TRT: The Complete Evidence on Testosterone Replacement Therapy

The Testosterone Decline: Facts and Context

Testosterone declines with age. Men at age 30 average around 700 ng/dL (total testosterone). By age 70, this drops to around 500 ng/dL. The decline rate is roughly 1% per year after age 30, though there's enormous individual variation.

This is normal aging, not disease. But the question is: how much of this normal decline reflects true hypogonadism (inadequate testosterone production) versus age-related decline in healthy men?

The answer matters because there's been a massive expansion in testosterone replacement therapy (TRT) prescriptions over the past two decades, driven partly by marketing and partly by genuine concern about age-related testosterone decline and its effects on vitality, muscle, mood, and cognition.

The Cardiovascular Controversy: TRAVERSE 2023 Resolves It

For years, the biggest barrier to TRT was fear of cardiovascular events. The 2010 TTrials study suggested increased heart attack risk with testosterone replacement. This created a "cardiovascular black box" around TRT.

But that fear was based on limited evidence in old men with pre-existing cardiovascular disease. What about younger men without cardiac risk?

The TRAVERSE trial (published in NEJM 2023) finally provided the answer: a randomised, controlled study of 5,204 men (average age 72) with low testosterone or cardiovascular disease randomised to testosterone replacement or placebo. Over four years, cardiovascular events were nearly identical in both groups. Testosterone replacement did not increase heart attack or stroke risk.

This was definitive. The cardiovascular concern, which had haunted TRT for over a decade, was essentially resolved. Testosterone replacement, when done properly in men without active coronary disease, doesn't increase cardiovascular events.

Symptoms vs Lab Values: The Real Diagnostic Dilemma

Here's the nuance that gets lost: total testosterone number doesn't determine whether someone needs replacement. Symptoms do.

A man with testosterone of 400 ng/dL might have classical hypogonadal symptoms: fatigue, low libido, erectile dysfunction, poor recovery, mood symptoms. Another man with the same 400 ng/dL might feel completely fine.

The difference often comes down to SHBG (sex hormone-binding globulin), the protein that carries testosterone in your blood. If SHBG is high, much of your testosterone is bound and unavailable to tissues. If SHBG is low, your free testosterone is higher despite similar total testosterone levels.

Free testosterone (or calculated free testosterone) is more relevant than total testosterone. A man with total testosterone of 500 ng/dL but SHBG of 15 nmol/L (low) might have more bioavailable testosterone than a man with total testosterone of 700 ng/dL but SHBG of 50 nmol/L (high).

This is why UK NICE guidelines (2015) recommend checking both total and free testosterone before considering replacement, and critically, recommend symptoms-based assessment, not lab-value-based assessment alone.

When TRT Actually Makes Sense

TRT is appropriate when:

• Total testosterone is consistently below 300 ng/dL (10.4 nmol/L) OR free testosterone is below 225 pg/mL (7.8 pmol/L), AND
• The man has symptoms consistent with hypogonadism: fatigue, low libido, erectile dysfunction, poor mood, loss of muscle, poor recovery.

TRT is not appropriate when:

• Testosterone is in the low-normal range but the man feels fine. (Why treat a lab number?)
• Testosterone is low but the man's symptoms aren't consistent with hypogonadism (might be depression, sleep apnoea, or other conditions).
• Active prostate cancer, untreated severe sleep apnoea, or uncontrolled hypertension.

The Prostate Myth: Testosterone Doesn't Cause Prostate Cancer

One of the most persistent fears about TRT is that it causes or accelerates prostate cancer. This myth persists despite decades of evidence against it.

The logic seemed right: testosterone drives prostate growth; prostate cancer is testosterone-dependent; therefore, more testosterone should increase cancer risk.

But the evidence shows otherwise. Men with high natural testosterone have the same prostate cancer rates as men with low testosterone. Men on TRT who are monitored don't show increased cancer detection. A 2017 meta-analysis in the European Urology Journal of 42 studies found no increased prostate cancer risk with testosterone replacement.

What happens is: TRT can accelerate prostate growth in men who already have benign prostate hyperplasia (BPH). This is not cancer; it's benign enlargement. It can worsen urinary symptoms, but it doesn't cause cancer.

So the appropriate approach: check PSA and digital rectal exam before starting TRT. Monitor PSA annually (if it rises >1.4 ng/mL/year, investigate). But don't avoid TRT due to cancer fear—the risk isn't there.

Forms of TRT: What Actually Gets Used in the UK

Injectable testosterone: Testosterone propionate (injected weekly) or testosterone enanthate/cypionate (injected weekly or every two weeks). Most effective, most physiological, most affordable. Standard dose is 125-200 mg weekly. This maintains stable testosterone levels and mimics natural secretion reasonably well.

Transdermal (gels and patches): Testosterone gel applied daily or patches applied weekly. Convenient but variable absorption. Dose ranges from 50-100 mg daily. More expensive than injections.

Oral testosterone undecanoate: Taken with fatty meals. Less physiological (causes spiking and troughing) but convenient. Not widely used in UK practice.

UK guidelines favour injectable testosterone as first-line, given efficacy and cost.

The Testicular Atrophy Problem: Why hCG Matters

Testosterone replacement suppresses your body's own testosterone production (via suppression of LH and FSH, the pituitary hormones that drive testicular testosterone synthesis). Over months, this leads to testicular atrophy: your testicles shrink.

This is reversible if TRT is stopped, but it can take months to recover full testicular function and sperm production. If fertility is a concern, this matters.

The solution: add hCG (human chorionic gonadotropin), which mimics LH and maintains testicular stimulation and sperm production even during TRT. Standard dosing is 250-500 IU twice weekly subcutaneously.

Men concerned about fertility should be on hCG from the start of TRT, not added later as an afterthought. This preserves testicular function and fertility potential.

Aromatisation and Oestrogen: The Balance

Some of your testosterone converts to oestradiol (via the enzyme aromatase). This is normal. Men need some oestrogen for bone health, mood, and sexual function.

But excessive aromatisation causes problems: man boobs (gynecomastia), water retention, sexual dysfunction, mood issues. Some men over-aromatise due to high body fat, certain genetic variants, or liver disease.

The solution is not to avoid TRT; it's to manage aromatisation. An aromatase inhibitor (anastrozole, letrozole) can be added if oestrogen-related side effects occur. But routine aromatase inhibition isn't recommended—some oestrogen is good.

Oestradiol should be kept in the range of 20-30 pg/mL (75-110 pmol/L). Above that, add aromatase inhibitor. Below that, reduce it.

Long-Term Commitment: TRT Is Lifelong

This is the part nobody emphasises enough: testosterone replacement is a lifelong commitment. You can't do TRT for a few years and then stop without consequences. Your body's own testosterone production is suppressed. You'll drop to hypogonadal levels when you stop. You'll feel terrible.

Some men naturally recover testicular function after stopping TRT, particularly if they were on it for a short time. But many don't. Once you start, the expectation should be lifelong.

This is fine if you actually need it and benefit from it. But it should be an informed decision, not something you drift into because a clinic offered it.

The Assessment Protocol That Actually Works

Before starting TRT, get:

• Total testosterone (ideally two measurements, early morning, fasting)
• Free or calculated free testosterone
• SHBG
• FSH, LH (to assess whether low testosterone is from pituitary or testicular)
• PSA and digital rectal exam
• Haemoglobin (TRT increases red blood cell production)
• Lipid panel
• Liver and kidney function

Then decide: does this man have hypogonadism (low testosterone) AND hypogonadal symptoms? If yes, TRT is appropriate. If no, it's not.

The Bottom Line: TRT is Effective But Requires Proper Stewardship

Testosterone replacement works. When done properly in men with genuine hypogonadism and symptoms, it improves fatigue, libido, mood, recovery, and muscle. The cardiovascular concerns are resolved. The cancer fears are overstated.

But it requires: proper diagnosis (symptoms plus low testosterone, not low testosterone alone), baseline monitoring, ongoing follow-up, management of side effects, and informed consent that it's lifelong.

Too much TRT is prescribed based purely on low lab values. Too little is withheld from men who would genuinely benefit due to outdated cancer fears. The right balance is symptoms-based assessment with lab confirmation and proper safety monitoring.