Seth D. Cohen1 and Irwin Goldstein2
(1)
Advanced Urological Care, New York, NY, USA
(2)
San Diego Sexual Medicine, San Diego, CA, USA
Irwin Goldstein
Email: dr.irwingoldstein@comcast.net
Keywords
DiagnosisManagementFemale sexual arousal disorderForward-looking infrared
Commentary by Annamaria Giraldi, M.D., Ph.D., F.E.C.S.M.
22.1 Introduction
Women have more sexual health concerns in general than men, and women with sexual health problems have significant impairment of their life quality [1]. Ironically, the study, diagnosis, and treatment of women with sexual health concerns are limited. Following Masters and Johnson’s groundbreaking work in the early 1970s, there was a flurry of scientific inquiry into the etiology and treatment of female sexual dysfunction [2]. With the introduction of an oral treatment for erectile dysfunction, sildenafil, a second wave of scientific enthusiasm regarding female sexual dysfunction evolved. Now with the support from various medical and surgical societies like the International Society for Sexual Medicine (ISSM) and the International Society for the Study of Women’s Sexual Health (ISSWSH) , new treatment models are being studied and utilized to treat female sexual problems.
Although female sexual arousal disorder (FSAD) is prevalent, it is often not well defined or understood. The current definition of FSAD discussed below is based on the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition Revised (DSM-IV-TR), which includes a requirement that the woman has concomitant distress. According to the DSM-IV , the diagnostic criteria to define sexual arousal disorder are (1) persistent or recurrent inability to attain, or to maintain until completion of the sexual activity, an adequate lubrication-swelling response of sexual excitement, (2) the disturbance causes marked distress or interpersonal difficulty, and (3) the sexual dysfunction is not better accounted for by another axis I disorder (except another sexual dysfunction) and is not due exclusively to the direct physiological effects of a substance (e.g., a drug of abuse, a medication) or a general medical condition [1, 3, 4]. Oftentimes medications such as selective serotonin reuptake inhibitors (SSRIs) can lead to such sexual dysfunctions including arousal and desire dysfunction. Thus, the DSM definition of arousal disorder may be limited in its ability to appropriately classify some of these patients.
It is worth noting that FSAD is rarely a solitary diagnosis. Since hypoactive sexual desire disorder (HSDD) is frequently diagnosed in these patients, a new disorder was proposed for the DSM-5: sexual interest/arousal disorder [5].
The term sexual arousal has been labeled in a variety of ways [6, 7]. Some authors discuss sexual arousal as if it is synonymous with genital arousal ; however, it, and possibly orgasm, involves (1) information processing of relevant stimuli, (2) arousal in a general sense, (3) incentive motivation, and (4) genital response [3]. Desire may be experienced once sexual stimuli have triggered arousal. Arousal and desire co-occur and reinforce each other. Women’s subjective arousal may be minimally influenced by genital congestion. Some experts in the field of women’s sexual health feel that women do not assess their experience of arousal to any large extent from genital sensations; this appears to be especially so at low and moderate levels of arousal. Genital engorgement becomes more important for women at higher levels of arousal [2]. An absence of desire any time during the sexual experience designates disorder. Arousal disorder subtypes are proposed that separate an absence of subjective arousal from all types of sexual stimulation, from an absence of subjective arousal when the only stimulus is genital [3].
Most current research on sexual arousal in women assumes that the lack of sexual arousal is due to a lack of excitation, with little attempt to differentiate between inhibited sexual desire and lack of desire [8]. According to Bancroft and Jensen’s research on the central nervous system’s response to sexual excitement, it is the balance between excitatory and inhibitory systems that determines whether sexual arousal occurs [9, 10]. In addition, the authors postulate that individuals vary in their propensity for both sexual excitation and inhibition. The voluntary inhibition of sexual response can be seen as an adaptive trait, as a means for an individual to avoid risks that would be associated with a given situation. However, for some, sexual inhibition can be uncontrollably elevated, resulting in significant stress and bother as in cases of persistent genital arousal disorder [1].
The cause of FSAD is multifactorial and may include psychological problems such as depression or anxiety disorders, relationship conflicts, partner performance and technique problems, issues relating to prior abuse, medical illness, medications, menopause, stress, or gynecological problems that make sexual activity uncomfortable.
22.2 Etiology
Maintaining sexual health during menopause is a challenge because the progressive decline in sex hormones interacts with the aging process. The biological changes in hormone levels, specifically the decrease in estrogen in menopausal women, and the vaginal changes that ensue as a result can significantly affect arousal. Menopause occurs when the ovaries stop producing estrogen, the hormone that controls the reproductive cycle. Anything that damages the ovaries or blocks estrogen effects can cause premature menopause. This includes chemotherapy in the setting of malignancy or surgery to remove the ovaries; in these cases, early menopause is a side effect [11]. Vaginal atrophy and dryness associated with low estrogen levels can cause arousal to take longer or be harder to achieve. Often the first noticeable change associated with menopause is reduced vaginal lubrication during arousal, as less estrogen results in reduced blood circulation to the vulva, clitoris, and vagina [12]. Lastly, psychological and contextual factors have a significant influence on organic components of sexual arousal.
22.3 Assessment
During the evaluation of women with FSAD, common symptoms range from low interest in sex, decreased arousal and orgasmic capabilities, and diminished genital sensation and blood flow during sexual stimulation as well as pain due to lack of lubrication. When assessing these patients, it is important to address any predisposing factors that can exacerbate or alleviate symptoms. If the patient is in a current sexual relationship, both partners need to be evaluated to understand the aforementioned factors. A multidisciplinary approach is recommended to achieve an optimal outcome. Especially for lifelong sexual dysfunctions like FSAD, developmental sexual abuse and past relationships, as part of the past history, are also very relevant. Lastly, assessing comorbidities that may contribute to the woman’s sexual dysfunction is germane to tailoring an appropriate treatment regimen.
The assessment of female genital arousal is generally considered difficult in comparison with that of men [13]. Arousal and arousal problems are best assessed using a biopsychosocial approach exploring predisposing, precipitating, and maintaining factors with the woman [1]. Levin pointed out that the relationship between vaginal lubrication and sexual arousal is uncertain [14]. Although lubrication does usually increase during sexual arousal, it may not be maintained, especially after a lengthy period of stimulation. Because measuring vaginal lubrication or swelling can be difficult, studies dating back to the 1970s investigating genital response in women have mainly assessed pulse amplitude in the vaginal wall (VPA), using vaginal photoplethysmography [15, 16]. Although reproducible increases in VPA occurred in response to erotic stimuli, subjective sexual arousal was low or nonexistent [17].
Vaginal Doppler ultrasound (US) has been used to assess blood flow changes within vaginal and clitoral tissues. Huang et al. studied blood flow improvement within vaginal tissues after application of local estrogen [18]. The authors used color Doppler flow imaging to observe the flow spectrum of the genitourinary tract in 78 cases of postmenopausal females on local estrogen. The Doppler parameters included the vaginal wall, urethra resistance index (RI), and systolic/diastolic ratios [19].
There is no consensus on recommended routine laboratory tests for the evaluation of women with sexual arousal concerns. Blood testing should be dictated by clinical suspicion based on the history and physical examination. If appropriate, the clinician may assess multiple androgen and estrogen values including total testosterone, free testosterone, sex hormone-binding globulin (SHBG), dihydrotestosterone (DHT), estradiol, and progesterone. Pituitary function may be measured using luteinizing hormone (LH) , follicle-stimulating hormone (FSH), and prolactin levels. Thyroid-stimulating hormone (TSH) should be measured to exclude subclinical thyroid disease.
22.4 Treatment
FSAD is a complex problem with multiple overlapping etiologies. Thus, there are many treatment options with the optimal therapy depending on the etiology of the problem. Available therapeutic options include adjustment of medications, counseling, treatment of depression or anxiety, stress and fatigue reduction, sex therapy, devices, and hormone replacement therapy.
22.5 Hormone Supplementation
There is some evidence pointing to the effect of estradiol on sexual arousability in women [19, 20]. Overall, data suggest that topical or systemic estrogen supplementation is effective and may improve vaginal lubrication and decrease vaginal dryness and irritation. Dennerstein et al. investigated the effects of estrogen and progesterone on female sexual behavior in 49 women who had undergone hysterectomy and bilateral salpingo-oophorectomy in a double-blind placebo-controlled crossover study. Over a 12-month period, each woman received 3 months each of ethinyl estradiol, 50 μg/day; levonorgestrel, 250 μg/day; a combination of the two (Nordiol); and placebo. Significant differences between medications were found with regard to sexual desire, enjoyment, and orgasmic frequency. The most beneficial effects, in terms of improvement in arousal, occurred with use of ethinyl estradiol [17].
Although no androgen therapies are currently approved by the Food and Drug Administration for FSAD, they are being used “off label” in clinical practice. Androgens play an important role in healthy female sexual function, especially in stimulating sexual interest and in maintaining desire. Androgens are also vital for the health and maintenance of vaginal tissues including the vulva, vestibule, and vagina. Thus, many sexual medicine providers use off-label testosterone supplementation to improve FSAD symptoms.
There are multiple reasons why women can have low androgen levels, with the most common being age (menopause), a history of oophorectomy, and the use of oral contraceptives. Symptoms of androgen deficiency include absent or greatly diminished arousal, sexual motivation and/or desire, and persistent unexplainable fatigue or lack of energy. Although there are no androgen preparations that have been specifically approved by the FDA for the treatment of androgen deficiency in women, androgen therapy has been used off label to treat low arousal, low libido, and sexual dysfunction in women for over 40 years.
Although there are sparse data on the role of testosterone in female arousal, there appears to be a considerable positive response to androgens [21]. Historically, androgens were identified predominantly with male sexual function, contributing to a lack of recognition of the effects of androgens in women. Androgens, including testosterone, are necessary not only for reproductive function and hormonal balance in women but represent important precursors for the biosynthesis of estrogens. We know that androgens have multiple biochemical effects in the body including, but not limited to, sexual desire, bone density, muscle mass and strength, mood, energy, and psychological well-being. However, sex steroid hormone actions are quite complex and involve critical enzymes and critical hormone receptors that also determine tissue exposure, tissue sensitivity, and tissue responsiveness.
Systemic testosterone can be administered via transdermal application or intramuscular injection or with a subcutaneous pellet. The dose for any systemic testosterone given to women is at one-tenth the dose administered to men. When checking laboratory values, it is important to keep women’s free testosterone in a range of 0.6–0.8 ng/dl. It is important to discuss with the patient the strategy of serial blood testing to address safety concerns during treatment including any side effects from androgen supplementation.
22.6 Nonhormonal Supplementation
Sexual motivation is encouraged, sustained, and ended by a number of central nervous system neurotransmitter and receptor changes induced, in part, by the action of the central neurotransmitter dopamine. The activation of dopamine receptors may be a key intermediary in the stimulation of incentive sexual motivation and sexual reward. These neurotransmitters and receptor changes in turn activate central sexual arousal and desire. Contemporary animal research reveals that dopamine neurotransmitter systems may play a critical intermediary role in the central regulation of sexual arousal and excitation, mood, and incentive-related sexual behavior. Nonhormonal neuropeptides like oxytocin and prolactin have also been utilized in this clinical setting with good success [6].
Vasoactive agents including phosphodiesterase inhibitors (PDEi’s) have been investigated in several studies for treatment of FSAD. In a small proportion of the studies, women with FSAD endorsed a beneficial effect on arousal, while in most of the studies, vasoactive agents had no effect when compared with placebo. Smaller studies in populations with other medical conditions have shown more consistent effects. As such, PDEi’s may be beneficial in specific groups of women with FSAD (for review, see [4]) [22].
Bupropion , which is a noradrenaline and dopamine reuptake inhibitor with nicotinic antagonist properties originally marketed as an antidepressant, may have a beneficial effect on women with sexual arousal disorder [6, 21]. In one placebo-controlled trial [21], bupropion produced an increase in desire and frequency of sexual activity when compared with placebo. Segraves et al. [6] investigated the role of sustained release bupropion in a randomized, double-blind, placebo-controlled, multiple-site escalating-dose 112-day trial. Outcomes were measured by investigator-rating and self-administered questionnaires. The changes in sexual functioning questionnaire (CSFQ) indicated that bupropion had significant effects on increasing measures of sexual arousal, orgasm, and sexual satisfaction. Traditional antidepressant dosing starts at 150 mg twice a day; however, low-dose bupropion at 75 mg twice a day can achieve an optimal improvement in sexual arousal potential.
Other dopamine agonists used are cabergoline administered at 0.5 mg up to three times per week and ropinirole 0.25 mg administered daily [23]. Oxytocin lozenges, linked to improved arousal and desire, are administered at 250 IU sublingually 30 min to 1 h before sexual activity. Research with oxytocin has shown marked improvement in a number of components of sexual function, including arousal and orgasm. Lastly, amphetamine salts including dextroamphetamine/amphetamine (Adderall) and other drugs used to treat attention deficit disorder have been increasingly useful in helping women to concentrate and thus improving arousal [23, 24].
Lastly, flibanserin and bremelanotide , two drugs in development, may show promise for the future of FSAD treatments. Flibanserin is a nonhormonal treatment for premenopausal women with HSDD [25, 26]. Flibanserin is a 5-HT1A receptor agonist and 5-HT2A receptor antagonist that was initially investigated as an antidepressant [27, 28]. Preclinical evidence suggested that flibanserin targets the above receptors preferentially in selective brain areas, restores a balance between inhibitory and excitatory effects, and may show benefit in the treatment of FSAD [29, 30].
Bremelanotide is a drug under development for female sexual dysfunction, hemorrhagic shock, and reperfusion injury. It functions by activating the melanocortin receptors MC1R and MC4R, to modulate inflammation and limit ischemia [31]. Bremelanotide was originally tested for intranasal administration in treating female sexual dysfunction, but this application was temporarily discontinued in 2008 after concerns were raised over adverse side effects including elevated blood pressure. As of December 2014, the company is conducting a human phase 3 study using a subcutaneous drug delivery system that appears to have little effect on blood pressure [32].
22.7 Conclusion
In a comprehensive textbook on couple’s sexual health, it is important and appropriate to have a detailed chapter on the biologically focused management of FSAD. Increasing numbers of clinicians will manage women with these types of sexual health concerns since more and more women will expect such management. In addition, those clinicians who want to maximize overall women’s healthcare delivery will increasingly engage in the management of women’s sexual health concerns, in addition to the traditional focus on continence and urological conditions. In the future, it will become increasingly more difficult for female urologists and urogynecologists not to provide at least first-line sexual healthcare to women. Non-pharmacological treatments of FSAD have also been introduced and studied and include mindfulness training, couple therapy with focus on adequate sexual stimulation, and the use of lubricants.
The basic premise of biologically focused management of FSAD is that the normal physiologic processes regulating sexual arousal are altered by biologic pathology. How each specific medical condition modulates female arousal requires additional clinical and basic science investigation. If the biologic basis of the arousal disorder can be diagnosed by history and physical examination and laboratory testing, management outcome may be successfully directed to the source of pathophysiology. Of the many challenges facing healthcare professionals today, the first is to improve the ability to accurately diagnose women with sexual health concerns and the second is to ensure that women receive the best evidence-based available management options.
Commentary: Diagnosis and Management of Female Sexual Arousal Disorder
Annamaria Giraldi3
(3)
Sexological Clinic, Psychiatric Center Copenhagen, Institute of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark
The definition of female sexual arousal disorder (FSAD) attempts to coalesce physical and psychological aspects of the condition, although the current definition primarily focuses on the physical manifestations of arousal. However, approaching FSAD objectively requires an understanding of both the physical and psychological characteristics that can impact sexual desire and arousal. In the preceding chapter, Cohen and Goldstein describe the physical findings and symptoms of FSAD, providing an in-depth perspective on diagnosis and treatment. In progressing through the etiologies of FSAD, the authors focus on physical causes of the condition, and although they touch on relationship issues as a consideration during assessment of affected women and indicate the negative impacts of psychotropic medications, the “tangible” aspects of the condition are hewed to closely.
In the following commentary, this perspective is expanded with a thought-provoking discussion of the meaning and individual nature of arousal in women. More importantly, a discussion of broad etiologic categories of female sexual arousal which include strictly psychological, strictly genital, and combined causes is highlighted. The distinctions between these etiologies are critical and undoubtedly impact treatment approaches; one can certainly imagine that treatment for arousal disorder stemming from psychological causes can differ significantly from that arising from physical causes. It is essential that clinicians and mental health professionals who treat women with FSAD consider these distinctions and approach these women accordingly so as to maximize the potential for treatment success.
The Editors
Commentary
In the previous chapter, the definition and clinical treatment of female sexual arousal disorder (FSAD) were described. When thinking about FSAD, one should ask what women really mean when they talk about arousal. In the DSM-IV-TR and ICD-10, the diagnostic criteria for FSAD focus on the physical responses of the genitals, as increased blood flow results in tumescence of the genitals and vaginal lubrication, which is highly influenced by age, vascular response, and neurologic and endocrine state [1–4]. So, is it only the physical genital response that women describe when they refer to sexual arousal? Some women may describe the physical genital response, whereas others may talk about being “turned on” and “feeling excited” and describe a more subjective picture not necessarily focused on the genitals. Interestingly, the DSM-III-R described arousal as either an impaired genital response or lack of a subjective sense of sexual excitement [5], with the latter portion of the definition excluded in the DSM-IV. Consequently, most recent epidemiological studies have focused on the physical genital response in assessing the prevalence of arousal problems, showing a steep increase with age and menopause attributable to hormonal and vascular changes [6].
Janssen and colleagues state that arousal can be described by two components in which the mind’s processing of sexual stimuli is of importance: (1) conscious and unconscious processing leading to an automatic genital response and (2) a cognitive process appraising the sexual content of the stimulus [7, 8]. Based on these observations, FSAD can be described as both a diminished genital response and/or a lack of appraisal of the response in the genitalia and absence of a reaction to sexual stimuli.
In 2003, Basson et al. suggested a new classification of FSAD including (1) genital sexual arousal disorder, with a focus on the genital response; (2) subjective arousal disorder, with a focus on the woman having absent or diminished feelings of sexual arousal (excitement or pleasure), even though the genital response is intact; and (3) combined sexual arousal disorder including difficulties in both genital and subjective arousal [9]. These definitions encompass a broad group of women. Genital FSAD would embrace women with a clear genital impairment such as postmenopausal women and women with adverse effects stemming from antihormonal treatment after breast cancer or after radiation therapy or surgery involving the pelvic floor. The subjective FSAD would include women that might have problems with recognizing, processing, or appraising their genital response, consequently with a lack of subjective excitement, and the combined definition would encompass women with problems in both domains. However, the suggested classifications were not incorporated into any broadly applied diagnostic systems. Instead, in the recent changes in the DSM-5, a new disorder was created, female sexual interest/arousal disorder (FSAID) [1, 4], which has led to significant debate [10–12]. One of the major drawbacks of the FSAID definition is that women with a predominantly genital arousal disorder, such as that resulting from antihormonal treatment or pelvic radiation therapy, but with intact desire (spontaneous or receptive) would not be diagnosed with FSAID despite their problem stemming from a lack of arousal.
There is evidence that, especially for women, genital sexual arousal responses do not always coincide with the subjective experience of being aroused and “turned on” and that the women’s experience may be based more on the interpretation of the situation than on the genital response [13, 14]. Thus, for some women, the objective and subjective aspects of arousal do not coincide. As such, are arousal problems in women without any evident impairment of genital response due to an inability to identify sexual cues from their genitals as suggested by Barlow et al. and not a lack of genital response [15]? There is likely more than one answer—some women may have a genital impairment, whereas others may have normal genital response but do not recognize it as they are more focused on the lack of subjective arousal. Alternatively, some women may not receive sufficient sexual stimuli or do not fully perceive the stimuli they receive.
In the post-phosphodiesterase 5 inhibitor (PDE5i) era, several studies have investigated the possible beneficial effect of PDE5i’s for women with FSAD alone or combined with desire or orgasmic disorders [16]. The majority of these studies showed that while PDE5i’s increase both vaginal and clitoral blood flow along with vaginal lubrication, they do not, in a majority of the studies, improve female sexual function significantly when compared with placebo. This may reflect the fact that most studies evaluated premenopausal women, in whom the genital response is unlikely to be impaired, and the complaints were better accounted for by a “subjective FSAD” or the fact that even though the women had an increased genital arousal, whether or not they perceived it, it did not alter their phenomenological or subjective sense of arousal. For them, unlike many men using the same drugs, increased vasocongestion did not correlate with an increased sense of erotic arousal.
So what are the clinical and research implications? First, we need to specify what we mean when we talk about FSAD, both as researchers and clinicians. Is it objective or subjective arousal or a combination? Different disciplines may focus on different aspects of FSAD, which will have implications for how we approach the problem and which questions we apply to research, diagnosis, and defining individualized treatments. An ongoing debate about the definition of FSAD is necessary, not only to clarify the diagnostic criteria, which will help identify affected women, but ultimately to benefit all the women who are candidates for treatment and who are currently overlooked. With our female patients, we need to explore how women define arousal and how they individually interpret it.
A better understanding of FSAD will also have implications for treatment choice. Some studies have shown beneficial effects of PDE5i’s in women where it is more likely that there is a biologically determined genital component of dysfunction, such as women with spinal cord injury (for a review, see [16]) or the many postmenopausal women in whom estrogen treatment relieves the symptoms of genital FSAD [16–18]. On the other hand, women with subjective FSAD may benefit from approaches that help focus the woman’s attention on an increased genital response. The studies from Brotto have shown that mindfulness training that focuses on recognizing what is happening in the body found a positive effect on self-assessed genital wetness despite little or no change in actual physiological arousal and a marginally significant improvement in subjective and self-reported physical arousal during an erotic stimulus [19]. Other studies have shown that distraction is associated with lower levels of genital arousal [20]. An interesting new pharmacological concept is to develop pharmacological treatment that enhances both the genital response using a PDE5i and the sensitivity to recognize the sexual cue from the genitals using testosterone, as described by Poels et al. [21]. Both the pharmacological as well as the psychotherapeutic treatments need to be further investigated to better define efficacy and the group of patients who may benefit from these approaches.
In conclusion, arousal is not just arousal and may be perceived differently by individual women, clinicians, and researchers. Furthermore, the definitions of arousal disorders have changed with every new version of the DSM, with the focus shifting between genital and subjective aspects. Our continued clinical and research experiences continuously drive the development of a better understanding of pathologic mechanisms and subsequent treatment modalities, integrating medical and psychotherapeutic approaches.
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