheral and arousal [53, 54]. Targeting any combination central sensitization – is adaptive because it of these dimensions can, in theory, diminish facilitates the accurate prediction and detec- the subjective experience of visceral pain tion of future threats. Like somatic pain, fear is (Table 19.3). The co‐occurrence of visceral tightly coupled with a distinct threat that has a discomfort with negative affect and sympa- discrete beginning and end. Like visceral pain, thetic activation creates ideal physiological anxiety is diffusely focused, without an identi- conditions for the consolidation and mainte- fiable threat to defend against (or with all nance of robust emotional memories related threats being equally salient) and persists long to visceral pain [127–130]. after a significant threat has passed. The dif- ference is that anxiety further distorts sensory and affective dimensions of potential threats ­Summary (degree of threat, salience, context cues, and avoidance). Genito‐pelvic pain emerges from a series of dynamic interactions between molecular, cellular, systems, behavioral, and psychologi- ­Novel Future Directions cal factors. Nociceptive signals are function- ally amplified by sensory afferent neurons The temporal patterns of genito‐pelvic pain that detect noxious stimuli, spatially general- may provide insight into the respective con- ized by spinal cross‐talk, and temporally pro- tributions of peripheral versus central nervous longed by spinal cord central sensitization. Table 19.3 Therapeutic mechanisms of action targeting nociception in genito‐pelvic pain.

Medications Mechanism(s) of action Pain indications

Ta rget: primary afferent excitability Capsaicin ● Hyperpolarization of capsaicin receptors with sustained use ○ Mechanical and thermal allodynia/hyperalgesia ● Possible inhibition of neighboring P2X 3 receptors Local anesthetics ● Prevents neuronal firing by blocking voltage‐gated sodium channels ○ Cutaneous mechanical and heat hyperalgesia, including pain (lidocaine, lidocaine plaster, ● Possible desensitization of transient receptor potential ankyrin 1 due to neuroproliferation prilocaine, bupivacaine, ● Reduced efficacy in inflamed tissue ○ Can be used to assess contributions of cutaneous pain mepivacaine) ● Reduced efficacy in nerve lesion pain, which alters functional mechanisms properties of sodium channels Nav1.7 and Nav1.8 ○ Nerve blocks may not alleviate referred pain Corticosteroids ● Prevents formation of arachidonic acid by inhibiting ○ Inflammatory pain (may be limited to increased mast cells) (hydrocortisone, cortisone, phospholipase ○ Pain associated with allergic reactions prednisone, triamcinolone, ● Limits degree of inflammation by curtailing lymphocyte ○ Stop use if pain does not dissipate, as side effects with betamethasone, dexamethasone) migration and cytokine expression prolonged use can contribute to genito‐pelvic pain ● Inhibits delayed hypersensitivity reactions Topical estrogen ● Increases epithelial thickness, elasticity and tissue integrity ○ Pain onset associated with natural or pharmacologically‐ (17 β ‐estradiol, conjugated ● Improves vaginal lubrication induced changes in estrogen levels estrogens) ● ○ Inhibits P2X3 excitability through estrogen receptor‐α binding on Lubrication reduces pain with traction C‐fiber nociceptors

● P2X3 antagonists Inhibits rapid inflammatory response induced by adenosine ○ Mechanical allodynia and hyperalgesia (AF‐219) triphosphate ○ Potentially “burning” pain induced by mechanical pressure

Ta rget: peripheral sensitization Nonsteroidal anti‐inflammatories ● Inhibits cyclooxygenase‐1 and ‐2 activity ○ Pain related to wounds (e.g. vulvar fissures) (ibuprofen, naproxen, aspirin) ● Short‐term reduction in inflammatory mediators, such ○ Inflammatory pain prostaglandins Reservatrol and salicylic acid ● Activates 5 ′ adenosine monophosphate‐activated protein kinase ○ Mechanical allodynia associated with interleukin‐6 ● Inhibits extracellular signal regulated kinase and mammalian expression and primed hyper‐responsivity to target of rapamycin signaling pathways prostaglandin E2 ● Reservatrol has poor bioavailability unless combined with salicylic acid

Chapter No.: 1 Title Name: c19.indd Comp. by: Date: 22 Mar 2018 Time: 11:31:55 AM Stage: WorkFlow: Page Number: 272 Table 19.3 Therapeutic mechanisms of action targeting nociception in genito‐pelvic pain. Ta rget: spinal cord central sensitization ● γ α δ ○ Medications Mechanism(s) of action Pain indications Gabapentinoids Inhibits reuptake of ‐aminobutryic acid by modulating ‐2‐ subunit Neuropathic pain (gabapentin, pregabalin) voltage‐dependent calcium channel activity in spine and brain ○ Mechanical allodynia, thermal hyperalgesia, cold ● Modulates spinal descending inhibition hyperalgesia Ta rget: primary afferent excitability ● Inhibits primary afferent hyperactivity and ectopic activity in ○ Preoperative use to limit nociceptive sensitization in central Capsaicin ● Hyperpolarization of capsaicin receptors with sustained use ○ Mechanical and thermal allodynia/hyperalgesia peripheral and wide dynamic range neurons nervous system ● Possible inhibition of neighboring P2X 3 receptors ● Independent of endogenous opioid system ● Local anesthetics Prevents neuronal firing by blocking voltage‐gated sodium channels ○ Cutaneous mechanical and heat hyperalgesia, including pain Other antiepileptic medications ● Blocks potassium and voltage‐gated sodium channels, yielding ○ Neuropathic pain (lidocaine, lidocaine plaster, ● Possible desensitization of transient receptor potential ankyrin 1 due to neuroproliferation (carbamazepine, reduced glutamate and/or increased γ ‐aminobutryic acid activity prilocaine, bupivacaine, ● Reduced efficacy in inflamed tissue ○ Can be used to assess contributions of cutaneous pain benzodiazepines, topiramate) ● Inhibits glutamate signaling mepivacaine) ● Reduced efficacy in nerve lesion pain, which alters functional mechanisms ● Targets γ ‐aminobutryic acid receptors, transporters and/or properties of sodium channels Nav1.7 and Nav1.8 ○ Nerve blocks may not alleviate referred pain enzymatic degradation Corticosteroids ● Prevents formation of arachidonic acid by inhibiting ○ Inflammatory pain (may be limited to increased mast cells) Tricyclic antidepressants ● Blockade of voltage‐gated sodium channels in periphery ○ Neuropathic pain, including thermal and mechanical (hydrocortisone, cortisone, phospholipase ○ Pain associated with allergic reactions (amitriptyline, imipramine, ● Blocks reuptake of serotonin and norepinephrine; dopamine to hyperalgesia prednisone, triamcinolone, ● nortriptyline, desipramine) ○ Limits degree of inflammation by curtailing lymphocyte ○ Stop use if pain does not dissipate, as side effects with lesser extent Potentially useful in pain due to central sensitization, betamethasone, dexamethasone) migration and cytokine expression prolonged use can contribute to genito‐pelvic pain ● Modulates endogenous opioid system through inhibition of N‐methyl‐D‐aspartate‐induced spinal ● Inhibits delayed hypersensitivity reactions ● Long‐term: δ ‐opioid receptor modulation hyperalgesia ● Topical estrogen Increases epithelial thickness, elasticity and tissue integrity ○ Pain onset associated with natural or pharmacologically‐ Opioids ● Binds primarily to spinal μ ‐opioid receptors, with some δ ‐ & ○ Alters subjective perception of pain severity and (17 β ‐estradiol, conjugated ● Improves vaginal lubrication induced changes in estrogen levels (codeine, hydrocodone, κ ‐opioid receptor binding unpleasantness estrogens) ● ○ ● Inhibits P2X3 excitability through estrogen receptor‐α binding on Lubrication reduces pain with traction oxycodone, hydromorphone, Duration of analgesia corresponds with duration of stable blood ○ Very effective for acute pain (e.g. postsurgical pain) oxymorphone, fentanyl, C‐fiber nociceptors levels of medication ○ Preferred use after failed trials of other centrally‐acting ● morphine) ● P2X3 antagonists Inhibits rapid inflammatory response induced by adenosine ○ Mechanical allodynia and hyperalgesia Estrogen attenuates opioid receptor activity medications ● (AF‐219) triphosphate ○ Potentially “burning” pain induced by mechanical pressure Sustained use suppresses hypothalamic‐ pituitary‐gonadal axis ○ Short‐acting opioids used for intermittent “breakthrough” or ● Chronic use (>10 years) increases nociception (poorly understood “flare‐like” pain Ta rget: peripheral sensitization mechanisms) ○ Physiological tolerance is expected and should not be confused with addiction Nonsteroidal anti‐inflammatories ● Inhibits cyclooxygenase‐1 and ‐2 activity ○ Pain related to wounds (e.g. vulvar fissures) (ibuprofen, naproxen, aspirin) ● Short‐term reduction in inflammatory mediators, such ○ Inflammatory pain Ta rget: emotional learning prostaglandins d‐Cycloserine ● Partial agonist at the glycine recognition site of the glutamatergic ○ Thought to target fear memories at low doses when delivered ● ′ ○ Reservatrol and salicylic acid Activates 5 adenosine monophosphate‐activated protein kinase Mechanical allodynia associated with interleukin‐6 N‐methyl‐D‐aspartate receptor that yields antagonist‐like effects 1 h prior to memory reactivation ● expression and primed hyper‐responsivity to Inhibits extracellular signal regulated kinase and mammalian (50–300 mg) ○ prostaglandin E2 With extended use (6–8 weeks), reduces neuropathic target of rapamycin signaling pathways mechanical allodynia ● Reservatrol has poor bioavailability unless combined with ● β β ○ salicylic acid Propranolol Blocks epinephrine and norepinephrine at 1‐ and 2‐adrenergic Reduces norepinephrine‐induced strengthening of emotional receptors (fear) memories when they are formed (consolidation) and revised (reconsolidation)

Chapter No.: 1 Title Name: c19.indd Comp. by: Date: 22 Mar 2018 Time: 11:31:55 AM Stage: WorkFlow: Page Number: 273 274 Textbook of Female Sexual Function and Dysfunction

Understanding the rules by which these dysfunction, or other insults – reflects the nerves function – and especially how these body’s adaptations to a threat, not the origi- rules are violated in the chronic pain state – is nal threat itself. Etiological factors are dis- key in uncovering the mechanisms driving tinct from the physiological alterations that persistent genito‐pelvic pain. Therefore, dis- eventually become part of the disease of tinct sensory abnormalities can point to chronic pain over years and decades. The unique alterations in peripheral, spinal, and/ noble goal of identifying and treating sus- or brain physiology that bias sensory pected etiology (i.e. the acute phenotype) perception. may ultimately detract from opportunities to Pain pathophysiology – caused by injury, target mechanisms of the chronic phenotypes infection, hormonal deficiency, pelvic floor of genito‐pelvic pain.

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20

Psychological Management of Provoked Vestibulodynia Caroline F. Pukall and Sophie Bergeron

Abstract

Vulvodynia represents a unique challenge for health‐care professionals, as it intersects two poorly understood conditions: pain and sexual health problems. This chapter focuses on the psychosocial aspects of provoked vestibulodynia – the most common subtype of vulvodynia – highlighting its diagnosis and assessment, and emphasizing that measuring pain and sexuality outcomes are useful in terms of validating the patient’s experience as well as tracking treatment progression. Psychosocial factors – including sexuality, sexual partners, relationship dynamics, mood, and cognitive/ emotional responses to the pain – are discussed in light of the importance of these factors in the expression of vulvodynia. Psychological interventions and their efficacy are reviewed, and the ­conclusion that individual and group psychological treatments represent empirically validated and safe options for provoked vestibulodynia is made. Keywords: vulvodynia; provoked vestibulodynia; psychosocial factors; mood; sexuality; pain; assessment; relationships; psychological interventions; cognitive behavioral therapy

Take a multidimensional approach to the assessment of the woman’s pain and sexuality, validate her pain experience, discuss contributing factors, and include the partner in the assessment when possible. Address anxiety, mood, and post traumatic stress disease comorbidities, especially if they reach clinical levels. Throughout treatment, target pain and sexuality concurrently; obtain pain ratings and re‐assess sexual function periodically to facilitate the identification of factors that affect the pain experience and associated sexual difficulties, provide psychoeducation to help patients espouse a multifactorial view of their pain and its impact on sexuality; create specific short‐term goals addressing pain reduction and improved sexual function and satisfaction to structure the treatment, and to instill hope in women and their partners

­Provoked Vestibulodynia Ideally, a comprehensive treatment program for women with vulvodynia will target these Pain Characteristics two components, as women complain as much about the pain as they do about the Vulvodynia, or unexplained chronic vulvo- sexual difficulties associated with it, and vaginal pain, represents a unique challenge these two symptom domains are relatively for health‐care professionals in terms of independent of one another [1]. Mental the intersection of two poorly understood health‐care professionals who treat women conditions: pain and sexual health problems. with vulvodynia, therefore, should be

Textbook of Female Sexual Function and Dysfunction: Diagnosis and Treatment, First Edition. Edited by Irwin Goldstein, Anita H. Clayton, Andrew T. Goldstein, Noel N. Kim, and Sheryl A. Kingsberg. © 2018 John Wiley & Sons Ltd. Published 2018 by John Wiley & Sons Ltd. 282 Textbook of Female Sexual Function and Dysfunction

­comfortable in the domains of both pain vulvodynia. If the health‐care provider is management and sex therapy; an empirically unable to make a diagnosis of a known cause validated treatment protocol combining of vulvar pain, then the patient is diagnosed these two complimentary approaches has with vulvodynia [8]. In the majority of cases, been developed for groups [2], couples [3], the patient has pain localized to the vulvar and individuals [4, 5]; and can be obtained by vestibule and, therefore, her diagnosis is pro- contacting the authors of this chapter. voked vestibulodynia. It is possible that the The pain of provoked vestibulodynia is health‐care provider believes that there is an typically characterized as severe, located at associated biomedical factor that may be the vaginal entrance, and experienced in playing a role in the pain experience, such as response to pressure [6]. Activities that elicit inflammation or hormonal changes. In these the pain can be sexual (e.g. those involving cases, the provider may initiate treatment for vaginal pressure/penetration) or nonsexual this possible associated factor [9]. A referral (e.g. tampon insertion, bicycle riding); usu- to a pelvic floor physical therapist is also ally, women with provoked vestibulodynia ­typically made if one is available because will present to health‐care professionals with many women with provoked vestibulodynia complaints of pain during sexual activities have overactive pelvic floor muscles that involving vaginal pressure/penetration. may be contributing to the vestibulodynia. Although many adjectives are used to In addition, a referral to a mental health‐care describe the pain of provoked vestibulo- professional with knowledge of vulvodynia dynia, some of the most common descriptors could then be made, so that the patient can are burning, cutting, sharp, and searing [7]. focus on various biopsychosocial elements Despite the fact that medical professionals involved in the expression of the pain and often will cite “no observable cause” when associated psychological, relationship, and diagnosing a patient with provoked vestibu- sexual difficulties. lodynia (a diagnosis of exclusion), many ­factors that are not routinely assessed in a Assessment typical examination room and/or via medical tests – from vestibular hyperin- A mental health‐care professional should nervation resulting in hypersensitivity, to complete a comprehensive evaluation of the ­heightened pelvic floor muscle tension, following: medical, psychological, and gen- to neural responses – are associated with the eral health history; vulvar pain history, ­experience of this pain [6]. As such, the including pain characteristics, and treatment pain experience should be validated even in attempts and outcomes; sexuality, including the face of a lack of observable findings, current function, satisfaction, and distress, and the correlates should be explained to the and any past childhood trauma and maltreat- person with provoked vestibulodynia. ment; and individual and couple relationship factors (Table 20.1). This information would Diagnosis then be used to confirm or refine the initial diagnosis, and would lead to areas of focus in The diagnosis and treatment of provoked terms of psychotherapeutic intervention. vestibulodynia are discussed in depth in Ideally, the initial assessment as well as Chapter 22. Briefly, the diagnosis is typically treatment progress should involve some made by a medical professional, who rules ­validated measures and/or scales, especially in/out known causes of vulvar pain such as for the core symptomatology of provoked an infection (e.g. candidiasis) or dermato- vestibulodynia: pain and sexual dysfunction logic disease of the vulva (e.g. lichen sclero- (see the referenced recommendations for sus). If a diagnosis of a known cause of vulvar vulvodynia clinical trials [10].) Scales and/ pain is made, then the patient does not have or questionnaires assessing the following Psychological Management of Provoked Vestibulodynia 283

Table 20.1 General and specific domains for a comprehensive pain and psychosocial assessment.

General domain Specific domains

Medical history Surgical history Medical conditions and treatments (past and current) Previous and current vulvodynia‐related diagnoses Bowel and bladder function Past and current prescription medication use Past and current use of nonprescriptives (e.g. vitamins, supplements) Psychological history Mental health conditions and treatments (past and present) Past abuse (sexual, physical, verbal) or neglect, current abuse General health history History of injuries or falls affecting the genito‐pelvic and lower back areas Vulvar pain history Time since onset Temporal pattern Duration Location Quality Factors that elicit the pain Intensity Primary or secondary presentation Treatment attempts and outcomes Sexuality Desire Arousal Orgasm Pleasure Frequency of sexual activity Satisfaction with sexual activity Sexual repertoire Pain with sexual activity Sexual distress Sexual trauma/negative experiences/ongoing sexual victimization Individual factors Thoughts, emotions, and behaviors associated with the pain (e.g. avoidance, fear of pain, pain coping) Couple relationship factors, Couple interactions that accompany the pain if relevant Current relationship dynamic (e.g. strengths, areas of conflict, couple’s pain coping style, sexual and nonsexual intimacy) aspects of the pain experience can be useful: progression of the patient throughout the vulvovaginal pain intensity, quality, and treatment process. On this scale, zero would affect, as well as sexual function, the effects indicate “no pain at all” and ten would indi- of the vulvovaginal pain on quality of life, cate “pain as bad as you can imagine” [10]. interference of the pain with sexual activity, This basic information – especially when and depressive and anxiety symptoms. Using pain ratings decrease over the course of validated measures is useful for making com- treatment – can contribute to instilling hope, parisons with clinical norms and for tracking further motivating the patient to be an active treatment progress. However, obtaining a participant in her recovery. In the case where large amount of information in this manner pain ratings change (increase or decrease), is not always feasible in a clinical setting. specific factors (e.g. levels of anxiety, rela- A simple zero‐to‐ten numerical rating tionship dynamics with partner, sexual scale can be used to measure pain intensity at arousal) related to those experiences can be the beginning of treatment and to follow the discussed in order to delineate what factors 284 Textbook of Female Sexual Function and Dysfunction

affect the pain experience. To this end, a pain ­problems and lower sexual satisfaction as diary can also be useful in keeping track of compared to men who are partnered with such factors. In addition, a numerical rating women who do not have provoked vestibulo- scale can be used to track progress in the dynia. But do these sexual issues affect the experience of sexual desire and arousal, and overall relationship in any way? serve the same purpose of reinforcing treat- ment gains. Measuring pain and sexuality Relationship Dynamics outcomes can validate the patient’s experi- ence and communicate the mental health A recent line of investigation has examined professional’s interest in seeing improvement whether couples with provoked vestibulo- in these domains. In addition, it is important dynia report lower relationship adjustment to communicate to the patient that her pro- than nonaffected couples. Although a sys- gress is not expected to be linear, and that tematic review concluded that affected ups and downs are typical – and, in fact, use- ­couples do not experience lower relationship ful in understanding the complexity of her satisfaction in comparison to control groups experience. Indeed, many factors can impact or norms on validated measures [16], some the experience of vulvovaginal pain. studies have demonstrated evidence of sig- nificantly lower relationship adjustment in couples affected by vulvodynia [17]. This ­Psychosocial Factors ­discrepancy has led some researchers to ­suggest that “relationship satisfaction” or Sexuality and Sexual Partners “relationship adjustment” may be too global a construct; perhaps examining more spe- Numerous studies indicate that women with cific aspects of relationship dynamics may provoked vestibulodynia report significantly yield differences between provoked vestibu- lower levels of sexual desire, arousal and lodynia and nonprovoked vestibulodynia ­satisfaction, more difficulty reaching orgasm, affected couples, and partly explain the lower frequencies of intercourse, more nega- development and maintenance of associated tive attitudes toward sexuality, and more sexual difficulties. sexual distress than pain‐free controls [6]. Recently, specific relationship variables Studies have also shown that women with have been shown to be associated with vulvodynia report more distress about their ­sexuality and pain outcomes in women with body image, more anxiety and self‐awareness provoked vestibulodynia, such as partner with exposure of their bodies during sexual responses to the pain, degree of relationship activity, and a more negative genital self‐ and sexual intimacy, levels of empathy, and image than control women [6]. With all of amount of self‐disclosure and ambivalence these negative sexual consequences, one over emotional expression. Partner responses might question why over 80% of women with to pain can be solicitous (providing attention provoked vestibulodynia continue to engage and sympathy), negative (demonstrations in sexual activities involving vaginal pres- of hostility), and facilitative (encouraging sure/penetration [11]. Reasons can include ­adaptive coping). For example, in provoked the following: to feel closer to their partner, vestibulodynia, a solicitous response would to avoid losing their partner, to protect their be a partner suggesting to stop engaging in all partner, and to fulfill their duties as a sexual sexual activity, a negative response would be a partner [12–14]. At the same time, some partner expressing anger, and a facilitative studies have indicated that partners of response would be a partner expressing posi- women with provoked vestibulodynia also tive feelings about the woman engaging in tend to report more sexual difficulties [15]. any sexual activity. In a series of studies con- For example, they report more erectile ducted with couples coping with pr­ ovoked Psychological Management of Provoked Vestibulodynia 285 vestibulodynia, Rosen, Bergeron, and col- over emotional expression reported signifi- leagues found that both solicitous and nega- cantly better sexual function and satisfaction, tive responses were detrimental to women’s less depressive symptoms, and better dyadic pain and couples’ sexual well‐being, whereas adjustment than couples in which both were facilitative responses were beneficial to both high in ambivalence over emotional expres- members of the couple [18–20]. In addition, a sion or in which one member was high and study examining women’s intimacy found the other was low [24]. This recent pattern of that higher levels of self‐reported sexual findings suggests that couples who can be ­intimacy were associated with higher sexual intimate, communicate more openly about satisfaction, sexual function, and pain self‐ sexuality, and coregulate emotions effectively efficacy (i.e. the degree to which one believes together may experience less pain‐related that they can manage the pain effectively) [21]. negative impacts on their sexuality, relation- Empathic responses and self‐disclosure – two ship, and mood. components of intimacy – have also been found to improve sexuality in couples: in an Other Relationships: Peers observational study involving 50 provoked and the Health‐Care Community vestibulodynia affected couples, both part- ners’ observed and reported greater empathic Provoked vestibulodynia can be considered responses were associated with their better by some people to be a “private” pain given sexual satisfaction and lower sexual distress. its location and negative effects on sexuality. Furthermore, both partners’ greater per- Although approximately two‐thirds of ceived self‐disclosure was associated with women reported discussing their pain with their better sexual satisfaction [22]. In another their sexual partner, only 40% reported feel- study involving the same sample, greater ing comfortable talking about it with a family observed empathic response and perceived member. This number dropped to just over self‐disclosure in women were associated one quarter when asking about comfort talk- with their higher quality of life. Women and ing about the pain with female acquaintances partners’ greater empathic response were [25]. Coupled with the findings that many associated with both partners’ higher rela- affected women believe that people think tionship adjustment [23]. their condition is an excuse to avoid inter- Ambivalence over emotional expression course, and that approximately half of them (AEE) has also been examined in couples who sought medical care reported feeling with provoked vestibulodynia. Ambivalence stigmatized by their physicians [26], these over emotional expression is defined as the results highlight affected women’s sense of extent to which one is comfortable with the feeling alone in dealing with their pain and way they express emotions. Being high in may explain some of their hesitancy and dif- ambivalence over emotional expression indi- ficulties in finding appropriate health care. cates that the way in which one expresses Indeed, many women with chronic vulvar emotions (or does not) is personally prob- pain are silent sufferers; one study reported lematic and carries with it negative personal that less than 50% of women who met criteria consequences, such as feeling inadequate or for vulvodynia sought treatment and, of fearing to hurt someone else, whereas being these, only 1.4% received an appropriate low in ambivalence over emotional expres- diagnosis [11]. Anecdotal evidence suggests sion involves managing emotions in a less that women with vulvodynia receive little internally conflicted way and, overall, is sug- validation for their symptoms in health‐care gestive of better emotion regulation. In a settings, with many being told their pain is sample of over 250 couples with provoked “all in their heads” due to the absence of visible vestibulodynia, those in which both mem- pathology. It has been well established that bers were found to be low in ambivalence women with vulvodynia are a­ pprehensive to 286 Textbook of Female Sexual Function and Dysfunction

speak about their pain with others, and that and anxiety symptoms tend to be comorbid feelings of isolation and invalidation of their in the general population as well as in chronic pain are common [27]. pain populations, and this association appears to play a role in provoked vestibulo- Cognitive and Emotional dynia as well. Results of an epidemiological Responses to the Pain study suggest that anxiety and depression may both precede and follow the develop- Many women with provoked vestibulodynia ment of vulvodynia. This study reported that report feelings of shame, inadequacy, and low the odds of chronic vulvar pain were four self‐esteem; these feelings should be exam- times more likely among women with a ined in treatmen,t as they may play a role in ­history of depression or anxiety as compared the pain experience. Psychological factors to nonaffected women. Furthermore, vulvo- that have been associated with higher pain dynia was associated with a new or recurrent intensity and sexual impairment include: pain onset of mood or anxiety disorder, suggest- catastrophizing, fear of pain, pain hypervigi- ing a reciprocal relationship among anxiety, lance, lower vulvar pain self‐efficacy (the depression, and vulvodynia [29]. In another degree to which one believes that one can multiethnic population‐based study, Iglesias‐ manage the pain effectively), negative attribu- Rios et al. found that women who screened tions about the pain, avoidance, anxiety, and positive for posttraumatic stress disorder depression [6]. Although prospective studies were twice as likely to report vulvodynia [30]. examining the role of psychological factors in Posttraumatic stress disorder is a debilitating provoked vestibulodynia are rare, one such psychiatric disorder that may develop after study that followed 222 women with pro- unresolved trauma, such as childhood vic- voked vestibulodynia over two years found timization. It is characterized by intrusive that increases in pain self‐efficacy were asso- re‐experiencing of the traumatic event, ciated with reductions in pain intensity [28]. avoidance behaviors, hypervigilance, and This relationship was partially mediated by emotional numbing, as well as by activation lower avoidance of painful activities (i.e. of the physiological and neuroendocrine engaging in more intercourse attempts). The ­systems. In sum, psychological factors, same pattern of results was found for changes including psychiatric disorders, may be asso- in sexual satisfaction as the outcome. ciated with both the onset and maintenance of vulvodynia and, thus, warrant clinical Mood attention by mental health professionals.

Several studies indicate that women with The Role of Childhood Victimization vulvar pain report higher levels of depressive symptoms than nonaffected women [6], Childhood sexual and physical abuse may play although these results have not been consist- a role in the development of chronic vulvar ently replicated. It is noteworthy that in many pain. In two population‐based studies, of the studies that do report higher levels of women with vulvodynia were more likely to depressive symptoms, the levels are not nec- have reported sexual abuse and severe physi- essarily within the clinical range. A similar cal abuse, as well as living in fear of abuse, pattern emerges with anxiety symptoms: when compared to nonaffected women many studies report that women with pro- [31, 32]. This pattern was also shown in a voked vestibulodynia exhibit higher levels of large‐scale cross‐sectional study of sexually anxiety symptoms compared to women active female adolescents with dyspareunia. without provoked vestibulodynia [6]. Indeed, Those with dyspareunia were more likely to it has been well established that depressive report a history of sexual abuse and fear of Psychological Management of Provoked Vestibulodynia 287 physical abuse compared to sexually active progression is usually consecutive and based adolescents without dyspareunia [33]. It on ‘trial‐and‐error’; however, recently, King appears as though childhood victimization and colleagues have suggested a more algo- can increase one’s risk for developing chronic rithmic approach based on physical exami- vulvar pain, and there is some suggestion nation findings and laboratory tests when that it might also affect sexual function and deciding on specific treatments [35]. Lastly, mood. In a study of women with dyspareu- some have argued that starting with more nia, victims of childhood sexual abuse invasive treatments, such as surgical inter- reported significantly lower levels of sexual vention, should be considered given its high functioning and psychological well‐being effectiveness and low side‐effect profile [36]. compared to women reporting no sexual Still others have stated that concurrent or abuse [33]. However, less is known about integrative (i.e. multidisciplinary) treat- the impact of broader forms of childhood ments, if possible, might be more efficacious interpersonal trauma on provoked vestibulo- in terms of outcome [37, 38], although, at dynia affected couples’ adaptation to current present, there is no empirical evidence to symptomatology. In a recent study involving support any particular combination and/or 50 such couples, women’s greater occurrence sequence of treatments [9]. of childhood maltreatment was associated with their lower sexual function and higher Psychological Interventions: anxiety, whereas partners’ maltreatment was What do they Target? associated with their lower sexual function, lower couple satisfaction, and higher anxiety, Psychological interventions focus on reduc- as well as women’s lower couple satisfaction ing pain and distress, improving sexual and higher anxiety. Both women’s and ­function and satisfaction, and strengthening ­partners’ greater occurrence of childhood the romantic relationship by targeting the maltreatment were associated with higher thoughts, emotions, behaviors, and couple affective pain intensity ratings for women interactions associated with the experience [34]. Overall, findings suggest that childhood of pain and sexual difficulties. Such interven- interpersonal trauma is not only a risk factor tions can be delivered in individual, couple, for the onset of provoked vestibulodynia but or group formats [36, 39, 40]. Cognitive also complicates couples’ adjustment to the behavioral therapy is the most commonly sexual, psychological, and relationship reper- used and most studied psychological treat- cussions of vulvodynia and, as such, should be ment for provoked vestibulodynia to date [9]. given careful attention in the treatment plan. In the first phase of cognitive behavioral therapy, psycho‐education is provided about a multidimensional view of pain and its nega- ­Treatment tive impact on sexuality, as well as on the role of psychological and relationship factors in The typical treatment plan for a woman the maintenance of provoked vestibulodynia. with provoked vestibulodynia starts with Self‐exploration of the genitals and localiza- treatments that are considered noninvasive tion of the pain are generally introduced at (e.g. psychological interventions, pelvic floor this stage, as is the regular use of a pain and physical therapy) and, depending on her sexuality diary to raise awareness about response to treatment, may progress to which psychological and relationship factors ­medical treatments (e.g. gabapentin, topical influence pain, arousal, and desire, and to ­hormones). If these treatments fail, surgical track progress. The second step involves tar- intervention (if the pain is limited to the geting individual coping strategies that may ­vestibule) may be recommended. Treatment lead to increased pain and sexual difficulties, 288 Textbook of Female Sexual Function and Dysfunction

such as pain catastrophizing, hypervigilance Significant Psychological Distress: to pain, avoidance of sexual activity, fear of How to Deal with it pain, and excessive anxiety. If in a couple therapy format, securing the attachment In some cases, psychological distress will bond is another relationship factor that can reach clinical levels and this aspect of the be addressed, as well as partner solicitous woman’s presentation will become more and negative responses, emotion coregula- ­central. At this point, mental health profes- tion between partners, and sexual and rela- sionals may need to move beyond pain tionship intimacy within the couple. One and sexuality‐focused cognitive behavioral helpful multitarget strategy is to increase therapy. Reasons for elevated psychological each partner’s capacity for empathic response distress can range from a history of child- and self‐disclosure. The aim of this second hood maltreatment to significant relation- step is to enable women and their partners to ship conflict, including intimate partner make better use of approach behaviors, physical, sexual and/or psychological vio- i.e. engaging in sexual activity to achieve a lence. Childhood maltreatment can become positive outcome, optimal emotion regula- the focus of treatment if briefer cognitive tion, communication, and self‐assertiveness, behavioral therapy interventions are ineffec- while reconnecting with each other through tive in reducing pain and improving sexual nonsexual physical and emotional intimacy, function, and the woman is ready to attend to expanding their sexual repertoire to steer this aspect of her past more directly. In such the focus away from intercourse, and shar- instances, the mental health professional ing mutual experiences of desire and arousal should have sufficient experience and train- in a nonthreatening, nonpainful context. ing in trauma‐informed psychotherapy, Exercises associated with this step may and childhood maltreatment should not be include breathing and meditation; discussing presented as the sole cause of provoked views about the impact of the pain on their ­vestibulodynia given that chronic pain is a romantic and sexual relationship; identifying complex, multifactorial phenomenon. distressing thoughts, emotions and couple Namely, focusing on childhood maltreat- interactions; familiarizing themselves with ment to the exclusion of other potential exac- what facilitates arousal and desire; commu- erbating factors could prolong treatment nicating sexual preferences and needs; and unnecessarily and be less helpful. Focusing using cognitive defusion to decatastrophize on childhood maltreatment should not pain‐related thoughts and emotions. eclipse the need to work on reducing pain Although traditionally prescribed in sex and improving sexuality. therapy, Kegel exercises and vaginal dilation Significant relationship conflict, disen- exercises are best done with a pelvic floor gagement, or trauma should be addressed in physical therapist. Toward the end of treat- couple therapy, especially since these factors ment, the mental health professional will may interfere with other ongoing treatments help in skill consolidation and maintenance for provoked vestibulodynia. Women with of gains, helping the woman or couple attrib- pre‐existing psychiatric disorders could be in ute these gains to the efforts they deployed in need of more intensive psychotherapy to and outside of therapy. Follow‐up sessions cope with the added burden of provoked are recommended when possible. Finally, in ­vestibulodynia. In addition, women with terms of a timeline, cognitive behavioral ­primary provoked vestibulodynia onset therapy can be delivered in 10–12 sessions, (i.e. the pain has been present since the first but mental health professionals are encour- occasion of vaginal pressure/penetration) aged to adapt their pace and sequence of may benefit less from treatment than those interventions to the specific clinical presen- who have secondary provoked vestibulo- tation of the woman or couple. dynia (i.e. the pain developed after a period Psychological Management of Provoked Vestibulodynia 289 of time during which pain‐free vaginal 13‐week treatment period [2]. Intent‐to‐treat ­pressure/penetration activities were possi- multilevel analyses showed that participants ble) [41]. For example, a nonrandomized of both groups reported statistically signifi- treatment study assessing outcome of women cant reductions on pain from baseline to with provoked vestibulodynia who received post‐treatment and six‐month follow‐up, various multimodal interventions (ranging although the cognitive behavioral therapy from topical lidocaine gel to surgery) demon- group reported significantly more pain strated that women with primary provoked ­reduction at the six‐month follow‐up. At vestibulodynia had lower success rates than post‐treatment, women randomized to the women with secondary provoked vestibulo- cognitive behavioral therapy condition were dynia [42]. Taking pain onset into considera- significantly more satisfied with their treat- tion may help guide treatment planning and ment, displayed significantly less pain cata- allow for more reasonable goals to be set. strophizing, and reported significantly better Finally, women who have tried multiple global improvements in the domain of treatments with no success, or women ­sexuality than women assigned to the topical who have experienced many negative side application. Findings suggest that cognitive effects or complications from past treat- behavioral therapy may yield positive out- ments – leading them to lose faith in ever comes on more dimensions of provoked improving their condition and quality of ­vestibulodynia than does a topical treatment. life – may prove more challenging to treat. In a randomized trial involving a mixed They may require additional psychological group of 50 women with vulvodynia, Masheb support and/or psychotherapy targeting et al. also found that cognitivebehavioral their lack of trust in the mental health profes- therapy, delivered in an individual format, sional or their difficulty engaging in treat- yielded significantly greater pain reduction ment for fear of being disappointed yet again. and improved sexual function than support- ive psychotherapy [5]. In a pilot study, Efficacy of Psychological Corsini‐Munt et al. prospectively examined Interventions the preliminary efficacy of a 12‐session man- ualized cognitive behavioral therapy couple Bergeron and colleagues investigated the effi- intervention in nine couples in which the cacy of a combination of group cognitive woman was diagnosed with provoked vesti- behavioral therapy in two randomized trials bulodynia [3]. Findings showed significant of women diagnosed with provoked vestibu- improvements in women’s pain, as well as in lodynia. In the first study, which compared sexuality outcomes, pain‐related thoughts, vestibulectomy, electromyographic biofeed- anxiety, and depressive symptoms for both back, and cognitive behavioral therapy, members of the couple, in addition to high intent‐to‐treat analyses indicated that partici- treatment satisfaction. In an effort to apply pants who took part in cognitive behavioral third generation cognitive behavioral therapy therapy reported significant improvements in interventions to provoked vestibulodynia, pain at a six‐month follow‐up, although sig- Brotto and colleagues prospectively evalu- nificantly less than vestibulectomy partici- ated a four‐session mindfulness‐based, group pants [43]. At a 2.5‐year follow‐up, their psychoeducational intervention in an uncon- ratings of pain during intercourse – the most trolled study of 85 women with provoked relevant functional outcome – were equiva- vestibulodynia [45]. Participants reported lent to those of women having undergone significant improvements from pre‐ to post‐ vestibulectomy [44]. In another study, women treatment in pain self‐efficacy, catastrophiz- with provoked vestibulodynia were randomly ing, hypervigilance, as well as sexual distress assigned to either a corticosteroid cream or and pain during gynecological examination. to group cognitive behavioral therapy for a Overall, these studies demonstrate that 290 Textbook of Female Sexual Function and Dysfunction

­individual and group psychological treat- use of acupuncture in a mixed group of ments represent empirically validated, nonin- women with vulvodynia [49]. Thirty‐six vasive, and safe therapeutic options for ­participants were randomly assigned to the provoked vestibulodynia, whereas couple acupuncture or to the wait‐list control interventions remain to be rigorously assessed ­condition. Women who took part in acu- using randomized controlled trial designs. puncture received 10 sessions, at a pace of twice weekly for five weeks. At post‐­ Predictors of Psychological treatment, relative to those in the control Treatment Outcome condition, participants in the acupuncture condition reported significantly less vulvar Very few studies to date have focused on pain and dyspareunia, as well as significantly identifying predictors of treatment outcome greater improvements in sexual function. for psychological approaches to provoked Considering that acupuncture is devoid of vestibulodynia. One randomized controlled adverse effects, additional controlled studies trial comparing cognitive behavioral therapy are warranted. to a medical management option showed that for the cognitive behavioral therapy con- Interdisciplinary Treatments dition higher levels of pretreatment fear of pain and catastrophizing predicted higher An interdisciplinary model of care is espoused pain intensity at six‐month follow‐up, by many experts in the field, as per the rec- whereas higher levels of pretreatment pain ommendations of the Fourth International self‐efficacy were associated with less pain Consultation on Sexual Medicine for the at follow‐up. Psychological factors did not treatment of vulvodynia [9]. One of the first predict sexual functioning outcomes for steps involved in achieving optimal applica- ­cognitive‐behavioral therapy in this study tion and success of this model is to educate [46]. This pattern of results suggests that patients about the interdependency of bio- such intra‐individual factors may not be the medical, cognitive, affective, behavioral, and most relevant for understanding women’s relationship factors in the onset and mainte- response to psychological interventions. nance of their pain. Advantages of this model Given that relationship factors have been may include more engaged and hopeful found to play an important role in the experi- patients and health‐care professionals, ence of sexual difficulties associated with increased coherence among the various provoked vestibulodynia, they may be more ­professionals on the treatment team, multiple meaningful predictors of sexuality outcomes dimensions of provoked vestibulodynia following treatment. It may also be fruitful to being targeted simultaneously rather than examine in future research whether they play sequentially, and higher patient treatment a role in mediating change during couple satisfaction. cognitive‐behavioral therapy. There are only two published, uncontrolled quantitative studies evaluating a multimodal Alternative Treatments approach to the treatment of provoked vesti- bulodynia, with both reporting significant When traditional treatment options fail, improvements in women’s sexual function some women turn to alternative treatments and pain [37, 38]. These multimodal treat- in an effort to relieve their pain. Two uncon- ments integrated sex therapy and physical trolled prospective pilot studies showed that therapy in a nonstandardized manner, such participants reported improvements in pain that not all participants received the same and sexuality after taking part in acupunc- combination and duration of interventions. ture and hypnosis [47, 48]. One randomized Spoelstra et al. also provided educational wait‐list controlled pilot study examined the materials, included the partner when ­possible Psychological Management of Provoked Vestibulodynia 291 and appropriate, and in some cases, per- therapy, are necessary preliminary steps on formed vestibulectomy, all in a stepwise the path to validate multimodal treatment ­fashion from what was considered to be the “least” to the “most” invasive treatments [37]. A retrospective qualitative study of 29 ­Conclusions women with vulvodynia having taken part in a multidisciplinary treatment program sug- Provoked vestibulodynia is a complex, gests that 27 reported a significant benefit, ­multifactorial pain condition that results with nine being pain free at post‐treatment in significant sexual impairment and psy- [50]. This program consisted of psychother- chological distress for afflicted women; apy, physical therapy, and dietary recom- ­preliminary evidence suggests partners suf- mendations. Another study using the same fer negative consequences as well. Studies design was conducted among 19 women involving both clinical and population‐based with vulvodynia who took part in a multi- samples have shown that many psychosocial modal treatment comprised of group cogni- factors are associated with the onset and tive behavioral therapy, physical therapy, and maintenance of provoked vestibulodynia, regular medical appointments. Results indi- including anxiety, depression, posttraumatic cated that participants reported increased stress disorder, child maltreatment, and knowledge and tools to manage their pain, other pain‐related coping styles, such as improved psychological well‐being, a sense ­catastrophizing, hypervigilance, and lower of validation and support, and an enhanced levels of self‐efficacy. Psychological interven- sense of empowerment [51]. These positive tions targeting these factors, with a view to and clinically relevant findings emphasize reducing pain and improving sexual func- the need for randomized trials aimed at eval- tion, have been shown to be efficacious. uating the efficacy of an integrated approach These interventions may need to be modu- to care, over and above the efficacy of single lated based on the clinical presentation of modalities, and including a broad range of the woman or couple. Although less well vali- outcomes. To this effect, more randomized dated, alternative treatments seem promis- controlled trials assessing the outcome of ing and warrant further study given their lack single modalities, such as pelvic floor physical of negative side effects and popular appeal.

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feelings of invalidation and isolation among therapeutic approach to provoked women with vulvodynia. Psychol Health vestibulodynia. J Sex Med. 2011;8:489. Med. 2012;17:589. 38 Backman G, Widenbrant M, Bohm‐Starke N, 28 Davis SNP, Bergeron S, Bois K, et al. et al. Combined physical and psychosexual A prospective 2‐year examination of therapy for provoked vestibulodynia – cognitive and behavioral correlates of An evaluation of a multidisciplinary provoked vestibulodynia outcomes. Clin J treatment model. J Sex Med. 2008; Pain. 2015;31:333. 45:378. 29 Khandker M, Brady SS, Vitonis AF, et al. 39 Pukall CF, Mitchell LS, Goldstein AT. The influence of depression and anxiety on Non‐medical, medical, and surgical risk of adult onset vulvodynia. J Womens approaches for the treatment of provoked Health. 2011;20:1445. vestibulodynia. Curr Sex Health Rep. 30 Iglesias‐Rios L, Harlow SD, Reed BD. 2016;8:240. Depression and posttraumatic stress 40 Bergeron S, Corsini‐Munt S, Aerts L, et al. disorder among women with vulvodynia: Female sexual pain disorders: A review of Evidence from the population‐based the literature on etiology and treatment. woman to woman health study. J Womens Curr Sex Health Rep. 2015;7:159. Health. 2015;24:557. 41 Pukall CF. Primary and secondary provoked 31 Khandker M, Brady SS, Stewart EG, et al. vestibulodynia: A review of overlapping and Is chronic stress during childhood distinct factors. Sex Med Rev. 2016;4:36. associated with adult‐onset vulvodynia? 42 Heddini U, Bohm‐Starke N, Nilsson K, et al. J Womens Health. 2014;23:649. Provoked vestibulodynia – Medical factors 32 Harlow B, Stewart EG. Adult‐onset and comorbidity associated with treatment vulvodynia in relation to childhood outcome. J Sex Med. 2012;9:1400. violence victimization. Am J Epidemiol. 43 Bergeron S, Binik YM, Khalifé S, et al. 2005;161:871. A randomized comparison of group 33 Leclerc B, Bergeron S, Binik Y, et al. cognitive‐behavioral therapy, surface History of sexual and physical abuse in electromyographic biofeedback, and women with dyspareunia: Association with vestibulectomy in the treatment of pain, psychosocial adjustment, and sexual dyspareunia resulting from vulvar functioning. J Sex Med. 2010;7:971. vestibulitis. Pain. 2001;91:297. 34 Corsini‐Munt S, Bergeron S, Rosen NO, 44 Bergeron S, Khalife S, Glazer H, et al. et al. A dyadic perspective on childhood Surgical and behavioral treatments for maltreatment for women with provoked vestibulodynia – Two‐and‐one‐half‐year vestibulodynia and their partners: follow‐up and predictors of outcome. associations with pain and sexual and Obstet Gynecol. 2008;111:159. psychosocial functioning. J Sex Res. 45 Brotto LA, Basson R, Smith KB, et al. 2017;54(3):308. Mindfulness‐based group therapy for 35 King M, Rubin R, Goldstein AT. Current women with provoked vestibulodynia. uses of surgery in the treatment of genital Mindfulness. 2015;6:417. pain. Curr Sex Health Rep. 2014;6:252. 46 Desrochers G, Bergeron S, Khalifé S, et al. 36 Goldstein A, Klingman D, Christopher K, Provoked vestibulodynia: Psychological et al. Surgical treatment of vulvar predictors of topical and cognitive‐ vestibulitis syndrome: Outcome behavioral treatment outcome. Behav Res assessment derived from a postoperative Ther. 2010;48:106. questionnaire. J Sex Med. 2006;3:923. 47 Curran S, Brotto L, Fisher H, et al. The 37 Spoelstra SK, Dijkstra JR, van el MF, et al. ACTIV study: Acupuncture treatment in Long‐term results of an individualized, provoked vestibulodynia. J Sex Med. multifaceted, and multidisciplinary 2010;7:981. 294 Textbook of Female Sexual Function and Dysfunction

48 Pukall C, Kandyba K, Amsel R, et al. 50 Munday P, Buchan A, Ravenhill G, et al. Effectiveness of hypnosis for the treatment of A qualitative study of women with vulvar vestibulitis syndrome: A preliminary vulvodynia II. Response to a multidisciplinary investigation. J Sex Med. 2007;4:417. approach to management. J Reprod Med. 49 Schlaeger JM, Xu N, Mejta CL, et al. 2007;52:19. Acupuncture for the treatment of 51 Brotto LA, Yong P, Smith KB, et al. Impact vulvodynia: A randomized wait‐list of a multidisciplinary vulvodynia program controlled pilot study. J Sex Med. on sexual functioning and dyspareunia. 2015;12:1019. J Sex Med. 2015;12:238. 295

21

Musculoskeletal Management of Pelvic and Sexual Pain Disorders Sara K. Sauder, Fiona McMahon, and Amy Stein

Abstract

The ideal candidate for pelvic floor physical therapy intervention is the patient who has musculo- skeletal dysfunction or has been treated by her clinician for pathology but has not experienced pain resolution. The pathophysiology of pelvic floor dysfunction involves disruption to the functional anatomy of the pelvic floor and can be the primary or secondary cause of a range of painful ­conditions. Pelvic floor physical therapists are important and often essential members of the ­medical team caring for women with sexual pain. Keywords: pelvic floor physical therapy; pelvic floor muscle dysfunction; manual therapy; ­biofeedback; vulvar pain; sexual pain; vulvodynia; sexual dysfunction; women’s health physical therapy; vestibulodynia; dyspareunia; pelvic floor muscles

Ideal candidates for pelvic floor physical therapy referral are pelvic pain patients with musculoskeletal dysfunction or those who have been treated by clinicians for pelvic pathology but have not experienced symptom resolution. The pathophysiology of pelvic floor dysfunction involves impairment in the functional anatomy of the pelvic floor, which can be the primary or secondary cause of a wide range of painful conditions. Dysfunction in the myofascial system can result in painful myofascial trigger points and shortened tissues throughout the body, including the pelvic floor. Neural tension, entrapment between structures, or mechanical pressure on nerves can create acute and chronic pain preventing optimal pelvic floor function.

­Introduction pelvic musculoskeletal disorders contributes to this gap in care [4]. Undiagnosed musculo- Approximately 50% of all American adults skeletal pain can lead to comorbidities that are currently affected by painful musculo- may make diagnosis and treatment difficult. skeletal diseases, disorders, or injuries [1]. Physical therapists (physiotherapists) spe- Furthermore, the musculoskeletal system cialize in the assessment and treatment of may contribute to a majority of chronic pel- functional deficits of the musculoskeletal sys- vic and sexual pain symptoms [2, 3]. Over tem. The purpose of physical therapy interven- half of the estimated 10 million women with tion is to return patients to optimal function. sexual pain go without proper diagnosis or Treatment goals are determined by both the adequate treatment. It is likely that the lack patient and the physical therapist in order to of recognition by medical professionals of meet the patient’s specific needs and goals.

Textbook of Female Sexual Function and Dysfunction: Diagnosis and Treatment, First Edition. Edited by Irwin Goldstein, Anita H. Clayton, Andrew T. Goldstein, Noel N. Kim, and Sheryl A. Kingsberg. © 2018 John Wiley & Sons Ltd. Published 2018 by John Wiley & Sons Ltd. 296 Textbook of Female Sexual Function and Dysfunction

For example, penetrative sexual intercourse Physical therapy begins with a detailed his- may be an endpoint for one patient but not tory of a woman’s bowel, bladder, and sexual another. function along with the details of any epi- Specifically, pelvic floor physical therapists sodes of pain. The physical therapist deter- focus on structural impairments of the spine, mines the possible underlying neural and sacrum, hips, pelvis, pelvic floor muscles, musculoskeletal factors contributing to a connective tissue and nerves. Functional def- patient’s pain, as this informs the objective icits may include difficulty with sitting, assessment. For example, if the physical ther- standing, or walking; pain or difficulty with apist hypothesizes that the spine is involved, sexual activity; and difficulty with bowel and then this might be one of the first areas to be bladder function. The personal and sensitive examined. Similarly, if the pelvic floor mus- nature of these complaints, as well as a cles are likely driving the patient’s symptoms, patient’s uncertainty as to the cause of her then the therapist will prioritize a pelvic floor symptoms, can make it uncomfortable for examination. The evaluation is mainly her to engage in frank discussions with her ­performed at the first appointment; however, providers. This hesitancy may lead to a delay components of the evaluation are likely in seeking appropriate care, which may, in to extend throughout several follow‐up turn, cause an acute dysfunction to progress appointments. Classically, the physical thera- to a chronic problem. pist assesses and treats at the same time. Ideal candidates for pelvic floor physical Depending on the diagnosis, pelvic floor therapy referral are patients with pelvic treatments may last only a few sessions or, for floor musculoskeletal dysfunction or those complex symptoms or impairments, they who have been treated by clinicians for may continue a year or more. Some diagno- ­pelvic pathology but have not experienced ses, such as stress incontinence and some symptom resolution. Clinicians can identify types of dyspareunia, do not require more appropriate patients by palpating the vulva, than a few treatments. Treatment of sexual performing a digital examination of the dysfunction, urogenital or pelvic pain, how- ­vaginal and rectal muscles, and performing ever, may be quite involved and resolution of a moist cotton swab test on the vestibule. symptoms may take months or even years. If the patient reports reproduction of any Despite this, in some cases physical therapy of her sexual pain symptoms with this exami- can be the most effective means of managing nation, she is likely affected by pelvic floor pain over the long term, with the least risk for dysfunction [5]. Box 21.1 details the recom- adverse side effects. mended components of a pelvic floor muscle screening examination. ­Pelvic Floor Anatomy

Box 21.1 Nantes criteria for the diagnosis Pelvic floor physical therapists evaluate of pudendal neuralgia. from the head to the toes, but pay special attention to the area between the diaphragm ●● Pain in the area innervated by the pudendal and knees. Within this area are the spine, nerve extending from anus to clitoris. pelvic bones, hips, pelvic floor muscles, ●● Pain is more severe when sitting. connective tissue, pelvic nerves, and pelvic ●● Pain does not awaken patients from sleep. organs. The pelvic floor muscles form a ●● Pain with no objective sensory impairment sling laterally from one hip joint to the other ●● Pain relieved by diagnostic pudendal and anteriorly to posteriorly from pubic block. symphysis to the sacrum and coccyx From Labat JJ [12]. (Figure 21.1) Pelvic floor integrity is main- tained by proper skeletal alignment and the Musculoskeletal Management of Pelvic and Sexual Pain Disorders 297

Colon Abdominal Sacrum muscles Ovary

Uterus Rectum Bladder Coccyx bone Pelvic bone

Cervix Urethra Vagina Levator ani Urethral muscle sphincter Anus muscle Pelvic floor Labia majora muscles

Figure 21.1 Female urogenital system – mid‐sagittal section. Used with permission from Amy Stein, DPT, BCB‐PMD, Heal Pelvic Pain. New York: McGraw‐Hill; 2009 [83]. coordinated actions of pelvic floor muscles, internus can contribute to pain with sitting, urethral and anal sphincters, lumbosacral dyspareunia, and constipation. Spasm of plexus, ligaments, and connective tissues the coccygeus and piriformis may mimic (also called the endopelvic fascia) [6]. coccyx pain with sitting and sexual activity Striated muscles, connective tissue, and (Figure 21.3). Additionally, overactivity in ligaments provide mechanical support for muscles surrounding the urethra can create pelvic organs. Pelvic floor muscles are made urethral discomfort, dysuria, and incomplete of Type 1 slow twitch and Type 2 fast twitch bladder voiding [9]. skeletal fibers [7]. This multimodal pelvic The pelvic floor muscles are primarily floor musculature assists with core stability innervated by the pudendal nerve. This is the and closure of the urogenital hiatus and is only nerve in the pelvic area that has motor, responsible for voluntary control of bowel, sensory and autonomic functions. The bladder, and sexual functions. pudendal nerve has three branches: the dor- The individual pelvic floor muscles have sal clitoral, posterior labial (perineal), and unique clinical characteristics that the pelvic inferior rectal. These branches provide sen- floor physical therapist considers. For exam- sory, motor, and sympathetic innervation to ple, the ischiocavernosus and bulbospongio- the vulva and vagina. Injury to the entire sus can cause urinary urgency and frequency nerve or any of its branches may result in uro- that may create distress and reduce interest genital pain, dyspareunia, and female genital in intimacy (Figure 21.2) [8]. The transverse arousal disorder. In addition, because of the perinei muscles are the site of most episioto- autonomic functions of the nerve, the patient mies and/or tearing during vaginal delivery. may experience autonomic symptoms of Even after the trauma has healed these increased heart rate and blood pressure, ­muscles may develop significant scarring digestive difficulties leading to bloating, diar- that can impede muscle expansion and cause rhea and constipation, urinary symptoms of pain with penetration. With overactivity incomplete emptying and difficulty initi­ ating, or myofascial trigger points, the obturator and sexual function problems with orgasm 298 Textbook of Female Sexual Function and Dysfunction

Clitoris

Urethra Ischiocavernosus

Vagina Bulbocavernosus

Vestibule Transversus Perineal body perineum

Anus Levator ani: Pubococcygeus Anal sphincter Iliococcygeus Gluteus maximus Coccyx bone

Figure 21.2 Female pelvic floor anatomy. Used with permission from Amy Stein, DPT, BCB‐PMD, Heal Pelvic Pain. New York: McGraw‐Hill; 2009 [83].

Piriformis muscle Sacrum

Obturator internus

Coccygeus muscle

Coccyx bone

Pelvic bone

Anal canal Levator ani muscle

Figure 21.3 Coccygeus, piriformis, and obturator internus muscles. Used with permission from Amy Stein, DPT, BCB‐PMD, Heal Pelvic Pain. New York: McGraw‐Hill; 2009 [83].

and lubrication [10, 11]. Pudendal nerve pain also contribute to pelvic and sexual pain [13]. is often referred to as pudendal neuralgia, These nerves include the ilioinguinal, iliohy- which is currently defined by the Nantes cri- pogastric, genitofemoral, and post­erior and teria (Box 21.1) [12]. Injuries to other nerves lateral femoral cutaneous nerves. Careful Musculoskeletal Management of Pelvic and Sexual Pain Disorders 299

Obturator n. Lateral femoral n. Genitofemoral Genital br. Anterior femoral n. nerve Femoral br. Iliohypogastric n. Dorsal br. Pudendal Ilioinguinal n. nerve Perineal br. Inferior (rectal) br. Perineal br. Posterior femoral cutaneous nerve Thigh br. Inferior cluneal br.

Figure 21.4 Cutaneous nerves of the vulva, thigh, and groin. Used with permission from A. Lee Dellon, MD, PhD, from www.Dellon.com. (See plate section for color representation of the figure) assessment of the sensory distributions of Damage or an insult to the pelvic floor may these nerves is important for effective treat- injure the connective tissue or fascia, which ment of pelvic pain syndromes (Figure 21.4). then may become a primary or a secondary Connective tissue is a key component of contributor to pelvic and sexual pain disor- the pelvic floor and covers its structures. It is ders, ranging from mild to significant in composed primarily of collagen and elastin. severity [16]. The collagen provides tensile strength, while the elastin provides flexibility [14]. More than 12 types of collagen have been identi- ­Pathophysiology fied in the human body [15]. The main struc- of Sexual Pain tural components of pelvic connective tissue are Type I and Type III collagen. Type 1 is The pathophysiology of pelvic floor dysfunc- strong and organized into large fibers; Type tion involves impairment in the functional III collagen is randomly organized branched anatomy of the pelvic floor. This can be the fibers and is found in flexible fascia. Fascia is primary or secondary cause of a range of a type of connective tissue that is found painful conditions. Any process that interrupts throughout the abdominopelvic region. the integrity of pelvic neuromusculoskeletal 300 Textbook of Female Sexual Function and Dysfunction

or connective tissue can result in dysfunction Myofascial system dysfunction has been of the bowel, bladder, and sexual activity, or shown to be an important contributor to pel- problems with core stability or abdominopel- vic pain; up to 78% of women with chronic vic organ support and function. Pelvic floor pelvic pain may suffer from some form of impairments leading to sexual pain include myofascial dysfunction [3]. overactive pelvic floor muscles, skeletal Prolonged pelvic floor muscle contraction abnormalities, myofascial restrictions, and due to habit or lack of awareness can also inflammation. Neuromuscu­loskeletal cause myofascial trigger points and restric- impairments cause somatosensory stimula- tions. Detrimental holding patterns may also tion that may result in inhibition or excita- be secondary to painful or noxious stimuli tion of visceral functions; this effect is called from various pelvic disorders, such as vulvo- the somatovisceral reflex. This reflex can dynia, vestibulodynia, persistent genital cause diffuse pain throughout the pelvis and arousal disorder, bladder pain syndrome, can contribute to dyspareunia. irritable bowel syndrome, and incontinence The cause of overactive pelvic floor [23]. These conditions contribute to muscle ­muscles is not always clear. Due to the overactivity because of muscle guarding, ­physiology and biomechanics of the lum- shortening of skeletal sarcomeres and con- bosacropelvic region, muscle overactivity nective tissue, reduction in the mobility and may result from chronic straining, poor pos- range of motion of nerves, decreased blood tures in the sitting, standing, or toileting flow, decreased tissue perfusion, and the positions, dysfunctional gait patterns, previ- development of myofascial trigger points ous sexual or physical abuse, or harmful [24, 25]. In turn, pelvic floor muscle overac- repetitive movements from a sport or tivity can cause or contribute to pain in these work activity. Overactive pelvic floor mus- disorders. cles may also result from childbirth injuries, Muscle and connective tissue abnormali- infection, a traumatic event, cancer‐related ties and myofascial trigger points result in treatments, and abdominal or pelvic surgery. localized, referred, or radiating pain and ten- Autoimmune disorders and inflammatory derness [26]. As a result, the affected areas conditions, including fibromyalgia, ulcera- exhibit increased restrictions and decreased tive colitis, interstitial cystitis, inflammatory mobility, which further perpetuate the pain bowel disorders, and endometriosis, can also cycle. Common areas of myofascial pain and contribute to pelvic floor muscle overactivity trigger points are in the back, thigh, gluteal, [7, 17, 18]. Regardless of the initial insult, dis- abdominal, and pelvic floor muscles. Altered ruption of appropriate movement patterns connective tissue tension may result in tis- results in dysfunctional modifications of sue hypoxia leading to sensations of burn- the pelvic floor musculature and connective, ing, itching, tingling, cold, shooting, and/or visceral, and neural tissues [19–21]. sharp pain [20, 27, 28]. Additionally, overac- Biomechanical abnormalities due to mus- tive pelvic floor muscles cause decreased culoskeletal causes, such as scarring and blood flow through both muscle and mucosa, adhesions, skeletal misalignment, tissue leading to hypoxia and excessive lactic acid lengthening or shortening, and muscular production. asymmetry, may be the primary cause of Chronic muscle overactivity can also affect myofascial trigger points, shortened myo‐sar- the pannicular layer of fascia by limiting its comeres and connective, visceral, and neural mobility, creating pain with small move- restrictions from reduced range of motion ments. Fascia is sensitive due to its innerva- [20]. Myofascial trigger points are hyperirri- tion and vascular supply. Fascial restrictions table points or nodules in skeletal muscle secondary to surgical trauma, limited muscle that possess high levels of inflammatory expansion, or scarring may limit movement mediators and sensitized nociceptors [22]. that can lead to pain. Restrictions of the Musculoskeletal Management of Pelvic and Sexual Pain Disorders 301 deepest layer of fascia, the visceral layer, can An extensive discussion of this topic is given create widespread abdominopelvic pain and/ in Chapter 22. Specifically, decreased levels of or ambiguous or difficult to reproduce pain. estrogen and testosterone in the pelvic tissues An assessment of the fascial layers is per- may increase pain by causing epidermal formed in a physical therapy examination to ­thinning, leading to reduced pliability, tear- determine if there is a visceral component to ing, inflammation, and infection. It is impor- a patient’s sexual pain [29]. tant for the pelvic floor physical therapist to Decreased mobility of the pelvic viscera recognize these findings and communicate due to adhesions and fascial restrictions may them to the appropriate medical professional result in pain or altered function of the organ on the patient’s team. Additionally, recogni- itself, as well as spasms in adjacent muscular tion of hormonal changes affecting the tissue that further perpetuate the pain. The ­vulvovaginal tissues helps the therapist better body may also perform compensatory move- qualify expectations and prognosis when ments to accommodate a reduced range of counseling the patient. motion in a restricted organ system, exacer- bating or creating additional musculoskeletal dysfunction [30]. Inflammatory visceral ­Musculoskeletal Evaluation conditions can cause viscerosomatic reflexes that trigger visceral and nociceptive afferent The authors believe that examining the neurons that contribute to myospasticity and external and internal pelvic neuromusculo- palpable pelvic tissue texture changes [28]. skeletal structures and the pelvic floor is a The result is somatic dysfunction and poten- necessary component of a routine pelvic tial nervous system upregulation [31, 32]. examination. Box 21.2 summarizes a mini- An upregulated nervous system, including mal screening examination for nonphysical central and peripheral sensitization, is com- therapists. A musculoskeletal evaluation is mon in patients with chronic pelvic and especially recommended prior to a diagnos- ­sexual pain. Central sensitization results tic laparoscopy or hysterectomy in patients from changes in the brain and spinal cord undergoing these procedures for chronic pel- related to an increase in nociceptive sensitiv- vic pain of unknown cause [4, 35]. In a recent ity. These changes can be captured through study of almost 4000 women who had hyster- electrophysiological and imaging techniques. ectomies for chronic pelvic pain, fewer than Increases in excitability of the synaptic neu- 25% had endometriosis at the time of surgery. rons in central nociceptive pathways result in In those with a preoperative diagnosis of hypersensitivity, hyperalgesia, and allodynia endometriosis, almost half did not actually [33]. Peripheral sensitization is a form of have endometriosis at surgery [36]. In those functional plasticity of the nociceptor and patients without a clear surgical explanation results in increased sensitivity of peripheral for their pelvic pain, musculoskeletal causes nerve endings. The nociceptor becomes may not have been adequately assessed hypersensitive because the action potential pre‐operatively, resulting in a treatment of impaired nerve endings is decreased; intervention that was likely to be inappropri- therefore, a smaller stimulus is able to initiate ate and ineffective. a pain signal. Both of these types of upregula- A pelvic floor physical therapist’s evalua- tion of the nervous system may contribute to tion begins with an extensive subjective his- provoked and unprovoked sexual pain. tory taking, focusing on the patient’s past and Hormonal deficiencies are a common cause current pain symptoms, as well as bowel, of sexual pain in women of all ages. Any phar- bladder, and sexual function. It is imperative maceutical agent or endocrine disorder that to uncover not just the current pain symp- affects local sex hormone levels has the toms but also the symptoms present when potential to create vulvovaginal pain [34]. sexual dysfunction began. The physical 302 Textbook of Female Sexual Function and Dysfunction

Box 21.2 Minimal screening pelvic floor neuromuscular examination for nonphysical therapists.

Specific attention vaginally and/or rectally to ●● levator ani muscles evaluate muscles for: ●● obturator internus muscles ●● ischial spine, for Tinel’s sign at pudendal ●● visible surface scarring nerve ●● tenderness ●● ilio‐inguinal, ilio‐hypogastric and gen- ●● tension: high, low, normal itofemoral nerves at lower abdomen ●● ability of patient to consciously release ●● sacroiliac joints tight muscles ●● lumbosacral spine ●● tight muscle or connective tissue bands ●● pubic symphysis ●● symmetry, hypertrophy, or atrophy. ●● groin Structures to include in evaluation: ●● observation of gait that may be abnormal with hip disorders. ●● superficial vulvar muscles ●● anal sphincter

­therapist must ask questions that may ini- symmetry to be sure that the muscles have tially appear unrelated to a patient’s pain appropriate and balanced tension to allow for complaints. Determining bladder and bowel optimal function. Improper pull of pelvic health status in a woman with sexual dys- musculature secondary to pelvic obliquities function is necessary because the pelvic floor will irritate nerves and affect blood and lym- muscles, connective tissue, vasculature, phatic vessels that, in turn, can create pain ­lymphatics and blood flow that are essential symptoms. for normal sexual function also affect the Inadequate hip range of motion, labral bladder and bowels. Additionally, obtaining a tears, or improper glide or impingement of history of any injuries is crucial to assist in the greater trochanter in the acetabulum may determining if, for instance, a hernia or hip cause pelvic and sexual pain symptoms that labral tear could be contributing to a wom- seem unrelated to the actual hip joint; thus an’s sexual pain complaints. Box 21.3 shows the hip needs to be specifically assessed [37]. recommended questions to include in a Without a proper hip range of motion and physical therapy evaluation. joint stabilization, other muscle groups A thorough neuromusculoskeletal exami- attempt to compensate [38]. This may lead to nation is then performed to determine if muscle overactivity in the pelvic floor, which there are one or more underlying impair- may cause sexual dysfunction and sexual ments causing the symptoms of sexual pain. pain complaints. This examination includes assessment of the Nerves are assessed via spinal joint mobili- bony alignment of the spine, pelvis, and hips zation, palpation, neural tensioning, and body in addition to assessment of muscles, con- mapping. The pelvic floor physical therapist nective tissues, and nerves. Muscle function determines if the source of nerve pain is at the is assessed through examination of length, spine by mobilizing spinal joints. The open- tension, strength, endurance, and coordina- ing or closing of a spinal facet joint during tion. The primary muscles evaluated are the flexion or extension can create pain along the pelvic floor, hip, and core muscles, with distal distribution of a nerve [39]. Additionally, other muscle groups examined as needed. gentle percussion of a nerve is informative if it An assessment of the fascial layers is also reproduces a patient’s pain; this is a positive performed. Pelvic alignment is assessed for Tinel’s sign [40]. Neural tension testing Musculoskeletal Management of Pelvic and Sexual Pain Disorders 303

Box 21.3 Physical therapy evaluation questions. 1) Do you have any urinary or fecal inconti- 12) How do you cleanse your vulvovaginal nence or difficulty controlling flatulence? area? 2) Do you have strong urinary or fecal urges? 13) Have you had a hysterectomy or any 3) Do triggers like running water or getting other abdominopelvic surgery? home from being out give you a sudden, 14) Are your ovaries intact? intense urge to urinate? 15) When did your discomfort begin? Is it 4) When your urine/stool flow stops, does it intermittent or constant? feel as if your bladder/bowel is empty? 16) If you were once able to orgasm, can you 5) Does your urine flow straight into the orgasm now? What stimulates an orgasm ­toilet, curve to the side or does it hit your for you? thigh or anus? 17) Is your discomfort constant? 6) How frequently do you urinate during the 18) What makes your discomfort better? Worse? day? Night? 19) What is the lowest your discomfort gets 7) Is urination or defecation uncomfortable on a scale of 1/10? What is the highest or painful? your discomfort gets on a scale of 1/10? 8) Do you have any vulvovaginal or anal 20) Do you think you will be able to resolve itching or burning? this discomfort? 9) With sexual activity, do you have pain at 21) What do you think is going on? penetration, deep pain or postorgasmic 22) Does stress change your discomfort? pain? 23) What medications are you taking? Any 10) Do you have or have you had painful hormonal contraception or hormonal ­periods? When did it start and has it therapy? ­gotten better or worse? 24) Have you had an injury to your back, hip, 11) Touch where your discomfort is. Does it or pelvis? What sports have you partici- change? pated in? involves placing a specific nerve into a state of examination between the labia, and assess- tension to see if this reproduces a patient’s ment of the vestibule for pain, allodynia, pain complaint [41]. The nerve is then placed and inflammation. The physical therapist in a position of laxity via movement of a distal may consult with dermatology, gynecology, component, such as the head or foot, to assess or urology colleagues if there are signs of whether the pain is reduced. This helps the pathology. therapist distinguish between either the mus- With patient consent, the therapist then cle or the nerve as the source of the pain. performs an internal examination of the Body mapping is a helpful means of assessing vagina and/or the rectum, depending on the if a sexual pain runs along the course of a patient’s subjective history and complaints. nerve [40]. The therapist compares the pain The internal assessment allows the physical distribution to a dermatomal map to identify therapist to determine the health of the vagi- which nerves or spinal levels need to be nal tissue and pelvic floor muscles [4, 20]. addressed. Figure 21.4 shows cutaneous The therapist determines if the vaginal walls nerves of the vulva, thigh, and groin. are supple and well lubricated or nonpliable, The pelvic floor physical therapist per- dry, and friable. Muscle tone and mobility is forms a brief vulvar screening examination in determined via gentle digital pressure into order to rule out intrinsic vulvar pathology. each muscle and gentle gliding across muscle This includes retraction of the clitoral pre- fibers. The therapist assesses if the muscles puce to assess for phimosis, separation and are tense or lax and determines the presence 304 Textbook of Female Sexual Function and Dysfunction

or absence of discrete trigger points and ten- vulvodynia had significant improvement in der points within specific muscles of the pel- sexual pleasure and reduced pain with inter- vic floor. As the patient bears down, the course following physical therapy interven- therapist evaluates the anterior, posterior, tions or vulvar desensitization exercises in and lateral vaginal walls for laxity and the combination with cognitive behavioral ther- likelihood of pelvic organ prolapse, and apy [47, 48]. Additional research supporting assesses whether the patient is able to con- the use of pelvic floor physical therapy for tract, relax, and lengthen the pelvic floor. the treatment of pelvic and sexual pain shows The therapist also determines if a patient’s significant improvement in sexual function, pain complaint is reproducible. As men- anxiety, and pain intensity during intercourse tioned previously, the pelvic floor muscles [7, 44, 49–51]. Moreover, pelvic floor physi- are capable of producing symptoms that cal therapy is recommended by experts for mimic those from an organ or different area the treatment of vulvodynia and interstitial of the body. Without proper palpation, this cystitis/painful bladder syndrome [52–54]. important information would be missed. Physical therapy intervention for the dys- functional pelvic floor incorporates a com- prehensive approach addressing specific ­Physical Therapy Treatment tissue characteristics, strength, alignment, of Pelvic and Sexual Pain and neuromuscular control. Manual therapy is a hands‐on approach to correct tissue Disorders restrictions, improve alignment, and enhance blood flow. Different manual techniques may Evidence‐based literature supporting the be used to achieve different objectives. The effectiveness of pelvic floor physical therapy manual physical therapy techniques covered for pelvic and sexual pain disorders is stead- in this chapter are myofascial release, joint ily increasing. Like research on other hands‐ mobilization, neural mobilization, scar on therapeutic modalities, studies have been ­tissue mobilization, visceral manipulation, hindered by the challenge of creating stand- and vestibule desensitization. Nonmanual ardized treatment regimens and appropriate techniques discussed include behavioral control and sham physical therapy groups. modifications, stress and anxiety manage- Despite this, emerging research has demon- ment, exercise training, breathing practice, strated the benefit of physical therapy in and bowel and bladder retraining. Adjunctive ­various pain syndromes, such as chronic low physical therapy modalities are also reviewed. back pain and fibromyalgia, as well as pelvic floor dysfunction [42–44]. Research studies and expert opinion ­Physical Therapy Treatment ­support the efficacy of physical therapy Techniques interventions for pelvic and sexual pain. In a study conducted by Anderson and col- Myofascial Release and Trigger leagues, participants significantly reduced Point Release their use of pain medication over baseline following instruction in a self‐trigger point As referenced in the pathophysiology sec- release protocol using a therapeutic wand tion, myofascial and connective tissue [45]. Additionally, Gentilcore‐Saulnier dem- restrictions and myofascial trigger points are onstrated that pelvic floor physical therapy common findings in pelvic and sexual pain improved pelvic floor muscle control disorders. Therefore, it is essential to address in women with pelvic pain symptoms [46]. these findings as a first line of physical ther- In other studies, participants with provoked apy treatment. The myofascia is a system of Musculoskeletal Management of Pelvic and Sexual Pain Disorders 305 connective tissue that envelops all of the sympathetic activity as measured by changes body’s muscles and bones. Dysfunction in in heart rate, skin conductance, and blood this system can result in painful myofascial pressure [60]. trigger points and shortened tissues ­throughout the body, including the pelvic Neural Mobilization floor. The physical therapist identifies restric- tions and trigger points by palpating for a Several nerves provide sensory innervation local twitch response, for changes in myofas- to the pelvic floor, with the pudendal nerve cial tissue mobility, for tenderness and/or for providing autonomic, motor, and sensory referring pain. The myofascial release tech- innervation. In order to avoid irritation, nique involves finding restrictions or lack of nerves require adequate mobility through movement in tissues and then applying surrounding anatomical structures. Neural ­gentle pressure and stretch to these tissues. tension (the reduction in nerve mobility), Myofascial trigger point release uses com- entrapment between structures, or mechani- pression on the tender area or nodule and cal pressure on nerves can create acute and applying a sustained hold into the superficial chronic pain that prevent optimal function of or deep musculature. Both techniques assist the pelvic floor. Treating the mechanical in normalizing tissue mobility and the length‐ causes of neural tension is an objective of tension ratio of the sarcomeres [55, 56]. neural mobilization [61]. The physical thera- pist also treats the surrounding tissue to clear Joint Mobilization restrictions and ensure adequate blood flow to the nerve. In cases of pelvic floor dysfunction, it is important to assess the range of motion in Scar Tissue Mobilization the joints of the spine, sacroiliac joints, and hips. Dysfunction in these joints can perpet- Scars within the pelvic and abdominal region uate dysfunction within the pelvic floor [57]. may cause pain by preventing the proper Joint mobilization is indicated when there is movement of the pelvic and abdominal pain or lack of motion at a joint. The physical ­viscera, muscles, nerves, and fascia. Scar therapist distinguishes between physiologic mobilization requires gentle movement of the motion of the joint and accessory motion of scar to prevent and treat adhesions both at the joint. Physiologic motion is the grossly the surface and in deeper layers of the tissue observable motion of the joint; an example is [62]. Care is taken to avoid placing pressure flexion of the hip joint. Accessory motion is directly on top of the scar during the prolif- the motion of the joint surfaces in relation- erative phase of healing, so as to not stimulate ship to one another. In the example of hip the development of keloid scar tissue. flexion, the accessory motion is the down- ward glide of the femoral head relative to the Visceral Manipulation acetabulum. To improve range of movement, the therapist treats a restricted accessory Visceral manipulation restores an organ’s motion to enhance the physiologic motion of ­ability to glide freely among adjacent struc- the joint [58]. In a meta‐analysis, Hing tures in order to reduce pain and improve showed that joint mobilization with move- function. The research of Jean‐Pierre Barral ment techniques is effective in decreasing suggests that visceral manipulation may pain in addition to increasing limb strength increase local serotonin, activity of smooth and range of motion of joints [59]. Joint muscle, and local tissue metabolism [30]. Due mobilization has also been shown to act on to the complex interaction of the pelvic organs the sympathetic nervous system, reducing and pelvic muscles, visceral manipulation has 306 Textbook of Female Sexual Function and Dysfunction

the potential to offer profound relief to Working to remedy these dysfunctions is a patients with pelvic floor dysfunction [63]. In key goal in the treatment of pelvic floor a 2007 study, visceral manipulation signifi- dysfunction. cantly improved sexual function and quality of Bowel and bladder retraining techniques life in women experiencing vulvodynia [64]. encompass education and behavior ­modification to reduce urge and frequency. Vestibule Desensitization In addition to manual interventions, patients with bowel and bladder frequency are taught Vestibule desensitization is a process in to gradually increase their intervoid interval. which the patient is presented with increas- Therapists may teach interventions that help ing mechanical pressure to the vestibule in calm bowel and bladder urge, such as mental order to increase the mechanical pain thresh- distraction, diaphragmatic breathing, and old. This allows her to experience ­vestibule quick pelvic floor contractions. palpation outside of the sexual experience. With this intervention, anxiety and fear that Exercise Training might come with intimacy are removed. This allows the patient to experience a potentially Exercise improves mood and builds confi- noxious stimulus without the expectation of dence and self‐efficacy in women living penetration. A stimulus is first provided via with chronic pelvic pain [67]. Physical thera- gentle vestibule pressure with a moist cotton pists evaluate their patients’ current physical swab. As the patient accommodates to this abilities and tolerances in order to create an mechanical input, it is no longer painful. effective and safe exercise plan. Exercise She can then progress towards increased can retrain faulty movement patterns and pressure at the vestibule and the vagina. strengthen weak muscles, which can improve Cognitive behavioral therapy is an adjunct the stability of the pelvic girdle. in the process of vulvar desensitization. It can help women manage fear of and response Breathing Practices to pain. In a 2015 study, the use of vulvar desensitization techniques in combination Breathing practice is a vital component of with cognitive behavioral therapy produced pelvic and sexual pain rehabilitation. Deep significant improvement in the McCoy diaphragmatic breaths facilitate mobilization Female Sexuality Questionnaire, sexual of the pelvic and abdominal contents and can pleasure, and vaginal lubrication [48]. reduce the anxiety experienced by many patients. Additionally, it is a tool to minimize Bowel and Bladder Retraining pain [68, 69]. Physical therapists may work closely with mind–body practice instructors Pelvic floor muscle dysfunction can cause as patients may gain additional pain reduc- difficulty with bowel and bladder voiding, tion benefits from therapies focusing on resulting in urgency, frequency, the sensation ­controlled breathing such as yoga, tai chi, qi of incomplete emptying, postvoid dribbling, gong, and meditation [70]. and incontinence [65, 66]. In the authors’ experience, patients may engage in habits such as “just in case voiding”, which can ­Adjunctive Modalities ­contribute to urgency and frequency and interfere with relaxed, pleasurable sexual Many modalities can be used as adjuncts to activity. In addition, women with pelvic floor the manual, strengthening, and neuromus- muscle overactivity may have difficulty with cular interventions employed by pelvic floor bowel function, leading to constipation, physical therapists. They can aid in pain bloating, constipation, anal fissures, and reduction, strengthening, and muscular the feeling of incomplete evacuation [41]. coordination. In the authors’ opinion, these Musculoskeletal Management of Pelvic and Sexual Pain Disorders 307 modalities should not, however, be the sole Women affected by cancer may have interventions employed for patients with ­anatomic alterations in their vagina and sur- ­pelvic floor dysfunction. rounding myofascia due to surgery and/or pelvic radiation therapy; these changes often Biofeedback cause sexual pain and interfere with sexual function [37]. Vaginal dilators help to Biofeedback allows the patient to assess the ­maintain or regain vaginal length and capac- activity of her muscles in real time. ity. Success with these tools, especially in Electromyography (EMG) biofeedback is irradiated patients, may be higher with the commonly used to display the activity of help of a pelvic floor physical therapist. muscles with digital feedback using a visual Pelvic floor physical therapists may pre- or auditory medium. Biofeedback can help scribe the use of dilators and wands in vari- patients learn when they are effectively per- ous ways for different functions. A patient forming pelvic floor muscle activation or with deep layer trigger points in muscles relaxation, thereby allowing them to break such as the coccygeus and obturator internus the cycle of pain and reactive spasm [71]. In may benefit from sigmoid shaped pelvic cases where pelvic floor muscle strength wands, which allow her to more easily reach should be increased, biofeedback can give trigger points and myofascial restrictions the patient feedback on the quality of their deep within the pelvic bowl. active pelvic floor muscle contractions. Whether a patient needs strengthening or Ultrasound relaxation, it is the authors’ experience that she must have enough myofascial mobility to Ultrasound uses low frequency and intensity perform contraction and relaxation of the sound waves to generate thermal effects in pelvic floor. Poor myofascial mobility may treated tissue. The effects of ultrasound may prevent her from successfully using biofeed- improve blood flow and stimulate healing. back and increase her frustration. Currently, the available research shows con- flicting evidence on the effectiveness of ultra- Vaginal Dilator and Wand use sound in the treatment of musculoskeletal pain disorders [72–74]. There are no trials Dilators and wands are tools that can that address the use of ultrasound for the stretch shortened pelvic floor tissues and treatment of overactive pelvic floor muscle muscles. They can also be used for vulvo- dysfunction or pelvic pain. Therefore, the vaginal desensitization. Dilators are made uncertain therapeutic benefit must be weighed from different materials, including silicone, against the cost of treatment when determin- plastic, and glass, that affect both their ing whether or not to use ultrasound. rigidity and slipperiness. Some patients may find softer silicone dilators more com- Electrical Stimulation fortable and others may opt for a more rigid variety. For patients suffering from introital Electrical stimulation has two functions. At dyspareunia, vestibulodynia, and vaginis- low intensities, electrical stimulation may be mus, dilators help to continue manual used for pain relief by blocking pain signals treatment and desensitization of pelvic tis- from reaching the brain; this is the mecha- sues in between physical therapy visits. nism of transcutaneous electrical stimulation. Dilators come in different diameters and At higher intensities, electrical stimulation are often sold as a set. If the patient’s goal is stimulates weak muscles to contract. Effective to accommodate a partner’s penis or a sex electrical stimulation for the treatment of pel- toy, she will gradually and ­progressively vic pain can be done by placing leads over the increase the size of dilators until a size sim- S2‐4 spinal levels [75]. Other options for lead ilar to her goal is reached. placement include the T12‐L2 spinal level 308 Textbook of Female Sexual Function and Dysfunction

and even as high as T6‐T7. It is important manual techniques to provide a treatment that the physical therapist works closely with approach that is truly biopsychosocial the patient to educate her and incorporate and complies with the key tenants of the her feedback when deciding on lead place- Neuromatrix Theory of pain.” [78]. ment for pelvic pain management. Home Exercise Programs Dry Needling Home exercise programs are essential to In some states in the United States, physical patients’ success in physical therapy. A home therapists may legally perform dry needling. program accelerates a patient’s progress Dry needling is the insertion of thin mono- between physical therapy visits and empow- filament needles, as used in the practice of ers her to prevent symptom reoccurrence acupuncture, into myofascial trigger points after discharge. Home exercise programs are and other myofascial structures, to treat individualized and consist of a combination painful musculoskeletal disorders. The inser- of education and exercises to improve pain tion of needles into trigger points can gener- and sexual response. ate a local twitch response. It is hypothesized that the local twitch response provides a strong input back into the nervous system, ­Treatments with Physician which can break the cycle of holding, ten- Collaboration sion, and irritability within that trigger point [76]. Other hypotheses involve cholinergic, If a patient’s pelvic pain or sexual dysfunction serotonergic, and endogenous opioid path- is recalcitrant and physical therapy techniques ways [77]. In the pelvic floor muscles, dry are not sufficient to eliminate symptoms, col- needling is used on myofascial trigger points laboration with a physician is necessary. The and tender points that have not responded to physician can prescribe oral medications that manual physical therapy. reduce muscle overactivity, anxiety, and neu- ropathic pain. The use of low‐dose vaginal or Mind–Body Practices rectal diazepam suppositories may also assist in relaxing an overactive pelvic floor [79]. Physical therapists can help guide patients Physicians may provide trigger point injec- towards central and peripheral desensitiza- tions or dry needling of myofascial trigger tion through progressive relaxation and points. In patients with severe pelvic floor guided imagery. The physical therapist can muscle overactivity, botulinum toxin injec- teach deep diaphragmatic breathing and can tions into specific resistant muscles may be also emphasize the benefits of mind–body useful [80]. The therapist may enhance the practices such as tai chi and yoga. All of these proposed treatment by attending the physi- techniques downregulate the nervous sys- cian visit with the patient and demonstrating tem, so that patients can tolerate treatment and confirming the areas in the pelvic floor more easily. Cardiovascular exercise, positive that may benefit from these strategies. thinking, and proper sleep hygiene are other downregulating practices. This approach, in combination with physical therapy for tissue and biomechanical dysfunctions, is an effec- ­Treatment for Specific tive biopsychosocial strategy for the pelvic Sexual Pain Diagnoses pain patient. Hilton and Vandyken state, “Neurodynamic treatment, imagery, dynamic Sexual pain may stem from a combination of movement, theories, and cognitive behavio- the following impairments: pelvic floor mus- ral approaches blend together with careful cle overactivity, scarring, local or widespread Musculoskeletal Management of Pelvic and Sexual Pain Disorders 309 inflammation, chronic infection, neural ten- about impending touch/penetration of the sion, abnormal breathing patterns, connec- vulva and vagina. tive tissue restrictions, musculoskeletal In women with vaginismus, the pelvic floor abnormalities, or nervous system sensitiza- physical therapist typically does not do an tion. Additionally, visceral diagnoses, such as internal examination or internal treatment interstitial cystitis or painful bladder syn- for the first several appointments. The first drome, may be misdiagnosed or lumped into few treatments may consist of developing a cluster of diagnoses for sexual pain. As trust with the patient, teaching her about her such, physical therapy interventions for sex- genital anatomy, external biofeedback, and ual pain often need to systematically address manual work away from the vulva. In addi- more than one impairment at a time, and tion, the patient can be taught to do home care is individualized for each patient. exercises to relax her pelvic floor muscles using stretches, breathing techniques, and Vaginismus patient‐initiated dilator use with a long‐ stemmed moist cotton swab. Vaginismus is a commonly misunderstood Internal examination and internal manual sexual pain diagnosis. This disorder results therapy is only appropriate once the from the combination of overactivity and patient gives consent and when she can spasm of the pelvic floor muscles and anxiety attain a relaxed state in treatments. This is

Case 1 Sara is a 19‐year‐old female reporting inability to contributes to connective tissue restriction. wear a tampon, undergo a gynecological exami- These impairments are possibly leading to nation, or have vaginal penetration with a finger patient’s pain in the posterior vestibule. or penis without severe pain. She reports she Internal vaginal examination is not appro- has never been able to insert anything into her priate at this time secondary to the patient’s vagina since her first attempt to do so at age 12. inability to relax during evaluation. Examination is remarkable for: Treatment:

●● patient displays adductor tension and ●● correct structural abnormalities of pelvis; uncontrolled pelvic floor muscles spasms ●● scar massage to left side perineum and with visual assessment of vulva; superficial vagina; ●● normal appearing genitalia; ●● treat pelvic floor muscle overactivity and ●● normal appearing hymen; tissue restrictions with manual therapy ●● diffuse pain throughout the posterior vesti- and via EMG biofeedback with relaxation bule with a moist cotton swab but no sig- exercises and diaphragmatic breathing and nificant pain lateral to the urethral meatus; then progress to internal manual treatment ●● inability to perform internal vaginal exami- techniques; nation with therapist’s finger; ●● treat connective tissue restrictions; ●● connective tissue restrictions at entire bony ●● educate patient in dilator home program pelvis, bilateral adductors, and abdomen; and progress to larger dilator sizes ●● right side pelvic innominate posteriorly Outcome: rotated with right sacral side bend; After twelve sessions, once a week, patient is ●● hip and leg length normal. able to use a medium plus dilator, use a tam- Assessment: significant pelvic floor, adduc- pon, and undergo gynecological examination tor, and abdominal muscle overactivity with minimal to no discomfort. 310 Textbook of Female Sexual Function and Dysfunction

­demonstrated by a calm appearance on her The pelvic floor muscles typically are con- face, a decrease in her attempts to adduct tracted with minimal relaxation when the her thighs, and a reduction in the appear- body is experiencing chronic pelvic pain, ance of pelvic floor muscle spasms that are causing residual effects along an involved obvious by merely looking at the vulva. nerve. It is theorized that this is a protective Additional treatments for the patient with mechanism, perhaps as a means of guarding vaginismus include a vaginal dilator pro- reproductive organs. Therefore, it is often gram in which she uses progressively larger necessary to treat the muscle and fascia of dilators, internal manual work with param- the vulva in cases of neurogenic pain. In the eters that put the patient in charge of her above example, even after the dysfunction at discomfort, and biofeedback to retrain pel- the L1‐L2 facet has resolved, the downstream vic floor muscle and diaphragm holding pat- sequelae of overactive pelvic floor muscles terns. If the patient has an intimate partner, may not resolve spontaneously and may it is key to bring the partner into treatment require intervention. The physical therapist for education on the diagnosis, what they must then use the techniques mentioned can do to help, and what they can expect above to return the pelvic floor muscles to during intimacy now and in the future. In normal function. cases in which psychosocial factors remain a Physical therapists teach their patients to significant barrier to patient progression, a perform active pelvic floor muscle relaxation referral for cognitive behavioral therapy is exercises through breathing techniques and warranted. stretches in order to maintain the effects of physical therapy. In the above example, if the Vulvodynia original upper lumbar dysfunction was cre- ated as a result of a repeated behavioral habit, Vulvodynia is defined as vulvar pain of at such as a poor sleeping or sitting position, least three months’ duration, without clear then these habits will be addressed and identifiable cause, which may have potential retrained. associated factors [81]. Pelvic floor physical This is an example of how to treat just one therapists treat vulvodynia based on what case of vulvodynia. Because sexual pain they discern is the neuromusculoskeletal symptoms may superficially appear similar in root of the pain. If vulvar pain stems from a different patients, it is imperative for the pel- neuropathic origin, the therapist will assess vic floor physical therapist to determine the the course of the involved nerve to determine root cause(s) of pain for each individual if the pain is initiated proximally or distally. patient. For example, in a patient who has a lumbar facet joint that restricts flexion, extension, or Vestibulodynia rotation, this restriction can create irritation along the entire route of the genitofemoral Under the umbrella of the vulvodynia classi- nerve. As the genitofemoral nerve innervates fication is the more specific diagnosis of ves- part of the vulva, it may be the source of the tibulodynia, the term for pain confined to the vulvodynia. An appropriate musculoskeletal vulvar vestibule. The vestibule, which is assessment of the lumbar spine will reveal embryologically derived from the endoderm, this to the therapist. Intervention options for is different from the rest of the vulva lateral correcting difficulty of spinal facet move- to Hart’s line (ectoderm) and from the vagina ment at a specific segment or segments will (mesoderm). It is this embryologic difference include either using a muscle contraction that underlies the vestibule’s specific suscep- that will create movement in a joint, forced tibility to a sexual pain syndrome, emphasiz- mobilization of the facet, or manipulation of ing the need for proper examination of the the joint itself. vestibule. Musculoskeletal Management of Pelvic and Sexual Pain Disorders 311

Case 2 Beth is a 42‐year‐old female reporting pain at Assessment: scarring on the left side of peri- left side of perineum during intercourse for neum secondary to a episiotomy during her one year. She reports a 5/10 “burning pain” second vaginal delivery which extends into with initial penetration, which worsens to the vagina. This creates pain and tearing upon 7/10 with repeated thrusting; it is not affected stretching during penetration and thrusting by bowel or bladder patterns. Sometimes she because of limited tissue mobility. Pelvic floor notices minimal amounts of bright red blood muscles are overactive due to this scarring on her toilet paper when wiping after sex. and recurrent pain experienced from penetra- Patient is still able to orgasm, but orgasms are tion. Because pelvic floor muscles are never shorter and less enjoyable and after orgasm completely relaxed they are weak. Therefore, she feels a strong urge to urinate. Patient also the rhythmic contraction of these muscles states she has pain with sitting which started during orgasms is not as strong and the after the birth of her second child. orgasms are perceived as “muted”. In addition, the inability of the pelvic floor muscles to Exam is remarkable for: relax after orgasm produces intense urinary ●● negative moist cotton swab test of the urge sensations as the overactive pelvic floor vestibule; muscles and fascia apply an external pull and ●● reproduction of symptoms with palpation pressure on the bladder. of left side superficial and deep transverse Treatment: perineal muscles; ●● evidence of scarring of the perineum from ●● correct structural abnormalities in pelvis a healed episiotomy extending towards and coccyx; the left; ●● massage of the episiotomy scar tissue; ●● pelvic floor muscles globally overactive and ●● treat pelvic floor muscle overactivity; tender to palpation; however, palpation ●● treat connective tissue restrictions; does not reproduce patient’s pain during ●● educate patient in dilator home program. intercourse; Outcome: ●● restriction in connective tissue mobility at After six weekly sessions, she no longer has entire bony pelvis; pain with intercourse and has minimal and ●● left side of pelvis (innominate bone) is ele- intermittent pain with sitting. Orgasms have vated and coccyx is deviated to the left and returned to her pre‐morbid intensity and sat- side bent left; isfaction levels; no intense urinary urges occur ●● hip and leg length normal. after orgasm.

Neuroproliferation‐Associated nociceptors in the vestibular mucosa. In ves- Vestibulodynia tibulodynia resulting from neuroproliferative In a patient with vestibulodynia, it is neces- changes, allodynia will be present through- sary for the pelvic floor physical therapist to out the entire vestibule when examined with determine if she has had lifelong pain at the a moist cotton swab [82]. vestibule or if it is of new onset. The therapist Patients with neuroproliferative vestibulo- must also determine if the patient has a his- dynia benefit from interventions that reduce tory of inflammatory issues, such as a severe the physical changes resulting from chronic allergic reactions or chronic vulvovaginal pain. These interventions may include pelvic candidiasis. A history of chronic inflamma- floor muscle relaxation, pelvic and skeletal tion or lifelong introital pain sugge­ sts alignment corrections, hip mobilizations, ­vestibulodynia caused by a proliferation of movement retraining, retraining of breathing 312 Textbook of Female Sexual Function and Dysfunction

patterns, connective tissue manipulation, posterior vestibule. Treatment interventions and trigger point releases. In most cases of for patients with vestibulodynia caused by neuroproliferative vestibulodynia, the patient overactive pelvic floor muscles include pelvic may benefit from consultation with a physi- floor muscle relaxation, pelvic and skeletal cian for further management, such as topical alignment corrections, hip mobilizations, capsaicin or vulvar vestibulectomy. If a movement retraining, correcting breathing patient subsequently has a vestibulectomy, a patterns, connective tissue manipulation, postoperative pelvic floor physical therapy and trigger point releases. assessment is crucial to identify and reduce any remaining myofascial dysfunction. ­Hormonally‐Induced Vestibulodynia Caused By Overactive Dyspareunia Muscles Overactive pelvic floor muscles may also It is important for the pelvic floor physical cause allodynia of the vulvar vestibule. therapist to recognize through history‐tak- However, in contrast to neuroproliferative ing and examination when hormonal changes vestibulodynia, women with vestibulodynia cause or contribute to sexual pain. Although secondary to overactive pelvic floor muscles pelvic floor interventions cannot replace sys- (specifically the puborectalis and pubococcy- temic or local hormone deficiencies, they geus muscles) have pain only in the posterior may reduce the effects of low sex hormone vestibule [82]. In addition, it is important to levels, such as tearing and pain. Proper educate the patient that the hypoxia and the assessment of the clitoral glans, prepuce, resulting increase in lactic acid caused by the labia minora, vestibule, urethra, and vagina underlying overactive pelvic floor muscles will give the therapist information about the induce a superficial burning in the vestibular role of hormones in the patient’s pain. mucosa. This is especially important as the Pelvic floor physical therapy manual work allodynia at the vestibule “does not feel like a to the vulvovaginal and rectal tissues pro- tight muscle” to most patients. The pelvic motes increased blood flow, which, in turn, floor physical therapist may or may not notice brings increased oxygen and nutrition to a lifelong pattern of discomfort with attempted fragile tissue, potentially improving its qual- vaginal penetration be it sexual or nonsexual ity. Education about sexual position, assistive (i.e. with a tampon or speculum). It is possible devices, lubricants, and vaginal moisturizers for a girl to hold her pelvic floor muscles con- can be provided during treatments to assist in tracted as a response to constipation or anxi- reducing the patient’s sexual pain symptoms. ety, or as a behavioral habit. As she ages, it is Often women are unaware that their sexual unlikely that she will learn to relax her pelvic pain is a result of a reduction of vulvovaginal floor muscles on her own because she is usu- sex hormones. In these situations, the thera- ally unaware that she has been chronically pist must discuss their objective findings and contracting them. In other patients, the con- assessment with the patient’s referring medi- tracted pelvic floor muscle holding pattern cal professional so that appropriate medical may have begun much more recently. Perhaps management can be provided. the patient is a teacher who is unable to leave her classroom to urinate and chronically delays micturition. It is for these reasons that ­Conclusion obtaining a thorough hi­ story is an essential part of a physical therapist’s assessment. Neuromusculoskeletal problems cause or The patient with vestibulodynia caused by contribute to chronic pelvic and sexual pain overactive pelvic floor muscles may have disorders in many women. Patients suffering allodynia and hyperalgesia in a single small from these disorders benefit when health area of the posterior vestibule or the entire professionals screen for musculoskeletal Musculoskeletal Management of Pelvic and Sexual Pain Disorders 313

Case 3 Maureen is a 54‐year‐old female with com- ­consultation with a gynecologist for possible plaints of pain with sexual intercourse, urinary treatment and to rule out vulvar dermatoses. urgency and frequency, and mild urinary She likely has painful intercourse, urinary incontinence. She began to have painful inter- urgency, frequency, and incontinence due to course five years ago; the pain was initially genitourinary syndrome of menopause, pel- minimal but has progressively worsened to a vic floor muscle overactivity, and connective 7/10. She began having urinary urgency and tissue restrictions. frequency one year ago and has had mild uri- Treatment: nary incontinence for six months. She says she needs to urinate twice an hour, but if she ●● patient referred to a physician for possible drinks coffee or wine she urinates three times hormonal therapy; an hour; sometimes she does not make it to ●● treat pelvic floor muscle overactivity and the bathroom in time and has some inconti- vulvar trigger points with manual therapy nence. She also reports mild incontinence techniques; with laughing or coughing. The combination ●● treat clitoral phimosis with gentle stretch- of dyspareunia, urinary urgency, frequency, ing techniques and educate patient how to and incontinence has severely decreased her do this at home; interest in sexual intercourse. She has been ●● treat connective tissue restrictions; menopausal for three years. She has not been ●● educate patient in dilator home program treated with systemic or local hormones. with a small plus dilator and progress to larger dilator sizes; Examination is remarkable for: ●● teach patient how to re‐educate bladder ●● labia minora with partial resorption, par- to allow for longer periods between tial clitoral phimosis, small glans clitoris, urination. inability to retract prepuce to visualize Outcome: ­clitoral corona; She was prescribed a compounded topical ●● reproduction of urinary urge with palpation estradiol 0.01%/testosterone 0.1% gel to of bulbospongiosus and ischiocavernosus apply on the vulva and vestibule. She had internally and externally; elimination of her urinary incontinence ●● reproduction of painful intercourse with pal- after six weeks of topical hormone use and pation of deep vaginal pelvic floor muscles; weekly physical therapy intervention. By ●● globally bilateral vaginal pelvic floor the third week of physical therapy she was ­muscles severely overactive; able to wait one hour between urination ●● diffuse pain throughout vestibule with breaks; by the fourth weeks she was able to q‐tip test; wait 1.5 hours and after eight weeks of ●● connective tissue restrictions at entire bony treatment, she was able to wait two hours pelvis, bilateral adductors, and abdomen; between urination breaks and reported no ●● no pelvic obliquities; more than 2/10 discomfort with sexual ●● hip and leg length normal. intercourse. After twelve weeks of physical Assessment: visible signs of vulvovaginal therapy intervention, her dyspareunia had atrophy and scarring that warrant a resolved.

­disorders in their medical history and physi- that improve impairments and reduce pain cal examination and refer to skilled pelvic from pelvic floor dysfunction. Pelvic floor floor physical therapists for a thorough physical therapists are valuable and often ­evaluation. Physical therapy intervention essential members of the medical team consists of a variety of effective modalities ­caring for women with sexual pain. 314 Textbook of Female Sexual Function and Dysfunction

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22

Medical Management of Dyspareunia and Vulvovaginal Pain Andrew T. Goldstein and Susan Kellogg Spadt

Abstract

Approximately 17–19% of women in the United States suffer from dyspareunia. Due to the ­multifactoral etiology of dyspareunia, it is critically important for the sexual medicine clinician to perform a comprehensive and methodical evaluation of the woman who presents with this issue. This chapter provides an overview of the components of the medical history, psychosocial history, physical examination, and laboratory tests that can guide the clinician’s diagnosis and treatment of sexual pain. Once this thorough evaluation has been performed a more accurate differential ­diagnosis can be developed. The differential diagnosis will then guide a more targeted treatment strategy that will be discussed in this chapter. Keywords: vulvodynia; vestibulodynia; vulvar vestibule; dyspareunia; neuroproliferative; ­overactive pelvic floor muscle dysfunction; vestibulectomy; combined hormonal contraceptives

In general, a woman with sexual pain will see several clinicians in an effort to evaluate and treat her condition. As a result, she may feel marginalized and patronized, which can add to the burden of her illness. Treatment should be chosen according to the characteristics of the individual case and the possible associated factors, rather than as a one‐size‐fits‐all approach. The use of combined hormonal contraceptive agents is highly associated with vestibulodynia, the most common cause of dyspareunia in premenopausal women. The authors endorse changing to a long acting reversible contraceptive (LARC) and treatment with topical cream comprised of estradiol 0.01% and testosterone 0.05–0.1% for women whose pain history supports the diagnosis of a hormonally associated vestibulodynia (e.g. use of combined hormonal contraceptives or GrNH Agonists; women after menopause or during lactation). Pain throughout the entire vulvar vestibule may be associated with pathology within the mucosa of the vestibular endoderm, whereas pain confined solely to the posterior vestibule commonly suggests overactive pelvic floor muscle dysfunction. The authors recommend botulinum toxin Type A be used to augment pelvic floor physiotherapy in the treatment of women with with overactive pelvic floor muscle dysfunction.

­Introduction United States suffer from dyspareunia (i.e. pain experienced during penetrative As discussed in Chapter 18, a large number ­sexual activities) [1]. As previously examined of women suffer from vulvovaginal pain and in Chapter 18, the International Society for dyspareunia. A 2003 study showed that the Study of Vulvovaginal Disease (ISSVD), approximately 17–19% of women in the The International Society for the Study of

Textbook of Female Sexual Function and Dysfunction: Diagnosis and Treatment, First Edition. Edited by Irwin Goldstein, Anita H. Clayton, Andrew T. Goldstein, Noel N. Kim, and Sheryl A. Kingsberg. © 2018 John Wiley & Sons Ltd. Published 2018 by John Wiley & Sons Ltd. 320 Textbook of Female Sexual Function and Dysfunction

Women’s Sexual Health (ISSWSH), and the that the patient has “hormonally associ­ International Pelvic Pain Society (IPPS) ated vestibulodynia”. An appropriate recently developed a nomenclature to help ­treatment regimen might be to stop the differentiate among various causes of vulvar anti‐androgenic medication and use topi­ pain and vulvodynia (Figure 18.3) [2]. This cal hormones on the vulvar vestibule. nomenclature emphasizes that “treatment ●● Case 2: A 35‐year‐old woman reports the should be chosen according to the character­ sudden onset of introital dyspareunia, vul­ istics of the individual case and the possible var burning, urinary frequency, and pain associated factors, rather than as a one‐size‐ with defecation. Her examination reveals a fits‐all approach”. For instance, physical ther­ retracted perineum, tenderness of the per­ apy could be recommended if musculoskeletal ineum to palpation, severe tenderness of factors were suspected, whereas surgery the posterior vestibule (without tenderness could be recommended if neuroproliferation in the anterior vestibule), and tight and was identified as a primary contributing tender levator ani muscles. All laboratory ­factor [2]. tests were normal. A thorough medical Due to the multifactoral etiology of dys­ history elucidates that the pain began three pareunia, it is critically important for the months after the patient began an aggres­ sexual medicine clinician to perform a com­ sive exercise regimen in preparation for prehensive and methodical evaluation of the her upcoming wedding. Further question­ woman who presents with this issue [3]. ing reveals that she is having severe anxiety Therefore, the first half of this chapter pro­ in anticipation of her marriage because her vides an overview of the components of the fiancé has been emotionally abusive and medical history, psychosocial history, physi­ focused on her weight. The combination of cal examination, and laboratory tests that these data suggests that her pain is can guide the clinician’s diagnosis and treat­ “­provoked vestibulodynia associated with ment of sexual pain. Once this thorough overactive pelvic floor muscle dysfunc­ evaluation has been performed, a more accu­ tion”. In this situation, however, the patient rate differential diagnosis can be developed. would likely be better served by a treat­ The differential diagnosis will then guide a ment regimen consisting of cognitive more targeted treatment strategy that will be behavior therapy, relationship counseling, discussed in the second half of this chapter. and pelvic floor physical therapy, rather Two cases can be used to illustrate this than a medical or surgical treatment. ­evaluation and treatment approach.

●● Case 1: A 28‐year‐old women initially ­Evaluation develops introital dyspareunia, which over several months becomes a constant Medical History nonprovoked burning pain. A physical examination reveals significant atrophy, A patient’s narrative of her illness provides pain throughout the entire vestibule, and information that is essential in the determi­ severe erythema at the glandular ostia. nation of the correct diagnosis of the pre­ A thorough medical history reveals that senting complaint. However, a woman’s the pain began three months after the experience of dyspareunia is often more patient began an anti‐androgenic treat­ complicated and may be less “straight for­ ment for acne (spironolactone), and ward” than other medical conditions. ­laboratory testing reveals that the patient’s In addition to pain, an affected woman may free testosterone level was less than 25% of experience embarrassment, shame, guilt, loss the expected value of a woman her age. of self‐esteem, frustration, depression, and The combination of these data suggests anxiety. Therefore, it is important for a Medical Management of Dyspareunia and Vulvovaginal Pain 321

­clinician to use communication skills While each clinician must establish his/her that enhance openness, comfort, trust, and own routine, the authors have found it espe­ confidence. cially helpful to provide a new patient the In general, a woman with sexual pain will first 10 minutes of the interview to give her see several clinicians in an effort to evaluate narrative of the experience of her condition. and treat her condition [2]. As a result, she A useful prompt for this narrative might be, may feel patronized, marginalized, or ostra­ “Complete this sentence….I was feeling fine cized from these previous encounters, until…” Before she starts, she is asked to try which can add to the burden of her illness. It to be as specific as possible and to try to is essential for the clinician to address these ­follow a sequential timeline of her disease feelings in order to establish a constructive process. She is allowed to speak virtually and trusting relationship. Furthermore, a uninterrupted for this time. Frequently, a clinician should refrain from being either patient will cry, and there may be moments too formal or too casual when obtaining the of silence, but this can be cathartic and con­ medical history. Eye to eye contact should veys the message that she will not be rushed, be maintained. Providers should avoid being ignored, or devalued in the clinician–patient careless with words, as patients with high relationship. If there is not enough time to levels of distress may search for meaning in focus on a specific complaint during a single everything that is said. A clinician should visit, the patient should be reassured of the not display extreme reactions such as sur­ importance of her problem and scheduled prise, grimaces, or laughter while the patient for a follow‐up appointment to address that provides her narrative [4]. Privacy and issue alone. assurances of confidentiality are essential After completing the patient’s history, it when conducting the interview. Some may be necessary to clarify her expectations. patients may want a spouse, sexual partner, She may have several different complaints, so relative, or friend present during the inter­ it will be important to determine which of view or examination. While this may allow these she feels is her chief complaint. For the patient to feel more comfortable, it example, she may complain of generalized might also inhibit the patient from disclos­ vulvar pain and burning, pain during inter­ ing pertinent aspects of her medical, social, course, decreased libido, and difficulty relationship, or sexual history. When possi­ achieving orgasm. While it is possible that a ble, there should be some time allotted for single intervention might address all of these the patient and the clinician to discuss a issues, it is likely that a sequence of treat­ sexual history privately [4]. ments will be needed. While it is important to ask direct ques­ After both an accurate history of present tions to obtain specific information, such as illness and chief complaint have been estab­ medication usage, it is equally essential to lished, additional information should be ask open‐ended questions that allow a gathered that may help the clinician narrow patient to describe her experience of the the differential diagnosis. Past medical, condition. This process can be facilitated by social, sexual, surgical, and medication his­ encouraging the patient to give as much tory often provides essential information. detailed information as possible. Avoid the A list of questions that the authors have temptation to frequently interrupt the found valuable in the differential diagnosis patient’s narrative. Throughout the whole of sexual pain can be found in Table 22.1 process, displaying empathy, understanding, [4]. Validated questionnaires for specific and acceptance is essential. Repeating the disorders can also be used to aid in the information back to the patient to confirm diagnosis of some pain disorders, including the accuracy of her history is also an impor­ irritable bowel syndrome [5], endometrio­ tant component [4]. sis [6], and interstitial cystitis/bladder pain 322 Textbook of Female Sexual Function and Dysfunction

Table 22.1 Useful questions when obtaining a sexual pain history.

Do you have a history of: Suggestive of what condition

Physical, sexual, and emotional abuse or anxiety? overactive pelvic floor muscle dysfunction, VAG Low back or hip pain? overactive pelvic floor muscle dysfunction Urinary urgency, frequency, hesitancy, or sensation overactive pelvic floor muscle dysfunction, IC of incomplete emptying? Chronic constipation, rectal fissures, pain with bowel overactive pelvic floor muscle dysfunction, IBS movements Oral contraceptive pill use (especially OCPs with HPVD 20 mμ or less of ethinyl estradiol, or the progestins norgestimate or drospirenone) preceding or during the onset of symptoms? Ovarian suppression by Lupron, Depo‐Provera? HPVD Treatment of breast cancer with Aromitase inhibitors HPVD or Tamoxifen Decreased libido or decreased vaginal lubrication HPVD prior to the onset of dyspareunia? Perimenopausal or menopausal symptoms such as HPVD, AV hot flashes and night sweats? Contact allergies or skin sensitive to chemicals? IPVD, NPPVD Recurrent (culture positive) yeast infections? IPVD, NPPVD Persistent yellowish vaginal discharge? DIV, LP, TRICH, STI, SA Severe burning or an allergic reaction to a topical IPVD, NPPVD medication on the vulva or in the vagina? Burning after intercourse? IPVD, NPPVD, HPVD, PVD, LP, LS, SA Pain since first attempt at intercourse without any NPPVD, overactive pelvic floor muscle dysfunction pain‐free sex? Pain with first tampon use? NPPVD, overactive pelvic floor muscle dysfunction Increased sensitivity of the umbilicus? NPPVD Postcoital spotting or bleeding? VGF, LS, LP, DIV Vulvar itching? LS, LP, DIV, LSC, VIN, plasma cell vulvitis Night‐time scratching? LS, LSC Diarrhea? IBS Mid‐cycle spotting or pain? Endo Pain is worse in sexual positions with deep thrusting? Endo, IBS, adenomyosis Vulvar ulcerations, tears, fissures? RC, LS, LP, AV, LSC Painful periods? Endo Chronic pelvic pain? Endo, overactive pelvic floor muscle dysfunction, PID Feeling of an obstruction in the vagina? overactive pelvic floor muscle dysfunction, VAG, rectocele Pain beginning after childbirth? AV, VGF, overactive pelvic floor muscle dysfunction, HAPVD Dribbling after urination? Urethral diverticulum, overactive pelvic floor muscle dysfunction Medical Management of Dyspareunia and Vulvovaginal Pain 323

Table 22.1 (Continued)

Do you have a history of: Suggestive of what condition

Changes in coloration or architecture of the labia LS, LP, female genital cutting or vulva? Decreased clitoral sensation? LS Frequent bicycle riding? PN Aggressive abdominal muscle strengthening or overactive pelvic floor muscle dysfunction Pilates? Pain mainly at the clitoris? Postherpetic neuralgia, PN Pain with sex is intermittent (i.e. sometimes it is overactive pelvic floor muscle dysfunction pain free)? Do you have oral lesions or bleeding gums? LP, mucous membrane pemphigoid History of high‐risk human papilloma virus or VIN cervical dysplasia?

KEY: overactive pelvic floor muscle dysfunction = pelvic floor dysfunction; IC = interstitial cystitis; HAPVD = hormonally associated provoked vestibulodynia; NPPVD = neuroproliferative associated vestibulodynia; IPVD = Inflammation associated vestibulodynia; PN = pudendal neuralgia; LS = lichen sclerosus; LP = lichen planus; AV = atrophic vaginitis (Genitourinary Syndrome of Menopause); DIV = desquamative inflammatory vaginitis; PID = pelvic inflammatory disease; IBS = irritable bowel syndrome; VGF = vulvar granuloma fissuratum; endo = endometriosis; VIN = vulvar intraepithelial neoplasia; LSC = lichen simplex chronicus; VAG = vaginismus syndrome [7, 8]. A recently developed vali­ own ability to achieve a goal), anxiety and dated instrument – Vulvar Pain Assessment depression, all of which could positively Questionnaire – can also be extremely or negatively affect the pain. ­useful in the evaluation of dyspareunia as ●● comorbid mental health conditions and well as ­following progress of treatment [9]. treatments; previous treatment attempts and outcomes; current relationship: strengths, areas of conflict including Psychosocial History potential verbal and physical abuse, how they cope with the pain as a couple, emo­ When a patient reports symptoms of dys­ tional and nonsexual physical intimacy; pareunia or genital pain the questions should childhood trauma including abuse and address [9]: neglect, and any adult nonconsensual or ●● pain characteristics, such as time since negative sexual experience. onset, temporal pattern, duration, loca­ tion, quality, elicitors, intensity, and Medication History whether the pain is primary or secondary; ●● sexuality: desire, arousal, orgasm, fre­ Many medications can cause dyspareunia. quency of and satisfaction with sex, sexual Therefore, it is essential to develop a timeline repertoire, sexual distress; of medication use and compare it to the ●● thoughts, emotions, behaviors, and couple timeline of the patient’s sexual pain history. interactions that accompany the pain expe­ In general, more than 90% of women take rience, in particular, avoidance behaviors, prescription medications; therefore, a dis­ conflict and negative, solicitous or facilita­ cussion of the most commonly prescribed tive partner responses, pain attributions, medications and their association with dys­ catastrophizing, hypervigilance, fear of pareunia is warranted. In addition, it is pain, self‐efficacy (i.e. the belief of one’s important to note that patients frequently do 324 Textbook of Female Sexual Function and Dysfunction

not disclose use of herbal supplements to common for a woman with chronic inflam­ ­clinicians; thus, it is important to ask about mation to self‐diagnosis the cause as “chronic herbs, vitamins, and alternative therapies yeast infections”. In reality, this may or may when inquiring about medication history [10]. not be the cause of her signs and symptoms if Antibiotics are one of the most common the diagnosis has not been aided by clinical prescription medications used by women. microscopy and/or culture [15]. Studies also While antibiotics do not directly cause sexual suggest that clinician‐aided diagnosis of pain, long‐term exposure does predispose ­candidiasis is frequently incorrect and lacks women to alteration in the gut and vaginal confirmatory fungal culture [16]. Clinically, flora, and chronic yeast infections, which the authors note that some women have a may be a causative agent of the pain. difficult time localizing their sexual pain. Combined hormonal contraceptives (e.g. They may incorrectly identify the location of oral contraceptive pills, transdermal patch, their dyspareunia; localizing it to the vagina ­vaginal ring) are the second most common while an examination reveals that the pain is prescription medication used by reproduc­ originating from the vulva or bladder. tive‐aged women. The use of these agents is highly associated with vestibulodynia, the Physical Examination most common cause of dyspareunia in pre­ menopausal women. Although not all women All women with dyspareunia should undergo who use combined hormonal contraceptives a thorough physical examination. While this develop sexual pain, in at least one case‐­ examination focuses primarily on the uro­ control study, women who used oral contra­ genital system, additional organ systems may ceptives were 9.3 times more likely to develop need to be assessed depending on informa­ vestibulodynia than controls [11]. Several tion gathered during the medical history. authors suggest that women who use or have The goal of the physical examination is to used low‐dose ethinyl estradiol oral contra­ gather data to determine the etiology of the ceptives are more likely to develop vestibulo­ sexual pain. This requires a meticulous and dynia [12]. The proposed mechanism linking methodical examination. In addition, if the combined hormonal contraceptives to sexual examiner can identify the correct location pain is that combined hormonal contracep­ and reproduce a woman’s pain, she feels vali­ tives use results in elevated sex hormone dated as this shows her that her sexual pain is binding globulin and decreased free circulat­ real and has a physical origin. In addition, it ing testosterone, which may result in dys­ inspires confidence that the practitioner will function of the androgen dependent mucin be able to treat her pain. glands and atrophy of the endodermal It is useful if the patient watches the physical mucosa of the vulvar vestibule, placing a examination to establish a common nomen­ woman at risk for chronic inflammation and clature for the parts of the urogenital system. dyspareunia [13]. The authors use mirror examinations and/or a Lastly, approximately 20% of reproductive‐ video colposcope linked to a monitor to show aged women use prescription medications the patient our findings that are related to her for anxiety and depression. Psychotropic experience of pain and to include her in the medications are frequently implicated as a monitoring of treatment progress. It should cause of alterations in female sexual desire be noted that consent should be obtained and lubrication. Both of these can contribute before taking any digital images [17]. to dyspareunia due to their adverse effects on During colposcopic examination of the vaginal lubrication and sexual arousal [14]. vulva, commonly referred to vulvoscopy, It is important to recognize that some important findings that can be observed aspects of a patient’s self‐reported medical include: infection, trauma, and dermatitis history may be inaccurate. For instance, it is (Figure 22.1). Specifically, the observer Medical Management of Dyspareunia and Vulvovaginal Pain 325 should note any inflammation, induration, disease of the vulva (Figure 22.2). While excoriation, fissures, ulceration, lichenifi­ erythema is a nonspecific finding, erythema cation, hypopigmentation, hyperpigmenta­ near the ostia of the Bartholin and Skene tion, scarring, or architectural changes, glands is suggestive of vestibulodynia which may be evidence of a dermatologic (Figure 22.3).

Figure 22.1 Examination of the vulva with a colposcope.

Figure 22.2 Vulvar lichen sclerosus. Changes seen include complete resorption of the labia minora, complete phimosis of the glans clitoris, and Figure 22.3 Cotton swab test of the vulvar narrowing of the introitus. vestibule. 326 Textbook of Female Sexual Function and Dysfunction

A sensory examination of the vulva is per­ formed using a moistened cotton swab (called the “Q tip test”) to determine if there are areas that exhibit an abnormal pain response. Women with sexual pain often exhibit localized or generalized “allodynia”, the perception of pain upon provocation by a normally nonpainful stimulus and “h­yperpathia”, pain provoked by very light touch during the Q tip test. This examina­ tion should be performed systematically to ensure that all areas of the anogenital region are tested. Initially, the medial thigh, but­ Figure 22.4 Erythema of the ostia of the Bartholin tocks, and mons pubis are palpated. These gland in a patient with hormonally associated areas are typically painless and this allows vestibulodynia. the patient to become comfortable with the examination. Then, labia majora, clitoral prepuce, perineum, and interlabial sulci commonly overactive pelvic floor muscle should be evaluated. Pain in these areas dysfunction [18]. would suggest a process that is affecting the A speculum examination of the vagina is whole anogenital region, including vulvar the next step in the physical examination of a dermatoses, v­ ulvovaginal infections, or neu­ woman with dyspareunia. In general, a pedi­ ropathic processes such as pudendal neural­ atric‐sized Graves or Pederson speculum gia. The labia minora are then gently should be used and all efforts should be used palpated. Firstly, the medial labia minora are to insert the speculum through the hymeneal gently touched with the cotton swab lateral ring without touching the vulvar vestibule. to Hart’s line, which is the lateral boundary Initially, the vagina should be examined for of the vulvar vestibule. The cotton swab is evidence of abnormal vaginal discharge. then used to gently palpate the vestibule at A cotton swab should be used to collect some five locations: at the ostia of the Skene glands discharge for pH testing, wet mount, and (lateral to the ­urethra), at the ostia of the potassium hydroxide (KOH) preparation. Bartholin glands (4 and 8 o’clock on the ves­ In addition, a culture should be obtained and tibule), and at 6 o’clock at the fossa navicula­ sent for speciation and sensitivity. Important ris (Figure 22.4). Patients with vestibulodynia findings while visualizing the vagina include will frequently experience allodynia with the atrophy, erythema, erosions, ulcerations, cotton swab palpation confined to the tissue abnormal discharge, or synechiae. of the vulvar vestibule but have normal sen­ A manual examination is then performed sation lateral to this anatomic landmark. If with one finger instead of the usual two fin­ the pain is localized to the vestibule, it is gers. The examiner’s index finger is inserted important to determine if the pain affects through the hymen without touching the the entire vestibule or just the posterior por­ vestibule. The urethra and bladder trigone tion of vestibule. Pain throughout the entire are gently palpated. Intrinsic tenderness of vestibule may be associated with the possi­ the urethra may be suggestive of a urethral bility of an intrinsic pathology within the diverticulum or bladder pain syndrome/ mucosa of the vestibular endoderm, whereas interstitial cystitis, while tenderness of the pain confined to the posterior vestibule sug­ bladder may be suggestive of either bladder gests that the pain might be associated with pain syndrome/interstitial cystitis or endo­ a pathology extrinsic to the vestibule, most metriosis. The levator ani muscles are then Medical Management of Dyspareunia and Vulvovaginal Pain 327 palpated for hypertonicity, tenderness, be examined with a microscope on both low ­weakness, and trigger points, which can be and high power magnification. The saline evidence of overactive pelvic floor muscle slide is examined for normal squamous dysfunction (also known as levator ani ­epithelial cells, increased white blood cells ­syndrome or vaginismus). Because overac­ (more than one white blood cell per ­epithelial tive pelvic floor muscle dysfunction is such cell), ­pathogens such as hyphae (yeast cells), an important and common cause of dyspare­ ­trichomonas, parabasal cells, clue cells, and unia, an additional chapter in this textbook is normal flora such as lactobacilli. As micro­ devoted to the evaluation and treatment of scopic examination frequently misses overactive pelvic floor muscle dysfunction ­candidiasis and trichomoniasis, a culture (Chapter 21). obtained at the time of vaginal inspection The ischial spine is then located and the should be sent for speciation and sensitivity. pudendal nerve is palpated as it enters Alcock’s In addition, if there is significant leukorrhea, canal. Tenderness of the pudendal nerve is a swab should be obtained for an immuno­ suggestive of pudendal neuralgia or pudendal chromatographic assay for trichomonas. nerve entrapment. Next, a bimanual examina­ tion is performed to assess the uterus and Histology adnexa (ovaries and fallopian tubes). Abnormalities in the size, shape, or contour A vulvar or vaginal biopsy should be obtained may be indicative of a leiomyoma. A diffusely if there are specific findings on colposcopic enlarged, “boggy” and tender uterus may be examination of the vulva suggestive of a der­ evidence of adenomyosis. Tenderness of the matoses, intraepithelial neoplasia, or neopla­ adnexa can often be a sign of ovarian cysts, sia. It is unlikely, however, that the biopsy will sexually transmitted infection, pelvic inflam­ prove useful if the physical findings are solely matory disease, or endometriosis. A rectovag­ nonspecific erythema. After prepping the inal examination is then performed to assess area with iodopovidone solution, the biopsy the rectovaginal septum and the posterior cul‐ should be obtained at the edge of any ulcera­ de‐sac. Thickening or nodularity of the sep­ tions or erosions if present using a 4 mm tum, nodularity of the uterosacral ligaments, punch biopsy or small Tischler biopsy forcep. or obliteration of the posterior cul‐de‐sac are Biopsies can be closed with one or two suggestive of endometriosis. Traumatic neu­ stitches of absorbable suture such as 4‐0 romas can also be a source of significant pain Vicryl‐rapide (Ethicon, Inc., Somerville, NJ) in women who have had prior vaginal surgery, to aid in wound healing. including repair of lacerations or episiotomies The authors recommend that all vulvovag­ incurred during childbirth. inal biopsies should be sent with a descrip­ tion of the physical findings and a differential Testing diagnosis to the attention of a pathologist who specializes in dermatologic disorders Wet Mount and Cultures (a dermatopathologist). When persistent or As previously discussed, vaginal discharge extensive vulvovaginal ulcerations are pre­ should be examined by wet preparation, pH, sent, a second biopsy may be obtained and and potassium hydroxide testing. Specifically, sent in Michel’s transport media for direct vaginal discharge should be obtained on two immunofluorescence to rule out the immu­ cotton swabs from the upper third of the nobullous diseases such as mucous mem­ vagina, and the pH of the discharge should be brane pemphigoid [19]. This additional tested. One swab is used to make a slide with biopsy should only be carried out when the saline and the other swab is combined with more common sources of ulceration, such as potassium hydroxide. The wet mount should genital herpes, have been ruled out. 328 Textbook of Female Sexual Function and Dysfunction

Serum Testing there is evidence of overactive pelvic floor muscle dysfunction. Serum hormone testing can be useful in women with dyspareunia. Because hor­ monal abnormalities can be involved in ­Treatment ­vestibulodynia and vaginal pain, blood should be obtained for serum estradiol, total Unfortunately, there are few randomized, testosterone, free testosterone, albumin, pro­ placebo controlled trials that have examined lactin, sex hormone binding globulin, and treatments for vestibulodynia. In addition, follicle stimulating hormone. An elevated even though some of the existing studies prolactin level can cause anovulation and were well designed when they were con­ atrophic changes. Herpes type‐specific serol­ ducted, none differentiated among the differ­ ogy should be obtained in women with symp­ ent subtypes of vestibulodynia as outlined in toms of generalized vulvar burning or the 2015 nomenclature. As such, it is possible tingling, or in those with pain concentrated that some treatment options would have in the clitoris (clitorodynia). shown better efficacy if they targeted only a specific subgroup of vulvar pain/vulvodynia. Additional Testing For example, one could hypothesize that cap­ saicin – which blocks the release of sub­ Referrals for additional tests should be based stance‐P to desensitize the sensory nerves on findings during the history and physical located in the vestibular mucosa – would examination. Radiographic or ultrasono­ work better in a subgroup of women with graphic imaging may be appropriate to eval­ “neuroproliferative associated vestibulo­ uate the uterus, ovaries, pelvis, or lumbosacral dynia” than in a mixed cohort of women that spine (particularly if sacroliliac joint dysfunc­ have vestibulodynia secondary to other tion is suspected in relation to pelvic floor causes (e.g. hormonal, inflammatory, muscu­ hypertonus). Specifically, a 3 Telsa MRI of loskeletal, etc.). However, it is still worth the pelvis may reveal entrapment of the reviewing the previously published studies to pudendal nerve in women with unilateral illustrate the many different approaches that vulvar pain or clitorodynia. A MRI of the have been taken to treat vestibulodynia. In sacrum and lumbar spine is appropriate in addition, it may allow us to contemplate women with an abnormal genital sensory future trials that will target specific sub­ examination. Diagnostic laparoscopy may be groups of vestibulodynia with treatments necessary if there is significant evidence of targeting particular associated pathologies. endometriosis or utero‐ovarian pathology In the past, the typical treatment plan for a that does not respond to initial conservative woman with dyspareunia and/or vulovovagi­ management. Colonoscopy, barium enema, nal pain started with treatments that are con­ and/or a CT scan with contrast may be used sidered noninvasive (e.g. psychological to rule out pathology of the lower gastroin­ treatments, physical therapy), and then, testinal tract if deep thrusting dyspareunia is depending on treatment response, pro­ present along with dyschezia, hematochezia, gressed to medical treatments (lidocaine, or symptoms consistent with inflammatory gabapentin, topical hormones, etc.), and then bowel disease. Cystoscopy (with or without to surgical intervention if the pain is con­ hydrodistention) may be used to evaluate any fined to vestibule. Treatment progression unexplained microscopic or gross hematuria was usually based on “trial and error” [20]. or aid in the diagnosis of interstitial cystitis/ More recently, the authors have favored a bladder pain syndrome. An electromyelo­ more algorithmic approach, deciding on spe­ gram may be used to assess the tone and cific treatments based on history, physical strength of the levator ani muscles when examination finding and laboratory tests Medical Management of Dyspareunia and Vulvovaginal Pain 329

Nonmedical Treatments (Figure 22.5) [18]. Lastly, some have argued that concurrent or integrative (i.e. multidis­ Despite their widespread use in the ciplinary) treatments, if possible, might be ­multimodal treatment of other chronic more efficacious in terms of outcome [20]. pain conditions, nonmedical treatments are

VESTIBULODYNIA pain confined to the vestibule

TENDERNESS THROUGHOUT THE PAIN THROUGHT ENTIRE VESTIBULE BUT GREATER ENTIRE VESTIBULE AT 4, 6, 8 O’CLOCK

INFLAMMATORY VESTIBULODYNIA PE: Erythema, induration and tenderness of vestibular and vaginal mucosa, leukorrhea, cervicitis/ectropion HORMONALLY ASSOCIATED HX: Chronic infections, allergic reactions, VESTIBULODYNIA copious yellowish discharge PE: Gland ostia are erythematous, LABS: Wet mount with increased leukocytes, mucosal pallor with overlying polymorphisms in IL1RA, MBL, IL1B erythema, decreased size of labia CAUSES: Desquamative inflammatory vaginitis, minor and clitoris. chronic candidiasis, severe allergic reaction LABS: High sex hormone binding (Latex, semen, spermicide, vaginal creams) globulin, low free testosterone, high TREATMENT: Interferon 1. 5 million units SQ number of CAG repeats in the TIW for 12 doses, montelukast, enoxaparin, Androgen Receptor NEUROPROLIFERATION cutaneous lysate CAUSES: Hormonal contraceptives, spironolactone, Tamoxifen, aromatase inhibitors, oophorectomy, amenorrhea, lactation. TREATMENT: Stop offending

CONGENTIAL NEUROPROLIFERATIVE PERSISTENT VESTIBULODYNIA PE: Tenderness of the entire vestibule (anterior and ACQUIRED NEUROPROLIFERATIVE posterior) from Hart’s line to the hymen, often with erythema that worsens after touch with cotton VESTIBULODYNIA swab. Umbilical hypersensitivity in approximately PE: Tenderness, erythema throughout the 60% of women. entire vestibule LABS: Histology shows an increased density of c-afferent LABS: Histology shows an increased density nociceptors (if using immunohistochemical of c-afferent nociceptors (if using stains S-100 or PGP 9) and increased number of mast immunohistochemical stains S-100 or PGP 9) cells. and increased number of mast cells. HISTORY: Pain since first tampon use, speculum Polymorphisms in IL1RA, MBL, IL1B insertion, and coitarche. No pain free sex. Often late HISTORY: Persistent or chronic yeast coitarche > 25 years old infection, severe or recurrent allergic TREATMENT: Capsaicin 0.025% 20 minutes QHS for reaction. May be associated with urticarial, 12 weeks. Vulvar vestibulectomy. hives, and “sensitive skin” TREATMENT: Capsaicin 0.025% 20 minutes QHS for 12 weeks, topical gabapentin 4% cream, subcutaneous Botulinum toxin infections, if failed conservative treatments then vulvar vestibulectomy. Adapted from King, M., Rubin, R., Goldstein, A. Current Uses of Surgery for the Treatment of Genital Pain. Current Sexual Health Reports. 2014, Oct 3. Volume 6, Issue 4, pp 252–258.

Figure 22.5 Vulvar pain diagnostic and treatment algorithm. 330 Textbook of Female Sexual Function and Dysfunction

PAIN EXTENDS OUTSIDE THE VESTIBULE (physical exam only, not subjective)

PUDENDAL NEURALGIA PE: Severe tenderness when palpating PAIN CONFINED TO THE the pudendal nerve at the ischial POSTERIOR VESTIBULE spine, most commonly unilateral or significantly greater on one side, tenderness and hypertonus of obturator internus muscle. LABS: 3 Tesla MRI may show entrapment or scar tissue adjacent to the pudendal nerve in Alcock’s canal. CAUSES: Pain of the anus, perineum, labia, and clitoris. Pain is exacerbated when sitting on hard surfaces and is improved when lying prone or OVERACTIVE (HYPERTONIC) PELVIC FLOOR standing. May have symptoms of MUSCLE DYSFUNCTION persistent genial arousal disorder PE: Tenderness and erythema of the posterior (PGAD). Pain improved temporarily vestibule only. Hypertonus of levator ani with pudendal nerve block. History of muscles, retracted perineum, tenderness to deep coccyx trauma, hip pain, traumatic palpation of the perineum, post-coital fissure in vaginal delivery, labral tear of hip. posterior vestibule. TREATMENT: Serial pudendal nerve - Pain at 4, 8 o’clock if hypertonus of blocks, oral gabapentin, oral pubococcygeus muscle pregabulin, pudendal nerve - Pain at 6 o’clock if hypertonus of puborectalis neuromodulation, pudendal nerve muscle radio-frequency ablation, pudendal - Urinary frequency, urgency, hesitancy, and nerve neurolysis sensation of incomplete emptying if hypertonus of the coccygeus muscles - Constipation, rectal fissures, hemorrhoids if hypertonus of puborectalis muscle LABS: elevated muscle tone measured with EMG CAUSES: Associated with anxiety, lower back pain, scoliosis, hip pain, “holding urine”, excessive core strengthening exercises PERSISTENT GENITAL AROUSAL TREATMENT: Pelvic floor physical therapy, PE: Allodynia of clitoris, sometimes tenderness diazepam 10 mg suppositories, vaginal dilators, of pudendal nerve home pelvic floor exercise, intramuscular LABS: MRI of sacrum may reveal Tarlov cyst, botulinum toxin injections, cognitive behavior MRI of lumbar spine may show disc herniation. therapy, hypnosis, yoga (relaxation – not Tr y ascending nerve blocks to find location of strengthening) “lesion”: dorsal nerve of the clitoris pudendal nerve block epidural. HISTORY: Very disturbing sensation of arousal, can result suicidal ideation. Sometimes begins when starting or stopping psychotropic medications that increase dopamine or epinephrine TREATMENT: Treat overactive pelvic floor muscle dysfunction (see left ), treat pudendal neuralgia (see above). Chantix, Ambien, SSRI’s, periclitoral Botulinum injections

Figure 22.5 (Continued)

sometimes absent from algorithms pub­ women with sexual pain and include: cogni­ lished in the medical literature. These tive behavioral therapy, pelvic floor physio­ ­treatments can be instrumental in the com­ therapy (physical therapy), and alternative prehensive multidisciplinary treatment of treatments. Medical Management of Dyspareunia and Vulvovaginal Pain 331

Interdisciplinary Treatments controlled trial using lidocaine failed to show any benefit of this medication and the major­ There are only two published, uncontrolled ity of the noncontrolled trials showed efficacy quantitative studies evaluating a multimodal in the range of 50%, the authors do not approach to the treatment of genital pain, ­recommend lidocaine as a long‐term man­ with both reporting major improvements in agement option for vestibulodynia [7]. women’s sexual function and pain [21, 22]. These multimodal treatments integrated sex Capsaicin therapy and physiotherapy in a nonstand­ The rationale for the use of capsaicin in the ardized manner, such that not all partici­ treatment of vulvodynia is based on pants received the same combination and increased vanilloid receptor innervation duration of interventions. Another retro­ found in women with this condition. spective qu­ alitative study evaluated 29 Capsaicin binds to the vanilloid receptor women with vulvodynia who had taken part receptors located in the peripheral terminals in a multidisciplinary treatment program of nociceptors [25]. After hyperesthesia to consisting of psychotherapy, physiotherapy, the initial capsaicin exposure, capsaicin pro­ and dietary advice. Of the 29 women, 27 duces a long‐lasting desensitization to burn­ reported a significant benefit, including nine ing and pain [26]. One prospective and one women who were pain free at the end of the retrospective case series have evaluated the interventions [23]. Another study of 19 efficacy of capsaicin cream in vestibulodynia women with v­ulvodynia who had multi­ [27, 28]. Neither were controlled studies. modal treatment included group cognitive However, despite the significant discomfort behavioral therapy, physical therapy, and experienced by the patients with the use of regular medical appointments. Participants capsaicin, the majority reported a significant reported increased knowledge and tools to reduction in dyspareunia. Therefore, despite manage the pain, improved psychological the flaws in the available literature, the well‐being, a sense of validation and sup­ authors feel that capsaicin should be offered port, and an enhanced sense of empower­ to patients suspected of having neuroprolif­ ment [24]. Though promising, the findings erative associated vestibulodynia prior to of these studies emphasize the need for ran­ undergoing vulvar vestibulectomy. domized trials aimed at evaluating the effi­ cacy of an integrated approach to care, over Botulinum Toxin Type A and above the efficacy of single treatments. Botulinum toxin Type A (Botox®) inhibits the release of glutamate and substance‐P from Medical Treatments nociceptive neurons [29]. Current hypothe­ ses suggest that the inhibition of these nocic­ Lidocaine eptors may improve peripheral and central Local anesthetics such as lidocaine exert their sensitization associated with vulvodynia. In analgesic activity via the blockade of sodium addition, botulinum toxin Type A blocks the channels on peripheral nociceptors and by release of acetylcholine at the neuromuscular blocking transmission of discharges from junction causing localized muscle paralysis peripheral sensory nerves. Both neuroprolif­ [30]. This effect may be useful in the treat­ eration and sensitization of the vestibular ment of overactive pelvic floor muscle nociceptors have been suggested as possible ­dysfunction. The efficacy of botulinum toxin mechanisms of the pain in vestibulodynia. Type A has been evaluated in one double‐ Therefore, the theory behind the use of local blind placebo controlled randomized anesthetics is to achieve long‐lasting desensi­ ­controlled trial, two case series, and two tization of these nociceptors [7]. However, as case reports [7]. While the one randomized the only double‐blind, randomized, placebo controlled trial of botulinum toxin Type A 332 Textbook of Female Sexual Function and Dysfunction

showed no improvement as compared to pla­ Hormonal Treatments cebo, the noncontrolled studies have shown In a nonplacebo controlled study, Burrows very significant efficacy. In one open label and Goldstein showed that a topical cream study in women of women who had failed that combined estradiol 0.01% and testoster­ conservative therapy for overactive pelvic one 0.1% reduced visual analogue pain floor muscle dysfunction, 83% reported dys­ scores from 7.5 to 2.0 in 50 consecutive pareunia after 24 weeks after injection of up women with vestibulodynia in whom the ini­ to 300 units of botulinum toxin Type A [31]. tiation of combined oral contraceptive pills Therefore, given the results of the majority of was associated with vestibulodynia onset studies and the clinical experience of the [34]. In a randomized controlled trial, Foster authors, we recommend botulinum toxin et al. showed that topical estradiol reduced Type A be used to augment pelvic floor vulvar pain sensitivity in menopausal women ­physiotherapy in the treatment of women with mixed vulvovaginal complaints [35]. with dyspareunia and vestibulodynia associ­ Lastly, Yount and colleagues reported that ated with overactive pelvic floor muscle 88% of 201 women treated with estradiol dysfunction. alone or in combination with biofeedback had at least a 70% reduction in their pain Corticosteroids [36]. Therefore, the authors endorse topical Despite the fact that most studies show cream comprised of estradiol 0.01% (or topi­ ­elevated inflammatory cytokines in the ves­ cal estriol 0.03%) and testosterone 0.05–0.1% tibular mucosa of women with vestibulo­ for all women who have vestibulodynia that dynia, the majority of data suggests that affects the entire vestibule. This is especially topical corticosteroids are minimally effective true if the history supports the diagnosis of a in treating vestibulodynia [7]. Therefore, due hormonally associated vestibulodynia, such to the lack of efficacy of low dose corticoster­ as history of combined hormonal contracep­ oids and potential side effects of high potency tives use, hormonal control of endometrio­ corticosteroids, the authors do not recom­ sis, oophorectomy, lactation, when treated mend topical corticosteroids for the manage­ with GRNH agonists, perimenopause, or ment of dyspareunia or vestibulodynia. menopause.

Interferon Systemic Medications Interferon is a signaling protein that down­ Leo and Dewani conducted a literature review regulates the expression of proinflammatory regarding the effectiveness of oral antidepres­ cytokines [32]. Additionally, interferon is sant medication in treating vulvodynia [37]. potent mast cell inhibitor and it has been Their review included two randomized con­ suggested that mast cells have a role in the trolled trials, one quasi‐experimental trial, initiation of neuroproliferative associated seven nonexperimental studies, and three vestibulodynia [33]. One randomized control case reports. The majority of the cases dis­ trial, three case series, and one case study cussed in the reports reviewed received tricy­ have examined the efficacy of interferon in clic antidepressant treatment. The results of vestibulodynia [7]. The majority of these randomized controlled trials of systemic tri­ studies found modest improvement with cyclic antidepressants provide evidence that submucosal vestibular interferon injections. they should not be used for vestibulodynia. Though more studies are needed, the authors Therefore, despite the widespread use of tri­ believe that interferon may play a role if cyclic antidepressants, a first‐line treatment treatment of inflammation associated vesti­ for vulvodynia, we recommend that antide­ bulodynia if this treatment is initiated shortly pressant medication not be used for the man­ after the onset of symptoms. agement of vestibulodynia. Medical Management of Dyspareunia and Vulvovaginal Pain 333

Anticonvulsant therapy has been recom­ Woodruff and Parmley were the first mended in the treatment of vulvodynia. authors to describe vulvar vestibulectomy in However, convincing evidence to support 1983 [43]. Their procedure consisted of the this therapeutic option is lacking. Spoelstra excision of a semicircular segment of per­ and colleagues performed a review of the ineal skin, the mucosa of the posterior vulvar available peer‐reviewed literature, including vestibule, and the posterior hymeneal ring. two case reports, three retrospective studies, Three centimeters of the vaginal mucosa was two nonrandomized prospective studies, and then undermined and approximated to the one open‐label pilot trial study [38]. Given perineum. Since this original procedure, sev­ the mixed results of these studies and poten­ eral variations of the procedure have been tial side effects, the authors of this chapter described to help decreased complications, concur with their recommendation to wait such as dehiscence of the vaginal advance­ for the results of an National Institutes of ment flap as well as to improve operative suc­ Health‐funded multicentered randomized cess [41]. Of all the variations, the authors of controlled trial to be completed before rec­ this chapter strongly believe that the best ommending the use of anticonvulsants for version of this procedure is a complete vulvar vulvodynia [39]. vestibulectomy with vaginal advancement. This procedure includes the excision of the Surgical Treatment mucosa of the entire vulvar vestibule, includ­ ing the mucosa adjacent to the urethra [44]. As discussed earlier, one subcategory of By removing all of the vestibular mucosa, all ­vestibulodynia is a neuroproliferative associ­ of the hyperpathic areas are removed. ated vestibulodynia in which there is up to a Complications of vestibulectomy occur, 10‐fold increase in the density of C‐afferent though they are infrequent. Specifically, nociceptors in the vulvar vestibular endo­ complications include bleeding, infection, derm [40]. Due to the increased density increased pain, hematoma, wound dehis­ of C‐afferent nociceptors, women with cence, scar tissue formation, and Bartholin ­neuroproliferative‐associated vestibulo­ cyst formation. The risk of these complica­ dynia experience allodynia and hyperpathia tions can be reduced if appropriate surgical at the vulvar vestibule. In women with neu­ techniques are used. Since the risks of com­ roproliferative‐associated vestibulodynia plication are low, they should be realistically who have failed conservative treatment with presented when counseling patients about topical capsaicin, vulvar vestibulectomy surgical treatment for vestibulodynia [42]. with vaginal advancement can be performed The authors want to emphasize that despite to remove the abnormal vestibular endo­ the very high success rates of surgery, the old derm. Since this first published report in adage that the success of surgery is made 1983, there have been over 40 published before walking into the operating room by peer‐reviewed papers examining variations choosing the appropriate surgical candidate of vulvar vestibulectomy [41]. A 2010 meta‐ is especially true in the case of vulvodynia. analysis of 33 previous studies revealed that The surgery should only be performed in vulvar vestibulectomy provided significant women with neuroproliferative‐associated relief of dyspareunia in 78.5% of patients, vestibulodynia. Women who have pain con­ some relief in 88.8% of patients, and no relief fined to the posterior vestibule, therefore, are in 12.2% [42]. In the nine studies that typically not surgical candidates, as they reported improvement in sexual function as most likely have vestibulodynia secondary to a measure of surgical success, all nine overactive pelvic floor muscle dysfunction. reported significant improvement in sexual In addition, women who have allodynia of function following vestibulectomy. the entire vestibule should undergo a clinical 334 Textbook of Female Sexual Function and Dysfunction

trial of topical estradiol and testosterone regarding the use of the fractional CO2 laser cream (while off combined hormonal contra­ for vulvovaginal pain. ceptivess) to rule in or to exclude hormonally associated vestibulodynia. ­Conclusions Emerging Therapies A comprehensive history and physical Laser therapy for the treatment of dyspareu­ examination is essential in the evaluation nia and vulvovaginal pain is an area of devel­ and treatment of women with sexual pain oping research. In Murina’s pilot study of 70 disorders and/or vulvodynia. In addition, a women treated with micro‐ablative frac­ thorough psychosocial evaluation must be tional CO2 laser to the vulvar vestibule, included to fully understand the pain expe­ improvement was reported in dyspareunia rience of women with dyspareunia. While and pain scores, with gradual improvement past treatments were somewhat empirical occurring over four months of follow‐up in nature, the new vulvodynia nomencla­ [45]. Two‐thirds of women reported they ture and subcategories of vulvodynia will were either “very improved” or “improved”. enable clinician to implement a more tar­ No major adverse events were reported. geted and logical treatment approach. In Multicenter studies are underway. The addition, the new nomenclature will facili­ authors await the results of further studies tate the design of superior quality studies before making definitive recommendations by researchers.

References

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12 Greenstein A, Ben‐Aroya Z, Fass O, et al. provoked vestibulodynia. J Sex Med. Vulvar vestibulitis syndrome and estrogen 2011;8:489–496. dose of oral contraceptive pills. J Sex Med. 23 Munday P, Buchan A, Ravenhill G, et al. A 2007;4:1679–1683. qualitative study of women with 13 Goldstein AT, Belkin ZR, Krapf JM, et al. vulvodynia: II. Response to a Polymorphisms of the androgen receptor multidisciplinary approach to management. gene and hormonal contraceptive induced J Reprod Med. 2007;52:19–22. provoked vestibulodynia. J Sex Med. 24 Sadownik LA, Seal BN, Brotto LA. 2014;11: 764–771. Provoked vestibulodynia‐women’s 14 Clayton AH, Campbell BJ, Favit A, et al. experience of participating in a Symptoms of sexual dysfunction in patients multidisciplinary vulvodynia program. treated for major depressive disorder: a J Sex Med. 2012;9:1086–1093. meta‐analysis comparing selegiline 25 Tympanidis P, Casula MA, Yiangou Y, et al. transdermal system and placebo using a Increased vanilloid receptor VR1 patient‐rated scale. J Clin Psychiatry. innervation in vulvodynia. Eur J Pain. 2007;68:1860–1806. 2004;8:129–133. 15 Ferris DG, Nyirjesy P, Sobel JD, et al. 26 Baron R. Capsaicin and nociception: from Over‐the‐counter antifungal drug misuse basic mechanisms to novel drugs. Lancet. associated with patient‐diagnosed 2000;356:785–787. vulvovaginal candidiasis. Obstet Gynecol. 27 Steinberg AC, Oyama IA, Rejba AE, et al. 2002;99:419–425. Capsaicin for the treatment of vulvar 16 Ledger WJ, Monif GR. A growing concern: vestibulitis. Am J Obstet Gynecol. inability to diagnose vulvovaginal 2005;192:1549–1553. infections correctly. Obstet Gynecol. 28 Murina F, Radici G, Bianco V. Capsaicin 2004;103:782–784. and the treatment of vulvar vestibulitis 17 Berle I. Clinical photography and patient syndrome: a valuable alternative? rights: the need for orthopraxy. J Med MedGenMed. 2004;6:48. Ethics. 2008;34: 9–92. 29 Cui M, Khanijou S, Rubino J, Aoki KR. 18 King M, Rubin R, Goldstein A. Current Subcutaneous administration of botulinum uses of surgery for the treatment of genital toxin A reduces formalin‐induced pain. pain. Curr Sex Health Rep. 2014;6:6. Pain. 2004;107:125–133. 19 Raghu AR, Nirmala NR, Sreekumaran N. 30 Bentsianov B, Zalvan C, Blitzer A. Direct immunofluorescence in oral lichen Noncosmetic uses of botulinum toxin. planus and oral lichenoid reactions. Clin Dermatol. 2004;22:82–88. Quintessence Int. 2002;33:234–239. 31 Morrissey D, El‐Khawand D, Ginzburg N, 20 Landry T, Bergeron S, Dupuis MJ, et al. Botulinum toxin A injections into Desrochers G. The treatment of provoked pelvic floor muscles under electromyo­ vestibulodynia: a critical review. Clin J graphic guidance for women with Pain. 2008;24:155–171. refractory high‐tone pelvic floor 21 Backman H, Widenbrant M, Bohm‐Starke dysfunction: a 6‐month prospective pilot N, Dahlof LG. Combined physical and study. Female Pelvic Med Reconstr Surg. psychosexual therapy for provoked 2015;21:277–282. vestibulodynia‐an evaluation of a 32 Keisseier BC. The mechanism of action of multidisciplinary treatment model. J Sex interferon‐β in relapsing multiple sclerosis. Res. 2008;45:378–385. CNS Drugs. 2011;25(6):491–502. 22 Spoelstra SK, Dijkstra JR, van Driel MF, 33 Bornstein J, Cohen Y, Zarfati D, et al. Weijmar Schultz WC. Long‐term results of Involvement of heparanase in the an individualized, multifaceted, and pathogenesis of localized vulvodynia. Int J multidisciplinary therapeutic approach to Gynecol Pathol. 2008;27:136–141. 336 Textbook of Female Sexual Function and Dysfunction

34 Burrows LJ, Goldstein AT. The treatment 40 Bohm‐Starke N, Hilliges M, Falconer C, of vestibulodynia with topical estradiol and Rylander E. Increased intraepithelial testosterone. Sex Med. 2013;1:30–33. innervation in women with vulvar 35 Foster DC, Palmer M, Marks J. Effect of vestibulitis syndrome. Gynecol Obstet vulvovaginal estrogen on sensorimotor Invest. 1998;46:256–260. response of the lower genital tract: a 41 Goldstein AT, Klingman D, Christopher K, randomized controlled trial. Obstet et al. Surgical treatment of vulvar Gynecol. 1999;94:232–237. vestibulitis syndrome: outcome 36 Yount JJ, Solomons CC, Willems JJ, et al. assessment derived from a Effective nonsurgical treatments for vulvar postoperative questionnaire. J Sex Med. pain. Women’s Health Dig. 1997;3:88–93. 2006;3:923–931. 37 Leo RJ, Dewani S. A systematic review of the 42 Tommola P, Unkila‐Kallio L, Paavonen J. utility of antidepressant pharmacotherapy in Surgical treatment of vulvar vestibulitis: a the treatment of vulvodynia pain. J Sex Med. review. Acta Obstet Gynecol Scand. 2013;10:2497–2505. 2010;89:1385–1395. 38 Spoelstra SK, Borg C, Weijmar Schultz 43 Woodruff JD, Parmley TH. Infection of the WC. Anticonvulsant pharmacotherapy for minor vestibular gland. Obstet Gynecol. generalized and localized vulvodynia: a 1983;62:609–612. critical review of the literature. J Psychosom 44 Goldstein A. Surgical techniques: surgery Obstet Gynaecol. 2013;34:133–138. for vulvar vestibulitis syndrome. J Sex Med. 39 Brown CS, Foster DC, Wan JY, et al. 2006;3:559–562. Rationale and design of a multicenter 45 Murina F, Karram M, Salvatore S, Felice R. randomized clinical trial of extended Fractional CO2 Laser Treatment of the release gabapentin in provoked vestibule for patients with vestibulodynia vestibulodynia and biological correlates of and genitourinary syndrome of menopause: response. Contemp Clin Trials. a pilot study. J Sex Med. 2013;36:154–165. 2016;13:1915–1917. 337

Part V

Future

Chapter No.: 1 Title Name: p05.indd Comp. by: Date: 22 Mar 2018 Time: 11:32:37 AM Stage: WorkFlow: Page Number: 337 339

23

Future Developments and Research James A. Simon

Abstract

Medication and device development for women’s sexual health has lagged significantly behind both scientific advances and comparable innovations in men’s sexual health. Testosterone therapy for hypogonadism is just one example. As such, women are forced to use male products at scaled down doses, or compounded products with their variabilities of formulation and absorption, and without the benefit of a package insert outlining any risks. While proprietary and confidentiality restric- tions limit some of the thrilling developments reviewed here, the innovative landscape remains exciting. Future developments will, ultimately, depend upon the market and financial success of currently approved therapies.

Keywords: future therapies; drug development for sexual dysfunction; regulatory pathways; Food and Drug Administration (FDA); clinical trials

­Introduction: Historical perspective. While other regulatory bodies and Regulatory Perspective (i.e. The European Medicines Agency) have not always agreed with the Food and Drug The history of product development in the Administration (FDA) on the approval of treatment of female sexual dysfunction has female sexual therapies (e.g. Intrinsa®, dis- been riddled with failures [1]. The difficulties cussed later), such disparities in approval include different regulatory criteria for men’s are the exception. versus women’s products even for the same Estrogens, whether endogenous or exoge- chemical entity (described later), as well as nous, are largely adjunctive for sexual inappropriate efficacy evaluations carried ­benefits [3]. That is, without adequate estro- over from treatments for male erectile dys- genization, sexual function can be signifi- function (e.g. counting sexual events, which cantly limited. Estrogen therapies (both are only tangentially associated with female systemic and local) are widely available to sexual desire [2]). This section reviews the treat vulvar and vaginal atrophy (genitouri- development landscape for several products nary syndrome of menopause). Systemic in various therapeutic areas of women’s sex- estrogen treatments are also FDA approved ual health. While the focus here is on phar- for vasomotor symptoms and prevention of maceutical medications, a few devices for bone loss to delay or reduce osteoporosis sexual dysfunction are also reviewed. The risk. Significant concerns about the long‐ vantage point for this section is strictly a US term risks of such estrogen or estrogen and

Textbook of Female Sexual Function and Dysfunction: Diagnosis and Treatment, First Edition. Edited by Irwin Goldstein, Anita H. Clayton, Andrew T. Goldstein, Noel N. Kim, and Sheryl A. Kingsberg. © 2018 John Wiley & Sons Ltd. Published 2018 by John Wiley & Sons Ltd. 340 Textbook of Female Sexual Function and Dysfunction

progestin therapies continue to abound, women, regulatory barriers and their associ- despite evidence documenting safety in early ated costs have prevented approval. menopausal women [4–8]. Because of such Testosterone patches (Intrinsa®) failed to controversy regarding the risk/benefit achieve FDA approval for treatment of hypo- ­balance of systemic hormonal treatments, active sexual desire disorder because of per- testosterone therapies for women have lan- ceived safety concerns requiring long‐term guished in development following a series of (i.e., 5 years) safety studies focused on cardio- regulatory failures. vascular disease (i.e. triggering of stroke and A brief overview of testosterone’s regula- myocardial ischemia events) and breast can- tory history will be illustrative and facilitate cer risks. These potential risks were assumed an understanding of other women’s sexual to be valid based on estrogen’s risks, and the health developments. Testosterone therapy temporally simultaneous FDA‐IntrinsaTM has been the mainstay of “off‐label” treat- advisory committee and publication of the ment for peri‐ and postmenopausal women Women’s Health Initiative estrogen‐only arm with low sexual desire and other sexual dys- [23]. With the absence of such risks in the functions (i.e. reduced clitoral sensitivity) clinical development ­program, Intrinsa® was [9–14]. Prior to the clinical development of deemed clinically effective by the FDA’s advi- testosterone patches for women (Intrinsa®, sory committee in 2004, based upon multiple Proctor and Gamble), most clinical trials randomized, placebo‐controlled clinical tri- were investigator initiated, of limited sample als in postmenopausal women. The concerns size, and employed subcutaneous implants about cardiovascular and breast cancer [15], intramuscular injections [16], or oral safety, however, resulted in the withdrawal of therapies [17, 18]. Each of these approaches the Intrinsa® application. Even in the absence had significant and distinct disadvantages: of long‐term safety data, the testosterone subcutaneous implants required a surgical patch was approved for marketing in Europe procedure, albeit a minor one, every 4–6 by the European Medicines Agency based months; intramuscular injections could be upon the exact same efficacy and safety data. accompanied by supraphysiological serum Transdermal testosterone gel for women testosterone concentrations and associated (LibigelTM; BioSante) also failed to achieve side effects (acne, hirsutism); oral medica- FDA regulatory approval for the treatment of tion had adverse effects on lipids and hypoactive sexual desire disorder in post- ­lipoproteins due to their “first‐pass” liver menopausal women due to inadequate metabolism. These testosterone therapies, ­efficacy, presumably due to the very high pla- however, did have positive effects on various cebo effect [24]. In a five‐year FDA Special aspects of female sexual functioning, espe- Protocol Assessment safety trial, there was cially in surgically menopausal women no indication of increased risk for cardiovas- [18–21], who often have a profound testos- cular disease or breast cancer through terone deficiency. But similar results were approximately four years (unpublished data) also documented in naturally menopausal before the company discontinued the study women [22]. These benefits included due to insufficient resources [25]. increases in the number of satisfying sexual AndroFeme® (Lawley Pharmaceuticals Ltd.) events, improved sexual desire, (often with is a 1% daily testosterone cream specifically improved arousal/orgasm/pleasure scores, formulated for use in women that is available decreased sexual concerns, improved sexual in Australia. It has been shown to increase sex- responsiveness and better self‐image), along ual motivation [26]. with decreased sexual distress. All of these The therapeutic need for testosterone in endpoints were documented using validated women is currently being satisfied by the instruments. Yet, despite efforts to obtain growing use of compounded testosterone FDA approval for testosterone therapy in products with little regulatory oversight and Future Developments and Research 341 no package insert articulating the risks or the countries were hampered by: (i) approval use of men’s testosterone products of which only for surgically menopausal women, (ii) there are now about 30 varieties, including prior authorization by the government was generic formulations that are FDA approved strictly enforced, and (iii) costs of the prod- for men. Male testosterone products require uct were set too high by the manufacturer, a dose adjustment for female use (in general deterrent both to the patient attempting to one‐tenth of the male dose). buy it “out of pocket”, and to private insurers The disparity between the approval of tes- considering adding it to their formulary. tosterone products for men versus women A sample of future products in develop- stems largely from a completely different set ment is listed here [27]. Products are listed in of criteria for approval, and the cost differ- alphabetical order. ences thereof. Briefly speaking, men’s ­testosterone products are approved for AMAG Pharmaceuticals hypogonadism, indicated by a serum testos- terone level that is below normal, and any AMAG Pharmaceuticals acquired the exclu- associated symptoms. Approval requires sive US rights to bremelanotide from Palatin safely returning the serum concentration of Technologies, Inc. in early 2017. Palatin was testosterone to the normal male range. developing targeted, receptor specific pep- Safety is adequately satisfied by a six‐month tide therapeutics for the treatment of various safety study, although review and updating diseases with significant unmet medical need of this safety hurdle is underway at the FDA. and commercial potential. In this context, In women, however, approval is for the AMAG‐Palatin is developing bremelanotide, ­complex biopsychosocial phenomena, a melanocortin peptide agonist, specifically, ­hypoactive sexual desire disorder (Chapters 5 a MC4r agonist, for sexual dysfunction. This and 6). For development of testosterone on‐demand, self‐administered auto‐injector products for use in women, the therapy therapy is used in anticipation of sexual must: (i) restore testosterone concentrations activity. Bremelanotide targets endogenous into the normal female range; (ii) effectively pathways involved in sexual desire and treat the specific symptom of low desire; and arousal. Following a successful phase 2B ran- (iii) reduce the distress of having low desire. domized, placebo‐controlled, dose ranging That is, efficacy in women must satisfy three clinical trial in more than 1200 premenopau- different endpoints at once, while docu- sal women with acquired, generalized hypo- menting safety during a five‐year study. active sexual desire disorder, Clayton et al. [28] reported highly significant benefits on desire, arousal, and orgasm. Also noted were ­The Marketplace statistically significant decreases in desire‐ related distress and increases in sexual events Large amounts of capital are necessary for and patient satisfaction. Bremelanotide was the development of medications or devices generally well tolerated. The most common and the initial marketing of a newly FDA‐ adverse events were nausea, headache, and approved product is extremely costly. This is flushing (generally described by study par- particularly critical in a new therapeutic ticipants as mild/moderate). More recently, ­category like women’s sexual health, where the results of two phase 3 efficacy trials and public and practitioner education must also the open label roll‐over safety extension be advanced. The Intrinsa® testosterone study were reported [29]. These so called patch was approved for marketing in the RECONNECT studies also showed statisti- then European Union, but was withdrawn in cally significant and clinically meaningful 2010 for financial (i.e. business) reasons. improvement when compared to ­placebo in Sales of the product in several European sexual desire and distress. About 60% of 342 Textbook of Female Sexual Function and Dysfunction

enrolled study subjects on bremelanotide sexual cues and reduces the inhibitory completed the trial, and about 80% of patients response to such cues. To document this dual that completed the Phase 3 efficacy studies control concept, and the efficacy of the two elected to participate in the open label roll‐ therapies, Emotional Brain conducted a dou- over safety extension study. Side effects were ble‐blind, randomized, placebo‐controlled similar to those reported in Phase 2B. trial with Lybrido and Lybridos in 56 patients At a similar time to its acquisition of suffering from hypoactive sexual desire dis- Palatin, AMAG also acquired from order. Each study subject served as her own Endoceutics, Inc. the marketing rights to a control, with all study subjects receiving vaginal dehydroepiandrosterone product, Lybrido, Lybridos, or matching placebo for prasterone (aka VaginormTM or IntrarosaTM). one month each during three consecutive Prasterone is a steroid indicated for the treat- months. The order of the three treatments ment of moderate to severe dyspareunia, a was randomized with a one‐week washout symptom of vulvar and vaginal atrophy, due between them. Sexual satisfaction was to menopause. As preliminary studies for the assessed following each sexual event using treatment of vulvovaginal atrophy [30, 31] the sexual arousal response self‐assessment suggested a benefit for other sexual dysfunc- questionnaire. Women with low sensitivity tions, Endoceutics is embarking on a sepa- to sexual cues and hypoactive sexual desire rate study in women without vulvovaginal disorder reported significantly more sexual atrophy to assess Intrarosa’sTM benefit for satisfaction during sexual events when using ­hypoactive sexual desire disorder. Lybrido compared to placebo, while women with high inhibition to sexual cues and Emotional Brain ­hypoactive sexual desire disorder reported significantly more sexual satisfaction during Based on the early writings of Drs John sexual events when using Lybridos compared Bancroft [32] and Michael A. Perelman [33] to placebo. At the time of writing, these suggesting that loss of sexual desire could results are still unpublished, as is the propri- result from two entirely different phenom- etary instrument to ascertain whether a ena, either too much inhibition or not enough woman with hypoactive sexual desire disor- stimulation, Emotional Brain, Inc. embarked der has high inhibition or low excitation. on the development of a personalized medi- Such discrimination would be required to cine approach to the treatment of hypoactive assess which of the two products would best sexual desire disorder, using two separate serve the women with hypoactive sexual clinical treatments. These two treatments are desire disorder. Phase 3 trials are planned. based upon the documented time from a rise in serum testosterone to a clinically recog- S1 Biopharma nized increase in sexual desire [34], and then either increasing stimulation or decreasing S1 Biopharma, Inc. is developing Lorexys®. inhibition to sexual cues. Described in detail An investigational new drug application in three separate consecutive published (IND) for this therapy, a combination prod- manuscripts [35–37], the two resulting uct consisting of bupropion and trazodone as ­products, Lybrido and Lybridos, consisted a treatment for hypoactive sexual desire dis- of formulations to increase excitation order in women, was filed with the FDA in and decrease inhibition, respectively. 2012. Bupropion, (Wellbutrin®, and others) is Testosterone/sildenafil (Lybrido), as its con- a norepinephrine and dopamine reuptake stituents would suggest, increases the brain’s inhibitor prescribed for more than 20 years response to sexual cues and enhances geni- in the treatment of major depression and tal sexual response. Testosterone/buspirone smoking cessation, and used off‐label to treat (Lybridos) increases the brain’s response to sexual side effects of selective serotonin Future Developments and Research 343 reuptake inhibitors. Bupropion is mildly acti- improved safety profile, (ii) faster onset of vating and is usually dosed in the morning to action, (iii) avoidance of first‐pass metabo- avoid sleep disturbances. It has been demon- lism and potential inactivation of the drug by strated to improve sexual function in women the liver, and (iv) more sustained and con- with hypoactive sexual desire disorder when trolled delivery of the drug over time, leading used alone at relatively high doses [38]. to less fluctuation or sudden spikes in circu- Trazodone (Desyrel®, Oleptro®, and others) lating drug levels. is an antidepressant of the serotonin antago- Strategic Science & Technologies is devel- nist reuptake inhibitor class acting as a 5‐ oping a prescription product for female sex- HT2A receptor antagonist and a moderate ual arousal disorder using topical sildenafil 5‐HT reuptake inhibitor. Trazodone also has and Strategic Science & Technologies’ propri- anxiolytic and sleep‐inducing (hypnotic) etary technology containing 5% sildenafil cit- effects. Psychosexual side effects of trazo- rate by weight. Due to the skin’s highly done reported in women include increased protective barrier, the stratum corneum, topi- libido, priapism of the clitoris and spontane- cal delivery approaches have been mostly lim- ous orgasms [39–41]. A small clinical trial of ited to small, uncharged molecules. trazodone has demonstrated prosexual KNOSISTM overcomes these challenges using effects as well [42]. Using both these agents two novel features: (i) by producing a hostile together in a time release formulation is biophysical environment for the active phar- thought to “cancel out” the alerting (bupro- maceutical ingredient, thereby increasing its pion) and sedating (trazodone) side effects free energy and creating a positive chemical while the prosexual effects are additive. potential, which drives the active pharmaceu- In the so‐called Phase 2a Trial 1000, two tical ingredient into the skin; and (ii) by pre- dose combinations of Lorexys® were com- venting the formation of hydrogen bonds pared to bupropion in an open label, three‐ between the active pharmaceutical ingredient way, cross‐over design of 30 premenopausal and the stratum corneum, which can inhibit women with hypoactive sexual desire disor- the ability of the active pharmaceutical ingre- der. The results of this trial were presented at dient to permeate into the tissue. the 4th International Consultation on Sexual Results from preclinical functional and Medicine 2015 in Madrid, Spain. Compared molecular biology studies have shed light on to bupropion alone, the Lorexys® treatment an analogous nitric oxide–cyclic guanosine group had a significantly greater number of monophosphate biological pathway present responders based on multiple assessments in female genital tissue. Deduced by means (desire domain of the Female Sexual Function of immunohistochemistry methods in Index, Female Sexual Distress Scale Revised, female tissue sections, the phosphodiester- and the Patient Global Impression of ase type 5 isoenzyme is expressed in vascu- Change). Moderate sedation was the most lar smooth muscle cells of human clitoral common side effect (unpublished). More corpus cavernosum, the vagina, and the labia extensive trials are planned. minora [43–45]. Collectively, these struc- tures play a central role in mediating the Strategic Science & Technologies, LLC female genital arousal response, thus provid- ing the basis of support for the development Strategic Science & Technologies, LLC has a of Strategic Science & Technologies’ topical proprietary topical drug delivery technology sildenafil for this critical unmet medical (KNOSISTM), which provides targeted local need. delivery of active pharmaceutical ingredients. A Phase 1 pharmacokinetic and safety trial Targeted local delivery has several advantages with topical sildenafil clearly demonstrated according to the company: (i) significantly successful delivery of sildenafil across the lower systemic exposure resulting in an vulvar skin and vaginal epithelium and into 344 Textbook of Female Sexual Function and Dysfunction

the systemic circulation. No significant sys- omized to one of three dosage strengths temic or dermal adverse effects were seen (0.6 mg, 1.2 mg, 1.8 mg) or a matching pla- with applications of 1–2 g of topical sildena- cebo, and treated over the course of 84 days. fil, considered sufficient to deliver a thera- The primary endpoint of the study was to peutic dose of sildenafil (data unpublished). compare the nasal testosterone gel to placebo Strategic Science & Technologies recently on the occurrence of orgasm. Secondary completed a Phase 2 proof‐of‐concept study endpoints included the change from baseline in premenopausal and postmenopausal in sexually‐related distress due to female women with female sexual arousal disorder. orgasmic disorder, and the change in sexual The Phase 2, double‐blind, placebo‐­ functioning and sexual event satisfaction. controlled, two‐way cross‐over clinical trial According to a press release (28 May 2014 evaluated the efficacy and safety of topical from Trimel Pharmaceuticals Corp.), TefinaTM sildenafil in women with female sexual 0.6 mg (the lowest of three doses tested) led arousal disorder following a single 2 g dose to a statistically significant increase in the (71 mg sildenafil) applied to the local vulvar‐ average number of orgasms during the 84‐ vaginal target site. The study enrolled a total day treatment period of 2.3 ­versus 1.7 for the of 31 women with female sexual arousal dis- placebo arm (p = 0.0015). The secondary order, 15 premenopausal and 16 postmeno- endpoints were noted to have improved, but pausal, and assessed genital response using a no data were reported. TefinaTM was vaginal photoplethysmograph and perceived described as “well tolerated” with no reported sexual arousal with a Likert‐scale question- serious adverse events. To date this study has naire and arousometer device (data pending/ not been published. unpublished, Dr. Cindy Meston, University Femprox® is an alprostadil‐based 0.4% top- of Texas at Austin). Secondary objectives ical cream applied directly to the clitoris and included time to onset of action and safety. G‐spot before coitus. It was developed for the treatment of female sexual interest/ Other Companies and Products arousal disorder. It contains prostaglandin E1 as the active ingredient and a proprietary TefinaTM, an intranasal “on demand” testos- permeation enhancer (NexACT), which terone gel, is being developed by Acerus facilitates the delivery of the drug into the Pharmaceuticals Corp., a Canadian pharma- circulation. Apricus Biosciences has com- ceutical company (formerly Trimel Pharma). pleted nine clinical studies to date, including TefinaTM is intended for the treatment of a 98 patient Phase 2 study in the United women with acquired orgasmic disorder. States, and a near 400 patient Phase 3 study The gel is a 0.6 mg nasal application of testos- in China demonstrating a statistically signifi- terone (2–6 h before sexual activity). TefinaTM cant dose‐dependent increase in sexual func- has been studied in a Phase 2, double‐blind, tion (assessed by the Female Sexual Function placebo‐controlled study of 253 pre‐ and Index), while reducing sexually‐related dis- postmenopausal women experiencing tress with mild topical irritation as the only acquired female orgasmic disorder, charac- adverse event [46]. Femprox® exerts a local, terized by a markedly reduced intensity of relaxant effect on vulvar and clitoral blood orgasmic sensations, or by a marked delay in, vessels in women, leading to increased blood marked infrequency or absence of orgasm, flow. The resultant increase in vaginal lubri- that has persisted for a minimum duration of cation and sensory feedback is believed to approximately six months and causes clini- produce a clinically significant increase in cally significant distress in the individual. sexual arousal in women with female sexual Conducted in the United States, Canada, and arousal disorder or female sexual interest/ Australia, study participants were rand- arousal disorder. Future Developments and Research 345

Mona Lisa Touch® Laser developed by Deka Development continues for this agent for M.E.L.A. Srl in Italy and sold in the United breast cancer resistant patients, a population States by Cynosure/Hologic has been FDA that can often benefit from vulvovaginal atro- cleared for the treatment of vaginal atrophy phy/genitourinary syndrome of menopause due to menopause and the resulting symp- treatment without estrogens, and which may toms. Recently, preliminary data for use of this also have hypoactive sexual desire disorder. laser have been published for the treatment of Almost 10 years ago, initial reports of radi- vulvovestibulitis syndrome and dyspareunia ofrequency treatments for vaginal laxity unrelated to menopausal changes. These pre- appeared in the literature [49]. Viveve, Inc. liminary results suggest significant benefits continues these investigations in hopes of for vulvovestibulitis syndrome associated pain obtaining FDA approval for this indication. and improved sexual function [47]. Vaginal laxity can be a sexual problem for Lasofoxifene (Pfizer Inc., Sermonix some women and their male partners. Lack Pharmaceuticals Inc.), a selective estrogen of adequate friction and indirect stimulation receptor modulator (e.g. tamoxifene, of the clitoris can result from laxity. Because toremifene, raloxifene, ospemifene), failed to radiofrequency energy can be “tuned” to pro- achieve regulatory approval for osteoporosis vide a depth of penetration associated with prevention and vulvovaginal atrophy in 2006, protein denaturation and resultant new col- and osteoporosis treatment in 2009, due to lagen development, it is thought that this FDA concerns over benefit/risk for those treatment can lead to vaginal tightening and indications, despite significant fracture improved sexual function including orgas- reduction and a 70% decrease in breast can- mic function [50]. Several small preliminary cer risk. Lasofoxifene has demonstrated effi- studies appear to confirm the benefits of this cacy for vulvovaginal atrophy and improved approach, including one with 12 months of sexual function in several clinical studies [48]. “long‐term” safety data [51–53].

­References

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27 Kingsberg SA, Clayton AH, Pfaus JG. The sexual desire disorder and female sexual female sexual response: current models, arousal disorder. J Sex Med. neurobiological underpinnings and agents 2013;10(3):791–809. currently approved or under investigation 36 Poels S, Bloemers J, van Rooij K, et al. for the treatment of hypoactive sexual Toward personalized sexual medicine (part desire disorder. CNS Drugs. 2): testosterone combined with a PDE5 2015;29(11):915–933. inhibitor increases sexual satisfaction in 28 Clayton AH, Althof SE, Kingsberg S, et al. women with HSDD and FSAD, and a low Bremelanotide for female sexual sensitive system for sexual cues. J Sex Med. dysfunctions in premenopausal women: a 2013;10(3):810–823. randomized, placebo‐controlled dose‐ 37 van Rooij K, Poels S, Bloemers J, et al. finding trial. Womens Health (Lond). Toward personalized sexual medicine (part 2016;12(3):325–337. 3): testosterone combined with a 29 Clayton A, Kingsberg S, Simon J, et al. Serotonin1A receptor agonist increases Efficacy of the Investigational Drug sexual satisfaction in women with HSDD Bremelanotide for Hypoactive Sexual and FSAD, and dysfunctional activation of Desire Disorder: Results From the sexual inhibitory mechanisms. J Sex Med. RECONNECT Studies. American Society 2013;10(3):824–837. of Psychopharmacology Annual Meeting 38 Segraves RT, Clayton A, Croft H, et al. (ASCPP‐NCDEU); Miami Beach, FL; 2017. Bupropion sustained release for the 30 Bouchard C, Labrie F, Derogatis L, et al. treatment of hypoactive sexual Effect of intravaginal desire disorder in premenopausal women. dehydroepiandrosterone (DHEA) on the J Clin Psychopharmacol. 2004;24(3): female sexual function in postmenopausal 339–342. women: ERC‐230 open‐label study. 39 Gartrell N. Increased libido in women Horm Mol Biol Clin Investig. receiving trazodone. Am J Psychiatry. 2016;25(3):181–190. 1986;143(6):781–782. 31 Labrie F, Archer D, Bouchard C, et al. Lack 40 Pescatori E, Engelman JC, Davis G, of influence of dyspareunia on the Goldstein I. Priapism of the clitoris: a case beneficial effect of intravaginal prasterone report following trazodone use. J Urol. (dehydroepiandrosterone, DHEA) on 1993;149(6):1557–1559. sexual dysfunction in postmenopausal 41 Battaglia C, Venturoli S. Persistent genital women. J Sex Med. 2014;11(7):1766–1785. arousal disorder and trazodone. 32 Bancroft J, Graham CA, Janssen E, Sanders Morphometric and vascular modifications SA. The dual control model: current status of the clitoris. A case report. J Sex Med. and future directions. J Sex Res. 2009;46(2–3): 2009;6(10):2896–2900. 121–142. 42 Eraslan D, Ertekin E, Ertekin BA, Ozturk O. 33 Perelman MA. The sexual tipping point: Treatment of insomnia with hypnotics a mind/body model for sexual medicine. resulting in improved sexual functioning in J Sex Med. 2009;6(3):629–632. post‐menopausal women. Psychiatr Danub. 34 Tuiten A, Van Honk J, Koppeschaar H, 2014;26(4):353–357. et al. Time course of effects of testosterone 43 Ückert S, Oelke M, Waldkirch E, et al. administration on sexual arousal in women. Cyclic adenosine monophosphate and Arch Gen Psychiatry. 2000;57(2):149–153; cyclic guanosine monophosphate‐ discussion 155–156. phosphodiesterase isoenzymes in human 35 Bloemers J, van Rooij K, Poels S, et al. vagina: relation to nitric oxide synthase Toward personalized sexual medicine (part isoforms and vasoactive intestinal 1): integrating the “dual control model” into polypeptide‐containing nerves. Urology. differential drug treatments for hypoactive 2005;65(3):604–610. 348 Textbook of Female Sexual Function and Dysfunction

44 Ückert S, Oelke M, Albrecht K, et al. 49 Millheiser LS, Pauls RN, Herbst SJ, Chen Immunohistochemical description of cyclic BH. Radiofrequency treatment of vaginal nucleotide phosphodiesterase (PDE) laxity after vaginal delivery: nonsurgical isoenzymes in the human labia minora. vaginal tightening. J Sex Med. 2010;7(9): J Sex Med. 2007;4(3):602–608. 3088–3095. 45 Ückert S, Oelke M, Albrecht K, et al. 50 Alinsod RM. Transcutaneous temperature Expression and distribution of key enzymes controlled radiofrequency for orgasmic of the cyclic GMP signaling in the human dysfunction. Lasers Surg Med. clitoris: relation to phosphodiesterase type 2016;48(7):641–645. 5 (PDE5). Int J Impot Res. 51 Sekiguchi Y, Utsugisawa Y, Azekosi Y, et al. 2011;23(5):206–212. Laxity of the vaginal introitus after 46 Zhang M, Liao QP, Yao C, et al. childbirth: nonsurgical outpatient [Multicenter randomized, double‐blind, procedure for vaginal tissue restoration and placebo‐controlled trial of prostaglandin improved sexual satisfaction using low‐ E1 cream for female sexual arousal energy radiofrequency thermal therapy. disorder]. Beijing Da Xue Xue Bao. J Womens Health (Larchmt). 2013;22(9): 2010;42(6):727–733. 775–781. 47 Murina F, Karram M, Salvatore S, Felice R. 52 Krychman M, Rowan CG, Allan BB, et al. Fractional CO2 laser treatment of the Effect of single‐treatment, surface‐cooled vestibule for patients with vestibulodynia radiofrequency therapy on vaginal laxity and genitourinary syndrome of menopause: and female sexual function: the VIVEVE I a pilot study. J Sex Med. 2016;13(12): randomized controlled trial. J Sex Med. 1915–1917. 2017;14(2):215–225. 48 Kingsberg S, Simon J, Symons J, Portman D. 53 Vicariotto F, DE Seta F, Faoro V, Raichi M. Lasofoxifene as a Treatment for Sexual Dynamic quadripolar radiofrequency Dysfunction in Postmenopausal Women. treatment of vaginal laxity/menopausal 21st Annual Fall Scientific Meeting Sexual vulvo‐vaginal atrophy: 12‐month efficacy Medicine Society of North America and safety. Minerva Ginecol. (SMSNA); Las Vegas, NV; 2015. 2017;69(4):342–349. 349

Index

Page locators in bold indicate tables. Page locators in italics indicate figures.

a ANS see autonomic nervous system absent ejaculation (male) 131–132 antibiotics 324 absent orgasm 224 anticonvulsants 333 ACOG see American Congress of antidepressants Obstetricians and Gynecologists dyspareunia and vulvovaginal pain acupuncture 290 324, 332 acute venous dilation 266 female orgasmic illness syndrome 241 adjunctive modalities 306–308 future developments and adrenergic regulation 110, 116 research 342–343 AEE see ambivalence over emotional expression hypoactive sexual desire disorder 79, 83–84 afferent pathway neurobiological endocrinology 70–71 arousal disorders 111–112 antihistamines 241 female orgasm disorder 225 antipsychotics 79 orgasm disorders 186 anxiety pelvic and sexual pain disorders 301 arousal disorders 129 sexual pain disorders 259, 264, 267 dyspareunia and vulvovaginal pain 324 agomelatine 84 pelvic and sexual pain disorders 306 alprostadil 152–153 persistent genital arousal disorder 163 Althof, Stan 3 provoked vestibulodynia 283, 286–288 AMAG Pharmaceuticals 341–342 aquaporin (AQP) 112 ambivalence over emotional expression arousal disorders (AEE) 285 anatomy and physiology of arousal 107–125 American Congress of Obstetricians and assessment of sexual response 134–135, Gynecologists (ACOG) 249 135, 136 amphetamines 241 diagnosis of FGAD 149–150 amygdala 186, 189, 227 diagnosis of PGAD 165–166 androgens see individual hormones; ovarian DSM classification 103–104 steroid hormones effects of partner dysfunction in delta5‐androstenediol 148 women 131–132 delta4‐androstenedione 61–63, 71, 86 epidemiology 105 anhedonic orgasm 224 ESSM assessment methods 14 anorexia nervosa 76 etiology of sexual arousal 128–131, 161–162 anorgasmia 224 genital and extragenital responses 107, 108

Textbook of Female Sexual Function and Dysfunction: Diagnosis and Treatment, First Edition. Edited by Irwin Goldstein, Anita H. Clayton, Andrew T. Goldstein, Noel N. Kim, and Sheryl A. Kingsberg. © 2018 John Wiley & Sons Ltd. Published 2018 by John Wiley & Sons Ltd.

Chapter No.: 1 Title Name: bindex.indd Comp. by: Date: 22 Mar 2018 Time: 11:32:46 AM Stage: WorkFlow: Page Number: 349 350 Index

arousal disorders (cont’d ) bridge with breathing 214 health and lifespan bupropion 83–84, 85, 233, 342–343 considerations 132–134 buspirone 342 hemodynamics 108–110, 109, 115–116 ISSWSH classification 104–105 c models of arousal 127–128 cabergoline 83, 231–232, 233 modulation by sex steroid hormones calcitonin 111 113–117, 114 cancer neurobiological endocrinology 148–150, arousal disorders 134 153–155 female orgasm disorder 228–229 neurologic interventions 156 orgasm disorders 208 neurotransmitters 110–112, 116 pelvic and sexual pain disorders 307 nonpharmacological treatments 135–136 candidiasis 324 nosology 103–105, 147, 162–163 capsaicin 328, 331 pathophysiology and medical management capsaicin receptors 260 of FGAD 145–160 cardiovascular disease (CVD) 230 pathophysiology and medical management Case of the Female Orgasm, The (Lloyd) 198 of PGAD 161–171 cataplexy 241 physiology of female genital arousal cauda equina syndrome 164, 168 responses 146 cavernous tissue 180 PRESIDE study 105 cell cultures 327 prevalence of PGAD in the United central nervous system (CNS) States 161 activation of excitatory systems 44 psychological management 127–144, 150, anatomy and neurochemistry of sexual 162, 166 desire 25–51 risk factors for women with FGAD 147–148 appetitive and consummatory risk factors for women with PGAD phases 28–29 163–165 attractivity, proceptivity, and receptivity 30 subjective arousal 107–108, 146–147 Basson’s circular feedback model 30, 31 treatment of FGAD 150–156 CNS agents 85 treatment of PGAD 166–168 excitation, inhibition, and disinhibition of vaginal lubrication 112–113, 115–116 sexual responses 35–40, 37, 38 autoimmune disorders 300 disinhibition 39–40 autonomic nervous system (ANS) 110–112 excitation 36–38 inhibition 38–39 b female genital arousal disorder 155–156 balanitis 212 female orgasm disorder 224, 232–233 Bartholin gland 325–326, 325, 326 glutamate in ventrolateral portion of Basson, Rosemary 30, 31, 43, 128, 200, 200 ventromedial hypothalamus 41–42 biofeedback 307, 332 incertohypothalamic dopamine 41 biomechanical abnormalities 297, 300 inhibition of inhibitory systems 44 biopsychosocial model 53–55, 54 introduction to sexual desire 25–26 bladder pain syndrome 259, 326–327, 328 lordosis 30–31, 33–34, 38–44 bladder retraining 306 Masters and Johnson’s EPOR model body image 129 29–30, 29, 35 botulinum toxin 308, 331–332 melanocortins 41 bowel retraining 306 menopause 32–33, 45–46 breathing practice 306 opioid receptors 39, 42 bremelanotide 45–46, 153, 341–342 orgasm disorders 184–189 Index 351

ovarian steroid hormones 31–34, 36–44 cognition 286 ovulatory cycles 31–32, 32 cognitive behavioral therapy (CBT) pacing behavior 42–43 arousal disorders 136–137 patterns of brain activation 34–35, 35 hypoactive sexual desire disorder 55–56 relevance of animals to humans 45–46 orgasm disorders 207 sexual approach behaviors 40 pelvic and sexual pain disorders 306 sexual behavior of human females 31–33 coital cephalalgia 240–241 sexual behaviors in animals and humans collagen 299 26–31 colposcopy 215, 324–325, 325 sexual brain stimuli 26–28 complementary and alternative therapies 290 sexual pain disorders 257 conditioned pain modulation 270 sexual positions 33 congenital factors 252 sexual tipping point model 27, 36, 37, 38 consent 303–304 solicitations 40–42 corticosteroids 332 structure of female sexual behavior 28–31 couples/marital therapy studying CNS regulation of female sexual arousal disorders 137–138 desire 34–35 hypoactive sexual desire disorder 56 treatments for HSDD 45–46, 45 orgasm disorders 206–207 wiring diagram of neurochemical provoked vestibulodynia 289–290 pathways 27, 28 crying 241 central sensitization 268–271, 268, 301, 306 CSFQ‐FC see Changes in Sexual Functioning cerebellum 188 Questionnaire cervix culture and religion anatomy and physiology of arousal 111 arousal disorders 129–130 CNS anatomy and neurochemistry of sexual orgasm disorders 200–202 desire 33, 42 psychological management 54 female genital arousal disorder 148 CUV see clito‐urethro‐vaginal peripheral and central neural bases of orgasm CVD see cardiovascular disease 183, 185 Changes in Sexual Functioning Questionnaire d (CSFQ‐FC) 213 Decreased Sexual Desire Screener 80 childhood sexual abuse 130–131, 286–288 deep muscle hyperalgesia 264–265, 269 cholesterol 60–61, 147 dehydroepiandrosterone (sulfate) cingulate cortex 188–189 female genital arousal disorder 148, 150 circular feedback model (Basson) 30, 31 hypoactive sexual desire disorder 83, 86 circular model of sexual response (Whipple neurobiological endocrinology 61–63, 71 and Brash‐McGreer) 199–200, 199 delayed ejaculation (male) 131–132 Clinical History of the Medical and Surgical delayed orgasm 224 Disease of Women, A (Barnes) 248 Dennerstein, Lorraine 3 clitoral hood 212, 214–216 depression clitoris arousal disorders 129 female genital arousal disorder 152 dyspareunia and vulvovaginal pain 324 gross anatomy 180, 182–183 female orgasmic illness syndrome 241 histology 179–180, 181 future developments and research 342–343 musculoskeletal management 215 hypoactive sexual desire disorder 22, 78, orgasm disorders 179–180, 182–185 79, 83–84 clitorodynia 167 neurobiological endocrinology 70–71 clito‐urethro‐vaginal (CUV) complex 184, 184 provoked vestibulodynia 283, 286 CNS see central nervous system psychological management 53–54 352 Index

desire disorder 13 medication history 323–324 desquamative inflammatory vaginitis 232 musculoskeletal management 312 desvenlafaxine 84 nonmedical treatments 329–330 device strategies 151–152 nosology 247–248, 319–320 diabetes mellitus physical examination 324–327, 325, 326 arousal disorders 133 provoked vestibulodynia 286–287, 290 female orgasm disorder 228 psychosocial history 323 hypoactive sexual desire disorder 77 serum testing 328 neurobiological endocrinology 75 sexual history 320–323, 322–323 Diagnostic and Statistical Manual of Mental surgical management 333–334 Disorders (DSM) treatment 328–334 arousal disorders 103–104 wet mount and cultures 327 female genital arousal disorder 147 dysphoria 241 female orgasm disorder 222–223 female orgasmic illness e syndrome 239–240 early development 67 hypoactive sexual desire disorder 19–20, ear pain 241–242 25–26 ED see erectile dysfunction International Society for the Study of education and training Women’s Sexual Health 2 algorithm incorporating specific medical orgasm disorders 175–176 condition 11, 12 sexual pain disorders 252–253 basic structured approach to diazepam 308 patients 10–11 dilators 307 competencies for undergraduate, graduate, dildos, female genital arousal and postgraduate levels 7–9, 8 disorder 151–152 conclusion and recommendations 12 direct masturbation training 207 disease or therapy specific factors 11, 12 dopamine elements of structured approach to CNS anatomy and neurochemistry of sexual patients 10 desire 36–38, 40–41, 45 ESSM assessment methods 11–12 hypoactive sexual desire disorder 84–85 arousal disorder 14 neurobiological endocrinology 70 desire disorder 13 orgasm disorders 187–188 orgasmic disorder 15 dry needling 308 female sexual health care for practicing DSM see Diagnostic and Statistical Manual of clinicians 9–11 Mental Disorders female sexual health care for sexual dysorgasmia 241 medicine specialists 11–12 dyspareunia and vulvovaginal pain 319–336 graduate and postgraduate (level 2 and 3) 9 additional testing 328 International Society for the Study of anatomy and physiology 266 Women’s Sexual Health 3–4 diagnostic and treatment modified nine‐field diagram 11 algorithm 329–330 orgasm disorders 208 emerging therapies 334 psychological management 55 epidemiology 250–253 sexuality 9 evaluation 320–328 sexual medicine 7–16 histology 327 undergraduate (level 1) 8–9 hormonally‐induced dyspareunia 312 electrical stimulation 307–308 interdisciplinary treatments 331 electromyography (EMG) 215, 307, 328 medical management 331–333 EMA see European Medicines Agency Index 353 embryological factors 252 f EMG see electromyography facial pain 241–242 emotion 284–286, 288 faking orgasm 201 Emotional Brain 342 fascial restrictions 300–301 emotional intimacy see intimacy FCAD see female cognitive arousal disorder empathy 284–285, 288 FDA see Food and Drug Administration endocrine disorders see neurobiological female cognitive arousal disorder endocrinology (FCAD) 145, 147 endometriosis 301, 326–327 female genital arousal disorder (FGAD) 104 environmental stressors 129 diagnosis 149–150 epidural nerve block 242 neurobiological endocrinology 148–150, epilepsy 226–227 153–155 EPOR see excitation, plateau, orgasm, neurologic interventions 156 resolution nosology 147 erectile dysfunction (ED) 131, 224 pathophysiology and medical Erotic Stimulus Pathway (Reed) 199 management 145–160 erythema of the ostia of the Bartholin physiology of female genital arousal gland 325–326, 325, 326 responses 146 ESSM see European Society for Sexual Medicine psychological management 150 estradiol risk factors for women with arousal disorders 115, 117 FGAD 147–148 CNS anatomy and neurochemistry of sexual subjective arousal 146–147 desire 33–34, 36–38, 40–44 treatment 150–156 dyspareunia and vulvovaginal pain 324 female orgasm disorder (FOD) female genital arousal disorder 149–150, diagnosis of women with FOD 229–230 154–155 DSM classification 222–223 female orgasm disorder 231 future developments and research 344 neurobiological endocrinology 61–62, genital responses prior to, during and 66, 68 immediately after female sexual pain disorders 251 orgasm 221–222 estrogen ISSWSH classification 222–224, 233 arousal disorders 114–117 neurologic disorders 225–229 female genital arousal disorder 148–149, nosology 222–224, 233 154–155 nosology and epidemiology 175–177 neurobiological endocrinology 61, 63, pathophysiology and medical 66–71 management 221–237 sexual pain disorders 260–261 prevalence 221 vaginal lubrication 112–113 psychological management 229 see also ovarian steroid hormones risk factors for women with FOD 224–229 estrogen receptors 260–261, 267 treatment of women with FOD 230–233 estrone 61, 63 female orgasmic illness syndrome (FOIS) European Medicines Agency central aversive symptoms 240–241 (EMA) 339–340 DSM classification 239–240 European Society for Sexual Medicine ISSWSH classification 239–240 (ESSM) 11–12, 13–15 nosology 239–240 excitation, plateau, orgasm, resolution (EPOR) pathophysiology and medical model 29–30, 29, 35 management 239–243 excitatory neurochemical agonists 155–156 peripheral aversive symptoms 241–242 exercise training 306 presentation 239 354 Index

female prostate 183 Goldstein, Andrew 3 female sexual arousal disorder (FSAD) Goldstein, Irwin 1, 3 103–104, 147, 344 gonadotropin releasing hormone 63, 65–66 female sexual distress scale (FSDS) 205 Graziottin, Alessandra 2 Female Sexual Function Forum 2–3 GSM see genitourinary syndrome of menopause Female Sexual Function Index (FSFI) GVD see generalized vulvodynia arousal disorders 128 female genital arousal disorder 149 h hypoactive sexual arousal disorder 81 happy baby pose 214 orgasm disorders 205, 213 HAT see Holistic Assessment and Therapies Female Sexual Function Questionnaire headache 240–241 (SFQ‐28) 213 hemodynamics female sexual interest/arousal disorder arousal disorders 108–110, 109, 115–116 (FSIAD) 20, 25–26, 104, 344 female genital arousal disorder 146 FGAD see female genital arousal disorder sex steroid hormones 115–116 flibanserin 45–46, 85, 156, 233 sexual pain disorders 265–266 FOD see female orgasm disorder hippocampus 187, 189, 227 FOIS see female orgasmic illness syndrome histidine methionine 111 Food and Drug Administration (FDA) 339–341 histology foot pain 241–242 clitoris 179–180, 181 FSAD see female sexual arousal disorder dyspareunia and vulvovaginal pain 327 FSDS see female sexual distress scale vagina 180, 181 FSFI see Female Sexual Function Index Holistic Assessment and Therapies (HAT) FSIAD see female sexual interest/arousal model 203–204 disorder home exercise programs 308 functional magnetic resonance imaging hormonally‐induced dyspareunia 312 (fMRI) 186–188, 222 hormonally‐mediated vestibulodynia 167 future developments and research 339–348 hormonal therapies AMAG Pharmaceuticals 341–342 arousal disorders 117 Emotional Brain 342 CNS anatomy and neurochemistry of sexual historical and regulatory desire 32–33 perspective 339–341 dyspareunia and vulvovaginal pain 332 marketplace 341–345 female genital arousal disorder 153–155 other companies and products 344–345 female orgasm disorder 230–232 S1 Biopharma 342–343 future developments and research 342 Strategic Science & Technologies, LLC historical and regulatory perspective 340–341 343–344 hypoactive sexual desire disorder 86–87 hormones see sex steroid hormones g HSDD see hypoactive sexual desire disorder generalized vulvodynia (GVD) 248 hyperprolactinemia genetic factors 250 female genital arousal disorder 148 genital atrophy 116 hypoactive sexual desire disorder 76, genital pain 241 82–83, 85 genitourinary syndrome of menopause (GSM) hypertension 147, 228 female genital arousal disorder 149–150, hyperthyroidism 153–154 hypoactive sexual desire disorder 76, future developments and research 345 81–82, 83 persistent genital arousal disorder 162 neurobiological endocrinology 74–75 glutamate 41–42, 44 hypnosis 290 Index 355 hypoactive sexual desire disorder (HSDD) inhibitory neurochemical antagonists 155–156 CNS anatomy and neurochemistry of sexual insular cortex 189 desire 25–51 interferon 332 comorbidities 22 internal assessment 303–304, 309–310, depression 22 326–327 diagnosis 80–82 International Classification of Disease direct treatment of HSDD 85–87 (ICD‐10) 20–21, 25, 252 DSM classification 19–20, 25–26 International Consultation in Sexual epidemiology 21–22 Medicine 9 future developments and research 342–343 International Pelvic Pain Society (IPPS) historical and regulatory 249, 320 perspective 340–341 International Society for the Study of ICD classification 20–21, 25 Vulvovaginal Disease (ISSVD) ISSWSH classification 20–21, 25 248–249, 319–320 neurobiological endocrinology 59–75, 82 International Society for the Study of Women’s nosology 19–21 Sexual Health (ISSWSH) older women 21–22 approval of sildenafil 1 pathological conditions associated with low arousal disorders 104–105 sexual desire 75–80 dates and locations of annual meetings 3, 4 pathophysiology and medical management dyspareunia and vulvovaginal 59–100 pain 319–320 PRESIDE study 21–22 education and training 3–4 process of care 82, 85 female genital arousal disorder 147 psychological management 53–57 female orgasm disorder 222–224, 233 therapeutic strategies 82–87 female orgasmic illness treatments 45–46, 45 syndrome 239–240 WISHeS study 22 Female Sexual Function Forum 2–3 hypogastric nervous system 148 history 1–5 hypogonadotropic hypogonadism hypoactive sexual desire disorder female genital arousal disorder 148 20–21, 25 hypoactive sexual desire disorder 65, 74, New Perspectives in Female Sexual 76, 80 Dysfunction 1–2 hypopituitarism 76, 83 on‐line forum 2 hypothalamus 186 orgasm disorders 176, 212 hypothalamus–pituitary–ovary axis 63–65 persistent genital arousal disorder 162–163 hypothyroidism presidency 2–3 hypoactive sexual desire disorder 76, recent developments 4 81–82, 83 sexual pain disorders 249 neurobiological endocrinology 74 interstitial cystitis 259, 326–327, 328 intimacy i arousal disorders 128, 130–132, 136 ICD see International Classification of Disease hypoactive sexual desire disorder incertohypothalamic dopamine 41 54–55, 78 individual sex therapy 137–138 orgasm disorders 200 infertility 133 pelvic and sexual pain disorders 297, 306 inflammation provoked vestibulodynia 284–285, 288 pelvic and sexual pain disorders 300, 301 intravaginal dynamometry 215 persistent genital arousal disorder 164–165 invalidation 285–286, 291 sexual pain disorders 251, 266–269 IPPS see International Pelvic Pain Society 356 Index

ISSVD see International Society for the Study sexual pain disorders 271, 272–273 of Vulvovaginal Disease medication‐related pathophysiologies 229, ISSWSH see International Society for the 230, 323–324 Study of Women’s Sexual Health melanocortins 41 j menopause arousal disorders 116, 117, 133 Johnson, Virginia see Masters, William and CNS anatomy and neurochemistry of sexual Johnson, Virginia desire 32–33, 45–46 joint mobilization 305 female genital arousal disorder 148, k 149–151, 153–154 future developments and Kaplan, Helen Singer 128, 137, 199 research 342–345 Kegel exercises 288 historical and regulatory keratin pearls 212 perspective 339–341 kisspeptin‐1 65, 66, 73 neurobiological endocrinology 63, 65, l 68–72 labia majora 214, 216 persistent genital arousal disorder 162 labia minora 214, 216 surgically induced menopause 75–76, lactation 71 340–341 raloxifene 345 menstrual cycle see ovulatory cycle Leiblum, Sandra 2 Meston, Cindy 3, 344 leiomyoma 327 metabolic syndrome levothyroxin 83 arousal disorders 133–134 lidocaine 331 female genital arousal disorder 147 local anesthesia 165–166 female orgasm disorder 228, 230 lordosis 30–31, 33–34, 38–44 hypoactive sexual desire disorder 77 lubrication see vaginal lubrication neurobiological endocrinology 75 luteinizing hormone 63, 65, 66 microablative fractional CO2 laser 334 mind–body practices 308 m mindfulness techniques macroprolactinemia 81 arousal disorders 137 magnetic resonance imaging (MRI) 166, hypoactive sexual desire disorder 55–56 186–188, 222, 328 orgasm disorders 207 Malpighian epithelium 180 pelvic and sexual pain disorders 306, 308 marital therapy see couples/marital therapy provoked vestibulodynia 288, 289 Masters, William and Johnson, Virginia modified nine‐field diagram 11 EPOR model 29–30, 29, 35 mood 286 model of arousal 127–128 MRI see magnetic resonance imaging sex therapy 55–56 MS see multiple sclerosis sexual response cycle 198–199, 199 multiple sclerosis (MS) 79, 227 masturbation see self‐stimulation muscle weakness 241 medical management musculoskeletal management dyspareunia and vulvovaginal pain 331–333 adjunctive modalities 306–308 female genital arousal disorder 150–156 case studies 309, 311, 313 female orgasm disorder 230–233 categories of myofascial and musculoskeletal female orgasmic illness syndrome 240–242 dysfunction 216–217 hypoactive sexual desire disorder 82–87 diagnosis 212 persistent genital arousal disorder 162, evaluation of musculoskeletal 166–168 function 212–216 Index 357

evaluation of pelvic and sexual pain role of androgens 71–72 disorders 301–304 role of estrogens and progesterone 69–71 history taking 212–213 role of kisspeptin in female sexual desire 73 hormonally‐induced dyspareunia 312 role of metabolic diseases 75 musculoskeletal interventions 217 role of oxytocin in female sexual desire 73 myofascial interventions 217 role of prolactin in female sexual desire 74 neuromotor interventions 217 role of thyroid hormones in female sexual orgasm disorders 211–220 desire 74–75 outcomes and follow‐up 218 secretion and production of sex steroids overview of treatment options 217 62, 62 pathophysiology of sexual pain 299–301 sex hormone levels 63, 64, 65 pelvic floor anatomy 296–299, 297–299 steroid biosynthesis and persistent genital arousal disorder 216 metabolism 60–61, 60 physical examination 213–215, 213–214 therapeutic strategies for hypoactive sexual physiotherapy 295–313 desire disorder 82 screening/prevention 218 see also sex steroid hormones sexual pain disorders 251, 295–317 neurochemistry see central nervous system sexual response cycle 211–212 neurologic dysfunction techniques of the physical therapist 304–306 female genital arousal disorder 156 treatment for specific sexual pain diagnoses female orgasm disorder 225–230 308–312 hypoactive sexual desire disorder 79 treatments with physician sexual pain disorders 251 collaboration 308 neuromotor interventions 217 muted orgasm 224 neuronal cross‐talk 264–265 myofascial dysfunction 216–217 neuropeptide Y 111 myofascial trigger points 300, 304–305, 308 neuroproliferative vestibulodynia 167, 311–312, 328 n neurotransmitters NANC see nonadrenergic noncholinergic adrenergic regulation 110, 116 National Vulvodynia Association (NVA) 249 afferent pathways 111–112 neural mobilization 305 arousal disorders 110–112, 116 neural tensioning 302–303 female orgasm disorder 224, 232–233 neurobiological endocrinology neurobiological endocrinology 66, 70 early development 67 nitrergic regulation 110–111, 116 effects of sex hormones variation on brain, nonadrenergic noncholinergic sexual function and behavior 67–75 neurotransmitters 111, 116 factors modulating secretion of GnRH and orgasm disorders 187–188 gonadotropins 65–66 New Perspectives in Female Sexual female genital arousal disorder 148–150, Dysfunction 1–2 153–155 New Sex Therapy, The (Kaplan) 137 female orgasm disorder 224, 229–232 nipple stimulation 185 hypoactive sexual desire disorder 59–75 nitrergic regulation 110–111, 116 menopause 63, 65, 68–72 nitric oxide synthase (NOS) 110–111, origin of sex steroids 62–63 115, 180 ovulatory cycle 62–63, 64, 68–72 nociception 257, 258–271, 259, 272–273, 301 plasma transport of sex steroids 61–62 nonadrenergic noncholinergic (NANC) puberty 63, 65, 67–68 neurotransmitters 111, 116 regulation of hypothalamus–pituitary–ovary noncontractile connective tissue axis 63–65 restriction 216–217 358 Index

NOS see nitric oxide synthase functional anatomy 179–184 nucleus accumbens 186–188 functional changes during arousal and NVA see National Vulvodynia Association orgasm 183–184 genital responses prior to, during and o immediately after female orgasm obesity 77–78 221–222 older women genital sensation and projections to the arousal disorders 133 brain 185 CNS anatomy and neurochemistry of sexual gross anatomy of the clitoris 180, 182–183 desire 32–33, 45–46 gross anatomy of the vagina 182, 183 hypoactive sexual desire disorder 21–22 help‐seeking and point of contact 205 neurobiological endocrinology 72 histology of the clitoris 179–180, 181 see also menopause histology of the vagina 180, 181 oophorectomy 72, 250 history taking 212–213 opioid receptors 39, 42 innervation of female sexual organs 182 opioids ISSWSH classification 176, 222–224, 233, hypoactive sexual desire disorder 79–80 239–240 neurobiological endocrinology 66 musculoskeletal management 211–220 sexual pain disorders 260 neurologic disorders 225–229 oral contraception nosology 175–176, 212, 222–224, 233, CNS anatomy and neurochemistry of sexual 239–240 desire 31–32 orgasms within the cultural framework dyspareunia and vulvovaginal pain 324 200–202 female genital arousal disorder 149 outcomes and follow‐up 218 hypoactive sexual desire disorder 79 pathophysiology and medical management sexual pain disorders 250–251, 261 of FOD 221–237 orgasm disorders pathophysiology and medical management assessment 205–206 of FOIS 239–243 brain activity and correlates of peripheral aversive symptoms 241–242 orgasm 184–189 peripheral and central neural bases of brain activity related to orgasm 185 orgasm 179–195 categories of myofascial and musculoskeletal persistent genital arousal disorder 216 dysfunction 216–217 physical examination 213–215, 213–214 central aversive symptoms 240–241 presentation of FOIS 239 clinical context and considerations 202–204 PRESIDE study 176 clito‐urethro‐vaginal complex 184, 184 prevalence of FOD 221 common beliefs/myths around orgasm 204 psychological management 197–210, 229 concepts and definitions of orgasm 197–198 risk factors for women with FOD 224–229 corollary animal studies 189 role of different brain components in cultural context and orgasm 185–189 considerations 200–202 screening/prevention 218 diagnosis 206, 212 sexual response cycle 198–200, 199, 200, diagnosis of women with FOD 229–230 211–212 DSM classification 175–176, 222–223, treatment of women with FOD 230–233 239–240 vascularization of female sexual organs 182 epidemiology 176–177 WISHeS study 177 evaluation of musculoskeletal function orgasmic disorder 15 212–216 orgasmolepsy 240 expectations and fears 205–206 ospemifene 155 Index 359 ovarian steroid hormones see sex steroid pelvic surgery 148 hormones perineal structures 216–217, 297 ovulatory cycle peripheral nervous system (PNS) CNS anatomy and neurochemistry of sexual female orgasm disorder 225 desire 31–32, 32 orgasm disorders 184–189 neurobiological endocrinology 62–63, 64, sexual pain disorders 251, 257 68–72 peripheral sensitization 268–270, 268 sexual pain disorders 266 persistent genital arousal disorder (PGAD) oxytocin 73, 222, 233 diagnosis 165–166 etiology of sexual arousal 161–162 p musculoskeletal management 216 pacing behavior 42–43 nosology 162–163 pain see sexual pain pathophysiology and medical palpation 215 management 161–171 paralysis 241 prevalence of PGAD in the United paraventricular nucleus of the hypothalamus States 161 (PVN) 186–187 psychological management 162, 166 Parish, Sharon 3 risk factors for women with PGAD 163–165 Parkinson’s disease 227 treatment 166–168 paroxetine 83–84 persistent vulvar pain 249–250 PCOS see polycystic ovarian syndrome Peyronie’s disease 132 PE see premature ejaculation PGAD see persistent genital arousal disorder pelvic floor phantom orgasms 226 adjunctive modalities 306–308 phosphodiesterase 5 inhibitors 45–46, 153 anatomy 296–299, 297–299 see also sildenafil case studies 309, 311, 313 physical examination coccygeus, piriformis, and obturator dyspareunia and vulvovaginal pain 324–327, internus muscles 298 325, 326 cutaneous nerves of the vulva, thigh, and internal assessment 303–304, 309–310, groin 299 326–327 evaluation for musculoskeletal management musculoskeletal management 213–215, 301–304 213–214 female orgasm disorder 222, 224, 229, 230 physiotherapy female pelvic floor anatomy 298 adjunctive modalities 306–308 female urogenital system 297 case studies 309, 311, 313 hormonally‐induced dyspareunia 312 dyspareunia and vulvovaginal pain 330–331 medical management of dyspareunia and evaluation of pelvic and sexual pain vulvovaginal pain 320, 327 disorders 301–304 musculoskeletal management 213–217, hormonally‐induced dyspareunia 312 295–317 pathophysiology of sexual pain 299–301 pathophysiology of sexual pain 299–301 pelvic floor anatomy 296–299, 297–299 persistent genital arousal disorder 163, pelvic and sexual pain disorders 295–313 166–167 techniques 304–306 physiotherapy 295–313 treatment of pelvic and sexual pain provoked vestibulodynia 288 disorders 304 techniques of the physical therapist 304–306 treatment for specific sexual pain treatment for specific sexual pain diagnoses diagnoses 308–312 308–312 treatments with physician treatments with physician collaboration 308 collaboration 308 360 Index

pleasure dissociative orgasm disorder 224 relationship dynamics 284–285 PLISSIT Model 204 sexuality and sexual partners 284 polycystic ovarian syndrome (PCOS) 134 targets of psychological postcoital dysphoria 241 interventions 287–288 postcoital tristesse 241 treatment 287–291 posttraumatic stress disorder (PTSD) 286 psychiatric disorders 163, 165, 166 pregnancy psychological management arousal disorders 132–133 arousal disorders 127–144 female orgasm disorder 225–226 assessment for orgasm disorders 205–206 orgasm disorders 204 assessment of sexual response 134–135, pregnenolone 61 135, 136 premature ejaculation (PE) 131 biopsychosocial model 53–55, 54 premature orgasm 224 clinical considerations 203–204 PRESIDE study 21–22, 105, 176 clinical context of orgasm process of care 82, 85 dysfunctions 202–203 progesterone common beliefs/myths around orgasm 204 arousal disorders 116–117 concepts and definitions of orgasm 197–198 CNS anatomy and neurochemistry of sexual couple/marital therapy 56 desire 33–34, 40–41, 45 cultural context of orgasm dysfunctions 202 female genital arousal disorder 148 diagnosis for orgasm disorders 206 neurobiological endocrinology 61, 62, dyspareunia and vulvovaginal pain 323, 331 69–71 effects of partner dysfunction in sexual pain disorders 261, 266 women 131–132 prolactin etiology of sexual arousal 128–131 female genital arousal disorder 150 expectations and fears 205–206 female orgasm disorder 222, 231–232 female genital arousal disorder 150 neurobiological endocrinology 66, 74 female orgasm disorder 229 prostaglandin E1 152–153, 344 follow‐up and referral 208 provoked vestibulodynia (PVD) health and lifespan alternative treatments 290 considerations 132–134 anatomy and physiology 259–260 help‐seeking and point of contact 205 assessment 282–284, 283 hypoactive sexual desire disorder 53–57 childhood victimization 286–288 integrating psychotherapy in multimodal cognitive and emotional responses to treatments 56 pain 286 models of arousal 127–128 dealing with psychological distress 288–289 nonpharmacological treatments for arousal diagnosis 282 disorders 135–136 dyspareunia 286–287, 290 orgasm disorders 197–210 efficacy of psychological orgasms within the cultural framework interventions 289–290 200–202 epidemiology 250, 251 outcomes 56 interdisciplinary treatments 290–291 pelvic and sexual pain disorders 306 mood 286 persistent genital arousal disorder 162, 166 nosology 248 predisposing, precipitating, maintaining, pain characteristics 281–282 and contextual factors 54 peers and the healthcare community provoked vestibulodynia 281–294 285–286 psychotherapy/sex therapy approaches predictors of treatment outcome 290 55–56, 136–138 psychological management 281–294 sexual pain disorders 252 psychosocial factors 284–287 sexual response cycle 198–200, 199, 200 Index 361

treatment of orgasm disorders 206–208 selective serotonin reuptake inhibitors PTSD see posttraumatic stress disorder (SSRI) 70–71, 79 puberty 63, 65, 67–68 self‐diagnosis 324 pudendal neuralgia 296, 297–298, 327 self‐disclosure 284–285, 288 pudendal neuropathy 147–148 self‐stimulation 185, 207, 287 purinergic receptors 113 sensitization 268–271, 268, 301, 306 purinoreceptors 259–261 sensory neuropathy 163, 165, 167 PVD see provoked vestibulodynia SERM see selective estrogen receptor PVN see paraventricular nucleus of the modulator hypothalamus serotonin q CNS anatomy and neurochemistry of sexual desire 44 Q tip test 325–326, 325, 326 female orgasm disorder 232–233 quadriped with pelvic tilting 213 hypoactive sexual desire disorder 78 r neurobiological endocrinology 70–71 radiation therapy 148 serum testing 328 radiculopathy sex hormone binding globulin 149, 150, 155 female genital arousal disorder 148, 156 sex steroid hormones female orgasm disorder 227–229, 232 arousal disorders 113–117, 114 persistent genital arousal disorder 163–164, CNS anatomy and neurochemistry of sexual 164, 166–168 desire 31–34, 36–44 recurrent vulvovaginal candidiasis 267 effect on androgen and estrogen referred pain 262–265 receptors 116–117 relational factors effect on genital blood flow and vaginal arousal disorders 130–132, 134–135, 137–138 lubrication 115–116 commitment and duration 130 effect on genital tissue structure 114–115 female orgasm disorder 224, 229 effects on brain, sexual function and partner dysfunction 131–132 behavior 67–75 provoked vestibulodynia 284–285, 288–290 effect on vaginal innervation and smooth sex therapy 137–138 muscle contractility 116 religion see culture and religion factors modulating secretion of GnRH and rhythmic entrainment model 207–208 gonadotropins 65–66 ropinirole 233 female genital arousal disorder 148–150, 153–155 s female orgasm disorder 222, 230–232 S1 Biopharma 342–343 hypoactive sexual desire disorder 59–75 sacral spinal nerve root (SSNR) radiculopathy origin of sex steroids 62–63 female genital arousal disorder 156 pelvic and sexual pain disorders 301 female orgasm disorder 227–229, 232 persistent genital arousal persistent genital arousal disorder 164, disorder 165–166 164, 168 plasma transport of sex steroids 61–62 Sarhmann progression 214 regulation of hypothalamus–pituitary– scar tissue mobilization 305 ovary axis 63–65 screening/prevention secretion and production of sex hypoactive sexual desire disorder 80–82 steroids 62, 62 musculoskeletal management 218 sex hormone levels 63, 64, 65 pelvic and sexual pain disorders 301–302 sexual pain disorders 250–251, seizures 226–227, 240 260–261, 266 selective estrogen receptor modulator steroid biosynthesis and (SERM) 155 metabolism 60–61, 60 362 Index

sex therapy nosology 247–249, 252–253 arousal disorders 137–138 novel future directions 271 hypoactive sexual desire disorder 55–56 pathophysiology of sexual pain 299–301 orgasm disorders 204, 205–208 pelvic floor anatomy 296–299, 297–299 provoked vestibulodynia 287–288 peripheral and central sensitization sexual approach behaviors 40 268–271, 268 sexual history peripheral/neuroproliferation 251 arousal disorders 134–135, 135 persistent vulvar pain 249–250 dyspareunia and vulvovaginal pain physiotherapy 295–313 320–323, 322–323 prevalence 253 orgasm disorders 212–213 psychological management 252 provoked vestibulodynia 282, 283 psychological management of PVD sexuality 281–294 education and training 9 referred pain 262–265 provoked vestibulodynia 284 somatic and visceral pain 261–265, 262, WISHeS study 21–22 265, 271 sexual pain disorders subjective pain perception 257–258, acute and chronic pain 257–258, 262, 271 267–268, 270 symptom patterns and mechanisms by pain adjunctive modalities 306–308 type 263 anatomy and physiology of sexual pain techniques of the physical 257–280 therapist 304–306 arousal disorders 132 therapeutic mechanisms of action 271, associated factors 252 272–273 background 247 treatment for specific sexual pain brain function 270–271 diagnoses 308–312 case studies 309, 311, 313 treatments with physician Consensus terminology (2015) 249 collaboration 308 DSM classification 252–253 vascular pain 265–266 embryological/congenital factors 252 see also dyspareunia and vulvovaginal pain; epidemiology 249–252 vaginismus; vestibulodynia; vulvodynia evaluation for musculoskeletal management sexual positions 33 301–304 sexual response cycle 198–200, 199, 200, female orgasmic illness syndrome 211–212 241–242 sexual tipping point model (Perelman) 27, future developments and research 345 36, 37, 38 genetic factors 250 SFQ‐28 see Female Sexual Function hormonal factors 250–251 Questionnaire hormonally‐induced dyspareunia 312 sildenafil 1, 111, 153, 342–344 hormonal regulation 260–261, 266 smooth muscle impacts 253 arousal disorders 116 inflammation 251, 266–269 female genital arousal disorder 146, ISSVD classification 248–249 152–153 medical management of dyspareunia and orgasm disorders 180 vulvovaginal pain 319–336 sneezing 241 musculoskeletal management 251, soft tissue 148–149 295–317 solicitations 40–42 neurologic dysfunction 251 somatic pain 261–265, 262, 265 nociception 257, 258–271, 259, 272–273 somatovisceral reflex 300 Index 363 speculum examination 326 transgender surgery 117 spinal cord injury 225–226, 232 transperineal ultrasound 215–216 SSNR see sacral spinal nerve root traumatic brain injury 225 SSRI see selective serotonin reuptake inhibitors trazodone 86, 343 steroid hormones see sex steroid hormones Trendelenberg test 213 stigma 285–286 Stork test 213 u Strategic Science & Technologies, ultrasound 307, 328 LLC 343–344 urethral diverticulum 326–327 subjective arousal 107–108, 146–147 urethral prolapse 167 subjective pain perception 257–258, 262, 271 urinary tract symptoms 78 substance P 111 substances of abuse 79–80 v surgically induced menopause 75–76, vagina 340–341 gross anatomy 182, 183 surgical management 333–334 histology 180, 181 orgasm disorders 180, 183, 185 t vaginal dilation 288, 307 tadalafil 153 vaginal laxity 345 Tarlov cysts vaginal lubrication female genital arousal disorder 148, 156 arousal disorders 112–113, 115–116, female orgasm disorder 232 132, 135 persistent genital arousal disorder 162, female genital arousal disorder 146, 148, 163, 167–168 150–151, 153–154 temporal lobe 227 lubricants/moisturizers 132, 135, 150–151, testosterone 153–154 arousal disorders 116–117 possible mechanisms of vaginal CNS anatomy and neurochemistry of sexual transudation 112–113, 113 desire 32, 33–34 purinergic receptors and vaginal dyspareunia and vulvovaginal pain 324 moisture 113 female genital arousal disorder 148–150, sex steroid hormones 115–116 153–155 vaginismus female orgasm disorder 229, 230–231 epidemiology 252–253 future developments and research 342 medical management 327 historical and regulatory perspective musculoskeletal management 309–310 340–341 nosology 247–248 hypoactive sexual desire disorder 76, 82, validation 285–286, 291 83, 86–87 vardenafil 153 neurobiological endocrinology 61–63, vascular pain 265–266 67–68, 71–72 vasodilation agents 152–153 sexual pain disorders 250–251, 261 ventral tegmental area 186–188 thyroid hormone 74–75, 229–231 vestibule 214, 216 tibolone 87 vestibule desensitization 306 topical agents vestibulodynia arousal disorders 135 anatomy and physiology 260, 262, female genital arousal disorder 152–155 266–267 female orgasm disorder 232 caused by overactive muscles 312 future developments and epidemiology 250–252 research 343–344 hormonally‐mediated vestibulodynia 167 364 Index

vestibulodynia (cont’d ) epidemiology 250–253 medical management 324, 325, 328, generalized vulvodynia 248 331–334 medical management 328, 331–334 musculoskeletal management 310–312 musculoskeletal management 310 neuroproliferative vestibulodynia 167, nosology 247–249, 320 311–312, 328 vulvoscopy 215, 324–325, 325 nosology 248–249 vulvovaginal atrophy 342, 345 persistent genital arousal disorder 167 vulvovaginal pain see dyspareunia and psychological management of PVD 281–294 vulvovaginal pain vibrators 151–152 VVS see vulvar vestibulitis syndrome vilazodone 84 visceral manipulation 305–306 w visceral pain 261–265, 262, 265, 271, 301 wands 307 vortioxetine 84 wet mount 327 vulvar granuloma fissuratum 167 Women’s International Study of Health and vulvar lichen sclerosus 325 Sexuality (WISHeS) 21–22, 177 vulvar vestibulectomy 333–334 vulvar vestibulitis syndrome (VVS) 248, 345 z vulvodynia zona reticularis 62–63 Figure 1.1 Sandra Leiblum, PhD, first president of the International Society for the Study of Women’s Sexual Health, presiding over the business meeting.

Textbook of Female Sexual Function and Dysfunction: Diagnosis and Treatment, First Edition. Edited by Irwin Goldstein, Anita H. Clayton, Andrew T. Goldstein, Noel N. Kim, and Sheryl A. Kingsberg. © 2018 John Wiley & Sons Ltd. Published 2018 by John Wiley & Sons Ltd.

Chapter No.: 1 Title Name: bins.indd Comp. by: Date: 22 Mar 2018 Time: 11:32:53 AM Stage: WorkFlow: Page Number: a1 Medical illness and sexuality

Pre-existing sexual difficulties and resources, body image, gender

Threat of the disease (stage etc.)

Disease and therapy specific factors with possible impact on sexual function

Body image Affective reaction Coping and resilience

Changes in sexual needs and couple dynamics

Individual clinical sexual dysfunction syndrome

Figure 2.1 Algorithm incorporating the specific medical condition.

Dual control model

- Physiological and + Physiological and organic issues organic issues

- Psychosocial, cultural + Psychosocial, cultural and behavioral issues and behavioral issues

Sexual tipping point®

Inhibition Excitation

Variable and dynamic process

Figure 4.1 Sexual tipping point model of sexual excitation and inhibition. Cultural, psychological, and physiological factors conspire to tip the balance either toward excitation or inhibition. Sexually functional individuals maintain a degree of lability in the balance, and an ability to have it tipped toward either excitation or inhibition. Persons with hypoactive sexual desire disorder are likely to have the balance weighed down by inhibition. This can occur because of hypofunctional excitation, hyperfunction inhibition, or a combination of the two. After Perelman [67].

Chapter No.: 1 Title Name: bins.indd Comp. by: Date: 22 Mar 2018 Time: 11:32:53 AM Stage: WorkFlow: Page Number: a2 Prefrontal cortex

Medial Striatum preoptic area Nucleus Caudate Putamen accumbens nucleus

Zona Ventral Dorsal incerta

Ventral pallidum Mesocortical

Mesolimbic Amygdala

Hippocampus Nigrostriatal

VTA SN

Dopaminergic projections

Glutamatergic projections

GABAergic projections

Figure 4.2 A wiring diagram of sexual excitation and inhibition in the mammalian brain that reflects current understanding of neuroanatomical and neurochemical pathways. VTA: Ventral tegmental area; SN: substantia nigra. Modified from Kingsberg et al. [119].

Chapter No.: 1 Title Name: bins.indd Comp. by: Date: 22 Mar 2018 Time: 11:32:53 AM Stage: WorkFlow: Page Number: a3 Behavioral Motivation Consummation Satiety state wanting Liking inhibition Learning Genital responses

Pleasure

Excitement Plateau Orgasm Refraction

SRL Genital IPL S1 IPL dIPFC vIOT Ins ClausCvIOT Ins laus FO Ins FO Ins Temp FO Ins vIOT pole vITG

aMCC aMCC dMPFC pACC Pelvic M1 sACC pACC Brain vmPFC Cb HT networks HT HT HT vmPFC

Amy Med-temp AmyAMed-temp my Med-temp Amy Med-temp VS vmPFC vmPFC vmPFC HT HT HT HT VP VP

OFC OFCOFC

Encoding Sexual arousalOrgasm De-arousal Method brief VSS (photo) Long VSS (film) Penis stimulation Poststimulation odours

Figure 4.6 Patterns of brain activation in response to sexual stimulation as a function of the EPOR stages of sexual response. From Georgiadis et al. [23].

Chapter No.: 1 Title Name: bins.indd Comp. by: Date: 22 Mar 2018 Time: 11:32:53 AM Stage: WorkFlow: Page Number: a4 Excitation Inhibition (arousal, desire, interest) (reward/satiety, stress, or aversion)

Hormones Hormones Experience/expectation Experience/expectation (circulating levels/ (circulating levels/ (previous sexual encounters) (previous sexual encounters) actions in brain) actions in brain)

Arousability Arousability

Attention Attention

Sensory input from genitals Sensory input from incentives Sensory input from genitals Sensory input from incentives (perception of arousal) (olfactory/visual/auditory) (perception of arousal) (olfactory/visual/auditory)

Net behavioral output Net behavioral output (interest/solicitation/pursuit/copulation) (interest/solicitation/pursuit/copulation)

Figure 4.7 Neurochemical mechanisms of sexual excitation and inhibition. From Pfaus and Scepkowski [120].

Chapter No.: 1 Title Name: bins.indd Comp. by: Date: 22 Mar 2018 Time: 11:32:53 AM Stage: WorkFlow: Page Number: a5 Excitation Inhibition – Inhibitory Excitatory ++Inhibitory Excitatory – Drugs or states Drugs or states Drugs or states Drugs or states that inhibit that activate that activate that inhibit DA 5-HT NE opioids ECBs OT DA MCs NE 5-HT opioids OT ECBs MCs

Figure 4.8 Neurochemical mechanisms of sexual excitation within a tipping point model. Left: sexual excitation. Right: Sexual inhibition. From Pfaus [6].

Treatments for HSDD

Figure 4.9 Treatments for sexual desire disorders and their potential mechanisms of action in the brain. From Pfaus [121].

Depression, anxiety, gender Illness, medication, surgery, Biology Psychology conflict, sexual or physical neurobiology, vascular and abuse, alcohol or drug hormonal conditions abuse

Upbringing, cultural Quality of current and past and religious concerns, Sociocultural Interpersonal relationships, partner contextual issues such as performance and technique, privacy, different shifts STDs

Figure 5.1 Biopsychosocial model of sexual response.

Chapter No.: 1 Title Name: bins.indd Comp. by: Date: 22 Mar 2018 Time: 11:32:53 AM Stage: WorkFlow: Page Number: a6 Internal Perception of a External stimuli SEXUAL stimuli STIMULUS Dreams, fantasies, Olfactory, tactile, memories, love, gustative, physical drive PSYCHOPLASTICITY auditive, visual NEUROPLASTICITY Modulated by Sexual hormones

AUTONOMIC EMOTIONAL MOTOR COGNITIVE System AFFECTIVE System System System

GENITAL, BEHAVIORAL AND CLINICAL CORRELATES

Figure 8.1 Physiology of sexual desire/interest and central arousal. (Adapted from [6].)

Lumen + K Paracellular Transcellular

RTJ RTJ, RLIS AQPs R LIS Na+, K+ K+

Na+ Basement membrane Capillary blood

Figure 8.3 Mechanisms of transvaginal epithelial permeability.

Pre-accident condition Pre-operative condition

Cauda equina L4-5 healthy L4 disc L5-S1 disc Vertebral herniation body impinging the cauda equina L5 Intervertebral disc

S1 Sagittal view of the S2 lumbar spine

Figure 11.1 Schematic representation of a herniated intervertebral disc at L5‐S1 impinging on, and irritating, the nerve roots of the cauda equina. If the radiculitis affects the sacral spinal nerve roots (SSNR) various neurogenic sexual dysfunctions, such as persistent genital arousal disorder (PGAD), may be experienced. Several cures of men and women with PGAD secondary to radiculitis of the SSNR have been realized with minimally‐invasive out‐patient lumbar spine surgery.

Chapter No.: 1 Title Name: bins.indd Comp. by: Date: 22 Mar 2018 Time: 11:32:53 AM Stage: WorkFlow: Page Number: a7 Clitoral glans

Urethral opening Corpus cavernosum Bulb of vestibule

Vaginal opening Crus of clitoris Anterior vaginal wall

Prostata foeminina ducts

Figure 13.1 Anatomy of the CUV complex. Schematic representation of the external and internal clitoris and the vaginal opening. The insert, an anterior vaginal wall obtained from a cadaver [15, 21], represent the intimate relationships between all the different anatomical structures involved in the female sexual pleasure.

IH CO UM TC OX CM

Figure 13.2 Descriptive “tapestry” representation of brain activity in response to clitoral self‐stimulation leading up to, during, and after orgasm in each of six women. Each woman’s tapestry consists of 80 columns, each column representing a Brodmann area. Each row represents a successive two‐second sample of functional MRI activity, starting at the top. The relative magnitude of brain activity in each region at each time period is represented as brightness. The shorter vertical bars to the right of each tapestry represents the onset and duration of orgasm; the longer bars represent the onset and duration of clitoral self‐stimulation. Note the maximum activation in widespread brain regions during orgasm, in contrast to the variable patterns of regional brain activity leading up to, and after, orgasm. These descriptive data and those in the subsequent figures comprise part of the doctoral dissertation of Dr Nan Wise at Rutgers University. Dr Eleni Frangos collaborated in portions of the research.

Chapter No.: 1 Title Name: bins.indd Comp. by: Date: 22 Mar 2018 Time: 11:32:53 AM Stage: WorkFlow: Page Number: a8 post insl pfc ant cing nacc amyg hpc SII post cing pcl pc vta

Mid stim > Early stim

Orgasm > Mid stim

Orgasm > Early recovery

Early recovery > Late recovery

Figure 13.3 Preliminary group fMRI data (N = 10) providing evidence that maximum overall activation in widespread regions of the brain was observed at orgasm. Multiple brain “sections” are shown, representing the regions identified by the labels above them. The data were generated by subtracting one 10‐second epoch from another. Thus, activity during the first 10 s of stimulation (“Early stim”) was subtracted from the 10‐s activity midway between the start of stimulation and the start of orgasm (“Mid stim”). The activity at mid‐stim was subtracted from the 10‐s epoch starting when the women pressed a button indicating initiation of orgasm. The subsequent postorgasm responses were comparably subtracted as indicated (“recovery” refers to the phase after the women pressed the button to indicate the end of their orgasm). Abbreviations: amyg: amygdala; ant cing: anterior cingulate cortex; hpc: hippocampus; nacc: nucleus accumbens; pc: parietal cortex; pcl: paracentral lobule; pfc: prefrontal cortex; post cing: posterior cingulate cortex; post insl: posterior insula; SII: Supplementary sensory cortex (operculum); vta: ventral tegmental area.

Chapter No.: 1 Title Name: bins.indd Comp. by: Date: 22 Mar 2018 Time: 11:32:53 AM Stage: WorkFlow: Page Number: a9 N Accumbens Septum Ant hypothalamus Amygdala

Hippocampus Post hypothalamus Operculum (S2) Post cingulate ctx

Post insula Periaqueductal grayParacentral lobule Post parietal ctx

Figure 13.4 Preliminary group data providing evidence of regional activation pattern “going over” into orgasm. The group activity in each region during the 10 seconds immediately prior to the button press was subtracted from the 10 seconds immediately after the button press, by which the women indicated the start of their orgasm. Brain areas activated at criterion of z = 1.65 are labeled by a square; those at a criterion of z = 1.55 are labeled by a circle. Brain areas from the brain stem analysis are labeled by an asterisk and are activated at a criterion of z = 1.0. While the latter two z criteria are lower than customary, the data are shown in order to represent activity in brainstem regions represented by very few voxels, which might otherwise be subject to a type 2 error.

Obturator n. Lateral femoral n. Genitofemoral Genital br. Anterior femoral n. nerve Femoral br. Iliohypogastric n. Dorsal br. Pudendal Ilioinguinal n. nerve Perineal br. Inferior (rectal) br. Perineal br. Posterior femoral cutaneous nerve Thigh br. Inferior cluneal br.

Figure 21.4 Cutaneous nerves of the vulva, thigh, and groin. Used with permission from A. Lee Dellon, MD, PhD, from www.Dellon.com.

Chapter No.: 1 Title Name: bins.indd Comp. by: Date: 22 Mar 2018 Time: 11:32:53 AM Stage: WorkFlow: Page Number: a10