Neuroendocrinology of Hypoactive Sexual Desire Disorder (HSDD): The Basics James A. Simon, MD, CCD, NCMP, IF, FACOG Clinical Professor Department of Ob/Gyn George Washington University Washington, DC Medical Director Women s Health & Research Consultants Washington, DC www.jamesasimonmd.com James A Simon, MD, PC @JamesASimonMD
Disclosures 2016 Owner/Board of Directors: James A. Simon, MD, PC; Women s Health & Research Consultants Advisory Board/Consultant: Dr. James A. Simon has served (within the last year) or is currently serving as a consultant to or on the advisory boards of: AbbVie, Inc. (North Chicago, IL), Allergan, Plc (Parsippany, NJ), AMAG Pharmaceuticals, Inc. (Waltham, MA), Amgen Inc. (Thousand Oaks, CA), Apotex, Inc. (Toronto, Canada), Ascend Therapeutics (Herndon, VA), Azure Biotech, Inc. (River Vale, NJ), JDS Therapeutics, LLC (Purchase, NY), Merck & Co., Inc. (Whitehouse Station, NJ), Millendo Therapeutics, Inc. (Ann Arbor, MI), Noven Pharmaceuticals, Inc. (New York, NY), Novo Nordisk (Bagsvrerd, Denmark), Nuelle, Inc. (Mountain View, CA), Perrigo Company, PLC (Dublin, Ireland), Radius Health, Inc. (Waltham, MA), Regeneron Pharmaceuticals, Inc. (Tarrytown, NY), Roivant Sciences, Inc. (New York, NY), Sanofi S.A. (Paris, France), Sebela Pharmaceuticals, Inc. (Roswell, GA), Sermonix Pharmaceuticals, Inc. (Columbus, OH), Shionogi Inc. (Florham Park, NJ), Sprout Pharmaceuticals (Raleigh, NC), Symbiotec Pharmalab (Indore, India), TherapeuticsMD (Boca Raton, FL), Valeant Pharmaceuticals (Laval, Canada). Speaker: He has also served (within the last year) or is currently serving on the speaker s bureaus of: Amgen Inc. (Thousand Oaks, CA), Eisai, Inc. (Woodcliff Lake, NJ), Merck (Whitehouse Station, NJ), Noven Pharmaceuticals, Inc. (New York, NY), Novo Nordisk (Bagsvrerd, Denmark), Shionogi Inc. (Florham Park, NJ), Valeant Pharmaceuticals (Laval, Canada). Grants/Research: In the last year he has received or is currently receiving grant/research support from: AbbVie, Inc. (North Chicago, IL), Actavis, PLC. (Dublin, Ireland), Agile Therapeutics (Princeton, NJ), Bayer Healthcare LLC., (Tarrytown, NY), GlaxoSmithKline (Brentford, United Kingdom), New England Research Institute, Inc. (Watertown, MA), Novo Nordisk (Bagsvrerd, Denmark), Palatin Technologies (Cranbury, NJ), Symbio Research, Inc. (Port Jefferson, NY), TherapeuticsMD (Boca Raton, FL). Patent and Trademark Holder: U.S. Patent: 4,816,257, March 28, 1989: "Method for Producing an In Vivo Environment Suitable for Human Embryo Transplant.", U.S. Trademark: Reg. No. 3,446,895, Registered June 10, 2008: You talk I ll Listen. We ll Plan Together., U.S. Trademark: Reg. No. 3,676,269, Registered September 1, 2009: U.S. Trademark: Reg. No. 3,760,080, Registered March 16, 2010: Women s Health & Research Consultants & Design, U.S. Trademark Serial No.:86-714,153. DR. SIMON SAYS Registered February 2, 2016. Stock Shareholder and/or other Financial Support: Dr. Simon is a stockholder (direct purchase) in Sermonix Pharmaceuticals (Columbus, OH).
Learning Objectives: Upon completion of this lecture participants should: Have a basic understanding of the neuroendocrinology of HSDD. Appreciate the potential sites of therapeutic intervention based on our current understanding of that neuroendocrinology.
The Sexual Response Cycle Modified by Kaplan (1974) and Georgiadis et al. (2012) Kaplan HS The new sex therapy. New York: Brunner/Mazel 1974. Georgiadis JR, Kringelbach ML, Pfaus JG. Nat Rev Urol 2012;9:486-98.
Neurobiological & Behavioral Elements of Sexual Response Georgiadis JR, Kringelbach ML, Pfaus JG. Nat Rev Urol 2012;9:486-98.
Processing of Sexual Cues & Stimuli Integration of Signals
Prefrontal Cortex Controls Executive Function Pfaus JG Pathways of sexual desire. J Sex Med 2009;6:1506-33
Evolutionary Imperative: Peak Desire during Ovulation Pfaus et al. (2015) Physiology of Reproduction (Vol 2) Academic Press: NY; Stanislaw, Rice (1988) Arch Sex Behav, 17, 499-508; Wallen (1982) Science, 217, 375-376
Central Regulation of Desire/Arousal Estrogen Progesterone (+) Adapted from Clayton & Hamilton. Female Sexual Dysfunction. Obstet Gynecol Clin North Am 2009; 36: 861-876. (-) Serotonin
Neural Pathways Regulating Sexual Desire in the Brain: Integration of Excitation and Inhibition Excitatory Inhibitory Goldstein I, Kim NN, Clayton AH et al: Hypoactive Sexual Desire Disorder: International Society for the Study of Women s Sexual Health Expert Consensus Panel Review. Mayo Clinic Proceedings, in press.
Glutamate: 2-Way Communicator in the Brain
Selective Regulation of Glutamate Neurons by 5-HT Glutamate neurons can be selectively activated or inhibited due to different locations and types of 5-HT receptors on glutamate neurons 5-HT 1A (inhibit glu neuron) 5-HT 2A (activate glu neuron) Stahl SM. CNS Spectrums 2015;20:1-6. Stahl et al. J Sex Med 2011; 8: 815-827.
Glutamate Neuron Activity May Be Elevated in HSDD Preferential stimulation of 5-HT 2A receptors LOW DESIRE Low DA & NE High 5-HT 5-HT 2A (activation) Increased Glutamate Release Stahl SM. CNS Spectrums 2015;20:1-6. Stahl et al. J Sex Med 2011; 8: 815-827.
Flibanserin Appears to Work Through This Glutamate Network From: Stahl SM, Sommer B, and Allers KA. Multifunctional pharmacology of flibanserin: Possible mechanism of therapeutic action in hypoactive sexual desire disorder. J Sex Med 2011;8:15 27.
Neural Plasticity: Animal Studies Adaptive changes in brain structure and function in response to: Stress External environment Hormonal milieu (estrogens, in particular) Associated with changes in sexual response Desire & arousal Most data from rodent studies (mating, pregnancy & postmenopausal models)
Neural Plasticity: Estrogens and Neurite Growth non-estrous Lumbosacral motor neurons estrous Van der Horst & Holstege. J Neurosci 1997; 17:1122-1136 E 2 membrane excitability (rapid effects) Similar changes occur with repetitive neural activity (learning/ memory) Neurons that fire together wire together Donald Hebbs
Patterns of Cortical Activation and Deactivation by Erotic Visual Cues (PET Scan) Decreased activation, observed primarily in the left hemisphere, is shown in red and increased activation, observed primarily in the right hemisphere, is shown in green. Minimal deactivation was observed in the right hemisphere and minimal activation was observed in the left hemisphere. Goldstein I, Kim NN, Clayton AH et al: Hypoactive Sexual Desire Disorder: International Society for the Study of Women s Sexual Health Expert Consensus Panel Review. Mayo Clinic Proceedings, in press. MRI adapted from Holstege G, How the emotional motor system controls pelvic organs, J Sex Med, in press.
Differences in Brain Structure in Women with HSDD Example of Experience-Based Neuroplasticity? Decreased Gray Matter Increased White Matter Alterations in: Salience attribution to sexual stimuli Perception of bodily sexual responses Attentional mechanisms Lower orgasmic function Decreased axonal function? Increased inhibitory circuitry? Bloemers et al. J Sex Med 2014; 11: 753-767.
Current Treatments for HSDD and Their Hypothetical Mechanism(s) of Action
What Is The Neuroendocrinology of HSDD? Goldstein I, Kim NN, Clayton AH, DeRogatis LR, Giraldi A, Parish SJ, Pfaus J, Simon JA, Kingsberg SA, Meston C, Stahl SM, Wallen K, Worsley R. Hypoactive Sexual Desire Disorder: International Society for the Study of Women s Sexual Health (ISSWSH) Expert Consensus Panel Review. Mayo Clin Proc (in press)
Summary and Conclusion Sexual desire depends on the activation of neurochemical systems for sexual excitation by erotic cues, driven most directly by dopamine and norepinephrine. Sexual inhibition is a normal function of satiety, driven by brain opioid, serotonin, and endocannabinoid systems. HSDD may occur if sexual excitation is too weak, or sexual inhibition too strong, or a combination of both. Lack of sexual desire can also occur as an adaptation of neural systems to a chronic lack of sexual pleasure (i.e. a learned behavior use it or lose it ).