Let's Start a Conversation

LET’S START A CONVERSATION Low Sexual Desire in Women

LET’S START A CONVERSATION Vaginal and Sexual Health at Midlife

This educational activity is jointly provided by the North Carolina Academy of Family Physicians (NCAFP) and Spire Learning.

This activity is supported by an educational funding donation provided by AMAG Pharmaceuticals, Inc. LET’S START A CONVERSATION Low Sexual Desire in Women

LET’S START A CONVERSATION Vaginal and Sexual Health at Midlife

PROGRAM OVERVIEW Approximately 32 million postmenopausal women in the US suffer from symptomatic GSM, yet less than 10% of symptomatic women receive treatment. This live meeting series will provide family physicians with the knowledge and skills they need to recognize signs and symptoms of GSM, address barriers to care, and select appropriate therapies for the treatment of GSM in postmenopausal women.

TARGET AUDIENCE Family physicians

LEARNING OBJECTIVES At the conclusion of this live activity, family physicians should be better able to: • Recognize the signs and symptoms of genitourinary syndrome of menopause (GSM) • Describe the prevalence of GSM, its impact on postmenopausal sexual health, and current barriers in care • Review nonpharmacologic and pharmacologic treatment options for GSM, with a focus on recently approved therapies • Discuss management of GSM in breast cancer survivors LET’S START A CONVERSATION Low Sexual Desire in Women

LET’S START A CONVERSATION Vaginal and Sexual Health at Midlife

ACCREDITATION AND DISCLAIMER STATEMENTS This live activity, Let’s Start a Conversation: Vaginal and Sexual Health at Midlife has been reviewed and is acceptable for up to 1.00 Prescribed credit(s) by the American Academy of Family Physicians. Physicians should claim only the credit commensurate with the extent of their participation in the activity. AMA/AAFP Equivalency: AAFP Prescribed credit is accepted by the American Medical Association as equivalent to AMA PRA Category 1 Credit(s)™ toward the AMA Physician’s Recognition Award. When applying for the AMA PRA, Prescribed credit earned must be reported as Prescribed credit, not as Category 1.

HOW TO RECEIVE CREDIT To receive credit for your participation in this educational activity: • Read the objectives and other introductory CME information • Complete the preassessment prior to the start of the activity • Participate in the GSM presentation • Complete the postassessment and evaluation at the conclusion of the activity If you are seeking Prescribed credit, you must complete the postassessment and evaluation at the conclusion of the activity.

LEVELS OF EVIDENCE Levels of evidence are provided for any patient care recommendations made during this presentation. Level A (randomized controlled trial/meta-analysis): High-quality, randomized controlled trial (RCT) that considers all important outcomes. High-quality meta-analysis (quantitative systematic review) using comprehensive search strategies Level B (other evidence): A well-designed, nonrandomized clinical trial. A nonquantitative systematic review with appropriate search strategies and well-substantiated conclusions. Includes lower-quality RCTs, clinical cohort studies, and case-controlled studies with nonbiased selection of study participants and consistent findings. Other evidence, such as high-quality, historical, uncontrolled studies, or well-designed epidemiologic studies with compelling findings, is also included Level C (consensus/expert opinion): Consensus viewpoint or expert opinion Each rating is applied to a single reference in the presentation, not the entire body of evidence on the topic. LET’S START A CONVERSATION Low Sexual Desire in Women

LET’S START A CONVERSATION Vaginal and Sexual Health at Midlife

OFF-LABEL STATEMENT The faculty does not intend to discuss non–FDA-approved or investigational agents for the treatment of GSM. Participants should appraise the information presented critically and are encouraged to consult appropriate resources for any product or device mentioned in this activity.

LET’S START A CONVERSATION Low Sexual Desire in Women

LET’S START A CONVERSATION Vaginal and Sexual Health at Midlife

FACULTY PRESENTERS Activity Chair: Lisa Larkin, MD, FACP, NMCP, IF Owner and President Lisa Larkin, MD, and Associates Founder & CEO Ms.Medicine Cincinnati, OH Dr Lisa Larkin is a board-certified internist, business owner, and entrepreneur practicing internal medicine and women’s health in both academic and private practice since 1991 in Cincinnati, Ohio. She received her medical degree from the Yale University School of Medicine in New Haven, Connecticut, and then completed an internal medicine residency with the University of Chicago Hospitals, Pritzker School of Medicine, in Chicago, Illinois. Dr Larkin is owner and President of Lisa Larkin, MD, and Associates, an independent multi-specialty internal medicine and women’s health Direct Primary Care practice, as well as founder and CEO of Ms.Medicine, a concierge women’s healthcare organization. Dr Larkin is also founder and Executive Director of the nonprofit Cincinnati Sexual Health Consortium, and serves as Director of Women’s Corporate Health for TriHealth. She formerly (2012-2016) served as Associate Professor and Division Director of Midlife Women’s Health at the University of Cincinnati (UC) College of Medicine and as Director of the UC Health Women’s Center. Dr Larkin is a Fellow of the American College of Physicians and the International Society for the Study of Women’s Sexual Health (ISSWSH), and is certified as a menopause clinician by the North American Menopause Society (NAMS). Additionally, she serves on the board of directors of ISSWSH and the board of trustees of NAMS.

Dr Larkin is passionate about raising the standard of evidence-based care for women and devotes considerable time to women’s health advocacy efforts. Most recently, she launched a direct-to- consumer breast cancer risk assessment and prevention program. Considered a national expert in menopause management and sexual medicine, Dr Larkin is also well known as a clinician and community educator, publisher, lecturer, and expert media resource. Her work has led to publications in peer-reviewed journals such as Menopause, Mayo Clinic Proceedings, and OBG Management. Disclosure Statement: Advisory Board: AMAG Pharmaceuticals, Inc; Amgen Inc; Procter & Gamble Co; TherapeuticsMD, Inc Consultant: AMAG Pharmaceuticals, Inc; Amgen Inc; Procter & Gamble Co; TherapeuticsMD, Inc Speaker: AMAG Pharmaceuticals, Inc; Amgen Inc; Procter & Gamble Co; TherapeuticsMD, Inc LET’S START A CONVERSATION Low Sexual Desire in Women

LET’S START A CONVERSATION Vaginal and Sexual Health at Midlife

FACULTY PRESENTERS (CONT’D) Becky Lynn, MD, FACOG, IF Associate Professor of Obstetrics and Gynecology Director, Center for Sexual Health Saint Louis University Saint Louis, MO Dr Becky Lynn is Director of the Center for Sexual Health and an Associate Professor of Obstetrics and Gynecology at Saint Louis University in Missouri. She earned her medical degree from Georgetown University School of Medicine in Washington, DC, completed her residency in obstetrics and gynecology at Barnes-Jewish Hospital in Saint Louis, and then practiced at the University of Missouri, Columbia, before joining the faculty of Saint Louis University in 2015. Dr Lynn is a Fellow of the International Society for the Study of Women’s Sexual Health (ISSWSH) and the American College of Obstetricians and Gynecologists (ACOG), as well as President of the Saint Louis Obstetrical and Gynecological Society. She is a certified sexual counselor, and completed her training at Sexual Medicine Associates in West Palm Beach, Florida. Currently, she is working towards her Master’s in Business Administration at the Richard A. Chaifetz School of Business of Saint Louis University. Dr Lynn’s research interests include vaginal treatments for genitourinary syndrome of menopause and the effects of cannabis on the sexual experience. She has spoken nationally and internationally on women’s sexual health, and is known for her patient/partner education YouTube channel that features monthly videos highlighting topics relating to sexual health and women’s health in general. She has also made several appearances in podcasts, television, radio, and print. Dr Lynn is a member of many professional societies, including the International Society for the Study of Vulvovaginal Disease, ACOG, ISSWSH, the International Society for the Study of Sexual Medicine, and the World Professional Association for Transgender Health. Her work has led to publications in peer-reviewed journals such as the Journal of Clinical Endocrinology and Metabolism and Sexual Medicine. Disclosure Statement: Speaker: AMAG Pharmaceuticals, Inc; Bausch Health Companies Inc (formerly Valeant Pharmaceuticals International, Inc); TherapeuticsMD, Inc; Viveve Medical, Inc Shareholder: AMAG Pharmaceuticals, Inc; Palatin Technologies, Inc; TherapeuticsMD, Inc

LET’S START A CONVERSATION Low Sexual Desire in Women

LET’S START A CONVERSATION Vaginal and Sexual Health at Midlife

FACULTY PRESENTERS (CONT’D) Andrea J. Singer, MD, FACP, CCD Associate Professor, Departments of Medicine and Obstetrics and Gynecology Georgetown University Medical Center Director, Women’s Primary Care Medical Director, Fracture Liaison Service for Secondary Fracture Prevention Medical Director, Executive Health Program MedStar Georgetown University Hospital Washington, DC Dr Andrea J. Singer is Director of Women’s Primary Care in the Department of Obstetrics and Gynecology at MedStar Georgetown University Hospital in Washington, DC. She is also Director of Bone Densitometry, Medical Director of the Fracture Liaison Service for Secondary Fracture Prevention, as well as Medical Director of the Executive Health Program. Dr Singer is an Associate Professor in the Departments of Medicine and Obstetrics and Gynecology at Georgetown University Medical Center, where she is Director of the Reproduction Module and Human Sexuality Course at the School of Medicine. She earned her medical degree from the Albert Einstein College of Medicine in Bronx, New York, before completing a residency in internal medicine at Georgetown University Medical Center. Dr Singer holds a Sexual Health Certificate in Sexual Counseling and Sexuality Education from the University of Michigan School of Social Work, and is a Certified Clinical Densitometrist. Additionally, she is Chief Medical Officer for the National Osteoporosis Foundation. Dr Singer’s clinical areas of expertise and research are women’s primary care, osteoporosis, bone densitometry, secondary fracture prevention, menopause, sexual health, and medical and gynecologic disease. She is well known as a clinician, researcher, and educator, and has been invited to deliver women’s health presentations at national and international events. She is an invited Fellow of the American College of Physicians and a member of many other professional societies, including the International Society for the Study of Women’s Sexual Health, the North American Menopause Society, the American Society for Bone and Mineral Research, the Preferred Partners Network of the National Osteoporosis Foundation, and the International Society for Clinical Densitometry. Additionally, she serves as Section Editor for Bone Health for the Journal of Women’s Health and as a reviewer for the Journal of Sexual Medicine, American Journal of Obstetrics and Gynecology, and Osteoporosis International. Disclosure Statement: Advisory Board: TherapeuticsMD, Inc Consultant: TherapeuticsMD, Inc Speaker: TherapeuticsMD, Inc LET’S START A CONVERSATION Low Sexual Desire in Women

LET’S START A CONVERSATION Vaginal and Sexual Health at Midlife

AGENDA 5 minutes Welcome and Introductions 15 minutes GSM: Impact on Sexual Health & Making the Diagnosis 5 minutes Evaluation and Management of GSM 15 minutes Tailoring GSM Treatment Regimens 5 minutes Management of GSM in Breast Cancer Survivors 10 minutes Q&A 5 minutes Postassessment and Evaluation Please complete the preassessment located in your meeting handout before the program begins.

Sponsorship and Support

This educational activity is jointly provided by the North Carolina Academy of Family Physicians (NCAFP) and Spire Learning.

This activity is supported by an educational funding donation provided by AMAG Pharmaceuticals, Inc.

1 Faculty and Disclosures Activity Chair Lisa Larkin, MD, FACP, NMCP, IF Owner and President Lisa Larkin, MD, and Associates Founder & CEO Ms.Medicine Cincinnati, OH

Disclosure Statement: Advisory Board: AMAG Pharmaceuticals, Inc; Amgen Inc; Procter & Gamble Co; TherapeuticsMD, Inc Consultant: AMAG Pharmaceuticals, Inc; Amgen Inc; Procter & Gamble Co; TherapeuticsMD, Inc Speaker: AMAG Pharmaceuticals, Inc; Amgen Inc; Procter & Gamble Co; TherapeuticsMD, Inc

Faculty and Disclosures (Cont’d) Faculty Presenter Becky Lynn, MD, FACOG, IF Associate Professor of Obstetrics and Gynecology Director, Center for Sexual Health Saint Louis University Saint Louis, MO

Disclosure Statement: Speaker: AMAG Pharmaceuticals, Inc; Bausch Health Companies, Inc (formerly Valeant Pharmaceuticals International, Inc); TherapeuticsMD, Inc; Viveve Medical, Inc Shareholder: AMAG Pharmaceuticals, Inc; Palatin Technologies, Inc; TherapeuticsMD, Inc

2 Faculty and Disclosures (Cont’d) Faculty Presenter Andrea J. Singer, MD, FACP, CCD Associate Professor, Departments of Medicine and Obstetrics and Gynecology Georgetown University Medical Center Director, Women’s Primary Care Medical Director, Fracture Liaison Service for Secondary Fracture Prevention Medical Director, Executive Health Program MedStar Georgetown University Hospital Washington, DC Disclosure Statement: Advisory Board: TherapeuticsMD, Inc Consultant: TherapeuticsMD, Inc Speaker: TherapeuticsMD, Inc

Levels of Evidence

Levels of evidence are provided for any patient care recommendations made during this presentation.

• Level A (randomized controlled trial/meta-analysis): High-quality, randomized controlled trial (RCT) that considers all important outcomes. High-quality meta-analysis (quantitative systematic review) using comprehensive search strategies • Level B (other evidence): A well-designed, nonrandomized clinical trial. A nonquantitative systematic review with appropriate search strategies and well-substantiated conclusions. Includes lower-quality RCTs, clinical cohort studies, and case-controlled studies with nonbiased selection of study participants and consistent findings. Other evidence, such as high-quality, historical, uncontrolled studies, or well-designed epidemiologic studies with compelling findings, is also included • Level C (consensus/expert opinion): Consensus viewpoint or expert opinion Each rating is applied to a single reference in the presentation, not the entire body of evidence on the topic.

3 Off-Label Statement

The faculty does not intend to discuss non–FDA-approved or investigational agents for the treatment of GSM.

Participants should appraise the information presented critically and are encouraged to consult appropriate resources for any product or device mentioned in this activity.

Learning Objectives

At the conclusion of this live activity, family physicians should be better able to: • Recognize the signs and symptoms of genitourinary syndrome of menopause (GSM) • Describe the prevalence of GSM, its impact on postmenopausal sexual health, and current barriers in care • Review nonpharmacologic and pharmacologic treatment options for GSM, with a focus on recently approved therapies • Discuss management of GSM in breast cancer survivors

4 Anne

• 60-year-old healthy woman who presents with complaints of dryness, and pain with sexual activity • Menopause at age 52; initial mild hot flashes that have resolved • Lubricants initially helpful but now no longer adequate • In past, enjoyable sex life but now, because of pain, not sexually active for 12 months • Both she and her husband are distressed

• Vulvovaginal atrophy (VVA) renamed genitourinary syndrome of menopause (GSM) to more accurately reflect the breadth of the condition and the organs impacted • VVA represents 1 component of GSM

Portman DJ, et al. Menopause. 2014;21:1063-1068.

5 GSM

• Highly prevalent, affecting 50%-70% of postmenopausal (PM) women • Progressive condition • Worsens with time from menopause • Loss of estrogen leads to physical changes in the labia majora, minora, clitoris, vestibule, vagina, and bladder • Common signs: – Introital narrowing – Reduced elasticity and dryness – Pallor/erythema – Loss of vaginal rugae – Tissue fragility

– Telescoping urethra Images courtesy of Murray A. Freedman, MD

The North American Menopause Society. Menopause. 2013;20(9):888-902. Freedman MA. https://www.menopausemgmt.com/vaginal-ph-estrogen-and-genital-atrophy/. Accessed February 11, 2019.

GSM: Histologic and Cytologic Changes

Premenopause Postmenopause

Superficial cells Superficial cells

Intermediate cells Intermediate cells

Parabasal cells Parabasal cells

Reiter S. Int J Gen Med. 2013;6:153-158. Freedman MA. https://www.menopausemgmt.com/vaginal-ph-estrogen-and-genital-atrophy/. Accessed February 11, 2019. Kalloo NB, et al. J Clin Endocrinol Metab. 1993;77(3):692-698.

6 Symptoms of GSM

Genital Sexual Urinary Tract Dryness* Lack lubrication Urgency Burning Discomfort/pain (dyspareunia)* Dysuria Irritation Impaired function Recurrent UTI Women may present with some or all symptoms; a physical exam is required to exclude other diagnoses.

Of 500 postmenopausal women with vaginal discomfort: 85% reported vaginal dryness 52% reported pain during intercourse

*Most bothersome symptoms. UTI, urinary tract infection. Portman DJ, et al. Menopause. 2014;21:1063-1068. Simon JA, et al. Menopause. 2013;20:1043-1048.

Symptoms Associated With Menopause

• Up to 85% of women experience VMS VMS GSM: Vaginal dryness/Dyspareunia • VMS peaks 1-2 years prior to and 1-2 years after the final Menopause menstrual period Vasomotor symptoms • GSM develops later, worsens with time from menopause GSM symptoms • Most common symptoms of GSM: vaginal dryness and dyspareunia -2 0 2 Years

VMS, vasomotor symptoms. Nelson HD. Lancet. 2008;371(9614):760-770. Kronenberg F. Ann N Y Acad Sci. 1990;592:52-86. Bachmann GA, et al. Am Fam Physician. 2000;61(10):3090-3096. Dennerstein L, et al. Obstet Gynecol. 2000;96(3):351-358.

7 Increase in Vaginal Dryness With Aging and Years Beyond Menopause

50 Dryness increased significantly in late 47 perimenopause and postmenopause (P < 001). 40 32 30 25 21

Percent 20

10 3 4 0 Pre- Early Late Post- Post- Post- menopause Perimenopause Perimenopause menopause menopause menopause (n = 172) (n = 148) (n = 106) 1 Year 2 Years 3 Years (n = 72) (n = 54) (n = 31)

Dennerstein L, et al. Obstet Gynecol. 2000;96:351-358.

GSM and Recurrent UTIs

• Vaginal pH changes with menopause and the loss of estrogen • The acidic environment before menopause discourages the growth of pathogenic bacteria • After menopause, treatment with estrogen results in reduction in vaginal pH and reduction in UTIs

Reproductive Stage Estrogen Vaginal pH Colonization

Premenopause Replete 4.5 Lactobacilli

Pathogenic coliforms Postmenopause Deficient > 6 like E. coli

Maloney C, et al. J Am Med Dir Assoc. 2001;2(2):51-55. Simunic V, et al. Int J Gynaecol Obstet. 2003;82(2):187-197. Raz R. Int J Antimicrob Agents. 2001;17(4):269-271.

8 64 million postmenopausal women in the US

Wysocki S, et al. Clin Med Insights Reprod Health. 2014;8:23-30.

50% (32 million) of postmenopausal women suffer from symptomatic GSM1

Wysocki S, et al. Clin Med Insights Reprod Health. 2014;8:23-30.

9 Only 50% 50% 50% of women (16 million) (32 million) (16 million) of women seek never treated4 of postmenopausal women treatment2,3 suffer from symptomatic GSM1

1. Wysocki S, et al. Clin Med Insights Reprod Health. 2014;8:23-30. 2. Kingsberg SA, et al. J Sex Med. 2013;10(2):1790-1799. 3. MacBride MB, et al. Mayo Clin Proc. 2010;85(1):87-94. 4. Krychman M, et al. J Sex Med. 2017;14(3):425-433.

25% using OTC moisturizers and lubricants2

50% 7% of women 50% of women (32 million) treated with (16 million) prescription never treated2 of postmenopausal women medication3 suffer from symptomatic GSM1

18% past users of prescription meds OTC, over-the-counter. 2 1. Wysocki S, et al. Clin Med Insights Reprod Health. 2014;8:23-30. who discontinued 2. Krychman M, et al. J Sex Med. 2017;14(3):425-433. 3. IMS Health Plan Claims (April 2008-March 2011).

10 Most Commonly Reported Negative Effects of Vaginal Discomfort Among Postmenopausal Women in the US

Reduced quality-of-life 12%

Interferes with partner 15% relationship

Makes patient feel old 35%

Negative effects on sex life 41%

0% 10% 20% 30% 40% 50%

n = 1622

Nappi RE, et al. Maturitas. 2010;67(3):233-238.

CLOSER Survey: Clarifying Vaginal Atrophy’s Impact on Sex and Relationship Survey

4167 married or cohabitating postmenopausal women with VVA symptoms and 4174 partners 9 countries: Canada, Denmark, Finland, France, Great Britain, Italy, Norway, Sweden, US

64% Painful sex Postmenopausal 59% women with VVA symptoms 30% stopped having sex due Loss of libido 64% Male partners of 52% postmenopausal to vaginal women with VVA symptoms discomfort Avoidance of 58% intimacy 78%

0% 50% 100%

Simon JA, et al. Menopause. 2014;21:137-142.

11 The Menopause Transition, GSM, and Sexual Dysfunction

Early Menopausal Transition Late Menopausal Transition (Year 1, mean age 49) (Year 8, mean age 57)

12%

With Sexual 42% Dysfunction 58% Without Sexual Dysfunction 88%

Dennerstein L, et al. Fertil Steril, 2002;77(Suppl 4):S42-S48.

Health Care Providers Infrequently Discuss Symptoms of GSM With Their Patients!

Discuss VVA with HCPs HCPs initiate conversation 80 67 62 62 60 54 56 50 44 40

Mean change (%) (%) Mean change 20 15 10 13 10 NR* 0 REVEAL-US 2008 VIVA-US 2010 VIVA-INT 2010 REVIVE-US 2012 REVIVE-EU 2014 Women's EMPOWER-US 2016 Data for individual studies can be found in specific references cited in Krychman; **NR = not reported HCPs, health care providers. CLOSER: Clarifying Vaginal Atrophy’s Impact on Sex and Relationship EMPOWER: Women’s EMPOWER survey REVEAL: Revealing Vaginal Effects at Mid-Life REVIVE: Real Women’s Views of Treatment Options for Menopausal Vaginal Changes VIVA: Vaginal Health: Insight, Views, & Attitudes WVM: Women’s Voices in Menopause Krychman M, et al. J Sex Med. 2017;14(3):425-433.

12 Why Don’t HCPs Ask Women About Symptoms of GSM or Sexual Health Concerns?

• Don’t think it is an issue for the patient 50%-70% • Don’t want to offend the patient 73% of women want their provider to ask! • Lack of training and skills 44% of medical schools lack a sexual health curriculum; minimal education in IM, FM, and ObGyn residency • Personal embarrassment or discomfort • Believe the topic is too complex to bring up in a short visit Become comfortable with one question, and make it part of your routine! “Do you have any sexual health concerns today?” • Don’t think there are effective treatments There are!

FM, family medicine; HCP, health care provider; IM, internal medicine; ObGyn, obstetrics/gynecology. Sexual Health Discussion Survey 2009.

Screen for GSM (Please!)

• Ask one question and make it part of your routine exam!

“Are you having any sexual health concerns you would like to discuss?”

13 Screen for GSM (Please!)

• History: – Menopause status/years beyond menopause – Screen for medications that may be impacting vaginal symptoms (aromatase inhibitors) – Ask about use of over-the-counter (OTC) products •Exam: – External exam: rule out vulvar dermatopathology, findings consistent with GSM – Speculum exam, bimanual as indicated • Educate: – Mirror; educate on anatomy and findings – Review where to apply local therapies

Management of GSM

Goal of therapy: alleviate symptoms, preserve sexual function, prevent UTIs

14 Treatment Options for GSM

Regular sexual activity Solo, partner, device Activity Dilators Pelvic floor physical therapy

Lubricants Moisturizers Nonhormonal Topical lidocaine Laser

Vaginal estrogen therapy Vaginal DHEA Hormonal Ospemifene Systemic estrogen therapy

DHEA, dehydroepiandrosterone. North American Menopause Society. Menopause. 2013;20(9):888-902.

First-Line Therapy

• Activity – Regular sexual activity – Pelvic floor physical therapy – Vaginal dilators

• OTC vaginal lubricants and moisturizers – Moisturizers: hydrate tissue; use several times a week – Lubricants: used prior to and during sexual activity – Very effective for many women – Do not treat physiologic changes related to estrogen loss

North American Menopause Society. Menopause. 2013;20(9):888-902.

15 Anne: Evaluation and Management

• Severe symptoms; no longer sexually active • “Failed OTC” • Exam: severe GSM; erythematous and tender vestibule, narrowed introitus, telescoping urethra • Mirror; educate; discuss application of moisturizers • Consider dilators

Anne: Needs Prescription Treatment

• Discuss FDA-approved products • How do you choose??? – No head-to-head comparison studies – Select based on: • Patient preference •Cost

16 Pharmacologic Treatments for GSM in 2018

Maintenance Type Generic Name Brand Name Starting Dose Notes Dose 0.5-1 g 17b-estradiol Estrace®, generic 0.5-1g/d x 2 week 1-3 x week Vaginal Cream 0.5-1 g Conjugated estrogens Premarin® 0.5-1g/d x 2 week 1-3 x week 17b-estradiol 4 or 10 mcg/d for 4 or 10 mcg/d Approved 2018 Imvexxy™ gel caps 2 weeks 2 x week 4 mcg lowest dose Vagifem®, 10 mcg/d for 10 mcg/d Vaginal Inserts Estradiol hemihydrate Yuvafem® 2 weeks 2 x week DHEA Intrarosa® 6.5 mg/d 6.5 mg/d Approved 2016 2 mg releases Change every Vaginal Ring 17b-estradiol Estring® 7.5 mcg/d 90 days SERM Ospemifene Osphena® 60 mg/d, po 60 mg/d, po Approved 2014 Apply to vestibule Topical 4% aqueous Lidocaine before sexual Lidocaine lidocaine activity North American Menopause Society. Menopause. 2013;20(9):888-902. Faubion SS, et al. Mayo Clin Proc. 2017;92(12):1842-1849.

How to Choose?

• All effective Estradiol Options: Cream, Ring, Tablets, Gel Caps • No head-to-head Conjugated Estrogen Creams comparison Oral SERM: Ospemifene Prasterone/DHEA • Patient preference

• Applicator vs none Images not available for handout due to copyright restrictions. •Cost

SERM, selective estrogen receptor modulator.

17 All Vaginal Estrogens Carry the Estrogen Class Boxed Warning

• All vaginal estrogen products have the FDA-mandated class label despite NO randomized controlled trials from vaginal estrogen products

Comparing Local Vaginal Estrogen Options

Serum Generic Brand Starting Maintenance Annual Dose Type Estradiol Level Name Name Dose Dose Estradiol (PM < 20 pg/mL) 0.5-1 gm Approx. 17b-estradiol Estrace® 0.5-1 gm/d x 2 week Vaginal 1-3 x week 7 mg/year Cream Conjugated 0.5-1 gm Premarin® 0.5-1 gm/d x 2 week estrogens 1-3 x week 17b-estradiol 4 or 10 mcg/d 4 or 10 mcg/d 0.5 mg/year 4.8 pg/mL Imvexxy™ gel caps for 2 weeks 2 x week (4 mcg gel caps) (4 mcg gel caps) Vaginal 8.0 pg/mL Inserts Estradiol Vagifem®, 10 mcg/d 10 mcg/d Approx. (using 10 mcg hemihydrate Yuvafem® for 2 weeks 2 x week 1 mg/year Vagifem) Vaginal 2 mg releases Change every Approx. 17b-estradiol Estring® 4.6 pg/mL Ring 7.5 mcg/d 90 days 2.7 mg/year OCPs Estradiol 1 mg/d 365 mg/year

OCPs, oral contraceptive pills. Naumova I, et al. Int J Womens Health. 2018;10:387-395.

18 WHI OS

Vaginal estrogen users compared to nonusers had similar risk of: • Invasive breast cancer •Stroke • Colorectal cancer Safety of • Endometrial cancer VE •VTE • CHD • Death

CHD, coronary heart disease; VE, vaginal estrogen; VTE, venous thromboembolism; WHI OS, Women’s Health Initiative Observational Study. Crandall CJ, et al. Menopause. 2018;25(1):11-20.

FDA-Approved Treatment Options

NEWER OPTIONS Estradiol Prasterone6 Hemihydrate Tabs 10 mcg4 Conjugated Estradiol Estradiol Ospemifene5 Estradiol Estrogen Vaginal 2 Gel Caps 1 Cream 3 Cream Ring 4 mcg7

1970- 1980- 1985- 1990- 1995- 2000- 2005- 2010- 2015- 2020 1979 1984 1989 1994 1999 2004 2009 2014 2019

VVA Atrophic vaginitis Dyspareunia Dyspareunia VVA Dyspareunia Atrophic vaginitis Dyspareunia

Newer FDA options are approved for dyspareunia, the most bothersome symptom of VVA/GSM

1. US FDA. CDER. Premarin NDA 020216. Label 2/2/2016. 5. US FDA. CDER. Osphena NDA 203505. Label 10/26/2018. 2. US FDA. CDER. Estrace NDA 086069. Label 8/17/2005. 6. US FDA. CDER. Intrarosa NDA 208470. Label 2/13/2018. 3. US FDA. CDER. Estring NDA 020472. Label 11/1/2017. 7. US FDA. CDER. IMVEXXY NDA 208564. Label 5/29/2018. 4. US FDA. CDER. Vagifem NDA 020908. Label 11/1/2017.

19 Ospemifene

• Selective estrogen receptor modulator (SERM) • FDA-approved to treat moderate-to-severe dyspareunia • Oral, daily • Side effect: vasomotor symptoms • Anti-estrogenic breast effects in preclinical trials • Not approved in the US for women with or at high risk for breast cancer • Not contraindicated in Europe in breast cancer survivors who have completed treatment

US FDA. CDER. Osphena NDA 203505. Label 10/26/2018.

Vaginal Prasterone (DHEA)

• FDA-approved in 2017 for moderate- • Does not have estrogen class to-severe dyspareunia label—no boxed warning • Daily, intravaginal insert • Warning in breast cancer survivors • Non-estrogen but not contraindicated • Endogenous steroid (DHEA) converted into androgens and estrogen • Most common side effect: vaginal discharge Generic Brand Starting Maintenance Name Name Dose Dose

DHEA Intrarosa® 6.5 mg/d 6.5 mg/d

US FDA. CDER. Intrarosa NDA 208470. Label 2/13/2018.

20 Comparison of the Labels: Warnings and Serum Estradiol Levels

Estradiol Vaginal Gel Caps (Imvexxy)1 Vaginal Prasterone (Intrarosa)2

Estradiol

Cmax (pg/mL) Cavg (0-24) (pg/mL) 4 mcg 4.8 (2.3) 3.6 (1.8) 10 mcg 7.3 (2.4) 4.6 (2.3) Placebo 5.5 (3.4) 4.3 (2.8)

Placebo (N=9) INTRAROSA (N=10)

Cmax (pg/mL) 3.33 (±1.31) 5.04 (±2.68) Estradiol AUC0-24 (pg•h/mL) 66.49 (±20.70) 96.93 (±52.06)

1. US FDA. CDER. Intrarosa NDA 208470. Label 2/13/2018. 2. US FDA. CDER. IMVEXXY NDA 208564. Label 5/29/2018.

Vaginal CO2 Laser for Treatment of GSM

• FDA 510(k)-cleared (“incision, excision, ablation of soft tissues”) • Fractionated beams of light penetrate small areas of tissue creating small wounds in the mucosal epithelium • Causes chemotaxis, neo-collagenesis, angiogenesis, epithelialization • Histologic evidence of benefit • Well-tolerated • Widely available and marketed • Only small prospective trials; none placebo-controlled • No randomized controlled trial or long-term safety data

21 Vaginal CO2 Laser for Treatment of GSM (Cont’d)

2016

Anne: When to Refer

• Fails to respond to therapy

• Breast cancer survivor

22 Breast Cancer Survivors and GSM

• Unmet medical need; majority of women go undiagnosed and untreated • Younger women, earlier onset • More severe GSM due to treatment: – Chemotherapy Growing by – Oophorectomy 250,000 per year – Radiation therapy – Adjuvant endocrine therapy • Huge impact on quality of life • Clinicians are reluctant to treat due to lack of evidence regarding safety of available therapies

American Breast Cancer Foundation. http://www.abcf.org/think-pink-education/breast-cancer-stats. Accessed February 5, 2019.

Management of GSM in Breast Cancer Survivors

ACOG 20121 Menopause 20182

1. ACOG Committee on Practice Bulletins-Gynecology. Obstet Gynecol. 2012;119(3):666-682. 2. Faubion SS, et al. Menopause. 2018;25(6):596-608.

23 First-Line Therapies for the Management of GSM in Breast Cancer Survivors

• Education • Sex therapy • Lubricants • Moisturizers • Topical lidocaine • Dilators • Pelvic floor physical therapy

Faubion SS, et al. Menopause. 2018;25(6):596-608.

Treatment Considerations for Local Hormone Therapy in Breast Cancer Survivors

Individual Patient Factor More Desirable Candidates Less Desirable Candidates

Stage 0,1, 2, or metastatic with limited life 3, or metastatic with extended life expectancy expectancy Grade Low or intermediate High Lymph Nodes No Yes Hormone Receptor Status Negative Positive Endocrine Therapy Tamoxifen Aromatase inhibitors Risk of Recurrence Low High Time Since Diagnosis Remote Recent Symptom Severity Severe Mild Nonhormone Therapies Failed Effective Effect on Quality of Life Severe Mild

Faubion SS, et al. Menopause. 2018;25(6):596-608.

24 Stepwise Management of GSM in Breast Cancer Survivors

First Line: Shared Decision- Consider: Making Education Sex Therapy Individual Patient Local Vaginal Lubricants Factors Estrogen Moisturizers Vaginal DHEA Topical Lidocaine Consultation with Ospemifene Dilators Oncologist Vaginal Laser Pelvic Floor PT

Is one product preferred? No data – Topical/vaginal estrogen = estrogen warning label – Vaginal DHEA and ospemifene = warning in breast cancer survivors/not contraindicated

Faubion SS, et al. Menopause. 2018;25(6):596-608.

GSM: Take-Home Messages

• Highly prevalent and negatively impacts QOL and sexual function • Remains underdiagnosed and undertreated • HCPs should routinely ask about GSM, examine, offer therapy/refer • First-line therapy = OTC lubricants + moisturizers • Second-line therapy – Vaginal estrogen – Vaginal DHEA – Ospemifene – Laser therapy • Second-line may be options for breast cancer survivors in consultation with oncologist

QOL, quality of life.

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Vaginal Dryness Bothersome symptoms of the vagina and vulva (outer lips of the vagina) increase during and after the menopause transition or may start several years after menopause. The decrease in estrogen with menopause is a major contributor to vaginal dryness, itching, burning, discomfort, and pain during intercourse or other sexual activity. Vaginal atrophy is the medical term that describes these changes. The genitourinary syndrome of menopause includes bothersome vaginal atrophy often combined with urinary symptoms. Vaginal atrophy may significantly affect your quality of life, sexual satisfaction, and relationship with your partner. Unlike hot flashes, which generally improve with time, vaginal symptoms typically worsen with time because of aging and a prolonged lack of estrogen. Menopause and aging can affect the vagina in the following ways:  Vaginal tissues become thin, dry, and less elastic, with decreased secretions and lubrication  Vaginal infections increase (as the healthy acidic pH of the vagina becomes more alkaline)  Discomfort with urination and increased urinary tract infections can occur  Fragile, dry, inflamed vaginal tissues may tear and bleed  Women with menopause induced by cancer treatments may have additional injury to the vaginal tissues from chemotherapy or pelvic radiation  Aromatase inhibitors, taken by many women with breast cancer, result in extremely low estrogen levels, often causing severe symptoms of vaginal dryness and decreased lubrication  Vaginal changes often result in pain with sexual activity or pelvic exams  Women with discomfort from vaginal atrophy often engage in less frequent intercourse or other sexual activity, which can cause the vagina to become shorter, narrower, and less elastic  Pain, narrowing of the vagina, and involuntary tightening of vaginal and pelvic muscles (known as vaginismus) can intensify to the point where sexual intercourse or other sexual activity is no longer pleasurable or even possible Treatment options The good news is that effective treatment options, such as nonhormone remedies or different forms of low-dose estrogen applied directly to the vagina, are available. These can be combined for optimal symptom relief. Nonhormone remedies  Vaginal lubricants reduce discomfort with sexual activity when the vagina is dry by decreasing friction. Water-soluble products or those with silicone are advised, because the oil in some products may cause vaginal irritation. There are many effective brands available without a prescription.  Vaginal moisturizers line the wall of the vagina and maintain vaginal moisture and should be used several times weekly at bedtime.  Regular sexual stimulation promotes vaginal blood flow and secretions. Sexual stimulation with a partner, alone, or with a device (such as a vibrator) can improve vaginal health.  Expanding your views of sexual pleasure to include “outercourse” options such as extended caressing, mutual masturbation, and massage provide a way to remain sexually intimate in place of intercourse.  Vaginal dilators can stretch and enlarge the vagina if it has become too short and narrow or if involuntary tightening occurs, preventing comfortable sexual activity. Dilators can be purchased and used with the guidance of a gynecologist, physical therapist, or sex therapist. Remember, the vagina can diminish in size, and its supporting muscles can weaken, so “use it or lose it”!  Pelvic floor exercises can strengthen weak vaginal muscles and relax tight ones. Vaginal estrogen therapy  An effective and safe treatment, low-dose local estrogen is applied directly to the vagina to restore vaginal health and relieve vaginal dryness and discomfort with sexual activity. Improvements usually occur within a few weeks, although complete relief may take several months. This even may be an option for women with a history of breast or uterine cancer but only after careful consideration of risks and benefits with a healthcare provider and oncologist.  Government-approved low-dose vaginal estrogen products are available by prescription as vaginal creams (used two or three nights/week), a vaginal estradiol tablet (used twice/week), and an estradiol vaginal ring (changed every 3 months). All are highly effective. You may wish to try several different forms and choose the one you prefer.  Standard doses of estrogen therapy provided to treat hot flashes also treat vaginal dryness, although some women still benefit from additional low-dose vaginal estrogen treatment. If only vaginal symptoms are present, low doses of estrogen applied to the vagina are recommended. Other prescription therapies  Ospemifene is an oral tablet taken daily for the treatment of painful intercourse caused by vaginal atrophy. Ospemifene is an estrogen agonist/antagonist, which means it works like estrogen in some tissues and opposes estrogen’s actions in others.  Dehydroepiandrosterone (DHEA) is a hormone-containing insert placed in the vagina nightly for the treatment of painful intercourse caused by vaginal atrophy. Although DHEA can be converted in the body to other hormones, including estrogen, blood levels of hormones do not appear to increase with vaginal use of low-dose DHEA.

Note: Vaginal symptoms not related to menopause include yeast infections, allergic reactions, and certain skin conditions, so consult your healthcare provider if symptoms do not improve with treatment.

Treatment Options Summary Vaginal lubricants (nonprescription). Many available products. Vaginal moisturizers (nonprescription). Many available products. Vaginal estrogen therapy (prescription required)  Estrace or Premarin vaginal cream (0.5-1 g, placed in vagina 2-3 times/week; generic available).  Estring (small, flexible estradiol ring placed in vagina and changed every 3 months; 7.5 µg/d).  Vagifem (estradiol tablet placed in vagina twice/week; 10 µg; generic available).  Imvexxy (estradiol softgel insert placed in vagina twice/week; 4 µg, 10 µg). Vaginal “exercise”  Sexual activity (with or without a partner).  Stretching exercises with lubricated vaginal dilators.  Pelvic floor physical therapy. Ospemifene (Osphena; prescription required). An oral tablet that treats painful intercourse caused by vaginal atrophy. Intravaginal dehydroepiandrosterone (Intrarosa; prescription required). A hormone vaginal insert that treats painful intercourse caused by vaginal atrophy.

This MenoNote, developed by the NAMS Education Committee of The North American Menopause Society, provides current general information but not specific medical advice. It is not intended to substitute for the judgment of a person’s healthcare provider. Additional information can be found at www.menopause.org. Copyright © 2018 The North American Menopause Society. All rights reserved. NAMS grants permission to healthcare providers to reproduce this MenoNote for distribution to women in their quest for good health.

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