Five core things to remember when prescribing testosterone

Testosterone is being touted as a cure-all on social media, but physicians should only provide testosterone replacement therapy for people who have biochemical evidence of testosterone deficiency, according to Choosing Wisely Canada. This recommendation is echoed in numerous guidelines, including the Endocrine Society, which published clinical practice guidelines for testosterone replacement therapy in men with hypogonadism in 2018.A diagnosis of hypogonadism requires both clinical and biochemical confirmation, and physicians should investigate the etiology, explained Dr. Adam Millar, an endocrinologist at Mount Sinai Hospital in Toronto and associate professor at the University of Toronto. Dr. Millar gave a presentation on testosterone replacement therapy in a recent Canadian Society of Endocrinology and Metabolism webinar.Know who to screen for testosterone deficiencyScreening everyone born a male for testosterone deficiency is not a reasonable option; testing should be prompted by clinical symptoms, which are well-known to be non-specific. Studies suggest that the symptoms of low libido, a decrease in morning erections and mild erectile dysfunction are better at indicating low testosterone levels than other symptoms, Dr. Millar said.Physicians should ask all men with type 2 diabetes about sexual function as hypogonadism is common in this population. More guidance is available in the Diabetes Canada clinical practice guidelines chapter on sexual dysfunction and hypogonadism. Note that the risk of hypogonadism in men with type 1 diabetes is the same as the general population.Learn what tests to order to screen for testosterone deficiencyTestosterone levels should be measured in a fasting state before 10 a.m. on at least two occasions, Dr. Millar said. Physicians should consider ordering total testosterone, as well as either free testosterone or bioavailable testosterone. By ordering both, there’s less chance of error caused by variations in sex-hormone binding globulins that could be altering the total testosterone concentrations.In Canada, most labs use a measured value of total testosterone and a calculated value of both free and bioavailable testosterone, Dr. Millar said. There’s a test called a free androgen index, but Dr. Millar advised against using it as it is “very inaccurate.”Unfortunately, there’s no consensus on the cut-off for testosterone levels to diagnose hypogonadism. Every guideline has a different level of total testosterone concentration where physicians should consider treatment, with the Endocrine Society saying less than 9.2 nmol/L, the International Society for Sexual Medicine (ISSM) stating less than 8 nmol/L (but adding physicians can consider a trial of treatment at concentrations below 12 nmol/L). Dr. Millar advises Canadian physicians to “choose what their cut-off is and try their best to be consistent.”Physicians should also order tests for luteinizing hormone (LH) and follicle stimulating hormone (FSH) levels to investigate if the cause of testosterone deficiency is primary or secondary hypogonadism. Those tests’ results will guide what to test next to further determine etiology. For example, if the tests’ results suggest primary hypogonadism, a physician may order a karyotype to investigate Klinefelter syndrome.Physicians may also include tests to rule out other medical contraindications to testosterone therapy. This includes a complete blood count and prostate-specific androgen (PSA).Physicians don’t need to order liver function tests when testing for testosterone deficiency.Understand the etiologyPart of diagnosing hypogonadism is to figure out the cause. For some, there may be underlying conditions to notice, from a hypothalamic or pituitary tumour to conditions that could be treated, like obesity or opioid addiction.“We shouldn’t just slap on testosterone therapy as a band-aid solution without asking why did this occur in the first place, and are there other things to treat,” Dr. Millar said.Various conditions or syndromes, trauma (including torsion and head trauma), chemotherapy, radiation, obesity, androgenic-anabolic steroid withdrawal, opioid use and infection can all cause hypogonadism. It could be primary hypogonadism, where there are abnormalities at the testicular level, or it could be secondary hypogonadism, where the problems originate in the hypothalamus or pituitary. It could also be a combination of both. The gonadotropin levels (LH and FSH) can provide clues to the etiology.Whatever the cause, there is usually an impairment of spermatogenesis. In some cases, those with secondary hypogonadism may have spermatogenesis restored with gonadotropin therapy.Be aware of contraindicationsThe Endocrine Society guidelines recommend against testosterone treatment therapy in men planning to start a family because the treatment may cause reduced sperm production and decreased fertility. Dr. Millar said he discusses this when he has a young patient, and suggests banking sperm prior to treatment in some cases.The guidelines also recommend not providing testosterone replacement therapy in men with breast or prostate cancer, a PSA greater than 4 ng/mL (or 3 ng/mL with risk factors), untreated obstructive sleep apnea, elevated hematocrit, severe lower urinary tract symptoms, uncontrolled heart failure, stroke or myocardial infarction within six months or thrombophilia.Physicians should also discuss prostate cancer risk and the possibility of prostate monitoring when treating patients 55 years old or older, or at age 40 for those at high risk.The Endocrine Society guidelines recommend testosterone replacement therapy to “induce and maintain secondary sex characteristics and correct symptoms of testosterone deficiency.” It’s available in intramuscular, topical and oral formulations.Testosterone cypionate and testosterone enanthate are available as intramuscular injections. The advantages of these formulations are that they are low cost, familiar to many physicians and patients and there is flexibility with timing of dose (i.e., every week or every two weeks).“It does cause these peaks and troughs in testosterone levels over the duration of the injection. This could potentially lead to differences in red blood cell concentration. It can lead to fluctuations in mood, symptoms, etc.,” Dr. Millar said. There is also a higher risk of erythrocytosis than with other formulations.Transdermal gels are available at various concentrations. It’s used daily and there are fewer fluctuations in serum testosterone concentrations. There’s a potential risk of transferring the testosterone onto others with direct skin-to-skin contact, and it can result in skin irritation. Also, while it works for many, “some people just don’t absorb it well,” Dr. Millar said.There are oral formulations of testosterone undecanoate available in Canada. With an oral formulation, there’s no risk of transference. A rise in blood pressure may occur and physicians should check patients’ blood pressure at baseline and monitor for hypertension.No studies have shown that one formulation is superior to another. “The best one is really the one that matches up best to your patient; the one that achieves physiologic testosterone levels, the one that results in the best safety for your patients, the one that they will be the most adherent to and the one that ultimately achieves the patient’s goals,” Dr. Millar said.Let patients know what to expectA 2025 review in Canadian Family Physician of the benefits of testosterone therapy in people with age-related testosterone deficiency suggests it may increase lean body mass by an average 1.6 kg in older men. The evidence doesn’t support any impact on sexual function, strength, fatigue or cognition in this population.The Endocrine Society guidelines cite a review suggesting treatment improves libido, erectile function and sexual activity compared to placebo in those with hypogonadism and low libido at baseline. It also may improve bone mineral density. The effect of testosterone replacement therapy on mood appears slight, the guidelines note.The benefits are not seen right away, said Dr. Leonardo Seligra, a urologist and andrologist in São Paulo, Brazil, in a May 2026 ISSM podcast. He said it takes about three months to see an effect on libido and, “and at least a year to have all the benefits of the endocrinology or the bone mineral density.”Results of a large randomized control trial involving men with hypogonadism and cardiovascular disease, or at risk of cardiovascular disease, provide more information around the safety of testosterone replacement therapy in that population. It was published in the New England Journal of Medicine in 2023 and called the TRAVERSE trial. It involved 5,246 men aged 45 to 80 years old taking placebo or transdermal testosterone for a mean of 21 months, with a followup of 33 months. The trial results suggest that transdermal testosterone replacement therapy was noninferior to placebo when it came to the risk of major adverse cardiac events.Despite the promising results on cardiovascular safety, researchers recorded higher rates of atrial fibrillation, fractures, nonfatal arrhythmias warranting intervention or acute kidney injury in the testosterone group. “All these things are being investigated further,” Dr. Millar said.The overall incidence of prostate cancer was no different between the two groups.It’s reasonable to follow up with patients within three to four months to reassess their symptoms, blood count, testosterone and PSA levels, Dr. Millar said. A dose adjustment should also be followed up in three to four months, otherwise physicians can see patients with normal lab results after another six months to a year.Poor adherence or persistence to therapy is reported in studies (including TRAVERSE) and in practice. “One common reason is that men stop when they don’t feel the symptoms that prompted testing are improving,” Dr. Millar wrote in an email to the Medical Post. “That is why it’s important to understand why each patient is seeking treatment, set realistic expectations about which symptoms are likely to respond, and plan a reassessment so that therapy is stopped deliberately if it isn’t helping rather than simply lapsing.”

Five core things to remember when prescribing testosterone

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