Testosterone Replacement Therapy (TRT)

From testicular extracts to isolated testosterone

A historical review in The Journal of Urology traces the study of testicular function through John Hunter's testicular transplantation experiments in 1767 and Arnold Berthold's later link between the effects of castration and a substance secreted by the testes. It dates the start of organotherapy to 1889, when Charles-Edouard Brown-Séquard announced that injecting himself with testicular extracts had restored his physical and mental abilities, and it dates the isolation of testosterone to 1935.

A 2002 study in the Medical Journal of Australia prepared extracts from dog testes by Brown-Séquard's methods and found testosterone concentrations four orders of magnitude below what is needed for a biological effect. The authors concluded that his reported rejuvenation illustrates the placebo response that androgen treatment can evoke, and they cautioned against empirical testosterone use in older men unless hypogonadism has been substantiated.

Growth in prescribing and the guideline era

The American Urological Association (AUA) guideline of 2018 opens by noting a marked increase in testosterone prescriptions over the preceding decade, and the American College of Physicians (ACP) evidence report of 2020 states that treatment rates in adult men in the United States had risen over two decades. Both documents present this rise as the reason for issuing clinical guidance.

Several professional guidelines followed in the period covered by the sources reviewed: the Endocrine Society guideline (2018), the AUA guideline (2018), the ACP guideline (2020) and successive editions of the European Association of Urology (EAU) guidelines on sexual and reproductive health. Each addresses a somewhat different population, which matters for how their statements are read.

Names and scope

Testosterone replacement therapy (TRT) is the common name for prescribed testosterone given to men with testosterone deficiency. The Endocrine Society guideline uses the phrase testosterone therapy in men with hypogonadism, and the EAU guideline uses the abbreviation TTh. This page covers men only. Hormone treatment in women and in transgender care is outside its scope and is described on other Machipedia pages, including Testosterone Therapy in Women.

TRT is a member of the family described on the Machipedia page Hormone Replacement Therapy, which lists it as testosterone replacement therapy in men. That page covers the wider family and is not duplicated here.

Classical and late-onset hypogonadism

The EAU guideline defines male hypogonadism as a clinical syndrome of symptoms, with or without signs, together with biochemical evidence of testosterone deficiency. It classifies the condition as primary, with a testicular origin, or secondary, with a hypothalamic or pituitary origin. Late-onset hypogonadism refers to adult-onset deficiency that is often diagnosed when no classical cause is found, and the guideline notes that the distinction between functional and organic forms remains debated.

The ACP uses a different frame. Its guideline and evidence report address men with age-related low testosterone and men without well-established medical conditions known to cause hypogonadism. Results from that group should not be read as applying to classical hypogonadism, and the reverse also holds.

What the therapy is

Testosterone therapy is a prescription treatment that raises circulating testosterone in men whose levels are low. Guidelines discuss approved formulations and note that choice among them takes into account patient preference, formulation-specific adverse effects, treatment burden and cost. The ACP evidence report reviewed trials of transdermal and intramuscular products. This page does not describe products, doses or schedules.

Diagnosis and oversight

The Endocrine Society guideline recommends diagnosing hypogonadism only in men with symptoms and signs consistent with testosterone deficiency and unequivocally and consistently low serum testosterone. It recommends measuring a morning fasting total testosterone with a reliable assay, repeating the measurement to confirm, and investigating the cause of deficiency. It also calls for a discussion of benefits, risks and monitoring before treatment, and for monitoring that includes symptoms, adverse effects, testosterone, hematocrit and prostate cancer risk during the first year.

The guidelines reviewed come from societies of endocrinologists, urologists and internal medicine physicians, which indicates the clinical settings in which the treatment is usually directed. The sources reviewed do not describe practitioner registers or training standards specific to testosterone prescribing.

Established indication

The Endocrine Society recommends testosterone therapy for men with symptomatic testosterone deficiency to induce and maintain secondary sex characteristics and to correct symptoms of hypogonadism, after discussing benefits and risks. The EAU guideline regards symptomatic men with total testosterone below 12 nmol/L and no specific contraindications as suitable candidates, and reports that benefits are greatest for sexual symptoms. When used this way, testosterone therapy is a standard medical treatment rather than a complementary practice.

Elective and anti-aging use

The FDA states that testosterone products are approved only for men who lack or have low testosterone together with an associated medical condition, and the class-wide labeling retains a limitation of use for age-related hypogonadism. The EAU guideline does not recommend therapy for men with normal testosterone, for weight reduction, or to improve cognition, vitality or physical strength. The ACP suggests against starting treatment in men with age-related low testosterone to improve energy, vitality, physical function or cognition.

Clinics may market testosterone for energy, body composition or healthy aging. The sources reviewed here do not evaluate clinic marketing, and the trial evidence summarized below does not support carrying results from men with confirmed deficiency to men with normal levels. Related Machipedia pages on Hormone Pellet Therapy, Peptide Therapy and Human Growth Hormone Anti-Aging describe other hormone-related practices separately.

The Testosterone Trials

The Testosterone Trials (TTrials), published in the New England Journal of Medicine in 2016, assigned 790 men aged 65 or older with a serum testosterone below 275 ng per deciliter and symptoms suggesting hypoandrogenism to testosterone gel or placebo gel for one year, across three linked trials. Treatment raised testosterone to the mid-normal range for younger men and was associated with increased sexual activity, desire and erectile function.

Walking distance did not differ significantly in the Physical Function Trial, although it did when all participants were pooled. Vitality scores showed no significant benefit, and mood and depressive symptoms were slightly better with testosterone. Adverse event rates were similar, but the authors stated that the number of participants was too small to draw conclusions about risk.

Systematic review for the ACP

The evidence report prepared for the ACP covered 38 randomized trials of at least six months and 20 long-term observational studies in men without underlying organic causes of hypogonadism. It found that testosterone therapy improved sexual functioning and quality of life, with small effects and low to moderate certainty, and had little to no effect on physical functioning, depressive symptoms, energy and vitality, or cognition.

The reviewers judged harms evidence insufficient or of low certainty for most outcomes. No trial was powered for cardiovascular events or prostate cancer, trials often excluded men at higher risk, few ran beyond one year, and observational studies were limited by confounding by indication and contraindication. The report concluded that long-term efficacy and safety were unknown.

Cardiovascular safety and the dispute

The FDA's 2025 page states that reports of stroke, heart attack and death in men taking testosterone products led to a 2014 advisory committee meeting and ultimately to the TRAVERSE trial. TRAVERSE, a randomized, double-blind, placebo-controlled noninferiority trial, enrolled 5,246 men aged 45 to 80 with symptoms of hypogonadism, two low fasting testosterone values and preexisting or high risk of cardiovascular disease. Major adverse cardiac events occurred in 7.0 percent of the testosterone group and 7.3 percent of the placebo group (hazard ratio 0.96, 95 percent confidence interval 0.78 to 1.17), meeting the noninferiority margin.

The same trial observed a higher incidence of atrial fibrillation, acute kidney injury and pulmonary embolism with testosterone. A fracture substudy of TRAVERSE reported clinical fractures in 3.50 percent of the testosterone group and 2.46 percent of the placebo group (hazard ratio 1.43), so testosterone did not lower fracture incidence. TRAVERSE was funded by AbbVie and others, and treatment lasted a mean of about 22 months.

Meta-analysis and the open question

A 2022 individual-participant-data meta-analysis of 35 trials in 5,601 men found similar cardiovascular event rates with testosterone and placebo (odds ratio 1.07, 95 percent confidence interval 0.81 to 1.42) and concluded there was no evidence of increased short-term to medium-term risk, with a paucity of long-term data. The EAU guideline likewise states that no study can exclude longer-term events and asks for further confirmation of the pulmonary embolism and atrial fibrillation findings, so the question of long-term cardiovascular risk is described as open rather than settled.

What the sources reviewed do not cover

The sources reviewed for this page do not report separate meta-analytic results on anemia, bone density or body composition, so those outcomes are not summarized here beyond the fracture findings above. No Cochrane review of testosterone therapy in men with hypogonadism was identified in the PubMed searches run for this page, which used terms for Cochrane, testosterone, hypogonadism and older men.

When guidelines advise against starting

The Endocrine Society recommends against starting therapy in men who are planning fertility in the near term or who have breast or prostate cancer, a palpable prostate nodule, elevated prostate-specific antigen without further urological evaluation, elevated hematocrit, untreated severe obstructive sleep apnea, severe lower urinary tract symptoms, uncontrolled heart failure, a myocardial infarction or stroke within the last six months, or thrombophilia.

The EAU guideline lists untreated breast cancer, locally advanced or metastatic prostate cancer, a desire for fathering children, a hematocrit of 54 percent or higher and uncontrolled heart failure as absolute contraindications. It names severe lower urinary tract symptoms, a baseline hematocrit of 48 to 50 percent and a family history of venous thromboembolism as relative ones.

Erythrocytosis, prostate and sleep apnea

The EAU guideline identifies erythrocytosis, a rise in red cell concentration, as the most common adverse effect, and says a hematocrit above 54 percent requires action. It reports no increased prostate cancer risk in the literature reviewed while stating that long-term prospective data are needed, and it advises caution in prostate cancer survivors. It finds no evidence that therapy causes or worsens mild, moderate or treated severe sleep apnea.

Effects on fertility

The EAU guideline states that testosterone therapy suppresses gonadotropins and spermatogenesis, and that men wishing to father children should not receive it. A 2022 review of suppression of spermatogenesis by testosterone replacement and anabolic-androgenic steroids reports that recovery after stopping is described mainly in observational studies, that spontaneous recovery is often seen, that its timing is highly variable, and that some men need hormonal stimulation or assisted reproduction. The authors note limited randomized data.

Regulator summaries and label changes

On 28 February 2025 the FDA announced class-wide labeling changes: TRAVERSE results added to all testosterone labels, retention of the limitation of use for age-related hypogonadism, removal of boxed warning language about increased cardiovascular risk, and a blood pressure warning or product-specific blood pressure information. The FDA page states that required ambulatory blood pressure studies confirmed a class-wide increase in blood pressure with testosterone.

A trade news report dated 19 June 2026 describes a further request from the US Department of Health and Human Services to remove the age-related hypogonadism limitation and to narrow the prostate cancer contraindication to metastatic disease. The report presents these as requested changes rather than final label revisions, and the FDA page used above predates them, so the current label should be checked directly.

This page is information only and is not medical advice. Testosterone therapy is a prescription treatment that is chosen, monitored and stopped with a clinician, and sources reviewed do not support starting it without a confirmed diagnosis.