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The neurobiology of bremelanotide for the treatment of hypoactive sexual desire disorder in premenopausal women

Published online by Cambridge University Press:  18 January 2021

James G. Pfaus ,
Amama Sadiq ,
Carl Spana  and
Anita H. Clayton
James G. Pfaus
Affiliation:
Centro de Investigaciones Cerebrales, Universidad Veracruzana, Xalapa, Veracruz, Mexico
Amama Sadiq*
Affiliation:
AMAG Pharmaceuticals, Inc., Waltham, Massachusetts, USA
Carl Spana
Affiliation:
Palatin Technologies, Inc., Cranbury, New Jersey, USA
Anita H. Clayton
Affiliation:
Department of Psychiatry and Neurobehavioral Sciences, University of Virginia, Charlottesville, Virginia, USA
*
*Author for correspondence: Amama Sadiq, MD, MPH Email: [email protected]
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Abstract

Hypoactive sexual desire disorder (HSDD) is a common female sexual dysfunction and is estimated to affect approximately 10% of women in the United States. It has been suggested that HSDD is associated with an imbalance of hormone and neurotransmitter levels in the brain, resulting in decreased excitation, increased inhibition, or a combination of both. Evidence suggests neurotransmitters, including dopamine (DA), norepinephrine, and serotonin, as well as hormones such as estradiol and testosterone, contribute to female sexual desire and response. Current treatments for HSDD include psychotherapy, and two US Food and Drug Administration-approved medications for premenopausal women: flibanserin, a serotonin mixed agonist and antagonist, and bremelanotide, a melanocortin receptor (MCR) agonist. Melanocortins are endogenous neuropeptides associated with the excitatory pathway of the female sexual response system. MCRs are found throughout the body, including the brain. Bremelanotide is an MCR agonist that nonselectively activates several of the receptor subtypes, of which subtype 4 (MC4R) is the most relevant at therapeutic doses. MC4R is predominantly expressed in the medial preoptic area (mPOA) of the hypothalamus in the brain, and is important for female sexual function. Animal studies suggest that bremelanotide may affect female sexual desire by activating presynaptic MC4Rs on neurons in the mPOA of the hypothalamus, leading to increased release of DA, an excitatory neurotransmitter that increases sexual desire. This review presents what is known about the mechanism of action of bremelanotide in the context of treating HSDD.

Keywords

DopamineGABAhypoactive sexual desire disordermelanocortin receptor agonistnorepinephrineserotonin
Type
Review
Information
CNS Spectrums , Volume 27 , Issue 3 , June 2022 , pp. 281 - 289
Copyright
© The Author(s), 2021. Published by Cambridge University Press

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References

Goldstein, I, Kim, NN, Clayton, AH, et al. Hypoactive sexual desire disorder: International Society for the Study of Women's Sexual Health (ISSWSH) expert consensus panel review. Mayo Clin Proc. 2017;92(1):114–128.CrossRefGoogle Scholar
Parish, SJ, Goldstein, AT, Goldstein, SW, et al. Toward a more evidence-based nosology and nomenclature for female sexual dysfunctions-part II. J Sex Med. 2016;13(12):1888–1906.CrossRefGoogle Scholar
Rosen, RC, Shifren, JL, Monz, BU, Odom, DM, Russo, PA, Johannes, CB. Correlates of sexually related personal distress in women with low sexual desire. J Sex Med. 2009;6(6):1549–1560.CrossRefGoogle ScholarPubMed
Shifren, JL, Monz, BU, Russo, PA, Segreti, A, Johannes, CB. Sexual problems and distress in United States women: prevalence and correlates. Obstet Gynecol. 2008;112(5):970–978.CrossRefGoogle ScholarPubMed
McCool, ME, Zuelke, A, Theurich, MA, Knuettel, H, Ricci, C, Apfelbacher, C. Prevalence of female sexual dysfunction among premenopausal women: a systematic review and meta-analysis of observational studies. Sexual Med Rev. 2016;4(3):197–212.CrossRefGoogle ScholarPubMed
Traeen, B, Martinussen, M, Öberg, K, Kavil, H. Reduced sexual desire in a random sample of Norwegian couples. Sex Relationship Ther. 2007;22(3):303–322.CrossRefGoogle Scholar
Sanders, SA, Graham, CA, Milhausen, RR. Predicting sexual problems in women: the relevance of sexual excitation and sexual inhibition. Arch Sex Behav. 2008;37(2):241–251.CrossRefGoogle ScholarPubMed
Pyke, RE, Clayton, AH. Psychological treatment trials for hypoactive sexual desire disorder: a sexual medicine critique and perspective. J Sex Med. 2015;12(12):2451–2458.CrossRefGoogle ScholarPubMed
Kingsberg, SA, Rezaee, RL. Hypoactive sexual desire in women. Menopause. 2013;20(12):1284–1300.CrossRefGoogle ScholarPubMed
Sprout Pharmaceuticals, Inc. Addyi (flibanserin) Prescribing Information. Raleigh, NC: Sprout Pharmaceuticals, Inc.; 2019.Google Scholar
Palatin Technologies, Inc.Vyleesi (bremelanotide) Prescribing Information. Cranbury, NJ: Palatin Technologies, Inc.; 2020.Google Scholar
Kingsberg, SA, Clayton, AH, Portman, D, et al. Bremelanotide for the treatment of hypoactive sexual desire disorder: two randomized phase 3 trials. Obstet Gynecol. 2019;134(5):899–908.CrossRefGoogle ScholarPubMed
Rosen, RC, Barsky, JL. Normal sexual response in women. Obstet Gynecol Clin North Am. 2006;33(4):515–526.CrossRefGoogle ScholarPubMed
Pfaus, JG. Pathways of sexual desire. J Sex Med. 2009;6(6):1506–1533.CrossRefGoogle ScholarPubMed
Gray, JA. The Neuropsychology of Anxiety. Oxford, UK: Oxford University Press; 1987.Google Scholar
Bancroft, J, Janssen, E. The dual control model of male sexual response: a theoretical approach to centrally mediated erectile dysfunction. Neurosci Biobehav Rev. 2000;24(5):571–579.CrossRefGoogle ScholarPubMed
Perelman, MA. The sexual tipping point: a mind/body model for sexual medicine. J Sex Med. 2009;6(3):629–632.CrossRefGoogle ScholarPubMed
Clayton, AH, Hamilton, DV. Female sexual dysfunction. Obstet Gynecol Clin North Am. 2009;36(4):861–876.CrossRefGoogle ScholarPubMed
Matuszewich, L, Lorrain, DS, Hull, EM. Dopamine release in the medial preoptic area of female rats in response to hormonal manipulation and sexual activity. Behav Neurosci. 2000;114(4):772–782.CrossRefGoogle ScholarPubMed
Pfaus, JG, Kippin, TE, Coria-Avila, G. What can animal models tell us about human sexual response? Annu Rev Sex Res. 2003;14:1–63.Google ScholarPubMed
Georgiadis, JR, Kringelbach, ML, Pfaus, JG. Sex for fun: a synthesis of human and animal neurobiology. Nat Rev Urol. 2012;9(9):486–498.CrossRefGoogle ScholarPubMed
McClintock, MK. Group mating in the domestic rat as a context for sexual selection: consequences for the analysis of sexual behavior and neuroendocrine responses. Adv Study Behav. 1984;14:1–50.CrossRefGoogle Scholar
Beach, FA. Sexual attractivity, proceptivity, and receptivity in female mammals. Horm Behav. 1976;7(1):105–138.CrossRefGoogle ScholarPubMed
Emery, DE. Effects of endocrine state on sociosexual behavior of female rats tested in a complex environment. Behav Neurosci. 1986;100(1):71–78.CrossRefGoogle Scholar
Erskine, MS. Solicitation behavior in the estrous female rat: a review. Horm Behav. 1989;23(4):473–502.CrossRefGoogle ScholarPubMed
Paredes, RG, Alonso, A. Sexual behavior regulated (paced) by the female induces conditioned place preference. Behav Neurosci. 1997;111(1):123–128.CrossRefGoogle ScholarPubMed
Mendelson, SD, Pfaus, JG. Level searching: a new assay of sexual motivation in the male rat. Physiol Behav. 1989;45(2):337–341.CrossRefGoogle ScholarPubMed
Pfaus, JG, Mendelson, SD, Phillips, AG. A correlational and factor analysis of anticipatory and consummatory measures of sexual behavior in the male rat. Psychoneuroendocrinology. 1990;15(5–6):329–340.CrossRefGoogle ScholarPubMed
Pfaus, JG, Smith, WJ, Coopersmith, CB. Appetitive and consummatory sexual behaviors of female rats in bilevel chambers. I. A correlational and factor analysis and the effects of ovarian hormones. Horm Behav. 1999;35(3):224–240.CrossRefGoogle Scholar
Agmo, A. Lack of opioid or dopaminergic effects on unconditioned sexual incentive motivation in male rats. Behav Neurosci. 2003;117(1):55–68.CrossRefGoogle ScholarPubMed
Agmo, A. Unconditioned sexual incentive motivation in the male Norway rat (Rattus norvegicus). J Comp Psychol. 2003;117(1):3–14.CrossRefGoogle Scholar
Kingsberg, SA, Clayton, AH, Pfaus, JG. The female sexual response: current models, neurobiological underpinnings and agents currently approved or under investigation for the treatment of hypoactive sexual desire disorder. CNS Drugs. 2015;29(11):915–933.CrossRefGoogle ScholarPubMed
Pfaus, J, Giuliano, F, Gelez, H. Bremelanotide: an overview of preclinical CNS effects on female sexual function. J Sex Med. 2007;4(Suppl 4):269–279.CrossRefGoogle ScholarPubMed
Ückert, S, Bannowsky, A, Albrecht, K, Kuczyk, MA. Melanocortin receptor agonists in the treatment of male and female sexual dysfunctions: results from basic research and clinical studies. Expert Opin Invest Drugs. 2014;23(11):1477–1483.CrossRefGoogle ScholarPubMed
Arnow, BA, Millheiser, L, Garrett, A, et al. Women with hypoactive sexual desire disorder compared to normal females: a functional magnetic resonance imaging study. Neuroscience. 2009;158(2):484–502.CrossRefGoogle ScholarPubMed
Woodard, TL, Nowak, NT, Balon, R, Tancer, M, Diamond, MP. Brain activation patterns in women with acquired hypoactive sexual desire disorder and women with normal sexual function: a cross-sectional pilot study. Fertil Steril. 2013;100(4):1068–1076.CrossRefGoogle ScholarPubMed
Hull, EM, Lorrain, DS, Du, J, et al. Hormone-neurotransmitter interactions in the control of sexual behavior. Behav Brain Res. 1999;105(1):105–116.CrossRefGoogle ScholarPubMed
Bianchi-Demicheli, F, Cojan, Y, Waber, L, Recordon, N, Vuilleumier, P, Ortigue, S. Neural bases of hypoactive sexual desire disorder in women: an event-related FMRI study. J Sex Med. 2011;8(9):2546–2559.CrossRefGoogle Scholar
Holstege, G. How the emotional motor system controls the pelvic organs. Sex Med Rev. 2016;4(4):303–328.CrossRefGoogle ScholarPubMed
Eves, PC, Haycock, JW. Melanocortin signalling mechanisms. Adv Exp Med Biol. 2010;681:19–28.CrossRefGoogle ScholarPubMed
Cawley, NX, Li, Z, Loh, YP. 60 years of POMC: biosynthesis, trafficking, and secretion of pro-opiomelanocortin-derived peptides. J Mol Endocrinol. 2016;56(4):T77–T97.CrossRefGoogle ScholarPubMed
Ericson, MD, Lensing, CJ, Fleming, KA, Schlasner, KN, Doering, SR, Haskell-Luevano, C. Bench-top to clinical therapies: a review of melanocortin ligands from 1954 to 2016. Biochim Biophys Acta Mol Basis Dis. 2017;1863(10 Pt A):2414–2435.CrossRefGoogle ScholarPubMed
Gantz, I, Fong, TM. The melanocortin system. Am J Physiol Endocrinol Metab. 2003;284(3):E468–E474.CrossRefGoogle ScholarPubMed
Tao, YX. The melanocortin-4 receptor: physiology, pharmacology, and pathophysiology. Endocr Rev. 2010;31(4):506–543.CrossRefGoogle Scholar
Gelez, H, Poirier, S, Facchinetti, P, et al. Neuroanatomical distribution of the melanocortin-4 receptors in male and female rodent brain. J Chem Neuroanat. 2010;40(4):310–324.CrossRefGoogle ScholarPubMed
Diamond, LE, Earle, DC, Rosen, RC, Willett, MS, Molinoff, PB. Double-blind, placebo-controlled evaluation of the safety, pharmacokinetic properties and pharmacodynamic effects of intranasal PT-141, a melanocortin receptor agonist, in healthy males and patients with mild-to-moderate erectile dysfunction. Int J Impot Res. 2004;16(1):51–59.CrossRefGoogle ScholarPubMed
Rosen, RC, Diamond, LE, Earle, DC, Shadiack, AM, Molinoff, PB. Evaluation of the safety, pharmacokinetics and pharmacodynamic effects of subcutaneously administered PT-141, a melanocortin receptor agonist, in healthy male subjects and in patients with an inadequate response to Viagra. Int J Impot Res. 2004;16(2):135–142.CrossRefGoogle ScholarPubMed
Hadley, ME. Discovery that a melanocortin regulates sexual functions in male and female humans. Peptides. 2005;26(10):1687–1689.CrossRefGoogle ScholarPubMed
Diamond, LE, Earle, DC, Heiman, JR, Rosen, RC, Perelman, MA, Harning, R. An effect on the subjective sexual response in premenopausal women with sexual arousal disorder by bremelanotide (PT-141), a melanocortin receptor agonist. J Sex Med. 2006;3(4):628–638.CrossRefGoogle Scholar
Pfaus, JG, Shadiack, A, Van Soest, T, Tse, M, Molinoff, P. Selective facilitation of sexual solicitation in the female rat by a melanocortin receptor agonist. Proc Natl Acad Sci U S A. 2004;101(27):10201–10204.CrossRefGoogle ScholarPubMed
Rössler, AS, Pfaus, JG, Kia, HK, Bernabé, J, Alexandre, L, Giuliano, F. The melanocortin agonist, melanotan II, enhances proceptive sexual behaviors in the female rat. Pharmacol Biochem Behav. 2006;85(3):514–521.CrossRefGoogle ScholarPubMed
Molinoff, PB, Shadiack, AM, Earle, D, Diamond, LE, Quon, CY. PT-141: a melanocortin agonist for the treatment of sexual dysfunction. Ann NY Acad Sci. 2003;994:96–102.CrossRefGoogle ScholarPubMed
Micevych, PE, Meisel, RL. Integrating neural circuits controlling female sexual behavior. Front Syst Neurosci. 2017;11:42.CrossRefGoogle ScholarPubMed
Tobiansky, DJ, Roma, PG, Hattori, T, Will, RG, Nutsch, VL, Dominguez, JM. The medial preoptic area modulates cocaine-induced activity in female rats. Behav Neurosci. 2013;127(2):293–302.CrossRefGoogle ScholarPubMed
Roberts, E. Gamma-aminobutyric acid. Scholarpedia. 2007;2(10):3356.CrossRefGoogle Scholar
US Food and Drug Administration. Low Sexual Interest, Desire, and/or Arousal in Women: Developing Drugs for Treatment--Guidance for Industry. October 2016. https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM526362.pdf. Accessed February 4, 2021.Google Scholar
US Food and Drug Administration. The Voice of the Patient: Female Sexual Dysfunction. June 2015. https://www.fda.gov/files/drugs/published/The-Voice-of-the-Patient--Female-Sexual-Dysfunction.pdf. Accessed February 4. 2021.Google Scholar
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