Hypoactive Sexual Desire Disorder: International Society for the Study of Women's Sexual Health (ISSWSH) Expert Consensus Panel Review

The objective of the International Society for the Study of Women’s Sexual Health expert consensus panel was to develop a concise, clinically relevant, evidence-based review of the epidemiology, physiology, pathogenesis, diagnosis, and treatment of hypoactive sexual desire disorder (HSDD), a sexual dysfunction affecting approximately 10% of adult women. Etiologic factors include conditions or drugs that decrease brain dopamine, melanocortin, oxytocin, and norepinephrine levels and augment brain serotonin, endocannabinoid, prolactin, and opioid levels. Symptoms include lack or loss of motivation to participate in sexual activity due to absent or decreased spontaneous desire, sexual desire in response to erotic cues or stimulation, or ability to maintain desire or interest through sexual activity for at least 6 months, with accompanying distress. Treatment follows a biopsychosocial model and is guided by history and assessment of symptoms. Sex therapy has been the standard treatment, although there is a paucity of studies assessing efficacy, except for mindfulness-based cognitive behavior therapy. Bupropion and buspirone may be considered off-label treatments for HSDD, despite limited safety and efficacy data. Menopausal women with HSDD may benefit from off-label testosterone treatment, as evidenced by multiple clinical trials reporting some efficacy and short-term safety. Currently, flibanserin is the only Food and Drug Administrationeapproved medication to treat premenopausal women with generalized acquired HSDD. Based on existing data, we hypothesize that all these therapies alter central inhibitory and excitatory pathways. In conclusion, HSDD significantly affects quality of life in women and can effectively be managed by health care providers with appropriate assessments and individualized treatments. a 2016 Mayo Foundation for Medical Education and Research. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/) n Mayo Clin Proc. 2017;92(1):114-128 H ypoactive sexual desire disorder (HSDD), the most prevalent female sexual health problem, was considered the persistent or recurrent deficiency or absence of sexual fantasies and desire for sexual activity with marked distress or interpersonal difficulty not otherwise accounted for by a general medical or psychiatric condition. An HSDD may be primary or secondary, lifelong or acquired, or generalized or situational. The broadened definition of HSDD may include any of the following: (1) lack of motivation for sexual activity as manifested by either reduced or absent spontaneous desire (sexual thoughts or fantasies) or reduced or absent responsive desire to erotic cues and stimulation or inability to maintain desire or interest through sexual activity or (2) loss of desire to initiate or participate in sexual activity, including behavioral responses such as avoidance of situations that could lead to sexual activity, that is, not secondary to sexual pain disorders, and is combined with clinically significant personal distress that includes frustration, grief, incompetence, loss, sadness, sorrow, or worry. Women with HSDD have been found to have impaired body image, self-confidence, From Sexual Medicine, Alvarado Hospital, San Diego, CA (I.G.); Institute for Sexual Medicine, San Diego, CA (N.N.K.); Department of Psychiatry and Neurobehavioral Sciences and Obstetrics and Gynecology, University of Virginia, Charlottesville (A.H.C.); Maryland Center for Sexual Health, Johns Hopkins University School of Medicine, Baltimore (L.R.D.); Affiliations continued at the end of this article. CONSENSUS RECOMMENDATIONS 114 Mayo Clin Proc. n January 2017;92(1):114-128 n http://dx.doi.org/10.1016/j.mayocp.2016.09.018 www.mayoclinicproceedings.org n a 2016 Mayo Foundation for Medical Education and Research. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). and self-worth and to feel less connected to their partners. Total health care expenditures compared with a control patient cohort were higher for women with HSDD, including outpatient office visits, prescription medication use, and other medical services, including radiology, laboratory, and outpatient procedures. Comorbidities include depression and fatigue, similar to chronic conditions such as diabetes and back pain. Research on the neuroendocrine central mechanisms of sexual desire has led to an improved understanding of the underlying pathogenesis of this biopsychosocial condition. Misunderstandings about HSDD exist, leaving few clinicians feeling competent to inquire about or treat this condition. Despite the existence of numerous publications on HSDD, what has been lacking is a concise resource that assists the clinician (internists/primary care physicians, gynecologists, urologists, and advanced practice providers) in competently screening the female patient for HSDD and providing appropriate therapeutic options in a biopsychosocial paradigm. To this end, the International Society for the Study of Women’s Sexual Health (ISSWSH) commissioned a panel of experts to write a concise review of the state-of-theart understanding of the neural circuitry that regulates sexual desire, including a plausible explanation for persistent states of both normal and hypoactive sexual desire; a description of current onand off-label treatment strategies, including their benefits and pitfalls; and a discussion of the rationale for using various therapies. METHODS In January 2016, the ISSWSH executive committee chose co-chairs for this project to identify potential panelists based on individuals’ publications and research. After a planning conference call with the chosen experts, panelists were asked to individually perform an evidence-based literature review in their respective topics, identifying high-quality publications that they judged to be important and pertinent to the topic. Literature selection criteria were not systematically defined but were based on the expertise and experience of each panelist. The panel of 13 researchers and clinicians convened in Dallas, Texas, to present and discuss the current state of knowledge of HSDD. Participants declared potential conflicts of interest and were ISSWSH members and nonmembers. Panelists deliberated on the history, pathogenesis, diagnostic process, and treatment of HSDD and were assigned to writing groups for the development of this article. The ISSWSH is a not-for-profit multidisciplinary academic and scientific organization dedicated to supporting the highest standards of ethics and professionalism in the research, education, and clinical practice of women’s sexual health. The ISSWSH received an unrestricted grant from industry for the development of this document. No industry representatives were present in the closed committee meetings; there was no industry participation in the evidence selection, discussion, or creation of this document; and there was no attempt by industry to influence its content. History of HSDD and Nosology Historically, the diagnoses of female sexual dysfunctions have been made principally by clinical presentation and patient history rather than by nosology based on etiology, pathogenesis, and clinical phenomenology. Development of the diagnostic concept of HSDD is closely tied to the evolution of the Diagnostic and Statistical Manual of Mental Disorders (DSM) system, the diagnostic classification system of the American Psychiatric Association. The diagnostic category of HSDD has existed for approximately 30 years, with its antecedents labeled differently but defined in a similar manner. The definition has evolved with the text-revised versions of the DSM-IV and the DSM-5. In the DSM-5, HSDD has been eliminated as a distinct nosologic entity and has been replaced with an amalgamation of the DSM-IV HSDD and female sexual arousal disorder diagnoses, termed female sexual interest/arousal disorder. This revised classification has been controversial among experts in the area of sexual medicine because there is little empirical support or validation of the new diagnostic category/ criteria in contemporary clinical research. Concern over what some consider to be the inappropriate elimination of the diagnostic HYPOACTIVE SEXUAL DESIRE DISORDER: ISSWSH REVIEW Mayo Clin Proc. n January 2017;92(1):114-128 n http://dx.doi.org/10.1016/j.mayocp.2016.09.018 www.mayoclinicproceedings.org 115 category of HSDD in DSM-5 has resulted in the development of an autonomous nosology for female sexual dysfunctions by two international panels of experts in sexual medicine (the ISSWSH Nomenclature Committee and the International Consultation in Sexual Medicine). Importantly, the ISSWSH nosology retains HSDD as a distinct diagnostic entity, consistent with what many believe to be empirically based clinical experience. This classification system is also consistent with the International Statistical Classification of Diseases and Related Health Problems, 10th Revision (ICD-10) nomenclature system, which is used throughout the world and applies to both the somatic and psychiatric diagnostic systems. In the ICD-10, HSDD (ICD-10 code F 52.0) is represented as an independent diagnostic category, as it had been in the DSM system before DSM-5. Epidemiology Hypoactive sexual desire disorder is a common but frequently undiagnosed condition. Initially, epidemiologic studies examining the prevalence of low desire in women did not take into account the associated bother and distress, a cardinal symptom of HSDD. However, they did associate lower quality-of-life measures (eg, physical and emotional satisfaction with sexual partners and general happiness) in women with low desire compared with women with no sexual problems. In later studies that examined low sexual desire with distress in large cohorts of premenopausal and postmenopausal women in the general population, the overall prevalence of HSDD ranged from approximately 8% to 19%. These studies also found associations between distressing low sexual desire and lower health-related quality of life, as well as psychosocial factors such as dissatisfaction with sex life, partner, or marriage and negative emotional states, including frustration, hopelessness, anger, poor self-esteem, and loss of femininity. When subgroups were further characterized, women with a current spouse or partner were more likely to experience concomitant distress with low sexual desire than nonpartnered women. In addition, self-assessed poor health, thyroid disease, and urinary incontinence were associated with increased probability of distressing low sexual desire. There was also a marked association between depression and anxiety and distressing low sexual desire. Interestingly, although the prevalence of low sexual desire increased with age and was higher in naturally menopausal women, the prevalence of associated distress declined with increasing age. Similarly, in a study of US and European women aged 20 to 70 years, the occurrence of low desire increased with age and distress about low desire decreased, resulting in relatively constant prevalence rates of distressing low sexual desire with age (12%-19% in the United States and 6%-13% in Europe). One potential limitation of populationbased surveys is that the data are selfreported, with no independent verification. Thus, it is important that a multicenter, longitudinal, observational study of women with clinically diagnosed HSDD was initiated in 2008 and completed enrollment of 1592 participants into an HSDD registry. Among the baseline findings, one-third of the 1088 premenopausal women had symptoms or a clinical diagnosis of depression. In a subgroup of 426 premenopausal women and 174 postmenopausal women with HSDD, a significant proportion (54% premenopausal; 66% postmenopausal) had concomitant arousal or lubrication problems. These data illustrate the importance of accurately and completely assessing patients presenting with HSDD to detect any possible concomitant conditions and optimize treatment. Physiologic Mechanisms Modulating Sexual Desire Sexual desire has been studied in both the clinical and laboratory settings. Validated patient-reported instruments (eg, the Female Sexual Function Index) enable clinically sensitive assessment of changes in sexual desire. In animal studies, sexual desire can be reliably inferred from behaviors that anticipate or solicit sexual interaction or otherwise indicate sexual interest. These behaviors and underlying cognitive, emotional, and regulatory processes are controlled by brain systems involved in sexual excitation and inhibition. MAYO CLINIC PROCEEDINGS 116 Mayo Clin Proc. n January 2017;92(1):114-128 n http://dx.doi.org/10.1016/j.mayocp.2016.09.018 www.mayoclinicproceedings.org Neural Regulation. Key regions in the brain that regulate sexual desire include the prefrontal cortex, locus coeruleus, medial preoptic area, paraventricular nucleus, and rewardand attention-processing centers of the ventral tegmental area and the nucleus accumbens (Figure 1). Sexual excitation involves the actions of brain dopamine, melanocortin, oxytocin, vasopressin, and norepinephrine. These neurotransmitters coordinate pathways in the hypothalamus, limbic system, and cortex to process and respond to sexual stimuli. Sexual inhibition involves brain opioid, serotonin, and endocannabinoid systems that are activated normally during sexual refractoriness or as a function of primary aversion or secondary avoidance. These inhibitory systems blunt the ability of excitatory systems to be activated. A large aggregate of animal and human literature on the psychopharmacology of sexual motivation and desire reports that sexual desire can be inhibited by drugs or conditions that (1) decrease brain dopamine levels, (2) augment the action of brain serotonin specifically through serotonin 2A Limbic integrator Conscious awareness/evaluation Regulation/ reward ACC