Sexuality. The Pharmacologic Treatment of Female Sexual Dysfunction: Future Reality or Wishful Thinking? Risks of Opening the Medicine Cabinet

Transcription

1 5 th Annual Meeting of the North American Menopause Society October 5, 4 Washington, DC Low Libido at Midlife: Will the Answer Ever Be in Our Medicine Cabinets? The Pharmacologic Treatment of Female Sexual Dysfunction: Future Reality or Wishful Thinking? Disclosures New England Research Institutes Research consultant Jan L. Shifren, M. D. Associate Professor of Obstetrics, Gynecology, and Reproductive Biology Harvard Medical School Director, Mass General Midlife Women s Health Center Massachusetts General Hospital Physiology Interpersonal Relationships Sexuality Psychology Sociocultural Influences Risks of Opening the Medicine Cabinet Medicalizing normal changes in sexual desire and response that are associated with aging, life stage, and psychological and social factors Pharmacologic treatment is not indicated, if there is no associated personal distress

2 EROS-Clitoral Therapy Device Efficacy of Sildenafil Citrate in Women with Sexual Arousal Disorder FSD women (9 pre/ postmp) No FSD women ( pre/ postmp) Sensation 9% 58% Lubrication 8% % Ability to achieve orgasm Sexual satisfaction 55% 4% 8% 5% Possible mechanism of action: Clitoral blood flow Double-blind, placebocontrolled trial 78 women with arousal disorder Age: 8 to 7 years No difference in efficacy between sildenafil and placebo Any endpoint at any dose Increase From Baseline (%) 5 4 Satisfaction With Sexual Life Estrogenized Estrogen-deficient (n=4/85) (n=8) 5 (n=8/9) (n=) Sildenafil (mg) Billups KL, et al. J Sex Marital Ther ;7:45 Basson R, et al. J Womens Health Gend Based Med. ;:67 Sildenafil Treatment of Women with Antidepressant-Associated Sexual Dysfunction Bupropion Treatment of HSDD in Premenopausal Women Primary Endpoint: Clinical Global Impression Sildenafil vs. PL:.8 (P.)(difference in change from baseline) Secondary Endpoints: SFQ, ASEX, UNM-SFI Sildenafil group had higher mean improvement vs. PL for all domains, except pain Significant difference in change from baseline for ability to reach orgasm & orgasm satisfaction 98 premenopausal women w/ treated depression New sexual dysfunction after SRI use Sildenafil 5- mg vs. PL prior to sex for 8 weeks Side effects: headache, flushing, dyspepsia Nurnberg HG, et al. JAMA 8;:95-44 Changes in Arousal Scores Randomized, double blind, placebo-controlled study 66 Premenopausal women, non-depressed Bupropion SR -4 mg/d x days Inhibits both dopamine & norepinephrine reuptake Significant CSFQ total score & pleasure, arousal, orgasm subscales Side effects: agitation, HTN, insomnia, dry mouth, tremor, rare seizures Seagraves RT, et al. J Clin Psychopharmacol 4;4:9-4 Changes in Orgasm Scores

3 Low Dose Local Estrogens for Treatment of Vaginal Atrophy & Dyspareunia Ospemifene Effectively Treats Vulvovaginal Atrophy in Postmenopausal Women Vaginal cream: E & CE (.5- gram, - times/week) Vaginal ring (Q months) Vaginal tablet ( times/week) Ospemifene 6 mg significantly decreased most bothersome moderate to severe symptom of vaginal dryness & dyspareunia compared with placebo Bachmann GA, Komi JO, et al. Menopause ;7:48 Score Score 6 4 Testosterone Injections and Sexual Function 5 4 Sexual Desire B 4 Weeks Sexual Arousal B Weeks Coitus/wk B 4 B 4 Weeks Weeks control estradiol estradiol + testosterone injection P<. Sherwin & Gelfand. Psychosom Med 987; 49: 97 Sexual Fantasies Use of a Transdermal Testosterone Patch in Hypoactive Sexual Desire Disorder Phase clinical trials - 4-weeks - Multicenter, double-blind, placebo-controlled 95 surgically & 549 naturally menopausal women on ET or EPT with HSDD Randomized groups - - Testosterone mcg/d Simon JA, et al. J Clin Endocrinol Metab 5; 9:56 Buster J, et al. Obset Gynecol 5; 5:944 Shifren J, et al. Menopause 6; :77

4 Increase in Total Satisfying Sexual Activity Sexuality Domains in Naturally Menopausal Women 4 Wk. Frequency Change From Baseline (SEM) INTIMATE SM p=. INTIMATE SM % increase from baseline % 74% % 5% Simon JA, et al. J Clin Endocrinol Metab 5; 9:56 Buster J, et al. Obset Gynecol 5; 5:944 p=. TTP Mean Change From Baseline (SEM) Desire Arousal Orgasm Pleasure Shifren et al. Menopause; 6; : 77 Decreased Concerns Testosterone Responsiveness Self-image p<.; p<. vs. placebo Combined Estrogen & Testosterone Risk of Breast Cancer in Menopausal Women Participants Person-Years Cases (no.) RR (95% CI) Never Users 557,577,647 Past Users 6, (.8-) Current Users E only 46,8 85. (.-.) E + P.6 (.4-.7) E + T 5, (.-.6) T only 6.5 (.8-7.9) Nurses Health Study - prospective cohort (978-) ( mill person-yrs) st Epidemiologic study to assess androgen HT & breast cancer Significant risk breast cancer in E + P & E + T users Study Limitations Methyltestosterone (Estratest) principal T compound studied 98% E + T users were prior HT users & study did not account for type or duration of prior HT use in T users T users younger, more benign breast disease, more alcohol Testosterone Vaginal Cream The Oprah Winfrey Prescription ( ~/ th male dose) % Testosterone cream Compounded by pharmacist Apply.5 grams topically nightly Dispense 45 grams (~ month supply) NO Data on Safety or Efficacy! Goal: serum testosterone level within normal range for women (FTI = Total T/SHBG x.47; Normal < 4.5) Tamimi et al. Arch Intern Med 6; 66:48 4

5 Testosterone Products in Use for Women Testosterone patch (Intrinsa) approved in Europe for surgically menopausal women w/ HSDD on HT, but no longer being manufactured Off-label use of testosterone products approved for men Effect of Vaginal Testosterone Treatment on Testosterone Levels Testosterone Levels (ng/dl) weeks n= postmenopausal women with vulvar lichen sclerosis Joura EA, et al. Obstet Gynecol 997;89:87 LibiGel Phase III Pivotal Trials: No statistically significant difference in ANY endpoint c/w placebo Safety Data: not released Median Free T (pg/ml) LibiGel mcg/day Intrinsa mcg/day Baseline Month Month Month Month 6 Month of Treatment biosantenews@biosantepharmaceuticals.ccsend.com (.) Testosterone Dose-Response: Postmenopausal Women without Sexual Dysfunction Study Design - 7 Postmenopausal hysterectomized women +/- BSO - Concurrent transdermal estradiol (5 mcg) - vs. IM Testosterone (, 6.5,.5, 5 mg) Q wk x 4weeks Results (c/w placebo) - Supraphysiologic T levels with all doses above mg - Sexual thoughts/desire & frequency sexual activity (BISFW) increased significantly only in women treated with T 5 mg - PGWB composite score & vitality domain increased significantly in women treated with T.5 & 5 mg - Lean body mass (.8 kg), chest press, stair-climb power increased significantly only in women treated with T 5 mg - Increased sexual function in women only with supraphysiologic T Huang et al. Menopause 4; :6 5

6 Effects of DHEA on Sexual Function, Well-Being and Menopausal Symptoms in Postmenopausal Women with Low Libido Effect of Intravaginal DHEA on Sexual Function in Postmenopausal Women PLACEBO DHEA (5 P value mg) Sabbatsberg Sexual NS Self-Rating Scale Satisfying Sexual NS Events (per month) Psychological General NS Well-Being MENQUOL NS Change from Baseline (Mean + SD) Randomized, double blind study x 6 weeks 9 Postmenopausal women with low libido DHEA (5 mg): acne & increased hair growth Panjari M, et al. J Sex Med 9;6: 579 MENQUOL Sexual Domain: () Change in sexual desire, () Vaginal dryness during intercourse, () avoiding intimacy Labrie F, et al. Menopause 9;6:9 Androgen Therapy Potential Risks Hirsutism, Acne Virilization - clitorimegaly, voice changes Liver dysfunction Adverse lipid changes ( HDL) Fluid retention with edema, hypertension, exacerbation of heart disease Psychological changes Potential estrogen risks - VTE s, Breast cancer Virilization of female fetus Androgen Use in Menopausal Women Carefully selected women Physiologic reason for testosterone Alternative etiologies & treatments considered Well informed Risks, benefits, off-label, OTC limitations Goal - Physiologic testosterone levels Monitor Response, side effects, Free T, lipids, LFT s Research Long term safety 6

7 Flibanserin Centrally acting neurotransmitters (Serotonin, Dopamine, Norepinephrine) may modulate sexual excitement and inhibition Flibanserin is a 5-HT A -agonist & 5-HT A - antagonist, with theoretical pro-sexual effects Several large Phase III DBRCTs PRE-menopausal women with hypoactive sexual desire disorder (HSDD) Most common AEs: nausea, dizziness, fatigue, somnolence Borsini F, et. al. CNS Drug Rev. ;8:7 Sexual Function Endpoint Flibanserin Efficacy Results in Premenopausal Women Mean change from baseline (over 4 weeks): Flibanserin ( mg qhs) subtracted change P-value Satisfactory Sexual Events Desire (ediary) NS Distress (FSDS-R) <. Desire (FSFI) <. Flibanserin led to significant increase in number of SSEs c/w PL, but did not demonstrate significant improvement in desire (ediary) (co-primary endpoint) Study 5.7 NDA -56 FDA May, McCoy FSQ Apomorphine in Premenopausal Women with Sexual Desire & Arousal Disorders Baseline Dopamine Agonist, FDA approved for Parkinson s Used off-label for male ED & emergency emetic AEs: nausea, vomiting, dizziness, HA, BP DBRCT x weeks: Apomorphine SL (- mg/day) vs. PL 6 premenopausal women, 47% completed crossover study Caruso, et al. Urology 4; 6:955 Apomorphine P value (Apo vs.pl) Desire..4. <.5 Arousal.4..6 <.5 Orgasm.5..7 <. Enjoyment.7.4 <.5 Satisfied..5 <. Frequency Intercourse.5. <. Bremelanotide Melanocortin agonist - analog of naturally occurring hormone, alpha-msh (melanocyte-stimulating hormone) In Phase B Trial of PRE-menopausal women with FSD, bremelanotide (.5 mg &.75 mg SC) significantly increased sexual arousal, desire & number of sexually satisfying events, & decreased associated distress Effective in both women with hypoactive sexual desire disorder (HSDD) and combined HSDD/female sexual arousal disorder (HSDD/FSAD) Most common AEs: facial flushing, nausea, vomiting Elevated BP seen with nasal formulation not seen with SC formulation 7

8 Lybrido/Lybridos Avlimil Treatment of Female Sexual Dysfunction (proprietary herbal formulation) Combination therapy designed to target specific causes of HSDD Lybrido: Sublingual testosterone surrounded by sildenafil for women with HSDD and low arousal Lybridos: Sublingual testosterone surrounded by 5 HT A - agonist (Buspirone) for women with HSDD and sexual inhibition Taken ~ -6 hours prior to planned sexual activity to increase sexual motivation/libido Phase b studies ongoing in US Van Rooij K, et al. J Sex Med ;:79 & 8 & 84; Level of Desire Sage, kudzu root, red clover, capsicum pepper, licorice, bayberry fruit, valerian root, ginger root, black cohosh Randomized, double blind, placebo-based study 65 Women x months (NEARLY) identical to active product Executive Summary on product website Satisfaction with Sexual Life 8