madman
Super Moderator
Androgen Therapy in Women with Testosterone Insufficiency: Looking Back and Looking Ahead (2022)
Abdulmaged M. Traish and Abraham Morgentaler
Abstract
In women, androgens not only serve as precursors for the biosynthesis of estrogens but also exert a critical physiological role in sexual function, bone health, mood, behavior, and cognition. Despite research in the 1940s establishing the physiological role of testosterone (T) in women’s health and the substantial benefits of T therapy (TTh) in women, the use of TTh in women today is rare, with little awareness of its value and safety within the medical community. We have identified several factors that have contributed to this situation, including The rationale and use of androgens in women are not taught in medical schools; residual fear from the Women’s Health Initiative study that sex hormones are associated with increased breast cancer risk; and absence of regulatory approved T products for women in most parts of the world, except Australia. Although concerns regarding the efficacy and safety of TTh in women with sexual dysfunction have been appropriately addressed in randomized, placebo-controlled, studies TTh in women is prescribed by only a small percentage of physicians, and women who choose this treatment must use products intended for men as off-label treatment or find products via compounding pharmacies. Looking forward, we envision the possibility within the near future of symptomatic women with T insufficiency finding sympathetic health care providers who will recognize and appropriately treat their condition without negative judgment, allowing these women to experience the health and well-being associated with robust T levels. For this vision to occur, it will require education in medical school and postgraduate training, and broader acceptance of the science of TTh in women, noting its benefits and excellent safety profile.
Introduction
It is commonly believed that medical science moves forward inexorably, with researchers and clinicians constantly on the lookout for novel and useful treatments for various conditions afflicting humankind. Regrettably, our experience over many decades fails to support this notion. We have been dismayed by the failure of the medical community to recognize and embrace the use of testosterone (T) therapy (TTh) in women with T insufficiency and sexual dysfunction, despite remarkably powerful evidence of its benefits and safety dating back to the 1940s.
More than 80 years later, the use of TTh in women is rare, and there are no Food and Drug Administration (FDA)-approved T formulations indicated for use in women in the United States. Recently, a topical T formulation ‘‘Androphile’’ has been approved for use in women with hypoactive sexual desire disorder (HSDD) by the Australian Therapeutic Goods Administration and has been available in pharmacies across Australia since April 2021. We are not aware of any other testosterone products for women approved by regulatory agencies in any other countries.
Here, we provide a historical perspective and review key studies from the past demonstrating the importance of TTh in women, discuss events that have negatively impacted the adoption of this valuable therapeutic treatment, and consider how greater awareness of the value of TTh in women will improve the health and well-being of women across the world.
*An Historical Perspective on TTh in Women with Sexual Dysfunction
*The Era of Clinical Trials of TTh in Women with Sexual Dysfunction
*Effects of TTh on Other Metabolic Function in Women
*Safety of TTh in Women
Events Negatively Impacting Adoption of TTh in Women
In our view, several key events have contributed to the failure of the medical community to recognize the importance of androgen insufficiency in women and to adopt the treatment of affected women. These include (1) response to the publication of findings from the Women’s Health Initiative (WHI), (2) lack of approval for T formulations for women by the U.S. FDA, (3) the Endocrine Society Guidelines on TTh in women with T deficiency and (4) lack of education and training of health care professionals (HCPs) in this field.
-The WHI study
-Absence of FDA-approved T formulations for women
-The Endocrine Society Guidelines on TTh in women
-Lack of education regarding women’s sexual health
Looking Ahead
The limited awareness of the importance of T insufficiency in women is an excellent example of how medical science fails to progress in a straight line from compelling research to clinical practice. Indeed, as reviewed earlier, much of the fundamental information regarding both the impact of T insufficiency and the benefits of treatment with TTh has been known for 80 years. And yet, the plight of affected women is that they are unlikely to be diagnosed, and even less likely to be treated. If they do receive treatment, it will be off-label via compounded medications since there are no regulatory-approved T products available throughout most of the world.
The impact of this is enormous, affecting millions of women in the United States alone, depriving them (and their partners) of satisfying sexual relations, strength, and vigor. How can this be rectified? Looking ahead, we see a number of steps that will be necessary to alter this course. First, the research must and will continue. We are confident this will occur, as an increasing number of investigators around the world have demonstrated interest in T and its effects on women.
Funding is likely to improve as the false fears generated by the WHI regarding sex hormones continue to fade. Of course, there is always the risk of another study being published that grabs headlines and sets back the field, but this becomes less likely as the foundational science becomes more established. Research alone will not be enough, however, as we have already seen.
Second, the lack of education regarding women’s sexual dysfunction, and T insufficiency, need to be addressed during medical education and training. Inclusion of this topic in formal curricula will go a long way to creating a sense among trainees that T insufficiency is a condition that merits serious attention, no less than the hundreds of other medical conditions taught in medical school.
Third, it will be helpful if professional organizations lend their support to the importance of diagnosing and treating women with T deficiency. Investigators and clinicians should consider promoting this concept within their own societies.
Fourth, it is to be hoped that one or more T products for women obtain regulatory approval in the United States and other countries. It is, of course, a business decision for pharmaceutical companies to decide whether to pursue the development of such a product, entailing considerable costs and efforts, which must be balanced against the likelihood of successful adoption of the treatment once approval is obtained.
We believe enough time has passed since the last FDA submission for a T product for women for there to be a more receptive attitude by regulatory agencies, which appear to have been spooked the last time by the firestorm caused by the WHI and rampant fears of serious adverse events with HRT, none of which have proven correct over the ensuing two decades. Although compounded T products are effective for women, the availability of an approved product by a regulatory agency such as the FDA would provide considerable comfort to prescribing HCPs and to patients alike and would go a long way toward making it easier for affected women to receive treatment.
Looking ahead, we are very encouraged by the recommendations and conclusions of the ‘‘The Global Consensus Position Statement’’ on the use of TTh for women.100–103 This position statement is a valuable resource for all clinicians who are treating women complaining of HSDD. The recommendations of this Position Statement are evidence-based on data derived from randomized controlled clinical trials and metaanalyses. The panel recommended that the diagnosis of HSDD must involve a careful and complete clinical assessment and contributing factors to sexual dysfunction in women be determined and managed before commencing TTh.
The international panel was clear in its recommendations and conclusions that the only evidence-based indication for TTh for women is for HSDD treatment, given that the contemporary available data provide a modest therapeutic benefit. The Position Statement provided a clear and firm indication for TTh in women as well as the potential adverse effects of this therapy and highlighted knowledge gaps remaining to be bridged. Although meta-analyses of the available data showed no severe adverse events during physiological T use in women, caution needs are exercised.
Looking back, we are struck by the failure of science to effect meaningful change in clinical practice for women with T insufficiency over such a long period of time. Looking forward, we are encouraged by numerous developments in the field, perhaps especially by the growing calls to make women’s health a priority. We can easily envision a time in the not-too-distant future when women with symptoms of T insufficiency are evaluated respectfully and without dismissing the importance of their symptoms, undergo a prompt and thorough evaluation, and are offered effective treatment when appropriate. The consequences of this vision are not only improved health and well-being for those women, but also a happier existence for their families, friends, and society as a whole.
Abdulmaged M. Traish and Abraham Morgentaler
Abstract
In women, androgens not only serve as precursors for the biosynthesis of estrogens but also exert a critical physiological role in sexual function, bone health, mood, behavior, and cognition. Despite research in the 1940s establishing the physiological role of testosterone (T) in women’s health and the substantial benefits of T therapy (TTh) in women, the use of TTh in women today is rare, with little awareness of its value and safety within the medical community. We have identified several factors that have contributed to this situation, including The rationale and use of androgens in women are not taught in medical schools; residual fear from the Women’s Health Initiative study that sex hormones are associated with increased breast cancer risk; and absence of regulatory approved T products for women in most parts of the world, except Australia. Although concerns regarding the efficacy and safety of TTh in women with sexual dysfunction have been appropriately addressed in randomized, placebo-controlled, studies TTh in women is prescribed by only a small percentage of physicians, and women who choose this treatment must use products intended for men as off-label treatment or find products via compounding pharmacies. Looking forward, we envision the possibility within the near future of symptomatic women with T insufficiency finding sympathetic health care providers who will recognize and appropriately treat their condition without negative judgment, allowing these women to experience the health and well-being associated with robust T levels. For this vision to occur, it will require education in medical school and postgraduate training, and broader acceptance of the science of TTh in women, noting its benefits and excellent safety profile.
Introduction
It is commonly believed that medical science moves forward inexorably, with researchers and clinicians constantly on the lookout for novel and useful treatments for various conditions afflicting humankind. Regrettably, our experience over many decades fails to support this notion. We have been dismayed by the failure of the medical community to recognize and embrace the use of testosterone (T) therapy (TTh) in women with T insufficiency and sexual dysfunction, despite remarkably powerful evidence of its benefits and safety dating back to the 1940s.
More than 80 years later, the use of TTh in women is rare, and there are no Food and Drug Administration (FDA)-approved T formulations indicated for use in women in the United States. Recently, a topical T formulation ‘‘Androphile’’ has been approved for use in women with hypoactive sexual desire disorder (HSDD) by the Australian Therapeutic Goods Administration and has been available in pharmacies across Australia since April 2021. We are not aware of any other testosterone products for women approved by regulatory agencies in any other countries.
Here, we provide a historical perspective and review key studies from the past demonstrating the importance of TTh in women, discuss events that have negatively impacted the adoption of this valuable therapeutic treatment, and consider how greater awareness of the value of TTh in women will improve the health and well-being of women across the world.
*An Historical Perspective on TTh in Women with Sexual Dysfunction
*The Era of Clinical Trials of TTh in Women with Sexual Dysfunction
*Effects of TTh on Other Metabolic Function in Women
*Safety of TTh in Women
Events Negatively Impacting Adoption of TTh in Women
In our view, several key events have contributed to the failure of the medical community to recognize the importance of androgen insufficiency in women and to adopt the treatment of affected women. These include (1) response to the publication of findings from the Women’s Health Initiative (WHI), (2) lack of approval for T formulations for women by the U.S. FDA, (3) the Endocrine Society Guidelines on TTh in women with T deficiency and (4) lack of education and training of health care professionals (HCPs) in this field.
-The WHI study
-Absence of FDA-approved T formulations for women
-The Endocrine Society Guidelines on TTh in women
-Lack of education regarding women’s sexual health
Looking Ahead
The limited awareness of the importance of T insufficiency in women is an excellent example of how medical science fails to progress in a straight line from compelling research to clinical practice. Indeed, as reviewed earlier, much of the fundamental information regarding both the impact of T insufficiency and the benefits of treatment with TTh has been known for 80 years. And yet, the plight of affected women is that they are unlikely to be diagnosed, and even less likely to be treated. If they do receive treatment, it will be off-label via compounded medications since there are no regulatory-approved T products available throughout most of the world.
The impact of this is enormous, affecting millions of women in the United States alone, depriving them (and their partners) of satisfying sexual relations, strength, and vigor. How can this be rectified? Looking ahead, we see a number of steps that will be necessary to alter this course. First, the research must and will continue. We are confident this will occur, as an increasing number of investigators around the world have demonstrated interest in T and its effects on women.
Funding is likely to improve as the false fears generated by the WHI regarding sex hormones continue to fade. Of course, there is always the risk of another study being published that grabs headlines and sets back the field, but this becomes less likely as the foundational science becomes more established. Research alone will not be enough, however, as we have already seen.
Second, the lack of education regarding women’s sexual dysfunction, and T insufficiency, need to be addressed during medical education and training. Inclusion of this topic in formal curricula will go a long way to creating a sense among trainees that T insufficiency is a condition that merits serious attention, no less than the hundreds of other medical conditions taught in medical school.
Third, it will be helpful if professional organizations lend their support to the importance of diagnosing and treating women with T deficiency. Investigators and clinicians should consider promoting this concept within their own societies.
Fourth, it is to be hoped that one or more T products for women obtain regulatory approval in the United States and other countries. It is, of course, a business decision for pharmaceutical companies to decide whether to pursue the development of such a product, entailing considerable costs and efforts, which must be balanced against the likelihood of successful adoption of the treatment once approval is obtained.
We believe enough time has passed since the last FDA submission for a T product for women for there to be a more receptive attitude by regulatory agencies, which appear to have been spooked the last time by the firestorm caused by the WHI and rampant fears of serious adverse events with HRT, none of which have proven correct over the ensuing two decades. Although compounded T products are effective for women, the availability of an approved product by a regulatory agency such as the FDA would provide considerable comfort to prescribing HCPs and to patients alike and would go a long way toward making it easier for affected women to receive treatment.
Looking ahead, we are very encouraged by the recommendations and conclusions of the ‘‘The Global Consensus Position Statement’’ on the use of TTh for women.100–103 This position statement is a valuable resource for all clinicians who are treating women complaining of HSDD. The recommendations of this Position Statement are evidence-based on data derived from randomized controlled clinical trials and metaanalyses. The panel recommended that the diagnosis of HSDD must involve a careful and complete clinical assessment and contributing factors to sexual dysfunction in women be determined and managed before commencing TTh.
The international panel was clear in its recommendations and conclusions that the only evidence-based indication for TTh for women is for HSDD treatment, given that the contemporary available data provide a modest therapeutic benefit. The Position Statement provided a clear and firm indication for TTh in women as well as the potential adverse effects of this therapy and highlighted knowledge gaps remaining to be bridged. Although meta-analyses of the available data showed no severe adverse events during physiological T use in women, caution needs are exercised.
Looking back, we are struck by the failure of science to effect meaningful change in clinical practice for women with T insufficiency over such a long period of time. Looking forward, we are encouraged by numerous developments in the field, perhaps especially by the growing calls to make women’s health a priority. We can easily envision a time in the not-too-distant future when women with symptoms of T insufficiency are evaluated respectfully and without dismissing the importance of their symptoms, undergo a prompt and thorough evaluation, and are offered effective treatment when appropriate. The consequences of this vision are not only improved health and well-being for those women, but also a happier existence for their families, friends, and society as a whole.
