madman
Super Moderator
History of testosterone therapy through the ages (2022)
Mary Rostom, Ranjith Ramasamy, and Taylor P. Kohn
The symptoms of testosterone deficiency have been known throughout history with evidence dating back to the twenty-first century BCE when men were castrated to be docile and obedient servants. Experimentation ingesting mammalian testicles began during the reign of the Roman empire and continued through the nineteenth century with claims that the substance found within these testicles could improve energy, erectile function, and urination. In the twentieth century, studies transplanting animal testes onto other castrated animals suggested that a substance produced in the testicle was responsible for systemic effects. Then in 1929, Adolf Butendant was the first to isolate testosterone, and shortly after synthetic formulations of testosterone were created. While testosterone therapy is an important treatment for testosterone deficiency, the history of testosterone therapy has not been without abuse from doping scandals in the twentieth century and the use of testosterone therapy for conversion therapy and treatment of psychiatric disease. Today, there are clear and appropriate clinical uses of testosterone set by the American Urological Association to treat clinically significant testosterone deficiency. Still, even with such guidelines, the potential for misuse and abuse remains high in physicians and athletes. There is a long history that has led to the development of testosterone therapy and when used appropriately can significantly improve the quality of life for men with testosterone deficiency.
INTRODUCTION
Testosterone is a hormone produced in the Leydig cells of the testicle and is responsible for male sexual differentiation and development. While locally produced, testosterone affects the entire body regulating sex drive, bone mass, fat distribution, muscle strength as well as various other bodily functions [1]. Prevalence of testosterone deficiency is estimated to be about 10–25% and strongly associated with advancing age, with symptoms including fatigue, sexual dysfunction, bone pain, and decreased endurance [2]. Testosterone therapy (TT) has been shown to improve these symptoms in men who have low circulating levels of the hormone [1]. While TT plays an important role in the symptomatic improvement of testosterone deficiency, historically TT has often been seen as a “fountain of youth” dating back to the Roman Empire [3]. From experimentation throughout the ages, TT has experienced a circuitous path to its current use and even abuse [4, 5]. The goal of this review is to discuss the history of TT and identify the significant events that impacted the development of TT used in practice today.
HISTORY OF TESTOSTERONE THERAPY THROUGHOUT THE CENTURIES
Even thousands of years before the discovery of the hormone testosterone, scholars understood that some component of the testicles was important for the health and vitality of men. Historical evidence of eunuchs dates to the twenty-first century BCE with eunuchs having served in numerous functions including courtiers, tenor singers, concubines, royal guards, government officials, and guardians of women [6]. Ancient Chinese and Byzantine empires even created armies of eunuchs following the belief that castration would create more obedient servants [3]. In the first century Roman empire, Gaius Plinius Secundus recommended partaking of animal testicles for symptoms of fatigue and erectile dysfunction [5]. In Baghdad in the eighth century, Mensue the Elder prescribed testicular extracts for similar symptoms [3]. Some centuries later, Albert Mangus (1193–1280) began prescribing powdered hog testicles mixed with wine to men that he felt would gain energy and livelihood from his concoction [7]. Little, however, is known as to the outcomes of this early experimentation.
It was not until the nineteenth century, that more formal investigation began to identify the role of this mysterious testicular component. In 1849, Arnold Berthauld performed a study on roosters—first castrating the roosters and observing that this decreased aggressiveness and prevented the roosters from fighting with one another. He then retransplanted testicles back into castrated roosters and found that they regained their aggression. From his experiments, he concluded that there was a productive relationship in which testicles secrete a substance that then acted throughout the body [8, 9].
Using Berthauld’s experiments as a basis for his own, CharlesÉdouard Brown-Sequard published a revolutionary paper in 1889, in which he injected himself with blood from his testicular veins, mixed with one part semen and one part “juice” from a dog or guinea pig testes. His mixture gained worldwide attention as he claimed personal life-changing effects, such as increased strength, improved urinary stream, ability to work long hours, and tremendous increases in physical strength [5, 10, 11]. While Brown-Sequard’s claims were likely far-fetched and potentially overblown, they did create a whirlwind of experimentation, and the pressure to artificially replicate the effects of testosterone heightened [3, 12].
Berthauld’s experiments continued to inspire twentieth-century scientist George Frank Lydston. In 1915, starting with animals and then moving to humans, he took Berthauld’s transplantation methods to a new level. Patients that received testicular transplants reported greater “endurance and vigor” in all aspects of life, especially in sexual function [10, 13]. Leo Stanley followed Lydston’s lead in 1920 when he implanted the testicles of deceased inmates or rams into other prisoners. Prisoners who previously suffered from erectile dysfunction found themselves to have more frequent and longer-lasting erections as well as a 50% increase in visual acuity. Even in those patients where the implant became necrotic, Stanley reimplanted testicles into the abdominal wall and reported a return of the positive effects [14]
Though the scientific accuracy and replicability of these transplant studies remain unclear, the strong outcomes that were reported motivated researchers to perform more refined investigations. In 1926, scientists extracted 20 mg of fluid from bovine testicles and injected various castrated animals with the extract, resulting in remasculinization [15]. Researchers then sought to isolate the component of testicular fluid which could be responsible for masculinization. Inspired by his work isolating estrone from the urine of pregnant women, Adolf Butendant isolated the hormone for the first time in 1929 after examining 15,000 L of urine from Berlin policemen and determining that testosterone was the principal hormone in his samples [16]. Just 10 years later, building off the work of various other biochemists, Leopold Ruzicka synthesized testosterone for the first time in 1939 [5].
WIDESPREAD DISTRIBUTION OF SYNTHESIZED TESTOSTERONE
Soon after testosterone was synthesized, various formulations were developed for the treatment of testosterone deficiency as displayed in Fig. 1. From the 1920s to the 1970s oral formulations were initially widely distributed but found to be inactivated by first-pass metabolism and toxic to the liver due to a 17-alpha structure [17]. After the dismissal of oral testosterone from clinical practice, physicians began using subdermal testosterone pellets that were effective for 1–2 years [18]. Various other formulations including buccal testosterone, injectable testosterone, testosterone suppositories, and oral formulations that were absorbed by the lymph to surpass first-pass metabolism (testosterone undecanoate) were all marketed. Unfortunately, many of these formulations failed to achieve steady hormone levels [19].
In the 1980s, a breakthrough occurred when the first formulations of transdermal testosterone were created and applied to scrotal skin. Initially, these formulations caused severe skin irritation. Thus, once non-irritative transdermal testosterone gels became available, they became the treatment of choice for testosterone deficiency [19]. The non-irritative transdermal formulation can be used on the abdomen, shoulders, or even on the scrotum (though in lower doses). Along with gels, intramuscular injections of testosterone that have been in use since 1937 are also commonly used [20].
MISUSES OF TESTOSTERONE THERAPY
While the discovery of safe and useful testosterone formulations has been tremendously important in the treatment of clinically significant testosterone deficiency, there has been a dark side to the history of TT. Physicians in the early twentieth century believed that homosexuality was due to hormonal imbalances and thus treated homosexual men with TT and even implanted testicular tissue into homosexual men [21]. In addition, both male and female patients that suffered from various psychological diseases such as depression and bipolar disorder were treated with injections of testosterone, often causing irreversible changes to the women [22].
Beginning in the 1950s, both male and female athletes began doping with testosterone for advantages in weightlifting and various field and sporting events. Dr. John Ziegler, a physician from California, secretly prescribed testosterone to US East coast bodybuilders [23]. The Russians followed in 1954 when they nearly swept the Vienna weightlifting championship [24]. Outside of weightlifting, documents found after the fall of the German Democratic Republic that sporting officials had been secretly forcing various athletes to take testosterone from 1966 to 1990 [4]. By the 1980s, the use of testosterone supplementation spilled into the public where, rather than just athletes as the target market, young men began using it to boost their physical appearance [25] and [23]. Despite regulatory efforts by the US government classifying all testosterone products as schedule III controlled substances in the Anabolic Steroids Control Act, use continued as testosterone was illegally smuggled into the US from Mexico, Russia, Egypt, Eastern Europe, and India [23]. To this day, testosterone is still considered a widely used substance of abuse. The prevalence of the problem is underestimated.
CURRENT AUA GUIDELINES ON CLINICALLY APPROPRIATE USE OF TESTOSTERONE THERAPY
Despite the unfortunate abuse of TT, it plays a tremendously important role in the treatment of clinically significant testosterone deficiency. In combination with clinical symptoms, a testosterone level found to be below 300 ng/dL on two separate morning laboratory draws is the threshold set by the American Urological Association by which physicians diagnose testosterone deficiency. Clinical symptoms include reduced energy, reduced endurance, diminished physical performance, fatigue, erectile dysfunction, bone pain, and lack of sex drive. TT is appropriate for use in testosterone deficiency due to both primary and secondary causes. It is important to follow up testosterone levels on these patients every 6–12 months and consider cessation of therapy if the TT does not improve clinical symptoms, even after reaching therapeutic levels. In patients with fertility concerns, alternatives to TT include aromatase inhibitors, selective estrogen receptor modulators, and human chorionic gonadotropin [1].
CONCLUSIONS
The importance of testosterone on the development and functioning of the entire body has been speculated since ancient times. Often viewed historically as a “fountain of youth,” for hundreds of years, individuals have taken advantage of consumers by marketing useless “miracle formulations” for economic gain. In more recent history, TT has been forced on vulnerable patient populations and used to enhance athletes’ performance—both causing severe irreversible side effects. While inappropriate use can be harmful to patients, isolation, and synthesis of testosterone have been tremendously important in the treatment of clinically significant testosterone deficiency. Supported by strong evidence, there are clear and appropriate clinical indications for TT. TT is often misprescribed by physicians and misused by the public. There is much work to be done in creating public health awareness of the long-term side effects that decrease the misuse and abuse of testosterone formulations while identifying men with testosterone deficiency and providing much-needed restoration.
Mary Rostom, Ranjith Ramasamy, and Taylor P. Kohn
The symptoms of testosterone deficiency have been known throughout history with evidence dating back to the twenty-first century BCE when men were castrated to be docile and obedient servants. Experimentation ingesting mammalian testicles began during the reign of the Roman empire and continued through the nineteenth century with claims that the substance found within these testicles could improve energy, erectile function, and urination. In the twentieth century, studies transplanting animal testes onto other castrated animals suggested that a substance produced in the testicle was responsible for systemic effects. Then in 1929, Adolf Butendant was the first to isolate testosterone, and shortly after synthetic formulations of testosterone were created. While testosterone therapy is an important treatment for testosterone deficiency, the history of testosterone therapy has not been without abuse from doping scandals in the twentieth century and the use of testosterone therapy for conversion therapy and treatment of psychiatric disease. Today, there are clear and appropriate clinical uses of testosterone set by the American Urological Association to treat clinically significant testosterone deficiency. Still, even with such guidelines, the potential for misuse and abuse remains high in physicians and athletes. There is a long history that has led to the development of testosterone therapy and when used appropriately can significantly improve the quality of life for men with testosterone deficiency.
INTRODUCTION
Testosterone is a hormone produced in the Leydig cells of the testicle and is responsible for male sexual differentiation and development. While locally produced, testosterone affects the entire body regulating sex drive, bone mass, fat distribution, muscle strength as well as various other bodily functions [1]. Prevalence of testosterone deficiency is estimated to be about 10–25% and strongly associated with advancing age, with symptoms including fatigue, sexual dysfunction, bone pain, and decreased endurance [2]. Testosterone therapy (TT) has been shown to improve these symptoms in men who have low circulating levels of the hormone [1]. While TT plays an important role in the symptomatic improvement of testosterone deficiency, historically TT has often been seen as a “fountain of youth” dating back to the Roman Empire [3]. From experimentation throughout the ages, TT has experienced a circuitous path to its current use and even abuse [4, 5]. The goal of this review is to discuss the history of TT and identify the significant events that impacted the development of TT used in practice today.
HISTORY OF TESTOSTERONE THERAPY THROUGHOUT THE CENTURIES
Even thousands of years before the discovery of the hormone testosterone, scholars understood that some component of the testicles was important for the health and vitality of men. Historical evidence of eunuchs dates to the twenty-first century BCE with eunuchs having served in numerous functions including courtiers, tenor singers, concubines, royal guards, government officials, and guardians of women [6]. Ancient Chinese and Byzantine empires even created armies of eunuchs following the belief that castration would create more obedient servants [3]. In the first century Roman empire, Gaius Plinius Secundus recommended partaking of animal testicles for symptoms of fatigue and erectile dysfunction [5]. In Baghdad in the eighth century, Mensue the Elder prescribed testicular extracts for similar symptoms [3]. Some centuries later, Albert Mangus (1193–1280) began prescribing powdered hog testicles mixed with wine to men that he felt would gain energy and livelihood from his concoction [7]. Little, however, is known as to the outcomes of this early experimentation.
It was not until the nineteenth century, that more formal investigation began to identify the role of this mysterious testicular component. In 1849, Arnold Berthauld performed a study on roosters—first castrating the roosters and observing that this decreased aggressiveness and prevented the roosters from fighting with one another. He then retransplanted testicles back into castrated roosters and found that they regained their aggression. From his experiments, he concluded that there was a productive relationship in which testicles secrete a substance that then acted throughout the body [8, 9].
Using Berthauld’s experiments as a basis for his own, CharlesÉdouard Brown-Sequard published a revolutionary paper in 1889, in which he injected himself with blood from his testicular veins, mixed with one part semen and one part “juice” from a dog or guinea pig testes. His mixture gained worldwide attention as he claimed personal life-changing effects, such as increased strength, improved urinary stream, ability to work long hours, and tremendous increases in physical strength [5, 10, 11]. While Brown-Sequard’s claims were likely far-fetched and potentially overblown, they did create a whirlwind of experimentation, and the pressure to artificially replicate the effects of testosterone heightened [3, 12].
Berthauld’s experiments continued to inspire twentieth-century scientist George Frank Lydston. In 1915, starting with animals and then moving to humans, he took Berthauld’s transplantation methods to a new level. Patients that received testicular transplants reported greater “endurance and vigor” in all aspects of life, especially in sexual function [10, 13]. Leo Stanley followed Lydston’s lead in 1920 when he implanted the testicles of deceased inmates or rams into other prisoners. Prisoners who previously suffered from erectile dysfunction found themselves to have more frequent and longer-lasting erections as well as a 50% increase in visual acuity. Even in those patients where the implant became necrotic, Stanley reimplanted testicles into the abdominal wall and reported a return of the positive effects [14]
Though the scientific accuracy and replicability of these transplant studies remain unclear, the strong outcomes that were reported motivated researchers to perform more refined investigations. In 1926, scientists extracted 20 mg of fluid from bovine testicles and injected various castrated animals with the extract, resulting in remasculinization [15]. Researchers then sought to isolate the component of testicular fluid which could be responsible for masculinization. Inspired by his work isolating estrone from the urine of pregnant women, Adolf Butendant isolated the hormone for the first time in 1929 after examining 15,000 L of urine from Berlin policemen and determining that testosterone was the principal hormone in his samples [16]. Just 10 years later, building off the work of various other biochemists, Leopold Ruzicka synthesized testosterone for the first time in 1939 [5].
WIDESPREAD DISTRIBUTION OF SYNTHESIZED TESTOSTERONE
Soon after testosterone was synthesized, various formulations were developed for the treatment of testosterone deficiency as displayed in Fig. 1. From the 1920s to the 1970s oral formulations were initially widely distributed but found to be inactivated by first-pass metabolism and toxic to the liver due to a 17-alpha structure [17]. After the dismissal of oral testosterone from clinical practice, physicians began using subdermal testosterone pellets that were effective for 1–2 years [18]. Various other formulations including buccal testosterone, injectable testosterone, testosterone suppositories, and oral formulations that were absorbed by the lymph to surpass first-pass metabolism (testosterone undecanoate) were all marketed. Unfortunately, many of these formulations failed to achieve steady hormone levels [19].
In the 1980s, a breakthrough occurred when the first formulations of transdermal testosterone were created and applied to scrotal skin. Initially, these formulations caused severe skin irritation. Thus, once non-irritative transdermal testosterone gels became available, they became the treatment of choice for testosterone deficiency [19]. The non-irritative transdermal formulation can be used on the abdomen, shoulders, or even on the scrotum (though in lower doses). Along with gels, intramuscular injections of testosterone that have been in use since 1937 are also commonly used [20].
MISUSES OF TESTOSTERONE THERAPY
While the discovery of safe and useful testosterone formulations has been tremendously important in the treatment of clinically significant testosterone deficiency, there has been a dark side to the history of TT. Physicians in the early twentieth century believed that homosexuality was due to hormonal imbalances and thus treated homosexual men with TT and even implanted testicular tissue into homosexual men [21]. In addition, both male and female patients that suffered from various psychological diseases such as depression and bipolar disorder were treated with injections of testosterone, often causing irreversible changes to the women [22].
Beginning in the 1950s, both male and female athletes began doping with testosterone for advantages in weightlifting and various field and sporting events. Dr. John Ziegler, a physician from California, secretly prescribed testosterone to US East coast bodybuilders [23]. The Russians followed in 1954 when they nearly swept the Vienna weightlifting championship [24]. Outside of weightlifting, documents found after the fall of the German Democratic Republic that sporting officials had been secretly forcing various athletes to take testosterone from 1966 to 1990 [4]. By the 1980s, the use of testosterone supplementation spilled into the public where, rather than just athletes as the target market, young men began using it to boost their physical appearance [25] and [23]. Despite regulatory efforts by the US government classifying all testosterone products as schedule III controlled substances in the Anabolic Steroids Control Act, use continued as testosterone was illegally smuggled into the US from Mexico, Russia, Egypt, Eastern Europe, and India [23]. To this day, testosterone is still considered a widely used substance of abuse. The prevalence of the problem is underestimated.
CURRENT AUA GUIDELINES ON CLINICALLY APPROPRIATE USE OF TESTOSTERONE THERAPY
Despite the unfortunate abuse of TT, it plays a tremendously important role in the treatment of clinically significant testosterone deficiency. In combination with clinical symptoms, a testosterone level found to be below 300 ng/dL on two separate morning laboratory draws is the threshold set by the American Urological Association by which physicians diagnose testosterone deficiency. Clinical symptoms include reduced energy, reduced endurance, diminished physical performance, fatigue, erectile dysfunction, bone pain, and lack of sex drive. TT is appropriate for use in testosterone deficiency due to both primary and secondary causes. It is important to follow up testosterone levels on these patients every 6–12 months and consider cessation of therapy if the TT does not improve clinical symptoms, even after reaching therapeutic levels. In patients with fertility concerns, alternatives to TT include aromatase inhibitors, selective estrogen receptor modulators, and human chorionic gonadotropin [1].
CONCLUSIONS
The importance of testosterone on the development and functioning of the entire body has been speculated since ancient times. Often viewed historically as a “fountain of youth,” for hundreds of years, individuals have taken advantage of consumers by marketing useless “miracle formulations” for economic gain. In more recent history, TT has been forced on vulnerable patient populations and used to enhance athletes’ performance—both causing severe irreversible side effects. While inappropriate use can be harmful to patients, isolation, and synthesis of testosterone have been tremendously important in the treatment of clinically significant testosterone deficiency. Supported by strong evidence, there are clear and appropriate clinical indications for TT. TT is often misprescribed by physicians and misused by the public. There is much work to be done in creating public health awareness of the long-term side effects that decrease the misuse and abuse of testosterone formulations while identifying men with testosterone deficiency and providing much-needed restoration.
