Understanding the Spectrum of Female Sexual Dysfunction

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3 Understanding the Spectrum of Female Sexual Dysfunction Bruce Kessel, MD Chair Jeanne Leventhal Alexander, MD; Sheila Bolour, MD; Mark Elliott, PhD; Lori Futterman, RN, PhD; Jannet Huang, MD; Lee Shulman, MD

4 Disclosures NONE Historically: Research Funding: National Cancer Institute, Wyeth Research, Proctor and Gamble, Vivus, Amgen Consultant/Speakers Bureau: Merck, P&G, Lilly, Bayer, Novartis, Wyeth, Boehringer Ingelheim, Amgen

5 FDA : Unlabeled Use of Products On August 18, 2015 the FDA approved the first ever drug for female sexual dysfunction: FLIBANSERIN ALL other Pharmacologic agents discussed are 100% Off label or Investigational. Exceptions: EROS, ArginMax, Zestra oil.

6 Outline Describe models of the Sexual Response Cycle Female Sexual Dysfunction Enumerate FSD Classifications Describe the prevalence of FSD Reviewe FSD differential diagnosis Describe patient attitudes toward a sexual history Appraise the current research related to FSD treatments

7 Female Sexual Response Cycle

8 Sexual Response Cycle Sexual Excitement/ Tension Arousal Plateau Orgasm Desire Resolution Time

9 Sexual Response Cycle Intimacy-Based Model Emotional Intimacy + Emotional and Physical Satisfaction + Motivates the sexually neutral woman To find/ be responsive to Sexual Stimuli Psychological and biological factors govern arousability Arousal and Sexual Desire Sexual Arousal

10 Female Sexual Response Summary of all data from Engineering Dept, MIT

12 Neurobiology of Sexual Response Cycle STAGE STIMULATORY INHIBITORY DESIRE Dopamine Testosterone Melanocortin Serotonin AROUSAL Dopamine Norepinephrine Serotonin Prolactin ORGASM Oxytocin Serotonin Prolactin

13 Female Sexual Dysfunction: Definitions and Classifications

15 Female Sexual Dysfunction: Classification Systems ICD-9: International Classifications of Diseases : Decreased Libido Not covered in codes in genitourinary chapters Alternative to sexual dysfunction codes in mental health section DSM-IV/DSM 5: Diagnostic and Statistical Manual of Mental Disorders International Consensus Development Conference

16 Female Sexual Dysfunction: Classifications: DSM-IV Sexual desire/interest disorder Arousal disorders Women s orgasmic disorder Dyspareunia and vaginismus

17 Sexual Desire/Interest Disorder Absent or diminished feelings of sexual interest or desire, absent sexual thoughts or fantasies, and a lack of responsive desire The lack of interest is considered to be beyond the normative lessening with life cycle and relationship duration

18 Arousal Disorders Subjective Sexual Arousal Disorder Absence of, or markedly diminished feelings of, sexual arousal (sexual excitement and sexual pleasure) from any type of sexual stimulation Vaginal lubrication or other signs of physical response still occur Genital Sexual Arousal Disorder Self-report of minimal vulvar swelling or vaginal lubrication from any type of sexual stimulation Subjective sexual excitement still occurs from non-genital sexual stimuli

19 Women s Orgasmic Disorder Despite the self-report of high sexual arousal/excitement, there is either a lack of orgasm, a markedly diminished intensity of orgasm, or a marked delay of orgasm from any kind of stimulation

20 Dyspareunia and Vaginismus Dyspareunia: Persistent or recurrent pain with attempted or complete vaginal entry and/or penile vaginal intercourse Vaginismus: The persistent or recurrent difficulties of the woman to allow vaginal entry of a penis, a finger, and/or any object, despite the woman s expressed wish to do so

21 Female Sexual Dysfunction: Classifications All disorders must be persistent or recurrent All disorders must cause personal distress Subtypes: A = Lifelong versus acquired B = Generalized versus situational type C = Etiologic origin (organic, psychogenic, mixed, unknown)

22 DSM 5 changes Sexual desire and arousal disorders combined: Female Sexual Interest/Arousal Disorder Vaginismus and Dyspareunia changed to: Genito- Pelvic Pain/Penetration Disorder Etiologic Origin deleted.

23 Female Sexual Dysfunction: Prevalence

24 Female Sexual Dysfunction: Prevalence the actual prevalence of sexual problems is still a matter for conjecture Dunn KM, et al. J Sex Marital Ther 2002;28:

25 Female Sexual Dysfunction: Prevalence Study Interest Lubrication/ Arousal Orgasm Total Bancroft Arch Sex Behav 2003;32: Laumann JAMA 1999;281: Geiss Urology 2003;62:514-8 Nazareth BMJ 2003;327: % 31.2% 9.3% 45% 31.6% 20.6% 25.7% 43% 28.8% 23.0% 17.8% 48% 16.8% 3.6% 18.9% 39.6%

26 Proportion of Women with Decreased Interest Menopausal Status SM SM NM Age yrs yrs yrs Decreased interest 45%* 34% 32% Distressed 66% 44% 24% HSDD 30% 15% 8% SM = surgically menopausal; NM = naturally menopausal; HSDD = hypoactive sexual desire disorder *p<0.05 vs. older SM and NM women p<0.05 vs. NM Lieblum SR, et al. ISSWSH 2002

27 Prevalence PRESIDE study Shifren et al, Obstet Gynecol 2008 Similar prevalence rate of 43.1% for any sexual problem Only 12% prevalence of distressing sexual problems Peaked in middle-aged women Correlates of distressing sexual problems included poor selfassessed health, low education level, depression, anxiety, thyroid conditions, and urinary incontinence

28 Sexual Dysfunction: Differential Diagnosis

29 Differential Diagnosis of Female Sexual Dysfunction Endocrine / Hormonal Causes Vascular, Neurogenic, Other Medical Gynecologic: Pain, Urinary Incontinence Pharmacologic: SSRI s/snri s, Aromatase inhibitors Psychosocial

30 Taking a Sexual History

31 Patient and Physician Issues About 85% of adults want to discuss sexual functioning with their physicians but believe that their physician doesn t want to or doesn t have time. They also report non-empathic responses, physician discomfort etc. Physicians hesitate to take Sexual History Lack of training in sexual medicine May not recognize healthy sexual activity as important Time constraints Etc. Marwick C. JAMA 1999;281: Maurice WL, Bowman MA. Sexual Medicine in Primary Care 1999;1-41

32 Treatment

33 Research Issues and Controversies FDA Draft Guidance for Industry: Primary endpoint: Number of Satisfying Sexual Events (SSEs) Lack of easily applicable objective measurement. Lack of correlation between physiologic measures of arousal and subjective arousal. Medicalization of female sexuality. Off-label use

34 Therapies for FSD Peripherally acting pharmacologic agents Centrally acting pharmacologic agents Hormones Herbs/supplements Devices

35 Peripherally Acting Pharmacologic Agents Phosphodiesterase 5 Inhibitors Neutral Endopeptidase Inhibitors Prostaglandin E1 agonists L-arginine, NMI-870, Yohimbine, REC2615, Phentolamine.

36 SSRI-Sildenafil RCT, n=49, mean age 37.1 years, placebo versus sildenafil. All patients had a depression that had responded to a serotonin reuptake inhibitor. Clinical Global Impression score improved in sildenafil group. Secondary outcomes: Consistent improvement in ability to reach orgasm.

37 Centrally Acting Pharmacologic Agents Dopamine agonists: (Apomorphine and Bupropion) Melanocortin agonists 5-HT1A agonists (Flibanserin) Combination products: Lorexys: Bupropion + Trazedone Lybrido: Testosterone + Sildenafil Lybridos: Testosterone + Buspirone

39 Spontaneous Orgasm After 6 weeks on adjunctive bupropion therapy she experienced a 3-hour, sudden onset, spontaneous orgasm while shopping. Biol Psychiatry 1996;40:1184

40 Libido (Patient Rated) Mean ± S.E. 0 Bupropion Placebo -5-10

41 SSRI Induced Sexual Dysfunction Desire Frequency Baseline 4 weeks Clinical Response Bupropion / / % Placebo / / %

42 The World s First Aphrodesiac

43 Alpha-Melanocyte-Stimulating Hormone PT-141 nasal spray: Bremelanotide Phase II studies in women have been completed with nasal spray and safety issues did not allow continuation to Phase III trials. Reformulated as a subcutaneous injection Phase III trials with a subcutaneous injection have been completed.

44 PT-141 Results in Postmenopausal Women

45 Bremelanotide: Subject Comments Premenopausal: 11/13 an increase in desire/arousal Sensation of arousal occurred minutes following dose. Of the 6 subjects who engaged in sexual activity, 5/6 initiated the encounter. Postmenopausal: It was like when we were dating in 30 s and 40 s. (Climax) quality was better-more intense, lasted longer. I was 100% into it; I was in the mood.

46 Flibanserin

47 Flibanserin: 5-HT 1A agonist; 5-HT 2A antagonist

48 Flibanserin Three pivatol phase 3 trials RCT s; 4 weeks baseline, 24 weeks therapy; Premenopausal women with generalized, acquired HSDD. Co-primary endpoints (SSE/Desire) Total of 3548 premenopausal women, mean age 36 yo. Significant improvements if SSE s and FSFI desire domain and significant decrease in distress score

49 Flibanserin: SSEs per 28 days Number Placebo 545 Flibanserin 542 Baseline Week

50 Flibanserin

51 Flibanserin AEs Most Common AE s were: Dizziness: Placebo 2.2% versus Flibanserin 11.4% Somnolence: Placebo 3.1% versus Flibanserin 11.2% Nausea: Placebo 3.7% versus Flibanserin 10.4%

52 Flibanserin: Systemic Review and Meta-Analysis; JAMA; April studies encompassing n=5914 women Increase in Satisfying Sexual Events (SSEs): Pooled mean differences for SSE change from baseline were 0.49 between flibanserin and placebo Changes in ediary-desire and FSFI-desire modest. Increased AE s in flibanserin group 10% of women were much or very much improved.

53 Flibanserin History and Controversies Initial development as antidepressant- did not show efficacy Kessel ca Consultancy Meeting; ca Speakers Bureau FDA submission 2009: Advisory committee voted unanimously against approval. FDA rejected Kessel s from B-I; Sold to Sprout. FDA submission 2013: Additional Phase III trial. Rejected by FDA: Modest efficacy and safety concerns.

54 Flibanserin History and Controversies FDA submission 2015: No new efficacy data. Advisory Committee voted 18-6 in favor of approval FDA approves with REMS: Risk Evaluation and Mitigation Strategies (Prescriber Certification; Patient-Provider Agreement Form etc) Science controversies: Marginal efficacy, Changing co-primary endpoints; Safety concerns; Off label use Policy controversies: FDA recognizes HSDD as an area of unmet clinical need.

55 Flibanserin History and Controversies Advocacy Against: Hypoactive sexual desire disorder: inventing a disease to sell low libido : J Med ethics 2015: there is no evidence that hypoactive sexual desire disorder is a medical condition. For: Even the Score : 26 approved products for men, none for women. Accused FDA of sexism/gender discrimination. Large letter writing campaign- Congress, FDA, consumer groups.

56 Hormonal Therapies Testosterone: Intrinsa (patch); Libigel (gel), Tefina (nasal gel) Estratest (Methyltestosterone) Evidence for improvement in sexual functioning. Tibolone Synthetic steroid metabolized to estrogenic, progestational and androgenic metabolites. Some evidence for treating FSD.

57 Use of a Testosterone Patch in Hypoactive Sexual Desire Disorder Objective To evaluate the safety and efficacy of a testosterone transdermal system (TTS) in surgically menopausal (SM) women with hypoactive sexual desire disorder (HSDD) Design Two 24-week, randomized, double-blind, multi-center phase III clinical trials (INTIMATE SM 1 and INTIMATE SM 2) Subjects Surgically menopausal women with HSDD on stable doses of oral or transdermal estrogen Randomization Placebo or TTS 300 mcg/day Simon JA, et al. Obstet Gynecol 2004;103(4 Suppl):64S Buster J, et al. Endocrine Society Abstract, June 2004

58 4 Week Frequency Change From Baseline (SEM) Increases in Total Satisfying Sexual Activity at 24 Weeks from SAL INTIMATE SM 1 INTIMATE SM 2 p= p= % increase from baseline 33% 74% 23% 51% Placebo TTS Simon JA, et al. Obstet Gynecol 2004;103(4 Suppl):64S Buster J, et al. Endocrine Society Abstract, June 2004, Utian W, et al. ISSWSH Abstract; October 2004

59 Increase in Desire at 24 Weeks from PFSF Mean Change From Baseline (SEM) % increase from baseline INTIMATE SM 1 INTIMATE SM 2 p= p= % 56% 18% 49% Placebo TTS Simon JA, et al. Obstet Gynecol 2004;103(4 Suppl):64S Buster J, et al. Endocrine Society Abstract, June 2004, Utian W, et al. ISSWSH Abstract; October 2004

60 Testosterone Patch Summary The 300 mcg/day T patch significantly increased satisfying sexual activity and desire in oophorectomized women with HSDD Overall, the T patch significantly improved sexual functioning, with improvements observed as early as 4 weeks FDA advisory board agreed that efficacy had been demonstrated but wanted long term safety studies. Simon JA, et al. Obstet Gynecol 2004;103(4 Suppl):64S Buster J, et al. Endocrine Society Abstract, June 2004; Nachtigall L, et al. NAMS Abstract, October 2004

61 Testosterone in Premenopausal Women Dose ranging RCT, women ages years with low free testosterone. Significant improvement in Satisfactory Sexual Events at one testosterone dose.

62 Other Androgens in Trials DHEA Ovule: Early studies demonstrate beneficial vaginal effects with reduction in dyspareunia and possible increases in libido. Phase III trials are in progress. Libigel: Phase III efficacy data disappointing. Phase III safety study has been concluded. Tefina: Nasal testosterone gel Lybrido/Lybridos: Sublingual testosterone combined with either sildenafil or buspirone

63 Status of Pharmacologic Therapies Product Testosterone Flibanserin Bremelanotide MoA Androgen receptor 5-HT2A antagonist/5-ht1a agonist Melanocortin agonist (MC1/MC4) Indication HSDD HSDD HSDD/FSAD Stage US: Rejected Approved elsewhere Approved Phase 3 completed

64 Status of Pharmacologic Therapies Product Bupropion/Traze done Testosterone + Sildenafil or buspirone Alprostadil MoA 5-HT2A antagonist DA/NE agonist %HT1A agonist Androgen receptor Prostaglandin E1 Indication HSDD HSDD FSAD Clinical Stage Phase 2a Phase 2 b Phase 2 b

65 Herbal Therapies for FSD Products: Elexia, Rendezvour for Her, Female V- Drive, Biogra for Women, Monkeying Around, Yohimbine Power Max, Arginmax, avlimil, Zestra Herbs: Yohimbine, Ginko Biloba, Ginseng, Damiana, Muira Puama, Maca etc

66 ArginMax Ginseng, Ginko biloba, Damiana leaf, L-arginine, Vitamins RCT, n=77: 73.5% reported improved satisfaction with overall sex life (37.2% placebo). Improvements in sexual desire, frequency of sexual intercourse/orgasm, and clitoral sensation. RCT, n=108: Desire, satisfaction improved in premenopausal women, Satisfaction improved in perimenopauasal women, NS changes in postmenopausal women.

67 ZESTRA Feminine massage oil applied to clitoris and labia Borage seed oil, evening primrose oil, angelica root, coleus forskohlii, ascorbyl palmitate, alpha tocopherol N=20; Improvements in desire, arousal and orgasm N=256 RCT using a different oil as control. Female Sexual Function Index: Zestra superior to Control for desire and arousal domains. AE: 14.6 % with genital burning.

68 Devices P.J. O Rourke, Writer and Humorist There are a number of mechanical devices which increase sexual arousal, particularly in women. Chief among these is the Mercedes-Benz 380 SL convertible. Hollywood: The Rabbit Vibrator: Has it s own Wikipedia page. Guest star in HBO s Sex and the City EROS

69 Rabbit Vibrator

71 Conclusions Female sexual dysfunction is highly prevalent Female sexual dysfunction is characterized as a disturbance in the sexual response cycle or pain. Many women simply do not talk about this disorder, Many physicians do not know how to adequately raise the issue with their patients, but clinicians must create an appropriate climate for taking a sexual history

72 Conclusions (cont.) Women may present with multidimensional complaints of diminished desire, arousal, and orgasm Causes include vascular, neurogenic, hormonal, and psychogenic disorders Workup should include a complete medical and gynecological exam, and selected laboratory testing Treatment continues to evolve for female sexual dysfunction

73 Questions & Answers

Psykiatri PCK/Sexologisk Klinik Medication for Female Sexual Dysfunction - where are we?

Psykiatri PCK/Sexologisk Klinik Medication for Female Sexual Dysfunction - where are we? Medication for Female Sexual Dysfunction - where are we? Annamaria Giraldi, Professor, MD, PHD Sexological Clinic Copenhagen, Denmark Disclosures Eli Lilly - lecturer Boehringer advisory board Pfizer -