Testosterone Replacement Therapy: Who It Helps and Who It Doesn't

Testosterone replacement is a well-established treatment for a specific, diagnosable condition. It is also sold, aggressively, to men who do not have that condition. Understanding which category you are in is most of the decision.

What hypogonadism actually is

Male hypogonadism is the failure of the testes to produce adequate testosterone, sperm, or both. It is a clinical diagnosis, meaning it requires two things at once: biochemical evidence of low testosterone on properly collected samples, and symptoms or signs consistent with androgen deficiency. Either one alone is not a diagnosis.

The system involved is a loop. The hypothalamus releases GnRH, which prompts the pituitary to release luteinising hormone and follicle-stimulating hormone. LH tells the Leydig cells in the testes to make testosterone; FSH supports sperm production. Testosterone circulating in the blood then feeds back to the hypothalamus and pituitary and turns the signal down. It is a thermostat.

Primary and secondary

Where the loop breaks determines the diagnosis, and this is why LH and FSH belong in every workup.

Primary hypogonadism is testicular failure. The pituitary is shouting and the testes cannot answer. Testosterone is low and LH and FSH are high. Causes include Klinefelter syndrome, previous mumps orchitis, testicular trauma or torsion, undescended testes, and damage from chemotherapy or radiation. Primary hypogonadism is generally permanent.

Secondary hypogonadism is a signalling problem upstream. Testosterone is low and LH and FSH are low or inappropriately normal, which is the tell: if the testes were failing, those numbers should be elevated. Causes include pituitary tumours, particularly prolactin-secreting ones, opioid use, glucocorticoids, obesity, obstructive sleep apnoea, haemochromatosis, head injury, and prior anabolic steroid use. Some congenital forms exist.

That distinction changes what happens next. A prolactinoma needs imaging and treatment in its own right, not testosterone. Opioid-induced suppression may resolve when the opioid does. Obesity and untreated sleep apnoea both suppress the axis and both frequently improve it when addressed. A man who is prescribed testosterone without anyone establishing why his level is low has been sold a symptom management strategy for an undiagnosed problem.

Symptoms, and the problem with them

The commonly cited symptoms are low libido, erectile difficulty, fatigue, loss of muscle mass and strength, increased body fat, low mood, irritability, poor concentration, reduced body hair and, over longer periods, reduced bone density.

Read that list again and note how unspecific most of it is. Fatigue, low mood, poor concentration and reduced libido are the presenting picture of major depression. They are also the picture of untreated obstructive sleep apnoea, hypothyroidism, iron deficiency, poorly controlled diabetes, chronic alcohol use, and simply not sleeping enough for two years.

The few features that point more specifically at androgen deficiency are the ones people mention least: loss of morning erections, reduced testicular volume, gynaecomastia, loss of body and facial hair, hot flushes. Those carry more diagnostic weight than fatigue does.

This is why an online questionnaire cannot diagnose you. It is also why a clinic that diagnoses you from a questionnaire is not diagnosing you. We go through the overlap in detail in low testosterone symptoms and why symptoms alone aren't enough.

Testing it properly

More bad TRT decisions come from bad testing than from anything else. A defensible workup has several components.

Time of day

Testosterone follows a daily rhythm, peaking in the morning and falling through the day, with the pattern most pronounced in younger men. A sample drawn in the afternoon can read low in a man whose morning level is entirely normal. Guidelines are consistent on this: the sample should be taken in the morning, generally in the first few hours after waking.

More than once

Testosterone varies day to day, and acute illness, poor sleep or recent heavy exercise can all pull a reading down transiently. A single low result is a reason to repeat the test, not a reason to start treatment. Two low morning results on separate days is the standard.

Total and free

Most circulating testosterone is bound to sex hormone binding globulin and to albumin. Total testosterone measures all of it. Free testosterone is the small unbound fraction. When SHBG is abnormal, total and free readings diverge, and the total becomes misleading.

SHBG is lowered by obesity, insulin resistance, hypothyroidism and steroid use, and raised by ageing, liver disease, hyperthyroidism and some anticonvulsants. So an obese man with a borderline-low total testosterone may have a perfectly adequate free level, and an older man with a normal-looking total may not. Free testosterone should be measured, or reliably calculated with SHBG and albumin, whenever the clinical picture and the total do not agree.

Guidelines have set the threshold for "low" around a total testosterone in the region of 300 ng/dL, with different professional bodies drawing the line slightly differently and laboratory reference ranges varying by assay. Treat any single published cut-off as a clinical starting point rather than a verdict.

The rest of the panel

A workup that stops at testosterone is incomplete. It should include LH and FSH, to separate primary from secondary. Prolactin, because an elevated prolactin points at the pituitary and can be the first sign of an adenoma. A full blood count for baseline haematocrit, because raising it is the most common adverse effect of treatment. PSA in men of an age where prostate cancer screening is relevant, together with a discussion about what a result would mean. Often also thyroid function, HbA1c, lipids, iron studies where haemochromatosis is plausible, and oestradiol in specific circumstances.

Our article on getting testosterone testing right goes through each of these and the common ways they get misread.

How it is given

There is no single best delivery method; there is the one that fits your tolerance, your schedule and your risk profile.

Injections of testosterone cypionate or enanthate, intramuscular or subcutaneous, are the most widely used. They are inexpensive and effective. Longer intervals produce a peak-and-trough pattern that some men feel as a cycle of good and bad weeks; smaller, more frequent doses smooth that out.

Topical gels and solutions are applied daily and give steadier levels. They carry a real and specific hazard: testosterone transfers by skin contact, and secondary exposure has caused premature virilisation in children and unwanted effects in female partners. Application sites must be covered and washed. This is a boxed warning, not a caution.

Long-acting injectable undecanoate is dosed at long intervals but is administered in a clinical setting under a risk management programme, because of a rare reaction involving oil entering the pulmonary circulation.

Subcutaneous pellets are implanted in a minor office procedure and release over months. Convenient, but not adjustable once in, and occasionally extrude or become infected.

Oral formulations and a nasal gel also exist. Modern oral testosterone is not the liver-toxic methylated compound of the past, but blood pressure increases have been observed and require monitoring.

Fertility. Read this section.

This is the most consequential thing in this article and it is the thing most often glossed over in a short consultation.

Testosterone taken from outside suppresses the loop. Your pituitary sees adequate testosterone in the blood, stops releasing LH and FSH, and the testes stop being told to work. Two things follow. Your own testosterone production shuts down, which is why testicular volume decreases on treatment. And the concentration of testosterone inside the testis, which is very much higher than in blood and is what sperm production depends on, collapses.

The result is a marked reduction in sperm count. In many men on standard replacement doses, sperm count falls to zero. This is reliable enough that exogenous testosterone has been studied as a male contraceptive.

Recovery after stopping is usual but not universal, and it is slow. Return of spermatogenesis is typically measured in many months, sometimes considerably longer, and in some men it does not return fully. Longer duration of use, higher doses and older age all make recovery less certain.

If you may want biological children, this must be discussed before you start. There are alternatives that raise testosterone by stimulating your own axis rather than replacing it, and there are adjuncts used alongside testosterone to preserve testicular function. Sperm banking before starting is straightforward and cheap relative to the alternative. Any of these is a better outcome than finding out at thirty-four. We treat this separately, at length, in TRT and fertility: the conversation that comes too late.

Risks worth understanding

Erythrocytosis. Testosterone stimulates red blood cell production. A rising haematocrit thickens the blood and raises thrombotic risk. This is the most common adverse effect and the main reason for routine bloodwork. It is manageable by dose reduction, changing delivery method or therapeutic phlebotomy, but only if someone is measuring it.

Sleep apnoea. Testosterone can worsen obstructive sleep apnoea. Given that untreated sleep apnoea also lowers testosterone, treating the second without addressing the first is a loop worth avoiding.

Prostate. Current evidence does not support the older belief that testosterone causes prostate cancer. It can nonetheless raise PSA and can stimulate an existing cancer, so known or suspected prostate cancer and male breast cancer are contraindications, and PSA monitoring is standard in men of screening age.

Cardiovascular. Earlier observational signals raised concern. A large randomised cardiovascular safety trial in men with hypogonadism and elevated cardiovascular risk subsequently did not find an increase in major adverse cardiac events relative to placebo. That was reassuring on the primary question, but the same trial recorded more pulmonary embolism, atrial fibrillation and acute kidney injury in the treated group. Blood pressure increases have also prompted labelling changes. The honest summary is that TRT in properly diagnosed men is not the cardiac hazard it was once feared to be, and it is not free of cardiovascular consequences either.

Other. Acne, oily skin, fluid retention, gynaecomastia, mood changes, and testicular atrophy.

The monitoring schedule

Follow-up bloodwork in the first year is typically at around three months and again at six to twelve months, then annually once stable. It should cover testosterone level and timing relative to the dose, haematocrit, PSA where age-appropriate, blood pressure, and a symptom review. Dose is adjusted to symptoms and to a mid-normal level, not to the top of the range and certainly not above it.

A provider who prescribes without a monitoring schedule is not managing your treatment. TRT risks and the monitoring that should come with it sets out what a responsible follow-up programme looks like.

What TRT is not

Testosterone declines gradually in most men from midlife onwards. That decline is slow, modest, and in most men does not take levels below the normal range. It is not the same thing as hypogonadism, and treating it as though it were is the basis of a very large amount of commercial activity.

Trials of testosterone in older men with age-related decline have found modest improvement in some sexual-function measures and little consistent benefit in vitality, cognition or physical function. That is a much smaller claim than the marketing makes.

Two things follow. First, TRT is not a performance product. Supraphysiological dosing to build muscle is not replacement therapy; it is anabolic steroid use, with a different risk profile, and it will suppress your own axis just as thoroughly. Second, starting testosterone in a man with normal levels is not treatment. It creates dependence on an external supply, suppresses natural production and fertility, and treats a condition he does not have. If your levels are normal and you feel terrible, the answer to why you feel terrible is somewhere else, and it is worth finding. We make this case fully in TRT is not an anti-ageing treatment.

If you are considering it

The sequence that makes sense is: describe the symptoms honestly, test properly, rule out the conditions that mimic low testosterone, establish whether the cause is primary or secondary, address anything reversible, and only then discuss replacement. If replacement is appropriate, settle the fertility question before the first dose and agree the monitoring schedule at the same time as the prescription.

Our hormone therapy service explains what an evaluation involves and what testing we require. If chronic stress and sleep are part of your picture, that is worth addressing in its own right. Hormone questions are not exclusively a male subject either; perimenopause is similarly under-recognised and frequently misattributed.

You can book a consultation to review your history and results with a clinician. No one can tell you before that conversation whether you have hypogonadism or whether treatment would be appropriate, and a service that promises either is not practising medicine.