Sexual Health: What s New in 2016

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Sexual Health: What s New in 2016 Financial Disclosures Husband full time employee Genomic Health No material in this presentation relates to this company Tami Serene Rowen Assistant Professor UCSF

1 Sexual Health: What s New in 2016 Financial Disclosures Husband full time employee Genomic Health No material in this presentation relates to this company Tami Serene Rowen Assistant Professor UCSF Department of ObGyn and Reproductive Sciences UCSF Gynecologic Fall Course October 29, 2016 Outline Review what s known about normal and abnormal female sex function Review Current Definitions and new Definitions Review the current treatments available for treating sexual dysfunction Look forward to what s in development Sexual Health Rights World Association of Sexuality Declaration of Sexual Rights: Grounded in universal human rights Sexuality is a source of pleasure & well being, contributes to fulfillment & satisfaction Sexual health is a state of physical, emotional, mental, and social wellbeing (WHO), not just absence of disease or dysfunction Sexual health requires positive and respectful approach/relationships, protection of diversity

2 What do we know about female sex function? Remember Anatomy Main external components: Labia majora ectoderm Labia minora endoderm Vestibule endoderm Posterior Fourchette Clitoris What are the main player in vulvovaginal health? Hormone receptors for estrogen AND testosterone Vaginal ph and lactobacilli key to microbiome Changes are cause of menopausal symptoms Innervation by pelvic nerves(s2 S4) AND vagus nerve Densest area of nerves is distal and anterior (possibly the G spot ) What are the main players in desire? What about Hormones in the Brain?

3 Review of Importance of Sex to Women Largest study(13882 women, 29 countries) 65% women sexually active in last year 38% in last week(inverse age relationship) Agrees with US data 20 37% reported sex was very/extremely important to life 76% women felt satisfactory sex is essential to maintain a relationship Sexual well being significantly correlated to self perceived overall health Coding and Definitions ICD 10 and FSD DSM-5= Mental, Behavioral and Neurodevelopmental Disorders vs ICD-10= Symptoms, Signs and Ill-Defined Conditions Laumann et al, 2006; Nicolosi et al, 2004; Lindau 2007 ICD 10 Examples Hypoactive Sexual Desire Disorder F52.0 Low Libido R68.82 Sexual Aversion Disorder F52.1 Female Sexual Arousal Disorder F52.22 Other Sexual Dysfunction not due to a substance or physiological consdition F28.8* Other specified conditions female genital organs N94.89 Postmenopasual atrophic vaginitis N95.2 ICD 10 and Pain Dyspareunia N94.1 Vulvodynia N94.818/9 Vulvar Vestibulitis N Atrophic Vaginitis N95.2 Dyspareunia not due to a substance or known physiological condition F52.6 Pelvic/Perineal Pain R10.2 Pain in joint, pelvic region and thighm25.559

4 Female Orgasmic Disorder Female Sexual Interest/Arousal disorder Female Sexual Disorders: DSM (F52.31) (F52.22) Presence of either of the following on all or almost all (75%- 100%) occasions of sexual activity: 1.Marked delay in, marked infrequency of, or absence of orgasm. 2.Markedly reduced intensity of orgasmic sensations Lack of, or significantly reduced, sexual interest/arousal as manifested by 3 of the following: 1. Absent/reduced interest in sexual activity 2. Absent/reduced sexual/erotic thoughts or fantasies 3.No/reduced initiation of sexual activity and unreceptive to partner s attempts to initiate 4. Absent/reduced sexual excitement/pleasure during sexual activity in almost all or all (75%-100%) sexual encounters 5. Absent/reduced sexual interest/arousal in response to any internal or external sexual/erotic cues (written, verbal, visual) 6. Absent/reduced genital or nongenital sensations during sexual activity in almost all or all (75%-100%) sexual encounters Symptoms persisted a minimum of 6 months and not better explained by a nonsexual mental disorder or consequence of severe relationship distress or other significant stressors and not due to effects of substance/medication or other medical condition American Psychiatric Association, DSM 5, 2013 Genito-Pelvic Pain/Penetration Disorder Female Sexual Disorders: DSM (F52.6) Persistent or recurrent difficulties with 1 or more of the following: 1.Vaginal penetration during intercourse 2. Marked vulvovaginal or pelvic pain during intercourse or penetration attempts 3. Marked fear or anxiety about vulvovaginal or pelvic pain in anticipation of, during, or as a result of vaginal penetration 4. Marked tensing or tightening of the pelvic floor muscles during attempted vaginal penetration. Symptoms persisted a minimum of 6 months and not better explained by a nonsexual mental disorder or consequence of severe relationship distress or other significant stressors and not due to effects of substance/medication or other medical condition American Psychiatric Association, DSM 5, 2013 How is this Different from DSM IV Sexual aversion deleted Dyspareunia/ vaginismus merged: Genito-pelvic pain/penetration disorder GPPPD Desire and arousal merged: FSIAD Must experience condition % of the time Minimum duration of 6 months Disorder causes significant distress Interpersonal difficulty removed The disorder NOT better explained by: nonsexual mental disorder consequence of severe relationship distress other significant stressors Specifiers severity scale: mild, moderate or severe. What are main concerns with FSAID No validated instruments for FSAID Research including men/women with sex complaints strict use of FSAID (3 + complaints) excluded 109/114 women using DSMV Sarin et al Arch Sex Behav 2013 Notabley, DSM IV was also restrictive 75% women/men excluded using strict criteria

What s New in 2016: FSAID ISSWSH and ICSM recommendations for reclassifying FSAID ISSWSH Subtypes Spontaneous Desire Responsive Desire Maintenance of Desire/Interest ICSM recommendations Maintenance

5 What s New in 2016: FSAID ISSWSH and ICSM recommendations for reclassifying FSAID ISSWSH Subtypes Spontaneous Desire Responsive Desire Maintenance of Desire/Interest ICSM recommendations Maintenance of separate/distinct categories for desire/arousal Clayton ISSM Beijing 2016 What is new in 2016 Pain Categories New categories of Pain Vulvar pain caused by a specific disorder* Infectious (eg, recurrent candidiasis, herpes) Inflammatory (eg, lichen sclerosus, lichen planus, immunobullous disorders) Neoplastic (eg, Paget disease, squamous cell carcinoma) Neurologic (eg, postherpetic neuralgia, nerve compression or injury, neuroma) Trauma (eg, female genital cutting, obstetrical) Iatrogenic (eg, postoperative, chemotherapy, radiation) Hormonal deficiencies (eg, genitourinary syndrome of menopause [vulvovaginal atrophy], lactational amenorrhea) * Women may have both a specific disorder (eg, lichen sclerosus) and vulvodynia Vulvodynia Vulvodynia vulvar pain of at least 3 months duration, without clear identifiable cause, which may have potential associated factors. The following are the descriptors: Localized (eg, vestibulodynia, clitorodynia) or generalized or mixed (localized and generalized) Provoked (eg, insertional, contact) or spontaneous or mixed (provoked and spontaneous) Onset (primary or secondary) Temporal pattern (intermittent, persistent, constant, immediate, delayed) Bornstein et al 2015 Consensus Vulvar Pain Terminology

6 Predictors of Sexual Health Physical and Emotional Health status is #1 predictor! Laumann et al, 1999; Laumann et al, 2006; Nicolosi et al, 2004; Lindau et al, 2007 Role of age Filled circle =desire open triangle= arousal filled square= orgasm open diamond=any. Shifren et al, Obstet Gynecol 2008 Other factors: Delivery Type: worse with OVD and episiotomy Medications: think SSRIs, CHC in some women Hayes,et al 2008; Dennerstein 2008 Treatment of sexual concerns Treat underlying disorders Address relationship Address psychosexual issues Sex Education Recalibrate expectations Sexual Enhancement treatments: gels and devices Pharmacotherapy? Some Principals for Exam The Layered Approach Surface Layer Nerve Layer Myofascial Layer Orthopedic Layer Organ Layer Body wide systems Coady Cont ObGyn 2015 Basics: Local Hormones Estrogens Demonstrated effect on vaginal vascularity and baseline moisture Regular use associated with increased sex activity Local estrogen do not require progesterone Can use Cream (cee vs Estradiol 3/week) Estring q 3 months Vagifem 2 3/week Compounded estrogen (0.03%) AND testosterone (0.02%) SERMs Ospemafine: until 8/15 only FDA approved tx for FSF Gass et al, 2011; Kovalevsky 2005, Lobo 2003, Basson 2004, Shifren 2000, Davis 2006, Nappi 2006

7 Question 45 Relationship Between Age and Androgens in Women Do you prescribe testosterone for your patients? TT (ng/dl) FT (pmol/l) DHEA-S ( mol/l) Androstenedione (nmol/l) (n=22) (n=97) (n=153) (n=140) (n=74) (n=109) Davison, S. L. et al. J Clin Endocrinol Metab 2005 Davison et al. J of Clin Endocrinology & Metabolism, 2005 Multiple Studies demonstrate relationship between androgens and desire SR Davis, et al Circulating androgen levels and self-reported sexual function in women JAMA, 294 (2005) Community based study 1021 women DHEAS associated with sex fnc, other androgens not sig JF Randolph Jr, et al Masturbation frequency and sexual function domains are associated with serum reproductive hormone levels across the menopausal transition J Clin Endocrinol Metab, 100 (2015) 3326 women DHEAS and circulating T associated with masturbation Summary of Testosterone Patch RCTs Difference versus placebo in Study n= Treatment PFSF PFSF SSE Arousa Desire PDS AE Braunstein , SM mcg/d NR 8* ~5* NS 6% Simon SM 300mcg/d % Davis SM 300 mcg/d % Shifren NM 300 mcg/d % % Davis no E2 150 or 300 mcg/d 1.4* ~10 ~8 ~ 11 0% S Wahlin Jacobsen, et al. Is there a correlation between androgens and sexual desire in women? J Sex Med, 2 (2015) 560 women Circulating androgens correlated to desire Panay NM (26% E2) 300 mcg/d 1.2 ~ % AE= Incidence of Adverse Events, FSFI=Female Sexual Function Index, FSDS=Female Sexual Distress Scale, NR= Not Reported, NS= Not significant, PFSF =Profile of Female Sexual Function, PDS= Personal Distress Scale, SSE=Satisfying = Sta s cally Significant (p<0.05) * = Significant differences only with 300 mcg/daily patch = women taking vaginal estrogens continued on stable dosing regimens

in women W Somboonporn, et al Testosterone for peri and postmenopausal women Cochrane Database Syst Rev, Cancer Hyperandrogenism in women because of polycystic ovary syndrome or high dose androgen

8 What do we know about Safety? Cardiovascular Disease RCTs have consistently shown that transdermal testosterone does not adversely affect known cardiovascular risk factors lipids, CRP, coagulation proteins, and insulin resistance in women W Somboonporn, et al Testosterone for peri and postmenopausal women Cochrane Database Syst Rev, Cancer Hyperandrogenism in women because of polycystic ovary syndrome or high dose androgen therapy in female to male transsexuals does not increase the risk of breast cancer Observationsal studies with mixed results re: sysemic T and breast cancer T patch users w/o incr breat CA in 2 years f/u NHS study saw 32 breast ca cases, associated w/ oral T use OV Ca data inconclusive T antiproliferative at endometrium, no incr in endo cancer Davis and Wallen Jacobsen Lancet 2015 AM Perrone, et al.jsex Med, 6 (2009) Major AE in women appear to be hirsutism, acne, and decrease HDL (only with oral T) over 1 2 year time frame Flibanserin Flibanserin: mixed post synaptic 5HT1A agonist and 5HT2A antagonist 5HT1A agonists could have pro sexual effects. Stimulating 5HT2A receptor has been associated with decreased sexual behavior (male rodents) Also activates dopamine D4 receptors Moderate affinity for 5HT2B and 5HT2C receptors. Flibanserin is thought to produce region specific elevations in dopamine and norepinephrine, and may help to offset inhibitory serotonergic activity impacting desire pathways Phase 1 studies started in 1995 for depression, HSDD studies started in 2002 Flibanserin: 4 RCTs, >11K Women Flibanserin for postmenopausal women Simon et al SNOWDROP trial Meonapuse 2014

So what s the newest evidence? The Controversy>>> JAMA Intern Med. 2016;176(4):453 462. doi:10.1001/jamainternmed.2015.

On closer look Addition of three unpublished trials conducted between 2006 and 2011: Alternate Dose Study, EU Study, and Terminated Study Flibanserin

67) between 100 mg flibanserin and placebo In premenopausal women only, this was 0.65 (95%CI,0.38 0.

9 So what s the newest evidence? The Controversy>>> JAMA Intern Med. 2016;176(4): doi: /jamainternmed Published online February 29, On closer look Addition of three unpublished trials conducted between 2006 and 2011: Alternate Dose Study, EU Study, and Terminated Study Flibanserin Major AE The pooled mean difference for change in mean SSEs from baseline was 0.49 (95% CI, ) between 100 mg flibanserin and placebo In premenopausal women only, this was 0.65 (95%CI, ) In studies using the FDA approved 100 mg once daily dose, this was 0.54 (95%CI, ) For published studies, the mean difference for SSEs was 0.58 (95%CI, ), and for unpublished studies, this was 0.31 (95%CI, ) The mean difference for ediary desire score mean change from baseline was 1.63 (95% CI, ) For FSFI desire, this was 0.27 (95%CI, ) in all women

10 Newest data on AE from JAMA article RR flibanserin compared to placebo Dizziness : 4.00 (95% CI, ) S Somnolence, 3.97 (95% CI, ) Nausea, 2.35 (95% CI, ) Fatigue, 1.64 (95% CI, ) The overall risk ratio for the 4 most common AEs was 2.86 (95% CI, ) Severe AEs were reported by 2 studies; in flibanserin users, the percentages were 4.2% and 6.0%, and 3.5% in controls Serious AEs were defined as those resulting in death, those that were immediately life threatening, those that required longer lasting hospitalization, or those were deemed serious for any other reason No difference Question Who has prescribed flibanserin? Addyi needs REMS Risk evaluation and mitigation strategy Based on data showing severe hypotension in people (mainly men(20/22)drinking 2 4 drinking within 10 minutes No restriction of drinking in clinical trials Filbaserin perfomred BETTER than placebo in driving/cognition studies Need to fill out prescriber registration Knowledge Assessment Now available online What s in the pipeline? For GSM: IV DHEA, estradiol supp, Test, tamoxifen Lasofoxifene (similar to ospemafine) Vaginal laser therapy (Velvet trail) One version already on market, mechanism unclear Milli Device For HSDD: bremelanotide Lybrido(s)(targeting based on subset of HSDD) Goldsetin ISSM Beijin 2016

11 Conclusions Female Sexual Health is complex but very important to women New research has opened door to physiologic factors Any treatment should be both medical and psychosocial Reliable and proven medical therapy for women with sexual problems is just now getting approved Delays based on both outcomes, safety concerns and politics Questions?

10/24/2014. Definitions and Epidemiology Physiology of Female Sexual Response Female Sexual Dysfunction

10/24/2014. Definitions and Epidemiology Physiology of Female Sexual Response Female Sexual Dysfunction None to report Tami Serene Rowen, M.D. M.S. Department of Obstetrics, Gynecology and Reproductive Sciences University of California, San Francisco October 24, 2014 Definitions and Epidemiology Physiology