madman
Super Moderator
Pharmacotherapy for female sexual dysfunctions (FSDs): what is on the market and where is this field heading? (2022)
Rossella E. Nappi, Lara Tiranini, Laura Cucinella, Ellis Martini, David Bosoni, Alessandra Righi, Chiara Cassani, and Barbara Gardella
ABSTRACT
Introduction: Female sexual dysfunctions (FSDs) are common in women of any age and have a huge impact on quality of life and relationships. They have a multifaceted etiology limiting the development of pharmacotherapies with a high rate of effectiveness. Safety issues are also a concern.
Areas covered: The authors report the most recent advances in pharmacotherapy for premenopausal and postmenopausal women with the main focus on hypoactive sexual desire disorders (HSDD) and associated sexual symptoms. Good levels of evidence have emerged for psychoactive agents, such as flibanserin and bremelanotide, as well as hormonal compounds (transdermal testosterone). The authors also report briefly on intravaginal DHEA (prasterone), local estrogen therapy (LET), and ospemifene to manage effectively vulvovaginal atrophy/genitourinary syndrome of menopause (VVA/GSM). In addition, they discuss promising therapeutic options highlighting the main reasons that hamper the availability of newly labeled products. Finally, they include the importance of the multimodal approach to address FSDs.
Expert opinion: Approved pharmacotherapies for FSD are limited. Validated multidimensional instruments and adequate objective measures of physical and mental responses to sexual external and internal incentives are mandatory to identify women suitable for chronic or on-demand treatments and to assess their pattern of response in research and practice.
1. Introduction
Several important advances contributed to our understanding of female sexual dysfunctions (FSDs) over the last few decades. It has become definitely clear that the biopsychosocial model is the key to guiding research and clinical care of women reporting sexual symptoms and associated distress across their life span. Indeed, biomedical variables interact with intrapersonal and interpersonal factors along with socio-cultural values to shape the individual experience with sex in women of any age. Moreover, it is now evident that each phase of the healthy sexual response (desire, arousal, and orgasm) may overlap in a variable way according to a wide range of internal and external stimuli, which ultimately modulate sexual satisfaction [1–4].
Medical education in sexual history taking is mandatory to train new generations of healthcare providers (HCPs) to be able to determine whether FSDs are lifelong or acquired, generalized, or situational, by collecting those bio-psychosocial factors that predispose, precipitate, or maintain sexual symptoms associated with distress [5]. The International Society for the Study of Women Sexual Health (ISSWSH) multidisciplinary, the international expert panel proposed a standard process of care (POC) that outlined recommendations for the identification of sexual problems in women and described core and advanced competencies in FSDs in daily consultation. In particular, the POC pinpointed the need for an accurate diagnosis to establish adequate management, which should include pharmacotherapies for specific conditions, such as hypoactive sexual desire disorder (HSDD) in both premenopausal and postmenopausal women and vulvovaginal atrophy/genitourinary syndrome of menopause (VVA/GSM) in postmenopausal women. On the other hand, the ISSWSH POC delineated a strategy for referral when clinicians become aware that there is an indication for nonpharmacological strategies, including physical and psychosexual therapies, alone or in combination with drugs [6].
*Here, we report the most relevant information about current pharmacotherapies for FSDs with a focus on HSDD and we look forward to the future, hoping that new research will offer a wider range of biomedical options for managing the individual woman.
2. Current pharmacological management of FSDs
2.1. Pharmacotherapies of HSDD
Two psychoactive agents are now available on the market, flibanserin in the U.S.A. and Canada and bremelanotide only in the U.S.A., to treat HSDD in premenopausal women officially, whereas the other two drugs, bupropion, and buspirone, are off-label [23]. A testosterone (T) cream (brand name Androfeme®) for daily use (1%; 0.5 ml equivalent to 5 mg) licensed for postmenopausal women with HSDD is available only in Australia [24]. However, in agreement with the conclusions of the Global Consensus Position Statement on the Use of Testosterone Therapy for Women, transdermal T approved in men can be used off-label at the dose studied in women treated with the previously available T patch (300 mcg per 24 hours) [25]. These pharmacotherapies of HSDD (Table 1) modulate the neuroendocrine substrates of the female sexual response, which are still under investigation because most of the available evidence was collected in animal models. Some experiments in humans and the use of functional brain imaging have helped to clarify the role of the complex network of excitatory (dopamine, noradrenaline, and melanocortin receptors (MC3R and MC4R)) and inhibitory (serotonin, endocannabinoid, and opioid systems) signals, modulating sexual desire, arousal, orgasm, and satisfaction. Specific nuclei in the brain stem, which maintain projections to various other brain areas and the spinal cord, release this array of molecules. It is likely that HSDD results from the interaction of the serotoninergic system with several neurochemical pathways and involves either a predisposition toward inhibitory pathways in the brain or a neuroadaptation of structures and functions resulting in decreased excitation and/or increased inhibition [26]. Even though circulating levels of sex steroids, namely T and estradiol, do not directly correlate with the diagnosis of HSDD [21], their role in priming excitatory sexual systems in the brain is plausible [27]. Other important neuromodulators linked to the activity of sex steroids and neurotransmitters/neuroactive agents include prolactin, a satiating hormone released following orgasm [28], and oxytocin and vasopressin, the so-called social neuropeptides playing a role in sexual behavior [29,30].
2.1.1. Flibanserin
2.1.2. Bremelanotide
2.1.3. Transdermal testosterone
2.1.4. Other available options
2.1.5. Addressing the VVA/GSM comorbidity in postmenopausal women with HSDD
3. Pharmacotherapies of FSDs in development
4. Multimodal therapy to manage FSDs
5. Conclusions
There are only a few treatments approved to manage FSDs effectively. Psychoactive agents are suitable mainly for premenopausal women, whereas hormonal compounds are the first-line choice for postmenopausal women. Psychosocial interventions alone, or combined with drugs, may be beneficial in both cases. Intensive investigation is mandatory to allow women informed choices by reducing the boundaries between physical and mental determinants of FSDs and involving the partner, whenever indicated. HCPs may benefit from the development of further psychometric instruments able to capture motivations and expectations of women consulting for sexual problems. Indeed, the magnitude of the effects of a given prescription seems to be rather subjective and even little changes over placebo may be relevant to some women as long as the treatment is safe. On the other hand, objective measures do not adequately reflect the clinical significance of treating women with FSDs.
6. Expert opinion
Rossella E. Nappi, Lara Tiranini, Laura Cucinella, Ellis Martini, David Bosoni, Alessandra Righi, Chiara Cassani, and Barbara Gardella
ABSTRACT
Introduction: Female sexual dysfunctions (FSDs) are common in women of any age and have a huge impact on quality of life and relationships. They have a multifaceted etiology limiting the development of pharmacotherapies with a high rate of effectiveness. Safety issues are also a concern.
Areas covered: The authors report the most recent advances in pharmacotherapy for premenopausal and postmenopausal women with the main focus on hypoactive sexual desire disorders (HSDD) and associated sexual symptoms. Good levels of evidence have emerged for psychoactive agents, such as flibanserin and bremelanotide, as well as hormonal compounds (transdermal testosterone). The authors also report briefly on intravaginal DHEA (prasterone), local estrogen therapy (LET), and ospemifene to manage effectively vulvovaginal atrophy/genitourinary syndrome of menopause (VVA/GSM). In addition, they discuss promising therapeutic options highlighting the main reasons that hamper the availability of newly labeled products. Finally, they include the importance of the multimodal approach to address FSDs.
Expert opinion: Approved pharmacotherapies for FSD are limited. Validated multidimensional instruments and adequate objective measures of physical and mental responses to sexual external and internal incentives are mandatory to identify women suitable for chronic or on-demand treatments and to assess their pattern of response in research and practice.
1. Introduction
Several important advances contributed to our understanding of female sexual dysfunctions (FSDs) over the last few decades. It has become definitely clear that the biopsychosocial model is the key to guiding research and clinical care of women reporting sexual symptoms and associated distress across their life span. Indeed, biomedical variables interact with intrapersonal and interpersonal factors along with socio-cultural values to shape the individual experience with sex in women of any age. Moreover, it is now evident that each phase of the healthy sexual response (desire, arousal, and orgasm) may overlap in a variable way according to a wide range of internal and external stimuli, which ultimately modulate sexual satisfaction [1–4].
Medical education in sexual history taking is mandatory to train new generations of healthcare providers (HCPs) to be able to determine whether FSDs are lifelong or acquired, generalized, or situational, by collecting those bio-psychosocial factors that predispose, precipitate, or maintain sexual symptoms associated with distress [5]. The International Society for the Study of Women Sexual Health (ISSWSH) multidisciplinary, the international expert panel proposed a standard process of care (POC) that outlined recommendations for the identification of sexual problems in women and described core and advanced competencies in FSDs in daily consultation. In particular, the POC pinpointed the need for an accurate diagnosis to establish adequate management, which should include pharmacotherapies for specific conditions, such as hypoactive sexual desire disorder (HSDD) in both premenopausal and postmenopausal women and vulvovaginal atrophy/genitourinary syndrome of menopause (VVA/GSM) in postmenopausal women. On the other hand, the ISSWSH POC delineated a strategy for referral when clinicians become aware that there is an indication for nonpharmacological strategies, including physical and psychosexual therapies, alone or in combination with drugs [6].
*Here, we report the most relevant information about current pharmacotherapies for FSDs with a focus on HSDD and we look forward to the future, hoping that new research will offer a wider range of biomedical options for managing the individual woman.
2. Current pharmacological management of FSDs
2.1. Pharmacotherapies of HSDD
Two psychoactive agents are now available on the market, flibanserin in the U.S.A. and Canada and bremelanotide only in the U.S.A., to treat HSDD in premenopausal women officially, whereas the other two drugs, bupropion, and buspirone, are off-label [23]. A testosterone (T) cream (brand name Androfeme®) for daily use (1%; 0.5 ml equivalent to 5 mg) licensed for postmenopausal women with HSDD is available only in Australia [24]. However, in agreement with the conclusions of the Global Consensus Position Statement on the Use of Testosterone Therapy for Women, transdermal T approved in men can be used off-label at the dose studied in women treated with the previously available T patch (300 mcg per 24 hours) [25]. These pharmacotherapies of HSDD (Table 1) modulate the neuroendocrine substrates of the female sexual response, which are still under investigation because most of the available evidence was collected in animal models. Some experiments in humans and the use of functional brain imaging have helped to clarify the role of the complex network of excitatory (dopamine, noradrenaline, and melanocortin receptors (MC3R and MC4R)) and inhibitory (serotonin, endocannabinoid, and opioid systems) signals, modulating sexual desire, arousal, orgasm, and satisfaction. Specific nuclei in the brain stem, which maintain projections to various other brain areas and the spinal cord, release this array of molecules. It is likely that HSDD results from the interaction of the serotoninergic system with several neurochemical pathways and involves either a predisposition toward inhibitory pathways in the brain or a neuroadaptation of structures and functions resulting in decreased excitation and/or increased inhibition [26]. Even though circulating levels of sex steroids, namely T and estradiol, do not directly correlate with the diagnosis of HSDD [21], their role in priming excitatory sexual systems in the brain is plausible [27]. Other important neuromodulators linked to the activity of sex steroids and neurotransmitters/neuroactive agents include prolactin, a satiating hormone released following orgasm [28], and oxytocin and vasopressin, the so-called social neuropeptides playing a role in sexual behavior [29,30].
2.1.1. Flibanserin
2.1.2. Bremelanotide
2.1.3. Transdermal testosterone
2.1.4. Other available options
2.1.5. Addressing the VVA/GSM comorbidity in postmenopausal women with HSDD
3. Pharmacotherapies of FSDs in development
4. Multimodal therapy to manage FSDs
5. Conclusions
There are only a few treatments approved to manage FSDs effectively. Psychoactive agents are suitable mainly for premenopausal women, whereas hormonal compounds are the first-line choice for postmenopausal women. Psychosocial interventions alone, or combined with drugs, may be beneficial in both cases. Intensive investigation is mandatory to allow women informed choices by reducing the boundaries between physical and mental determinants of FSDs and involving the partner, whenever indicated. HCPs may benefit from the development of further psychometric instruments able to capture motivations and expectations of women consulting for sexual problems. Indeed, the magnitude of the effects of a given prescription seems to be rather subjective and even little changes over placebo may be relevant to some women as long as the treatment is safe. On the other hand, objective measures do not adequately reflect the clinical significance of treating women with FSDs.
6. Expert opinion
