madman
Super Moderator
Medical Treatment of Female Sexual Dysfunction (2022)
Rossella E. Nappi, MD, PhD, Lara Tiranini, MD, Ellis Martini, MD, David Bosoni, MD, Alessandra Righi, MD, Laura Cucinella, MD
INTRODUCTION
A sexual problem associated with personal distress in women qualifies as a female sexual dysfunction (FSD).1 Although sexual symptoms are quite common across the life span, “true” dysfunction is less prevalent because many biopsychosocial determinants influence attitudes to report distressing problems with desire, arousal, orgasm, or experiences of sexual pain.2 The Prevalence of Female Sexual Problems Associated with Distress and Determinants of Treatment Seeking demonstrated that 43.1% of women reported sexual symptoms but only 22.2% reported sexually related personal distress.3 When distress was combined with a sexual problem, 12% experienced any FSD that was more common in women aged 45 to 64 years (14.8%) than in younger (10.8%) or older (8.9%) women.3
Recognition of FSD in the clinical setting should be universal as virtually every medical condition and associated treatments may carry a multidimensional impairment of healthy sexual function and behavior.4 However, motivation to seek help and assistance from health care providers (HCPs) may vary depending on a wide range of intrapersonal and interpersonal factors.5 A proactive approach is needed to educate women on common changes related to hormonal fluctuations, for instance at menopause, and risk factors, such as mood disorders and urinary incontinence, that may affect sexual response.6 However, it is essential to provide information on the full range of therapeutic options, from pharmacotherapies to psychosocial interventions,7 and on the importance to combine multiple strategies or involve the partner under some circumstances.
At present, the International Society for the Study of Women’s Sexual Health, the International Consultation of Sexual Medicine, and the American Foundation of Urologic Diseases published evidence-based consensus guidelines on definitions, nomenclature, diagnostic criteria, and classification systems of FSD that go beyond those provided in the DSM psychiatric compendia.9 The goal was to provide a common FSD coding in clinical settings worldwide, useful both in research and in practice. The main challenges included the frequent overlap of sexual symptoms, the multitude of causes within the frame of the biopsychosocial model, and the DSM-V redefinition of some disorders (Box 1) 1 that may ingenerate confusion in prescribing drugs approved for a specific diagnosis based on the DSM-IV-TR criteria, for instance, hypoactive sexual desire disorder (HSDD).10
Here, we report key elements for medical treatment of FSD considering three major areas of intervention: the sex hormonal milieu, the central nervous system (CNS) circuitries, and the neurovascular/neuromuscular system modulating urogenital sexual response.
Therapeutic Options
HCPs can screen for FSD according to their level of expertise and deliver at least basic counseling before eventually referring to sexual medicine specialists for specific care.4 At the core level, HCPs should be able to identify the most common sexual problems that cause distress, including low sexual desire, difficulty with sexual arousal and with orgasm, sexual pain/genito-pelvic pain, penetration dysfunction, medication-induced symptoms, and relationship conflicts.4 In addition, basic counseling itself may be a first-line treatment offering emotional relief, education, and empowerment, especially by dispelling myths and providing very simple strategies to cope with symptoms, for instance, advice on the use of lubricants.11,12 The therapeutic algorithm comprises a multidisciplinary approach, including pharmacologic and nonpharmacologic management. It is more likely that acquired, generalized FSD requires a biomedical approach, whereas lifelong or situational FSD needs a psychosexual approach.7,12 In any case, it is essential to address potential biopsychosocial modifiable risk factors (Fig. 1) contributing to FSD.
SEX HORMONE MILIEU
Circulating levels of sex steroids (estrogen, testosterone, progesterone), and their metabolites play a fundamental role in linking sexuality to reproduction. They target every tissue involved in the central and peripheral sexual response across the life span of women, and their effects become particularly evident when deprivation of sex steroids occurs.13–15 Within the CNS, sex steroids prime neural circuitries to be selectively responsive to sexual incentives creating a neurochemical state more likely to induce a sexual response.16 At the urogenital level, sex steroids exert a trophic effect and modulate the threshold of tissue response to external and internal stimuli throughout a neurochemical array regulating genital vasocongestion, vaginal lubrication, and clitoral engorgement.17,18 That being so, hypoestrogenic and even androgen-insufficient states along with the aging process itself can significantly induce FSD. They may depend on natural (eg, lactational amenorrhea, menopause), pathologic (eg, primary and secondary amenorrhea, premature ovarian insufficiency), and iatrogenic (for instance, surgical menopause and that induced by chemotherapy/ radiotherapy, and other hormonal treatments such as hormonal contraception, gonadotropin-releasing hormone analogs, glucocorticoids) causes.18–20
*At present, hormonal treatments are labeled only for use in postmenopausal women5,19 to relieve conditions such as HSDD10 and genitourinary syndrome of menopause (GSM), formerly known as vulvovaginal atrophy (VVA).21
Menopause Hormone Therapy
Menopause hormone therapy (MHT) is a therapeutic choice for healthy recently menopausal women reporting moderate to severe vasomotor symptoms and in need of bone loss prevention.22 It improves several aspects of quality of life, including GSM/VVA and sexual function.23,24
*Estrogens and progestogens
The impact of systemic MHT on sexual function has been mainly investigated as a secondary endpoint in clinical trials, with evidence of a small-to-moderate improvement in early menopausal women or in presence of menopausal symptoms, but not in unselected postmenopausal women.25 Type of molecules and their metabolites, dose, and route of administration should be considered in order to minimize the relative androgen insufficiency induced by exogenous estrogens.16 Indeed, transdermal estradiol has a lower impact on circulating sex hormone-binding globulin (SHBG) and free testosterone.26 Transdermal administration has been shown to improve sexual function in early postmenopausal women, evaluated through increased total female sexual function index (FSFI) score, more than oral estrogen formulations.27 Interestingly, lubrication and pain were the domains mostly influenced by the route of administration, whereas desire did not differ significantly between the two groups.27 Even the characteristics of combined progestogens in nonhysterectomized women23,24 and their metabolites may play a role in modulating sexual function due to their different impact on SHBG.16 However, there is no evidence of well-designed studies showing the superiority of a specific molecule and, therefore, the choice of the progestogens should be based on tolerability and safety.28
*Tibolone
Tibolone is a selective tissue estrogenic activity regulator approved in many countries, apart from the United States, for the treatment of menopausal symptoms and for osteoporosis prevention.29 Because of its multiple endocrine properties (estrogenic, progestogenic, and androgenic), tibolone has been specifically investigated in postmenopausal women with FSD, showing to be superior in improving desire, arousal, and satisfaction as compared with a conventional estro-progestogen combination.30 Tibolone has been also shown to induce a significant increase in clitoral circulation in postmenopausal women reporting FSD as compared with a combined estro-progestogen preparation.31
*Transdermal testosterone
Transdermal testosterone treatment at the dose of 300 mg per 24 hours was initially approved in Europe for managing HSDD in surgically menopausal women.32 Subsequent randomized controlled trials (RCTs) assessed efficacy and short-term safety in naturally menopausal women assuming or not a concomitant estrogen/estroprogestogen treatment.32 Recently, a systematic review and meta-analysis assessing potential benefits and risks of testosterone for women concluded that testosterone significantly increases sexual function in postmenopausal women with low libido associated with distress, more specifically improving desire, arousal, orgasm, responsiveness to sex stimuli, and increasing the frequency of satisfying sexual events (SSEs), whereas decreasing sexual distress and concerns.33 Safety profile of transdermal formulation is reassuring at the dose that approximates physiologic testosterone concentration in premenopausal women.33 Therefore, a global consensus position statement on the use of testosterone therapy in women confirmed HSDD in naturally or surgically menopausal women as the unique evidence-based indication,34 in particular in women with premature ovarian insufficiency.35 Clinical and biochemical monitoring should be planned to avoid any supraphysiologic dosage and assess the efficacy of transdermal testosterone. If the treatment is not effective following 6 months, then it should be stopped, and the indication of its use should be revised.22,36 Despite the agreement of the scientific community, at present, there are no available testosterone products approved for women in most countries, and HCPs are forced to prescribe off-label formulations for men at adjusted doses for women, raising concerns about misuse.36
*Oral Dehydroepiandrosterone
Cross-sectional studies suggest a positive impact of endogenous dehydroepiandrosterone (DHEA) on several aspects of well-being in women, including sexual function. However, RCTs have failed to demonstrate a significant effect of systemic therapy with DHEA on sexual function in menopausal women with normal adrenal function, whereas it may be beneficial when adrenal insufficiency coexists.34,37
Local Hormone Therapy
Systemic MHT improves symptoms associated with GSM/VVA in 75% of postmenopausal women, namely vaginal dryness and dyspareunia, but the risk-benefit profile is acceptable when other symptoms, mainly hot flashes, or prevention of osteoporotic fractures, represent the main indication for treatment.23,24
*Estrogens
Local estrogen therapy (LET) represents an effective strategy for maintenance of uro-gynecologic and sexual health when GSM/VVA symptoms are the most relevant concern at menopause.38 Products available include different estrogenic preparations, mainly estradiol, estriol, conjugated equine estrogens, promestriene, delivered through different formulations (cream, gel, pessaries, ring) to be used regularly twice/three times a week and safely up to 1 year.19,39 A Cochrane review including 30 trials concluded that approved local estrogenic treatments are all similarly effective in relieving vaginal dryness and dyspareunia, thus the choice should consider the patient’s preference.40 Even lower urinary tract symptoms, namely recurrent urinary tract infections (rUTI) and urge urinary incontinence, may benefit from LET,38 which is included as a prophylactic strategy in perimenopausal and postmenopausal women with uncomplicated rUTI in guidelines for urologists.41 Moreover, the North American Menopause Society stated that LET can be used for relieving concomitant vulvovaginal and urinary symptoms and in absence of improvement following 3 months should be discontinued.23 Ultralow dose preparations should be preferred to minimize systemic absorption, with circulating estradiol levels persistently remaining in the postmenopausal range.23,24,42 The role of minimal estrogenic absorption is still not clear in patients with a history of hormone-sensitive malignancies in terms of recurrence risk, particularly in breast cancer survivors (BCSs), who may present with severe symptoms associated with to use of antiestrogenic therapies.43 However, there is general agreement that ultralow dose vaginal estrogens may be considered in patients with severe symptoms unresponsive to nonhormonal approaches, after careful multidisciplinary evaluation of risks and benefits with the oncologic team, excluding those women assuming aromatase inhibitors (AIs).43,44 Indeed, recent results from a phase II placebo RCT pointed to the efficacy and safety of a 0.005% estriol vaginal gel in BCSs on AIs, with an initial increase in circulating estriol followed by normalization at 12 weeks, and constantly undetectable levels of circulating estradiol and estrone over time.45
*Dehydroepiandrosterone
DHEA, also known as prasterone, is an inactive precursor converted to estrogens and androgens in the target peripheral tissues, through a mechanism described as intracrinology.46 Vaginal DHEA formulation represents an innovation in the field of GSM because of its synergistic action of estrogens and androgens on vaginal and vulvar cells while minimizing any systemic absorption.14,46 RCTs have confirmed the efficacy of daily vaginal administration of prasterone 6.5 mg inserts in significantly improving VVA-associated dyspareunia in postmenopausal women and other VVA-associated symptoms.47,48 A significant improvement in desire, lubrication, orgasm, and sexual satisfaction has also been reported,49 supporting the crucial role of dyspareunia in driving the vicious circle of postmenopausal FSD.6 Preliminary data in BCSs on tamoxifen and aromatase AIs are promising but await further confirmation in order to recommend its use in high-risk populations.43
*Testosterone cream
A recent expert review concluded that there are still insufficient data to support the use of testosterone for the GSM/VVA treatment, but positive effects are biologically plausible both on genital and urinary health.14 Local testosterone is promising in BCSs on AIs, as aromatization to estradiol would be prevented.50 A double-blind RCT showed efficacy during a 24-week period by comparing an intravaginal T cream of 300 mcg to a placebo in the treatment of dyspareunia and vaginal dryness. Even sexual function was significantly improved, without significant changes in circulating sex steroids.51
*Ospemifene
Ospemifene is a selective estrogen receptor modulator with agonist action on vaginal epithelium and bone, partial agonistic action on the endometrium, and a neutral to antagonist effect on breast tissue.52 It is approved for treating vaginal dryness and dyspareunia and other GSM/VVA associated symptoms, displaying a high rate of clinical relevance.53 Almost every domain (desire, lubrication, arousal, orgasm, and pain) of sexual function significantly improved following 12 weeks of treatment with a 60 mg daily dose of oral Ospemifene 60 mg compared with placebo, when dyspareunia was the most bothersome symptom.54 Ospemifene represents an interesting alternative for women who do not respond to LET, who are not compliant with vaginal administration, or who present a high-risk profile for conventional estrogen therapy.55 Preliminary data suggest a potential use to relieve also bladder symptoms at menopause.56,57
CENTRAL NERVOUS SYSTEM CIRCUITRIES
CNS circuitries are major targets for sex steroids and mediate instinctual, emotional, and behavioral components of sexual response.58 Indeed, the neuroendocrine balance of excitatory (dopamine, noradrenaline, and melanocortin receptors [MC3R and MC4R]) and inhibitory (serotonin, the endocannabinoid, and opioid systems) signals modulate sexual desire, arousal, orgasm, and satisfaction is under the influence of the hormonal milieu along with other biopsychosocial inciters and suppressors.16 It seems likely that HSDD involves either a predisposition toward inhibitory pathways in the brain or a neuroadaptation of structures and functions resulting in a decreased excitation and/or an increased inhibition.59 This is the theoretic background for investigating psychoactive agents as an effective treatment for desire and arousal disorders, especially in premenopausal women.5
*Flibanserin
Flibanserin is a centrally acting medication with 5HT1A agonist and 5HT2A antagonist properties leading to an increase of dopamine and norepinephrine within the CNS.60 Flibanserin is the first drug in its class and has been approved to treat generalized acquired HSDD in premenopausal women.61 Pivotal phase III trials demonstrated significant efficacy of flibanserin 100 mg once daily at bedtime (qhs) in improving number of SSEs, level of sexual desire, and reduction of distress as compared with placebo after 24 weeks and up to 52 weeks in open arm.62 Efficacy on the number of SSEs, sexual desire, and sexual distress has been proven even in naturally postmenopausal women,63 but its eventual use is unlabeled. Flibanserin is a chronic drug with a controversial history of approval,64 and a systematic review and meta-analysis pointed to small clinical efficacy and significant side effects.65 Following approval, the FDA required a risk evaluation and mitigation strategy, in order to inform women about the risk of hypotension and syncope and further studies to investigate the interaction with alcohol.61,64 At present, the FDA requires a restriction on alcohol consumption with flibanserin with a safety labeling due to its interaction with some liver enzymes.66
*Bremelanotide
Bremelanotide, a melanocortin receptor agonist that promotes dopamine release because of high affinity for the MC4R in presynaptic neurons of the hypothalamus,67 has been also recently approved for the treatment of generalized acquired HSDD in premenopausal women.68 Bremelanotide is a self-administered, subcutaneously on-demand (approximately 45 minutes before anticipated sexual activity) medication marketed at the dose of 1.75 mg following the results of two pivotal phase III trials with an identical design69 and of a 52- week open-label extension study.70 Primary analyses demonstrated statistically significant and clinically meaningful improvements in sexual desire and related distress with bremelanotide as compared with placebo in premenopausal women with HSDD.69 Nausea, flushing, and headache were the most common treatment-emergent adverse events and occurred in around 10% of patients taking the active drug. No safety signals emerged during the 52-week open-label extension and benefits were maintained.70 It is recommended to use no more than one dose of bremelanotide in 24 hours and no more than eight doses per month. However, the drug is safe and has limited interactions with alcohol and with other drugs.71
*Other Psychoactive Drugs
Patients with mood disorders and those with SSRI-induced HSDD may gain some benefits from the off-label use of psychoactive agents (bupropion and buspirone) acting on the neuroendocrine balance modulating sexual response.67 Trazodone, another antidepressant with a sedative effect, has been also investigated as an antidote for FSD.72 Indeed, the positive modulation of the dopamine/serotonin ratio seems the key to helping women with sexual desire and arousal disorders.67,73 That being so, the dopamine agonist apomorphine, approved in men with erectile dysfunction, was tested sublingually (3 mg) in premenopausal women with desire and arousal disorders but side effects and lack of clinical relevance stopped further development.74
NEUROVASCULAR/NEUROMUSCULAR SYSTEM
The neurovascular/neuromuscular system is also influenced by sex steroids, which interplay with adrenergic, cholinergic, nonadrenergic, and noncholinergic neurotransmitters and other vasoactive substances, such as vasointestinal peptide and nitric oxide (NO). Coupled with the trophic effect of both estrogens and androgens on urogenital tissues, this array of molecules regulates genital vasocongestion, vaginal lubrication, and clitoral engorgement, as well as pelvic floor function which is critical to achieving orgasm.16,17
*PD5-inhibitors and other Vasoactive Agents
PDE5-inhibitors, especially sildenafil, have been tested in both premenopausal and postmenopausal women with poor evidence.75 In women with low desire, there is a discordance between genital and subjective measures of sexual response. Therefore, promoting vasodilation via sustained effects of NO in the vascular system in order to help engorgement of clitoral and vaginal tissues does not translate into an improvement of sexual function.5,76 Sildenafil may be a potential antidote for women who develop arousal disorder secondary to multiple sclerosis, diabetes, or antidepressant use.76 Even other vasoactive agents, such as topical NO donors, alprostadil (prostaglandin E1), or oral phentolamine mesylate (a combined a-1 and a-2 adrenergic agonist),5,74,77,78 were not further investigated.
FUTURE DIRECTIONS
There are not so many new candidate drugs to treat FSD, and the main challenge is to develop psychometrically sound instruments in order to capture the clinical relevance of specific therapeutic interventions.79 Moreover, it seems essential to combine different research approaches, ranging from genetic studies80 to molecular and cellular targets,74 and including psychosocial approaches, which is crucial to obtain meaningful results. An example is given by a personalized approach based on the phenotype prediction score, which included genetic, biological, and psychological markers with the aim to identify different phenotypes of women reporting sexual desire and arousal disorders.81 According to this model, it is likely that some women display a relatively insensitive excitatory system in the brain for sexual cues, whereas others display a dysfunctional activation of brain mechanisms for sexual inhibition.81 That being so, different combinations of drugs acting on the sex hormonal milieu, the CNS circuitries, and the neurovascular/neuromuscular system may serve specific therapeutic aims. Even though ongoing phase III clinical study programs using such a personalized approach are still lacking,7,77 an RCT suggested a positive effect of on-demand sublingual sildenafil (50 mg) plus testosterone (0.5 mg) in women with FSIAD due to low sensitivity to sexual cues. Similarly, when testosterone (0.5 mg) was combined with buspirone (10 mg), a meaningful result was observed in women with FSIAD due to high sensitivity to sexual cues.82 Other drugs remain experimental holding the promise of potential solutions.77,78,83
SUMMARY
Medical treatment of FSD is based on interventions that aim, on one hand, to restore the neuroendocrine balance by replacing hormonal deficiencies and, on the other hand, to potentiate the urogenital response to sexual stimulatory clues. Only a few evidence-based therapeutic options are, indeed, available to manage HSDD. They include flibanserin and bremelanotide in premenopause and transdermal testosterone in postmenopause. MHT may improve sexual function because of a more general positive effect on the health and quality of life of women.
Rossella E. Nappi, MD, PhD, Lara Tiranini, MD, Ellis Martini, MD, David Bosoni, MD, Alessandra Righi, MD, Laura Cucinella, MD
INTRODUCTION
A sexual problem associated with personal distress in women qualifies as a female sexual dysfunction (FSD).1 Although sexual symptoms are quite common across the life span, “true” dysfunction is less prevalent because many biopsychosocial determinants influence attitudes to report distressing problems with desire, arousal, orgasm, or experiences of sexual pain.2 The Prevalence of Female Sexual Problems Associated with Distress and Determinants of Treatment Seeking demonstrated that 43.1% of women reported sexual symptoms but only 22.2% reported sexually related personal distress.3 When distress was combined with a sexual problem, 12% experienced any FSD that was more common in women aged 45 to 64 years (14.8%) than in younger (10.8%) or older (8.9%) women.3
Recognition of FSD in the clinical setting should be universal as virtually every medical condition and associated treatments may carry a multidimensional impairment of healthy sexual function and behavior.4 However, motivation to seek help and assistance from health care providers (HCPs) may vary depending on a wide range of intrapersonal and interpersonal factors.5 A proactive approach is needed to educate women on common changes related to hormonal fluctuations, for instance at menopause, and risk factors, such as mood disorders and urinary incontinence, that may affect sexual response.6 However, it is essential to provide information on the full range of therapeutic options, from pharmacotherapies to psychosocial interventions,7 and on the importance to combine multiple strategies or involve the partner under some circumstances.
At present, the International Society for the Study of Women’s Sexual Health, the International Consultation of Sexual Medicine, and the American Foundation of Urologic Diseases published evidence-based consensus guidelines on definitions, nomenclature, diagnostic criteria, and classification systems of FSD that go beyond those provided in the DSM psychiatric compendia.9 The goal was to provide a common FSD coding in clinical settings worldwide, useful both in research and in practice. The main challenges included the frequent overlap of sexual symptoms, the multitude of causes within the frame of the biopsychosocial model, and the DSM-V redefinition of some disorders (Box 1) 1 that may ingenerate confusion in prescribing drugs approved for a specific diagnosis based on the DSM-IV-TR criteria, for instance, hypoactive sexual desire disorder (HSDD).10
Here, we report key elements for medical treatment of FSD considering three major areas of intervention: the sex hormonal milieu, the central nervous system (CNS) circuitries, and the neurovascular/neuromuscular system modulating urogenital sexual response.
Therapeutic Options
HCPs can screen for FSD according to their level of expertise and deliver at least basic counseling before eventually referring to sexual medicine specialists for specific care.4 At the core level, HCPs should be able to identify the most common sexual problems that cause distress, including low sexual desire, difficulty with sexual arousal and with orgasm, sexual pain/genito-pelvic pain, penetration dysfunction, medication-induced symptoms, and relationship conflicts.4 In addition, basic counseling itself may be a first-line treatment offering emotional relief, education, and empowerment, especially by dispelling myths and providing very simple strategies to cope with symptoms, for instance, advice on the use of lubricants.11,12 The therapeutic algorithm comprises a multidisciplinary approach, including pharmacologic and nonpharmacologic management. It is more likely that acquired, generalized FSD requires a biomedical approach, whereas lifelong or situational FSD needs a psychosexual approach.7,12 In any case, it is essential to address potential biopsychosocial modifiable risk factors (Fig. 1) contributing to FSD.
SEX HORMONE MILIEU
Circulating levels of sex steroids (estrogen, testosterone, progesterone), and their metabolites play a fundamental role in linking sexuality to reproduction. They target every tissue involved in the central and peripheral sexual response across the life span of women, and their effects become particularly evident when deprivation of sex steroids occurs.13–15 Within the CNS, sex steroids prime neural circuitries to be selectively responsive to sexual incentives creating a neurochemical state more likely to induce a sexual response.16 At the urogenital level, sex steroids exert a trophic effect and modulate the threshold of tissue response to external and internal stimuli throughout a neurochemical array regulating genital vasocongestion, vaginal lubrication, and clitoral engorgement.17,18 That being so, hypoestrogenic and even androgen-insufficient states along with the aging process itself can significantly induce FSD. They may depend on natural (eg, lactational amenorrhea, menopause), pathologic (eg, primary and secondary amenorrhea, premature ovarian insufficiency), and iatrogenic (for instance, surgical menopause and that induced by chemotherapy/ radiotherapy, and other hormonal treatments such as hormonal contraception, gonadotropin-releasing hormone analogs, glucocorticoids) causes.18–20
*At present, hormonal treatments are labeled only for use in postmenopausal women5,19 to relieve conditions such as HSDD10 and genitourinary syndrome of menopause (GSM), formerly known as vulvovaginal atrophy (VVA).21
Menopause Hormone Therapy
Menopause hormone therapy (MHT) is a therapeutic choice for healthy recently menopausal women reporting moderate to severe vasomotor symptoms and in need of bone loss prevention.22 It improves several aspects of quality of life, including GSM/VVA and sexual function.23,24
*Estrogens and progestogens
The impact of systemic MHT on sexual function has been mainly investigated as a secondary endpoint in clinical trials, with evidence of a small-to-moderate improvement in early menopausal women or in presence of menopausal symptoms, but not in unselected postmenopausal women.25 Type of molecules and their metabolites, dose, and route of administration should be considered in order to minimize the relative androgen insufficiency induced by exogenous estrogens.16 Indeed, transdermal estradiol has a lower impact on circulating sex hormone-binding globulin (SHBG) and free testosterone.26 Transdermal administration has been shown to improve sexual function in early postmenopausal women, evaluated through increased total female sexual function index (FSFI) score, more than oral estrogen formulations.27 Interestingly, lubrication and pain were the domains mostly influenced by the route of administration, whereas desire did not differ significantly between the two groups.27 Even the characteristics of combined progestogens in nonhysterectomized women23,24 and their metabolites may play a role in modulating sexual function due to their different impact on SHBG.16 However, there is no evidence of well-designed studies showing the superiority of a specific molecule and, therefore, the choice of the progestogens should be based on tolerability and safety.28
*Tibolone
Tibolone is a selective tissue estrogenic activity regulator approved in many countries, apart from the United States, for the treatment of menopausal symptoms and for osteoporosis prevention.29 Because of its multiple endocrine properties (estrogenic, progestogenic, and androgenic), tibolone has been specifically investigated in postmenopausal women with FSD, showing to be superior in improving desire, arousal, and satisfaction as compared with a conventional estro-progestogen combination.30 Tibolone has been also shown to induce a significant increase in clitoral circulation in postmenopausal women reporting FSD as compared with a combined estro-progestogen preparation.31
*Transdermal testosterone
Transdermal testosterone treatment at the dose of 300 mg per 24 hours was initially approved in Europe for managing HSDD in surgically menopausal women.32 Subsequent randomized controlled trials (RCTs) assessed efficacy and short-term safety in naturally menopausal women assuming or not a concomitant estrogen/estroprogestogen treatment.32 Recently, a systematic review and meta-analysis assessing potential benefits and risks of testosterone for women concluded that testosterone significantly increases sexual function in postmenopausal women with low libido associated with distress, more specifically improving desire, arousal, orgasm, responsiveness to sex stimuli, and increasing the frequency of satisfying sexual events (SSEs), whereas decreasing sexual distress and concerns.33 Safety profile of transdermal formulation is reassuring at the dose that approximates physiologic testosterone concentration in premenopausal women.33 Therefore, a global consensus position statement on the use of testosterone therapy in women confirmed HSDD in naturally or surgically menopausal women as the unique evidence-based indication,34 in particular in women with premature ovarian insufficiency.35 Clinical and biochemical monitoring should be planned to avoid any supraphysiologic dosage and assess the efficacy of transdermal testosterone. If the treatment is not effective following 6 months, then it should be stopped, and the indication of its use should be revised.22,36 Despite the agreement of the scientific community, at present, there are no available testosterone products approved for women in most countries, and HCPs are forced to prescribe off-label formulations for men at adjusted doses for women, raising concerns about misuse.36
*Oral Dehydroepiandrosterone
Cross-sectional studies suggest a positive impact of endogenous dehydroepiandrosterone (DHEA) on several aspects of well-being in women, including sexual function. However, RCTs have failed to demonstrate a significant effect of systemic therapy with DHEA on sexual function in menopausal women with normal adrenal function, whereas it may be beneficial when adrenal insufficiency coexists.34,37
Local Hormone Therapy
Systemic MHT improves symptoms associated with GSM/VVA in 75% of postmenopausal women, namely vaginal dryness and dyspareunia, but the risk-benefit profile is acceptable when other symptoms, mainly hot flashes, or prevention of osteoporotic fractures, represent the main indication for treatment.23,24
*Estrogens
Local estrogen therapy (LET) represents an effective strategy for maintenance of uro-gynecologic and sexual health when GSM/VVA symptoms are the most relevant concern at menopause.38 Products available include different estrogenic preparations, mainly estradiol, estriol, conjugated equine estrogens, promestriene, delivered through different formulations (cream, gel, pessaries, ring) to be used regularly twice/three times a week and safely up to 1 year.19,39 A Cochrane review including 30 trials concluded that approved local estrogenic treatments are all similarly effective in relieving vaginal dryness and dyspareunia, thus the choice should consider the patient’s preference.40 Even lower urinary tract symptoms, namely recurrent urinary tract infections (rUTI) and urge urinary incontinence, may benefit from LET,38 which is included as a prophylactic strategy in perimenopausal and postmenopausal women with uncomplicated rUTI in guidelines for urologists.41 Moreover, the North American Menopause Society stated that LET can be used for relieving concomitant vulvovaginal and urinary symptoms and in absence of improvement following 3 months should be discontinued.23 Ultralow dose preparations should be preferred to minimize systemic absorption, with circulating estradiol levels persistently remaining in the postmenopausal range.23,24,42 The role of minimal estrogenic absorption is still not clear in patients with a history of hormone-sensitive malignancies in terms of recurrence risk, particularly in breast cancer survivors (BCSs), who may present with severe symptoms associated with to use of antiestrogenic therapies.43 However, there is general agreement that ultralow dose vaginal estrogens may be considered in patients with severe symptoms unresponsive to nonhormonal approaches, after careful multidisciplinary evaluation of risks and benefits with the oncologic team, excluding those women assuming aromatase inhibitors (AIs).43,44 Indeed, recent results from a phase II placebo RCT pointed to the efficacy and safety of a 0.005% estriol vaginal gel in BCSs on AIs, with an initial increase in circulating estriol followed by normalization at 12 weeks, and constantly undetectable levels of circulating estradiol and estrone over time.45
*Dehydroepiandrosterone
DHEA, also known as prasterone, is an inactive precursor converted to estrogens and androgens in the target peripheral tissues, through a mechanism described as intracrinology.46 Vaginal DHEA formulation represents an innovation in the field of GSM because of its synergistic action of estrogens and androgens on vaginal and vulvar cells while minimizing any systemic absorption.14,46 RCTs have confirmed the efficacy of daily vaginal administration of prasterone 6.5 mg inserts in significantly improving VVA-associated dyspareunia in postmenopausal women and other VVA-associated symptoms.47,48 A significant improvement in desire, lubrication, orgasm, and sexual satisfaction has also been reported,49 supporting the crucial role of dyspareunia in driving the vicious circle of postmenopausal FSD.6 Preliminary data in BCSs on tamoxifen and aromatase AIs are promising but await further confirmation in order to recommend its use in high-risk populations.43
*Testosterone cream
A recent expert review concluded that there are still insufficient data to support the use of testosterone for the GSM/VVA treatment, but positive effects are biologically plausible both on genital and urinary health.14 Local testosterone is promising in BCSs on AIs, as aromatization to estradiol would be prevented.50 A double-blind RCT showed efficacy during a 24-week period by comparing an intravaginal T cream of 300 mcg to a placebo in the treatment of dyspareunia and vaginal dryness. Even sexual function was significantly improved, without significant changes in circulating sex steroids.51
*Ospemifene
Ospemifene is a selective estrogen receptor modulator with agonist action on vaginal epithelium and bone, partial agonistic action on the endometrium, and a neutral to antagonist effect on breast tissue.52 It is approved for treating vaginal dryness and dyspareunia and other GSM/VVA associated symptoms, displaying a high rate of clinical relevance.53 Almost every domain (desire, lubrication, arousal, orgasm, and pain) of sexual function significantly improved following 12 weeks of treatment with a 60 mg daily dose of oral Ospemifene 60 mg compared with placebo, when dyspareunia was the most bothersome symptom.54 Ospemifene represents an interesting alternative for women who do not respond to LET, who are not compliant with vaginal administration, or who present a high-risk profile for conventional estrogen therapy.55 Preliminary data suggest a potential use to relieve also bladder symptoms at menopause.56,57
CENTRAL NERVOUS SYSTEM CIRCUITRIES
CNS circuitries are major targets for sex steroids and mediate instinctual, emotional, and behavioral components of sexual response.58 Indeed, the neuroendocrine balance of excitatory (dopamine, noradrenaline, and melanocortin receptors [MC3R and MC4R]) and inhibitory (serotonin, the endocannabinoid, and opioid systems) signals modulate sexual desire, arousal, orgasm, and satisfaction is under the influence of the hormonal milieu along with other biopsychosocial inciters and suppressors.16 It seems likely that HSDD involves either a predisposition toward inhibitory pathways in the brain or a neuroadaptation of structures and functions resulting in a decreased excitation and/or an increased inhibition.59 This is the theoretic background for investigating psychoactive agents as an effective treatment for desire and arousal disorders, especially in premenopausal women.5
*Flibanserin
Flibanserin is a centrally acting medication with 5HT1A agonist and 5HT2A antagonist properties leading to an increase of dopamine and norepinephrine within the CNS.60 Flibanserin is the first drug in its class and has been approved to treat generalized acquired HSDD in premenopausal women.61 Pivotal phase III trials demonstrated significant efficacy of flibanserin 100 mg once daily at bedtime (qhs) in improving number of SSEs, level of sexual desire, and reduction of distress as compared with placebo after 24 weeks and up to 52 weeks in open arm.62 Efficacy on the number of SSEs, sexual desire, and sexual distress has been proven even in naturally postmenopausal women,63 but its eventual use is unlabeled. Flibanserin is a chronic drug with a controversial history of approval,64 and a systematic review and meta-analysis pointed to small clinical efficacy and significant side effects.65 Following approval, the FDA required a risk evaluation and mitigation strategy, in order to inform women about the risk of hypotension and syncope and further studies to investigate the interaction with alcohol.61,64 At present, the FDA requires a restriction on alcohol consumption with flibanserin with a safety labeling due to its interaction with some liver enzymes.66
*Bremelanotide
Bremelanotide, a melanocortin receptor agonist that promotes dopamine release because of high affinity for the MC4R in presynaptic neurons of the hypothalamus,67 has been also recently approved for the treatment of generalized acquired HSDD in premenopausal women.68 Bremelanotide is a self-administered, subcutaneously on-demand (approximately 45 minutes before anticipated sexual activity) medication marketed at the dose of 1.75 mg following the results of two pivotal phase III trials with an identical design69 and of a 52- week open-label extension study.70 Primary analyses demonstrated statistically significant and clinically meaningful improvements in sexual desire and related distress with bremelanotide as compared with placebo in premenopausal women with HSDD.69 Nausea, flushing, and headache were the most common treatment-emergent adverse events and occurred in around 10% of patients taking the active drug. No safety signals emerged during the 52-week open-label extension and benefits were maintained.70 It is recommended to use no more than one dose of bremelanotide in 24 hours and no more than eight doses per month. However, the drug is safe and has limited interactions with alcohol and with other drugs.71
*Other Psychoactive Drugs
Patients with mood disorders and those with SSRI-induced HSDD may gain some benefits from the off-label use of psychoactive agents (bupropion and buspirone) acting on the neuroendocrine balance modulating sexual response.67 Trazodone, another antidepressant with a sedative effect, has been also investigated as an antidote for FSD.72 Indeed, the positive modulation of the dopamine/serotonin ratio seems the key to helping women with sexual desire and arousal disorders.67,73 That being so, the dopamine agonist apomorphine, approved in men with erectile dysfunction, was tested sublingually (3 mg) in premenopausal women with desire and arousal disorders but side effects and lack of clinical relevance stopped further development.74
NEUROVASCULAR/NEUROMUSCULAR SYSTEM
The neurovascular/neuromuscular system is also influenced by sex steroids, which interplay with adrenergic, cholinergic, nonadrenergic, and noncholinergic neurotransmitters and other vasoactive substances, such as vasointestinal peptide and nitric oxide (NO). Coupled with the trophic effect of both estrogens and androgens on urogenital tissues, this array of molecules regulates genital vasocongestion, vaginal lubrication, and clitoral engorgement, as well as pelvic floor function which is critical to achieving orgasm.16,17
*PD5-inhibitors and other Vasoactive Agents
PDE5-inhibitors, especially sildenafil, have been tested in both premenopausal and postmenopausal women with poor evidence.75 In women with low desire, there is a discordance between genital and subjective measures of sexual response. Therefore, promoting vasodilation via sustained effects of NO in the vascular system in order to help engorgement of clitoral and vaginal tissues does not translate into an improvement of sexual function.5,76 Sildenafil may be a potential antidote for women who develop arousal disorder secondary to multiple sclerosis, diabetes, or antidepressant use.76 Even other vasoactive agents, such as topical NO donors, alprostadil (prostaglandin E1), or oral phentolamine mesylate (a combined a-1 and a-2 adrenergic agonist),5,74,77,78 were not further investigated.
FUTURE DIRECTIONS
There are not so many new candidate drugs to treat FSD, and the main challenge is to develop psychometrically sound instruments in order to capture the clinical relevance of specific therapeutic interventions.79 Moreover, it seems essential to combine different research approaches, ranging from genetic studies80 to molecular and cellular targets,74 and including psychosocial approaches, which is crucial to obtain meaningful results. An example is given by a personalized approach based on the phenotype prediction score, which included genetic, biological, and psychological markers with the aim to identify different phenotypes of women reporting sexual desire and arousal disorders.81 According to this model, it is likely that some women display a relatively insensitive excitatory system in the brain for sexual cues, whereas others display a dysfunctional activation of brain mechanisms for sexual inhibition.81 That being so, different combinations of drugs acting on the sex hormonal milieu, the CNS circuitries, and the neurovascular/neuromuscular system may serve specific therapeutic aims. Even though ongoing phase III clinical study programs using such a personalized approach are still lacking,7,77 an RCT suggested a positive effect of on-demand sublingual sildenafil (50 mg) plus testosterone (0.5 mg) in women with FSIAD due to low sensitivity to sexual cues. Similarly, when testosterone (0.5 mg) was combined with buspirone (10 mg), a meaningful result was observed in women with FSIAD due to high sensitivity to sexual cues.82 Other drugs remain experimental holding the promise of potential solutions.77,78,83
SUMMARY
Medical treatment of FSD is based on interventions that aim, on one hand, to restore the neuroendocrine balance by replacing hormonal deficiencies and, on the other hand, to potentiate the urogenital response to sexual stimulatory clues. Only a few evidence-based therapeutic options are, indeed, available to manage HSDD. They include flibanserin and bremelanotide in premenopause and transdermal testosterone in postmenopause. MHT may improve sexual function because of a more general positive effect on the health and quality of life of women.
