Understanding Testosterone Treatment for Men with Low Testosterone: Benefits, Risks, and What the Research Shows

Table of Contents

• Introduction: What is Hypogonadism?
• How Testosterone Works in Your Body
• Key Research Studies on Testosterone Treatment
• Proven Benefits of Testosterone Treatment
• Conditions Where Testosterone Shows Little Benefit
• Understanding the Risks and Safety Concerns
• Cardiovascular Risks: What the Research Shows
• Making Treatment Decisions: Balancing Benefits and Risks
• Source Information

Introduction: What is Hypogonadism?

In men, significant testosterone deficiency due to pituitary or testicular problems typically causes recognizable symptoms. These include decreased sex drive and sexual activity, loss of masculine characteristics and muscle mass, hot flashes, and anemia. Testosterone medications have been approved by regulatory agencies to treat this condition, known as hypogonadism, and are effective in correcting these clinical abnormalities in many men.

However, most men currently receiving testosterone treatment are middle-aged or older with only moderately low testosterone levels. These men often have a high burden of chronic diseases and nonspecific symptoms that overlap with normal aging symptoms. The benefits and risks of testosterone treatment in this population are less clear and remain controversial among medical experts.

This review examines available information about the benefits and risks of testosterone treatment in middle-aged and older men with moderate degrees of low testosterone. Understanding this balance is crucial for patients and doctors making treatment decisions together.

How Testosterone Works in Your Body

Many of testosterone's benefits and some risks come from how it acts in your body through different mechanisms. Testosterone has building-up (anabolic) effects on muscle and bone and stimulates red blood cell production through androgen receptor-mediated mechanisms. These are the primary ways testosterone helps maintain masculine characteristics and physical strength.

Testosterone also works through non-genetic mechanisms that increase penile blood flow and improve erectile function. The effects of testosterone on sexual desire and bone health are mediated largely through its conversion to 17β-estradiol. Testosterone is also converted to dihydrotestosterone (DHT), which stimulates prostate growth and has additional building-up effects on muscle and bone.

Testosterone and DHT increase penile blood flow and erections through a rapid increase in nitric oxide production (which is endothelium-dependent) and through inhibition of voltage-operated calcium channels or activation of potassium channels on smooth muscle (which are endothelium-independent). A metabolite of DHT called 5α-androstane-3α,17β-diol, which acts on the γ-aminobutyric acid receptor, has been linked to mood and emotional state.

Key Research Studies on Testosterone Treatment

Placebo-controlled trials conducted during the 1990s and early 2000s evaluated whether testosterone treatment in middle-aged and older men with low or low-normal testosterone levels would improve sexual function, bone density, and muscle mass and strength. Some trials suggested benefits, while others did not. For example, some studies showed testosterone treatment improved sexual activity and libido, increased lean body mass, and increased maximal muscle strength, but not all studies agreed.

In 2003, an Institute of Medicine committee concluded there was insufficient evidence that testosterone treatment in older men with hypogonadism had any clinically important benefit. They recommended a coordinated set of trials to determine testosterone's effectiveness in older men with low testosterone.

In response, seven trials called the Testosterone Trials (TTrials) were developed. These included 790 men with an average age of 72 years and average baseline testosterone level of 234 ng per deciliter (8.1 nmol per liter). Participants received daily transdermal testosterone or placebo gel for one year, with testosterone treatment increasing median levels to the middle of the normal range.

Before the TTrials completed, the FDA required manufacturers to conduct the TRAVERSE trial to assess cardiovascular safety. This trial enrolled 5,204 men with hypogonadism who had or were at increased risk for cardiovascular disease. Participants had a mean age of 63 years and baseline testosterone level of 227 ng per deciliter (7.9 nmol per liter). They received daily testosterone or placebo gel and were followed for an average of 33 months.

Around the same time, the Australian T4DM trial assessed whether testosterone treatment plus lifestyle intervention would prevent progression to or reverse type 2 diabetes. This trial enrolled 1,007 men with impaired glucose tolerance or newly diagnosed type 2 diabetes, with a mean age of 60 years and mean serum testosterone level of 395 ng per deciliter (13.7 nmol per liter).

Proven Benefits of Testosterone Treatment

The most consistent benefit of testosterone treatment in men with hypogonadism was improved sexual function. In the TTrials, testosterone treatment increased sexual activity by approximately 40% (0.58 sexual acts per week), libido by approximately 25%, and erectile function by approximately 35%. For context, in a study of U.S. adults aged 57-85 years, approximately 50% of participants aged 75-85 reported sexual activity with a partner two to three times monthly.

The increase in sexual activity included 12 measures of sexual activity, from flirting to intercourse. Increases were associated with increases in free testosterone and estradiol levels. In the TRAVERSE trial, testosterone treatment also increased sexual activity and libido but did not improve erectile function. In the TTrials, a small improvement in erectile function was observed (mean increase of 2.6 points on a 0-30 scale), compared to a 5.7-point increase with sildenafil in older men.

Testosterone treatment was associated with modest improvements in physical function. Among all TTrials participants, the increase in distance walked in the 6-minute walk test was 6-7 meters greater with testosterone than placebo. Testosterone also improved the perception of overall physical function, though the walking distance improvement didn't occur in men who walked slowly before treatment.

Nearly half of TRAVERSE participants reported depressive symptoms, with nearly 10% reporting severe depressive symptoms. Testosterone improved mood by 3-4% overall and among the 2-5% of participants with clinically significant depressive symptoms, though it didn't help men with formal major depressive disorder diagnoses. In the TTrials, testosterone increased positive affect scores by 3%, decreased negative affect scores by 6%, and decreased depressive symptom scores by 10%.

Testosterone improved energy slightly in various studies. In TRAVERSE, testosterone was associated with a 4-5% greater improvement in energy than placebo. Testosterone treatment generally increases hemoglobin levels. In the TTrials, half of anemic participants receiving testosterone had hemoglobin increases of at least 1.0 g per deciliter. In TRAVERSE, significantly more men receiving testosterone had corrected anemia, with one-third showing hemoglobin increases of at least 1.0 g per deciliter.

Testosterone treatment improves bone density and architecture. In the TTrials Bone Trial, 1 year of testosterone gel increased volumetric bone mineral density and bone strength by 7% in spinal trabecular bone, with smaller but significant increases in peripheral (mostly cortical) bone and hip. In a T4DM subtrial, 2 years of testosterone therapy increased cortical bone in the tibia and radius.

Conditions Where Testosterone Shows Little Benefit

Testosterone treatment that increases serum testosterone to mid-normal range has little effect on glucose metabolism in men with hypogonadism. In the TTrials, testosterone didn't change fasting glucose or glycated hemoglobin levels. Similarly, in a TRAVERSE subtrial, testosterone didn't decrease diabetes progression rates in prediabetic men or affect glycemic control in those with diabetes.

In the TIMES2 trial, testosterone didn't reduce glycated hemoglobin or fasting glucose levels in men with type 2 diabetes or metabolic syndrome. However, in the T4DM trial (which involved participants with higher baseline testosterone levels), testosterone plus lifestyle intervention for 2 years was associated with lower percentages of participants with 2-hour blood glucose levels of 200 mg per deciliter or higher compared to lifestyle intervention alone.

Testosterone treatment hasn't improved cognition in men without preexisting cognitive disease. In the TTrials, testosterone didn't improve delayed paragraph recall, visual memory, spatial ability, or executive function in men with age-related memory impairment, though it was associated with a 7% executive function improvement in all participants.

Understanding the Risks and Safety Concerns

Testosterone treatment carries several important risks that patients must understand. The treatment is associated with an increased risk of clinical fractures and pulmonary embolism, which are serious conditions requiring medical attention.

Contrary to historical concerns, testosterone treatment did not increase the risk of prostate cancer or acute urinary retention and did not worsen lower urinary tract symptoms in the major studies reviewed. This represents an important shift in understanding about testosterone's effects on prostate health.

The treatment does increase red blood cell production, which can lead to erythrocytosis (excess red blood cells). In the T4DM trial, 22% of participants developed hematocrit levels above 54%, which requires monitoring and potentially adjustment of treatment.

Patients should discuss these potential risks with their doctors and ensure appropriate monitoring during treatment, including regular blood tests and health assessments.

Cardiovascular Risks: What the Research Shows

Small trials and retrospective studies published since 2010 have yielded conflicting results about whether testosterone treatment increases cardiovascular risk. One randomized trial in older men with mobility limitations was stopped early due to increased cardiovascular events in the testosterone group, but another similar trial showed few cardiovascular events.

Two retrospective cohort studies found slightly higher rates of major adverse cardiovascular events (MACE) in testosterone-treated men, while another study did not. These studies were limited by differences in study populations, treatment regimens, duration, testosterone levels during treatment, and failure to properly evaluate cardiovascular events.

The TRAVERSE trial was specifically designed to determine whether testosterone treatment would increase cardiovascular risk in middle-aged and older men with hypogonadism who had preexisting cardiovascular disease or increased cardiovascular risk. The primary safety endpoint was MACE - a composite of nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death.

The results showed that testosterone treatment did not increase the risk of major cardiovascular events among men with preexisting cardiovascular disease. This represents important safety information for patients and doctors considering testosterone treatment.

Making Treatment Decisions: Balancing Benefits and Risks

The decision to use testosterone treatment in men with hypogonadism should be based on the severity of the testosterone deficiency and a careful assessment of potential benefits versus risks for each individual patient. Treatment isn't appropriate for all men with low testosterone levels.

Patients should consider their specific symptoms, overall health status, and personal health goals when discussing testosterone therapy with their doctors. The most consistent benefits appear in sexual function, anemia correction, and modest improvements in energy, mood, and physical function.

Patients with preexisting cardiovascular disease can be reassured that testosterone doesn't appear to increase major cardiovascular event risks, based on the TRAVERSE trial results. However, the increased risks of fractures and pulmonary embolism require careful consideration.

Regular monitoring during treatment is essential, including blood tests to check testosterone levels, red blood cell counts, and other relevant parameters. Treatment should be adjusted based on response and any side effects that develop.

Source Information

Original Article Title: Testosterone Treatment in Middle-Aged and Older Men with Hypogonadism

Authors: Shalender Bhasin, M.B., B.S., and Peter J. Snyder, M.D.

Publication: The New England Journal of Medicine, 2025;393:581-91

DOI: 10.1056/NEJMra2404637

This patient-friendly article is based on peer-reviewed research and aims to make complex medical information accessible to educated patients while preserving all essential data, findings, and clinical implications from the original research.