madman
Super Moderator
INTRODUCTION
Charles Edouard Brown-Séquard injected himself with a mixture containing liquid extracted from the testicles of dogs or guinea pigs in 1889 (Video 1). The therapy was injected 10 times over 3 weeks. Brown-Séquard observed physical changes: an increase in his forearm flexor strength, a more forceful urinary stream, the ability to defecate more efficiently, and a subjective improvement in his cognitive abilities. The once-proclaimed “Elixir of Life,” testosterone (T), has many well-studied anabolic, metabolic, and developmental properties that affect target organs in men and women. The potential uses of this compound prompted several teams of biochemists to race for isolation of the testicular hormone in the early twentieth century.’ The surge of athletes hoping to benefit from the anabolic effects of T began in the first half of the twentieth century. It was not until researchers controlled for exercise routines and protein intake that it was identified that testosterone leads to increases in strength, fat-free mass, and overall muscle mass in exercising men.” Testosterone replacement therapy(TTh), as it has become known, has proved to be an effective treatment strategy for improving the quality of life for hypogonadal men around the globe.
Low levels of circulating serum T characterize hypogonadism due to interference or malfunction of the hypothalamic-pituitary-gonadal axis (HPGA). It is estimated to affect 2 to 4 million men annually in North America alone. An estimated 1 in 10 men older than 60 years has a testosterone deficiency (TD) and 1 in 3 has diabetes.” By 2025, an estimated 6.5 million American men will be affected.*
T is a pleiotropic hormone that plays an essential role in the human body. Through its conversion to estrogen, T affects bone health and density. Male hypogonadism is the clinical condition representing symptoms and gonadal dysfunction of Leydig cells, resulting in decreased T, Sertoli cell/germ cells, and decreased sperm production.”There has been a renewed interest recently in the systemic role of T in pain, wellbeing, and cardiovascular function in both women and men.”
Therapeutic T levels are linked to improved sexual function, physical performance, strength, lean body mass, and cognitive function and have some cardiovascular benefits. Low T levels can lead to sarcopenia, increased adiposity, fatigue, lack of motivation, cardiovascular diseases, cancer, and all-cause mortality. Androgen deficiency signs and symptoms take time to manifest clinically in adolescents and young men, given the numerous pathways within the HPGA and reduced efficiency changes to hormonal levels. Experts have debated using TTh in men who might benefit from replacing declining hormone levels.” With the recent prolongation of life expectancy, especially in men, the question concerning T replacement in older men has become more important.
Considerations of Testosterone
*Testosterone production
*Measuring testosterone
*Age/environmental factors
Understanding Hypogonadism
Presentation
*Cardiovascular
*Sexual function
*Musculoskeletal strength
*Obesity/insulin efficiency
*Cognition/mood
*Prostate cancer
*Treatment
DELIVERY METHODS
POTENTIAL ALTERNATIVE USES
REPLACEMENT THERAPY VERSUS OPTIMIZATION
TTh is a T treatment regimen that results in therapeutic serum T levels. T optimization refers to optimizing T levels for maximum benefit and well-being without achieving supratherapeutic levels well above the established reference ranges. The US serum T reference ranges from 264 to 916 ng/dL for healthy, nonobese men. Many providers will not initiate T treatment if the total serum T is less than 264, despite having symptoms consistent with hypogonadism.
The Endocrine Society's stance on T optimization is that TTh when initiated, should raise serum total T only up to the mid-normal range, which is approximately 426 ng/dL. They also recommend that it should only be initiated when multiple unequivocal tests demonstrate low levels of serum total testosterone paired with signs and symptoms of TD. However, as recognized by the American Urological Association, there are men with total T levels greater than 300 ng/dL who exhibit conclusive and significant signs and symptoms of hypogonadism and have experienced symptomatic improvement with TTh. Thus, TTh aimed at raising serum total T to optimized therapeutic levels should be considered in those cases. The use of sound clinical judgment and discussing risks versus benefits with the patient is strongly encouraged.
Many studies demonstrating little or no benefit when initiating TTh provide little information about the maximum serum T levels attained in the men tested. Are the subject’s serum total T levels at the low standard or mid-standard value? More research should be conducted on the impact of optimized serum T levels on symptomatic hypogonadal men.
DISCUSSION
T, once touted as “the Elixir of Life,” is a hormone found in both men and women. In men, most T is produced by the Leydig cells in the testicles when stimulated by the LH. T has been shown to improve bone health and density. Therapeutic levels of T also increase sexual function and libido, physical performance, strength, lean body mass, and cognitive function. However, supratherapeutic levels can cause mood swings, increased sebum production resulting in acne, elevated estradiol levels, erythrocytosis, increased incidence of male pattern baldness, and can worsen sleep apnea.
Over the last 3 decades, there has been increased interest in TTh. This trend results from increasing obesity rates, an aging population, and endocrine disruptors in our foods and environment. In addition, there has been a surge in Men’s health clinics and online direct-to-consumer Web sites, making TTh much more readily accessible. The potential risks associated with supratherapeutic levels of T have created conflicting guidelines and treatment strategies for many organizations across the globe for diagnosing and prescribing hypogonadism. The inconsistency of standards has led to confusion and uncertainty among prescribers. Much of the confusion lies wherein the total serum T is in the low normal range, but signs and symptoms of hypogonadism still exist. T optimization should be considered within this realm with close follow-up and reevaluation of signs and symptoms after initiating TTh. Clinical judgment and provider-patient discussions about risk versus benefit are necessary.
These days there are many T delivery methods to consider. Longer-acting T injections, including T cypionate and enanthate, provide more patient advantages due to convenience and effectiveness. Other delivery forms include shorter-acting formulations in the form of daily gels, creams, transdermal patches, and daily capsules. Lastly, subcutaneously inserted T pellets last up to 4 to 6 months. In men considering having children, the contraindication of T is due to its negative effect on spermatogenesis, in these men. SERMs such as enclomiphene citrate provide normalization of T levels while having positive effects on sperm counts. Although these medications have proved effective and well tolerated, SERMs are not FDA-approved for treating hypogonadal men and have long been used off-label.
SUMMARY
As more men seek to increase their T levels, more long-term random control studies are needed to gain better insight into T optimization to support the anecdotal observation commonly experienced in the practice setting. In addition, studies evaluating the risks and benefits of effective off-label treatment options such as SERMs should be considered. Lastly, an ever-growing number of women are turning to TTh. In this population, there lies tremendous opportunity for research focused on T optimization and those undergoing gender transitional care.
Charles Edouard Brown-Séquard injected himself with a mixture containing liquid extracted from the testicles of dogs or guinea pigs in 1889 (Video 1). The therapy was injected 10 times over 3 weeks. Brown-Séquard observed physical changes: an increase in his forearm flexor strength, a more forceful urinary stream, the ability to defecate more efficiently, and a subjective improvement in his cognitive abilities. The once-proclaimed “Elixir of Life,” testosterone (T), has many well-studied anabolic, metabolic, and developmental properties that affect target organs in men and women. The potential uses of this compound prompted several teams of biochemists to race for isolation of the testicular hormone in the early twentieth century.’ The surge of athletes hoping to benefit from the anabolic effects of T began in the first half of the twentieth century. It was not until researchers controlled for exercise routines and protein intake that it was identified that testosterone leads to increases in strength, fat-free mass, and overall muscle mass in exercising men.” Testosterone replacement therapy(TTh), as it has become known, has proved to be an effective treatment strategy for improving the quality of life for hypogonadal men around the globe.
Low levels of circulating serum T characterize hypogonadism due to interference or malfunction of the hypothalamic-pituitary-gonadal axis (HPGA). It is estimated to affect 2 to 4 million men annually in North America alone. An estimated 1 in 10 men older than 60 years has a testosterone deficiency (TD) and 1 in 3 has diabetes.” By 2025, an estimated 6.5 million American men will be affected.*
T is a pleiotropic hormone that plays an essential role in the human body. Through its conversion to estrogen, T affects bone health and density. Male hypogonadism is the clinical condition representing symptoms and gonadal dysfunction of Leydig cells, resulting in decreased T, Sertoli cell/germ cells, and decreased sperm production.”There has been a renewed interest recently in the systemic role of T in pain, wellbeing, and cardiovascular function in both women and men.”
Therapeutic T levels are linked to improved sexual function, physical performance, strength, lean body mass, and cognitive function and have some cardiovascular benefits. Low T levels can lead to sarcopenia, increased adiposity, fatigue, lack of motivation, cardiovascular diseases, cancer, and all-cause mortality. Androgen deficiency signs and symptoms take time to manifest clinically in adolescents and young men, given the numerous pathways within the HPGA and reduced efficiency changes to hormonal levels. Experts have debated using TTh in men who might benefit from replacing declining hormone levels.” With the recent prolongation of life expectancy, especially in men, the question concerning T replacement in older men has become more important.
Considerations of Testosterone
*Testosterone production
*Measuring testosterone
*Age/environmental factors
Understanding Hypogonadism
Presentation
*Cardiovascular
*Sexual function
*Musculoskeletal strength
*Obesity/insulin efficiency
*Cognition/mood
*Prostate cancer
*Treatment
DELIVERY METHODS
POTENTIAL ALTERNATIVE USES
REPLACEMENT THERAPY VERSUS OPTIMIZATION
TTh is a T treatment regimen that results in therapeutic serum T levels. T optimization refers to optimizing T levels for maximum benefit and well-being without achieving supratherapeutic levels well above the established reference ranges. The US serum T reference ranges from 264 to 916 ng/dL for healthy, nonobese men. Many providers will not initiate T treatment if the total serum T is less than 264, despite having symptoms consistent with hypogonadism.
The Endocrine Society's stance on T optimization is that TTh when initiated, should raise serum total T only up to the mid-normal range, which is approximately 426 ng/dL. They also recommend that it should only be initiated when multiple unequivocal tests demonstrate low levels of serum total testosterone paired with signs and symptoms of TD. However, as recognized by the American Urological Association, there are men with total T levels greater than 300 ng/dL who exhibit conclusive and significant signs and symptoms of hypogonadism and have experienced symptomatic improvement with TTh. Thus, TTh aimed at raising serum total T to optimized therapeutic levels should be considered in those cases. The use of sound clinical judgment and discussing risks versus benefits with the patient is strongly encouraged.
Many studies demonstrating little or no benefit when initiating TTh provide little information about the maximum serum T levels attained in the men tested. Are the subject’s serum total T levels at the low standard or mid-standard value? More research should be conducted on the impact of optimized serum T levels on symptomatic hypogonadal men.
DISCUSSION
T, once touted as “the Elixir of Life,” is a hormone found in both men and women. In men, most T is produced by the Leydig cells in the testicles when stimulated by the LH. T has been shown to improve bone health and density. Therapeutic levels of T also increase sexual function and libido, physical performance, strength, lean body mass, and cognitive function. However, supratherapeutic levels can cause mood swings, increased sebum production resulting in acne, elevated estradiol levels, erythrocytosis, increased incidence of male pattern baldness, and can worsen sleep apnea.
Over the last 3 decades, there has been increased interest in TTh. This trend results from increasing obesity rates, an aging population, and endocrine disruptors in our foods and environment. In addition, there has been a surge in Men’s health clinics and online direct-to-consumer Web sites, making TTh much more readily accessible. The potential risks associated with supratherapeutic levels of T have created conflicting guidelines and treatment strategies for many organizations across the globe for diagnosing and prescribing hypogonadism. The inconsistency of standards has led to confusion and uncertainty among prescribers. Much of the confusion lies wherein the total serum T is in the low normal range, but signs and symptoms of hypogonadism still exist. T optimization should be considered within this realm with close follow-up and reevaluation of signs and symptoms after initiating TTh. Clinical judgment and provider-patient discussions about risk versus benefit are necessary.
These days there are many T delivery methods to consider. Longer-acting T injections, including T cypionate and enanthate, provide more patient advantages due to convenience and effectiveness. Other delivery forms include shorter-acting formulations in the form of daily gels, creams, transdermal patches, and daily capsules. Lastly, subcutaneously inserted T pellets last up to 4 to 6 months. In men considering having children, the contraindication of T is due to its negative effect on spermatogenesis, in these men. SERMs such as enclomiphene citrate provide normalization of T levels while having positive effects on sperm counts. Although these medications have proved effective and well tolerated, SERMs are not FDA-approved for treating hypogonadal men and have long been used off-label.
SUMMARY
As more men seek to increase their T levels, more long-term random control studies are needed to gain better insight into T optimization to support the anecdotal observation commonly experienced in the practice setting. In addition, studies evaluating the risks and benefits of effective off-label treatment options such as SERMs should be considered. Lastly, an ever-growing number of women are turning to TTh. In this population, there lies tremendous opportunity for research focused on T optimization and those undergoing gender transitional care.
