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Expert Opinion on Pharmacotherapy Publication details, including instructions for authors and subscription information: http://www.tandfonline.com/loi/ieop20
Why are there no FDA-approved treatments for female sexual dysfunction? Rossella E Nappi MD PhD
a
a
University of Pavia, IRCCS Policlinico San Matteo, Research Center for Reproductive Medicine, Gynecological Endocrinology and Menopause, Department of Clinical, Surgical, Diagnostic and Paediatric Sciences, Piazzale Golgi 2, 27100 Pavia, Italy +39 0382 501561; +39 0382 423233; Published online: 15 Jul 2015.
Click for updates To cite this article: Rossella E Nappi MD PhD (2015) Why are there no FDA-approved treatments for female sexual dysfunction?, Expert Opinion on Pharmacotherapy, 16:12, 1735-1738 To link to this article: http://dx.doi.org/10.1517/14656566.2015.1064393
PLEASE SCROLL DOWN FOR ARTICLE Taylor & Francis makes every effort to ensure the accuracy of all the information (the “Content”) contained in the publications on our platform. However, Taylor & Francis, our agents, and our licensors make no representations or warranties whatsoever as to the accuracy, completeness, or suitability for any purpose of the Content. Any opinions and views expressed in this publication are the opinions and views of the authors, and are not the views of or endorsed by Taylor & Francis. The accuracy of the Content should not be relied upon and should be independently verified with primary sources of information. Taylor and Francis shall not be liable for any losses, actions, claims, proceedings, demands, costs, expenses, damages, and other liabilities whatsoever or howsoever caused arising directly or indirectly in connection with, in relation to or arising out of the use of the Content. This article may be used for research, teaching, and private study purposes. Any substantial or systematic reproduction, redistribution, reselling, loan, sub-licensing, systematic supply, or distribution in any form to anyone is expressly forbidden. Terms & Conditions of access and use can be found at http:// www.tandfonline.com/page/terms-and-conditions
Editorial
Downloaded by [University of California, San Diego] at 21:30 22 August 2015
Why are there no FDA-approved treatments for female sexual dysfunction? 1.
Background
2.
Expert opinion
Rossella E Nappi University of Pavia, IRCCS Policlinico San Matteo, Research Center for Reproductive Medicine, Gynecological Endocrinology and Menopause, Department of Clinical, Surgical, Diagnostic and Paediatric Sciences, Pavia, Italy
After many years of research, female sexual dysfunction (FSD) is still an unmet clinical need because no FDA-approved treatments are available for women. The bio-psychosocial model is essential to understand whether a candidate drug induces a meaningful effect over placebo on sexual symptoms with a significant impact on women’s quality of life and partnership. Vasoactive agents, hormone therapy and psychoactive drugs have been investigated. Randomized placebo-controlled trials showing efficacy and safety, however, did not convince the FDA to approve either transdermal testosterone patch in postmenopausal women or the serotoninergic agent flibanserin in premenopausal women, for the treatment of hypoactive sexual desire disorder. The process of balancing efficacy and safety of a chronic treatment for a nonlife threatening condition, such as FSD, is very difficult in women of any age, but there is some hope that the gender gap in sexual medicine will soon come to an end. Insightful research centered on women’s needs and expectations and the availability of novel compounds, tested according to the new DSM-5 diagnostic criteria, will finally lead medical regulatory agencies to approve an effective and safe pharmacotherapy for FSD. Keywords: female sexual dysfunction, genito-urinary syndrome of menopause, hormone therapy, hypoactive sexual desire disorder, phosphodiesterase type 5 inhibitors, psychoactive drugs, sexual medicine, transdermal testosterone Expert Opin. Pharmacother. (2015) 16(12):1735-1738
1.
Background
According to the WHO revised definition, sexual health is a state of physical, emotional, mental, and social wellbeing, underpinned by human rights, in relation to sexuality. The promotion of safe, satisfying, responsible and autonomous sex lives includes policies to address sexual dysfunction in a bio-psychosocial perspective across the world [1]. During the past two decades, the field of sexual medicine has significantly grown to provide a standard of care for men and women reporting sexual problems in modern societies, but a gender gap is still present, with no FDA-approved products for the medical treatment of female sexual dysfunction (FSD) [2]. Historically, FSD includes hypoactive sexual desire, reduced subjective and/or physical genital arousal (poor sensation, vasocongestion, lubrication), sexual pain and inability to achieve orgasm/satisfaction. On the basis of the available literature, the new DSM-5 diagnostic criteria combined desire and arousal disorders (HSDD and FSAD in DSM-IV-TR, respectively) into female sexual interest/arousal disorder and sexual pain disorders (vaginism and dyspareunia) into genito-pelvic pain/penetration disorder, establishing additional criteria to characterize FSD [3]. Therefore, it is relevant to keep in mind that candidate drugs to treat FSD till now have been tested according to obsolescent diagnoses. 10.1517/14656566.2015.1064393 © 2015 Informa UK, Ltd. ISSN 1465-6566, e-ISSN 1744-7666 All rights reserved: reproduction in whole or in part not permitted
1735
Downloaded by [University of California, San Diego] at 21:30 22 August 2015
R. E. Nappi
Sexual health disorders have a complex etiology in both sexes and the medical approach has been less successful in women than in men, due to the difficulties in balancing benefits and risks of drugs for FSD, along with the awareness that primary end-points in clinical trials may not fully capture the wide spectrum of women’s sexual responses that are mostly shaped by intrapersonal and interpersonal factors [4]. The placebo effect was very high in randomized controlled trials (RCTs) [5] and the clinical relevance of some candidate drugs for the treatment of sexual symptoms has been considered modest in the context of an optimal multidisciplinary management of FSD [6]. In addition, the true epidemiology of FSD is far from being clear because in many cases sexual symptoms are just temporary reactions to situational challenges or, alternatively, are strongly related to specific medical conditions. However, in daily practice the problem of FSD is vast and distressful and the difficulties to find safe and effective treatments for maintaining a satisfactory sex life should inspire sexual experts, pharmaceutical companies and medical agencies to work in synergy in order to understand the real needs of women with sexual symptoms [4]. Initially, researchers have focused on the genital aspects of the sexual response in the attempt to treat women with the same vasoactive drugs [phosphodiesterase type 5 (PDE5) inhibitors] that have been widely accepted into medical practice for the treatment of erectile dysfunction. Indeed, women’s arousal is associated with increased blood flow to the vagina and clitoris, which results in clitoral erection, vaginal engorgement, changes in vaginal luminal diameter and vaginal lubrication. Even though the physiological effects of PDE5 inhibitors are fundamentally similar in both sexes, the few well-controlled studies examining the effects of these drugs, namely sildenafil, on sexual response in women have failed to demonstrate a significant effect in the management of FSAD, likely because of gender differences in the concordance between physiological and psychological components of sexual response. Some positive effects of PDE5 inhibitors were evident only in premenopausal women with clear medical conditions impairing genital response [7]. The experience with vasoactive drugs, therefore, supports the notion that sex steroids (estrogens, progestogens and androgens) are crucial in modulating neuroendocrine and neurovascular responses to internal and external stimuli and women should be studied according to ‘the hormonal factor’. Reproductive milestones (menarche, pregnancy, menopause) and endocrine changes (e.g., hormonal contraception, hormonal chemotherapies, other hormonal therapies) significantly inflect the sexual response at multiple levels (central nervous system, uro-genital organs) in a very unique way for each individual woman, depending on genetic and epigenetic bio-psychosocial pathways [8]. The most clear example of the link between sex steroids and sexual symptoms is given by the so-called genito-urinary syndrome of menopause (GSM), a chronic condition encompassing many clinical signs of uro-genital atrophy, that may occur as a result of hormonal deprivation after 1736
menopause, with a clear impact on the ability of peripheral organs to respond to sexual stimuli [9]. By managing GSM with the use of systemic and/or local hormone therapy (HT), a significant improvement of the pain domain (vaginal dryness and dyspareunia) is observed in women with menopausal symptoms because the atrophic signs ameliorate with estrogens. However, HT is not a comprehensive solution to treat FSD because a multitude of bio-psychosocial factors may influence the cascade effect of removing sexual pain on other sexual dimensions, including sexual desire [10]. HSDD, usually occurring after surgical menopause or in some women with natural menopause, is another example of the link between an endocrine condition, the so-called androgen insufficiency syndrome deriving from age and/or ovariectomy, and sexual symptoms. That being so, transdermal testosterone patch (TTP, 300 mcg/daily) was consistently effective and safe in the short term in postmenopausal women with sexual dysfunction due to HSDD [11]. However, these data from RCTs were not enough to induce the FDA to approve TTP when balancing clinical benefits and safety issues. TTP was, then, marketed in Europe in 2004 only to treat surgically (bilateral ovariectomy plus hysterectomy) menopausal women with HSDD, but it has been recently withdrawn due to low usage. Interestingly enough, in spite low desire was highly present in a large and ethnically diverse longitudinal study (SWAN), most of the women reported to be moderately or extremely sexual satisfied [12], indicating that the presence of sexual complaints does not mean, necessarily, to have FSD. In addition, both age and time since menopause may significantly affect the levels of distress driving women’s motivation to treatment. That being so, the decision to treat FSD in postmenopausal women with HT, including T, requires a well-balanced view in light of the publication of the Women’s Health Initiative studies [13]. In the meantime hormonal strategies were under evaluation for postmenopausal women, the burden of FSD in premenopausal women was considered also from a mental perspective by testing psychoactive agents for the treatment of HSDD. Indeed, some antidepressants produce sexual side effects. Moreover, research data suggest that sexual incentives and sexual inhibitory clues act on the neuroendocrine balance, which involves excitatory and inhibitory neurochemicals driving physical and genital arousal, according to the dual control model. Therefore, the FDA considered flibanserin, a compound inhibiting serotoninergic ‘anti-sexual’ effects and promoting ‘pro-sexual’ neurotransmitters, such as dopamine and norepinephrine. RCTs showed that flibanserin at the dose of 100 mg qhs (single daily dose at bedtime) displayed a statistically and clinically significant improvement in the number of satisfactory sexual events, level of sexual desire and reduction of distress relative to placebo after 24 weeks and up to 52 weeks of treatment in open arm [14]. However, flibanserin was not approved by the FDA, mainly because of safety issues and poor judgment of its clinical effect. Disappointment is evident in part of the scientific community, because the absence of FDA-approved products for FSD promotes
Expert Opin. Pharmacother. (2015) 16(12)
Why are there no FDA-approved treatments for female sexual dysfunction?
especially the use of male testosterone (T) products or T compounded at pharmacies for treating women, without any assessment of real efficacy and safety, along with a wide range of ‘miraculous’ products with no rigorous science-based evidence [15].
Downloaded by [University of California, San Diego] at 21:30 22 August 2015
2.
Expert opinion
Pharmacotherapy for treating FSD is still under investigation and the only way to finally obtain the approval for a labeled drug is to keep on doing insightful research centered on women’s needs and expectations, hopefully with novel available treatments. Multidimensional tools to translate changes in sexual domain scores into satisfactory sexual experiences are needed to quantify the impact of a candidate drug on partnership and personal distress. FSD is an unmet clinical condition not because of gender inequality by medical regulatory agencies that did not take good care of women, but as a consequence of overprotection by a group of experts lacking a multidimensional expertise. Indeed, by judging the effect of a candidate drug only in a reproductive perspective, the process of balancing efficacy and safety of a chronic treatment for a non-life threatening condition could be very difficult, especially in women of childbearing age, and even in the clinical practice of menopause. Although safety issues are equally important in both sexes, the need of a drug on a regular basis for several weeks in order to produce a meaningful sexual effect in women is the main reason for caution. It is fair enough to say that it has been much easier for the FDA to advice on off-hand drugs rapidly effective on a clearly Bibliography
Hawkes S. Sexual health: a post-2015 palimpsest in global health? Lancet Glob Health 2014;2:e377-8
2.
Goldstein I. Raising the glass ceiling: not all “men” are created equal. J Sex Med 2014;11:1885-7
3.
4.
5.
.
American Psychiatric Association. Highlights of changes from DSM-IV-TR to DSM-5. American Psychiatric Press, Washington DC; 2013 Nappi RE, Cucinella L. Advances in pharmacotherapy for treating female sexual dysfunction. Expert Opin Pharmacother 2015;16:875-87 Bradford A. Listening to placebo in clinical trials for female sexual dysfunction. J Sex Med 2013;10:451-9 A well-focused point of view on the importance of the placebo effect in
Declaration of interest RE Nappi had financial relationship (lecturer, member of advisory boards and/or consultant) with Bayer HealthCare AG, Boehringer Ingelheim, Ely Lilly, Gedeon Richter, HRA Pharma, Merck Sharpe & Dohme, Novo Nordisk, Pfizer Inc., Procter & Gamble Co, Shionogi Limited, TEVA Women’s Health Inc. The author has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.
clincial trials investigating the impact of drugs on sexual symptoms in women.
Papers of special note have been highlighted as either of interest () or of considerable interest () to readers. 1.
measurable response such as penile erection hardness in men. Therefore, the possibility to use on-demand drugs also for women should be evaluated in further studies taking into account the new DSM-5 diagnostic criteria. Somebody may argue that many chronic T treatments are available for men, and even a psychoactive agent used on a regular basis was approved for premature ejaculation. However, it should be acknowledged that testosterone cut-off plasma level was identified for male hypogonadism, as well as the intravaginal ejaculation latency time was easily measurable. In conclusion, I do hope we will stop carrying the flag of ‘disease mongering’ or of ‘the battle of sexes’, as far as FSD are concerned. Research is ongoing taking into account the bio-psychosocial model and my wish is that we will all stand at women’s side working hard on efficacy and safety, in order to finally get an FDA-approved treatment in the near future.
6.
7.
8.
9.
Bitzer J, Giraldi A, Pfaus J. A standardized diagnostic interview for hypoactive sexual desire disorder in women: standard operating procedure (SOP Part 2). J Sex Med 2013;10:50-7 Chivers ML, Rosen RC. Phosphodiesterase type 5 inhibitors and female sexual response: faulty protocols or paradigms? J Sex Med 2010;7:858-72 Nappi RE, Domoney C. Pharmacogenomics and sexuality: a vision. Climacteric 2013;16(Suppl 1):25-30 Portman DJ, Gass ML; Vulvovaginal atrophy terminology consensus conference panel. Genitourinary syndrome of menopause: new terminology for vulvovaginal atrophy from the international society for the study of women’s sexual health and the
Expert Opin. Pharmacother. (2015) 16(12)
..
North American Menopause Society. J Sex Med 2014;11:2865-72 An innovative definition to expand the concept of vulvo-vaginal atrophy and open the way to further studies in the field of menopausal sexual health.
10.
Wierman ME, Nappi RE, Avis N, et al. Endocrine aspects of women’s sexual function. J Sex Med 2010;7:561-85
11.
Davis SR, Worsley R. Androgen treatment of postmenopausal women. J Steroid Biochem Mol Biol 2014;142:107-14
12.
Avis NE, Brockwell S, Randolph JF, et al. Longitudinal changes in sexual functioning as women transition through menopause: results from the Study of Women’s Health Across the Nation. Menopause 2009;16:442-52
13.
Nappi RE, Davis SR. The use of hormone therapy for the maintenance of
1737
R. E. Nappi
.
(HSDD): development status of flibanserin. BJOG 2014;121:1328-31 15.
Goldstein I. Effect of food and drug administration decisions on sexual medicine research. J Sex Med 2014;11:2623-4
Thorp J Jr, Palacios S, Symons J, et al. Improving prospects for treating hypoactive sexual desire disorder
Downloaded by [University of California, San Diego] at 21:30 22 August 2015
14.
urogynecological and sexual health post WHI. Climacteric 2012;15:267-74 A cohompreensive review of the effects of hormone therapy in postmenopausal women suffering from sexual symptoms after the publication of WHI.
1738
Expert Opin. Pharmacother. (2015) 16(12)
Affiliation Rossella E Nappi MD PhD University of Pavia, IRCCS Policlinico San Matteo, Research Center for Reproductive Medicine, Gynecological Endocrinology and Menopause, Department of Clinical, Surgical, Diagnostic and Paediatric Sciences, Piazzale Golgi 2, 27100 Pavia, Italy Tel: +39 0382 501561; Fax: +39 0382 423233; E-mail: [email protected]
Expert Opinion on Pharmacotherapy Publication details, including instructions for authors and subscription information: http://www.tandfonline.com/loi/ieop20
Why are there no FDA-approved treatments for female sexual dysfunction? Rossella E Nappi MD PhD
a
a
University of Pavia, IRCCS Policlinico San Matteo, Research Center for Reproductive Medicine, Gynecological Endocrinology and Menopause, Department of Clinical, Surgical, Diagnostic and Paediatric Sciences, Piazzale Golgi 2, 27100 Pavia, Italy +39 0382 501561; +39 0382 423233; Published online: 15 Jul 2015.
Click for updates To cite this article: Rossella E Nappi MD PhD (2015) Why are there no FDA-approved treatments for female sexual dysfunction?, Expert Opinion on Pharmacotherapy, 16:12, 1735-1738 To link to this article: http://dx.doi.org/10.1517/14656566.2015.1064393
PLEASE SCROLL DOWN FOR ARTICLE Taylor & Francis makes every effort to ensure the accuracy of all the information (the “Content”) contained in the publications on our platform. However, Taylor & Francis, our agents, and our licensors make no representations or warranties whatsoever as to the accuracy, completeness, or suitability for any purpose of the Content. Any opinions and views expressed in this publication are the opinions and views of the authors, and are not the views of or endorsed by Taylor & Francis. The accuracy of the Content should not be relied upon and should be independently verified with primary sources of information. Taylor and Francis shall not be liable for any losses, actions, claims, proceedings, demands, costs, expenses, damages, and other liabilities whatsoever or howsoever caused arising directly or indirectly in connection with, in relation to or arising out of the use of the Content. This article may be used for research, teaching, and private study purposes. Any substantial or systematic reproduction, redistribution, reselling, loan, sub-licensing, systematic supply, or distribution in any form to anyone is expressly forbidden. Terms & Conditions of access and use can be found at http:// www.tandfonline.com/page/terms-and-conditions
Editorial
Downloaded by [University of California, San Diego] at 21:30 22 August 2015
Why are there no FDA-approved treatments for female sexual dysfunction? 1.
Background
2.
Expert opinion
Rossella E Nappi University of Pavia, IRCCS Policlinico San Matteo, Research Center for Reproductive Medicine, Gynecological Endocrinology and Menopause, Department of Clinical, Surgical, Diagnostic and Paediatric Sciences, Pavia, Italy
After many years of research, female sexual dysfunction (FSD) is still an unmet clinical need because no FDA-approved treatments are available for women. The bio-psychosocial model is essential to understand whether a candidate drug induces a meaningful effect over placebo on sexual symptoms with a significant impact on women’s quality of life and partnership. Vasoactive agents, hormone therapy and psychoactive drugs have been investigated. Randomized placebo-controlled trials showing efficacy and safety, however, did not convince the FDA to approve either transdermal testosterone patch in postmenopausal women or the serotoninergic agent flibanserin in premenopausal women, for the treatment of hypoactive sexual desire disorder. The process of balancing efficacy and safety of a chronic treatment for a nonlife threatening condition, such as FSD, is very difficult in women of any age, but there is some hope that the gender gap in sexual medicine will soon come to an end. Insightful research centered on women’s needs and expectations and the availability of novel compounds, tested according to the new DSM-5 diagnostic criteria, will finally lead medical regulatory agencies to approve an effective and safe pharmacotherapy for FSD. Keywords: female sexual dysfunction, genito-urinary syndrome of menopause, hormone therapy, hypoactive sexual desire disorder, phosphodiesterase type 5 inhibitors, psychoactive drugs, sexual medicine, transdermal testosterone Expert Opin. Pharmacother. (2015) 16(12):1735-1738
1.
Background
According to the WHO revised definition, sexual health is a state of physical, emotional, mental, and social wellbeing, underpinned by human rights, in relation to sexuality. The promotion of safe, satisfying, responsible and autonomous sex lives includes policies to address sexual dysfunction in a bio-psychosocial perspective across the world [1]. During the past two decades, the field of sexual medicine has significantly grown to provide a standard of care for men and women reporting sexual problems in modern societies, but a gender gap is still present, with no FDA-approved products for the medical treatment of female sexual dysfunction (FSD) [2]. Historically, FSD includes hypoactive sexual desire, reduced subjective and/or physical genital arousal (poor sensation, vasocongestion, lubrication), sexual pain and inability to achieve orgasm/satisfaction. On the basis of the available literature, the new DSM-5 diagnostic criteria combined desire and arousal disorders (HSDD and FSAD in DSM-IV-TR, respectively) into female sexual interest/arousal disorder and sexual pain disorders (vaginism and dyspareunia) into genito-pelvic pain/penetration disorder, establishing additional criteria to characterize FSD [3]. Therefore, it is relevant to keep in mind that candidate drugs to treat FSD till now have been tested according to obsolescent diagnoses. 10.1517/14656566.2015.1064393 © 2015 Informa UK, Ltd. ISSN 1465-6566, e-ISSN 1744-7666 All rights reserved: reproduction in whole or in part not permitted
1735
Downloaded by [University of California, San Diego] at 21:30 22 August 2015
R. E. Nappi
Sexual health disorders have a complex etiology in both sexes and the medical approach has been less successful in women than in men, due to the difficulties in balancing benefits and risks of drugs for FSD, along with the awareness that primary end-points in clinical trials may not fully capture the wide spectrum of women’s sexual responses that are mostly shaped by intrapersonal and interpersonal factors [4]. The placebo effect was very high in randomized controlled trials (RCTs) [5] and the clinical relevance of some candidate drugs for the treatment of sexual symptoms has been considered modest in the context of an optimal multidisciplinary management of FSD [6]. In addition, the true epidemiology of FSD is far from being clear because in many cases sexual symptoms are just temporary reactions to situational challenges or, alternatively, are strongly related to specific medical conditions. However, in daily practice the problem of FSD is vast and distressful and the difficulties to find safe and effective treatments for maintaining a satisfactory sex life should inspire sexual experts, pharmaceutical companies and medical agencies to work in synergy in order to understand the real needs of women with sexual symptoms [4]. Initially, researchers have focused on the genital aspects of the sexual response in the attempt to treat women with the same vasoactive drugs [phosphodiesterase type 5 (PDE5) inhibitors] that have been widely accepted into medical practice for the treatment of erectile dysfunction. Indeed, women’s arousal is associated with increased blood flow to the vagina and clitoris, which results in clitoral erection, vaginal engorgement, changes in vaginal luminal diameter and vaginal lubrication. Even though the physiological effects of PDE5 inhibitors are fundamentally similar in both sexes, the few well-controlled studies examining the effects of these drugs, namely sildenafil, on sexual response in women have failed to demonstrate a significant effect in the management of FSAD, likely because of gender differences in the concordance between physiological and psychological components of sexual response. Some positive effects of PDE5 inhibitors were evident only in premenopausal women with clear medical conditions impairing genital response [7]. The experience with vasoactive drugs, therefore, supports the notion that sex steroids (estrogens, progestogens and androgens) are crucial in modulating neuroendocrine and neurovascular responses to internal and external stimuli and women should be studied according to ‘the hormonal factor’. Reproductive milestones (menarche, pregnancy, menopause) and endocrine changes (e.g., hormonal contraception, hormonal chemotherapies, other hormonal therapies) significantly inflect the sexual response at multiple levels (central nervous system, uro-genital organs) in a very unique way for each individual woman, depending on genetic and epigenetic bio-psychosocial pathways [8]. The most clear example of the link between sex steroids and sexual symptoms is given by the so-called genito-urinary syndrome of menopause (GSM), a chronic condition encompassing many clinical signs of uro-genital atrophy, that may occur as a result of hormonal deprivation after 1736
menopause, with a clear impact on the ability of peripheral organs to respond to sexual stimuli [9]. By managing GSM with the use of systemic and/or local hormone therapy (HT), a significant improvement of the pain domain (vaginal dryness and dyspareunia) is observed in women with menopausal symptoms because the atrophic signs ameliorate with estrogens. However, HT is not a comprehensive solution to treat FSD because a multitude of bio-psychosocial factors may influence the cascade effect of removing sexual pain on other sexual dimensions, including sexual desire [10]. HSDD, usually occurring after surgical menopause or in some women with natural menopause, is another example of the link between an endocrine condition, the so-called androgen insufficiency syndrome deriving from age and/or ovariectomy, and sexual symptoms. That being so, transdermal testosterone patch (TTP, 300 mcg/daily) was consistently effective and safe in the short term in postmenopausal women with sexual dysfunction due to HSDD [11]. However, these data from RCTs were not enough to induce the FDA to approve TTP when balancing clinical benefits and safety issues. TTP was, then, marketed in Europe in 2004 only to treat surgically (bilateral ovariectomy plus hysterectomy) menopausal women with HSDD, but it has been recently withdrawn due to low usage. Interestingly enough, in spite low desire was highly present in a large and ethnically diverse longitudinal study (SWAN), most of the women reported to be moderately or extremely sexual satisfied [12], indicating that the presence of sexual complaints does not mean, necessarily, to have FSD. In addition, both age and time since menopause may significantly affect the levels of distress driving women’s motivation to treatment. That being so, the decision to treat FSD in postmenopausal women with HT, including T, requires a well-balanced view in light of the publication of the Women’s Health Initiative studies [13]. In the meantime hormonal strategies were under evaluation for postmenopausal women, the burden of FSD in premenopausal women was considered also from a mental perspective by testing psychoactive agents for the treatment of HSDD. Indeed, some antidepressants produce sexual side effects. Moreover, research data suggest that sexual incentives and sexual inhibitory clues act on the neuroendocrine balance, which involves excitatory and inhibitory neurochemicals driving physical and genital arousal, according to the dual control model. Therefore, the FDA considered flibanserin, a compound inhibiting serotoninergic ‘anti-sexual’ effects and promoting ‘pro-sexual’ neurotransmitters, such as dopamine and norepinephrine. RCTs showed that flibanserin at the dose of 100 mg qhs (single daily dose at bedtime) displayed a statistically and clinically significant improvement in the number of satisfactory sexual events, level of sexual desire and reduction of distress relative to placebo after 24 weeks and up to 52 weeks of treatment in open arm [14]. However, flibanserin was not approved by the FDA, mainly because of safety issues and poor judgment of its clinical effect. Disappointment is evident in part of the scientific community, because the absence of FDA-approved products for FSD promotes
Expert Opin. Pharmacother. (2015) 16(12)
Why are there no FDA-approved treatments for female sexual dysfunction?
especially the use of male testosterone (T) products or T compounded at pharmacies for treating women, without any assessment of real efficacy and safety, along with a wide range of ‘miraculous’ products with no rigorous science-based evidence [15].
Downloaded by [University of California, San Diego] at 21:30 22 August 2015
2.
Expert opinion
Pharmacotherapy for treating FSD is still under investigation and the only way to finally obtain the approval for a labeled drug is to keep on doing insightful research centered on women’s needs and expectations, hopefully with novel available treatments. Multidimensional tools to translate changes in sexual domain scores into satisfactory sexual experiences are needed to quantify the impact of a candidate drug on partnership and personal distress. FSD is an unmet clinical condition not because of gender inequality by medical regulatory agencies that did not take good care of women, but as a consequence of overprotection by a group of experts lacking a multidimensional expertise. Indeed, by judging the effect of a candidate drug only in a reproductive perspective, the process of balancing efficacy and safety of a chronic treatment for a non-life threatening condition could be very difficult, especially in women of childbearing age, and even in the clinical practice of menopause. Although safety issues are equally important in both sexes, the need of a drug on a regular basis for several weeks in order to produce a meaningful sexual effect in women is the main reason for caution. It is fair enough to say that it has been much easier for the FDA to advice on off-hand drugs rapidly effective on a clearly Bibliography
Hawkes S. Sexual health: a post-2015 palimpsest in global health? Lancet Glob Health 2014;2:e377-8
2.
Goldstein I. Raising the glass ceiling: not all “men” are created equal. J Sex Med 2014;11:1885-7
3.
4.
5.
.
American Psychiatric Association. Highlights of changes from DSM-IV-TR to DSM-5. American Psychiatric Press, Washington DC; 2013 Nappi RE, Cucinella L. Advances in pharmacotherapy for treating female sexual dysfunction. Expert Opin Pharmacother 2015;16:875-87 Bradford A. Listening to placebo in clinical trials for female sexual dysfunction. J Sex Med 2013;10:451-9 A well-focused point of view on the importance of the placebo effect in
Declaration of interest RE Nappi had financial relationship (lecturer, member of advisory boards and/or consultant) with Bayer HealthCare AG, Boehringer Ingelheim, Ely Lilly, Gedeon Richter, HRA Pharma, Merck Sharpe & Dohme, Novo Nordisk, Pfizer Inc., Procter & Gamble Co, Shionogi Limited, TEVA Women’s Health Inc. The author has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.
clincial trials investigating the impact of drugs on sexual symptoms in women.
Papers of special note have been highlighted as either of interest () or of considerable interest () to readers. 1.
measurable response such as penile erection hardness in men. Therefore, the possibility to use on-demand drugs also for women should be evaluated in further studies taking into account the new DSM-5 diagnostic criteria. Somebody may argue that many chronic T treatments are available for men, and even a psychoactive agent used on a regular basis was approved for premature ejaculation. However, it should be acknowledged that testosterone cut-off plasma level was identified for male hypogonadism, as well as the intravaginal ejaculation latency time was easily measurable. In conclusion, I do hope we will stop carrying the flag of ‘disease mongering’ or of ‘the battle of sexes’, as far as FSD are concerned. Research is ongoing taking into account the bio-psychosocial model and my wish is that we will all stand at women’s side working hard on efficacy and safety, in order to finally get an FDA-approved treatment in the near future.
6.
7.
8.
9.
Bitzer J, Giraldi A, Pfaus J. A standardized diagnostic interview for hypoactive sexual desire disorder in women: standard operating procedure (SOP Part 2). J Sex Med 2013;10:50-7 Chivers ML, Rosen RC. Phosphodiesterase type 5 inhibitors and female sexual response: faulty protocols or paradigms? J Sex Med 2010;7:858-72 Nappi RE, Domoney C. Pharmacogenomics and sexuality: a vision. Climacteric 2013;16(Suppl 1):25-30 Portman DJ, Gass ML; Vulvovaginal atrophy terminology consensus conference panel. Genitourinary syndrome of menopause: new terminology for vulvovaginal atrophy from the international society for the study of women’s sexual health and the
Expert Opin. Pharmacother. (2015) 16(12)
..
North American Menopause Society. J Sex Med 2014;11:2865-72 An innovative definition to expand the concept of vulvo-vaginal atrophy and open the way to further studies in the field of menopausal sexual health.
10.
Wierman ME, Nappi RE, Avis N, et al. Endocrine aspects of women’s sexual function. J Sex Med 2010;7:561-85
11.
Davis SR, Worsley R. Androgen treatment of postmenopausal women. J Steroid Biochem Mol Biol 2014;142:107-14
12.
Avis NE, Brockwell S, Randolph JF, et al. Longitudinal changes in sexual functioning as women transition through menopause: results from the Study of Women’s Health Across the Nation. Menopause 2009;16:442-52
13.
Nappi RE, Davis SR. The use of hormone therapy for the maintenance of
1737
R. E. Nappi
.
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Affiliation Rossella E Nappi MD PhD University of Pavia, IRCCS Policlinico San Matteo, Research Center for Reproductive Medicine, Gynecological Endocrinology and Menopause, Department of Clinical, Surgical, Diagnostic and Paediatric Sciences, Piazzale Golgi 2, 27100 Pavia, Italy Tel: +39 0382 501561; Fax: +39 0382 423233; E-mail: [email protected]
