Female Sexual Dysfunction: Current and Future Treatments

1. Female Sexual Dysfunction:Current and Future Treatments Stanley E. Althof, Ph.D. Executive Director Center for Marital and Sexual Health of South Florida Professor Emeritus Case Western Reserve University School of Medicine

2. Disclosures • Dr. Althof serves as a Principal Investigator, Consultant or Member of an Advisory Board to: • Abvie • Allergan • Eli Lilly • Ixchelsis • Palitan • Plethora • Promonescent • Sprout • S1 Pharma • SSI • Trimel • Vyrix

3. Female Sexual Function and Dysfunction

4. Treatment

5. HSDD Etiological Considerations • Organic hypotheses • Low T • Side effect of medication • Chronic illness • Substance abuse • Psychological hypotheses • Negative affects such as depression, anger, shame • Deteriorating interpersonal relationship • Sexual orientation • Sexual abuse • Unconventional sexual scripts

6. Medical Management of HSDD/FSIAD Change or discontinuation of medication Off Label Treatments • Hormone Therapy1 • Buproprion2 • Topical alprostadil3 • DHEA4 • Testosterone5 • PDE5i6 On the Horizon • Testosterone + PDE5i7 • Testosterone + serotonin receptor agonist8 • Bremelanotide9 • Flibanserin10 Nappi RE, Davis SR. Climacteric, 2012; 14(3):267-274 2. Segraves RT. Adv Psychosom Med, 2008: 29: 23-32. 3. Liao Q et al, J Sex Med, 2008, 5(8):1923-1931. 4. Fooladi E, Davis SR. Expert OpinPharmacother, 2012, 13(15): 2131-2142. 5. Kingsberg S et al. J Sex Med, 2007, 4(4 Pt 1):1001-1008. 6. Berman JR et al. J Urol, 2003, 170(6 Pt 1): 2333-2338. 7. Poels S et al, J Sex Med, 2013, 10(3): 810-823. 8. Bloemers J, et al J Sex Med, 2013, 10: 791-809. 9. Safarinejad MR. J Sex Med 2008, 5(4):887-897. 10. DeRogatis LR et al. J Sex Med, 2012, 9(4): 1074-1085

7. Mood and Female Sexual Dysfunction • The prevalence of age related female sexual dysfunction showed a strong correlation to depression indicating that low desire is more common in women with co-morbid medical and psychiatric disorders particularly chronic illness and mood disorders Hartmann et al. Menopause, 2004, 11:6 726-740

8. Off-Label Testosterone Options for HSDD • Testosterone transdermal patches (300 mcg) • Small amount of Testosterone gels approved for men • Compounded 1% testosterone cream or gel for women • Oral methyltestosterone (MT) • Testosterone enanthate injections • Subcutaneous pellets (50-150 mg/3-4 months) • Sublingual testosterone (.5-.75 mg)

9. Treatment Planning for HSDD • Delineate all the relevant psychological variables • Delineate all the relevant interpersonal variables • Delineate all the relevant biomedical variables • Decide in which order these issues should be addressed and by whom • Treatment planning is an interactive and shared process with the patient/couple

11. Psychological Intervention for FSD Individual Therapy • When the dysfunction is lifelong • When the issues are more personal than interpersonal • Negative mood, body image, orientation • When partner is unwilling or not motivated • When situation is chaotic • When patient has severe psychopathology • When she has no awareness of herself as a sexual being Conjoint Therapy • When the dysfunction is acquired • When the issues are more interpersonal than personal • Power and control struggles • Trust • Communication issues • Sexual repertoire • Transferential roadblocks • Managing discrepant levels of desire • When both partners have sexual dysfunctions

12. Efficacy of Psychological Intervention for Female HSDD • Efficacy rates for psychological treatment of female HSDD range between 52% to 74% • Treatments included cognitive-behavioral interventions that sought to enhance communication between partners, increase sexual skills and reduce sexual and performance anxiety • Mindfulness-“relaxed wakefulness” or “non-judgmental, present-moment awareness” is derived from Buddhist meditation Brotto et al, 2010,2008; Hawton et al, 1986; McCabe, 2001; Trudel et al, 2001

13. On the Horizon- Maybe?

14. Number of Approved Drugs Available for Women with Sexual Dysfunction Even the Score- www.eventhescore.org Number of Approved Drugs Available for Men with Sexual Dysfunction 26 2

15. Bremelanotide

16. Bremelanotide • Bremelanotide is being developed by Palatin for the treatment of FSD: • First-in-class melanocortin receptor 4 agonist • Originally developed as an intranasal formulation; the current subcutaneous administration provides an improved tolerability profile • On-demand use with rapid onset of activity and well-tolerated • Novel mechanism of action activating endogenous pathways involved in sexual response • Is a CNS-active drug, is not a sex hormone, and does not require the presence of sex steroids for activity • Evaluated in 31 clinical studies, in over 2,500 people, showing efficacy in both FSD and ED • Recently completed a large Phase 2B trial (Study 54) in HSDD, FSAD and HSDD/FSAD mixed patients with subcutaneous (pre-filled syringes) formulation

17. Overall Efficacy Outcomes SSEs Per Month FSFI TotalScore FSDS-DAO Total Score * ** * *** Placebo Placebo Placebo • *P<0.05 • **P<0.01 • ***P<0.001 0.75 mg 0.75 mg 0.75 mg 1.25 mg 1.25 mg 1.25 mg 1.75 mg 1.75 mg 1.75 mg 17

19. Flibanserin Aim: To assess the efficacy and tolerability of flibanserin, a postsynaptic 5-HT1A agonist/5-HT2A antagonist, in the treatment of premenopausal women with HSDD. Method: North American premenopausal women with HSDD (mean age 35 years) were randomized to 24 weeks of treatment with flibanserin 25 mg twice daily (N = 396), 50 mg twice daily (N = 392), 100 mg once daily at bedtime (N = 395), or placebo (N = 398). Main Outcome Measures: Co-primary endpoints were sexual events (SSE) and sexual desire score, measured daily using an eDiary. Secondary endpoints included a change in Female Sexual Distress Scale-Revised (FSDS-R) total score, Female Sexual Function Index (FSFI) total, desire domain scores, and Patient’s Global Impression of Improvement. Results: Flibanserin 100 mg once daily was associated with an increase in SSE (P < 0.01 vs. placebo) but the 25 mg and 50 mg twice daily doses were not. No group showed a significant increase in eDiary desire score vs. placebo. The most frequently reported adverse events in women receiving flibanserin were somnolence (11.8%), dizziness (10.5%), and fatigue (10.3%). Thorp J et al. Treatment of Hypoactive Sexual Desire Disorder in Premenopausal Women: Efficacy of Flibanserin in the DAISY Study. J. Sex. Med. 2012, 9: 793-804

20. Satisfying Sexual Events (SSEs) *P<0.05 * The mean absolute number of SSEs for the screening month (no-treatment month) and the baseline month (placebo month) ranged from 0.7 to 0.8 and 1.5 to 1.9, respectively. Thorp J et al. Treatment of Hypoactive Sexual Desire Disorder in Premenopausal Women: Efficacy of Flibanserin in the DAISY Study. J. Sex. Med. 2012, 9: 793-804

21. Female Sexual Function Index (FSFI): Total Score ** * *P<0.05 **P<0.01 The mean absolute FSFI Score for the screening month (no-treatment month) and the baseline month (placebo month) ranged from 17.09 to 18.22 and 21.52 to 22.75, respectively. Higher scores indicate a greater level of sexual function. Thorp J et al. Treatment of Hypoactive Sexual Desire Disorder in Premenopausal Women: Efficacy of Flibanserin in the DAISY Study. J. Sex. Med. 2012, 9: 793-804

22. Dual Control ModelIdentify and Treat the Motivational State Relative Insensitivity for Sexual Cues Sexually Inhibited 0.5 mg sublingual T + 0.5 mg sublingual T + PDE5i 5-HT1ara Bloemers J, et al J Sex Med, 2013, 10: 791-809; Poels S, et al J Sex Med 2013, 10: 810-823; van Rooij K, et al J Sex Med. 2013, 10: 824-837

23. Treatment Based Upon Presumed Etiology Low Sensitivity Sexually Inhibited • Administration of 0.5mg of sublingual T increases the sensitivity of the brain to sexual cues • T+PDE5i might enhance sexual responsiveness, especially in women with low sensitivity for sexual cues • Main Outcome Measures- Subjective: sexual satisfaction, genital arousal, sexual desire. Physiological: vaginal pulse amplitude. • Results. Women with low sensitivity show a marked improvement in sexual function in response to treatment with T+PDE5i5 relative to placebo and relative to T+5-HT1ara. • Administration of 0.5mg of sublingual T increases the sensitivity of the brain to sexual cues • might amplify sexual inhibitory mechanisms further in women prone to sexual inhibition • T+5-HT1ara might enhance sexual responsiveness, particularly in women exhibiting sexual inhibition • Main Outcome Measures- Subjective: sexual satisfaction, experienced genital arousal, sexual desire. Physiological: vaginal pulse amplitude • Results. Women with high inhibition show a marked improvement in sexual function in response to treatment with T+5-HT1ara relative to placebo and relative to T+PDE5i.

24. Conclusion • Exciting new treatments for FSIAD are on the horizon • There is a great need to have safe and effective drugs approved for female FSIAD • There is also a great need to investigate the efficacy of psychological and/or combined interventions for female FSIAD • Also, need drug development protocols for female orgasmic disorder, persistent genital arousal disorder and pain disorders

25. Conclusion • Exciting new treatments for male HSDD and FSAID are on the horizon • Drugs face serious regulatory challenges, especially the medications for FSAID. • EVEN THE SCORE • To date 24 drugs have been approved for men; only 2 drugs has been approved for dyspaurenia in women • There is a great need to have safe and effective drugs approved for both male HSDD and female FSIAD • There is also a great need to investigate the efficacy of psychological and/or combined interventions for male HSDD and female FSIAD

26. Treatments for HSDD • Medical • Change or discontinuation of medication • Estrogen & Testosterone • DHEA • Buproprion • Presently in clinical trials- • Centrally acting drugs • Psychological • Individual Therapy • Couples Therapy • Power and control struggles • Trust • Communication issues • Sexual repertoire

27. Treatment Outcome for HSDD Psychological Intervention • Significant improvements in marital adjustment, sexual satisfaction, sexual frequency, initiating of sexual activity, sexual responsivity, and masturbation Brotto, 2006; Hawton et al, 1991; Schover & LoPiccolo, 1982; Hurlbert, 1993; McCabe, 2001; Trudel et al , 2001

28. Treatment of Orgasmic Disorders

29. “The human female orgasm definitely exists [it] inspires interest, debate, polemics, ideology, technical manuals and scientific and [self-help] literature solely because it is so often absent.” Symonds, D. The Evolution of Human Sexuality, New York, Oxford Press, 1979

30. SSRI Induced Orgasmic Dysfunction • Sexual side effects of SSRI’s range from 22%-60% • Men appear to have more side effects than women • Examining the phases of sexual dysfunction that are affected Clayton reported that 59% of her sample had some dysfunction. • Looking at orgasmic dysfunction (OD) women: • 41.2% of women on Citalopram reported OD • 42.5% of women on Fluoxetine reported OD • 47.1 % of women on Venlafaxine or Sertraline reported OD • 50.% of women on Paroxetine reported OD Clayton A, Keller A & McGarvey E. (2006) Burden of phase-specific sexual dysfunction with SSRIs. Journal of Affective Disorders. 91: 27-32.

31. Orgasm in Menopause • My experience is that menopausal women frequently describe a change in the quality of orgasm in terms of: • Delay in achieving orgasm • Decreased frequency of achieving orgasm • Decreased intensity of the orgasm • Shortening of the orgasmic response

32. Treatment Approaches • Psychoanalytic • Issues of control and excitement • Cognitive-Behavioral • Interfering negative thoughts • Busy mind • Systems Theory • Partner issues • Pharmacologic • Device • vibrator • Bibliotherapy

33. Devices • “There are a number of mechanical devices which increase sexual arousal, particularly in women. Chief among these is the Mercedes-Benz 380SL." Lynn Lavner • “Women might be able to fake orgasms. But men can fake a whole relationship.” --Sharon Stone

34. Hitachi Magic Wand

35. Sildenafil for Antidepressant Induced Sexual Dysfunction • Sample included: • 100 premenopausal women between 18-50 (mean age 37) • Whose major depressive disorder was in remission • Taking an antidepressant for at least 8 weeks (mean was 28 weeks) • And reported satisfactory sexual function before onset of depression or antidepressant treatment Nunberg, G et al. JAMA, 2008, 300: 395-404

36. Sexual Dysfunction and Sildenafil • Mean number of sexual problems was 3 for the sildenafil group and 2.8 for the placebo group • 96% of the sample reported more than one complaint • Desire 87.8% • Subjective arousal 80.6% • Lubrication 79.6% • Orgasm delay 98.7% • Other difficulties 23.6% • (anorgasmia, lack of pleasure and pain Nunberg, G et al. JAMA, 2008, 300: 395-404

37. Results After 8 Weeks On Either Placebo or 50 or 100mg Sildenafil Nunberg, G et al. JAMA, 2008, 300: 395-404

38. Treating Anorgasmia • Directed Masturbation is the most frequently prescribed treatment for anorgasmia • Taught in individual, group, couples and bibliotherapy • Successive stages of directed masturbation train a women to locate and manually stimulate genital areas that bring her sexual pleasure • Process begins with visual exploration of the body, using a mirror and educational material depicting female anatomy • After identification of these areas the woman is instructed to apply manual stimulation to these regions • Amount and intensity of sexual stimulation is directly under the woman’s control • Not reliant on partner knowledge, skill or interest • Partner is invited to observe the woman stimulate herself • Practice desensitization for the woman to lessen anxiety • Partner observes how to stimulate the woman in the manner she wishes

39. Treatment Outcomes • Barbach reported that 92% of women (N=83) became orgasmic after 10 sessions of group directed masturbation • Delehanty reported that 82% of women (N=28) became orgasmic after 10 sessions of directed masturbation and assertiveness training in a group format • Comparing group treatment versus bibliotherapy • In the group format- • 100% of women became orgasmic with masturbation • 47% were orgasmic with intercourse • Bibliotherapy- • 47% became orgasmic with masturbation • 13% were orgasmic with intercourse Barbach LG (1974) Group treatment of pre-orgasmic women. Journal of Sex and Marital Therapy. 1: 139-145. Delehanty R (1982) Changes in assertiveness and changes in orgasmic response occuring with sexual therapy for pre-orgasmic women. Journal of Sex and Marital Therapy. 8: 198-208

40. Treatment Outcome • Few controlled studies have examined the exclusive effects of directed masturbation for treating secondary anorgasmia • Behavioral treatment interventions not shown to improve orgasmic ability include • Relaxation exercises • Kegel exercises • Sensate focus • Sexual communication training • Systematic desenitization

41. Coital Alignment Technique • In the missionary position the man positions himself up and forward of the woman • Benefits likely to result from more direct clitoral contact or paraurethral stimulation • 37% of women receiving instructions in CAT versus 18% who were instructed in direct masturbation reported a >50% improvement in orgasmic attainment with intercourse after 4 sessions. Hurlbert DF & Apt C (1995) Coital alignment technique and directed masturbation: a comparative study on female orgasm. Journal of Sex and Marital Therapy. 21: 21-29.

42. Dual Control Theory • Individuals vary in their propensity for both sexual excitement and inhibition of their sexual response • Important to assess if the woman does not know what excites her • Help her find fantasy, images, books, movies that enhance mental arousal • Important to assess extent of woman’s sexual inhibition e.g. fear of losing control, wetting herself, being heard by others • Find strategies to help lessen her inhibition Bancroft J & Janssen E. (2000) Neuroscience and Biobehavioral Reviews 24: 571-579.

43. Sex Therapy- Orgasmic Problems • Directed masturbation appears to be the most efficacious method • Bibliotherapy, videos • Adjunctive treatment includes: • A combination of individual or couple’s psychotherapy, sex education, sensate focus, sexual skills training, communication, body image work • Distractibility • Busy mind • Psychodynamic issues • Letting go • Giving up control • Father experienced as undependable Heiman J & Meston C, Annual Review of Sex Research, 1997, 8: 148-194;Heiman, 2006 Principles and Practice of Sex Therapy, 4th Edition

44. Sex Therapy- Orgasmic Problems • Partner issues • Performance anxiety • Unrealistic expectations • Unwillingness to change intercourse focus Heiman J & Meston C, Annual Review of Sex Research, 1997, 8: 148-194

45. Conclusion • Directed masturbation has been shown to be an empirically valid, efficacious treatment for women diagnosed with primary anorgasmia and may be beneficial for women with secondary anorgasmia who are uncomfortable touching their genitals. • If the woman is able to attain orgasm alone by masturbation, but not with her partner, it may prove more beneficial to address issues relating to communication and trust as well as to ensure that the woman is receiving adequate stimulation either via direct manual stimulation or intercourse positions designed to maximize clitoral stimulation. Meston C. Female orgasmic disorder: treatment strategies and outcome results. In: Women’s Sexual Function and Dysfunction: Study, Diagnosis and Treatment. Edited by Goldstein I, Meston C, Davis S & Traish A. Taylor & Francis, London, 2006.

46. Questions/Comments