Testosterone replacement therapy: Formulations, dosing, and what to expect

Testosterone replacement therapy works by raising serum testosterone into a therapeutic range, and in the Testosterone Trials gel treatment brought levels into the middle of the normal range for men 19 to 40 years old. The right TRT formulation depends on diagnosis, fertility goals, reversibility, and adverse effect risk. A low number alone is not enough to start treatment, and neither are symptoms without biochemical confirmation.

Key takeaways

• TRT should only be used in men with persistent symptoms plus consistently low testosterone, confirmed by repeat morning fasting tests and followed by an evaluation of the cause.^[1] That evaluation includes LH and FSH, and hematocrit and prostate cancer risk are checked before treatment starts.
• LH and FSH change treatment selection. High LH plus low testosterone points to primary hypogonadism, where TRT is usually required. Low or normal LH plus low testosterone points to secondary hypogonadism, where a treatment that stimulates the body’s own production, such as Enclomiphene, may be considered before TRT.
• Short acting testosterone enanthate or cypionate injections, given every few weeks, produce wider peaks and troughs than daily transdermal gel or long acting testosterone undecanoate injections given about every 3 months.^{[2] [3]}
• The Endocrine Society suggests aiming for testosterone in the middle of the normal range during treatment, and in the Testosterone Trials, dose adjusted gel raised levels to the mid normal range for men 19 to 40 years old.^{[1] [4]}
• The Endocrine Society recommends against starting TRT in men planning fertility in the near term and in men with breast or prostate cancer, elevated hematocrit, untreated severe obstructive sleep apnea, severe lower urinary tract symptoms, uncontrolled heart failure, or a heart attack or stroke within the last 6 months.^[1]
• Transdermal gels give steadier exposure but can transfer to partners or children through skin contact. Injectable testosterone is more often associated with erythrocytosis than gel.^[5]

Who TRT is actually for

TRT is indicated for men with clinical hypogonadism, which means persistent symptoms plus biochemical evidence of testosterone deficiency, not for “optimization” in men with normal testosterone.^[1]

Hypogonadism is a clinical syndrome caused by inadequate testosterone action. A single low result does not establish the diagnosis, and neither do symptoms alone. According to the Endocrine Society guideline, the diagnosis should be made only in men with consistent symptoms and unequivocally and consistently low testosterone, measured in the morning while fasting with an accurate assay and confirmed by a repeat test.^[1]

For treatment selection, the critical next step is classification. LH and FSH are gonadotropins, which are pituitary hormones that tell the testes to produce testosterone and support sperm production. High LH with low testosterone suggests primary hypogonadism, meaning the testes are failing to respond. Low or normal LH with low testosterone suggests secondary hypogonadism, meaning brain signaling is insufficient. That distinction determines whether TRT is appropriate or whether a fertility preserving option such as Enclomiphene may be considered first. For a fuller explanation, see Primary vs secondary hypogonadism and Alternatives to TRT.

Total testosterone can be misleading when sex hormone binding globulin (SHBG) is high or low. In men whose total testosterone is near the lower limit of normal, or who have a condition that alters SHBG, the Endocrine Society recommends obtaining free testosterone by equilibrium dialysis or an accurate formula.^[1] LH and FSH should be measured alongside testosterone before any treatment path is chosen, and depending on the pattern, further tests such as prolactin may follow.

How TRT works and what treatment targets look like

TRT works by supplying exogenous testosterone, which raises circulating testosterone levels but also suppresses LH and FSH through negative feedback.

Exogenous means the hormone comes from outside the body. Once serum testosterone rises, the brain reduces pituitary signaling, so endogenous production falls. That is why TRT can improve symptoms in properly selected men while also suppressing spermatogenesis and reducing testicular volume. The Endocrine Society recommends against starting TRT in men who are planning fertility in the near term.^[1]

In the Testosterone Trials, published in the New England Journal of Medicine in 2016, 790 men aged 65 or older with total testosterone below 275 ng/dL and symptoms used testosterone gel or placebo for 1 year. Treatment raised testosterone to the mid normal range for men 19 to 40 years old, moderately improved sexual function, and slightly improved mood and depressive symptoms, but did not improve vitality or walking distance.^[4] A 2016 analysis of the Sexual Function Trial in the Journal of Clinical Endocrinology and Metabolism, in 470 of these men with low libido, found that testosterone improved 10 of 12 measures of sexual activity, and that gains in desire and activity tracked the size of the rise in testosterone and estradiol, with no clear threshold level.^[6] Both enrolled only men with low testosterone at baseline.

TRT does not repair the cause of hypogonadism. It replaces the missing hormone. That is appropriate in primary hypogonadism and in men with secondary hypogonadism who are not candidates for, or do not respond to, stimulation therapy. The Endocrine Society recommends testosterone therapy for men with symptomatic testosterone deficiency, which does not include men with normal testosterone seeking body recomposition or anti aging benefits.^[1]

TRT formulations and dosing

TRT formulations include intramuscular injections, transdermal gels and patches, and oral testosterone undecanoate.^[2] Buccal, nasal, and pellet based systems are less commonly used.

Injectable formulations

Injectable TRT includes testosterone enanthate or cypionate and long acting testosterone undecanoate. Short acting testosterone enanthate or cypionate is commonly dosed at 250 mg every 2 to 3 weeks. According to a 2004 review in The Aging Male, the large swings in serum testosterone after conventional intramuscular injections cause unsatisfactory shifts in mood and sexual function in some men.^[2] Long acting testosterone undecanoate in castor oil is typically dosed at 1,000 mg every 10 to 14 weeks. In phase III studies summarized in the same review, it was as effective as testosterone enanthate with one quarter as many injections and more stable serum testosterone levels.^[2]

Transdermal gels

Transdermal testosterone gels come in 1% to 2% strengths and are applied once daily. The 2004 review reported that 1% gel at 50 to 100 mg per day restored normal testosterone levels and was as effective as a testosterone patch, with fewer side effects and higher patient satisfaction.^[2] Gels are also easy to stop, which matters when reversibility is a priority. Their major drawback is secondary transference through skin contact, which means the drug can be unintentionally transferred to a partner or child unless application and drying precautions are followed.

Oral and other options

Oral testosterone undecanoate capsules are taken twice daily with food, at doses that differ by product. Absorption depends heavily on dietary fat, and the 2004 review noted that serum levels on oral testosterone undecanoate generally fluctuate widely.^[2] U.S. labeling for oral testosterone undecanoate products carries a boxed warning for blood pressure increases, which makes careful patient selection important. Other testosterone therapy types include buccal systems, intranasal gels, and subdermal pellets, which may fit specific preferences or adherence patterns. Evidence for intranasal testosterone is more limited than for injections and gels, and long term comparative outcome data are lacking.

Testosterone injections vs gel

Testosterone injections and gel can both correct low testosterone, but short acting injections produce larger swings in levels while gels deliver steadier day to day exposure.^{[2] [3]}

The choice between injections and gel is often framed as convenience versus stability. A 2005 review in Expert Opinion on Pharmacotherapy noted that testosterone esters need to be injected every 2 to 4 weeks and that their pharmacokinetics cause fluctuations in mood, energy, and sexual function.^[3] Gels demand daily adherence, but they more closely mimic continuous replacement. A 2015 retrospective study in Sexual Medicine comparing men treated with gels, injections, and pellets found erythrocytosis more often with injections.^[5]

Erythrocytosis means an excessive rise in red blood cell mass. Hematocrit is the percentage of blood volume occupied by red blood cells. A 2010 meta-analysis of 51 studies in the Journal of Clinical Endocrinology and Metabolism found that testosterone therapy raised hematocrit by an average of 3.18 percentage points and hemoglobin by 0.80 g/dL compared with control.^[7]

Long acting testosterone undecanoate sits between these two practical experiences. It avoids the pronounced peak and trough pattern of shorter injections, but once administered it cannot be withdrawn quickly. That makes it less attractive as a starting formulation in men with higher baseline risk. Gels, by contrast, can be stopped immediately if hematocrit rises, edema develops, or another adverse effect appears.

How clinicians choose among TRT options

According to the Endocrine Society, the choice among approved formulations should weigh patient preference, pharmacokinetics, formulation specific adverse effects, treatment burden, and cost, with the aim of keeping testosterone in the middle of the normal range during treatment.^[1]

Head to head trials between testosterone therapy types are limited, so real world selection is pragmatic. In higher risk men, it often makes sense to start with short term formulations such as gels or oral agents rather than long acting depot testosterone undecanoate, because short term products can be stopped quickly if adverse effects appear. Long acting injectable testosterone undecanoate may take weeks to clear once given.

Monitoring also differs by product. With gels, the timing of the blood draw relative to application affects the result, and with injections, the point in the dosing interval matters, so underdosing and overdosing are common when blood timing is ignored. The Endocrine Society recommends a standardized monitoring plan that covers symptoms, adverse effects, and adherence, along with serum testosterone and hematocrit measurements.^[1]

The right starting point also depends on why the man is hypogonadal. If LH is low or normal, the testes may still be capable of producing testosterone, and a treatment that stimulates the body’s own production, such as Enclomiphene, may be considered instead of TRT, particularly when fertility matters. If LH is high, TRT is often the correct replacement strategy. For the complete lab sequence, see The complete low testosterone testing guide.

Contraindications and safety screening

TRT should not be started until fertility goals, hematocrit, prostate risk, and cardiovascular status have been screened.^[1]

The Endocrine Society recommends against starting TRT in men planning fertility in the near term and in men with breast or prostate cancer, a palpable prostate nodule or induration, PSA above 4 ng/mL (or above 3 ng/mL in men at increased risk of prostate cancer) without further urologic evaluation, elevated hematocrit, untreated severe obstructive sleep apnea, severe lower urinary tract symptoms, uncontrolled heart failure, a heart attack or stroke within the last 6 months, or thrombophilia.^[1] In common practice, a hematocrit of 54% or higher rules out starting treatment, while a baseline hematocrit of 48% to 50%, lower urinary tract symptoms with an IPSS above 19, and a family history of venous thromboembolism call for caution.

According to the Endocrine Society guideline, hematocrit is measured as part of standard monitoring, along with serum testosterone and prostate cancer risk evaluation, during the first year of treatment.^[1] Follow-up labs are repeated within the first months of treatment and then at regular intervals. The 2010 meta-analysis found no significant effect of testosterone on mortality, prostate, or cardiovascular outcomes, but its authors rated the evidence as low quality and limited by short follow-up.^[7]

The best cardiovascular safety data now come from TRAVERSE, published in the New England Journal of Medicine in 2023. In that randomized trial of 5,246 men aged 45 to 80 with preexisting or high risk of cardiovascular disease, followed for a mean of 33 months, testosterone gel was noninferior to placebo for major adverse cardiovascular events, although atrial fibrillation, acute kidney injury, and pulmonary embolism were more frequent in the testosterone group.^[8] A separate analysis of prostate safety in TRAVERSE found that the incidence of high grade prostate cancer was low and did not differ significantly between testosterone and placebo.^[9] These findings are reassuring, but they do not remove the need for formulation specific risk assessment, especially in men prone to high hematocrit, edema, or blood pressure elevation.

TRT should also not be presented as a treatment for diabetes, bodybuilding, or general anti aging. In a 2001 randomized trial of 61 healthy young men whose own testosterone was suppressed, higher testosterone doses increased muscle mass and strength but also raised hemoglobin and lowered HDL cholesterol, and sexual function and mood did not change at any dose.^[10] The benefits that justify treatment have been shown in symptomatic men with verified biochemical deficiency.^{[1] [4]}

Myth vs fact

Myth: A single low testosterone result means TRT is the next step.

Fact: Male hypogonadism requires persistent symptoms plus biochemical deficiency confirmed on repeat reliable testing.^[1] LH and FSH are needed to determine whether the man has primary hypogonadism, where TRT is often appropriate, or secondary hypogonadism, where a treatment that preserves the body’s own production, such as Enclomiphene, may be considered first.

Myth: Testosterone injections are always better than gel.

Fact: Injections and gel are both legitimate TRT options, but short acting injections cause wider fluctuations^[3] and are more often linked to erythrocytosis,^[5] while gels give steadier daily exposure but carry transference risk.

Myth: Long acting shots are the best starting point for everyone.

Fact: In higher risk men, short term formulations such as gels or oral agents are easier to stop quickly if adverse effects appear. Long acting testosterone undecanoate can keep levels stable with one injection about every 3 months,^[2] but it also persists for weeks after administration.

Myth: TRT is fertility neutral.

Fact: TRT suppresses LH and FSH, which can suppress spermatogenesis. The Endocrine Society recommends against starting TRT in men planning fertility in the near term.^[1] Men with low or normal LH may be evaluated for a fertility preserving option such as Enclomiphene rather than immediate replacement.

Myth: TRT is appropriate for optimization, anti aging, or muscle gain when testosterone is normal.

Fact: The trials that showed benefit, such as the Testosterone Trials, enrolled men with low testosterone and symptoms.^{[4] [6]} In healthy young men, raising testosterone increased muscle mass but also raised hemoglobin and lowered HDL cholesterol, without changing sexual function or mood.^[10]

Bottom line

Testosterone replacement therapy comes in several formulations, and the main differences are dosing schedule, level stability, reversibility, and adverse effect profile. Short acting injections can fluctuate, long acting testosterone undecanoate is steadier but slow to withdraw, gels provide stable daily exposure with transference risk, and oral testosterone undecanoate avoids injections but absorption is fat dependent and blood pressure monitoring matters. For the full diagnostic and treatment roadmap, see the Low Testosterone hub.

Veedma offers testing that includes total and free testosterone measured by LC-MS/MS with LH and FSH, or a review of lab results a man already has, with care from licensed providers. When appropriate, treatment is Enclomiphene or the Enclomiphene plus tadalafil tablet. Enclomiphene is not an FDA-approved drug; it is prescribed after a provider confirms the diagnosis and is compounded by a licensed U.S. pharmacy.

References

1. Bhasin S, Brito JP, Cunningham GR, et al. Testosterone Therapy in Men With Hypogonadism: An Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. 2018;103:1715-1744. PMID: 29562364
2. Jockenhövel F. Testosterone therapy–what, when and to whom?. Aging Male. 2004;7:319-24. PMID: 15799128
3. Harle L, Basaria S, Dobs AS. Nebido: a long-acting injectable testosterone for the treatment of male hypogonadism. Expert Opin Pharmacother. 2005;6:1751-9. PMID: 16086661
4. Snyder PJ, Bhasin S, Cunningham GR, et al. Effects of Testosterone Treatment in Older Men. N Engl J Med. 2016;374:611-24. PMID: 26886521
5. Pastuszak AW, Gomez LP, Scovell JM, et al. Comparison of the Effects of Testosterone Gels, Injections, and Pellets on Serum Hormones, Erythrocytosis, Lipids, and Prostate-Specific Antigen. Sex Med. 2015;3:165-73. PMID: 26468380
6. Cunningham GR, Stephens-Shields AJ, Rosen RC, et al. Testosterone Treatment and Sexual Function in Older Men With Low Testosterone Levels. J Clin Endocrinol Metab. 2016;101:3096-104. PMID: 27355400
7. Fernández-Balsells MM, Murad MH, Lane M, et al. Clinical review 1: Adverse effects of testosterone therapy in adult men: a systematic review and meta-analysis. J Clin Endocrinol Metab. 2010;95:2560-75. PMID: 20525906
8. Lincoff AM, Bhasin S, Flevaris P, et al. Cardiovascular Safety of Testosterone-Replacement Therapy. N Engl J Med. 2023;389:107-117. PMID: 37326322
9. Bhasin S, Travison TG, Pencina KM, et al. Prostate Safety Events During Testosterone Replacement Therapy in Men With Hypogonadism: A Randomized Clinical Trial. JAMA Netw Open. 2023;6:e2348692. PMID: 38150256
10. Bhasin S, Woodhouse L, Casaburi R, et al. Testosterone dose-response relationships in healthy young men. Am J Physiol Endocrinol Metab. 2001;281:E1172-81. PMID: 11701431