Hypoactive Sexual Desire Disorder in Women

Etiology

Female sexuality is controlled by complex interactions among physiological, psychological, anatomical, neurochemical, hormonal, pharmacological, and social factors.[1][2][9] Factors such as age, menopausal status, sociocultural challenges, stress, challenging relationships, medical comorbidities, medication interactions and adverse effects, and anatomic factors such as female genital mutilation (FGM) or circumcision, among others, play causative and contributory roles in the development of HSDD.[2][9][10] Other factors that have been associated with sexual disorders include life situations, ethnicity, and culture.[2] Unmarried or single women and Black women have been reported to suffer HSDD less than married females and White women.[3]

Psychosocial and interpersonal relationships with sexual partners may significantly affect the sexual desire of female partners.[7] Female circumcision, or FGM, is a common practice in some countries and cultures.[10] Various data have shown that circumcised females are more likely to experience low sexual desire, poor sexual satisfaction, poor sexual excitement with or without stimulation, and painful experiences during sexual intercourse.[10][11] Female sexual dysfunction and, by extension, HSDD are reported to be much more common among circumcised females than among their uncircumcised peers.[10][11][12][13]

Sex hormones such as progesterone, testosterone, and estrogen also modulate sexual desire and sexuality in females through their effects on various areas of the brain.[14] Sex hormones interact with various neurotransmitters, resulting in the control of sexual desire and enjoyment.[1][2] Some neurotransmitters are responsible for excitatory pathways, primarily controlled by dopaminergic substances, including dopamine and norepinephrine.[2][7] Dopamine enhances sexual excitement and desire, while norepinephrine (noradrenalin) enhances arousal and orgasm.[2][7][15] 

Inhibitory pathways for sexual desire and enjoyment occur primarily via the serotonergic system.[2][7][15] Excessive release of serotonin or a reduction in its metabolism may result in the loss of libido and reduced sexual desire or arousal. Selective serotonin reuptake inhibitors (SSRIs) may cause symptoms similar to those of HSDD by increasing serotonin levels. Medications and conditions that increase brain serotonin or decrease dopamine levels have been associated with HSDD.[2][7][16] 

Epidemiology

HSDD is the most common female sexual dysfunction.[17] Previous studies that assessed the prevalence of sexual desire disorders in females lacked a standardized definition, rendering the reported prevalence unreliable.[18][2] In recent years, many studies have documented the prevalence of HSDD based on the standardized definition defined in the DSM-IV, with emphasis on the inclusion of the presence of distress.[2][3][18] 

The Pharmacogenomics in Depression Study (PRESIDE) reported the prevalence of HSDD as ranging from 7.4% among women 65 years of age and older to 12.3% among women between 45 and 64 years of age. Younger women between the ages of 18 and 44 years had a prevalence of 8.9%.[2][3][10][18] Of note, in the same PRESIDE study, cumulative unadjusted prevalence of sexual desire disorder with and without distress was reportedly 38.7% among all age groups. To determine patients with distress in classifying a patient as having HSDD, the PRESIDE study used a Female Sexual Distress Scale (FSDS) score of ≥15 before diagnosing HSDD in such patients.[2][3]

In the Women's International Study of Health and Sexuality (WISHeS), another cross-sectional study conducted among female residents in the UK, France, Italy, Germany, and North America, the prevalence of HSDD ranged between 6 and 16% in Europe and between 9 and 26% in North America.[1][2] Studies have shown that although the prevalence of low libido increases with age, the prevalence of distress associated with this low libido simultaneously decreases. This trend makes HSDD more common among middle-aged women than among older and younger women. In addition, menopausal women have a much greater incidence of HSDD than non-menopausal women, whether such a menopausal state is natural or surgically induced.[3] Obesity, current smoking status, current depression, educational level, and hormone replacement therapy are other factors that have been associated with HSDD.[1][3][19] HSDD has also been associated with low self-esteem, dissatisfaction with sexual partners, emotional distress, back pain, fatigue, memory deficits, and relationship difficulties.[2][16][17]

Pathophysiology

Certain excitatory and inhibitory hormones and neurotransmitters affect the brain, which helps explain the pathophysiology of HSDD. The female genitalia are richly innervated by nerve fibers which transmit tactile and pleasurable sensations to the brain. These signals travel to brain regions like the insula and thalamus for processing. Visual stimuli also influence human sexuality.[20][21][22]

Neuroimaging studies have identified the sexual desire brain network (SDBN), which involves various brain regions responding to sexual stimuli. Atrophy in excitatory areas and hyperactivity in inhibitory areas of the brain are associated with HSDD.[20][21][22] Increased neuroimaging activity in brain regions, like the ventromedial prefrontal cortex, amygdala, and insula, during sexual inhibition may contribute to HSDD, while heightened activity in areas like the anterior cingulate cortex and ventral striatum during sexual excitation is associated with normal sexual response. The ventral occipitotemporal cortex (vOT) tracks sexual arousal and response to visual sexual stimuli, even with closed eyes, showing a preference for body parts.[9][23]

As previously mentioned, different neurotransmitters, such as dopamine, estrogen, and testosterone, contribute to increasing sexual desire and arousal. Conversely, serotonin, prolactin, and opioids have inhibitory effects on these processes. Notably, testosterone significantly influences sexual desire.[20][21][22] As women age, especially after menopause, there is a decrease in ovarian and adrenal production of testosterone. With surgical menopause, there is a 50% decrease in testosterone levels as compared to women who undergo menopause naturally.[24]

History and Physical

The evaluation of a patient with HSDD should encompass a thorough history and physical examination to help identify the underlying cause and duration of the sexual disorder, allowing the clinician to devise effective management strategies. A crucial initial step is to determine the primary concern or issue, which may include diminished sexual desire, arousal difficulties, vaginal dryness, insufficient response to foreplay, discomfort during sexual activity, or challenges in achieving orgasm. Gathering and documenting a comprehensive medical history is imperative, as this is pivotal in diagnosing HSDD. The evaluation process outlines key elements essential for assessing a patient with HSDD. (see Table 1. Assessing Patients with HSDD). 

Evaluation

Females with HSDD may present in different healthcare settings, including primary care offices, emergency departments, gynecology clinics, psychiatry clinics, and sexual health or therapy clinics.[7][25] A common challenge, however, is that many of these patients will not voluntarily provide relevant information that may suggest a proper diagnosis because of fear of embarrassment to themselves or the clinicians. Symptoms may be subtle or ignored. In addition, many healthcare professionals are either ill-equipped or do not have enough time to properly assess patients who have sexual desire or function concerns.[26] 

If there is suspicion of an underlying disease process as a cause for HSDD, laboratory evaluations may include a complete blood count, thyroid stimulation hormone level, vitamin D level, and prolactin level. Checking sex hormone steroid levels, including testosterone levels, is not recommended. Physical examination may be performed at the clinician's discretion.[26]

Gloria Bachmann surveyed attendees of a multispecialty annual meeting in which 1,946 physicians responded; approximately 60% of participants rated their knowledge of and their comfort level at diagnosing or managing female sexual dysfunctions as poor or fair.[27][28] Harsh et al also surveyed 53 resident physicians (78%) and faculty members (22%) of a university internal medicine clinic.[28] In that survey, approximately 90% of the participants reported that they were not confident in diagnosing HSDD. Many healthcare providers consider sexual desire disorders to be unrelated to their purview and/or professional expertise, feeling inadequately equipped to diagnose and adequately manage sexual disorders.

Eliciting and documenting an adequate history is critical for diagnosing HSDD. Key important points in assessing a patient with HSDD are listed below (see Table 1. Assessing Patients with HSDD). These key points include poor or low desire for sex, difficulty with sexual arousal; vaginal dryness; inability to respond adequately to foreplay, pain before, during, or after sexual activity; and delay or inability to reach orgasm or climax. It is important to note that not every woman with sexual desire disorder has HSDD, and it is also possible for a patient to have more than 1 sexual disorder.[29][30] 

To diagnose HSDD, it is critical to establish that such a patient has associated distress or interpersonal relationship concerns related to the expressed sexual disorder symptoms.[31] The presence of sexual disorder symptoms without associated distress excludes the diagnosis of HSDD. However, such symptoms may indicate the presence of sexual desire disorders other than HSDD. 

 Table 1. Assessing Patients with HSDD

Rosen et al developed the Female Sexual Function Index (FSFI) in the year 2000. This index measures scores in 6 domains: desire, lubrication, arousal, orgasm, satisfaction, and pain. Each domain is assessed on a scale from 1 to 5, with 1 being very low, 2 being low, 3 being moderate, 4 being high, and 5 being very high. The questions center on the patient's perception of each of these 6 domains over the last 4 weeks.[32][33] Wiegel et al conducted another study that cross-validated the FSFI and developed cutoff scores.[34] This study concluded that scores ≤26.55 out of 30 indicated sexual dysfunction.

Another option for screening patients is the Decreased Sexual Desire Screener (DSDS) tool, which is a short screening tool for HSDD that was developed by Rosen et al in 2007, based on the DSM-IV criteria for diagnosis of HSDD (see Table 2. Decreased Sexual Desire Screener).[29] This tool is easy to use, even for those without sexual health specialty training. With DSDS, a patient who answers "yes" to all questions 1 through 4 and "no" to all factors in part 5 meets the diagnostic criteria for generalized acquired HSDD.

Table 2. Decreased Sexual Desire Screener

Table 3. Interpretation of the DSDS Screen Results

According to the DSM-5, the duration of symptoms should be at least 6 months.[35] In addition, the DSM-5 removes the prerequisite of a female patient having "desire" dysfunction as a condition for diagnosing female sexual dysfunction. However, this distinction is limited to females.[3] Instead of "desire," the DSM-5 substitutes "interest" by combining HSDD and female sexual arousal disorder into 1 diagnosis termed female sexual interest/arousal disorder (FSIAD).[3][6]

The definition and assessment of desire have been significant points of contention in diagnosing HSDD.[35] Women's perception of desire is influenced by various factors such as emotional, psychological, cognitive, and interpersonal elements. Notably, the desire for sex may not always be the primary motivation for women to engage in sexual activity.[35] Many women have reported participating in sexual intercourse for reasons beyond desire, such as feeling obligated to satisfy their partner's needs, for emotional connection, or in exchange for nonsexual favors.

Consequently, since many women engage in sexual activity for motives other than desire, the absence of desire may not always clearly indicate a sexual disorder. The replacement of "desire" with "interest" and consolidation of female sexual disorder into FSIAD in the DSM-5 was done to specify the duration and severity of symptoms required for diagnosing a female sexual disorder, to avoid classifying normal female functioning as pathological and to underscore the fact that sexual experiences in females are best described as being "subjective and relational."[35][36][36][37][38]

Diagnosing Female Sexual Interest/Arousal Disorder

Three of the following 6 symptoms need to be present:

1. Absent or reduced interest in sexual activity
2. Absent or reduced sexual or erotic thoughts or fantasies
3. Absent or reduced initiation of sexual activity and typically unreceptive to a partner's attempts to initiate sex
4. Absent or reduced sexual excitement or pleasure during sexual activity in all or almost all (between 75% to 100%) of sexual encounters (in identified situational contexts if limited to specific situations or in all contexts if generalized)
5. Absent or reduced sexual interest or arousal in response to any internal or external sexual or erotic stimuli or cues
6. Absent or reduced genital or nongenital sensations during sexual activity in almost all or all (between 75% to 100 %) sexual encounters (with this being identified as situational if limited to specific contexts or in all contexts if generalized)

Three of the 6 symptoms listed above must be present for at least 6 months and need to be causing clinically significant distress.[37][38] The duration of the problem should be established during the assessment, including whether this has been lifelong or acquired and whether it is situational or generalized. Lifelong indicates the problem has been present since the patient became sexually active. Acquired indicates that the problem began after a time of relatively normal sexual function.

The problem should be categorized further as either generalized or situational. Generalized is described as when the problem is not limited to certain situations, partners, or stimulation. Situational is described as the problem occurring only with certain situations, partners, or stimulation. The severity should also be categorized as causing the patient mild, moderate, or severe distress.

Extracting etiological history is imperative in diagnosing HSDD or FSIAD. History about childhood female circumcision or genital mutilation, cultural orientation and upbringing about sexuality, and recent or previous history of genital tract trauma, including parturition-related trauma, may individually or collectively affect the sexual functionality of the glans clitoris and vestibule, which are associated with reception and perception of sexual stimuli.[3] Clitoral amputation or surgical damage of the clitoris and or surrounding genital tissue may affect the perception of sexual stimulation of such affected females.[10][12] 

Physiological, psychological, and sociological factors that may predispose to or perpetuate sexual desire or interest disorder should be sought.[2][3][17] Comorbidities like diabetes, cardiorespiratory disorders, liver disease, thyroid disease, pituitary disorders, neurological conditions, and malignancy have been associated with the development of sexual desire disorders.[3][17] A woman with a new onset of symptomatology coinciding with lifestyle changes, including a new relationship, newly diagnosed medical condition, and or treatment of a medical, surgical, psychological, or psychiatric disorder, may have a different etiology for the newly developed sexual desire disorder when compared to a female with similar symptoms but of much longer or lifelong duration, without an identifiable recent change in life situation.[29]

Adequate gynecological history should focus on identifying the menopausal status, particularly premature or surgical menopause, and other chronic gynecologic conditions that may cause dyspareunia, including vaginal atrophy, endometriosis, and pelvic inflammatory disease.[3][29] Eliciting current and previous medication history is equally important since antipsychotics, antidepressants, antihypertensives, corticosteroids, and hormones can all affect sexuality.[19][39] In some situations, further investigation may be required to exclude other medical comorbidities, to assess amenorrhea or oligomenorrhea, and especially to identify sex steroid deficiency.[26] The limitations in testosterone measurement make it difficult to correlate testosterone levels clinically with HSDD.[24]

Treatment / Management

Both nonpharmacological and pharmacological interventions are available for treating and managing HSDD.

1. Treatment with Counseling and Therapy

In most cases, the management of HSDD includes a combination of psychotherapy and pharmacotherapy.[2][3] Office-based counseling should be the first approach for managing female sexual dysfunction.[40][41] This involves providing patients with basic education about sexuality and recommended lifestyle changes to improve sexual desire, interest, and experience. Some of the psychotherapies that have been documented as helpful include cognitive behavioral therapy, basic psychosexual counseling, mindfulness meditation therapy, body awareness education, and relationship counseling. Initial management may include basic psychosexual counseling, which is an office-based therapy that focuses on educating patients about sexual physiology and anatomy, along with average normal responses to sexual stimulation and how such responses may be affected by natural developments, including aging, comorbidities and the quality of the relationship.[2][3][40][41](A1)

Cognitive behavioral therapy (CBT) is a more advanced therapy for patients who require a deeper exploration of thoughts and behaviors.[2][3][42] Many studies have documented the effectiveness of CBT in managing female sexual dysfunctions, including HSDD. Developed by Beck and Ellis, CBT premises that emotional distress and behavioral problems are products of maladaptive cognitions.[43] CBT focuses on strategies that change these maladaptive cognitions. Such changes result in relief or resolution of the emotional distress and problematic behaviors experienced by the patient being treated.(A1)

2. Treatment with FDA-approved Medications

The Food and Drug Administration (FDA)-approved medications for the management of female sexual dysfunction are limited.[44] Treatments target the sexual inhibitory and excitatory pathways that modulate responses to sexual stimulation or cues.[2]

A. Flibanserin: A serotonin 1A agonist and 2A antagonist, flibanserin decreases serotonin levels and increases norepinephrine and dopamine levels.[25] It was FDA-approved in August 2015 for the treatment of generalized, acquired HSDD in premenopausal women. It should be taken at a dose of 100 mg every night before bed and at least 2 hours after drinking alcohol because the most common adverse effects include dizziness and somnolence. Improvement in sexual desire should be noted after 4 to 8 weeks of use.[26]

B. Bremelanotide: In June 2019, the FDA approved bremelanotide for treating HSDD in premenopausal women.[25][45] Bremelanotide, a melanocortin agonist, is administered at a dose of 1.75 mg subcutaneously as needed once daily, approximately 45 minutes before the commencement of sexual activity. No more than 1 dose should be administered in 24 hours, and no more than 8 doses per month are recommended. Bremelanotide primarily activates presynaptic melanocortin receptor 4 (MC4R), which stimulates dopamine in brain areas that regulate arousal, motivation, and sexual appetite.[25] It should be used with caution in women with concerns for cardiovascular disease, and blood pressure should be monitored and well-controlled. Nausea is the most common reason for the discontinuation of therapy with bremelanotide.[46](A1)

3. Off-Label Medication Therapies

Off-label medications used to treat HSDD include testosterone and bupropion.

A. Bupropion: Bupropion, a dopamine and serotonin reuptake inhibitor, is 1 option for off-label treatment of female sexual dysfunction.[47] In addition to the antidepressant effects of the dopaminergic activities of bupropion, its enhancement of available dopamine in the brain areas that control sexuality could explain the effectiveness of bupropion in the management of HSDD when compared with placebo.[46](A1)

B. Testosterone: Available data show that testosterone treatment is effective in menopausal females with sexual desire dysfunction or decreased libido.[48] Data is mixed concerning the use of testosterone in premenopausal women, and further studies are needed for validation of its effectiveness. Most practice guidelines concerning testosterone supplementation for HSDD in women do not recommend testing testosterone levels because there are no established age-specific normal values for testosterone in women. A common approach to treatment with testosterone is to individualize the dosing to resolve the symptoms while keeping adverse effects to a minimum.[24]

Oral and intramuscular preparations of testosterone are not recommended for women as they result in high fluctuations in levels. Similarly, subcutaneous implants are also not recommended due to the inability to titrate doses. Compounded testosterone cream is also not recommended because of the inability to regulate its concentration. Transdermal formulations, including patches, gel, cream, or spray, are preferred for use in women. Careful hand washing should be performed after applying formulations to the upper thigh, back of the calf, or buttocks. The starting dose of testosterone gel for women is 5 mg/day (0.5 ml), which is one-tenth the starting dose used in men. Small increases can be made up to 10 mg/day (1.0 ml) if needed.[24]

Baseline lipid panel and liver function testing should be initially obtained and monitored yearly with the use of testosterone therapy in women. Clinical benefits may be seen in 6 to 8 weeks but 12 weeks of therapy may be needed to see maximal results.[24] Adverse effects may include acne, deepening of the voice, alopecia, adverse effects on lipid profile, and abnormal hair growth. On the other hand, testosterone is likely protective against the development of breast cancer. Therapy should be discontinued after 6 months if symptoms are not improved. Further studies on the long-term use of testosterone, the adverse effects, and metabolic and cardiovascular outcomes are needed.[49]

C. Flibanserin in postmenopausal women: Although flibanserin is FDA-approved for use in premenopausal women, it has only been effectively used off-label in early studies with postmenopausal women, showing significant improvements in sexual desire and satisfying sexual events and a decrease in distress related to low desire. Adverse effects were found to be similar to when used in premenopausal women and included tiredness, dizziness, headache, and nausea.[26] 

Differential Diagnosis

HSDD can be mimicked by conditions included in its relatively large differential diagnosis.[25] One is low sexual desire (LSD) disorder, which shares many symptoms and features with HSDD. However, LSD disorder does not require the associated distress, the presence of which is mandatory before diagnosing HSDD. Other conditions that may mimic HSDD include psychiatric conditions such as depression, obsessive-compulsive disorder, and personality disorders.[50]

Adverse effects related to some medications may cause symptoms that mimic HSSD. The serotonergic effects of medications such as selective serotonin receptor inhibitors (SSRIs), tricyclic antidepressants (TCAs), first-generation antipsychotics, and monoamine oxidase inhibitors (MAOIs) may mirror HSDD.[51] The development of sexual dysfunctions in patients taking these medications may be treated by reducing the dose or switching to other medications without requiring definitive HSDD treatment. Some antihypertensives, such as beta-blockers and calcium channel blockers, may also cause symptoms suggestive of HSDD.[52]

Other medical conditions, such as hyperprolactinemia, diabetes, connective tissue disorders, and liver disease, may produce symptoms mimicking HSDD.[52] Sexual trauma, physical trauma, and substance abuse or dependence are also in the differential diagnosis. Dysfunction resulting from sexual arousal, orgasm, or painful sex may be mistaken for HSDD, but treatment approaches for these dysfunctions may be completely different from those used for HSDD.

Prognosis

HSDD in women can have various prognoses depending on factors such as underlying causes, individual characteristics, and treatment effectiveness. While the overall prognosis can vary, with appropriate diagnosis and treatment, many individuals experience improvements in sexual desire and overall well-being. It's crucial for individuals experiencing HSDD to seek support from healthcare professionals who can provide personalized treatment recommendations and support throughout the process.

Patients with HSDD tend to have a good prognosis if diagnosed promptly and adequately treated. The challenges, however, include delays in diagnosis, which may be caused by several factors, including a lack of willingness of patients to seek help, failure of healthcare professionals to explore the possibility of HSDD in female patients presenting for other related or remotely connected reasons, and a lack of confidence in the competence and capability of healthcare providers to diagnose and adequately manage HSDD.

Complications

HSDD, if not promptly diagnosed and treated, may result in a lower quality of life, poor affect, lower self-esteem, lower happiness and satisfaction with partners, emotional distress, and overall dissatisfaction. Both physical and psychological complications may occur and can affect individual well-being, interpersonal relationships, and overall quality of life. Some potential complications of HSDD include relationship issues, decreased intimacy, and negative self-image. Patients with sexual dysfunctions have a 130% to 210% greater risk of having depression than patients without sexual dysfunctions. 

It is essential for individuals experiencing HSDD to seek support from healthcare professionals who can provide a comprehensive evaluation, offer appropriate treatment options, and address any associated complications. Open communication with partners and seeking therapy or support groups can also help navigate the challenges related to HSDD and improve overall well-being and relationship satisfaction.