9/23/2015 Disclosures The Biopsychosocial Perspective: • No financial disclosures to share Pharmacologic Treatment Possibilities Roya L. Rezaee MD, FACOG Assistant Professor, Department of Reproductive Biology Co-Director, Program for Sexual Health and Vulvovaginal Disorders 2 The Neurobiology of Female Sexual Function NeuralA. PET Basis scan – healthy of female HSDD B. PET scan – HSDD female Female sexual function appears to be modulated by specific neurotransmitters, brain structures, and neurohormones • Dopamine • Basal ganglia • Estrogen • Serotonin • Amygdala • Testosterone Images supplied courtesy of Gert Holstege • Insular cortex •Oxytocin MD PhD • Epinephrine • Neuroimaging studies comparing premenopausal women • Norepinephrine • Caudate nucleus • Endogenous opioids with and without HSDD reveals differences in brain activity a,b,c,d • Hypothalamus • Pheromones patterns when shown erotic stimuli. • For women with HSDD their prefrontal cortex is unable to • Spinal cord deactivate, frustrating their ability to feel sexual desire. •Pituitary • The prefrontal cortex is responsible for executive functions • Hippocampus such as coordination of tasks, problem solving and information analysis. Taylor M, et al. J Affect Disord. • Ventral tegmental area 2005;88:241-254. aDifferences in Brain Activity in Premenopausal Women with Hypoactive Sexual Desire Disorder Compared to Women without Sexual Dysfunction Basson R. N Engl J Med. bBrain activation patterns in women with acquired hypoactive sexual desire disorder and women with normal sexual 2006;354:1497-1506. function: a cross‐sectional pilot study. Fertility and Sterility 2013. cWomen with hypoactive sexual desire disorder compared to normal females: a functional magnetic resonance imaging study. Neuroscience 2009. dNeural bases of hypoactive sexual desire disorder in women: an event‐related fmri study. Journal of Sexual Medicine 2011. 1 9/23/2015 Role of Steroid Hormones Role of Steroid Hormones • Estradiol • Testosterone and DHT are most potent and • maintains vaginal lubrication, blood flow to clitoris, urethra and vagina almost entirely bound by albumin and SHBG • Produced in granulosa cells of the ovary in – Remaing 1-2% of total is freely circulating and premenopausal women available to estrogen and testosterone sensitive • Estrone, estriol present have lower numbers and less tissues (including brain and skin) affinity for receptors • SHBG synthesized in the liver • Postmenopause • estrogen deficient state – Estrogen increases, testosterone decreases synthesis • Produced by precursors dehydroepiandosterone (DHEA), dehydroepiandosterone sulphate(DHEAS) • Affected by medication via first pass and androstenedion (A4) in the adrenal glands and ovary metabolism Role of Steroid Hormones Sex Hormone-Binding Globulin • Prohormones: DHEAS, DHEA, A4 converted . SHBG is the carrier protein for estrogen and into testosterone (T) and dihydrotestosterone testosterone (DHT) – SHBG-bound fraction is unavailable for • Ovary via the theca cells produces 25% of T, biological activity 50% of A, and 20% of DHEA . Production regulated by estrogen- • Adrenal Gland produces 25% of T, 50% of A, testosterone balance 50% of DHEA and 100% of DHEAS – Remaining 30% of DHEA is peripheral conversion of – Estrogen stimulates SHBG production by DHEAS the liver • Testosterone is also produced in the central – Testosterone decreases SHBG synthesis nervous system starting from cholesterol – Implications for treatment Selby C. Ann Clin Biochem. 1990;27:532-541. 2 9/23/2015 CNS Effects of Hormones on Female Role of Neurotransmitters/Signaling Molecules Sexual Function • Exact central neuroendocrine mechanism remains unclear • Involved areas of the brain: brain stem, hypothalamus, forebrain (amygdala) • Excitatory factors • Estrogen, testosterone, melanocortin, oxytocin, dopamine and norepinephrine • Inhibitory Factors • Serotonin, prolactin, endogenous opioids • The Balance is…”the sexual tipping point.” Perlman MA. The sexual tipping point. J Sex Med 2009 Adapted from: Clayton AH. Psychiatr Clin North Am. 2003;26:673‐682; Ben Zion IZ et al. Mol Psychiatry. 2006;11:782‐786 Physiology of Sexual Function Central Nervous System Role of Neuroendocrine Molecules - Testosterone 5-HT Progesterone • On the cellular level it is nitric oxide (NO), vasoactive +/‐ + + + peptide (VIP) and acetylcholine (ACh) that interact for Melanocortins sexual arousal + Estrogen + + • Based upon penile erection and animal studies Desire Dopamine (DA) - • Sexual stimulation releases NO from vascular + epithelium 5-HT - • Stimulates guanylate cyclase to guanosine Prolactin - Subjective + Norepinephrine (NE) Excitement triphosphate into guanosine monophospate (cGMP) • Stimulates smooth muscle relaxation in the penile arteries and corpora cavernosum causing increased + blood flow Oxytocin Orgasm Berman JR et al. World J Urol 2002 Clayton A, Hamilton D. Psychiatr Clin N Am. 2010;33:323-338. *slide adapted from website herdesire.net 3 9/23/2015 Physiology of Sexual Function Peripheral Tissues: effects of neurotransmitters and hormones Role of Neuroendocrine System • Drive is triggered in the hypothalamus and activates the dopamine system Gonads • System is activated early, norepinephrine is released, Adrenals sexual excitation increases and desire to continue 5-HT sexual activity continues - • Estrogen • Heart rate, blood pressure increase suggesting the Maintain Genital Structure Nitric Oxide (NO) • Testosterone and Function activation of the noradrenergic system • Progestin + - 5-HT2A + • Neurobiology of the orgasm is unknown although NE includes the mesolimbic dopamine pathway, pudendal, + pelvic and hypogastric nerves Vasocongestion Sensation Clitoral and • Orgasm occurs with the release of contracting agents - Penile Tissue oxytocin and serotonin in the tissue 5-HT + + Prostaglandin E • Leads to rhythmic contractions of levator plate, Cholinergic Fibers uterus, vagina Clayton A, Hamilton D. Psychiatr Clin N Am. 2010;33:323-338. • Resolution varies *adapted slide from website herdesire.net Desire in the brain… Excitatory CS-UCS Integrator Inhibitory Appetitive responses ACC CPu CB1s DA +++ VP NAcc 5-HT Pir Ctx MSH ++ ArcN How does this translate into DA +++ , 5-HT NE CB1s , pharmacologic treatment options? mPOA VTA GnRH OT++ NE PVN DA +++ NE , 5-HT Sexual reward Tu VMH LS CS detector UCS detector Olfactory cue MeApd Sexual reward OT Pfaus J G, Ismail N and Coria-Avila G A (2010) Sexual Motivation. In: Koob G.F., Le Moal M. and Thompson R.F. 16 (eds.) Encyclopedia of Behavioral Neuroscience, volume 3, pp. 201–209 Oxford: Academic Press 4 9/23/2015 Drugs In Development or Approved for Low Desire : Biological Approaches for Low Desire Drug Name Drug Pharma Current Developmental Status Category Sponsor Flibanserin Non-hormonal Sprout Approved 8/2015 for • Increase androgens (locally(DHEA) and CNS agent Pharmaceuticals HSDD in premenopausal women, available 10/17/15 Lybrido (on demand oral sildenafil + Emotional Brain Phase II completed for HSDD systemically) tablet) testosterone Lybridos (on demand oral buspirone + Emotional Brain Phase II in progress for HSDD • Increase dopamine tablet) testosterone DHEA Vaginal Ovules Androgenic EndoCeutics, Inc. Phase III completed for VVA in postmenopausal • Increase norepinephrine (Prasterone) Precursor for VVA Bayer Women;future investigation for HSDD Bremelanotide (PT-141) melanocortin Palatin Phase IIB for FSAD completed • Modulate serotonin subq injection (PL6983) receptor modulator Technologies Phase III underway for HSDD/FSIAD Extended release daily oral bupropion and SP-1 Biopharma Phase III set to begin buspirone and bupropion trazodone • Melanocortins (LorexysTM) • PDE-5 Inhibitor 17 Sexual Desire: Estrogen Testosterone Biological Approaches Excitatory and Inhibitory Pathways Bupropion SR Lorexys Flibanserin Lybrido/Lybridos + Bremelanotide • Increase androgens (locally(DHEA) and Inhibitory Excitatory systemically) • Increase dopamine 5-HT Testoterone, Prolactin Estrogen, Opioids • Increase norepinephrine Dopamine Endocannabinoids Norepinephrine Oxytocin Melanocortins • Modulate serotonin • Melanocortins • PDE-5 Inhibitor Adapted from Pfaus J. J Sex Med. 2009;6:1506-1533. 20 5 9/23/2015 Published Randomized Studies Demonstrating Efficacy of Testosterone for Low Desire Testosterone in Postmenopausal Women Doses (mcg/d) Subjects (n) Estrogen - Testosterone Shifren et al, 2000 150/300 SM (75) + 5-HT Progesterone Braunstein, +/‐ + 150/300/450 SM (447) + + + et al 2005 Melanocortins Buster et al, 2005 300 SM (533) + Estrogen + + + Desire Dopamine (DA) Simon et al, 2005 300 SM (562) + - + Davis et al 2006 300 SM (61) + (patch) 5-HT - + (aromatase Prolactin - Subjective + Davis et al, 2006 300 SM (76) Norepinephrine (NE) inhibitors) Excitement Shifren et al, 2006 300 NM (486) + Liu et al, 2008 300 NM (431) + + Oxytocin Orgasm Davis et al, 2008 150/300 NM/SM (814) - Panay et al, 2010 300 NM (272) +/- groups NM= naturally menopausal SM= surgically menopausal Adapted from Clayton A, Hamilton D. Psychiatr Clin N Am. 2010;33:323-338 slide adapted from herdesire.net. Off-Label Testosterone Options Davis & Braunstein: Summary of Efficacy & Safety for Low Desire • Randomized, double-blind placebo controlled studies have • Testosterone transdermal patches established efficacy of transdermal patch for relieving symptoms of HSDD in naturally and surgically menopausal women with and • Testosterone gels and patches approved for men without concomitant estrogen or estrogen/ progesterone therapy • Compounded