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The Female Sexual Response: Current Models, Neurobiological Underpinnings and Agents Currently Approved or Under Investigation for the Treatment of Hypoactive Sexual Desire Disorder

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Abstract

How a woman responds to sexual cues is highly dependent on a number of distinct, yet related, factors. Researchers have attempted to explain the female sexual response for decades, but no single model reigns supreme. Proper female sexual function relies on the interplay of somatic, psychosocial and neurobiological factors; misregulation of any of these components could result in sexual dysfunction. The most common sexual dysfunction disorder is hypoactive sexual desire disorder (HSDD). HSDD is a disorder affecting women across the world; a recent in-person diagnostic interview study conducted in the USA found that an estimated 7.4 % of US women suffer from HSDD. Despite the disorder’s prevalence, it is often overlooked as a formal diagnosis. In a survey of primary care physicians and obstetrics/gynaecology specialists, the number one reason for not assigning an HSDD diagnosis was the lack of a safe and effective therapy approved by the US Food and Drug Administration (FDA). This changed with the recent FDA approval of flibanserin (Addyi™) for the treatment of premenopausal women with acquired, generalized HSDD; there are still, however, no treatments approved outside the USA. HSDD is characterized by a marked decrease in sexual desire, an absence of motivation (also known as avolition) to engage in sexual activity, and the condition’s hallmark symptom, marked patient distress. Research suggests that HSDD may arise from an imbalance of the excitatory and inhibitory neurobiological pathways that regulate the mammalian sexual response; top-down inhibition from the prefrontal cortex may be hyperactive, and/or bottom-up excitation to the limbic system may be hypoactive. Key neuromodulators for the excitatory pathways include norepinephrine, oxytocin, dopamine and melanocortins. Serotonin, opioids and endocannabinoids serve as key neuromodulators for the inhibitory pathways. Evolving treatment strategies have relied heavily on these crucial research findings, as many of the agents currently being investigated as treatment options for HSDD target and influence key players within these excitatory and inhibitory pathways, including various hormone therapies and centrally acting drugs, such as buspirone, bupropion and bremelanotide.

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Acknowledgments

The authors requested research results and summaries of theories of mechanism of action from each of the four companies with drugs in development for the treatment of HSDD, and wish to acknowledge the research and editorial assistance of the following people who provided that information: Jos Bloemers: Emotional Brain; Rich Franco: Sprout Pharmaceuticals; Rob Jordan: Palatin Technologies; and Rob Pyke: S1 Biopharma.

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Authors and Affiliations

  1. Departments of Reproductive Biology and Psychiatry, Case Western Reserve University School of Medicine, Cleveland, OH, USA

    Sheryl A. Kingsberg

  2. Department of Psychiatry and Neurobehavioral Sciences, University of Virginia, Charlottesville, VA, USA

    Anita H. Clayton

  3. Department of Psychology, Center for Studies in Behavioral Neurobiology, Concordia University, Montreal, QC, Canada

    James G. Pfaus

  4. MacDonald Women’s Hospital, Mailstop 5034, 11100 Euclid Avenue, Cleveland, OH, 44106, USA

    Sheryl A. Kingsberg

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  1. Sheryl A. Kingsberg
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Correspondence to Sheryl A. Kingsberg.

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The authors received no financial support for the preparation of this article.

Conflict of interest

Sheryl Kingsberg has received research/grant support from Palatin Technologies, Sprout Pharmaceuticals, TherapeuticsMD and Trimel Pharmaceuticals; has received consulting fees from Emotional Brain, Endoceutics, NovoNordisk, Nuelle, Palatin Technologies, Pfizer, Materna, Sermonix, Shionogi, Sprout Pharmaceuticals, SST, Teva, TherapeuticsMD and Trimel Pharmaceuticals; has received stock/stock options with Viveve; and testified at the 2015 FDA Advisory Committee meeting regarding flibanserin.

Anita H. Clayton has received research/grant support from Palatin Technologies and Trimel Pharmaceuticals; has received consulting fees from Palatin Technologies, S1 Biopharma, Sprout Pharmaceuticals and Trimel Pharmaceuticals; has received stock/stock options with S1 Biopharma; and testified at the 2015 FDA Advisory Committee meeting regarding flibanserin.

Jim Pfaus has received consulting fees from Emotional Brain and Palatin Technologies.

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Kingsberg, S.A., Clayton, A.H. & Pfaus, J.G. 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 29, 915–933 (2015). https://doi.org/10.1007/s40263-015-0288-1

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