Recent Trends in Testosterone Replacement Therapy

Although TRT has been gaining popularity over the years and is often prescribed for increasing libido and improving erectile function, the US FDA has only approved it for clinical hypogonadism, which is defined by The American Association of Clinical Endocrinologists as a decrease in sperm or testosterone production (testicular function).

Testosterone is produced by Leydig cells in the testes in males in response to luteinizing hormone from the anterior pituitary gland, and in females, it is made in the ovaries and adrenal glands. Testosterone has many biological effects and is essential for the development and maintenance of organs and physiological functions in males, while in females, it is an essential precursor to estrogen, and is associated with bone health, mood, and sexual function.
Male hypogonadism is defined by The American Association of Clinical Endocrinologists as a decrease in testicular function, that is, decrease in sperm or testosterone production. Classified as primary, secondary, or mixed, primary hypogonadism is due to dysfunction of the testes (in males), while secondary hypogonadism is due to dysfunction of the pituitary gland or the hypothalamus. Testosterone concentrations in men start to decline at an average of 1% to 2% per year from age forty. Symptoms of hypogonadism in men include erectile dysfunction, reduced libido, infertility, iron-deficiency anemia, depressed mood, alopecia, exhaustion, decline in muscle mass, increase in body fat, sleep disorder, and pathological fracture.

Currently, routine screening of men for low testosterone is not advised because of lack of adequate screening tools; however, men with symptoms of deficiency and consistently low serum testosterone levels may be tested for hypogonadism. While two commonly used assessments for diagnosis of clinical hypogonadism are the Androgen Deficiency in the Aging Male questionnaire and the Aging Males’ Symptoms scale, diagnosis is confirmed by measuring total testosterone, luteinizing hormone, and follicle-stimulating hormone levels.

Testosterone replacement therapy (TRT) has been gaining increased popularity, with a four-fold increase in the rate of TRT in men between 18 to 45 years in the US from 2003 to 2013. While TRT is often recommended to improve sexual function, bone density, muscle strength, and mood and behavior, FDA has only approved clinical hypogonadism for TRT in men, and it is not recommended for the treatment of age-related reduction in testosterone concentration. In women, vasomotor symptoms of menopause and breast cancer are additional FDA-approved indications. At the same time, FDA issued a safety bulletin in 2014 due to reports in 2013 and 2014 associating TRT with increased occurrence of myocardial infarction and stroke.

In men, TRT is often prescribed for increasing libido and improving erectile function; however, a review of 47 studies on sexual function showed 23 studies reporting beneficial effects with TRT, and 24 studies finding no improvement in any sexual-function endpoint. According to The American Urological Association, while TRT has no significant influence on erectile function in men with normal testosterone levels, TRT may increase sexual interest. TRT has been shown to increase bone density in the lumbar spine in middle-aged men with low testosterone levels, and increase bone density in the spine and hip in older men. Nevertheless, The National Osteoporosis Foundation in the US has not given recommendations for its use in patients with osteoporosis.

In women, the vasomotor symptoms of menopause, such as hot flashes, which are associated with irritability, poor concentration, and poor sleep, are usually treated with estrogen and progesterone. Adding TRT is recommended in case of treatment failure, and although there is minimal evidence of efficacy, TRT may be suitable for some patients. In breast and endometrial cancer, androgens in combination with the usual therapy options could slow or prevent tumor progression. As far as sexual function is concerned, TRT has been shown to improve sexual desire, sexual frequency, and sexual satisfaction in women.

There are several risks associated with TRT, including development/worsening of benign prostatic hyperplasia, development/ acceleration of prostate or breast cancer, increased lower urinary tract symptoms, liver toxicity, cardiovascular events, gynecomastia, worsening sleep apnea, increased risk of polycythemia, development/worsening of acne, and alopecia. Hirsutism, voice deepening, and weight gain are additional side effects in women.


Testosterone Replacement Therapy: Controversy and Recent Trends, Ashley S. Brown, PharmD, BCPS, BCPP, Amy Murray, PharmD; US Pharm. 2019; 44(8):17-23

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