Androgen replacement therapy

Medical uses

Males

Androgen replacement is the classic treatment of hypogonadism. It is also used in men who have lost the ability to produce androgens due to disease or its treatment. Testosterone replacement in men with hypogonadism has consistently shown to improve sexual function; including increases in libido and sexual activity. Erectile function was also shown to modestly improve in some studies of testosterone treatment for male hypogonadism, other studies did not show a benefit. Testosterone treatment in men with hypogonadism was shown to have modest improvements in physical activity, modest improvements in mood (but it did not improve mood in those with major depression), and some studies showed modest improvements in subjective energy levels and self reported physical fitness. Testosterone therapy was not shown to improve cognitive function in men with hypogonadism. Testosterone therapy was also shown to raise the hemoglobin (blood count) by 1 point in 33-50% of people, and increase bone density by up to 7% in the spine and hip, but the clinical significance of these changes is unclear.

Diabetes

The risks of diabetes and of testosterone deficiency in men over 45 (i.e., hypogonadism, specifically hypoandrogenism) are strongly correlated. Testosterone replacement therapies have been shown to improve blood glucose management. Still, "it is prudent not to start testosterone therapy in men with diabetes solely for the purpose of improving metabolic control if they show no signs and symptoms of hypogonadism."

Other studies have not shown a benefit in diabetes prevention or better diabetes control with testosterone therapy. One study showed testosterone therapy in older men with low testosterone not changing sugar levels or hemoglobin A1c (used as a marker of diabetes control, or for the diagnosis of diabetes) compared to placebo. In another trial from 2024, testosterone therapy for men with hypogonadism and prediabetes did not prevent the progression of prediabetes to diabetes and it did not improve diabetes control compared to placebo.

Females

Androgen replacement is used in postmenopausal women: the indications are to increase sexual desire; and to prevent or treat osteoporosis. Other symptoms of androgen deficiency are similar in both sexes, such as muscle loss and physical fatigue. The androgens used for androgen replacement in women include testosterone (and esters), prasterone (dehydroepiandrosterone; DHEA) (and the ester prasterone enanthate), methyltestosterone, nandrolone decanoate, and tibolone, among others.

Adverse effects

The Food and Drug Administration (FDA) stated in 2015 that neither the benefits nor the safety of testosterone have been established for low testosterone levels due to aging. The FDA has required that testosterone labels include warning information about the possibility of an increased risk of heart attacks and stroke.

In February 2025, the FDA removed the black box warning on prescription testosterone products regarding increased risk of adverse cardiovascular outcomes, following the results of the TRAVERSE trial which demonstrated no increased risk compared to placebo in men with hypogonadism. The FDA now requires labeling to include TRAVERSE trial data, and continues to monitor other potential risks such as increased blood pressure.

Heart disease

On January 31, 2014, reports of strokes, heart attacks, and deaths in men taking testosterone-replacement led the FDA to announce that it would be investigating this issue. The FDA's action followed three peer-reviewed studies of increased cardiovascular events and deaths. Due to an increased rate of adverse cardiovascular events compared to a placebo group, a randomized trial stopped early. Also, in November 2013, a study reported an increase in deaths and heart attacks in older men. Concerns have been raised that testosterone was being widely marketed without the benefit of data on efficacy and safety from large randomized controlled trials. As a result of the "potential for adverse cardiovascular outcomes", the FDA announced, in September 2014, a review of the appropriateness and safety of testosterone replacement therapy. However, when given to men with hypogonadism in the short- and medium-term (over a median of 33 months in the TRAVERSE trial), testosterone replacement therapy does not increase the risk of cardiovascular events (including strokes and heart attacks). The long-term safety of the therapy is not known yet.

Other

Other significant adverse effects of testosterone supplementation include acceleration of pre-existing prostate cancer growth in individuals who have undergone androgen deprivation; increased hematocrit, which can require venipuncture in order to treat; and, exacerbation of sleep apnea. A 2014 review said there was some evidence men with certain comorbidities may be at risk of adverse effects including sleep apnoea, metabolic syndrome and cardiovascular disease. Exogenous testosterone may also cause suppression of spermatogenesis, leading to, in some cases, infertility. It is recommended that physicians screen for prostate cancer with a digital rectal exam and prostate-specific antigen (PSA) level before starting therapy, and monitor PSA and hematocrit levels closely during therapy.

Some studies suggest that ART increases the risk of prostate cancer, although the results are not conclusive. This may be due to many men with risk factors for prostate cancer being excluded from testosterone replacement studies. The PSA (which is a screening blood test for prostate cancer) usually increases with testosterone therapy which may lead to a higher rate of prostate cancer testing, including imaging or biopsies. Although testosterone is theoretically hypothesized to increase prostate size, the effects of testosterone therapy on enlarged prostate or lower urinary tract symptoms (such as urinary urgency, hesitancy or incomplete emptying) is not known.

Testosterone therapy may increase the risk of blood clots, but those with blood clots in the trials were not tested for blood clotting disorders, possibly confounding the findings. Testosterone therapy was found to increase the risk of an irregular heartbeat due to atrial fibrillation in one study (3.5% vs 2.4%), but other studies (including meta analyses) have not found an increased risk.

Methods of administration

There are several artificial androgens, many of which are manipulations of the testosterone molecule referred to as anabolic-androgenic steroids. Androgen replacement is administered by patch, tablet, capsule, cream or gel; or depot injections given into fat or muscle.

Society and culture

MMA

Some UFC fighters used TRT until 2014 when the Nevada State Athletic Commission banned its use.

Regulation

As of September 2014, testosterone replacement therapy has been under review for appropriateness and safety by the Food and Drug Administration due to the "potential for adverse cardiovascular outcomes".

Frequency of use

In the United States usage increased from 0.5% in 2002 to 3.2% in 2013 and have since decreased to 1.7% in 2016.

A UK study in 2013 showed that prescriptions for testosterone replacement, particularly transdermal products, almost doubled between 2000 and 2010.

Research

Testosterone is being investigated as therapy for the following conditions:

• Erectile dysfunction
• Osteoporosis
• Diabetes mellitus
• Chronic heart failure
• Dementia, but the evidence base is small and the balance of benefit needs to be clarified

References

References

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