Hypoactive Sexual Desire Disorder (HSDD) is defined in the American Psychiatric Association Diagnostic and Statistical Manual of Mental Disorders (4th ed.) as persistent or recurrent deficiency or absence of sexual thoughts, fantasies and/or desire for, or receptivity to, sexual activity that is:1
- Accompanied by clinically significant personal distress or interpersonal difficulties
- Not otherwise accounted for by another medical disorder, drug/medication, or psychiatric condition
In 2013 the APA released its updated DSM V.2 In this publication, HSDD was merged with Female Sexual Arousal Disorder (FSAD) to form the new diagnosis Female Sexual Interest/Arousal Disorder (FSI/AD). The reasoning for this was the significant overlap between sexual arousal and desire. Hypoactive sexual desire disorder (HSDD) is the most common of the female sexual dysfunctions.3
HSDD has an important negative impact on a patient’s body image, self-confidence, and self-worth, as well as on their relationship with their partner. HSDD is also associated with a negative impact on functionality and daily living due to the great psychological burden. Women often feel less connected to their partner, which reduces communication and may ultimately lead to separation and divorce. Based on a survey of 31,581 women in the US, sexual problems are common. Having any sexual problem (lack of desire, arousal, and orgasm) was reported by 43.1 percent, and these problems caused distress in 11.5 percent of women.4
HSDD occurs in women of all ages but is continuously under-diagnosed and under-managed. The major factor for this is a lack of physician-patient communications regarding female sexual health and functioning.5-7 This fault is equally shared by these two groups as patients are reluctant to discuss sexual difficulties with their health providers and clinicians are reluctant to inquire about sexual health. Clinicians are so hesitant due to concerns of it being too time consuming and that they do not have the necessary knowledge and ability to diagnose and treat HSDD.
That’s why this article aims to enhance Ob/Gyn clinician awareness of this debilitating condition and to enhance their ability to diagnose and manage HSDD, with the ultimate goal of improving the quality of life of these women.
By definition, HSDD must be accompanied by clinically significant personal distress or interpersonal difficulties that is not otherwise accounted for by another medical disorder, medication, or psychiatric condition. [APA] When treating a woman with sexual complaints, clinicians should always keep in mind that it is common for more than one sexual disorder to coexist and overlap in a given woman, which complicates the diagnosis. [Figure 1]
That’s why clinicians must determine the primary disorder and how any comorbid sexual disorders, such as HSDD, sexual arousal disorder, orgasmic disorder, dyspareunia, or vaginismus, may have evolved over time.8-10
Figure 1: Overlap of Female Sexual Disorders8-10
HSDD is a complex and multifactorial disorder, and clinicians must take a biopsychosocial approach to engage with patients.11 Since this is a very sensitive discussion, most women don’t mention the symptoms to their healthcare providers. Based on recent data, 80 percent of women with self-reported HSDD did not mention it to a healthcare provider, and 50 percent reported that discomfort or embarrassment contributed to their unwillingness to seek treatment.4,8
Surveys consistently show that women want to talk about their sexual issues with healthcare providers but are reluctant to begin the conversation. For instance, one study of 3,807 healthy participants indicated that women do not seek help because they are embarrassed, worry that the provider will be embarrassed, fear that the problem may be minimized or classified as being “all in their head,” or that there are no treatments for their condition.12 Additional surveys of female patients have identified similar results. One such survey showed that only 8 percent of women aged 45-49 years of age and 12 percent aged 50-59 years had sought treatment of a sexually related disorder from their physician.13 On a similar note, another survey reported that nearly 70 percent of women were concerned that raising their sexual concerns would embarrass their physician.5
Conversely, healthcare professionals share their patients’ embarrassment regarding sexuality-related discussions. A survey of nearly 2000 clinicians cited embarrassment as a major obstacle to the initiation of sexuality-focused patient discussions. Adding to this reluctance was their concern regarding limited time for discussion and lack of training surrounding discussing and managing sexuality-related concerns. Approximately 60 percent of these clinicians rated their sexuality knowledge and comfort level as “fair” or “poor.”7
A survey of American Urogynecologic Society members found that 32 percent of physicians were not familiar with questionnaires to assess FSD. Furthermore, of those that were, only 13 percent used these questionnaires for screening purposes.14 Physicians also continue to minimize the prevalence of FSD as this same study found that 69 percent of members underestimate rates of FSD in their patients. Finally, despite receiving post-residency training in urogynecology, 50 percent of respondents stated that their FSD-related training was unsatisfactory.14 The strongest predictor of a physician taking a sexual history is whether or not they received training in communication skills.15 Additional clinician characteristics that have been demonstrated to enhance patient comfort in initiating and discussing sexual concerns are as follows:16
- Clinician has seen the patient before
- Clinician knows the patient
- Clinician appears genuinely concerned about the patient’s sexual wellness
- Clinician has a professional demeanor
- Clinician appears comfortable in discussing the topic
- Clinician has a kind and understanding demeanor
The annual well woman exam is an ideal time for clinicians to ask screening questions regarding sexual health. A few questions can easily be added to a screening survey along with questions about standard tests (PAP smear, mammogram). Example questions include “Has there been a decrease in your level of sexual desire/interest? If yes, are you bothered by this?” If these screening questions are positive, the clinician should ask more detailed questions during the interview to determine:10
- The woman’s primary concern that led to the distress
- The presence of lack of desire
- The presence of pain that affects the woman’s ability to be aroused
Several validated tools and questionnaires are available to assess female sexual dysfunction, including the Decreased Sexual Desire Screener (DSDS), the Female Sexual Function Index (FSFI), and the Female Sexual Distress Scale-Revised (FSDS-R).17-20 The DSDS (Figure 2) is the easiest to use in clinical practice as it consists of 4 questions that focus on what was normal for that patient in the past and what has changed, and a 5th question that asks about specific contributing factors.17
Figure 2: Decreased Sexual Desire Screener (DSDS)17
Pathophysiology of HSDD
In women, the sexual response is experienced when the balance of excitatory and inhibitory factors is tipped toward excitatory factors. Several neurotransmitters are involved in sexual response. Dopamine drives desire and responsiveness to sexual cues. Oxytocin is released after orgasm, providing a sense of intimacy and closeness. Melanocortin helps with arousal and desire through dopaminergic neurons. Norepinephrine increases sexual excitement and increases heart rate. On the other hand, serotonin inhibits sexual excitement.21 In fact, sexual dysfunction is a well-known side effect of the selective serotonin reuptake inhibitors (SSSRIs) that increase serotonin because of reuptake inhibition. Opioids and endocannabinoids also inhibit sexual function.11
Perelman’s “Sexual Tipping Point™” model provides insights into the mechanism of action of available treatment options. It proposes that psychosocial and physiological factors can both excite and inhibit the sexual response, as seen below in Figure 3.22,23
Figure 3: Etiology of HSDD – Imbalance Between Excitation/Inhibition22,23
Management of HSDD
Since the underlying causes of HSDD are multifactorial and include physiologic and psychosocial factors, a comprehensive treatment approach that includes psychotherapy, counseling, and pharmacologic therapies is optimal. The specific combination of approaches should be personalized for each individual woman. [Kingsberg 2007; Simon 2008] There are several pharmacologic treatment options, and even though testosterone, estrogen, and bupropion are also used, they are utilized off-label. Flibanserin is currently the only FDA-approved agent for the treatment of HSDD in premenopausal women, and a promising new agent, bremelanotide, is currently under FDA review.24-25
Flibanserin is a mixed postsynaptic 5-HT1A agonist and a 5-HT2A antagonist. It decreases the activity of serotonin, which in turn decreases sexual inhibition. It also increases dopamine by acting on the dopamine-4 receptor, which increases excitation. Overall, flibanserin tips the balance in favor of prosexual effects.26,27
The efficacy of flibanserin 100 mg once daily at bedtime (qhs) as a treatment for HSDD is supported by results from three randomized placebo-controlled trials involving over 11,000 North American premenopausal women.28-30 In these trials, flibanserin 100 mg at bedtime was associated with an increase in satisfying sexual events (SSE), an improvement in sexual desire (measured using the Female Sexual Function Index [FSFI]), and a decrease in sexual distress. However, the co-primary end point of change in desire score measured using a daily electronic diary (eDiary) did not reach statistical significance in either of the two early trials. An increasing body of data and expert opinion consequently suggested that the FSFI desire domain score is a more appropriate measure of sexual desire in women with HSDD than the daily eDiary desire score.31
Thus, a new randomized placebo-controlled trial was implemented in which the primary desire end point was changed to the FSFI desire domain score. This trial, known as BEGONIA, was a 24-week trial that encompassed over 1,000 patients – 542 received flibanserin, 545 received placebo.32 Study results demonstrated that flibanserin usage, in regards to the primary study endpoints, resulted in statistically significant increases (vs. placebo) in satisfying sexual events (P < 0.001) and improvement in sexual desire (P < 0.001). Similar results were shown for flibanserin usage in terms of improvements in sexual distress (P < 0.001) and distress associated with low sexual desire (P < 0.001). Additionally, the increase in the FSFI total score was statistically significant (P < 0.001). The most frequently reported adverse events in the flibanserin group were somnolence, dizziness, and nausea. Adverse events led to the discontinuation of treatment in 9.6 percent of women receiving flibanserin and 3.7 percent on placebo.32
Flibanserin is dosed once daily, at bedtime because it may cause sedation. It is contraindicated with the use of alcohol, with concomitant moderate or strong CYP3A4 inhibitors, and in patients with hepatic impairment.33 Because of concerns about somnolence, dizziness, syncope, and hypotension when taken with alcohol, the FDA required a boxed warning and a Risk Evaluation and Mitigation Strategy (REMS) program. Physicians, NPs, PAs, and pharmacists who dispense flibanserin must be trained on its use and prescribing/dispensing requirements, successfully complete a knowledge assessment, and enroll to be certified in the REMS program. In addition, before the patient is able to receive a prescription for flibanserin, the clinician must review and complete the REMS Patient-Provider Agreement Form with every patient.34
Another category of pharmacologic agents being investigated for use in HSDD are the melanocortin agonists. Their novel mechanism of action involves activating endogenous melanocortin hormone pathways involved in sexual arousal response. Of these, bremelanotide has completed several Phase III studies. Prior to these, a Phase 2B clinical trial of bremelanotide, at doses of 1.25 mg and 1.75, significantly increased sexual arousal, sexual desire, and the number of sexually satisfying events while decreasing associated distress in premenopausal women with FSD. Efficacy was seen in both women with hypoactive sexual desire disorder (HSDD) and combined HSDD/female sexual arousal disorder (FSAD). (Jordan 2013) Bremalanotide is administered subcutaneously via an autoinjector on an “as desired” basis.35,36
The two Phase 3 clinical trials known as Reconnect were randomized, double-blinded, placebo-controlled studies that compared the efficacy and safety of bremelanotide versus placebo in premenopausal women diagnosed with HSDD. The two trials enrolled nearly 1,300 women with HSDD. Bremelanotide at a dose of 1.75mg or placebo was self-administered by patients via an autoinjector as needed in anticipation of sexual activity. The efficacy trial period of each study consisted of a 24-week treatment evaluation period. The coprimary endpoints for the Phase 3 clinical trials were the Female Sexual Function Index: Desire Domain (FSFI-D) and the Female Sexual Distress Scale-Desires/Arousal/Orgasm (FSDS-DAO) Item 13. Satisfying sexual events was a secondary endpoint. The results of the two Phase 3 Reconnect studies of bremelanotide achieved the pre-specified coprimary efficacy endpoints of improvement in desire and decrease in distress associated with low sexual desire. Regarding improvement in desire, the results demonstrated a significant increase for bremelanotide compared to placebo in both trials, with p=0.0002 and p<0.0001. As for reduction in distress, bremelanotide demonstrated a statistically significant reduction in both trials versus placebo, with p<0.0001 and p=0.0057.37-39
In the preliminary review of the overall safety population (1,247 patients), bremelanotide appeared to be well tolerated. The most frequent adverse event was nausea, which was generally mild in nature. As for the impact of the concomitant use of bremelanotide and alcohol, a Phase 1 study was conducted in both men and women.40 Results of this study demonstrated no clinically significant pharmacokinetic interactions between alcohol and bremelanotide, either overall or by sex. Additionally, no significant drug-related hypotensive or orthostatic hypotensive effects were seen. The most adverse events were mild or moderate in nature. Treatment was discontinued by 18 percent of women taking bremelanotide, most commonly due to gastrointestinal adverse events, compared with 2 percent in the placebo group.36 If approved, bremelanotide’s “as needed” administration, efficacy, and tolerability profile make it a reasonable choice for many women with HSDD.
Off-label treatment options for HSDD include testosterone, estrogen, and bupropion. A 2017 meta-analysis of 7 randomized controlled studies of transdermal testosterone (with or without concomitant estrogen therapy) indicated that postmenopausal women treated with the transdermal testosterone patch experienced significant increases in sexual desire, sexual activity, satisfying sexual episodes, and orgasms, in addition to a significant decrease in personal distress compared with women in the placebo group. However, they also experienced androgenic adverse events, acne, and hair growth.41
In one study, a bupropion and trazodone combination was shown to improve sexual desire compared to bupropion alone, most likely owing to modulation of the dopamine, norepinephrine, and serotonin system.42 In a small study in women with HSDD, treatment with bupropion SR was associated with improvement in the Changes in Sexual Functioning Questionnaire (CSFQ) total score and scores in arousal and orgasm, but there was no improvement in the desire score or the Brief Index of Sexual Functioning in Women.42, 43) In post-menopausal women, estrogen is often used to treat the urogenital changes. Also, PD5 inhibitors have shown some benefit in certain populations.
Given the prevalence of HSDD and its associated distress, it is imperative that clinicians employ a proactive approach to identifying and treating women with HSDD. Evaluation for HSDD should become part of routine clinical assessments, and well-woman visits offer the perfect opportunity for clinicians to evaluate sexual health in women of all age groups. Women with HSDD can now be managed with flibanserin or several off-label entities. Bremelanotide, currently under review by the FDA, offers an attractive new treatment option. In closing, women’s healthcare clinicians need to have the skills necessary to effectively and efficiently diagnose and manage HSDD so they can improve their patients’ quality of life.
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- American Psychiatric Association. Statistical and Diagnostic Manual – 5th Edition (Text Revised)Washington, DC: American Psychiatric Association; 2013
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- Marick C. Survey says patients expect little physician help on sex. JAMA. 1999; 291:2173-2174.
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- Bachmann G. Female sexuality and sexual dysfunction: are we stuck on the learning curve? J Sex Med. 2006;3:639-645.
- Kingsberg S. Attitudinal survey of women living with low sexual desire. J Womens Health (Larchmt). 2014 Oct;23(10):817-23.
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- Shahawy S, Deshpande NA, Nour NM. et al. Cross-Cultural Obstetric and Gynecologic Care of Muslim Patients. Obstet Gynecol. 2015;126(5):969-973
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- American Association of Retired Persons. Sexuality at Midlife and Beyond. 2004 Update of Attitudes and Beviors. Accessed November 8 2018 at https://assets.aarp.org/rgcenter/general/2004_sexuality.pdf.
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- Clayton AH, Goldfischer ER, Goldstein I, et al. Validation of the decreased sexual desire screener (DSDS): a brief diagnostic instrument for generalized acquired female hypoactive sexual desire disorder (HSDD). J Sex Med. 2009;6:730-738.
- Derogatis LR, Komer L, Katz M, et al; VIOLET Trial Investigators. Treatment of hypoactive sexual desire disorder in premenopausal women: efficacy of flibanserin in the VIOLET Study. J Sex Med. 2012;9(4):1074-1085.
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- Rosen R, Brown C, Heiman J, et al. The Female Sexual Function Index (FSFI): a multidimensional self-report instrument for the assessment of female sexual function. J Sex Marital Ther. 2000;26:191-208.
- Croft HA. Understanding the Role of Serotonin in Female Hypoactive Sexual Desire Disorder and Treatment Options. J Sex Med. 2017 Dec;14(12):1575-1584. doi: 10.1016/j.jsxm.2017.10.068.
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