Testosterone & TRT

The OPTN canonical reference on testosterone and testosterone replacement therapy. Living document. Last meaningful expansion: 2026-04-07.

Testosterone physiology

Testosterone is the primary male androgen. It is produced mostly in the Leydig cells of the testes (around 95 percent) under signaling from the pituitary gland via luteinizing hormone (LH). A small amount is produced in the adrenal glands.

Production is regulated by the hypothalamic-pituitary-gonadal (HPG) axis: the hypothalamus releases gonadotropin-releasing hormone (GnRH), the pituitary responds by releasing LH and FSH, the testes respond to LH by producing testosterone. Testosterone in the bloodstream provides negative feedback to the hypothalamus and pituitary, modulating the loop.

This is the closed-loop system that exogenous testosterone disrupts. When you administer testosterone from outside, the pituitary sees plenty in the bloodstream and stops sending the LH signal. The testes stop producing their own. This is why TRT is, for most men, a long-term commitment once started.

What testosterone does in the male body

Testosterone has direct and indirect effects across multiple systems:

• Muscle: anabolic signaling, protein synthesis, satellite cell activation
• Bone: density maintenance via direct receptor activity and via aromatization to estradiol
• Libido and sexual function: central and peripheral effects on desire, arousal, erectile function
• Mood and cognition: dopamine modulation, executive function, motivation
• Cardiovascular: complex effects on lipids, vascular function, red blood cell production
• Body composition: fat distribution, lean mass, insulin sensitivity
• Sleep: deep sleep relationship is bidirectional

It is downstream of, and interacts with, almost everything else in the male endocrine system. Reading testosterone in isolation from sleep, stress, nutrition, and metabolic health misses most of the picture.

Reference range vs. optimal range

The adult male testosterone reference range on most US lab reports spans roughly 264 to 916 ng/dL. This is a statistical artifact of the sampled population, not a clinical target.

The level at which most men report feeling their best is roughly 600 to 900 ng/dL total T, with corresponding free T in the upper third of its range. This is not a guarantee for any individual man. It is a pattern that emerges from large datasets and clinical experience.

The Bhasin et al. analysis of the Framingham Heart Study established tighter reference ranges for healthy non-obese non-smoking young men, and that subgroup sits meaningfully higher than the full reference population. Those are the men most TRT decisions should be benchmarked against, not the broader population that includes everyone.

Causes of low testosterone

Low testosterone is a symptom, not a diagnosis. The useful question is always: low testosterone because of what?

Primary hypogonadism (testicular failure):

• Genetic conditions (Klinefelter syndrome)
• Testicular damage (mumps, trauma, torsion)
• Chemotherapy or radiation
• Autoimmune destruction
• Aging (modest, gradual)

Secondary hypogonadism (pituitary or hypothalamic):

• Pituitary tumors
• Head trauma
• Sleep apnea
• Obesity (a major and reversible cause)
• Chronic opioid use
• Anabolic steroid history
• Chronic stress and elevated cortisol
• Severe nutritional deficiencies
• Hyperprolactinemia

Mixed or unclear:

• Aging (some men have features of both)
• Metabolic syndrome
• Chronic illness

The treatment decision depends on the cause. A man with secondary hypogonadism from obesity may not need TRT at all if the underlying obesity is addressed. A man with primary hypogonadism almost certainly will. Skipping the diagnostic step and jumping straight to TRT is a common shortcut that leads to suboptimal long-term outcomes.

Delivery methods

Injection

Most common: testosterone cypionate or enanthate, dissolved in oil, administered intramuscularly or subcutaneously. The two esters (cypionate and enanthate) are functionally equivalent for most purposes.

Frequency: weekly is standard. Twice weekly produces more stable blood levels. Daily subcutaneous injection produces the most stable levels of all and is preferred by some men with sensitive estradiol responses.

Typical dose: 100 to 200 mg per week total, split or single dose, dialed by panel and symptoms.

Pros: cheapest, most adjustable, most predictable blood levels. Cons: requires self-injection (not a real con once you get over the first one).

Subcutaneous vs. intramuscular: SubQ is gentler, easier to self-administer, and produces equivalent blood levels in most men. IM is the traditional route. Either works.

Cream and gel

Compounded testosterone cream (typically applied to the scrotum or inner thigh) and brand-name gel (AndroGel, Testim) are the topical options. Cream is generally higher absorption than gel. Both are daily.

Pros: no needles, smoother delivery curve. Cons: transfer risk to family members, more variable absorption, often requires higher daily dose to achieve the same blood levels as injection.

Pellets

Pellets are small implants placed under the skin every 3 to 6 months. Convenient for set-and-forget. Hard to adjust if the dose is wrong (you wait it out).

Pros: no daily routine, no needles for months. Cons: expensive, not adjustable, occasional extrusion or infection at the implant site.

Oral

Newer oral formulations (Jatenzo, Tlando, Kyzatrex) avoid the liver toxicity of older oral testosterone (methyltestosterone) by being absorbed through the lymphatic system. They are convenient and FDA-approved.

Pros: no needles, no transfer risk, convenient. Cons: expensive, requires twice-daily dosing with food, blood pressure effects in some men.

Nasal

Natesto is an intranasal testosterone gel administered three times daily. Approved but uncommon.

What TRT will not fix

This is the section every TRT clinic should put on its landing page and almost none do.

• Bad sleep. Sleep apnea, insomnia, chronic short sleep. Most testosterone production happens during deep sleep. Fix the sleep first.
• Overtraining. Cortisol up, testosterone down, the answer is on the cortisol side.
• Chronic stress. Same mechanism.
• Obesity. Body fat aromatizes testosterone to estrogen. Lose the fat, the numbers move on their own.
• Bad relationships and meaning crises. Not testosterone problems.
• Poor nutrition. Severe calorie restriction or extreme dieting suppresses testosterone.

The men who get the best results from TRT are the ones who fixed all of this first and then realized they still felt off. Those men start from a high base, dial in fast, and feel the difference clearly. The men who use TRT as a shortcut tend to feel disappointed.

Common protocol structures

There is no single right protocol. The structure depends on your SHBG, your sensitivity to estradiol, your delivery preference, and whether fertility matters to you.

The most common starting protocol for an adult man with no fertility concerns:

• Testosterone cypionate 100-160 mg/week, split into twice-weekly subcutaneous injections
• No aromatase inhibitor at start (only added if E2 is symptomatically high after 6-8 weeks)
• No HCG (added only if testicular atrophy or fertility is a concern)
• Lab follow-up at 6 weeks, dose adjustment based on results, then quarterly

Variants:

• Daily SubQ for men who run high E2 or have variable response to twice-weekly
• Weekly IM for men who prefer fewer injections and tolerate the variability
• TRT + HCG for men who want testicular function preserved
• TRT + enclomiphene for men in transitional periods

Monitoring on TRT

Standard monitoring includes the full hormone panel (see bloodwork wiki), CBC for hematocrit, PSA annually, and a lipid + metabolic panel annually. Add DHT, prolactin, or thyroid markers if symptoms indicate.

Cadence: 6 weeks after any change, quarterly when stable, annually for the broader workup.

Risks and trade-offs of TRT

Honest version. TRT has real risks that should be weighed.

• Erythrocytosis (high hematocrit). The most common adverse effect. Manageable with monitoring and donation.
• Fertility suppression. Almost universal. Reversible in some men, partially or not at all in others.
• Testicular atrophy. Cosmetic concern for some men, otherwise harmless. HCG can prevent it.
• Acne and oily skin. Sometimes. Often manageable.
• Sleep apnea worsening. Rare but possible.
• Cardiovascular risk. The TRAVERSE trial (2023) substantially reset the cardiovascular concerns that had driven the FDA boxed warning. The current evidence does not support a meaningful cardiovascular risk increase for men with diagnosed hypogonadism on appropriate therapy.
• Prostate considerations. TRT does not appear to cause prostate cancer but can accelerate growth of an existing tumor. Hence the annual PSA monitoring.

The risk-benefit calculation is favorable for most men with documented low testosterone and symptoms, monitored properly. It is unfavorable for men using TRT recreationally without medical oversight.

Sources and further reading

• Bhasin S, et al. “Testosterone Therapy in Men with Hypogonadism: An Endocrine Society Clinical Practice Guideline.” J Clin Endocrinol Metab. 2018.
• Lincoff AM, et al. “Cardiovascular Safety of Testosterone-Replacement Therapy.” (TRAVERSE trial) NEJM. 2023.
• Mulhall JP, et al. “Evaluation and Management of Testosterone Deficiency: AUA Guideline.” J Urol. 2018.