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LET’S START A CONVERSATION Low Sexual Desire in Women

LET’S START A CONVERSATION

This educational activity is jointly providedVaginal by the North and Carolina Sexual Academy of Family Health Physicians at(NCAFP) Midlife 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

PROGRAM OVERVIEW A lack of interest in sex, or decreased desire, is a common female sexual problem that often goes unrecognized. Hypoactive sexual desire disorder (HSDD) is characterized by diminished feelings of sexual interest or desire that in turn causes distress. HSDD is estimated to affect from 10% to 46% of women in the United States, including women of all ages, regardless of menopausal status. This live meeting series will provide the latest updates in the diagnosis and management of HSDD to help improve the quality of life for your female patients, and will provide insights into: • Recognizing the prevalence ofLET’S HSDD andSTART barriers A toCONVERSATION care • Diagnosis using updated criteria, sexualVaginal health and Sexual communication Health at Midlife strategies, and validated screeners • The importance of identifying and treating common causes and comorbidities of low sexual desire • The range of nonpharmacologic, approved, and emerging pharmacologic and device-based therapies for HSDD

TARGET AUDIENCE Family physicians

LEARNING OBJECTIVES At the conclusion of this live activity, family physicians should be better able to: • Define hypoactive sexual desire disorder (HSDD) • Use communication strategies and screening tools to increase proactive discussions about sexual health as well as identification and diagnosis of female patients with HSDD • Recognize common causes and comorbidities of HSDD that should be treated before initiating targeted treatment for HSDD • Discuss efficacy and safety data for approved, emerging, and off-label treatments for HSDD LET’S START A CONVERSATION Low Sexual Desire in Women

ACCREDITATION AND DISCLAIMER STATEMENTS This live activity, Let’s Start a Conversation: Low Sexual Desire in Women 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 creditLET’S earned START must be reportedA CONVERSATION as Prescribed credit, not as Category 1. Vaginal and Sexual Health at Midlife 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 HSDD 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

OFF-LABEL STATEMENT The faculty intend to discuss/present information related to a non–FDA-approved or investigational use of a product/device, including the investigational use of for the treatment of HSDD. 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 Vaginal and Sexual Health at Midlife LET’S START A CONVERSATION Low Sexual Desire in Women

FACULTY PRESENTERS Activity Chair: Lisa Larkin, MD, FACP, NMCP, IF Owner and President Lisa Larkin, MD, and Associates Founder & CEO Ms.Medicine Cincinnati, OH LET’S START A CONVERSATION Dr Lisa Larkin is a board-certified internist,Vaginal businessand Sexual owner, Health and at entrepreneurMidlife 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 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

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 ofLET’S Medicine START in Washington, A CONVERSATION DC, completed her residency in obstetrics and gynecology at Barnes-Jewish HospitalVaginal in andSaint Sexual Louis, Health and then at Midlifepracticed 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 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

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 LET’S START A CONVERSATION Dr Andrea J. Singer is Director of Women’sVaginal Primary and Sexual Care Healthin the Department at Midlife 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

AGENDA 5 minutes Welcome and Introductions 5 minutes HSDD: Impact, Prevalence, Definitions 10 minutes How to Start the Conversation 10 minutes Screening and Diagnostic Tools for Practice 5 minutes Factors of the Female Sexual Response LET’S START A CONVERSATION 15 minutes Current and Emerging TherapeuticVaginal and StrategiesSexual Health at Midlife 5 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; TherapeuticsMD, Inc Consultant: AMAG Pharmaceuticals, Inc; Amgen Inc; Lupin Pharmaceuticals, Inc; Procter & Gamble Co; TherapeuticsMD, Inc Speaker: AMAG Pharmaceuticals, Inc; Amgen Inc; 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 intend to discuss/present information related to a non–FDA- approved or investigational use of a product/device, including the investigational use of testosterone for the treatment of HSDD.

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: • Define hypoactive sexual desire disorder (HSDD) • Use communication strategies and screening tools to increase proactive discussions about sexual health as well as identification and diagnosis of female patients with HSDD • Recognize common causes and comorbidities of HSDD that should be treated before initiating targeted treatment for HSDD • Discuss efficacy and safety data for approved, emerging, and off-label treatments for HSDD

4 Low desire is the most prevalent sexual health concern of women

5 Prevalence of : The PRESIDE Study

SEXUAL SEXUAL PROBLEM PLUS COMPLAINT PROBLEM DISTRESS Desire 38.7% 10%

Arousal 26.1% 5.4%

Orgasm 20.5% 4.7%

Any Dysfunction 44.2% 12%

Shifren JL, et al. Obstet Gynecol. 2008;112:970-978.

Women infrequently seek care for distressing sexual problems and they are frequently unaddressed!

6 PRESIDE: Few Women Seek Formal Care for Distressing Sexual Problems

Anonymous sources 9.1%

Never sought Formal healthcare or discussion with information their healthcare 14.5% provider (HCP) 34.5%

Informal discussion with non-healthcare N = 3239 women provider ≥ 18 years old 41.9%

Shifren JL, et al. J Womens Health. 2009;18:461-468.

Half of US Adults Believe Their HCP Would Dismiss Their Sexual Health Concerns

Level of Concern When Speaking to Physicians About Sexual Problems (Poll of 500 US Adults Age ≥ 25 years)

Doctor Would Dismiss Concerns 51% 20%

Doctor Would Be Uncomfortable 46% 23% There Would Be No Medical 46% 30% Treatment for Problem 0% 20% 40% 60% 80% 100% Adults Age ≥ 25 years (%)

Very Concerned Somewhat Concerned Marwick C. JAMA. 1999;281:2173-2174.

7 Low desire negatively A good sex life adds affects QOL, self- 10%-15% more value esteem, relationships, to a relationship, and overall health but a bad sex life negatively impacts a relationship by 50%-70%

Sexual Health Health

QOL – quality of life McCarthy BW. J Sex Med. 1997;23:231-240.

Impact of Low Desire on Emotional Health: WISHeS

Women who responded often, very often, or always

Bitter Normal Desire (n = 649) Ashamed HSDD (n = 129) Insecure Low Self-esteem Less Feminine Hopeless Inadequate Frustrated Unhappy Letting Partner Down

0 20406080100

Lieblum S, et al. Menopause. 2006;13:46-56. WISHeS – Women’s International Study of Health and Sexuality

8 Kate: Premenopausal

• 41 years old, healthy • Regular menses • Mentions casually during an annual wellness visit that she has been struggling with intimacy with her husband for several Image not available years and it has become a source of marital tension due to copyright

Do Ob/Gyns Ask About Sexual Health?

What percentage: • Routinely ask about sexual activity? 63% • Routinely ask about sexual issues? 40% • Routinely ask about sexual satisfaction? 29% • Routinely ask about sexual orientation? 28%

Ob/Gyns – obstetrician/gynecologists Sobecki JN, et al. J Sex Med. 2012;9:1285-1294.

9 Why Don’t Physicians Ask About Sexual Health?

• HCP embarrassment1,2 • Fear of embarrassing patient2 • Underestimation of prevalence • “Improving quality of life” not a high priority • Time constraints1,3 • Cultural or religious barriers4 • Consider other health issues as higher priorities5 • Lack of training in sexual health1 • Inadequate knowledge of available therapies1

1. Broekman CP, et al. Int J Impot Res. 1994;6:67-72. 2. Parish SJ, et al. Int J Women’s Health. 2013;5:437-447. 3. Baum N, et al. Patient Care. 1998(suppl):17-21. 4. Shahawy S, et al. Obstet Gynecol. 2015;126:969-973. 5. Kingsberg SA. Sex Reprod Menopause. 2004;2:199-203.

Step 1: Just Ask!

Legitimize importance of assessing sexual function; normalize as part of usual The ISSWSH history and physical Process of Care for the Identification of Are you currently involved Sexual Concerns in a relationship…sexual? and Problems in Women YES NO

Have your partners Do you have sexual included men, concerns women, or both? that you would like to What sexual discuss or that have concerns do you contributed to a lack have? of sexual behavior?

Parish SJ, et al. Mayo Clin Proc. 2019;94(5):842-856.

10 What Do I Ask?

Use a transition/ubiquity statement Pick one question

• Many women experience sexual • Do you have any sexual health changes with aging and concerns? menopause… • Do you have any concerns or • As part of my routine, I always questions about sexual ask my patients about sexual health….. functioning?

Normalize/universalize the conversations about sexual health issues

Sadovsky R, et al. J Sex Med. 2006;3:795-803.

Step 2: Elicit the story; Empathic Witnessing

Four Components to This Step The ISSWSH 1 Elicit the patient’s story Process of Care for the 2 Name/reframe attention to sexual Identification of problem or concern Sexual Concerns and Problems in 3 Empathic witnessing Women Referral to specialist or assessment 4 and treatment

Parish SJ, et al. Mayo Clin Proc. 2019;94(5):842-856.

11 Evaluation of a Specific Sexual Complaint

• How does the patient describe • Past or current physical, the problem? emotional, or sexual abuse? • How long has it been present? • Underlying guilt, depression, • Sudden or gradual? anger? • Partner-specific or situation- • Physical problems or pain? specific? • Partner sexual issues? • Precipitating events (emotional, • Ask about other domains of interpersonal, medical)? sexual health – arousal, orgasm • Relationship problems?

Kingsberg S. Obstet Gynecol Clin North Am. 2006;33(4):535-547.

Kate: Premenopausal With Low Desire and Distress • 41 years old, healthy • Regular menses • Distressing low desire for 4 years; was normal in the past • Absent spontaneous desire; never initiates, never masturbates • Interest does not change with the situation (ie, vacation) • Sexual activity has decreased to 1 time per month or less • Normal arousal and orgasm; no dryness or pain • Happily married for 15 years; no relationship issues other than around sex • Husband with normal sexual function • Denies unusual stressors and does not feel she is depressed or anxious

12 ISSWSH Definition: Hypoactive Sexual Desire Disorder Manifests as any of the following for a minimum of 6 months: • Lack of motivation for sexual activity manifested by either: – Reduced or absent spontaneous desire (sexual thoughts or fantasies) – Reduced or absent responsive desire to erotic cues and stimulation or inability to maintain desire or interest through sexual activity • Loss of desire to initiate or participate in sexual activity, including behavioral responses such as avoidance of situations that could lead to sexual activity, not secondary to sexual pain disorders

AND is combined with clinically significant personal distress that includes frustration, grief, incompetence, loss, sadness, sorrow, or worry

Parish SJ, et al. J Sex Med. 2016;13(12):1888-1906.

HSDD Diagnostic Considerations

Onset Context Characteristics

Generalized: Any situation, or Causes significant personal Lifelong any partner distress

Acquired: follows a period of Situational*: Certain types of Mild, moderate, or severe normal functioning situations or partners

*Situational – lack of desire due to relationship issues, partner’s sexual dysfunction, life stress, depression/anxiety that can be improved with lifestyle changes

Parish SJ, et al. J Sex Med. 2016;13:1888-1906.

13 Decreased Sexual Desire Screener (DSDS)

1. In the past, was your level of sexual desire/interest good and satisfying to you? No □ Yes □ If “NO” to Q1, 2, 3, or 4 = not generalized, acquired 2. Has there been a decrease in your level of sexual desire/interest? No □ Yes □ HSDD

3. Are you bothered by your decreased level of sexual interest? No □ Yes □

4. Would you like your level of sexual desire/interest to increase? No □ Yes □ If “YES” to all Q1-4 and “NO” to all Q5 factors = 5. Please check all the factors that you feel may be contributing to your current clinician to use best decrease in sexual desire/interest: No □ Yes □ judgment to confirm a A. An operation, depression, injuries, or other medical condition diagnosis of generalized, No □ Yes □ acquired HSDD B. Medications, drugs, or you are currently taking No □ Yes □ C. Pregnancy, recent childbirth, menopausal symptoms No □ Yes □ D. Other sexual issues you may have (pain, decreased arousal, orgasm) No □ Yes □ If “YES” to all Q1-4 and E. Your partner’s sexual problems “YES” to any Q5 factor = No □ Yes □ F. Dissatisfaction with your relationship or partner clinician to use best judgment to determine G. Stress or No □ Yes □ diagnosis*

*Comorbid conditions such as arousal or orgasmic disorder do not rule out a concurrent diagnosis of HSDD

Clayton AH, et al. J Sex Med. 2009;6:730-738.

Kate: Premenopausal With HSDD

Generalized, Acquired HSDD

14 ISSWSH Process of Care for HSDD

Clayton AH, et al. Mayo Clin Proc. 2018;93:467-487.

*Women with lifelong low sexual desire/interest without distress/bother may characterize themselves as asexual and should not be considered for treatment **Women in late reproductive years

Clayton AH, et al. Mayo Clin Proc. 2018;93:467-487.

15 Biopsychosocial Model of Female Sexual Response1,2

(eg, physical health, neurobiology, (eg, performance Biology Psychology endocrine function) anxiety, depression)

(eg, quality of current (eg, upbringing, and past relationships, cultural norms and Sociocultural Interpersonal intervals of abstinence, expectations) life stressors, finances)

1. Rosen RC, et al. Obstet Gynecol Clin North Am. 2006;334:515-526. 2. Althof SE, et al. J Sex Med. 2005;26:793-800.

Management of HSDD

Education and Behavioral Modification of Nonpharmacologic Pharmacologic Modifiable Risk Therapy/ Therapy Therapy Factors Psychotherapy

16 HSDD: Modifiable Factors

• Medical and Psychiatric Conditions • Substances of Abuse (legal, controlled, – Depression or illegal) – Urinary incontinence • Psychosocial Factors – Neurological disease – Relationship conflict – Cancer – Partner sexual dysfunction – Genitourinary syndrome of menopause –AIDS – Fatigue/insomnia – Endocrine disorders (thyroid, prolactin) –Stress • Medications – Mood disorder – Antidepressants – Poor body image – Antipsychotics • Sexual Factors – Barbiturates – Inadequate stimulation – Benzodiazepines – Poor attention focus on stimulation – Hypnotics – Poor sexual context – Hormones (esp. oral contraceptives) – Pain or diminished arousal

Parish SJ, et al. Sex Med Rev. 2016;4:103-120.

Kate: Premenopausal With HSDD

• OCPs until 2 years ago; No improvement of desire off OCPs • On SSRI (fluoxetine 10 mg) for 10 years; no change in dose; loss of desire did not correlate with start of SSRI • Physical exam normal including normal pelvic exam • Routine labs, TSH and prolactin normal

OCP – oral contraceptive pills SSRI – selective serotonin reuptake inhibitor TSH – thyroid-stimulating hormone

17 Kate: Educate and Modify

• Education about the complexity of female sexual response and the many factors that impact sexual health in women • Education about HSDD: the definition, and the many factors that specifically impact desire • Educate about the impact of psychosocial factors in HSDD • Educate about the biologic basis of HSDD • Discuss/educate about modifiable factors that impact desire: –OCPs – SSRIs – Interpersonal and psychological factors

Neural Basis of HSDD

Women with HSDD are unable to deactivate their prefrontal cortex making them unable to feel sexual desire Holstege G. Sex Med Rev. 2016;4:303-328.

18 Etiology of HSDD: Imbalance of Excitation and Inhibition1,2

• Dopamine • • Serotonin • Physiological/ • Opioids • Vasopressin Organic • Endocannabinoids • Norepinephrine

• Relationship conflict • Intimacy • Negative stress • Shared values Psychosocial/ • Negative beliefs • Romance Interpersonal about sex • Experience/behavior • Experience/behavior

1. Bancroft J, et al. J Sex Res. 2009;46:121-142. 2. Perelman MA. J Sex Med. 2009;6:629-632.

Hypothesis: How Treatment Impacts Desire

Clayton AH, et al. Mayo Clin Proc. 2018;93:467-487.

19 Behavioral and Psychotherapy Interventions

1. Cognitive behavioral therapy 2. Bibliotherapy 3. Sensate focus therapy 4. Mindfulness 5. Identification and treatment of past trauma 6. Cognitive restructuring 7. Understand HSDD as a metaphor for another issue 8. Reconnect to their sensual selves 9. Use of erotic materials 10. Surmount barriers to intimacy 11. Resolve interpersonal issues that cause/maintain HSDD

*Women with lifelong low sexual desire/interest without distress/bother may characterize themselves as asexual and should not be considered for treatment **Women in late reproductive years

Clayton AH, et al. Mayo Clin Proc. 2018;93:467-487.

20 Pharmacologic Management of HSDD

• FDA-Approved Agents – – Bremelanotide • Off-Label Agents – Testosterone • Topical, pellets, patches – – Buproprion

Flibanserin

• Approved by FDA in 2015 • First available treatment for generalized, acquired HSDD in premenopausal women (HSDD not caused by relationship issues, medications, or other medical issues) • Acts in the brain on neurotransmitters associated with desire to enhance excitation and decrease inhibitory response to sexual cues – Mixed serotonin and antagonist, and – Thought to produce region-specific elevations in dopamine and norepinephrine to offset inhibitory serotonergic activity

US FDA. CDER. Flibanserin NDA 022526. Label 5/2018.

21 Flibanserin (Cont’d)

• 100 mg at bedtime, daily1 • Takes 4-6 weeks to see a response1 • Updated Black Box Warning – discontinue alcohol at least 2 hours before taking at bedtime, or skip the dose for that evening – Do not consume alcohol until at least the morning after the previous bedtime dose2 • Also contraindicated with moderate to strong CYP-3A4 inhibitors – HIV drugs, fluconazole, antibiotics (ciprofloxacin, macrolides, calcium channel blockers (diltiazem, verapamil)1 • OCP not a contraindication (weak CYP-3A4) but caution1 • Clinicians and pharmacies must be certified to prescribe through the REMS program1

1. US FDA. CDER. Flibanserin NDA 022526. Label 5/2018. 2. https://www.fda.gov/news-events/press-announcements/fda-orders-important-safety-labeling- changes-addyi. Accessed June 25, 2019.

Flibanserin Efficacy: Pivotal Trials

Efficacy Endpoints Phase 3 Pivotal Studies Study 1471,2 Study 72,3 Study 752,4 Flibanserin Flibanserin Flibanserin 100 mg qhs 100 mg qhs 100 mg qhs SSE ✓✓✓

eDiary Desire – ✗✗

FSFI-Desire ✓✓✓

FSDS-R13 (Distress) ✓✓✓

FSFI-Total Score ✓✓✓

FSDS-Total Score ✓✓✓

Statistically significant separation from in 4-8 weeks (p < 0.05) 25% reduction in distress associated with low desire (p < 0.05) SSE – satisfying sexual events FSFI – Female Sexual Function Index 1. Katz M, et al. J Sex Med. 2013;10:1807-1815. 2. Fisher WA, et al. Sex Med Rev. 2017;5:445-460. FSDS – Female Sexual Distress Scale 3. Derogatis LR, et al. J Sex Med. 2012;9:1074-1085. 4. Thorp J, et al. J Sex Med. 2012;9:793-804.

22 Flibanserin Adverse Reactions1-3

Placebo Flibanserin 100 mg qhs Preferred Term N = 1905 N = 1543 N (%) N (%) Dizziness 41 (2.2) 176 (11.4) Somnolence 59 (3.1) 173 (11.2) 71 (3.7) 161 (10.4) Insomnia 46 (2.4) 75 (4.9) Dry mouth 17 (0.9) 37 (2.4) Anxiety 17 (0.9) 28 (1.8) Constipation 9 (0.5) 25 (1.6) Abdominal pain 15 (0.8) 23 (1.5) Sedation 3 (0.2) 20 (1.3) Vertigo 6 (0.3) 16 (1.0)

1. Derogatis LR, et al. J Sex Med. 2012;9:1074-1085. 2. Thorp J, et al. J Sex Med. 2012;9:793-804. 3. Katz M, et al. J Sex Med. 2013;10:1807-1815.

Flibanserin Interactions: Alcohol, SSRIs/SNRIs

• Previous alcohol contraindication based on earlier alcohol study: flibanserin 100 mg and alcohol dosed in the AM on an empty stomach1 – Flibanserin + 2 alcoholic drinks: 17% required intervention for hypotension – Flibanserin + 4 alcoholic drinks: 25% of subjects had orthostatic hypotension • New postmarketing data lightens alcohol restriction to 2 hours before dose2 • Pivotal phase 3 trials: no alcohol restriction and no increase in hypotension or syncope3 – Safety concerns raised by the FDA, including hypotension and syncope, are rare with proper bedtime dosing • Flibanserin did not exacerbate depression or anxiety in patients taking SSRI/SNRI but increased insomnia, dizziness, fatigue, dry mouth4 – Findings should not preclude concomitant use but consideration should be given

SSRI – selective serotonin reuptake inhibitor; SNRI – serotonin and norepinephrine reuptake inhibitor 1. Stevens DM, et al. J Clin Pharm Ther. 2017;42:598-606. 2. https://www.fda.gov/news-events/press-announcements/fda-orders-important-safety-labeling- changes-addyi. Accessed June 25, 2019. 3. Jofee HV, et al. N Engl J Med. 2016;374:101-104. 4. Clayton AH, et al. J Sex Med. 2018;15:43-51.

23 Bremelanotide (BMT)

• FDA-approved June 21, 2019 – Treatment of premenopausal women with acquired, generalized HSDD (low sexual desire that causes marked distress or interpersonal difficulty) NOT due to: • Co-existing medical or psychiatric condition, problems with the relationship, or the effects of a medication or drug substance • agonist – High affinity for the type-4 melanocortin receptor, and analog of the alpha-melanocyte-stimulating hormone – Melanocortin is known to be an excitatory neurotransmitter

US FDA. CDER. Bremelanotide NDA 210557. Label 6/2019.

Bremelanotide (cont’d)

• 1.75 mg via subcutaneous auto-injector to the abdomen or thigh as needed 45 minutes before anticipated sexual activity – Only one dose every 24 hours • Not recommended to use > 8 doses per month • Most common adverse effects in clinical trial were nausea, , and injection site reactions • Drug interactions: oral medications (slowed gastric emptying, decreases systemic exposure of )

US FDA. CDER. Bremelanotide NDA 210557. Label 6/2019.

24 Bremelanotide Presumed Mechanism of Action

Image not available due to copyright

In preclinical animal studies, efficacy was blocked by dopamine antagonist https://www.sec.gov/Archives/edgar/data/792977/000079297717000025/analystdaydeck.htm. Accessed February 19, 2019.

BMT RECONNECT Study Design

Study Population • Healthy, premenopausal Screening At-Home At-Home At-Home nonpregnant women ≥ 18 Month Placebo Study-Drug Self-Dosing year of age, in a current (confirm diagnosis) Self-Dosing Self-Dosing (1.75 mg BMT or stable relationship of at Month placebo via (efficacy least 6 months auto-injector) baseline) • Diagnosed with HSDD Placebo (symptoms present ≥ 6 No treatment Placebo BMT 1.75 mg months) • See appendix for other BMT 1.75 mg criteria

1 2 3–8 9–20 Study Month(s)

Clayton AH, et al. Poster presented at: The 30th ECNP Congress of Applied and Translational Neuroscience; September 2-5, 2017. Paris, France. Poster P.1.g.042.

25 Met Coprimary Endpoint: Improvement in Desire

Change in FSFI Desire Domain Score From Baseline to End of Core (Double-Blind) Phase 0.68 P < 0.0002 P < 0.0001 0.63 0.54 0.45

0.23 0.24 0.21

n = 316 n = 314 n = 290 n = 282 0. Study 301 Study 302

Placebo Bremelanotide 1.75 mg • Compared with placebo, women taking bremelanotide had significantly increased scores on the desire domain of the FSFI at 6 months • FSFI Desire Domain Score 1.2-6.0 Clayton AH, et al. Poster presented at: The 30th ECNP Congress of Applied and Translational Neuroscience; September 2-5, 2017. Paris, France. Poster P.1.g.042.

Met Coprimary Endpoint: Reduction in Distress

Change in FSDS-DAO Item 13 From Baseline to End of Core (Double-Blind) Phase 0. n = 316 n = 314 n = 290 n = 282 -0.25 -0.35 -0.42 -0.5 -0.74 -0.71 -0.75 P < 0.0001 P = 0.0057 -1. Study 301 Study 302

Placebo Bremelanotide 1.75 mg • Compared with placebo, women using bremelanotide had a significant reduction in distress as measured by FSDS-DAO Item 13 score at 6 months • FSDS-DAO Item 13 Score 0-4 DAO – Desire Arousal Orgasm Clayton AH, et al. Poster presented at: The 30th ECNP Congress of Applied and Translational Neuroscience; September 2-5, 2017. Paris, France. Poster P.1.g.042.

26 Responder Analysis: Global Assessment Questionnaire (GAQ)

Percentage Responders Defined by a Compared with the start of the study (prior Score of ≥ 5 on Question #3 of GAQ to taking the study drug), to what degree 70. do you think you benefited from taking the 58.3 58.2 study drug? 60. *P < 0.0001 *P < 0.0001

Very Very 50. Much No Much Worse Change Better 40. 36.1 35.5

30. Responder defined as score of ≥ 5 20. Women taking BMT reported significantly more benefit from 10. treatment compared with those taking placebo 0. Study 301 Study 302 Placebo BMT 1.75 mg Clayton AH, et al. Poster presented at: The 30th ECNP Congress of Applied and Translational Neuroscience; September 2-5, 2017. Paris, France. Poster P.1.g.042.

Safety Profile in Phase 3 Controlled Studies

Most Common Adverse Events (AEs) in > 2% of Subjects

Bremelanotide 301 Bremelanotide 302 Event n(%) n(%)

Placebo n = 319 BMT n = 324 Placebo n = 301 BMT = 303

Nausea 8 (2.5) 138 (42.6) 0 112 (37)

Flushing 2 (0.6) 85 (26.2) 1 (0.3) 42 (14.2)

Headache 8 (2.5) 32 (9.9) 5 (1.7) 37 (12.2)

https://www.sec.gov/Archives/edgar/data/792977/000079297717000025/analystdaydeck.htm. Accessed March 5, 2019.

27 BMT Safety

• Favorable safety profile1 • Phase 1 study found that it can be safely coadministered with ethanol2 • Treatment-emergent AEs led to treatment discontinuation/interruption in approximately 18% of women taking bremelanotide (vs 2% in placebo)1 • Most of the bremelanotide AEs causing withdrawal were gastrointestinal (11.1% in Study 301 and 7.6% in Study 302)1 • Contraindications: uncontrolled , known cardiovascular disease3 – Transient increase in , decrease in heart rate • Focal reported in 1% of patients3

1. Clayton AH, et al. Obstet Gynecol. 2018;131:186S. 2. Clayton AH, et al. Clin Ther. 2017;39:514-526. 3. US FDA. CDER. Bremelanotide NDA 210557. Label 6/2019.

Off-Label Systemic Testosterone for Low Desire: Patient Categories Supported by RCT Data

Surgically Naturally Postmenopausal menopausal postmenopausal women on no women on women on treatment hormone therapy

Postmenopausal SSRI/NSRI Women in late women with treatment- perimenopausal distressing low emergent low transition desire desire

No randomized controlled trial (RCT) data for premenopausal women

Davis SR. Lancet Diabetes Endocrinol. 2015;3:980-992.

28 Therapy in Women: A Reappraisal – An Endocrine Society Clinical Practice Guideline HSDD: • Late perimenopausal or postmenopausal women • 3-6 month trial of high physiologic doses of T to assess clinical response • Do not diagnose “androgen deficiency” or treat asymptomatic women • Use a transdermal formulation, if available – No FDA approved products in US – Only off-label use of male products or compounded testosterone are available – clinician must decide what they are comfortable using • Baseline level then 3-6 weeks and then q 6 months. Aim for mid-normal premenopausal range • No safety data beyond 2 years

Wierman ME, et al. J Clin Metab. 2014;99:3489-3510.

Testosterone Levels and Sexual Function: Postmenopausal Women • Low testosterone levels closely correlated with reduced coital frequency and loss of sexual desire1 • Significant positive relationship between free testosterone and ratings of sexual desire by interview questioning2 • Decline in libido greater after oophorectomy than after hysterectomy3

1. McCoy NL, et al. Maturitas. 1985;7:203-210. 2. Bachmann GA, et al. Maturitas. 1991;13:43-50. 3. Nathorst-Boos J, et al. Gynecol Obstet Invest. 1992;34:97-101.

29 Women Unlikely to Benefit From Testosterone Treatment for HSDD • Young women with normal ovarian function – other issues • Women in poor relationships • Women on high dose oral estrogen – high SHBG • Women with other sexual issues Image not available – treat those first (ie, VVA/GSM) due to copyright • Women who have never had satisfactory sexual function

SHBG – binding globulin VVA – vulvovaginal atrophy GSM – genitourinary syndrome of menopause

Testosterone Pellets, Injections: Dosing Matters

Physiologic Supraphysiologic dosing of dosing of testosterone testosterone

30 Kate: Discussion of Treatment Options

• Testosterone is not appropriate for Kate at this time – she is premenopausal with regular menses • Referral to couples therapy, sex therapy, behavioral therapy, or psychotherapy may be very helpful • Considerations for flibanserin – once daily for at least 4 to 6 weeks, alcohol consumption with 2 hours is contraindicated and patient must sign an informed consent • Considerations for bremelanotide – subcutaneous injection, nausea, transient increase in blood pressure and decrease in heart rate after administration, skin hyperpigmentation

Conclusions

• Sexual health concerns are highly prevalent and important to quality of life • All clinicians should initiate a discussion about sexual health with all patients – even if they are uncomfortable with management • HSDD is the most common female sexual dysfunction, underrecognized, and undertreated, but treatments are available and upcoming • The ISSWSH Process of Care for the Identification of Sexual Concerns and Problems in Women published in Mayo Clinic Proceedings is intended to be a helpful resource for primary care clinicians • Develop a network of sexual health clinicians (sex therapists, pelvic floor physical therapists, and sexual health clinicians) in your area to refer to

31 Questions?

Thank You Please complete the postassessment and evaluation located in your meeting handout.

32 Appendix

Prevalence of HSDD: Age and Reproductive Status

Women’s International Study of Health and Sexuality (WISheS) Prevalence of US Women with HSDD and Distress (According to Age and Reproductive Status)

30 26 25 20 14 14 15 9 10

US Women (%) US Women 5 0 Premenopausal Surgically Naturally Surgically (n = 414) Postmenopausal Postmenopausal Postmenopausal (n = 89) (n = 252) (n = 197)

Age 20-24 Years Age 50-70 Years

Lieblum S, et al. Menopause. 2006;13:46-56.

33 Low Sexual Desire Negatively Affects Self-Image and Partner Relationships

Online Survey: Premenopausal women with self-described low sexual desire (n = 306)

Affect your personal life? Affect relationship with your partner?

69% 67% 70% 70%

60% 60% 51% 50% 50% 35% 35% 40% 33% 40%

% of Patients of % 30% 30%

20% 20% 10% 10% 0% 0% Less Less Worry that partner Body image Self-confidence Self-worth connectedness communication will cheat

Kingsberg SA. J Womens Health. 2014;23:817-823.

Relative Frequency of Sexual Dysfunction

Drug Sexual Desire Sexual Arousal Orgasm Fluoxetine +++ ++ +++ Citalopram +++ +++ +++ Paroxetine +++ +++ +++ Sertraline +++ +++ +++ Venlafaxine +++ +++ +++ + + + Nefazadone + + + Vilazodone + + +

Clayton AH, et al. Postgrad Med. 2014;126:91-99.

34 Professional Organizations and Resources for Referrals

Organization Web Site Description International Society for the Study of www.isswsh.org Accurate information about women’s Women’s Sexual Health (ISSWSH) sexuality and sexual health American Association of Sexuality www.assect.org A resource to locate sexuality Educators, Counselors and Therapists educators, counselors, and therapists (ASSECT) Society for Sex Therapy and Research www.sstarnet.org A resource for locating sex therapists

North American Menopause Society www.menopause.org A resource for providers and patients (NAMS) on menopausal health and a resource to locate a NAMS certified menopause clinician American Cancer Society www.cancer.org Resource for comprehensive information about sex after cancer American Physical Therapy Association- www.womenshealthapta.org/pt- A resource to locate pelvic floor Section on Women’s Health locator physical therapists in your area

Off-Label, Nonhormonal Pharmacologic Therapy for HSDD Bupropion Buspirone

• Norepinephrine-dopamine reuptake • Presynaptic serotonin 5-HT1A inhibitor (NDRI) partial agonist • Investigated in several clinical trials • Decreases serotonergic tone for the treatment of HSDD • When added to SSRI for treatment • Bupropion improved sexual function of depression (BISF-W and CSFQ) but no effect – 58% of subjects treated with on frequency buspirone reported an improvement in sexual function compared with BISF-W – Brief index of Sexual Functioning in Women 30% treated with placebo CSFQ – Changes in Sexual Functioning Questionnaire Stahl SM, et al. Prim Care Companion J Clin Psychiatry. 2004;6:159-166. Segraves RT, et al. J Marital Ther. 2001;27:303-316. Loane C, et al. Brain Res. 2012;1461:111-118. Segraves RT, et al. J Clin Psychopharmacol. 2004;24:339-342. Landen M, et al. J Clin Psychopharmacol. 1999;19:266-271.

35 Mean Steroid Levels in Women (pg/mL)

Reproductive Natural Surgical Age Menopause Menopause

Estradiol 150 10-15 10

Testosterone 400 290 110

DHEA 5000 2000 1800

DHEAS 3,000,000 1,000,000 1,000,000

DHEA – dehydroepiandrosterone; DHEAS – dehydroepiandrosterone sulfate Buster J. In: Lobo R. Treatment of Postmenopausal Women. Boston, MA; Lippincott:1999. Judd HL, et. al. J Endocrinol Metab. 1974:39:1020-1024.

Other Testosterone References

OBG Management Vol. 30 No. 11 | November 2018

36 RECONNECT Trials: Key Entry Criteria

• Healthy premenopausal, nonpregnant women age ≥ 18 years, and currently in a stable (≥ 6 months) relationship • Diagnosed with HSDD (with/without decreased arousal) for ≥ 6 months • Experienced “normal” sexual function in the past for ≥ 2 years • Willing to engage in sexual activities ≥ 1x/month during the study • Had all of the following at screening: – Female Sexual Function Index (FSFI) total score < 26 (if diagnosed with HSDD with/without symptoms of decreased arousal) OR – FSFI desire domain (FSFI-D) score < 5 (if diagnosed with HSDD without decreased arousal) regardless of total FSFI score – Female Sexual Distress Scale – Desire/Arousal/Orgasm (FSDS-DAO) total score > 18

Clayton AH, et al. Poster presented at: The 30th ECNP Congress of Applied and Translational Neuroscience; September 2-5, 2017. Paris, France. Poster P.1.g.042.

Overall Subject Disposition Across Both RECONNECT Studies 301 & 302 (Integrated Data)

Integrated Data (Studies 301 & 302) Population Placebo BMT 1.75 mg Total n (%) n (%) n (%) Core Study Phase Randomized 632 (100) 635 (100) 1267 (100) Safety* 620 (98.1) 627 (98.7) 1247 (98.4) MITT** 606 (95.9) 596 (93.9) 1202 (94.9) Completers 493 (78.0) 363 (57.2) 856 (67.6)

OLE Study Phase Enrolled 430 (87.2) 254 (70.0) 684 (79.9) Completers 172 (40.0) 100 (39.4) 272 (39.8)

*Safety opulation = subjects who received at least one dose of study drug ** MITT or Modified Intent to Treat = subjects who received at least one dose of study drug AND had at least 1 post-dose follow-up visit

Slides provided as a courtesy of AMAG Pharmaceuticals, Inc. MRC-BMT-US-00018 01/19

37 Reasons for Premature Discontinuation: Integrated Studies 301 & 302 – Core Study Phase

Integrated Data (Studies 301 & 302)

Study Disposition Variables Placebo BMT 1.75 mg N = 620 N = 627 n (%) n (%)

Discontinuation of study drug 127 (20.5) 264 (42.1)

Adverse event 12 (1.9) 114 (18.2)

Withdrew consent 58 (9.4) 69 (11.0)

Lost to follow-up 28 (4.5) 52 (8.3)

Other 29 (4.7) 22 (3.5)

Slides provided as a courtesy of AMAG Pharmaceuticals, Inc. MRC-BMT-US-00018 01/19

38