Jill M. Krapf1, John E. Buster2 and Andrew T. Goldstein3
(1)
Department of Obstetrics and Gynecology, George Washington University School of Medicine, Washington, DC, USA
(2)
Division of Reproductive Endocrinology and Infertility, Women and Infants Hospital, Providence, RI, USA
(3)
The George Washington University School of Medicine, 3 Washington Circle NW, Suite 205, Washington, DC, 20027, USA
Andrew T. Goldstein
Email: obstetrics@yahoo.com
Keywords
ManagementHypoactive sexual desire disorder (HSDD)Female sexual interest/arousal disorderTestosterone therapy
21.1 Introduction
Low sexual desire is the most common of the female sexual dysfunctions, with about 10 % of premenopausal women and up to 52 % of postmenopausal women reporting reduced sexual desire [1, 2]. When low desire leads to personal distress and is not related to a psychological disorder, medication, or medical condition, it meets the criteria for diagnosis of hypoactive sexual desire disorder (HSDD) (DSM-IV 2000) [3]. In the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM), female sexual desire and arousal disorders were combined to form one disorder, sexual interest/arousal disorder (SIAD) (DSM-5) [4]. Female sexual interest/arousal disorder (FSIAD ) is characterized by reduced interest in sexual activity, reduced fantasies or thoughts about sex, reduced initiation and/or non-receptivity to partner’s attempts to initiate, reduced sexual pleasure, reduced response to erotic cues, and reduced genital or nongenital sensations during sexual encounters. The decision to combine HSDD and arousal disorder into one diagnosis raised concerns about the accuracy of the diagnosis and how this could affect treatment approaches for women with decreased sexual desire.
HSDD can be linked to situational circumstances, such as dysfunctional interpersonal relationships, or it can be caused by physiologic causes. Often these physiologic causes are iatrogenic, such as decreased androgen levels resulting from oral contraceptive pills or elevated serotonin levels caused by some antidepressants. In older women, HSDD is usually caused by a decline in androgen levels as a result of ovarian failure or following oophorectomy. A transdermal testosterone patch (Intrinsa® ) is approved in Europe and Australia based on clinical trials demonstrating efficacy in treatment of HSDD. Unfortunately, as of March 2015 (when this chapter was written), there are no medications approved by the US Food and Drug Administration (FDA), for the treatment of HSDD or FSIAD. However, there are medications in clinical development for the treatment of HSDD/FSIAD. It is the hope of the authors that one or more of these medications will prove to be efficacious and safe for the treatment of HSDD. As such, one goal of this chapter will be to discuss medications currently being studied for HSDD and the biologic mechanism on which they are based.
21.2 Physiologic Mechanisms of Sexual Desire
Sexual desire (libido) is modulated by the interactions of both sex steroids and neurotransmitters [5]. Although the exact central neuroendocrine mechanisms remain undiscovered, several areas of the brain including the hypothalamus and the amygdala appear important in sexual desire [6]. There are both excitatory and inhibitory factors that can influence sexual desire. Excitatory factors (neurotransmitters and hormones) include testosterone, melanocortin, oxytocin, dopamine, and norepinephrine [7]. Inhibitory factors include serotonin, prolactin, and endogenous opioids. It has been hypothesized that if the excitatory hormone and neurotransmitter levels are high, then sexual behavior is “tipped” in the direction of sexual desire and vice versa [5, 7]. This balance between excitation and inhibition is best described by Perelman’s sexual tipping point model [7].
21.3 Psychosocial Considerations
Normal female sexual desire often requires a safe environment, self-esteem, and an attractive and available partner. Situational HSDD, such as that which occurs with a dysfunctional relationship, external stressors, or loss of a partner, is a common cause of low desire [8]. Situational HSDD from adverse life events, particularly in younger women, can be managed with reassurance or relationship counseling. Sometimes a new and attractive partner is all that is needed. It is important that this issue be acknowledged and placed in context while the life events right themselves. Depression and other major psychiatric conditions can be serious or even life threatening [9, 10]. These disorders need to be identified and managed by a skilled psychiatrist or sex therapist. In situations where sexual desire is a chronic, long-term problem, more intensive psychotherapy may be necessary.
21.4 Management of Contributing Factors
Although psychological conditions, certain medications, and general medical conditions may cause or contribute to low sexual desire, a diagnosis of HSDD does not technically apply in these cases based upon the DSM definition. A list of conditions and medications associated with decreased sexual desire is presented in Table 21.1. Treatment generally involves managing these inciting factors or discontinuing and replacing offending medications. Patients should be counseled on the sexual side effects with a new diagnosis or initiating therapy that affects sexual function.
Table 21.1
Common contributing factors to low sexual desire
|
Psychological |
|
Depression |
|
Medications |
|
Antidepressants (selective serotonin reuptake inhibitors) |
|
Oral contraceptives |
|
Oral estrogens |
|
Glucocorticoids |
|
Chemotherapy |
|
Aromatase inhibitors |
|
General medical conditions |
|
Diabetes |
|
Hypertension |
|
Obesity |
|
Hypopituitarism |
|
Breast cancer |
|
Premature ovarian failure |
Low desire may be seen in the context of major depression, as well as a result of medications commonly used to treat depression. Antidepressants, particularly selective serotonin reuptake inhibitors (SSRIs) , are associated with decreased sexual desire in a dose-dependent fashion [10]. It may be necessary to adjust dosage levels or replace the medication to decrease sexual side effects. Mirtazapine and bupropion have the lowest rates of associated sexual dysfunction. Mirtazapine, the first noradrenergic and specific serotonergic antidepressant, has fewer sexual side effects than sertraline [11, 12]. Bupropion, a noradrenaline and dopamine reuptake inhibitor, has a low risk of sexual dysfunction, likely related to its limited effect on serotonergic neurotransmission [13, 14].
Oral contraceptives inhibit the mid-cycle surge of testosterone and can be a cause of HSDD in younger women [15]. Some progestins in oral contraceptives also potentiate depression and mood disorders, contributing to decreased sexual desire [16]. Discontinuing combined oral contraceptives and replacing with a long-acting reversible contraceptive option may be warranted. Premature ovarian failure may also be a cause of low sexual desire in younger women [17]. Pelvic floor surgery with musculoskeletal dysfunctions may impair sexual desire through fear of pain or perception of physical deformity. Endometriosis and pelvic adhesions can lead to severe dyspareunia and decreased sexual desire, resulting in an aversion to sex.
In postmenopausal women, oral estrogens commonly used in hormone replacement therapy increase SHBG and bind circulating testosterone, impairing testosterone action and decreasing its effects. Loss of testosterone effect can be a complicating factor in women with HSDD taking oral estrogens. Transdermal estrogens, in contrast, do not affect SHBG in the same manner [16]. Atrophic vaginitis commonly leads to dyspareunia, sexual aversion, and loss of sexual desire.
Decreased sexual desire can result from inadequate treatment or poor control of chronic diseases such as diabetes, hypertension, obesity, hypopituitarism, or breast cancer. Women afflicted with panhypopituitarism and adrenal insufficiency frequently suffer from HSDD [18]. Glucocorticoids suppress adrenal androgen production and may therefore be associated with low desire. Because they induce atrophy of the zona reticularis of the adrenal gland, the androgen suppression can be permanent in women who have been on long-term therapy [19].
Treatment of gynecologic cancer may also result in decreased desire. Pelvic radiation may induce premature ovarian failure, leading to decreased androgens. In treatment of breast cancer, chemotherapy and administration of antiestrogens, such as tamoxifen and aromatase inhibitors, may cause decreased sexual desire [20].
21.5 Role of Androgens in HSDD
In women, approximately half of testosterone is derived from the ovaries and adrenal glands, with the remaining half arising from precursors such as androstenedione and dehydroepiandrosterone (DHEA) through peripheral conversion. About 99 % of circulating testosterone is bound to sex hormone-binding globulin (SHBG) . During the reproductive years, testosterone secretion originates from the theca cells of the dominant ovarian follicle. A mid-cycle rise in testosterone occurs in conjunction with the luteinizing hormone (LH) surge and is directly linked to increased mid-cycle sexual desire, which occurs during the reproductive years but is lost after menopause [21, 22]. As women age, there is a slow and progressive decline in serum testosterone due to decreased ovarian and adrenal function [23]. The levels of prohormones such as DHEA-S and DHEA also fall with increasing age [24]. In addition, SHBG increases after menopause, especially in women treated with oral estrogen therapy, leading to decreased free testosterone [25, 26]. Unlike natural menopause, bilateral oophorectomy is associated with a 40–50 % decrease in serum testosterone levels [23].
21.6 Testosterone Therapy for HSDD
There is abundant research demonstrating that testosterone increases sexual desire and well-being in postmenopausal women with HSDD. Based upon this evidence, the transdermal testosterone patch is approved for treatment of women with HSDD in Europe and Australia. However, in the United States, the FDA has yet to approve a testosterone product for treating HSDD in women. There are many androgen and testosterone products under investigation, compounded preparations, and FDA-approved medications for men, which are commonly prescribed off label for women. Many of these alternative testosterone products are currently in phase 1 and 2 clinical trials .
21.6.1 Oral Testosterone
Methyltestosterone is available in doses of 1.25 or 2.5 mg per day and is usually prescribed in combination with conjugated estrogens (0.625 mg/day or 1.25 mg/day) as Estratest® (Solvay). The use of methyltestosterone is also associated with significant decreases in high-density lipoprotein (HDL) cholesterol and increased total cholesterol/HDL ratio, but a significant decrease in triglycerides. There are limited data but some high-quality, prospective, randomized clinical trial data exist on this treatment approach [27].
Micronized testosterone is available in custom formulations from compounding pharmacies, with oral or sublingual administration, and has been prescribed empirically. Micronized testosterone is generally not well absorbed orally. A buccal formulation (Striant) is FDA approved for use in men. In addition, custom-compounded sublingual and buccal formulations are available, but they have not been evaluated in clinical trials [28].
DHEA is a prohormone (converted to testosterone in vivo) available as an over-the-counter supplement in 25 or 50 mg tablets. Of the nine published randomized trials of oral DHEA for low sexual function in postmenopausal women, three showed a positive effect and the others failed to show a benefit. Although vaginally administered DHEA may improve vaginal atrophy with possible benefit in sexual function, oral DHEA does not have demonstrated efficacy in the treatment of HSDD [29].
21.6.2 Testosterone Matrix Patches
Transdermal testosterone delivered by matrix patch (Intrinsa®, Procter and Gamble) has been the most extensively studied formulation in women with HSDD. There are now seven randomized blinded, clinical trials involving the testosterone matrix patch involving nearly 3000 postmenopausal women with HSDD [30–36]. In the first four trials, the subjects were all women who had undergone oophorectomy [30–33]. Doses of 150 ug/day, 300 ug/day, or 450 ug/day were studied. These dose ranges approximated the lower and upper limits of endogenous testosterone production in premenopausal women.
All trials demonstrated dose-related, significant increases in sexual desire with testosterone patches versus placebo when the dose was maintained at 300 ug/day or greater. At 300 ug/day, the first five trials all demonstrated consistent increases in sexual desire and decreases in distress related to lack of sexual interest with few adverse effects. Interestingly, no treatment effect was seen with the 150 or the 450 ug/day dose, raising the possibility of a dose-response curve for testosterone. Side effects in these first five 24-week trials were minimal and included minor and reversible patch site irritation and hirsutism. A 300 ug/day testosterone matrix patch for women (Intrinsa®) was approved by the European Medicines Agency, the European Union’s equivalent of the US Food and Drug Administration, in 2006. Matrix patches for women, however, are still not available in the United States [37], and it was withdrawn from the European market because of poor sales.
Several alternatives for transdermal testosterone delivery are used off label for women with HSDD. Androderm® and Testoderm® are testosterone matrix patches FDA approved for use in men. These patches deliver supraphysiologic doses in women, which can lead to unwanted androgenic side effects. Some clinicians prescribe these products off label for women by cutting them down to size 1/5th to 1/10th doses. There is extensive information available on this product in men but not women [38].
21.6.3 Transdermal Testosterone Preparations
AndroGel® and Testim® are testosterone transdermal gels that are FDA approved in the United States for use in men. They are sometimes used off label in women by reducing the amount applied to about 1/5th to 1/10th doses. However, testosterone delivery is imprecise, and blood testosterone levels are needed to dose these preparations safely. There is extensive information available on this product in men but not women [39].
Testosterone in pluronic lecithin organogel (PLO) gel for transdermal administration may be compounded to treat women with HSDD. PLO gel testosterone is available in 10 cc syringes or small pumps, both of which deliver consistent dosing. One widely used regimen is testosterone in PLO gel, 32 mg/cc dosed at 1 cc given in the evening. The gel can be applied to the wrists, lower abdomen, thighs, or backs of the knees. These custom preparations require the monitoring of blood testosterone levels to be administered safely. Patients should be monitored clinically and with testosterone levels to document therapeutic delivery and to avoid supraphysiologic dosing. Even though compounded testosterone creams are among the most widely used androgen treatments of HSDD in women, there is only anecdotal information on this practice.
21.6.4 Testosterone Implants and Injectable Formulations
Custom-compounded testosterone pellets are also available for off-label use in women with HSDD. Testosterone implants of 25–100 mg can be purchased from compounding pharmacies. They are inserted subcutaneously with a trocar though a small incision using local anesthesia. The most common dose is 50 mg and the implants remain effective for 4–6 months. Implantation should be guided by monitoring testosterone levels [40].
Intramuscular testosterone injection products are approved for use in men. Testosterone can be injected in a slow-release form as a testosterone ester (cypionate, propionate, and enanthate). Doses are 25–50 mg every 2–4 weeks. In both open and blinded clinical trials, this agent is highly effective for treatment of HSDD, but this treatment requires frequent dosing and testosterone levels are not consistent [41, 42].
21.6.5 Intravaginal Dehydroepiandrosterone
Although oral preparations of dehydroepiandrosterone (DHEA) have not shown consistent benefit, intravaginal administration of DHEA positively affects vulvovaginal atrophy (VVA) as well as HSDD [43, 44]. In a multicenter randomized double-blind placebo-controlled trial of 218 postmenopausal women with VVA, intravaginal DHEA (prasterone) cream inserted nightly for 12 weeks increased sexual desire, arousal, organism, and dyspareunia in a time- and dose-dependent fashion [44]. Daily administration of intravaginal DHEA also significantly improved vaginal atrophy at 2 weeks, with minimal changes in serum estradiol or testosterone levels [45].
21.6.6 Intranasal Testosterone (TBS-2)
A low-dose nasal testosterone gel, TBS-2, has been investigated in women with female orgasmic disorder (FOD), as well as HSDD. In a randomized, parallel group study of 16 women with HSDD, women received five doses of TBS-2 or a testosterone patch for three consecutive days. Women receiving intranasal TBS-2 showed a significant increase in sexual arousal and sensuality as assessed by validated subjective arousal questionnaires compared to women who received the testosterone patch at both 30 min and 4.5 h after administration [46]. Although this medication has been primarily studied in FOD, it also holds promise in treatment of HSDD.
21.6.7 Testosterone with Phosphodiesterase Type 5 Inhibitor (T+PDE5i ) and Testosterone with 5-Hydroxytryptamine1A Receptor Agonist (T+5-HT1Ara )
Single doses of 0.5 mg sublingual testosterone have been shown to increase the sensitivity of the brain to sexual cues. However, in many women, particularly those with HSDD, the effects of testosterone alone may not be sufficient for achieving necessary levels of arousal and desire for sexual activity. While proposed etiologies of HSDD are widely varied, two prominent understandings of HSDD have emerged. The first describes HSDD as the result of an insensitive brain system for sexual cues, and the second assigns responsibility to overactive sexual inhibitory mechanisms [47, 48]. Thus, due to the divergent nature of these etiologies, two therapies are under development.
In a 2012 study conducted by Emotional Brain LLC in the Netherlands, women diagnosed with HSDD were divided into categories of high or low sensitivity to sexual stimuli by testing their preconscious attentional bias for sexual cues using a masked version of an emotional Stroop test. Participants were instructed to name the color of the masked words as quickly as possible and the length of time to vocal response was recorded. Thirty-two unambiguous neutral words from one category (furniture; examples are “chair” and “table”) and 32 unambiguous erotic words (examples are “penis,” “coitus,” and “vagina”) were presented to the participants. The differences between the mean reaction times of the erotic and the neutral words were used to categorize participants as having either “high sensitivity to sexual cues” (reaction time to neutral words < erotic words) and “low sensitivity to sexual cues” (reaction time to neutral words > erotic words) [48].
For women with low sensitivity, efforts were aimed at increasing sensitivity to sexual cues. Sexual stimulation causes the release of nitric oxide (NO) from nerves and endothelium, resulting in an increase in cyclic guanosine monophosphate (cGMP). The rise in cGMP is key in the relaxation of smooth muscle for the engorgement of erectile tissue. Phosphodiesterases (PDE5s) hydrolyze cGMP, and consequently PDE5 inhibitors (PDE5i’s) prolong the action of vasodilation. In order for PDE5i’s to act on vasodilation, central stimulation must be present. Thus, testosterone, which increases the brain’s response to sexual cues, combined with PDE5i, aimed to enhance genital sexual response, was coupled in a coinciding time-delay manner and tested in a double-blind, placebo-controlled crossover study with 56 women with HSDD [48].
Women were treated with testosterone 0.5 mg and PDE5i (sildenafil 50 mg) (T+PDE5i) 4 h prior to sexual activity. Participants were permitted to use the medication up to 14 times during a 4-week period with a minimum of 48 h between doses. Women taking the T+PDE5i for 4 weeks had an improved physiological and subjective sexual response as measured by institutional psychophysiological lab standards and by at-home evaluations as compared with women taking placebo. More specifically, participants on T+PDE5i showed increased preconscious attention for sexual cues as well as statistically significant increases in subjective sexual function, such as genital arousal and desire. Additionally, participants who were found to have low sensitivity to sexual cues demonstrated much greater benefit from T+PDE5i therapy than women assessed as having high sensitivity to sexual clues who did not have an increase in intensity or satisfaction of sexual events [48, 49].
In addition to being assigned to treatments of T+PDE5i and placebo for 4 weeks each, women in the trial were given 4 weeks of testosterone with 5-hydroxytryptamine1A receptor agonist (T+5-HT1Ara). The T+5-HT1Ara treatment was aimed at addressing overactive sexual inhibition processes. Serotonin or 5-hydroxytryptamine (5HT1A) is neurotransmitter important for mediating inhibitory mechanisms localized to the prefrontal cortex (PFC). As the PFC is an important regulator of inhibition and as 5HT1A is a critical neurotransmitter in the PFC, it was hypothesized that acute treatment with a 5HT1Areceptor agonist (5HT1Ara) could limit the effects of 5HT1A, thereby decreasing inhibition of sexual response. After acute administration, 5HT1Ara binds to somatodendritic autoreceptors of the raphe nuclei in the midbrain. The hyperpolarizing effect of activated 5-HT1A autoreceptors decreases both serotonergic firing activity and inhibition of serotonin release from the presynaptic terminal thereby reducing serotonin levels in the PFC. In a similar fashion to the T+PDE5i treatment, T+5-HT1Ara was designed to act maximally 3–6 h after administration [50].
In participants considered to have high inhibition, taking T+5-HT1Ara showed statistically significant increases in sexual satisfaction, desire, genital arousal and sexual function, and vaginal pulse amplitude (VPA) as compared with placebo. In contrast, the low-inhibition group did not show statistically significant changes in these areas. Furthermore, the low-inhibition group showed much greater improvement on these measures with treatment of T+PDE5i [50]. Therefore, as hypothesized, the low-sensitivity group responded best to T+PDE5i, while the high-sensitivity group showed the greatest improvements with the T+5-HT1Ara. Pharmacokinetic studies of the combined T (0.5 mg)+PDE5i showed that maximum concentration of serum total testosterone (mean Cmax 7.84 ± 3.69 ng/mL) was reached in 0.201 ± 0.043 h (time to maximum concentration, Tmax) and the half-life of testosterone (T1/2) was 0.598 ± 0.08 h. Given the relatively low Tmax and short T1/2, it is unlikely that these levels will produce any androgen-related side effects [51].
21.6.8 Safety of Testosterone Therapy
Consensus reports from the Endocrine Society and the North American Menopause Society have been cautionary regarding testosterone therapy in women [52, 53]. There are 60 years of publications and FDA transcripts examining the safety of testosterone administered to women [54–60]. FDA safety concerns focus mainly on cardiovascular and breast cancer risk in lieu of the Heart Estrogen Replacement Study and the Women’s Health Initiative Study. None of the studies report serious adverse effects due to transdermal or implanted testosterone in physiologic doses, even with doses that produce moderately supraphysiologic levels of testosterone [54, 60]. Hirsutism and acne are the major adverse reactions, which are dose related and generally reversible with discontinuation of medication. Not only does the literature not support an increased breast cancer risk with testosterone therapy, data may even indicate a beneficial role of testosterone in breast protection. Safety data from controlled studies spanning up to 2 years, as well as observational data from women receiving testosterone with postmenopausal hormone therapy regimens and testosterone-treated female-to-male transsexuals, provide much reassurance.
21.7 Non-testosterone Drugs in Development
21.7.1 Flibanserin
Flibanserin is a nonhormonal therapy that acts on the brain to increase sexual desire. While the exact mechanism of action is not clearly understood, flibanserin is a 5-HT1A agonist and 5-HT2A antagonist. In addition, flibanserin binds with moderate affinity to 5-HT2B, 5-HT2C, and dopamine D4 receptors [61]. This mixed interaction of flibanserin with serotonin and dopamine receptors is thought to inhibit sexually inhibitory serotonergic effects, while promoting dopaminergic effects that are associated with an excitatory impact on sexual function. In addition, serotonin exerts an inhibitory influence over adrenergic tone, and decreased serotonin levels can elevate norepinephrine, which is also known to stimulate sexual function and excitement. It has been suggested that the combined mechanisms of action of flibanserin normalize CNS neurotransmitter levels, enhancing sexual desire.
Flibanserin has been studied in three large phase 3 randomized, placebo-controlled trials [62–64] in which 3548 HSDD patients were treated—2310 with flibanserin and 1238 with placebo. Efficacy endpoints included the number of satisfying sexual events (SSEs) measured by daily electronic diary entries and scores on the desire domain of the female sexual function index (FSFI ). In addition, the trials used a revised version of the FSDS (FSDS-R) that included an additional question (Item 13) to specifically assess distress due to low sexual desire. After 24 weeks of treatment with flibanserin administered in a single daily dose at bedtime of 100 mg, statistically and clinically significant improvement relative to placebo was seen in the number of SSEs, level of sexual desire measured by the FSFI desire domain, and reduction of distress related to low sexual desire measured by FSDS-R item 13. The rate of serious adverse events (SAEs) in the flibanserin groups was ≤0.9 % and no SAE was considered related to treatment. The most common adverse events (AEs) reported by patients were dizziness, nausea, fatigue, and somnolence with frequencies of 9–12 % in the women taking flibanserin [62–64].
21.7.2 Bremelanotide
Bremelanotide (BMT) is a cyclic melanocortin peptide that acts as a melanocortin receptor 4 (MCR4) agonist. Though it was originally designed for sunless tanning, the synthetic analog of melanocyte-stimulating hormone (MSH), which activates the melanocortin receptors MC3R and MCR4 in the central nervous system, was found to increase sexual arousal and desire. During phase 2 trials, BMT administered intranasally showed promising results for the treatment of HSDD and FSIAD; however, reports of elevated blood pressures halted the trial [65].
In a phase 2B trial, BMT was reformulated as a lower dose, subcutaneous injection to measure efficacy for HSDD and/or FSAD treatment in premenopausal women. In a 4-week at-home trial, 1.75 mg BMT showed statistically significant improvements as compared with placebo in five measures of FSD: number of satisfying sexual events per month, total and sexual domain scores on the FSFI, and total and desire domain scores on the FSDS. BMT was associated with minimal and transient increases in blood pressure (~3 mmHg) that were limited to the first four hours after administration. Protocol-defined blood pressure withdrawal criteria were not met at higher frequency in BMT-treated subjects than in those taking placebo. Further studies on BMT dosing have suggested optimal increases in arousal, desire, and satisfaction with sexual events with 1.25 and 1.75 mg subcutaneous injections. At these doses, adverse events included nausea (22 % and 24 %, respectively), placebo 3 %; flushing (14 % and 17 %, respectively), placebo 0 %; and headache (9 % and 14 %, respectively), placebo 3 % [18, 19]. MC3R and MCR4 receptors are involved in many physiological systems and there may be theoretical risks of activating these receptors [65]. The long-term effects of BMT are unknown.
21.7.3 Bupropion with Trazodone
Although certain antidepressants may contribute to HSDD, restoring the balance of dopamine, serotonin, and norepinephrine may play a role in regulation sexual inhibition and exhibition. S1 Biopharma is investigating the combination of bupropion and trazodone for treatment of HSDD in phase 2a clinical trials, although no data is currently available.
21.8 Conclusion
Low sexual desire in women has many causes and contributing factors. Treatment should focus on identifying and addressing these conditions. While HSDD may be related to situational factors in young women, medications such as oral contraceptives and antidepressants are also common causes. HSDD in postmenopausal women is likely due to androgen deficiency. Testosterone therapy is the mainstay of treatment for these women, but most preparations are investigational or given off label, despite a reassuring safety and efficacy profile. There are a number of drugs currently in phase 2 and 3 clinical trials that show promise in treatment of HSDD. Continued research and long-term safety data are likely necessary to obtain FDA approval of a medication for the treatment of HSDD.
Commentary: Management of Hypoactive Sexual Desire Disorder (HSDD)
Marianne Brandon4
(4)
Wellminds Wellbodies, LLC, Annapolis, MD, USA
Hypoactive sexual desire disorder (HSDD), now part of the controversial new DSM-5 condition termed female sexual interest/arousal disorder (FSIAD), is one of the most common yet vexing female sexual dysfunctions to treat. This is due in part to the nuanced complexity of the interplay between physical and psychological factors that contribute to desire, as well as to our imperfect understanding of all etiologies of this condition. Given this complexity and multifactorial nature, HSDD/FSIAD represents a prototype condition benefiting from a biopsychosocial approach merging medical with psychotherapeutic treatments.
In the preceding chapter, Krapf, Goldstein, and Buster outline the known physiology of sexual desire, highlighting the excitatory and inhibitory neurotransmitters and brain regions essential in determining sexual desire. Discussing the known causes of low desire, including medications and medical conditions, the authors then segue into a discussion of the prominent role of androgens in sexual desire, providing a detailed discussion of current and upcoming treatment options for low desire. In the following complementary commentary, the broader approach to FSIAD is outlined, with a clear perspective on the rationale behind how and why obtaining a detailed sexual history is so critical to appropriate and complete treatment of this condition. How to merge medical and psychotherapies is then outlined, so that the reader develops a comprehensive overview of how to approach FSIAD.
Commentary
Drs. Kraph, Buster, and Goldstein offered an excellent and thorough review of the physiologic management of hypoactive sexual desire disorder in women. As they indicated, the assessment and treatment of psychosocial etiologies are equally important in the care of patients with desire concerns. Indeed, it was Dr. Goldstein himself who introduced the biopsychosocial model to me many years ago as I embarked on my specialization in sex therapy. This commentary will summarize an approach to assessing and treating the psychosocial aspects of desire disorders in women.
Most sexual medicine professionals would likely agree that desire disorders are among the most difficult to treat—largely due to the complex and often subtle psychological, relationship, and contextual dynamics that can interfere with libido. In spite of these challenges, surveys suggest that the majority of men and women consider sexual intimacy to be a vital aspect of a romantic relationship [1], and sexual satisfaction correlates with relationship satisfaction and life satisfaction [2]. As such, the experience of low desire can be extremely upsetting for a woman and/or her partner. In fact, fully one-third of women with low desire express distress about their lack of sexual interest [3]. Many of the women with low desire that I have worked with ruminate about this problem daily, feel tremendous guilt about depriving their partner of a critical aspect of intimacy, worry that their partner will leave or have an affair because of a lack of intimacy, and/or miss what was once a profound intimate experience making them feel vital, alive, and connected to their partner. However, it can also be the case that a woman’s distress about her low desire is the result of her partner’s negative reactions and she herself is not bothered by her lack of interest.
The diagnostic criteria for low desire in women have recently been modified from hypoactive sexual desire disorder (HSDD) as defined in the DSM-IV-TR [4] to the current DSM-5 classification of female sexual interest/arousal disorder (FSIAD) [5]. This recent modification is not without significant controversy. How to diagnosis low desire and even whether or not to regard low desire as a diagnosis in women [6] will likely remain contentious issues in the field of sexual medicine for some time. Indeed, female sexual medicine is a relatively new field, with still many unanswered questions. For example, recent research suggests that asexuality, or the absence of sexual attraction, may be normative for a subset of the population [7]. More research is clearly needed to clarify this hypothesis.
Currently, the diagnostic criteria for FSAID must include symptoms in at least three of the following categories: reduced interest in sexual activity, reduced fantasies or thoughts about sex, reduced initiation and/or non-receptivity to partner’s attempts to initiate, reduced sexual pleasure, reduced response to erotic cues, and reduced genital or nongenital sensations during sexual encounters. These symptoms must persist for a minimum of 6 months, cause a woman significant distress, and not be attributable to a mental disorder, medication, or substance abuse. Diagnosis also requires specification of whether the disorder is lifelong or acquired and generalized or specific to a situation and severity is rated as mild, moderate, or severe.
The assessment of low desire can be challenging for many reasons, not the least of which is a disturbing lack of training opportunities for physicians [8]. Time constraints, limitations on insurance reimbursement, and the potential awkwardness of discussing a patient’s intimacy concerns may also inhibit practitioners in assessing FSAID [9]. There are a variety of reliable and valid questionnaires that can assist in this process, including: the sexual interest and desire inventory-female (SIDI-F) [10], the decreased sexual desire screener (DSDS) [11], the female sexual distress scale-revised (FSDS-R) [12], and the female sexual function index (FSFI) [13].
Three principles may be considered the foundation for taking a sexual history: using a patient-centered approach, offering evidence-based diagnostic and treatment recommendations, and using a unified management approach for treatment [9]. Adherence to these basic principles ensures that the patient feels understood and receives state-of-the-art medical care. Desire concerns may cut to the core of her identity, as lovemaking is when she is most vulnerable and exposed. Thus, issues relating to her sexuality may be among the most difficult topics she will discuss with a medical professional in her lifetime.
In taking a sexual history, it is of course essential to maintain cultural and religious sensitivity, as well as to avoid an assumption of heterosexuality. It is also necessary to remain aware of your voice tone and other nonverbal cues that communicate information. As much as she is seeking relief for her symptoms, a patient may be acutely aware of your reactions and adjust her responses accordingly. A woman may thus not offer all necessary information during the initial assessment period, and instead, her story may unfold over multiple appointments. Indeed, she may not be ready to acknowledge to herself, or verbalize to another, information that is critical in understanding her low desire. For example, perhaps she is having an affair, or she is disgusted by the way her genitals changed following a traumatic childbirth, but she is too ashamed to admit this. Acute sensitivity when responding to her concerns is necessary.
A sexual history provides the practitioner with information to answer three critical questions: whether or not the patient has a disorder, what underlying organic and psychogenic factors contribute to the disorder, and whether or not the patient should be treated [14]. The sexual tipping point [15] is one comprehensive guide for evaluating the role that multiple biopsychosocial influences may have on the etiology of a woman’s low desire. This model conceptualizes low desire as being impacted by physiological, organic, psychosocial, and cultures issues. Thus, a woman’s psychological and medical health, the quality of her romantic and sexual relationship, and issues relating to the context of her life are all given consideration.
It is useful to ask a woman her understanding of her low libido and what, if any, treatment she has previously attempted. However, be prepared to probe her responses further. For example, it is not unusual for a patient to initially state, “Everything is perfect in my relationship except for my lack of desire,” only to verbalize upon further exploration that significant challenges involving such essential dynamics as power, trust, physical attraction, sexual technique, communication, or respect do exist but are difficult for her to articulate. The context of her current life is also relevant, including her stress level, sexual dysfunction in her partner, and parenting or eldercare responsibilities that can all interfere with her desire to make love. Historical issues relating to her sexual debut [16] or past trauma [17] can also impact her current experience of desire. In sum, sex drive can be a sensitive barometer of balance in just about any aspect of a woman’s life.
A thorough assessment enables a practitioner to determine whether or not treatment is indicated and, relatedly, which treatments to recommend. The biopsychosocial model of care necessitates that a woman’s psychological and biological treatment needs are all attended to. This is essential regardless of the etiology of a patient’s low desire. Ultimately, physiological etiologies have psychological ramifications, just as psychological issues eventually impact a woman’s biology [9, 18].
The initial phase of treatment may include education about FSAID, including a conversation about the differences between spontaneous and responsive sexual desire [19]. Specifically, it is considered non-dysfunctional for some women to feel open and responsive to a partner’s advances without ever feeling the spontaneous desire for sex. Prepare the patient that she will function as an active member of her treatment team, which will likely include a medical professional and sex therapist. Discussing the relatively high rates of sexual dysfunction and dissatisfaction in the general population [20] may help her feel less alone.
It will be helpful to have a list of qualified therapists as referral sources that you can offer your patient at this time. Even if your patient does not meet the diagnostic criteria for a sexual dysfunction, she may be struggling with her own or her partner’s expectations about her sexual function, and thus it is likely that a psychotherapy referral will be helpful. On this list you can include the organizations offering sex therapist referrals: the American Association of Sex Educators, Counselors, and Therapists (www.AASECT.org), the Society for Sex Therapy and Research (www.SSTARnet.org), and the International Society for the Study of Women’s Sexual Health (www.ISSWSH.org). You may also identify local therapist referral sources by contacting your state psychological association.
Therapists approach the treatment of low desire in women from a variety of perspectives. A focus on the development and cultivation of sexual excitatory mechanisms to support libido is generally more beneficial than attempting to decrease the inhibitory mechanisms making sex less appealing for her [21]. Evidence-based practice includes the development of mindfulness skills [22], therapy groups that focus on communication skills training, sensate focus, fantasy training, intimacy exercises and education [23, 24], and/or an intersystems model addressing familiar and intergenerational influences to low desire [25, 26]. Therapists will make decisions regarding whether individual therapy, couple therapy, or both are necessary. Patients may report that their progress in reaching their treatment goals is variable, in part because the desire disorders exhibit a strong placebo response [27] and in part because, as previously described, the etiologies of desire disorders can be so complex and multi-determined.
In sum, low desire concerns in women are classic mind-body phenomenon, requiring an integrated biopsychosocial treatment approach [28]. Communication among members of the treatment team is strongly encouraged, as it will help to ensure that the patient’s unique needs are being addressed. For further training opportunities in female sexual medicine, please see the International Society for the Study of Women’s Sexual Health (www.ISSWSH.org).
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