madman
Super Moderator
NEJM!
A 54-year-old woman presents with low libido, diminished arousal, and anorgasmia. She had undergone a hysterectomy and bilateral salpingo-oophorectomy at 49 years of age owing to menorrhagia and a family history of ovarian cancer. She has been using transdermal estradiol patches and topical vaginal estradiol and has no menopausal symptoms or dyspareunia. She is in a loving relationship with no major life stressors, does not have depression, and takes no other medication. All other clinical characteristics, including her weight and blood pressure, are normal. She has recently become aware that there may be treatment options for low libido and would like to discuss these with you. How would you respond?
Because there is no universal definition of normal sexual function, what constitutes sexual difficulty is determined by a person’s subjective definition of unsatisfactory sexual well-being. The condition is usually described as unsatisfactory interest, arousal, orgasm, or other aspects of sexuality (e.g., sexual self-image), and the symptoms often coexist. The term “sexual dysfunction” is used when at least one of the symptoms is of substantial concern to the affected person.1 Sexual dysfunction negatively affects mental health, vitality, and social functioning and has an overall effect on quality of life that is of similar magnitude to that associated with chronic back pain or diabetes.2
Classification of Sexual Dysfunction in Women
The classification of sexual dysfunction in women continues to evolve, with the International Classification of Diseases and Related Health Problems, 11th revision (ICD-11), providing substantive changes to the classification, and hence the diagnosis, of sexual dysfunctions.3 The ICD-11 recognizes that sexual response is influenced by a complex interplay of biologic, psychological, and social factors (Table 1). Hence ,sexual dysfunction is no longer defined as either related to or caused by a disease or medication (organic) or independent of an identifiable cause (nonorganic).3 This change is clinically important because it allows for associated factors to be recognized and, when possible, managed but does not prevent persons with associated factors from receiving treatment for sexual dysfunction.
Another modification is that the ICD-11 no longer categorizes all sexual dysfunctions according to male or female sex, because most determinants of sexual response are not sex-specific. Only arousal disorder in women and erectile dysfunction in men remain categorized as sex-specific sexual dysfunctions.3 Unlike the Diagnostic and Statistical Manual of Mental Disorders, fifth edition,4 the ICD-11 has retained hypoactive sexual desire dysfunction and arousal dysfunction as separate conditions because they have differing etiologic characteristics and risk factors and,in most cases, are associated with different psychological and biologic interventions.1 Table 1 provides descriptions of sexual dysfunctions.
Although sexual pain disorders may contribute to other sexual dysfunctions,5 both sexual pain disorders and persistent genital arousal disorder are classified separately in the ICD-113 and are not discussed in detail here. However, vaginalsymptoms that cause dyspareunia are common,and treatment options are described below.
*Prevalence of Sexual Dysfunction in Women
Common Contributing Health Conditions
Estrogen insufficiency is a hallmark of menopause, hypothalamic amenorrhea, hyperprolactinemia,hypopituitarism, and antiestrogen therapy (aromatase inhibitors or selective estrogen-receptor modulators). Low sexual desire may be related to estrogen-insufficiency symptoms such as hot flashes and night sweats, mood change, sleep disturbance,or vulvovaginal dryness.11 Low testosterone levels have not been consistently associated with low orgasm satisfaction; however, in one analysis,when sociodemographic factors were taken into consideration, low testosterone was independently associated with low orgasm satisfaction in premenopausal women.10 Serum testosterone levels have not been consistently associated with sexual function in postmenopausal women,12,13 but representative studies that use a more precise measurement of testosterone are still needed. Other endocrine disorders associated with a greater likelihood of sexual dysfunction include adrenal insufficiency (including adrenal suppression by systemic glucocorticoids),14 diabetes,15 and polycystic ovary syndrome.16
Chronic disease, particularly conditions that reduce mobility or cause chronic pain, mental health conditions, pelvic-organ prolapse, and cancer therapy may all contribute to sexual dysfunction.1 An array of psychosocial factors may underlie sexual dysfunction, including relationship difficulties, poor self-image, past or current abuse, stressors, and sociocultural beliefs and expectations.1,17 Both depressive symptoms and psychotropic medications are independently and bidirectionally associated with sexual dysfunction.18
Findings from a randomized, controlled trial suggest that the use of combined oral contraceptives may cause low sexual desire.19 However,simply switching contraceptive pills can provide substantial improvement in sexual function, irrespective of the androgenicity of the progestin in the new preparation.20 Other common medications can cause sexual dysfunction — notably cardiac and antihypertensive medications.1,17
*Assessment
*Management
Pharmacotherapy
Although estrogen therapy is not a treatment for generalized sexual dysfunction, hormone therapy should be considered for menopausal symptoms that are troubling to the patient, because symptom relief may reduce sexual symptoms. Dyspareunia due to estrogen insufficiency can be treated with a local topical vaginal estrogen cream, pessary, or ring; prasterone (a form of dehydroepiandrosterone for vaginal use); oral ospemifene;or vaginal moisturizers.44 Vaginal erbium and carbon-dioxide laser therapy have been promoted for relief of dyspareunia. However, in 2018 the Food and Drug Administration warned against the use of these therapies owing to insufficient evidence to support their efficacy and safety for the treatment of dyspareunia.45
Flibanserin and bremelanotide are approved in the United States for treatment in premenopausal women with generalized, acquired hypoactive sexual desire dysfunction. Flibanserin is thought to disinhibit pathways involved in sexual desire. Studies involving both premenopausaland postmenopausal women with hypoactivesexual desire dysfunction showed sufficient efficacy for the approval of flibanserin for premenopausal women in the United States.31 The efficacy of flibanserin is modest.31 In a meta analysis of eight trials including 5914 participants, flibanserin was shown to have increased the number of satisfying sexual experiences per month by 0.5 but with considerable side effects(e.g., dizziness, somnolence, nausea, and fatigue). Bremelanotide is a melanocortin receptor agonist that is thought to increase dopamine release and thus increase excitation in brain regions that are associated with sexual desire.46 A combined analysis of two trials involving 1267 participants showed a modest improvement in sexual desire and decrease in distress related to low sexual desire with bremelanotide but more nausea, flushing, and headache side effects than with placebo.32
There are no therapies approved in North America for postmenopausal women with hypoactive sexual desire dysfunction, but testosterone has been prescribed off-label for hypoactive sexual desire dysfunction since the 1940s.47 A transdermal testosterone patch was approved in Europe for surgically postmenopausal women having hypoactive sexual desire dysfunction despite adequate estrogen therapy,35 but the patch was removed from the market by the manufacturer when the approval was not extended to naturally menopausal women, despite clinical trial data showing efficacy of the patch in those women that was similar to that seen in surgically postmenopausal women.48 A transdermal 1% testosterone cream 49 has been approved in Australia for the treatment of postmenopausal women with hypoactive sexual desire dysfunction.
An international task force evaluated the available clinical trial data and concluded that transdermal testosterone therapy, which restores serum testosterone levels to approximately those seen in premenopausal women, is moderately effective for the treatment of postmenopausal hypoactive sexual desire dysfunction. Table 3 provides a summary of the trial evidence.23 The task force recommended against the use of oral testosterone therapy owing to potential adverse effects related to lipoprotein levels and inconsistent absorption.23 Clinical trial data have shown that transdermal testosterone, when administered at the recommended doses, may cause a small but significant increase in the likelihood of acne,growth of facial or body hair, and weight gain,and long-term safety data are lacking.34
Nonetheless, it has been estimated that more than 2 million prescriptions of testosterone are written each year for women in the United States, many of which are probably for compounded preparations.50 Compounded formulations are not subject to requirements for pharmacokinetic profiling, and their uncertain absorption may cause overdose and harm.23 The international task force recommendation that if an approved female-specific testosterone formulation is unavailable and testosterone therapy is considered indicated for treatment of postmenopausal hypoactive sexual desire dysfunction, the preferred option is a fractionated dose of a regulator-approved maleformulation.23 When transdermal testosterone is prescribed, regular monitoring of serum testosterone concentrations and clinical assessment for signs of androgen excess are recommended.23
Systemic dehydroepiandrosterone therapy has not been shown to improve sexual dysfunction in randomized, double-blind clinical trials involving women with intact adrenals 51 or with adrenal insufficiency.52 Bupropion and buspirone are psychotropic medications that have been used off label in patients with sexual dysfunction, but efficacy and safety data are insufficient, and currently neither therapy can be recommended.17
Effective pharmacotherapies for arousal and orgasm dysfunction are lacking. Small studies suggest potential benefits of phosphodiesterase-5 (PDE5) inhibitors for arousal difficulties in women with spinal cord injury 38 and antidepressant associated arousal dysfunction.37 PDF5 inhibitors have also shown promise for the treatment of genital arousal dysfunction in women with type 1 diabetes.39 There is no evidence of benefit of PDF5 inhibitor therapy in healthy women with arousal dysfunction.53
Guidelines
The International Society for the Study of Women’s Sexual Health has published processes of care for the identification of sexual concerns and problems in women 1 and for the assessment of hypoactive sexual desire dysfunction.17 The processes of care are valuable resources for enhancing the skills and capabilities of both primary health care providers and medical specialists. The Global Consensus Position Statement on Testosterone for Women, developed and endorsed by leading women’s health groups worldwide and available in 14 languages, provides comprehensive guidance regarding the use of testosterone therapy in women.23 The recommendations in this article align with these guidelines.
Areas of Uncertainty
Clarification of the prevalence of sexual dysfunction relies on an investment in quality epidemiologic studies that are inclusive of all women, irrespective of gender identity, sexual preference,and partner status. Furthermore, the understanding of the physiology of female sexuality has been constrained by the necessary reliance on animal models, anatomical and functional studies involving humans, and imaging. The uncertainty of the biologic features of the brain in sexual function in women hinders the understanding of dysfunction and in turn the development of pharmacotherapies. Clinical trials to further evaluate available psychosocial interventions and pharmacotherapies are still needed. Consequently, treatment algorithms, particularly regarding arousal and orgasm dysfunction, remain inadequate because they are limited to modification of contributing factors, counseling, and physical therapies.
Conclusions and Recommendations
With regard to the patient described in the vignette, I would seek to identify relationship issues, major psychosocial contributors, or modifiable factors and to determine whether the loss of libido was of meaningful concern to the patient. If the diagnosis of hypoactive sexual desire dysfunction was established, I would address any psychosocial issues as appropriate, and I would discuss treatment options. In most countries, the approach would involve off-label pharmacotherapy, with the most evidence-based option currently being the administration of transdermal testosterone at a dose appropriate for a female patient. Unfortunately, this case highlights the ongoing inadequacy of treatment options for women with sexual dysfunction.
A 54-year-old woman presents with low libido, diminished arousal, and anorgasmia. She had undergone a hysterectomy and bilateral salpingo-oophorectomy at 49 years of age owing to menorrhagia and a family history of ovarian cancer. She has been using transdermal estradiol patches and topical vaginal estradiol and has no menopausal symptoms or dyspareunia. She is in a loving relationship with no major life stressors, does not have depression, and takes no other medication. All other clinical characteristics, including her weight and blood pressure, are normal. She has recently become aware that there may be treatment options for low libido and would like to discuss these with you. How would you respond?
Because there is no universal definition of normal sexual function, what constitutes sexual difficulty is determined by a person’s subjective definition of unsatisfactory sexual well-being. The condition is usually described as unsatisfactory interest, arousal, orgasm, or other aspects of sexuality (e.g., sexual self-image), and the symptoms often coexist. The term “sexual dysfunction” is used when at least one of the symptoms is of substantial concern to the affected person.1 Sexual dysfunction negatively affects mental health, vitality, and social functioning and has an overall effect on quality of life that is of similar magnitude to that associated with chronic back pain or diabetes.2
Classification of Sexual Dysfunction in Women
The classification of sexual dysfunction in women continues to evolve, with the International Classification of Diseases and Related Health Problems, 11th revision (ICD-11), providing substantive changes to the classification, and hence the diagnosis, of sexual dysfunctions.3 The ICD-11 recognizes that sexual response is influenced by a complex interplay of biologic, psychological, and social factors (Table 1). Hence ,sexual dysfunction is no longer defined as either related to or caused by a disease or medication (organic) or independent of an identifiable cause (nonorganic).3 This change is clinically important because it allows for associated factors to be recognized and, when possible, managed but does not prevent persons with associated factors from receiving treatment for sexual dysfunction.
Another modification is that the ICD-11 no longer categorizes all sexual dysfunctions according to male or female sex, because most determinants of sexual response are not sex-specific. Only arousal disorder in women and erectile dysfunction in men remain categorized as sex-specific sexual dysfunctions.3 Unlike the Diagnostic and Statistical Manual of Mental Disorders, fifth edition,4 the ICD-11 has retained hypoactive sexual desire dysfunction and arousal dysfunction as separate conditions because they have differing etiologic characteristics and risk factors and,in most cases, are associated with different psychological and biologic interventions.1 Table 1 provides descriptions of sexual dysfunctions.
Although sexual pain disorders may contribute to other sexual dysfunctions,5 both sexual pain disorders and persistent genital arousal disorder are classified separately in the ICD-113 and are not discussed in detail here. However, vaginalsymptoms that cause dyspareunia are common,and treatment options are described below.
*Prevalence of Sexual Dysfunction in Women
Common Contributing Health Conditions
Estrogen insufficiency is a hallmark of menopause, hypothalamic amenorrhea, hyperprolactinemia,hypopituitarism, and antiestrogen therapy (aromatase inhibitors or selective estrogen-receptor modulators). Low sexual desire may be related to estrogen-insufficiency symptoms such as hot flashes and night sweats, mood change, sleep disturbance,or vulvovaginal dryness.11 Low testosterone levels have not been consistently associated with low orgasm satisfaction; however, in one analysis,when sociodemographic factors were taken into consideration, low testosterone was independently associated with low orgasm satisfaction in premenopausal women.10 Serum testosterone levels have not been consistently associated with sexual function in postmenopausal women,12,13 but representative studies that use a more precise measurement of testosterone are still needed. Other endocrine disorders associated with a greater likelihood of sexual dysfunction include adrenal insufficiency (including adrenal suppression by systemic glucocorticoids),14 diabetes,15 and polycystic ovary syndrome.16
Chronic disease, particularly conditions that reduce mobility or cause chronic pain, mental health conditions, pelvic-organ prolapse, and cancer therapy may all contribute to sexual dysfunction.1 An array of psychosocial factors may underlie sexual dysfunction, including relationship difficulties, poor self-image, past or current abuse, stressors, and sociocultural beliefs and expectations.1,17 Both depressive symptoms and psychotropic medications are independently and bidirectionally associated with sexual dysfunction.18
Findings from a randomized, controlled trial suggest that the use of combined oral contraceptives may cause low sexual desire.19 However,simply switching contraceptive pills can provide substantial improvement in sexual function, irrespective of the androgenicity of the progestin in the new preparation.20 Other common medications can cause sexual dysfunction — notably cardiac and antihypertensive medications.1,17
*Assessment
*Management
Pharmacotherapy
Although estrogen therapy is not a treatment for generalized sexual dysfunction, hormone therapy should be considered for menopausal symptoms that are troubling to the patient, because symptom relief may reduce sexual symptoms. Dyspareunia due to estrogen insufficiency can be treated with a local topical vaginal estrogen cream, pessary, or ring; prasterone (a form of dehydroepiandrosterone for vaginal use); oral ospemifene;or vaginal moisturizers.44 Vaginal erbium and carbon-dioxide laser therapy have been promoted for relief of dyspareunia. However, in 2018 the Food and Drug Administration warned against the use of these therapies owing to insufficient evidence to support their efficacy and safety for the treatment of dyspareunia.45
Flibanserin and bremelanotide are approved in the United States for treatment in premenopausal women with generalized, acquired hypoactive sexual desire dysfunction. Flibanserin is thought to disinhibit pathways involved in sexual desire. Studies involving both premenopausaland postmenopausal women with hypoactivesexual desire dysfunction showed sufficient efficacy for the approval of flibanserin for premenopausal women in the United States.31 The efficacy of flibanserin is modest.31 In a meta analysis of eight trials including 5914 participants, flibanserin was shown to have increased the number of satisfying sexual experiences per month by 0.5 but with considerable side effects(e.g., dizziness, somnolence, nausea, and fatigue). Bremelanotide is a melanocortin receptor agonist that is thought to increase dopamine release and thus increase excitation in brain regions that are associated with sexual desire.46 A combined analysis of two trials involving 1267 participants showed a modest improvement in sexual desire and decrease in distress related to low sexual desire with bremelanotide but more nausea, flushing, and headache side effects than with placebo.32
There are no therapies approved in North America for postmenopausal women with hypoactive sexual desire dysfunction, but testosterone has been prescribed off-label for hypoactive sexual desire dysfunction since the 1940s.47 A transdermal testosterone patch was approved in Europe for surgically postmenopausal women having hypoactive sexual desire dysfunction despite adequate estrogen therapy,35 but the patch was removed from the market by the manufacturer when the approval was not extended to naturally menopausal women, despite clinical trial data showing efficacy of the patch in those women that was similar to that seen in surgically postmenopausal women.48 A transdermal 1% testosterone cream 49 has been approved in Australia for the treatment of postmenopausal women with hypoactive sexual desire dysfunction.
An international task force evaluated the available clinical trial data and concluded that transdermal testosterone therapy, which restores serum testosterone levels to approximately those seen in premenopausal women, is moderately effective for the treatment of postmenopausal hypoactive sexual desire dysfunction. Table 3 provides a summary of the trial evidence.23 The task force recommended against the use of oral testosterone therapy owing to potential adverse effects related to lipoprotein levels and inconsistent absorption.23 Clinical trial data have shown that transdermal testosterone, when administered at the recommended doses, may cause a small but significant increase in the likelihood of acne,growth of facial or body hair, and weight gain,and long-term safety data are lacking.34
Nonetheless, it has been estimated that more than 2 million prescriptions of testosterone are written each year for women in the United States, many of which are probably for compounded preparations.50 Compounded formulations are not subject to requirements for pharmacokinetic profiling, and their uncertain absorption may cause overdose and harm.23 The international task force recommendation that if an approved female-specific testosterone formulation is unavailable and testosterone therapy is considered indicated for treatment of postmenopausal hypoactive sexual desire dysfunction, the preferred option is a fractionated dose of a regulator-approved maleformulation.23 When transdermal testosterone is prescribed, regular monitoring of serum testosterone concentrations and clinical assessment for signs of androgen excess are recommended.23
Systemic dehydroepiandrosterone therapy has not been shown to improve sexual dysfunction in randomized, double-blind clinical trials involving women with intact adrenals 51 or with adrenal insufficiency.52 Bupropion and buspirone are psychotropic medications that have been used off label in patients with sexual dysfunction, but efficacy and safety data are insufficient, and currently neither therapy can be recommended.17
Effective pharmacotherapies for arousal and orgasm dysfunction are lacking. Small studies suggest potential benefits of phosphodiesterase-5 (PDE5) inhibitors for arousal difficulties in women with spinal cord injury 38 and antidepressant associated arousal dysfunction.37 PDF5 inhibitors have also shown promise for the treatment of genital arousal dysfunction in women with type 1 diabetes.39 There is no evidence of benefit of PDF5 inhibitor therapy in healthy women with arousal dysfunction.53
Guidelines
The International Society for the Study of Women’s Sexual Health has published processes of care for the identification of sexual concerns and problems in women 1 and for the assessment of hypoactive sexual desire dysfunction.17 The processes of care are valuable resources for enhancing the skills and capabilities of both primary health care providers and medical specialists. The Global Consensus Position Statement on Testosterone for Women, developed and endorsed by leading women’s health groups worldwide and available in 14 languages, provides comprehensive guidance regarding the use of testosterone therapy in women.23 The recommendations in this article align with these guidelines.
Areas of Uncertainty
Clarification of the prevalence of sexual dysfunction relies on an investment in quality epidemiologic studies that are inclusive of all women, irrespective of gender identity, sexual preference,and partner status. Furthermore, the understanding of the physiology of female sexuality has been constrained by the necessary reliance on animal models, anatomical and functional studies involving humans, and imaging. The uncertainty of the biologic features of the brain in sexual function in women hinders the understanding of dysfunction and in turn the development of pharmacotherapies. Clinical trials to further evaluate available psychosocial interventions and pharmacotherapies are still needed. Consequently, treatment algorithms, particularly regarding arousal and orgasm dysfunction, remain inadequate because they are limited to modification of contributing factors, counseling, and physical therapies.
Conclusions and Recommendations
With regard to the patient described in the vignette, I would seek to identify relationship issues, major psychosocial contributors, or modifiable factors and to determine whether the loss of libido was of meaningful concern to the patient. If the diagnosis of hypoactive sexual desire dysfunction was established, I would address any psychosocial issues as appropriate, and I would discuss treatment options. In most countries, the approach would involve off-label pharmacotherapy, with the most evidence-based option currently being the administration of transdermal testosterone at a dose appropriate for a female patient. Unfortunately, this case highlights the ongoing inadequacy of treatment options for women with sexual dysfunction.
