Testosterone Replacement Therapy: Controversy and Recent Trends
Ashley S. Brown, PharmD, BCPS, BCPP; Amy Murray, PharmD
US Pharmacist. 2019;44(8):17-23.
Abstract and Introduction
Abstract
In recent years, testosterone replacement therapy (TRT) has received significant media attention, and the rate of testosterone use has increased notably. A reported association between testosterone use and increased occurrence of myocardial infarction and stroke prompted the FDA to issue a safety bulletin in 2014. Clinical hypogonadism is the only FDA-approved indication for TRT in men; it is not approved to treat age-related low testosterone. Although it is not indicated, TRT is often recommended to improve sexual function, bone density, body composition, muscle strength, mood, behavior, and cognition. The literature on the effectiveness of TRT for various conditions is largely mixed; therefore, current data on appropriate and potentially inappropriate use are important for pharmacists to keep abreast of and discuss with patients.
Introduction
Recently, the use of testosterone replacement therapy (TRT) has received a lot of media attention. Although its use is growing, there is much debate regarding TRT's risks and benefits.[1] From 2008 to 2012 in the United States, spending on TRT increased from $1 billion to $2 billion, and from 2003 to 2013 there was a fourfold increase in the rate of TRT in men aged 18 to 45 years.[2] In 2013 and early 2014, two studies reported an association between TRT and increased occurrence of myocardial infarction and stroke, prompting the FDA to issue a safety bulletin on January 31, 2014.[3] This article will discuss appropriate TRT use, available formulations and cost, side effects, trends, and the pharmacist's role in patient education, including counseling points.
Physiology
Testosterone, which is essential for the development and maintenance of organs and physiological functions in males, has many biological effects. In males, this hormone is produced by Leydig cells in the testes in response to luteinizing hormone from the pituitary gland. In females, testosterone is made in the ovaries and adrenal glands and is an essential precursor to estrogen; it is associated with mood, sexual function, and bone health.[4,5]
Indications and Other Uses
TRT in males with low concentrations of testosterone is controversial because this condition is often a normal sign of aging; testosterone concentrations in men naturally begin to decline at age 40 years, at an average of 1% to 2% per year.[5] Clinical hypogonadism, however, is an approved indication for TRT and is the only FDA-approved indication for TRT in men. The American Association of Clinical Endocrinologists (AACE) defines male hypogonadism as a decrease in testicular function (sperm or testosterone production) accompanied by signs or symptoms.[6] In women, additional FDA-approved indications include vasomotor symptoms of menopause (using a combination of esterified estrogens and methyltestosterone) and breast cancer. Despite having only the abovementioned FDA-approved indications, TRT is often recommended by prescribers—based on a presumption of low testosterone—for sexual function, bone density, body composition, muscle strength, mood, behavior, and cognition. Two areas of use that are beyond the scope of this article are TRT in sports—an ongoing controversy—and in female-tomale transgender patients.
Diagnosis
Based on a lack of data regarding screening tools, the Endocrine Society currently advises against routine screening of men for low testosterone.[7] However, it does recommend that men with symptoms or signs of testosterone deficiency and consistently low serum testosterone concentrations be tested for hypogonadism.[7] The healthcare provider should confirm that the patient has low testosterone concentrations on at least two occasions and should evaluate associated signs and symptoms via questionnaire. Commonly used assessments for diagnosis of clinical hypogonadism include the Androgen Deficiency in the Aging Male questionnaire and the Aging Males' Symptoms scale. Confirmatory diagnosis is made via total testosterone, luteinizing hormone, and follicle-stimulating hormone concentrations.[7] Circulating testosterone concentrations vary throughout the day, peaking in the early morning; therefore, fasting concentrations should be obtained between 8 AM and 10 AM.[6–8]
Conditions
Hypogonadism
Hypogonadism is classified as primary, secondary, or mixed. In males, primary hypogonadism results from dysfunction of the testes; secondary hypogonadism results from dysfunction of the pituitary or hypothalamus. See for a summary of laboratory values, causes, and symptoms of hypogonadism. Although there is no universal laboratory definition of hypogonadism, most laboratory reference ranges for males report total testosterone concentrations <300 ng/dL as diagnostic, with a reference range of 300 ng/dL to 1,000 ng/dL.[6–8]
Ashley S. Brown, PharmD, BCPS, BCPP; Amy Murray, PharmD
US Pharmacist. 2019;44(8):17-23.
Abstract and Introduction
Abstract
In recent years, testosterone replacement therapy (TRT) has received significant media attention, and the rate of testosterone use has increased notably. A reported association between testosterone use and increased occurrence of myocardial infarction and stroke prompted the FDA to issue a safety bulletin in 2014. Clinical hypogonadism is the only FDA-approved indication for TRT in men; it is not approved to treat age-related low testosterone. Although it is not indicated, TRT is often recommended to improve sexual function, bone density, body composition, muscle strength, mood, behavior, and cognition. The literature on the effectiveness of TRT for various conditions is largely mixed; therefore, current data on appropriate and potentially inappropriate use are important for pharmacists to keep abreast of and discuss with patients.
Introduction
Recently, the use of testosterone replacement therapy (TRT) has received a lot of media attention. Although its use is growing, there is much debate regarding TRT's risks and benefits.[1] From 2008 to 2012 in the United States, spending on TRT increased from $1 billion to $2 billion, and from 2003 to 2013 there was a fourfold increase in the rate of TRT in men aged 18 to 45 years.[2] In 2013 and early 2014, two studies reported an association between TRT and increased occurrence of myocardial infarction and stroke, prompting the FDA to issue a safety bulletin on January 31, 2014.[3] This article will discuss appropriate TRT use, available formulations and cost, side effects, trends, and the pharmacist's role in patient education, including counseling points.
Physiology
Testosterone, which is essential for the development and maintenance of organs and physiological functions in males, has many biological effects. In males, this hormone is produced by Leydig cells in the testes in response to luteinizing hormone from the pituitary gland. In females, testosterone is made in the ovaries and adrenal glands and is an essential precursor to estrogen; it is associated with mood, sexual function, and bone health.[4,5]
Indications and Other Uses
TRT in males with low concentrations of testosterone is controversial because this condition is often a normal sign of aging; testosterone concentrations in men naturally begin to decline at age 40 years, at an average of 1% to 2% per year.[5] Clinical hypogonadism, however, is an approved indication for TRT and is the only FDA-approved indication for TRT in men. The American Association of Clinical Endocrinologists (AACE) defines male hypogonadism as a decrease in testicular function (sperm or testosterone production) accompanied by signs or symptoms.[6] In women, additional FDA-approved indications include vasomotor symptoms of menopause (using a combination of esterified estrogens and methyltestosterone) and breast cancer. Despite having only the abovementioned FDA-approved indications, TRT is often recommended by prescribers—based on a presumption of low testosterone—for sexual function, bone density, body composition, muscle strength, mood, behavior, and cognition. Two areas of use that are beyond the scope of this article are TRT in sports—an ongoing controversy—and in female-tomale transgender patients.
Diagnosis
Based on a lack of data regarding screening tools, the Endocrine Society currently advises against routine screening of men for low testosterone.[7] However, it does recommend that men with symptoms or signs of testosterone deficiency and consistently low serum testosterone concentrations be tested for hypogonadism.[7] The healthcare provider should confirm that the patient has low testosterone concentrations on at least two occasions and should evaluate associated signs and symptoms via questionnaire. Commonly used assessments for diagnosis of clinical hypogonadism include the Androgen Deficiency in the Aging Male questionnaire and the Aging Males' Symptoms scale. Confirmatory diagnosis is made via total testosterone, luteinizing hormone, and follicle-stimulating hormone concentrations.[7] Circulating testosterone concentrations vary throughout the day, peaking in the early morning; therefore, fasting concentrations should be obtained between 8 AM and 10 AM.[6–8]
Conditions
Hypogonadism
Hypogonadism is classified as primary, secondary, or mixed. In males, primary hypogonadism results from dysfunction of the testes; secondary hypogonadism results from dysfunction of the pituitary or hypothalamus. See for a summary of laboratory values, causes, and symptoms of hypogonadism. Although there is no universal laboratory definition of hypogonadism, most laboratory reference ranges for males report total testosterone concentrations <300 ng/dL as diagnostic, with a reference range of 300 ng/dL to 1,000 ng/dL.[6–8]