madman
Super Moderator
ABSTRACT
Introduction: Testosterone therapy has been controversial since its synthesis from the 1930s to the present day. Testosterone’s history provides depth and context for current controversies.
Aim: To review the history of testosterone therapy from its initial synthesis in the 1930s to the modern-day.
Methods: Expert review of the literature.
Main Outcome Measures: Impactful events in the history of testosterone.
Results: By the 1940s there was already fascinating literature that described the many symptomatic benefits of testosterone therapy that are recognized today. Numerous early reports suggested testosterone therapy improved angina pectoris and peripheral vascular disease. The assertion by Huggins and Hodges (Cancer Res 1941;1:293e297) in 1941 that testosterone-activated prostate cancer (PCa) cast a pall for the next 70 years. The introduction of the radioimmunoassay in the 1970s shifted the diagnosis of testosterone deficiency from signs and symptoms to an undue emphasis on blood test results. The fear of PCa was the primary obstacle to the adoption of testosterone therapy for decades. Prescription rates increased as accumulated evidence showed testosterone therapy was not associated with increased PCa risks. The observation that androgenic stimulation of PCa reaches a maximum at relatively low testosterone concentrations—the saturation model—provided the theoretical framework for understanding the relationship between androgens and PCa and led to multiple case series documenting reassuring results of testosterone therapy in men with PCa. Recent concerns regarding cardiovascular risks also have diminished because new evidence suggests testosterone therapy might actually be cardioprotective. In 2016 the Testosterone Trials provided high-quality evidence of multiple benefits of testosterone therapy, nearly all of which had been recognized by clinicians by 1940.
Conclusions: If the past has any lessons for the future, it is likely that research will continue to demonstrate the health benefits of testosterone therapy, while it remains one of the most controversial topics in medicine.
INTRODUCTION
Most modern readers will be aware of the prominent place of testosterone (T) therapy among the most controversial topics of the past decade. However, few will be aware of the rich history of T, which was 1st synthesized more than 80 years ago and has been used for medical and non-medical purposes since that time. We present a review of the history of T from the perspective of 2 individuals who have been involved in this field for many decades, one as a researcher and the other as a clinician investigator.
We divided this review into 2 main sections. The 1st describes the discovery of T and the early years of its use as a therapeutic agent. This section is rich with observations and commentary that reflect the nature of science in that era, and we included several key passages from older articles and books to provide some flavor of those times and because many of these publications are not readily available to the modern reader. The 2nd section describes the modern history of T therapy through to the present day, noting key events and noteworthy publications and providing our perspectives on these events.
PART 1. THE EARLY YEARS OF TESTOSTERONE
*Discovery and Synthesis
*Early Clinical Experience With Testosterone
*Resistance to the Use of Testosterone
*Testosterone Therapy in Men With Vascular Disease
-Peripheral Vascular Disease
-Angina Pectoris
PART 2. RECENT HISTORY
The modern history of T deficiency and T therapy arguably begins with the introduction of the radioimmunoassay into clinical medicine in the 1970s. Indeed, this was the birth of modern endocrinology. For the 1st time, there was the ability to accurately, rapidly, and inexpensively measure minute concentrations of hormones in serum, an advance that permitted the determination of concentrations from milligrams per milliliter to nanograms per milliliter—a 1,000-fold improvement.
This was an enormous advantage, one that coincided with improved objective capabilities in many areas of medicine, including imaging techniques and the use of computers. The overall effect of these changes for T deficiency was to shift diagnosis from clinical presentation to laboratory values. This emphasis on objective data spawned the prevailing current approach to clinical practice that discourages treatment for many men with classic symptoms based on test results categorized as normal.
*Prostate Cancer
*Rise of Testosterone Therapy
*The Next Controversy: Overtreatment and a False Epidemic
*Cardiovascular Risk
*General Health Benefits
*Every clinician experienced with T therapy knows that one of the most important benefits of T therapy is what our patients tell us so often—they feel healthier, more vital, and with an improved sense of well-being.
TESTOSTERONE THERAPY TODAY AND IN THE FUTURE
T therapy has become a relatively common treatment for men with documented T deficiency. Clinicians observe a high rate of positive responses, often dramatic, in the areas of sexual desire, erectile function, energy, decreased fatigue, and improved mood. It is not unusual to hear a patient say he feels “younger” or “better than I’ve felt in years.” From a research perspective, the benefits of T therapy are well documented in several areas.
Despite the clarity of clinical results and scientific research, T therapy remains controversial. Critics continue to claim it has been over-marketed, resulting in overuse and abuse. Fears of PCa and CV risk persist despite a wealth of data that fail to support these concerns.
The controversial nature of the topic makes it challenging to predict what will happen to T therapy in the future. Some concerns appear to be emotional rather than based on fact.85 In addition, there are substantial differences in approach to treatment by medical specialties. Endocrinologists, for example, take a conservative approach to treatment, requiring strict adherence to biochemical thresholds before instituting treatment, whereas urologists are often more liberal with treatment, based on clinical presentation. The absence of consensus on basic questions, including who is a candidate for T therapy, represents a major hurdle for the field.
In the face of so much confusion and controversy, an International Expert Consensus Conference was held in Prague in 2015, involving 18 individuals from 12 countries, from endocrinology, urology, andrology, basic science, epidemiology, diabetology, and general medicine.86 There was unanimous agreement on several key points: T deficiency was a serious global problem; the evidence failed to support an increased risk of PCa or CV risk; total T was a useful but unreliable test to determine androgen status; and the possibility that T therapy is cardioprotective should be investigated, particularly in men with metabolic conditions such as diabetes and obesity.
An important detail was that the term “hypogonadism” should be replaced in most instances by “testosterone deficiency,” as we use in this text, because of its greater clarity, and similarly, “testosterone therapy” was favored over “testosterone replacement therapy.” 86
What will the future look like? We anticipate the introduction of more convenient treatment modalities such as oral formulations that achieve solid serum T concentrations without hepatotoxicity. Another consideration is long-lasting treatments that are not associated with side effects such as infertility and testicular atrophy. One promising idea is a slow-release human chorionic gonadotropin formulation, currently in development, designed to boost endogenous serum T for at least 2 months.
Another set of possibilities relates to the known properties of T therapy separate from its indication in the treatment of men with T deficiency. It seems reasonable to investigate whether short-term T treatments might have useful benefits in the treatment of trauma, sepsis, and perioperatively for major surgical operations such as radical cystectomy, or even for routine orthopedic procedures in which they could have value in promoting muscular repair and strength.
*If the past has any lessons for the future, T therapy research will continue to demonstrate new health benefits and continue to be one of the most controversial and fascinating topics in medicine.
Introduction: Testosterone therapy has been controversial since its synthesis from the 1930s to the present day. Testosterone’s history provides depth and context for current controversies.
Aim: To review the history of testosterone therapy from its initial synthesis in the 1930s to the modern-day.
Methods: Expert review of the literature.
Main Outcome Measures: Impactful events in the history of testosterone.
Results: By the 1940s there was already fascinating literature that described the many symptomatic benefits of testosterone therapy that are recognized today. Numerous early reports suggested testosterone therapy improved angina pectoris and peripheral vascular disease. The assertion by Huggins and Hodges (Cancer Res 1941;1:293e297) in 1941 that testosterone-activated prostate cancer (PCa) cast a pall for the next 70 years. The introduction of the radioimmunoassay in the 1970s shifted the diagnosis of testosterone deficiency from signs and symptoms to an undue emphasis on blood test results. The fear of PCa was the primary obstacle to the adoption of testosterone therapy for decades. Prescription rates increased as accumulated evidence showed testosterone therapy was not associated with increased PCa risks. The observation that androgenic stimulation of PCa reaches a maximum at relatively low testosterone concentrations—the saturation model—provided the theoretical framework for understanding the relationship between androgens and PCa and led to multiple case series documenting reassuring results of testosterone therapy in men with PCa. Recent concerns regarding cardiovascular risks also have diminished because new evidence suggests testosterone therapy might actually be cardioprotective. In 2016 the Testosterone Trials provided high-quality evidence of multiple benefits of testosterone therapy, nearly all of which had been recognized by clinicians by 1940.
Conclusions: If the past has any lessons for the future, it is likely that research will continue to demonstrate the health benefits of testosterone therapy, while it remains one of the most controversial topics in medicine.
INTRODUCTION
Most modern readers will be aware of the prominent place of testosterone (T) therapy among the most controversial topics of the past decade. However, few will be aware of the rich history of T, which was 1st synthesized more than 80 years ago and has been used for medical and non-medical purposes since that time. We present a review of the history of T from the perspective of 2 individuals who have been involved in this field for many decades, one as a researcher and the other as a clinician investigator.
We divided this review into 2 main sections. The 1st describes the discovery of T and the early years of its use as a therapeutic agent. This section is rich with observations and commentary that reflect the nature of science in that era, and we included several key passages from older articles and books to provide some flavor of those times and because many of these publications are not readily available to the modern reader. The 2nd section describes the modern history of T therapy through to the present day, noting key events and noteworthy publications and providing our perspectives on these events.
PART 1. THE EARLY YEARS OF TESTOSTERONE
*Discovery and Synthesis
*Early Clinical Experience With Testosterone
*Resistance to the Use of Testosterone
*Testosterone Therapy in Men With Vascular Disease
-Peripheral Vascular Disease
-Angina Pectoris
PART 2. RECENT HISTORY
The modern history of T deficiency and T therapy arguably begins with the introduction of the radioimmunoassay into clinical medicine in the 1970s. Indeed, this was the birth of modern endocrinology. For the 1st time, there was the ability to accurately, rapidly, and inexpensively measure minute concentrations of hormones in serum, an advance that permitted the determination of concentrations from milligrams per milliliter to nanograms per milliliter—a 1,000-fold improvement.
This was an enormous advantage, one that coincided with improved objective capabilities in many areas of medicine, including imaging techniques and the use of computers. The overall effect of these changes for T deficiency was to shift diagnosis from clinical presentation to laboratory values. This emphasis on objective data spawned the prevailing current approach to clinical practice that discourages treatment for many men with classic symptoms based on test results categorized as normal.
*Prostate Cancer
*Rise of Testosterone Therapy
*The Next Controversy: Overtreatment and a False Epidemic
*Cardiovascular Risk
*General Health Benefits
*Every clinician experienced with T therapy knows that one of the most important benefits of T therapy is what our patients tell us so often—they feel healthier, more vital, and with an improved sense of well-being.
TESTOSTERONE THERAPY TODAY AND IN THE FUTURE
T therapy has become a relatively common treatment for men with documented T deficiency. Clinicians observe a high rate of positive responses, often dramatic, in the areas of sexual desire, erectile function, energy, decreased fatigue, and improved mood. It is not unusual to hear a patient say he feels “younger” or “better than I’ve felt in years.” From a research perspective, the benefits of T therapy are well documented in several areas.
Despite the clarity of clinical results and scientific research, T therapy remains controversial. Critics continue to claim it has been over-marketed, resulting in overuse and abuse. Fears of PCa and CV risk persist despite a wealth of data that fail to support these concerns.
The controversial nature of the topic makes it challenging to predict what will happen to T therapy in the future. Some concerns appear to be emotional rather than based on fact.85 In addition, there are substantial differences in approach to treatment by medical specialties. Endocrinologists, for example, take a conservative approach to treatment, requiring strict adherence to biochemical thresholds before instituting treatment, whereas urologists are often more liberal with treatment, based on clinical presentation. The absence of consensus on basic questions, including who is a candidate for T therapy, represents a major hurdle for the field.
In the face of so much confusion and controversy, an International Expert Consensus Conference was held in Prague in 2015, involving 18 individuals from 12 countries, from endocrinology, urology, andrology, basic science, epidemiology, diabetology, and general medicine.86 There was unanimous agreement on several key points: T deficiency was a serious global problem; the evidence failed to support an increased risk of PCa or CV risk; total T was a useful but unreliable test to determine androgen status; and the possibility that T therapy is cardioprotective should be investigated, particularly in men with metabolic conditions such as diabetes and obesity.
An important detail was that the term “hypogonadism” should be replaced in most instances by “testosterone deficiency,” as we use in this text, because of its greater clarity, and similarly, “testosterone therapy” was favored over “testosterone replacement therapy.” 86
What will the future look like? We anticipate the introduction of more convenient treatment modalities such as oral formulations that achieve solid serum T concentrations without hepatotoxicity. Another consideration is long-lasting treatments that are not associated with side effects such as infertility and testicular atrophy. One promising idea is a slow-release human chorionic gonadotropin formulation, currently in development, designed to boost endogenous serum T for at least 2 months.
Another set of possibilities relates to the known properties of T therapy separate from its indication in the treatment of men with T deficiency. It seems reasonable to investigate whether short-term T treatments might have useful benefits in the treatment of trauma, sepsis, and perioperatively for major surgical operations such as radical cystectomy, or even for routine orthopedic procedures in which they could have value in promoting muscular repair and strength.
*If the past has any lessons for the future, T therapy research will continue to demonstrate new health benefits and continue to be one of the most controversial and fascinating topics in medicine.
