9/30/2016. Data and Women s Preferences Should Inform the Treatment of Hypoactive Sexual Desire Disorder: The Case for Pharmacologic Agents

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1 Data and Women s Preferences Should Inform the Treatment of Hypoactive Sexual Desire Disorder: The Case for Pharmacologic Agents Sources of Evidence for Physiological Mechanisms Modulating Sexual Desire Sheryl Kingsberg, PhD Chief, Division of Behavioral Medicine University Hospitals Case Medical Center MacDonald Women s Hospital Neurobiology Flibanserin RCTs Women with HSDD treated with flibanserin Professor, Departments of Reproductive Biology and Psychiatry Case Western Reserve University School of Medicine Cleveland OH, USA 3 Disclosures Biopsychosocial Model of Female Sexual Response Sheryl A. Kingsberg, PhD, is a consultant, investigator or on a scientific advisory board for Emotional Brain, Valeant, Endoceutics, Novo Nordisk, Palatin (e.g., physical health, neurobiology, endocrine function) Biology Psychology (e.g., performance anxiety, depression) Technologies, Pfizer, Shionogi, Materna, Nuelle, Bayer, TherapeuticsMD, Viveve and Acerus Pharmaceuticals. (e.g., upbringing, cultural norms and expectations) Sociocultural Interpersonal (e.g., quality of current and past relationships, intervals of abstinence, life stressors, finances) Rosen RC, Barsky JL. Obstet Gynecol Clin North Am. 2006;334: Althof SE, Leiblum SR, Chevret-Measson M, et al. J Sex Med. 2005;26:

2 Sexual Dysfunction: Definition & Diagnosis 1987 (DSM-III-R) Frequency + Sexual Dysfunction Persistently or recurrently deficient or absent sexual fantasies and desire for sexual activity 2000 (DSM-IV-TR) Frequency + Sexual Dysfunction + Distress Persistently or recurrently deficient or absent sexual fantasies and desire for sexual activity with marked distress or interpersonal difficulty; not otherwise accounted for by a general medical or psychiatric condition 2013 (DSM-5) Sexual Dysfunction + Distress + Frequency + Duration Lack of sexual interest/arousal as manifested by a preset number of indicators (with/without a specified frequency) with clinically significant distress, and has persisted 6 months; not otherwise accounted for by a general medical or psychiatric condition HSDD HSDD? FSIAD Hypoactive Sexual Desire Disorder (HSDD) (DSM IV) Persistent or recurrent deficiency or absence of sexual thoughts, fantasies and/or desire for sexual activity Causes marked personal distress or interpersonal difficulties Not better accounted for by another primary disorder, drug/medication, or general medical condition 1. Latif EZ, Diamond MP. Fertil Steril. 2013;100: Sungur MZ, Gunduz A. J Sex Med. 2014;11: HSDD = hypoactive sexual desire disorder FSIAD = female sexual interest/arousal disorder DSM IV-TR DSM-5 (2013): Changes To Nomenclature & Diagnosis Female hypoactive desire dysfunction and female arousal dysfunction were merged into a single syndrome Hypoactive (Sexual) Desire Disorder (HSDD) Female (Sexual) Arousal Disorder (FSAD) Increased precision: includes a preset number of indicators (with/without a specified frequency) and a minimum duration of 6 months to differentiate disorder from transient dysfunction (Female) Sexual Interest/Arousal Disorder (FSIAD) Female Sexual Interest/Arousal disorder (DSM 5) Lack of, or significantly reduced, sexual interest/arousal as manifested by 3 of 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 HSDD still exists as a core component of FSIAD Sungur MZ, Gunduz A. J Sex Med. 2014;11:

Prevalence of FSD: PRESIDE PET Scan Changes in Neural Activity in Response to Erotic Video OBJECTIVES: Estimate the prevalence of

related correlates NOT DETERMINED: Whether low desire with sexually related personal distress was primary or secondary to another illness;

(n=31,581 / 50,002) Women with HSDD have weaker activation in cerebral cortex in Rt Hemisphere Possibly representing muted response to

and perpetuates inhibitory neural pathways Shifren JL, Monz BU, Russo PA, Segreti A, Johannes CB. Obstet Gynecol. 2008;112(5):970-978.

002 Prevalence of Sexual Problems Associated with Distress (PRESIDE) Age-stratified Prevalence Desire 2868/28,447 Arousal 1556/28,461 Orgasm

3 Prevalence of FSD: PRESIDE PET Scan Changes in Neural Activity in Response to Erotic Video OBJECTIVES: Estimate the prevalence of self-reported sexual problems (any, desire, arousal, and orgasm), the prevalence of problems accompanied by personal distress, and describe related correlates NOT DETERMINED: Whether low desire with sexually related personal distress was primary or secondary to another illness; pain was not assessed POPULATION: 31,581 US female respondents 18 years of age from 50,002 households RESULTS*: Response rate was 63% (n=31,581 / 50,002) Women with HSDD have weaker activation in cerebral cortex in Rt Hemisphere Possibly representing muted response to sexual cues Women with HSDD have less deactivation in left hemisphere possibly representing Inability to deactivate higher order processing and perpetuates inhibitory neural pathways Shifren JL, Monz BU, Russo PA, Segreti A, Johannes CB. Obstet Gynecol. 2008;112(5): Holstege G. Sex Med Rev. DOI: Prevalence of Sexual Problems Associated with Distress (PRESIDE) Age-stratified Prevalence Desire 2868/28,447 Arousal 1556/28,461 Orgasm 1315/27,854 Any 3456/28, or older Arnow et al. (2009) Neuroscience, 158, Shifren JL, Monz BU, Russo PA, Segreti A, Johannes CB. Obstet Gynecol. 2008;112(5):

Key Regions in Brain Regulating Sexual Desire Etiology of HSDD: Imbalance Between Excitation/Inhibition Prefrontal cortex Locus coeruleus Medial

Endocannabinoids Reward and attention processing centers of the ventral tegmental area and nucleus accumbens Intimacy Shared values Romance

INHIBITION 13 Bancroft J, et al. J Sex Res. 2009;46:121-142. Perelman MA. J Sex Med 2009;6:629-32.

Shared values Romance Experience/behavior Physiological/ Organic Psychosocial/ Interpersonal Serotonin Opioids Endocannabinoids Relationship

4 Key Regions in Brain Regulating Sexual Desire Etiology of HSDD: Imbalance Between Excitation/Inhibition Prefrontal cortex Locus coeruleus Medial preoptic area (mpoa) Paraventricular nucleus Dopamine Oxytocin Melanocortin Vasopressin Norepinephrine Physiological/ Organic Serotonin Opioids Endocannabinoids Reward and attention processing centers of the ventral tegmental area and nucleus accumbens Intimacy Shared values Romance Experience/behavior Psychosocial/ Interpersonal Relationship conflict Negative Stress Negative beliefs about Sex Experience/behavior EXCITATION INHIBITION 13 Bancroft J, et al. J Sex Res. 2009;46: Perelman MA. J Sex Med 2009;6: Reward Center Circuitry Etiology of HSDD: Imbalance Between Excitation/Inhibition Dopamine Oxytocin Melanocortin Vasopressin Norepinephrine Intimacy Shared values Romance Experience/behavior Physiological/ Organic Psychosocial/ Interpersonal Serotonin Opioids Endocannabinoids Relationship conflict Negative Stress Negative beliefs about Sex Experience/behavior EXCITATION INHIBITION Kingsberg, Clayton Pfaus CNS Drugs, Bancroft J, et al. J Sex Res. 2009;46: Perelman MA. J Sex Med 2009;6:

This maladaptation is represented by the dysregulation of DA, NE and 5-HT. Correcting this imbalance in the PFC is the biological foundation to correcting the maladaptation.

5 Excitatory and Inhibitory Pathways Regulating Sexual Response How does this translate into pharmacologic treatment options? HSDD is a maladaptation of the brain where the PFC loses excitatory control over the reward/motivation structures of the brain (limbic system). This maladaptation is represented by the dysregulation of DA, NE and 5-HT. Correcting this imbalance in the PFC is the biological foundation to correcting the maladaptation. Similar maladaptation in depression/anxiety (chronic stress alters architecture of neurons changing synaptic interaction) differing in type and magnitude of dysregulation Kingsberg SA, Clayton A, Pfaus J. CNS Drugs, Reward Processing: Impaired Reward Circuitry Pathways Drugs Approved or In Development for Low Desire : Drug Name Drug Category Pharma Sponsor Current Developmental Status Consequence of the inhibitory and excitatory imbalance: HSDD and Depression Constructs and key features of depression and HSDD Anhedonia: The loss of interest in or reduced pleasure from rewarding activities Consummatory: Reduced ability to respond to pleasurable rewards Motivational: Reduced ability to seek out pleasurable rewards Avolition: The loss of motivation to seek out rewarding activities Experience-based neuroplasticity link between behavior and cellular (neuronal circuits), synaptic or molecular mechanisms Flibanserin 100 mg PO qhs at bedtime Bremelanotide subq injection Lybridos (on demand oral tablet) Lybrido (on demand oral tablet) Non-hormonal CNS agent melanocortin receptor modulator buspirone + testosterone sildenafil + testosterone Sprout Pharmaceuticals Palatin Technologies Emotional Brain Emotional Brain Approved 8/2015 for HSDD in premenopausal women, available 10/17/15 Phase IIB completed Phase III completed for HSDD/FSIAD Phase II completed for HSDD Phase II completed for HSDD Der-Avakian A, Markou A. Trends Neurosci. 2012:35:

Flibanserin Mixed post-synaptic 5HT 1A agonist and 5HT 2A antagonist. 5HT 1A agonists could have pro-sexual effects. 5HT 2A antagonists could have pro-sexual effects.

6 Flibanserin Mixed post-synaptic 5HT 1A agonist and 5HT 2A antagonist. 5HT 1A agonists could have pro-sexual effects. 5HT 2A antagonists could have pro-sexual effects. Has activity at dopamine D 4 receptors as well as moderate affinity for 5HT 2B and 5HT 2C receptors. Thought to produce region-specific elevations in dopamine and norepinephrine which offset inhibitory serotonergic activity = increased desire pathways. Serotonin may have a role in low desire by acting as a sexual satiety signal Study Design Three 24-week randomized, double-blind, placebo-controlled trials Population: Premenopausal women with acquired, generalized HSDD for 6 months Mean age: 36 years (19 55 yrs) Mean duration of HSDD: 5 years STUDY Study 1 VIOLET 1 Study 2 DAISY 2 Study 3 BEGONIA 3 TREATMENT (at bedtime) Flibanserin (50mg, 100mg); N = 585 Placebo; N = 295 Flibanserin (50mg, 100mg); N = 1183 Placebo; N = 398 Flibanserin (100 mg); N = 542 Placebo; N = Derogatis LR, et al. J Sex Med. 2012;9(4): Thorp J, et al. J Sex Med. 2012;9(3): Katz M, et al. J Sex Med. 2013;10(7): Mechanism of Action Study Design (cont.) CO-PRIMARY ENDPOINTS (Mean change from baseline at Week 24) No. of monthly SSEs (satisfying sexual events) Sexual desire Monthly sexual desire score via ediary (Studies 1 & 2) Desire domain of the Female Sexual Function Index (FSFI-D) (Study 3) SECONDARY ENDPOINTS (Mean change from baseline at Week 24) FSFI-D (Studies 1 & 2) Distress related to sexual desire [Question 13 of Female Sexual Distress Scale Revised (FSDS-R)] 5-HT=5-hydroxytryptamine (serotonin) receptor; 5-HT 1A=5-hydroxytryptamine (serotonin) receptor 1A; 5-HT 2A=5-hydroxytryptamine (serotonin) receptor 2A; DA=dopamine; GABA=gamma-aminobutyric acid; NE=norepinephrine.. N 24 6

CO-PRIMARY ENDPOINT: Satisfying Sexual Events (SSEs) CO-PRIMARY ENDPOINT: Sexual Desire Studies 1, 2 & 3 Number of monthly* SSEs Women indicated daily if they had experienced a sexual event.

standardized to a 28 day as follows: period Total monthly count of SSEs= 28 x (sum of the number of SSE entered)/(sum of number of days entered) Did you have a sexual event?

Gratifying, fulfilling, satisfactory, and/or successful - irrespective of whether women had an orgasm or whether the event was satisfying for the partner STUDIES 1 & 2 Monthly Sexual Desire Score

7 CO-PRIMARY ENDPOINT: Satisfying Sexual Events (SSEs) CO-PRIMARY ENDPOINT: Sexual Desire Studies 1, 2 & 3 Number of monthly* SSEs Women indicated daily if they had experienced a sexual event. If a sexual event occurred, the SSE primary endpoint was measured by the ediary question: Was the sex satisfying for you? standardized to a 28 day as follows: period Total monthly count of SSEs= 28 x (sum of the number of SSE entered)/(sum of number of days entered) Did you have a sexual event? Sexual intercourse, oral sex, masturbation, or genital stimulation by the partner Was the sex satisfying to you? Gratifying, fulfilling, satisfactory, and/or successful - irrespective of whether women had an orgasm or whether the event was satisfying for the partner STUDIES 1 & 2 Monthly Sexual Desire Score Daily record via ediary Indicate your most intense level of sexual desire no desire strong desire Monthly Sexual Desire Score = 28 day sum Range: 0 84 STUDY 3 Desire domain of the Female Sexual Function Index (FSFI-D) 1. Over the past 4 weeks, how often did you feel sexual desire or interest? 2. Over the past 4 weeks, how would you rate your level (degree) of sexual desire or interest? FSFI-D = [Q1 + Q2] x 0.6 Range: Derogatis LR, et al. J Sex Med. 2012;9(4): Thorp J, et al. J Sex Med. 2012;9(3): Katz M, et al. J Sex Med. 2013;10(7): Rosen R, et al. J Sex Marital Ther. 2000;26(2): RESULTS: No. of Monthly SSEs (Co-Primary) Mean Change from Baseline at Week * 1.8* 2.5** (n=280) (n=290) (n=365) (n=372) (n=532) Study 1 Study 2 Study 3 (n=536) Flibanserin showed a statistically significant improvement in the mean change from baseline at week 24 in number of monthly SSEs in all 3 pivotal studies. *P 1 versus PBO ** P < 001 versus PBO flibanserin Vehicle RESULTS: Sexual Desire (Co-Primary) Mean Change from Baseline at Week 24 ediary Desire FSFI-D Desire (n=280) (n=290) (n=365) (n=372) Study 1 Study * (n=532) (n=536) Study 3 flibanserin did not show a statistically significant improvement in desire using an ediary, but did using the validated FSFI-D instrument in Study 3. *P 1 versus PBO ** P < 001 versus PBO Flibanserin Vehicle

RESULTS: FSFI- Desire (Secondary) RESULTS: FSDS-R Q13 DISTRESS(Secondary) Mean Change from Baseline at Week 24 1.2 1.0 0.8 0.6 0.4 0.2 0.9 1 0.9 1 1.

studies using the validated FSFI-D instrument. * P < 001 versus PBO flibanserin Vehicle Mean Change from Baseline to Week 24-0.2-0.4-0.6-0.8-1.0-1.

0* (n=536) Study 1 Study 2 Study 3 flibanserin showed a consistent improvement in Distress across all 3 studies using the FSDS-R Question 13.

P-value not reported for secondary endpoints because the trials failed on the ediary co-primary efficacy endpoint 1.

Sexual Distress STUDIES 1, 2 & 3 Question 13 of Female Sexual Distress Scale - Revised (FSDS-R) Assessed over a 7-day recall period Phase 3 Results:

8 RESULTS: FSFI- Desire (Secondary) RESULTS: FSDS-R Q13 DISTRESS(Secondary) Mean Change from Baseline at Week * (n=280) (n=290) (n=365) (n=372) (n=532) (n=536) Study 1 Study 2 Study 3 Flibanserin showed a consistent improvement in sexual desire across all 3 studies using the validated FSFI-D instrument. * P < 001 versus PBO flibanserin Vehicle Mean Change from Baseline to Week (n=280) (n=290) (n=365) (n=372) (n=532) * (n=536) Study 1 Study 2 Study 3 flibanserin showed a consistent improvement in Distress across all 3 studies using the FSDS-R Question 13. * P < 001 versus PBO Flibanserin Vehicle 1. P-value not reported for secondary endpoints because the trials failed on the ediary co-primary efficacy endpoint 1. P-value not reported for secondary endpoints because the trials failed on the ediary co-primary efficacy endpoint SECONDARY ENDPOINT: Female Sexual Distress STUDIES 1, 2 & 3 Question 13 of Female Sexual Distress Scale - Revised (FSDS-R) Assessed over a 7-day recall period Phase 3 Results: flibanserin 100mg qhs increases SSE statistically significant separation from placebo in 4-8 weeks. How often do you feel bothered by low sexual desire? All data represent mean change from baseline for satisfying sexual events (SSE), standardized for a one month period. Treatment comparison by visit using Wilcoxon rank sum test (*p < 5 between treatment groups). Derogatis LR, et al. J Sex Res. 2011;48(6):

9 flibanserin 100mg qhs improves sexual desire statistically significant separation from placebo at 4 weeks All data represent change from baseline of least squares (LS) means. Treatment comparison by visit using ANCOVA (*p < 5 between treatment groups). Mean Change from Baseline in Key Endpoints by Visit Postmenopausal Women Study 130 (FAS, LOCF) Mean Change from Baseline ± SE SSEs Placebo Flibanserin 100 mg qhs FSFI-Desire 1.0 ** ** -0.1 ** ** ** 0.8 ** ** ** -0.2 * Week Week * FSDS-R13 (Distress) * ** Week ** *p<5; **p<1. flibanserin 100mg qhs reduces distress associated with low sexual desire PGI-I Anchored Responder Analysis 25% reduction in distress associated with low desire Placebo Flibanserin 100 mg qhs Study 147 Study 71 Study 75 Responders, % ±95% CI SSEs 39.0 FSFI- Desire FSDS-R13 SSEs FSFI- Desire FSDS-R13 SSEs FSFI- Desire FSDS-R13 All data represent change from baseline of least squares (LS) means. Treatment comparison by visit using ANCOVA (*p < 5 between treatment groups). reduction in score = improvement FSDS-R13 (0=never;4=always) Responder rates were higher in subjects receiving flibanserin compared to placebo across all three studies on all three major efficacy measures 9

10 FSFI-Desire Domain Study 147 (Flibanserin FAS and Responder Populations, LOCF) Common Adverse Events in 1% of Premenopausal Women 1. Over the past 4 weeks, how often did you feel sexual desire or interest? Almost never or never A few times (less than half the time) Sometimes (about half the time) Most times (more than half the time) Almost always or always 2. Over the past 4 weeks, how would you rate your level (degree) of sexual desire or interest? Very low or none at all Flibanserin 100 mg (FAS) Flibanserin 100 mg (Responders) Low Moderate High Very High 5 Preferred Term Placebo N = 1905 N (%) Flibanserin 100 mg qhs N = 1543 N (%) Dizziness 41 (2.2) 176 (11.4) Somnolence 59 (3.1) 173 (11.2) Nausea 71 (3.7) 161 (10.4) Fatigue 95 (5.0) 142 (9.2) 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) FAS=full analysis set. 5 bid = twice daily; qhs = once every evening. MedDRA version used for reporting: Includes Trials , , , , and PGI of Improvement: PGI-I Very Much/Much/Minimally Improved How is your condition today meaning decreased sexual desire and feeling bothered by it compared with when you started study medication? % Responders **** **** **** Flibanserin 100 qhs Placebo Adjusted p values * p < 5 ** p < 1 *** p < 01 **** p < 001 Week 24 FAS, LOCF Bremelanotide Bremelanotide completed Phase 3 trials First-in-class melanocortin receptor 4 agonist a synthetic peptide analog of the naturally occurring hormone alpha- MSH (melanocyte-stimulating hormone). 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 Evaluated in 31 clinical studies, in over 2,500 people, showing efficacy in both HSDD and ED Completed a large Phase 2B trial in HSDD, FSAD and HSDD/FSAD Mixed patients with subcutaneous (pre-filled syringes) formulation 10

Study 54 Clinical Data Satisfying Sexual Events (SSEs) The results of 327 premenopausal patients analyzed shows

Robust efficacy in all clinically key endpoints at all the 1.75 and some of the 1.

improves multiple domains of sexual function (FSFI) decreases distress associated with sexual dysfunction (FSDS-DAO)

75 mg dose analysis also demonstrated clinically meaningful and statistical significance SSE improvement from baseline to

88 (p=021) FSDS-DAO-total score mean change vs placebo -13.1 vs -6.

11 Study 54 Clinical Data Satisfying Sexual Events (SSEs) The results of 327 premenopausal patients analyzed shows clinically meaningful and statistically significant effects for BMT vs placebo. Robust efficacy in all clinically key endpoints at all the 1.75 and some of the 1.25 : FSFI total score, FSDS-DAO total score and SSEs. improves multiple domains of sexual function (FSFI) decreases distress associated with sexual dysfunction (FSDS-DAO) influences downstream behavior with an increase in SSEs. *P<5 * 1.75 mg dose analysis also demonstrated clinically meaningful and statistical significance SSE improvement from baseline to end-of-study 1.8 to 2.6 (p=21) FSFI-total score mean change vs placebo 4.56 vs 1.88 (p=021) FSDS-DAO-total score mean change vs placebo vs -6.8 (p=13) 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. Satisfying Sexual Events (SSEs) FSFI: Desire & Arousal Domain Scores *P<5 * ** 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. **P<1 11

5 mg, Buspiron=10 mg, Sildenafil=50 mg Sublingual route Oral route Pharmacokinetic curve of T Testosterone Pharmacokinetic curve of T *** ***P<01 T = 0 T = 1 T = 2 T = 3 T = 4 T = 5 T = 6 Time (hrs)

12 FSDS-DAO: Total Score Lybrido, Lybridos PKPD Lybrido and Lybridos have a unique release profile. Testosterone is released directly and sildenafil (Lybrido) or busprione (Lybridos) are release 2.5 hrs later so that the effects of the seperate components coincide T=.5 mg, Buspiron=10 mg, Sildenafil=50 mg Sublingual route Oral route Pharmacokinetic curve of T Testosterone Pharmacokinetic curve of T *** ***P<01 T = 0 T = 1 T = 2 T = 3 T = 4 T = 5 T = 6 Time (hrs) The mean absolute FSDS-DAO Score for the screening month (notreatment month) and the baseline month (placebo month) ranged from 38.9 to 41.7 and 30.5 to 33.3, respectively. Total score can range from 0 to 60. The higher the score the greater the distress associated with sexual dysfunction. Sildenafil/5HT 1A ra Pharmacokinetic and dynamice curve of Sildenafil and buspirone 47 Lybrido and Lybridos Testosterone/Sildenafil (Lybrido): increases the brain s response to sexual cues and enhances genital sexual response Testosterone/Buspirone (Lybridos): increases the brain s response to sexual cues and reduces the inhibitory response to sexual cues. Based on the concept of HYPERactive INHIBITORY response, HYPOactive EXCITATORY response or combination of both Thank You! Sheryl.Kingsberg@UHhospitals.org

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 -