Testosterone replacement after 40

After forty, many men notice fatigue, a decrease in libido, an increase in belly fat - and increasingly they hear that "testosterone is to blame." The Internet offers a simple solution: hormone replacement therapy. The editors figured out when TRT at this age has a scientific basis, and when it only masks other problems.

What happens to testosterone after 40

The level of testosterone in men gradually decreases with age. The Baltimore Longitudinal Study of Aging (Harman et al., 2001) found that total testosterone declines by an average of about 1% per year, and free testosterone declines more rapidly as sex hormone-binding globulin (SHBG) levels rise at the same time.

This decline is slow and very individual. A large part of men even in their 60s and 70s keeps testosterone within the normal range for young people. Population data of Travison et al. (2007) also show that hormone levels are strongly influenced not only by age, but also by weight, chronic diseases, and lifestyle.

The EMAS European Study of Aging Men (Wu et al., 2010) proposed strict criteria for so-called late-onset hypogonadism: the combination of at least three sexual symptoms (infrequent morning erections, decreased libido, erectile dysfunction) with low total and free testosterone. According to these criteria, true age-related hypogonadism turned out to be much rarer than commonly thought — about 2% of men aged 40–79.

So, "low testosterone after 40" is not a universal age norm that should be treated in everyone, but a condition that requires careful diagnosis. Many symptoms attributed to the hormone have other causes.

When TRT after 40 is really indicated

The Endocrine Society guideline (Bhasin et al., 2018) requires two conditions for the diagnosis of hypogonadism: characteristic symptoms and unambiguously low testosterone, confirmed by at least two morning fasting tests. One "bad" analysis is not a reason for therapy.

In addition, the doctor must find out the cause. For this, LH and FSH, prolactin, and ferritin, if necessary, are determined, and the pituitary gland is assessed. Secondary hypogonadism in a man after 40 is sometimes the result of a pituitary tumor, hemochromatosis, or taking opioid analgesics.

The guideline separately does not recommend the routine use of testosterone in all older men simply because of age and low hormone levels. Decisions are made individually, weighing the expected benefits and risks.

Below is a list of conditions that should be ruled out or corrected before talking about TRT. Each of them is able to reduce testosterone or mimic the symptoms of hypogonadism.

• obesity and insulin resistance, type 2 diabetes;
• obstructive sleep apnea;
• depression and chronic stress;
• acute illness, lack of sleep, excessive training with energy deficit;
• taking opioids, glucocorticoids, some psychotropic drugs;
• alcohol abuse, liver and kidney diseases.

What extensive studies have proven

The most important answers came from the Testosterone Trials (TTrials; Snyder et al., 2016), seven coordinated randomized trials in men 65 years of age and older with low testosterone. Over the course of a year, gel therapy moderately improved sexual function, slightly improved mood and symptoms of depression, increased bone mineral density and hemoglobin.

Meanwhile, TTrials showed no significant improvement in walking endurance or overall vital energy, and no change in cognitive function. That is, TRT is not an "elixir of youth", but a treatment with a specific, moderate set of effects.

Safety for the heart has long been considered a major issue. The TRAVERSE study (Lincoff et al., 2023) in more than 5,000 men aged 45–80 years with hypogonadism and high cardiovascular risk showed that therapy did not increase the frequency of major cardiovascular events compared with placebo.

However, atrial fibrillation, acute kidney injury, and pulmonary embolism were more frequently observed in the testosterone group. These signals are an argument in favor of careful patient selection and regular monitoring.

Contraindications and caution

There are a number of conditions in which TRT is not prescribed or is prescribed with special caution. The Endocrine Society and AUA guidelines list them quite clearly.

Absolute contraindications include prostate or breast cancer, unexamined elevated PSA or a prostate nodule, high hematocrit, severe untreated sleep apnea, decompensated heart failure. A recent heart attack or stroke is also a reason to postpone therapy.

For men after 40, urological aspects are especially important. Before the start, PSA is evaluated and, according to indications, a digital rectal examination is performed. Testosterone does not cause prostate cancer in healthy men, but it can stimulate the growth of an already existing tumor.

A separate issue is plans for children. Even after 40, many men want to become fathers, and exogenous testosterone suppresses spermatogenesis. This is discussed before starting treatment.

Finally, TRT is usually a long-term, often lifelong treatment. The patient should be prepared for regular visits and tests, and not consider the therapy as a short "course to cheer up".

Alternatives and supplements to therapy

For many men with borderline testosterone, lifestyle changes appear to be the most effective intervention. Losing weight in obese people can significantly increase hormone levels, and treating sleep apnea improves both well-being and hormonal profile.

Strength training 2-3 times a week, sufficient sleep (7-9 hours), limiting alcohol are simple steps recommended by all specialized societies. They will not replace TRT in true hypogonadism, but in borderline cases they can make it unnecessary.

If therapy is prescribed, lifestyle remains the basis: testosterone does not compensate for inactivity and excess calories, and cardiometabolic risks depend primarily on them.

It is also useful to be aware of nutritional supplements with promises to "raise testosterone." For most of them, there is no convincing evidence, and they can be justified only in the case of a confirmed deficiency, for example, of zinc or vitamin D.

Editorial conclusions

Testosterone does decrease after 40, but slowly, and remains normal in most men. True age-related hypogonadism is much less common than advertising and social networks suggest.

TRT in confirmed hypogonadism has modest benefits for sexual function, mood, bone, and hemoglobin, and according to TRAVERSE, it does not increase the risk of major cardiac events. However, it has contraindications and requires constant monitoring.

The first step is not a drug, but an examination, search for causes and lifestyle correction. We also recommend our articles "Andropause: symptoms and treatment", "TRT monitoring: tests and frequency" and "Testosterone and bone density".

List of used literature

1. Bhasin S, Brito JP, Cunningham GR, et al. Testosterone therapy in men with hypogonadism: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2018;103(5):1715–1744.
2. Harman SM, Metter EJ, Tobin JD, et al. Longitudinal effects of aging on serum total and free testosterone levels in healthy men. J Clin Endocrinol Metab. 2001;86(2):724–731.
3. Travison TG, Araujo AB, O'Donnell AB, et al. A population-level decline in serum testosterone levels in American men. J Clin Endocrinol Metab. 2007;92(1):196–202.
4. Wu FC, Tajar A, Beynon JM, et al. Identification of late-onset hypogonadism in middle-aged and elderly men. N Engl J Med. 2010;363(2):123–135.
5. Snyder PJ, Bhasin S, Cunningham GR, et al. Effects of testosterone treatment in older men. N Engl J Med. 2016;374(7):611–624.
6. Lincoff AM, Bhasin S, Flevaris P, et al. Cardiovascular safety of testosterone-replacement therapy. N Engl J Med. 2023;389(2):107–117.
7. Mulhall JP, Trost LW, Brannigan RE, et al. Evaluation and management of testosterone deficiency: AUA guideline. J Urol. 2018;200(2):423–432.