Understanding and Treating Female Sexual Dysfunction: An Update on Current Literature

INTRODUCTION

Sexuality is important to the quality of life of human beings, and sexual problems are common in women across all ages. Female sexual dysfunction (FSD) is an umbrella of conditions that may affect as many as 40 million women in the United States, with a community prevalence ranging from 30% to 80%.^1-5 There are several specific sexual dysfunctions that occur among women including hypoactive sexual desire disorder (HSDD), female sexual arousal disorder, female orgasmic disorder, and pain during sex, all of which are persistent, recurrent problems and cause personal distress.⁶ A woman may have one sexual disorder or one primary dysfunction and other comorbid conditions. HSDD is the most prevalent sexual dysfunction in women, impacting 1 in 10 women across all ages.^7,8 HSDD significantly reduces quality of life and self-worth, leading to profound societal and economic impact on patients.⁹ Sexuality is best understood from a biopsychosocial perspective and there can be a variety of etiologic causes of sexual problems including physiological and psychological causes of sexual problems, as well as diseases having downstream consequences on sexual function such as multiple sclerosis, autoimmune disorders, diabetes, and the use of medications such as antidepressants, anxiolytics, or anti-hypertensives.^2,5,10-12 By understanding the overlapping biopsychosocial etiologies, providers can determine the underlying causes of FSD and select appropriate treatment.¹³ Treatment is often multidisciplinary, including medical and psychological interventions. Despite its prevalence, health care providers struggle with asking about sexual concerns and treating sexual dysfunctions. This is due to several factors, including: lack of awareness of the latest guidelines; the uncomfortable nature of discussing the topic with patients; and the limited number of safe, effective therapies approved by the Food and Drug Administration (FDA).⁷ Flibanserin is currently the only FDA-approved treatment for premenopausal women with HSDD. Comparatively, there are more than two dozen medications commercially available for male sexual dysfunction; however, there are currently more than 70 clinical trials recruiting patients for clinical trials designed to evaluate treatments or determine prevalence of FSD.  

PHYSIOLOGY OF SEXUAL FUNCTIONING

There are a number of models posited to describe a healthy sexual response and most include at least three phases of sexual functioning: (1) desire; (2) arousal, which can occur in the brain and in the periphery; and (3) orgasm. These are impacted by excitatory neurotransmitters and hormones and inhibitory neurotransmitters and hormones.¹⁴ The primary hormones that have a positive effect on sexual functioning are estrogen, testosterone, and oxytocin. Estrogen and testosterone levels change throughout the menstrual cycle, peaking midcycle to improve receptivity and desire at the time when a woman is most fertile. Melanocortins also have a positive impact on dopamine and norepinephrine function (Figure 1).¹⁴

Figure 1. The primary hormones that have a positive effect on sexual functioning are estrogen, testosterone, and oxytocin. 14

Inhibiting neurohormonal effects on sexual function primarily come from prolactin and from the neurotransmitter, serotonin. Excessive prolactin production, known as hyperprolactinemia, has a negative impact on desire. This is found commonly in women who are breastfeeding or on antipsychotic medications. In the periphery, adequate hormonal function is necessary for functional anatomy, but some neuro- transmitters also have an effect in the periphery. Nitric oxide has a positive effect, as does norepinephrine, but they tend to be negatively impacted by serotoninergic activity. This may involve negative effects on sensation, including hyperalgesia, and diminished sensation in the genitalia (Figure 2).¹⁴

Figure 2. In the periphery, adequate hormonal function is necessary for functional anatomy, but some neurotransmitters also have an effect

Sexual function means being responsive to excitation and inhibition elements, and there are psychological, social, and cultural factors that can turn sexual desire on and off. The physiology of sexual function is a balance between excitatory and inhibitory chemicals. Physiologic and organic factors that contribute to excitation include: neurotransmitters such as dopamine, norepinephrine, and nitric oxide; hormonal neural modulators, such as oxytocin, vasopressin, and melanocortins; and sex steroids, such as estrogen and testosterone. These work in tandem to allow a sexual tipping point, ie, to become excited.¹⁵ These cellular components and the communication between cells also interact in a network, known as a sexual reward system. It has some specific circuitry, mostly involving glutamatergic projections and GABAergic neurons. Most of this activity involves the medial preoptic area and the nucleus accumbens. The physiology of sexual function includes excitatory chemicals, which are balanced against and blunted by inhibitory systems. These account for periods of sexual refractoriness, primary aversion, or secondary avoidance. Dysfunction occurs with hyperactive inhibition, hypoactive excitation, or both. Dynamic alterations in this balance also may be modulated or reinforced by experience and behavior, which represents neuroplasticity.

LATEST GUIDELINES FOR DIAGNOSING FSD

The Diagnostic and Statistical Manual of Mental Disorders (DSM)-5 reduces FSD classification into three dysfunctions: sexual interest/arousal disorder (which now includes HSDD); genito-pelvic pain/penetration disorder; and female orgasmic disorder (now differs from male sexual dysfunctions). Sexual aversion disorder sexual dysfunction due to a medical condition, and “not otherwise specified” are not included in FSD classification.¹⁶ Patients must experience symptoms of the disorder a minimum of 75% of the time before a diagnosis of FSD can be made (excluding substance-or medication induced disorders). Finally, and importantly, the condition must result in significant distress to the patient in order to qualify as FSD.¹⁶ With a new exclusion criterion and a new group of criteria that includes partner factors, relationship factors, individual vulnerability factors, cultural or religious factors, and medical factors, the DSM-5 has completely changed the sexual dysfunction categorization and,therefore, the subsequent diagnostic guidelines.¹⁶ There are those who disagree with the DSM-5 revisions, and suggest they will inadvertently exclude large numbers of patients with either low desire or arousal issues, but not both.^17,18 Clayton et al further argued some patients would be excluded under the new criteria because they present with an incomplete loss of receptivity.¹⁹ Under the new guidelines, sexual aversion disorder was removed altogether as a sexual dysfunction, in that the similarities between it and other phobias and anxiety disorders were more persuasive.

HYPOACTIVE SEXUAL DESIRE DISORDER

A more appropriate nomenclature for FSD was posited by the International Society for the Study of Women’s Sexual Health.²⁰ Criteria require that an individual with HSDD has any of the following symptoms for at least 6 months: (1) a lack of motivation for sexual activity as manifested by reduced or absent spontaneous desire; (2) reduced or absent responsive desire to erotic cues and to stimulation; or (3) a loss of the desire to initiate or participate in sexual activity. Other symptoms include a lack of sexual thoughts or fantasies, the inability to maintain desire or interest through sexual activity, and avoidance of situations that could lead to sexual activity. These symptoms, and the loss of desire, are not secondary to a sexual pain disorder and must be combined with clinically significant personal distress including frustration, aggravation, grief, incompetence, a sense of loss and/or feelings of anger, sadness, sorrow, dissatisfaction, or worry.²¹

PREVALENCE

Researchers have been studying FSDs for many years. The National Health and Social Life Survey included interviews with 1,749 women between the ages of 18 and 59 years. Approximately 43% of the women interviewed had a sexual complaint; among those, 33% lacked sexual interest, 25% had difficulty achieving orgasm, and 1 in 5 experienced pain during sex. Distress was not evaluated.²² The PRESIDE study did evaluate sexual complaints using the Changes in Sexual Functioning Questionnaire (CSFQ), and the Female Sexual Distress Scale (FSDS-R) to evaluate for sexually associated distress.⁸ The 31,581 female respondents (response rate of 63%), aged 18 years and older were from 50,002 households sampled from a national research panel representative of US women. Greater than 80% of respondents were white, more than half had a high school education, about 75% had a current partner, and 60% were premenopausal. Similar to the Laumann et al study,²² many of the same sexual complaints and problems were reported in the PRESIDE study.⁸ About 33% of respondents had complaints of desire, 25% had challenges with arousal, and 1 in 5 had issues with orgasm. However, when distress was added to the sexual complaint, the numbers dropped significantly: about 10% of women reported distressing low sexual desire and about 5% of women reported distressing low arousal or problems with orgasm function. Pain with sexual activity was not assessed. Extrapolated, this means nearly 50% of female patients will have sexual function concerns. This is not an insignificant problem. It affects many patients, even if they aren’t expressing it during regular office visits. Patients are often uncomfortable discussing sexuality because they are embarrassed and don’t realize it is an appropriate discussion to have with a health care professional. Providers cannot treat a problem if they don’t know it exists, so they must bring up the subject with patients.

MODIFIABLE FACTORS IMPACTING FSD

There are a number of modifiable factors impacting sexual functioning that should be addressed prior to a sexual disorder diagnosis. Various illnesses impact sexual functioning, such as psychiatric conditions, cardiovascular disease, neurological disorders, urological problems, and endocrine dysfunction, such as diabetes and thyroid disease.^23-38 The most common comorbid condition with FSD is depression, which was evaluated in the PRESIDE study. About 40% of the women with complaints of sexual function and distress also said they were depressed or were being treated with antidepressant medications.⁸ After adjusting for prevalence, about 6% of women with distress reported low desire without any comorbid depression, and about 3% of women reported distress plus low levels of arousal or distress with orgasmic dysfunction (Figure 3).³⁹

Figure 3. After adjusting for prevalence, about 6% of women with distress reported low desire without any comorbid depression, and about 3% of women reported distress plus low levels of arousal or distress with orgasmic dysfunction.

Depression and sexual dysfunction have a bidirectional relationship, meaning having one puts the person at increased risk for the other. One meta-analysis looked at more than 1,000 citations but ultimately included only eight; six of which had studies on depression looking at the risk for sexual dysfunction, and six involved sexual dysfunction and the risk for developing major depressive disorder.⁴⁰ Depression was associated with a 50% to 70% increased risk of developing sexual dysfunction, whereas having a sexual dysfunction was associated with a 130% to 210% increased risk of developing major depression.⁴⁰ The take-home message from this 2012 metaanalysis is that patients with depression should be assessed for FSD, and patients with FSD should be assessed for depression. A number of medications also contribute to an increased risk for developing sexual dysfunction, including antidepressants such as selective serotonin reuptake inhibitors (SSRIs), serotonin–norepinephrine reuptake inhibitors (SNRIs), and tricyclic antidepressants (TCAs).^41-49 Cardiovascular medications, such as beta blockers, alpha blockers, diuretics, lipid-lowering agents, and digoxin also contribute to sexual dysfunction. Oral contraceptives can also be associated with sexual dysfunction because of increasing levels of sex hormone-binding globulin, which lowers testosterone, and subsequently, sexual desire. The other medications that are often unrecognized as contributing to sexual dysfunction include chronic use of H2 blockers, opioids, and nonsteroidal anti-inflammatory drugs.^50-52

COMMUNICATION AND SCREENING

There is no “right” time to screen for FSD; it can occur anytime a health care provider feels it appropriate⁵³—no matter the primary reason the patient presented for an exam. It’s important that clinicians normalize FSD and not shy away from the topic out of fear of embarrassing patients. Informing patients that questions about sexual behavior are routine because it’s important to overall health and quality of life is a way of legitimizing the topic.⁵³ Practitioners should be aware when they see a patient who is peri- or postmenopausal that there are many vulvar and vaginal changes associated with menopause and the lack of estrogen to the genitourinary system. These can cause dryness with sexual activity or pain, either with vaginal penetration or touching. Even gentle caressing can be painful for some women. Many women are reluctant to admit to themselves or to their partners that this is an issue. They oftentimes don’t even tell their practitioners, which is why clinicians must broach the issue. It’s important to be mindful of body language and be comfortable with the terminology. Some experts have suggested sitting down rather than standing during these discussions with patients. This helps to convey the message that this is an issue worth making time for. Patients are more likely to answer honestly if the treating physician is comfortable talking about sex. Ask open-ended questions (for example, “What sexual concerns do you have?”), and give the patient time to respond. A moment of silence is normal. It is also imperative not to make assumptions about relationships and sexual partners. Just because a person is not in a relationship doesn’t mean they don’t have a sexual concern. In fact, a lack of involvement in a relationship may be the result of a sexual problem. When talking to patients about partners, use of gender-neutral pronouns is best whenever possible. Screening does not take long. When the individual has a sexual complaint, sexual assessments should include the following: • What is the nature of the problem, and what is the nature of the complaint? • Are there multiple complaints? • Does the complaint involve several phases of the sexual response cycle? • What is the duration of the problem? • How did the problem begin? Did it begin at a specific time with a situational change, with a diagnosis with another medical condition, postpartum, or the addition of a medication? • Is that complaint situational? Does it just involve a single partner in certain situations? • Is the complainant generalized, impacting all sexual situations? • What is their level of distress, and what is the nature of the distress? Did they previously have what they considered an adequate level of function such that they were satisfied? The Decreased Sexual Desire Screener (DSDS) is a simple and effective HSDD screening tool consisting of five questions and takes about 3 minutes to complete (Figure 4).⁵⁴ The first four questions relate to the following areas: (1) level of desire and satisfaction; (2) presence of decreased desire; (3) tolerance of decreased desire; and (4) need for improvement of desire. The fifth question looks at potentially modifiable variables. Some of these variables may be either the cause of lost sexual desire or corollary conditions. The answers to question five may help to provide information that helps address causative factors or conclude that the patient needs psychotherapy or pharmacologic treatment options. For example, if there’s dissatisfaction with the relationship of the partner, counseling may be appropriate. Although stress and fatigue are not specific risk factors, they may require workup.  

Figure 4. The Decreased Sexual Desire Screener is a simple and effective screening tool consisting of five questions and takes about 3 minutes to complete

If modifiable factors are present, such as a medical or psychiatric diagnosis, medications or other substances, these should be addressed prior to making a diagnosis or interventions for the sexual complaint. A physical exam may be needed if there are complaints of arousal or orgasmic dysfunction or sexual pain.

INTERVENTIONS IN FSD

The current standard of care for patients suffering with HSDD fall into several different categories, including nonpharmacological approaches and prescription medications.⁵⁵ Nonpharmacological treatments include counseling, psychotherapy, mindfulness training,and cognitive behavioral therapy (CBT). Many women use over-the-counter treatments for sexual dysfunction. These products are unregulated and have illustrated little efficacy above and beyond their placebo effect in clinical trials.⁵⁶ Until recently, all prescription medications, such as testosterone, bupropion, and buspirone, were used off-label in the treatment of HSDD. Flibanserin is now an FDA-approved option for HSDD in premenopausal women. NONPHARMACOLOGICAL TREATMENTS Sexual dysfunction can be the result of psychological, interpersonal, and/or biological factors. CBT is a straightforward treatment that may help women alter negative thoughts, beliefs and expectations that can interfere with sexual desire. It can help overcome negative beliefs about sex, improve communication with their partners, and resolve other underlying issues. There are a limited number of studies looking at psychotherapy in the treatment of FSD and HSDD, none of which utilize an adequate control paradigm. However, CBT and mindfulness-based therapy appear to have some utility based on open-label treatment studies.^57,58 Many women have sexual dysfunction as a result of abuse or negative experiences with past or current partners. Incorporating couples counseling into treatment can oftentimes bring those issues to the forefront. Couples who have had long-term sexual problems may have a number of new communication barriers related to the sexual dysfunction that didn’t exist before the dysfunction. In our cumulative experience, we have found couples therapy can be extremely helpful in those cases. If psychotherapy is deemed unnecessary or is ineffective, then it is reasonable to go directly to pharmacotherapy. Some experts have discussed combining psychotherapy with medication, but there are no good data to support this approach—yet. PHARMACOLOGIC TREATMENTSMeasuring Sexual Function The FDA evaluates pharmacologic treatments based on safety and efficacy and requires sponsors of investigational drugs to use validated measures of sexual function and distress in clinical trials. The Female Sexual Function Index desire domain (FSFI-D), the Female Sexual Distress Scale-Revised (FSDSR), and the number of satisfying sexual events (SSEs) are the most commonly used measures and were measures used in the pivotal trials for flibanserin. The FSFI is a 19-item, self-reported measure based on the prior 28 days and is validated by total score and subdomains including desire, arousal, lubrication, orgasm, pain and satisfaction. The FSDS-R was revised in 2008 to address low desire with the question, “How bothered are you by your low desire, and rate that as zero, one, two, three or four as never, rarely, occasionally, frequently, or always.” An SSE is defined as sexual intercourse, oral sex, masturbation,or genital stimulation by the partner with determination by the woman as to whether the event was gratifying, fulfilling, satisfactory, or successful; orgasm is not a requirement to meet this definition. Therefore, SSEs are not necessarily a reflection of desire, despite the FDA’s classification. SSEs were derived for this use from an erectile dysfunction model of successful sexual eventswhen drugs such as sildenafil citrate, vardenafil hydrochloride, and tadalafil were developed. It was easy to count whether a man had an adequate erection because his penis either was or was not rigid enough for intercourse. Desire is difficult to measure and is not necessarily a reflection of the number of SSEs that occur, in that SSEs may be removed from desire. For example, a woman may be very desirous but may not have a sexual event because her husband is out of town or she’s upset with him. Women may experience significantly improved desire or even arousal, but not choose to engage in sexual behaviors for a variety of different reasons, whether they are practical, behavioral, or interactional.⁵⁹Flibanserin Flibanserin is a multimodal agent of 5-hydroxytyptamin (5-HT)serotonin type 1A receptors and an antagonist of 5-HT type 2A receptors. Originally in development as an antidepressant, the compound was not more effective than placebo in treating major depression, but was found to improve scores on sexual desire endpoints. The mechanism by which the drug improves sexual desire and related distress is not known but is hypothesized to increase dopamine and norepinephrine (excitatory systems) and decrease serotonin (inhibitory neurotransmitter) in the prefrontal cortex.^60,61 The BEGONIA study⁶² compared flibanserin 100 mg once daily (n = 542) to placebo (n = 545) for 24 weeks. The average patient in the trial was 36 years old with generalized, acquired HSSD who had reduced or absent interest in sexual activity for about 5 years. The lack of desire couldn’t be explained by a drug, device, fatigue, recent birth, breastfeeding, or a hormonal imbalance. All patients in the trial were in a stable, monogamous relationship for at least 1 year, with an available sexually functional partner willing to try sexual activity one or more times a month. According to the study findings, the lack of desire didn’t prevent them from having some SSEs.⁶² Patients were having sex about five times a month whether or not they had interest, with 2.5 SSEs per month at baseline. Patients with female sexual arousal disorder (FSAD) and female orgasmic dysfunction (FOD) as their primary dysfunction were excluded. However, these patients were included in the study if FSAD and FOD were found to be secondary to their low desire. Flibanserin 100 mg at bedtime significantly increased the number of SSEs compared with placebo beginning at week 4, and continued to endpoint at 24 weeks. In addition, the desire score on the FSFI also increased by the fourth week of treatment.⁶² Flibanserin is currently the only FDA approved treatment for HSDD in premenopausal women.⁶³ The most common adverse events, somnolence, nausea, and fatigue, which occurred in about 10% of patients (Figure 5). Most of the adverse events were transient or episodic, mild to moderate in severity, and decreased over time. Flibanserin is also associated with weight loss, although the exact mechanism for why remains unknown. Flibanserin should not be mixed with alcohol due to hypotension or syncope-related adverse events.⁶² Clinically significant adverse events of hypotension and syncope were observed in three phase 1 studies of flibanserin that involved daytime dosing and either high exposure due to coadministration of a CYP3A4 inhibitor, direct administration of a supra-therapeutic dose of flibanserin,or concomitant significant alcohol use.⁶³

Figure 5. The most common adverse events in the phase 3 flibanserin trials included dizziness, somnolence and nausea. Most were mild to moderate in intensity and most began within the first 14 days of treatment.

The FDA has required a Risk Evaluation and Mitigation Strategy(REMS) to ensure the benefits of flibanserin outweigh the increased risk of hypotension and syncope due to an interaction with alcohol.⁶⁴ The side-effect profile has added to the debate about the drug,⁶⁵ but literature confirms the role the medication may play in women’s health.^63,66 Although increasing effects continue beyond 12 weeks of dosing, if no response is seen by week 8 of treatment, continued administration is not likely to be effective, according to the clinical data. Several other studies were used as pivotal studies for the FDA approval, such as SUNFLOWER, VIOLET, and DAISY.^67-69 All studies showed that flibanserin increased desire in 46% to 60% of patients (Figure 6). About 46% reported an increase in SSEs, 50% had an increase in their FSFI desire score, and about 60% had a decrease in sexually related distress.

Figure 6. The results were highly significant. By 24 weeks, 46% to 60% of patients had significant benefit from flibanserin when applying this responder analysis.

There were three significant study endpoints, according to the FDA: the number of SSEs, the impact of the treatment on desire, and the impact of the treatment on lowering distress. In each of these trials, the flibanserin group (100 mg at bedtime) was superior to placebo in the rise in number of SSEs, increased sexual desire, and decreased sexual distress. These were reproducible finding across all three of clinical trials (Figure 7).^{62, 67, 68} Testosterone Testosterone is commonly used as an off-label treatment for low sexual desire in postmenopausal women, and it has been shown to increase and improve sexual activity. ⁷⁰ Prior to the availability of flibanserin, trials were conducted for a testosterone patch with a 300-μg dose of transdermal testosterone for the treatment of HSDD in naturally and surgically postmenopausal women. Transdermal testosterone was studied in a number of placebo-controlled, randomized clinical trials.^71-73 Clinical trials of the testosterone patch showed a statistically significant increase in the number of SSEs and sexual desire, and a decrease in sexual distress. Although transdermal testosterone was never approved in the United States due to unrealized concerns regarding long-term safety, it was made available in Europe, and a number of additional studies were performed there. One such study was the APHRODITE trial.⁷⁴ Results showed that testosterone use in postmenopausal women with HSDD not only increased desire, but also statistically and significantly increased arousal, orgasm, and pleasure. It also reduced sexual concerns and increased sexual responsiveness and the woman’s self-image. Testosterone safety was assessed over 48 months. There were no clinically relevant changes in lipids, liver function tests, hematology, or carbohydrate metabolism. There was a small increase in blood pressure (< 2 mm Hg). There was also an increase in the rate of breast cancer, which was expected given the Surveillance, Epidemiology, and End Results database and the increase in the frequency of breast cancer with age.⁷⁴

Figure 7. In each of the three pivotal trials, the flibanserin group (100 mg at bedtime) was superior to placebo in the rise in number of SSEs, increased sexual desire, and decreased sexual distress.

Bupropion and Buspirone Bupropion and buspirone are two off-label mediations that have historically been used for treating HSDD. Bupropion is a norepinephrine-dopamine reuptake inhibitor that results in increased norepinephrine and dopamine function, and has been shown in small clinical trials to improve sexual function.^75-77 Bupropion sustained release 400 mg/day demonstrated an increase in arousal and orgasm scores in women with HSDD that were statistically significantly better than placebo over the course of a few months of treatment.⁷⁷ Buspirone is a unique partial agonist at the 5-HT1A receptor, which is associated with increased sexual desire. Buspirone has been shown to improve sexual function when added to SSRIs for treatment of depression, specifically for patients whose sexual dysfunction persisted despite improvement in their depression.⁷⁸ Landén et al showed that 58% of subjects treated with 30 to 60 mg/day of buspirone reported an improvement in sexual function, compared with 30% treated with placebo.⁷⁹ One important consideration is that dopamine receptor agonist drugs have a strong signal associated with impulse control disorders (n = 710; PRR = 277.6, P < .001).⁸⁰ The association was strongest for the dopamine agonists pramipexole (n = 410; PRR = 455.9, P < .001) and ropinirole (n = 188; PRR = 152.5, P < .001), with preferential affinity for the dopamine D3 receptor. A signal was also seen for aripiprazole, an antipsychotic classified as a partial agonist of the D3 receptor (n = 37; PRR = 8.6, P < .001). Increases in dopamine and have been associated with hypersexuality, in pathological gambling, and compulsive shopping.⁸⁰ There are many more studies under way with additional treatment options with unique mechanisms of action being investigated for future FDA approval.

MANAGING EXPECTATIONS

Once a patient has been identified as a candidate for treatment, it’s important to manage expectations through education that under promises and over delivers. Most patients will see some benefit in 6 to 8 weeks on medication. Focusing on when the patient is likely to see a benefit is more effective than discussing how beneficial the treatment may be. This approach sets low expectations for what a treatment is going to do, but gives patients a time frame for any anticipated changes.

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