Testosterone Replacement Therapy (TRT): Before You Start (Guide)

Most men who walk into my clinic asking about testosterone replacement therapy have already decided they want it. They’ve read the marketing from low-T clinics, they’ve seen the before-and-after photos, and they’ve convinced themselves that a single low reading on a lab report explains every problem in their life. My job in that first consultation is not to prescribe — it is to slow them down. TRT works exceptionally well for the right patient. For the wrong patient, it shuts down their fertility, raises their hematocrit into dangerous territory, and commits them to lifelong injections for a problem that was never hormonal to begin with. This article is the conversation I have before I write the prescription.

Who Actually Needs Testosterone Replacement Therapy

The American Urological Association’s 2018 guideline on testosterone deficiency, amended in 2024, is unambiguous: TRT is indicated for men with both a total testosterone below 300 ng/dL on two separate morning blood draws AND clinical symptoms consistent with deficiency [1]. Both criteria are required. A man with a testosterone of 250 ng/dL who feels fine does not need TRT. A man who feels exhausted but whose testosterone is 450 ng/dL does not need TRT either — his fatigue is caused by something else, and treating him with testosterone will not fix it.

The morning timing matters. Testosterone follows a circadian rhythm — it peaks between 7 and 10 AM and drops by as much as 30% by late afternoon. Drawing labs at 4 PM and calling the result “low” is one of the most common diagnostic errors I see in referrals from primary care. Before TRT is even on the table, I want two morning readings, taken on separate days, ideally fasted, between 7 and 10 AM.

I also want to know why the testosterone is low. This is the question most low-T clinics skip entirely. The hormone is produced by the testes under instruction from the pituitary gland, which itself is instructed by the hypothalamus. A breakdown anywhere along this chain produces low testosterone, but the treatment changes depending on where the breakdown is. Primary hypogonadism — where the testes themselves have failed — shows up with low testosterone and high LH and FSH. Secondary hypogonadism — where the pituitary is the problem — shows up with low testosterone and low or normal LH and FSH. The second pattern can be caused by pituitary tumors, sleep apnea, severe obesity, opioid use, or chronic illness, and many of these are reversible without TRT at all [2].

If your numbers are borderline and you have not yet ruled out the reversible causes, take the symptom check first before committing to lifelong therapy.

The 5 Tests I Run Before Writing a Prescription

A complete pre-TRT workup is not just a testosterone level. It is a panel that confirms the diagnosis, identifies the cause, and establishes baseline measurements I will need to monitor for the rest of the patient’s life on therapy.

• Two morning total testosterone readings. Drawn between 7 and 10 AM, on separate days, fasted if possible. Both must be below 300 ng/dL (10.4 nmol/L) per AUA criteria.
• Free or bioavailable testosterone. Total testosterone can be misleading in men with abnormal sex hormone binding globulin (SHBG) — common in obesity, diabetes, and aging. Free testosterone below 65 pg/mL with normal total can still mean true deficiency.
• LH and FSH. These tell me whether the problem is at the testicles or at the pituitary. They change the entire treatment conversation.
• Prolactin and a morning cortisol. A markedly elevated prolactin can indicate a pituitary adenoma, which requires an MRI of the pituitary before any hormone replacement is started.
• Baseline hematocrit, PSA, and lipid panel. Hematocrit because TRT raises red cell mass and can push it into thrombotic territory. PSA because TRT does not cause prostate cancer but can accelerate the growth of an undiagnosed one. Lipids because TRT can alter HDL.

What the TRAVERSE Trial Actually Showed

For more than a decade, the central unanswered question about TRT was whether it caused heart attacks. Earlier observational studies pointed in both directions, and the FDA added a cardiovascular warning to all testosterone products in 2015 based on the available data. The TRAVERSE trial, published in the New England Journal of Medicine in 2023, was the definitive randomized trial designed to answer this question. It enrolled 5,246 men aged 45-80 with confirmed hypogonadism and either pre-existing cardiovascular disease or high cardiovascular risk, and followed them for an average of 22 months [3].

The primary finding: testosterone therapy was non-inferior to placebo for major adverse cardiac events (cardiovascular death, non-fatal myocardial infarction, or non-fatal stroke). The rate was 7.0% in the testosterone group versus 7.3% in the placebo group. For the first time, we had robust randomized evidence that TRT in symptomatic hypogonadal men does not, on average, raise the risk of heart attack or cardiovascular death.

That is the headline. The footnotes are where the honest conversation lives. TRAVERSE also found that men on testosterone had statistically higher rates of atrial fibrillation (3.5% vs 2.4%), pulmonary embolism (0.9% vs 0.5%), and acute kidney injury (2.3% vs 1.5%) [3]. These are not catastrophic absolute rates, but they are real, and they are the reason I will not prescribe TRT to a man with active atrial fibrillation, a recent DVT, or unstable kidney function without a long conversation about whether the benefit is worth the added risk.

The Fertility Problem Nobody Mentions in the Brochure

This is the single most important conversation I have with men under 45 who are considering TRT, and it is the one most likely to be glossed over by commercial clinics. External testosterone shuts down the pituitary’s signal to the testicles. Within 3-6 months of starting therapy, the vast majority of men become functionally infertile — sperm counts drop, often to zero, and testicular size visibly decreases. In one prospective study of men on long-term testosterone, 65% became azoospermic within 4 months [4].

Recovery is not guaranteed. After stopping testosterone, most men regain sperm production within 6-24 months, but a meaningful minority do not recover to baseline at all, particularly men who were on therapy for several years or who already had marginal sperm parameters before starting. If you are under 45 and there is any possibility you want biological children, the conversation is not optional — it is mandatory before the first dose. The options at that point are: freeze sperm before starting TRT, use clomiphene citrate or anastrozole instead (which raise endogenous testosterone without suppressing the axis), or add hCG to TRT to maintain testicular function.

If fertility is on the table for you in any form, read the broader picture on male reproductive health before you commit to a treatment path that could remove the option.

Delivery Methods: What Each One Actually Feels Like

There are four mainstream delivery methods, and the choice is not trivial — it affects how steady your levels are, how often you think about your treatment, and what your partner and household are exposed to.

Intramuscular injections (testosterone cypionate or enanthate) are the most prescribed. Typically 100-200 mg once weekly or every two weeks, self-administered. Peaks and troughs are real — many men feel excellent for the first 4-5 days after an injection and progressively flatter as the next dose approaches. Splitting the weekly dose into two smaller injections smooths this out considerably, which is what I recommend for most men who report mood or energy swings.

Topical gels (testosterone 1% or 2%) applied daily to the shoulders or abdomen produce steadier levels than injections but carry a real risk of transference. A child or partner who touches the application site within 2-6 hours of application can absorb measurable testosterone — and case reports of accelerated puberty in children of TRT-using fathers exist [5]. I do not prescribe gels to men with young children in the household.

Subcutaneous pellets (Testopel) are implanted in the hip every 3-6 months. Set-and-forget convenience, very stable levels, but the dose cannot be adjusted once implanted, and if side effects develop, the pellets must be surgically removed.

Oral testosterone undecanoate (Jatenzo, Tlando) is newer and bypasses the liver toxicity that killed earlier oral forms. Twice-daily dosing, no injections, no gels — but expensive, and long-term cardiovascular data is still maturing.

The Monitoring Schedule I Use

Starting TRT is a 20-year commitment in most men. The monitoring is not optional — it is what distinguishes therapy from a vanity prescription, and it is where most low-T clinics fail their patients.

• 3 months after starting: Total testosterone (target mid-normal range, around 450-600 ng/dL), hematocrit, PSA, symptom review.
• 6 months: Repeat the 3-month panel. Adjust dose if levels are too high or symptoms are not controlled.
• 12 months and annually thereafter: Full panel including hematocrit, PSA, lipid panel, and a digital rectal exam if age-appropriate.
• Hematocrit above 54%: Reduce dose, increase dose interval, or refer for therapeutic phlebotomy. Do not ignore this — polycythemia from TRT is one of the few side effects with a clear thrombotic signal.
• PSA rise greater than 1.4 ng/mL in any 12-month period: Stop and reassess. TRT does not cause prostate cancer, but it will accelerate the growth of an undiagnosed one, and a sudden PSA velocity change while on therapy is not something to wait out.

If your PSA changes while on TRT, the trajectory matters more than the absolute number. Track it with the tool I built for exactly this scenario.

When TRT Is Not the Answer

Roughly 40% of men referred to my clinic for “low testosterone” leave with a treatment plan that does not involve testosterone at all. The reasons are usually one of three patterns. The first is reversible secondary hypogonadism — obesity, sleep apnea, opioid medications, alcohol overuse, or uncontrolled diabetes are suppressing the pituitary, and addressing the underlying cause restores testosterone to normal without lifelong therapy. The second is symptoms in the absence of biochemical deficiency — fatigue, low libido, and erectile dysfunction have many causes, and chasing testosterone numbers when the testosterone is normal is treating the wrong target. The third is a vascular cause masquerading as a hormonal one — particularly with erectile dysfunction, where the underlying issue is often cardiovascular rather than endocrine.

The last category is the one I worry about most. A man in his 50s with new erectile dysfunction and borderline-low testosterone is far more likely to have early cardiovascular disease than primary hypogonadism, and prescribing him testosterone without investigating his vascular health misses the diagnosis that will actually kill him.

Frequently Asked Questions About TRT

Dr. Muhammad Khalid

MBBS · FCPS (Urology) · MCPS (Gen. Surgery) · CHPE · CRSM · IMC #539472

Specialist urologist with 11+ years of clinical experience across tertiary teaching hospitals. Trained at Lady Reading Hospital and Khyber Teaching Hospital, Peshawar. Author of 5 peer-reviewed international publications in Cureus, WJSA, and AJBS. Procedural expertise: URS, PCNL, RIRS, TURP, TURBT, and major open urological surgery. Full profile →

This article is for educational purposes only and does not constitute medical advice. Always consult your physician or urologist for diagnosis and treatment decisions specific to your condition.