madman
Super Moderator
ABSTRACT
Background: The Global Consensus Position Statement on the Use of Testosterone Therapy for Women (Global Position Statement) recommended testosterone therapy for postmenopausal women with hypoactive sexual desire disorder (HSDD).
Aim: To provide a clinical practice guideline for the use of testosterone including identification of patients, laboratory testing, dosing, post-treatment monitoring, and follow-up care in women with HSDD.
Methods: The International Society for the Study of Women’s Sexual Health appointed a multidisciplinary panel of experts who performed a literature review of original research, meta-analyses, review papers, and consensus guidelines regarding testosterone use in women. The consensus was reached using a modified Delphi method.
Outcomes: A clinically useful guideline following a biopsychosocial assessment and treatment approach for the safe and efficacious use of testosterone in women with HSDD was developed including measurement, indications, formulations, prescribing, dosing, monitoring, and follow-up.
Results: Although the Global Position Statement endorses testosterone therapy for only postmenopausal women, limited data also support the use in late reproductive age premenopausal women, consistent with the International Society for the Study of Women’s Sexual Health Process of Care for the Management of HSDD. Systemic transdermal testosterone is recommended for women with HSDD not primarily related to modifiable factors or comorbidities such as relationship or mental health problems. Currently, available research supports a moderate therapeutic benefit. Safety data show no serious adverse events with physiologic testosterone use, but long-term safety has not been established. Before initiation of therapy, clinicians should provide informed consent. Shared decision-making involves a comprehensive discussion of off-label use, as well as benefits and risks. A total testosterone level should not be used to diagnose HSDD, but as a baseline for monitoring. Government-approved transdermal male formulations can be used cautiously with dosing appropriate for women. Patients should be assessed for signs of androgen excess and total testosterone levels monitored to maintain concentrations in the physiologic premenopausal range. Compounded products cannot be recommended because of the lack of efficacy and safety data.
Clinical Implications: This clinical practice guideline provides standards for safely prescribing testosterone to women with HSDD, including identification of appropriate patients, dosing, and monitoring.
Strengths & Limitations: This evidence-based guideline builds on a recently published comprehensive meta-analysis and the Global Position Statement endorsed by numerous societies. The limitation is that testosterone therapy is not approved for women by most regulatory agencies, thereby making prescribing and proper dosing challenging.
Conclusion: Despite substantial evidence regarding safety, efficacy, and clinical use, access to testosterone therapy for the treatment of HSDD in women remains a significant unmet need.
INTRODUCTION
Testosterone has been an important evidence-based, albeit controversial, therapy for women with hypoactive sexual desire disorder (HSDD). Over the past 2 decades, multiple publications consisting of original research, reviews, and meta-analyses have supported the use of testosterone therapy for HSDD in postmenopausal women.1e5 The Global Consensus Position Statement on the Use of Testosterone Therapy for Women (Global Position Statement) was recently published simultaneously in 4 journals, with authors representing 10 societies including the International Society for the Study of Women’s Sexual Health (ISSWSH) and endorsed by the ISSWSH and 10 other sexual medicine, endocrine, obstetrics and gynecology, and menopause societies.6e9 The Global Position Statement is the most comprehensive, evidence-based guideline to date, superseding all previous guidelines. It provided clinical guidance regarding the use of testosterone therapy in women, examining the effect on sexual function; well-being, mood, and cognition; musculoskeletal effects; cardiovascular and breast health; as well as androgenic side effects and adverse events. The conclusions were developed based on the systematic review and meta-analysis of the benefits and risks of testosterone therapy in women,5 and the clinical practice recommendations were based on the expert opinion and the consensus of the panelists. According to the Global Position Statement, the sole evidence-based indication for testosterone therapy is HSDD in postmenopausal women, using a biopsychosocial assessment and treatment model.6 The Global Position Statement provides the evidence and standard of care for the use of testosterone in women and serves as the basis for this clinical guidance document. There remains a need for a consensus clinical practice guideline that provides a comprehensive management strategy for the use of systemic testosterone in women with HSDD. The purpose of the present article is to provide specific recommendations regarding the identification of patients, laboratory testing, dosing, monitoring, and follow-up care in the consideration of testosterone therapy for HSDD in women.
CLASSIFICATION OF HSDD
EPIDEMIOLOGY OF MENOPAUSE AND IMPACT ON SEXUAL HEALTH
PHYSIOLOGY OF ANDROGENS IN WOMEN
Testosterone is a metabolic, vascular, and reproductive hormone in women.42-44 The production of testosterone in premenopausal women has been estimated to be approximately 0.2-0.25 mg/day.45 In premenopausal women, the median circulating testosterone levels are similar to those of estradiol and estrone, ranging from 300 to 400 pmol/L.46 Testosterone circulates in nanomolar concentrations in women, whereas estradiol circulates in picomolar concentrations.47 Testosterone and its precursors are synthesized by the ovaries and adrenal glands, with about 50% of circulating testosterone produced by peripheral conversion of these androgen precursors (Figure 1).48
Testosterone directly, or via its metabolism to 5a-dihydrotestosterone (5a-DHT) or aromatization to estradiol, modulates many biochemical and physiological pathways, thus regulating cellular metabolism (Figure 2).49,50 Testosterone influences sexual differentiation of the genitalia and the brain determines secondary sexual characteristics during development and sexual maturation, contributing to the maintenance of their functional state in adulthood, and modulates sexual behavior.44 5a-DHT is the most potent androgen and has the highest binding affinity to the androgen receptor (AR),4 whereas the testosterone precursors androstenedione and dehydroepiandrosterone (DHEA) are only weakly androgenic. In circulation, testosterone is loosely bound to albumin (~30-45%) and more strongly bound to SHBG (~65%) with a small fraction (1-3%) circulating as “free testosterone.”
Testosterone and 5a-DHT modulate cellular function by genomic and nongenomic mechanisms.51e53 The genomic mechanisms involve binding of testosterone or 5a-DHT to the AR with concomitant activation and translocation of the ARhormone complex into the nucleus and binding of the complex to androgen response elements on target genes (Figure 3). This reaction leads to recruitment of transcriptional factors and interaction with receptor coactivators or corepressors resulting in gene activation or repression and modification of cellular metabolism.54,55 The nongenomic action of androgens is thought to occur, in part, via binding of testosterone or 5a-DHT to a putative membrane AR or to the classical AR. These interactions elicit activation of G-protein coupled receptors and/or stimulation of intracellular kinases with a concomitant increase in the synthesis of second messengers.49,50 These nongenomic signaling events may regulate neural activity in the central nervous system, as suggested by human brain imaging studies.56,57 However, this has not been studied directly in the context of sexual function. Nevertheless, the wide expression of the AR in various tissues including the female central nervous system and genital and other reproductive tissues suggest that androgens play an important physiological role in female sexual function.58
MECHANISM OF ACTION OF SEX STEROIDS
*Central Mechanisms in Animal Models
*Central Mechanisms in Women
*Peripheral Mechanisms
*Regulation
*Maintenance
*Modulation
ROLE OF LABORATORY EVALUATION OF ANDROGEN LEVELS IN MANAGING HSDD
*How Is Testosterone Measured?
*What Is the Association Between Androgen Levels and Aging?
*Do Androgen Levels Correlate With Sexual Function and Predict HSDD?
*What Is the Rationale for Testosterone Therapy in Women?
*Are There Normal Values and Treatment Targets?
*Why Should Testosterone Be Measured?
CLINICAL TRIALS DATA REGARDING SAFETY OF TESTOSTERONE
*Short-Term Safety
*Long-Term Safety
*Future Strategies to Assess Safety
MANAGEMENT GUIDELINES
*Diagnosis of HSDD
*Biopsychosocial Treatment Model
*When to Treat
*Who to Treat
*Special Populations
*Antidepressant Treatment-Emergent Sexual Dysfunction
*Premature Ovarian Insufficiency and Early Menopause
*Formulation
*Dosing
*Monitoring
*Cost and Acquisition of Testosterone Products
*Is DHEA Effective for the Treatment of HSDD?
CONCLUSION
Government-approved testosterone therapy for women is not currently available worldwide, presumably because of the lack of long-term efficacy and safety data and the barriers to product development and approval. Systemic transdermal testosterone therapy is recommended by the Global Position Statement for postmenopausal women; in this Clinical Practice Guideline, testosterone is recommended for postmenopausal and late reproductive-age women with HSDD. Currently, available research supports a moderate therapeutic benefit. Available safety data show no serious adverse events with physiologic testosterone use, but long-term safety has not been established.5 Using established clinical guidelines, such as the ISSWSH POC for the management of HSDD,15 the diagnosis should include a thorough biopsychosocial clinical assessment that leads to the identification, modification, and management of contributing factors before testosterone therapy is considered. Before initiation of therapy, patients should receive informed consent, and shared decision-making should involve a comprehensive discussion of off-label use, as well as benefits and risks.140 A total testosterone level should not be used to diagnose HSDD. Total testosterone is recommended as the best available measure, rather than free or bioavailable testosterone or FAI. Transdermal formulations can be used cautiously with dosing appropriate for women, and signs of androgen excess and total testosterone levels must be monitored routinely to maintain women in the physiologic premenopausal range. The Global Position Statement, the National Academies of Science, Engineering, and Medicine Report, and this Clinical Practice Guideline recommend against the use of compounded testosterone.6,138
Although the FDA and other government agencies acknowledge the treatment of HSDD in postmenopausal women as a significant unmet need, barriers to regulatory approval for a female testosterone product are formidable. Most important is the lack of guidance as to the types of studies, endpoints, results, and safety data required for approval, in contrast to the clear pathway for testosterone products for men.159 More clinical trial evidence demonstrating longer and more robust testosterone safety data is integral to the development, submission, and regulatory approval of testosterone preparations specifically indicated and designed for women.
Background: The Global Consensus Position Statement on the Use of Testosterone Therapy for Women (Global Position Statement) recommended testosterone therapy for postmenopausal women with hypoactive sexual desire disorder (HSDD).
Aim: To provide a clinical practice guideline for the use of testosterone including identification of patients, laboratory testing, dosing, post-treatment monitoring, and follow-up care in women with HSDD.
Methods: The International Society for the Study of Women’s Sexual Health appointed a multidisciplinary panel of experts who performed a literature review of original research, meta-analyses, review papers, and consensus guidelines regarding testosterone use in women. The consensus was reached using a modified Delphi method.
Outcomes: A clinically useful guideline following a biopsychosocial assessment and treatment approach for the safe and efficacious use of testosterone in women with HSDD was developed including measurement, indications, formulations, prescribing, dosing, monitoring, and follow-up.
Results: Although the Global Position Statement endorses testosterone therapy for only postmenopausal women, limited data also support the use in late reproductive age premenopausal women, consistent with the International Society for the Study of Women’s Sexual Health Process of Care for the Management of HSDD. Systemic transdermal testosterone is recommended for women with HSDD not primarily related to modifiable factors or comorbidities such as relationship or mental health problems. Currently, available research supports a moderate therapeutic benefit. Safety data show no serious adverse events with physiologic testosterone use, but long-term safety has not been established. Before initiation of therapy, clinicians should provide informed consent. Shared decision-making involves a comprehensive discussion of off-label use, as well as benefits and risks. A total testosterone level should not be used to diagnose HSDD, but as a baseline for monitoring. Government-approved transdermal male formulations can be used cautiously with dosing appropriate for women. Patients should be assessed for signs of androgen excess and total testosterone levels monitored to maintain concentrations in the physiologic premenopausal range. Compounded products cannot be recommended because of the lack of efficacy and safety data.
Clinical Implications: This clinical practice guideline provides standards for safely prescribing testosterone to women with HSDD, including identification of appropriate patients, dosing, and monitoring.
Strengths & Limitations: This evidence-based guideline builds on a recently published comprehensive meta-analysis and the Global Position Statement endorsed by numerous societies. The limitation is that testosterone therapy is not approved for women by most regulatory agencies, thereby making prescribing and proper dosing challenging.
Conclusion: Despite substantial evidence regarding safety, efficacy, and clinical use, access to testosterone therapy for the treatment of HSDD in women remains a significant unmet need.
INTRODUCTION
Testosterone has been an important evidence-based, albeit controversial, therapy for women with hypoactive sexual desire disorder (HSDD). Over the past 2 decades, multiple publications consisting of original research, reviews, and meta-analyses have supported the use of testosterone therapy for HSDD in postmenopausal women.1e5 The Global Consensus Position Statement on the Use of Testosterone Therapy for Women (Global Position Statement) was recently published simultaneously in 4 journals, with authors representing 10 societies including the International Society for the Study of Women’s Sexual Health (ISSWSH) and endorsed by the ISSWSH and 10 other sexual medicine, endocrine, obstetrics and gynecology, and menopause societies.6e9 The Global Position Statement is the most comprehensive, evidence-based guideline to date, superseding all previous guidelines. It provided clinical guidance regarding the use of testosterone therapy in women, examining the effect on sexual function; well-being, mood, and cognition; musculoskeletal effects; cardiovascular and breast health; as well as androgenic side effects and adverse events. The conclusions were developed based on the systematic review and meta-analysis of the benefits and risks of testosterone therapy in women,5 and the clinical practice recommendations were based on the expert opinion and the consensus of the panelists. According to the Global Position Statement, the sole evidence-based indication for testosterone therapy is HSDD in postmenopausal women, using a biopsychosocial assessment and treatment model.6 The Global Position Statement provides the evidence and standard of care for the use of testosterone in women and serves as the basis for this clinical guidance document. There remains a need for a consensus clinical practice guideline that provides a comprehensive management strategy for the use of systemic testosterone in women with HSDD. The purpose of the present article is to provide specific recommendations regarding the identification of patients, laboratory testing, dosing, monitoring, and follow-up care in the consideration of testosterone therapy for HSDD in women.
CLASSIFICATION OF HSDD
EPIDEMIOLOGY OF MENOPAUSE AND IMPACT ON SEXUAL HEALTH
PHYSIOLOGY OF ANDROGENS IN WOMEN
Testosterone is a metabolic, vascular, and reproductive hormone in women.42-44 The production of testosterone in premenopausal women has been estimated to be approximately 0.2-0.25 mg/day.45 In premenopausal women, the median circulating testosterone levels are similar to those of estradiol and estrone, ranging from 300 to 400 pmol/L.46 Testosterone circulates in nanomolar concentrations in women, whereas estradiol circulates in picomolar concentrations.47 Testosterone and its precursors are synthesized by the ovaries and adrenal glands, with about 50% of circulating testosterone produced by peripheral conversion of these androgen precursors (Figure 1).48
Testosterone directly, or via its metabolism to 5a-dihydrotestosterone (5a-DHT) or aromatization to estradiol, modulates many biochemical and physiological pathways, thus regulating cellular metabolism (Figure 2).49,50 Testosterone influences sexual differentiation of the genitalia and the brain determines secondary sexual characteristics during development and sexual maturation, contributing to the maintenance of their functional state in adulthood, and modulates sexual behavior.44 5a-DHT is the most potent androgen and has the highest binding affinity to the androgen receptor (AR),4 whereas the testosterone precursors androstenedione and dehydroepiandrosterone (DHEA) are only weakly androgenic. In circulation, testosterone is loosely bound to albumin (~30-45%) and more strongly bound to SHBG (~65%) with a small fraction (1-3%) circulating as “free testosterone.”
Testosterone and 5a-DHT modulate cellular function by genomic and nongenomic mechanisms.51e53 The genomic mechanisms involve binding of testosterone or 5a-DHT to the AR with concomitant activation and translocation of the ARhormone complex into the nucleus and binding of the complex to androgen response elements on target genes (Figure 3). This reaction leads to recruitment of transcriptional factors and interaction with receptor coactivators or corepressors resulting in gene activation or repression and modification of cellular metabolism.54,55 The nongenomic action of androgens is thought to occur, in part, via binding of testosterone or 5a-DHT to a putative membrane AR or to the classical AR. These interactions elicit activation of G-protein coupled receptors and/or stimulation of intracellular kinases with a concomitant increase in the synthesis of second messengers.49,50 These nongenomic signaling events may regulate neural activity in the central nervous system, as suggested by human brain imaging studies.56,57 However, this has not been studied directly in the context of sexual function. Nevertheless, the wide expression of the AR in various tissues including the female central nervous system and genital and other reproductive tissues suggest that androgens play an important physiological role in female sexual function.58
MECHANISM OF ACTION OF SEX STEROIDS
*Central Mechanisms in Animal Models
*Central Mechanisms in Women
*Peripheral Mechanisms
*Regulation
*Maintenance
*Modulation
ROLE OF LABORATORY EVALUATION OF ANDROGEN LEVELS IN MANAGING HSDD
*How Is Testosterone Measured?
*What Is the Association Between Androgen Levels and Aging?
*Do Androgen Levels Correlate With Sexual Function and Predict HSDD?
*What Is the Rationale for Testosterone Therapy in Women?
*Are There Normal Values and Treatment Targets?
*Why Should Testosterone Be Measured?
CLINICAL TRIALS DATA REGARDING SAFETY OF TESTOSTERONE
*Short-Term Safety
*Long-Term Safety
*Future Strategies to Assess Safety
MANAGEMENT GUIDELINES
*Diagnosis of HSDD
*Biopsychosocial Treatment Model
*When to Treat
*Who to Treat
*Special Populations
*Antidepressant Treatment-Emergent Sexual Dysfunction
*Premature Ovarian Insufficiency and Early Menopause
*Formulation
*Dosing
*Monitoring
*Cost and Acquisition of Testosterone Products
*Is DHEA Effective for the Treatment of HSDD?
CONCLUSION
Government-approved testosterone therapy for women is not currently available worldwide, presumably because of the lack of long-term efficacy and safety data and the barriers to product development and approval. Systemic transdermal testosterone therapy is recommended by the Global Position Statement for postmenopausal women; in this Clinical Practice Guideline, testosterone is recommended for postmenopausal and late reproductive-age women with HSDD. Currently, available research supports a moderate therapeutic benefit. Available safety data show no serious adverse events with physiologic testosterone use, but long-term safety has not been established.5 Using established clinical guidelines, such as the ISSWSH POC for the management of HSDD,15 the diagnosis should include a thorough biopsychosocial clinical assessment that leads to the identification, modification, and management of contributing factors before testosterone therapy is considered. Before initiation of therapy, patients should receive informed consent, and shared decision-making should involve a comprehensive discussion of off-label use, as well as benefits and risks.140 A total testosterone level should not be used to diagnose HSDD. Total testosterone is recommended as the best available measure, rather than free or bioavailable testosterone or FAI. Transdermal formulations can be used cautiously with dosing appropriate for women, and signs of androgen excess and total testosterone levels must be monitored routinely to maintain women in the physiologic premenopausal range. The Global Position Statement, the National Academies of Science, Engineering, and Medicine Report, and this Clinical Practice Guideline recommend against the use of compounded testosterone.6,138
Although the FDA and other government agencies acknowledge the treatment of HSDD in postmenopausal women as a significant unmet need, barriers to regulatory approval for a female testosterone product are formidable. Most important is the lack of guidance as to the types of studies, endpoints, results, and safety data required for approval, in contrast to the clear pathway for testosterone products for men.159 More clinical trial evidence demonstrating longer and more robust testosterone safety data is integral to the development, submission, and regulatory approval of testosterone preparations specifically indicated and designed for women.
