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Testosterone Therapy: What the Guidelines and TRAVERSE Report

Por Benn Bluestein-Veyra, M.Sc. en Química Orgánica · Actualizado el 8 de noviembre de 2026

Testosterone therapy guidelines in the United States rest on two documents from 2018 and one trial from 2023. The Endocrine Society guideline recommends diagnosing hypogonadism only in men with symptoms and signs of testosterone deficiency and "unequivocally and consistently low serum T concentrations", confirmed by repeated fasting morning measurements, and sets a standardized monitoring plan built on serum testosterone, hematocrit and prostate assessment.^[1] The American Urological Association guideline of the same year centers the diagnosis on total testosterone, symptoms and signs, with on-treatment monitoring.^[2] TRAVERSE, the FDA-required cardiovascular safety trial, randomized 5,246 men and reported that testosterone was noninferior to placebo for major adverse cardiac events, with higher incidences of atrial fibrillation, acute kidney injury and pulmonary embolism in the testosterone group.^[3] FDA reviewed the trial and, on 28 February 2025, directed class-wide labeling changes; on its Testosterone Information page, current as of 23 June 2026, the agency states that it requested further updates in June 2026.^[4][5]

This page reports what each document states, attributed to its source, for licensed practitioners who document hormone prescriptions. Testosterone is a Schedule III controlled substance under 21 CFR 1308.13(f), so every statement here about dispensing sits inside the Controlled Substances Act.^[6] The diagnosis, the product and the monitoring plan remain the prescribing practitioner's decisions.

The Endocrine Society guideline ties diagnosis to symptoms plus repeated morning measurements

The 2018 guideline, written by a ten-member task force using the GRADE approach, recommends "making a diagnosis of hypogonadism only in men with symptoms and signs consistent with testosterone (T) deficiency and unequivocally and consistently low serum T concentrations."^[1] It recommends "measuring fasting morning total T concentrations using an accurate and reliable assay as the initial diagnostic test" and "confirming the diagnosis by repeating the measurement of morning fasting total T concentrations."^[1] In men whose total testosterone is near the lower limit of normal, or who have a condition that alters sex hormone-binding globulin, it recommends a free testosterone measurement by equilibrium dialysis or an accurate formula.^[1]

The guideline recommends against routine screening of the general male population (Recommendation 1.2), recommends distinguishing primary from secondary hypogonadism by measuring luteinizing hormone and follicle-stimulating hormone (1.3), and recommends further evaluation to identify the cause of androgen deficiency (1.4).^[1] It suggests against routinely prescribing testosterone to all men 65 years or older with low testosterone concentrations (2.4), and in men with type 2 diabetes who have low testosterone it recommends against testosterone therapy "as a means of improving glycemic control" (2.6).^[1]

The guideline lists the conditions in which it recommends against starting therapy

Recommendation 2.2 recommends against testosterone therapy in men planning fertility in the near term or with any of the following: "breast or prostate cancer, a palpable prostate nodule or induration, prostate-specific antigen level > 4 ng/mL, prostate-specific antigen > 3 ng/mL in men at increased risk of prostate cancer (e.g., African Americans and men with a first-degree relative with diagnosed prostate cancer) without further urological evaluation, elevated hematocrit, untreated severe obstructive sleep apnea, severe lower urinary tract symptoms, uncontrolled heart failure, myocardial infarction or stroke within the last 6 months, or thrombophilia."^[1] Its Table 7 gives the hematocrit figure behind "elevated hematocrit" as "Hematocrit > 48% (>50% for men living at high altitude)".^[1]

For treatment itself, the guideline suggests that clinicians "aim at achieving T concentrations in the mid-normal range during treatment with any of the approved formulations, taking into consideration patient preference, pharmacokinetics, formulation-specific adverse effects, treatment burden, and cost."^[1] The guideline's text that we could read contains no statement on compounded testosterone; its Table 6 lists testosterone formulations available outside the United States but not approved by FDA, and Table 8 marks oral methyltestosterone tablets as not recommended.^[1]

The monitoring plan the guideline sets is specific on timing and thresholds

Recommendation 3.1, an ungraded good practice statement, recommends evaluating the patient after treatment initiation "to assess whether the patient has responded to treatment, is suffering any adverse effects, and is complying with the treatment regimen."^[1] Recommendation 3.2 recommends a urological consultation "if during the first 12 months of testosterone treatment there is a confirmed increase in prostate specific antigen concentration >1.4 ng/mL above baseline, a confirmed prostate-specific antigen >4.0 ng/mL, or a prostatic abnormality detected on digital rectal examination", after which prostate monitoring "should conform to standard guidelines for prostate cancer screening based on the race and age of the patient."^[1]

Table 9 of the guideline, "Monitoring Men Receiving T Therapy", sets the intervals. Evaluate the patient at 3 to 12 months "after treatment initiation and then annually"; check hematocrit at baseline, 3 to 6 months "after starting treatment, and then annually"; and "If hematocrit is >54%, stop therapy until hematocrit decreases to a safe level", evaluating the patient for hypoxia and sleep apnea.^[1] PSA and digital rectal examination are checked at baseline and 3 to 12 months after starting treatment, and bone mineral density of the lumbar spine or femoral neck is measured after 1 to 2 years of therapy in hypogonadal men with osteoporosis.^[1]

The AUA guideline frames the same decision through total testosterone and on-treatment monitoring

The AUA guideline, published in the Journal of Urology in 2018, was developed by a multidisciplinary panel from a systematic review by the Mayo Clinic Evidence Based Practice Center, with statements graded Strong, Moderate or Conditional and supplemented by Clinical Principles and Expert Opinions.^[2] Its abstract states that "The care of testosterone deficient patients should focus on accurate assessment of total testosterone levels, symptoms, and signs as well as proper on-treatment monitoring to ensure therapeutic testosterone levels are reached and symptoms are ameliorated."^[2] It adds statements for patients "who are at risk for or have cardiovascular disease or prostate cancer as well as patients who are interested in preserving fertility", and it calls for longitudinal studies and trials of significant duration to provide more data on adverse events.^[2]

TRAVERSE reported noninferiority for major adverse cardiac events in 5,246 men

TRAVERSE (Testosterone Replacement therapy for Assessment of long-term Vascular Events and efficacy ResponSE in hypogonadal men) was designed as a randomized, double-blind, placebo-controlled, parallel-group, noninferiority, multicenter study in men 45 to 80 years of age with a serum testosterone concentration below 300 ng/dL, hypogonadal symptoms, and pre-existing cardiovascular disease or increased risk of it.^[7] The trial was to continue until at least 256 adjudicated major adverse cardiovascular events had occurred, to test whether an upper 95 percent confidence limit of 1.5 for the hazard ratio could be ruled out.^[7] The registry lists it as a Phase 4 interventional study sponsored by AbbVie with Endo, Acerus, Allergan and Upsher-Smith as collaborators, started 3 May 2018, completed 19 January 2023, with results first posted 13 March 2024 and an actual enrollment of 5,246.^[8]

The primary report, published in the New England Journal of Medicine in July 2023, enrolled 5,246 men who had two fasting testosterone levels below 300 ng per deciliter and compared a transdermal testosterone gel with a placebo gel.^[3] The primary cardiovascular safety end point was the first occurrence of death from cardiovascular causes, nonfatal myocardial infarction or nonfatal stroke. Mean treatment duration was 21.7 months and mean follow-up 33.0 months.^[3] A primary end-point event occurred in 182 patients (7.0 percent) in the testosterone group and 190 (7.3 percent) in the placebo group, hazard ratio 0.96, 95 percent confidence interval 0.78 to 1.17, P less than 0.001 for noninferiority.^[3]

The same report states that "A higher incidence of atrial fibrillation, of acute kidney injury, and of pulmonary embolism was observed in the testosterone group."^[3] The current AndroGel 1.62% label carries the venous thromboembolism figures from the trial: a numerically higher incidence of VTE (1.7 percent versus 1.2 percent), including pulmonary embolism events (0.9 percent versus 0.5 percent), and a mean between-group systolic blood pressure difference of 1.5 mm Hg at 36 months.^[9] FDA's Testosterone Information page states that after reviewing the results the agency "determined that the results of TRAVERSE did not demonstrate a new safety signal or trend in adverse cardiovascular outcomes with testosterone use."^[4]

The TRAVERSE sub-studies reported fractures, prostate events, glycemia, anemia, sexual function and mood

Fractures. In the full-analysis population of 5,204 men, after a median follow-up of 3.19 years, a clinical fracture occurred in 91 participants (3.50 percent) in the testosterone group and 64 (2.46 percent) in the placebo group, hazard ratio 1.43, 95 percent confidence interval 1.04 to 1.97; the authors reported that testosterone "did not result in a lower incidence of clinical fracture than placebo" and that fracture incidence "was numerically higher" with testosterone.^[10]

Prostate. Men with a PSA above 3.0 ng/mL or an International Prostate Symptom Score above 19 were excluded at entry. Over 14,304 person-years, high-grade prostate cancer occurred in 5 of 2,596 men on testosterone (0.19 percent) and 3 of 2,602 on placebo (0.12 percent), hazard ratio 1.62, 95 percent confidence interval 0.39 to 6.77; any prostate cancer, acute urinary retention, invasive procedures, biopsy and new pharmacologic treatment did not differ significantly, and "The PSA concentrations increased more in testosterone-treated than placebo-treated men."^[11] The authors framed the result as applying to a population "carefully evaluated to exclude those at high risk of prostate cancer".^[11]

Glycemia. Among 1,175 men with prediabetes and 3,880 with diabetes, progression from prediabetes to diabetes did not differ significantly between groups (omnibus P = 0.49), and glycemic remission and changes in glucose and hemoglobin A1c were similar; the authors concluded that testosterone "did not improve glycemic control" in this population.^[12] Anemia. Among 815 men with anemia at baseline, anemia corrected in a greater proportion of testosterone-treated than placebo-treated men at every time point assessed, 41.0 percent versus 27.5 percent at 6 months and 44.6 percent versus 39.2 percent at 48 months (P = 0.002), and fewer non-anemic men on testosterone developed anemia.^[13]

Sexual function. In the 1,161 men with low libido enrolled in the nested Sexual Function Study, testosterone was associated with a greater improvement in sexual activity than placebo at 6 and 12 months, maintained at 24 months, with improvement in hypogonadal symptoms and sexual desire "but not erectile function".^[14] Mood. Of 5,204 randomized men, 2,643 had significant depressive symptoms and 49 met criteria for late-life-onset low-grade persistent depressive disorder; testosterone was associated with "modest but significantly greater improvements in mood and energy but not cognition or sleep quality", with no significant difference in the small persistent-depressive-disorder subgroup.^[15]

FDA limited the approved indication in 2015, revised the class labeling in 2025 and requested further updates in June 2026

FDA states that testosterone products "are FDA-approved only for use in men who lack or have low testosterone levels in conjunction with an associated medical condition", giving as examples testicular failure from genetic problems or chemotherapy and hypothalamic or pituitary disorders, and that "None of the FDA-approved testosterone products are approved for use in men with low testosterone levels who lack an associated medical condition."^[4] The agency's 2025 page recounts the sequence: a January 2014 Drug Safety Communication warning of reported risks of stroke, heart attack and death; a September 2014 joint advisory committee meeting that led FDA to recommend an industry-wide trial in men with age-related hypogonadism; and "a March 2015 DSC informing of required labeling changes and urging caution when using testosterone products for low testosterone due to aging."^[5]

On 28 February 2025, after reviewing TRAVERSE and the required postmarket ambulatory blood pressure studies, FDA informed sponsors of class-wide changes: "adding the results of the TRAVERSE trial to all testosterone products; retaining “Limitation of Use” language for age-related hypogonadism; and removing language from the Boxed Warning related to an increased risk of adverse cardiovascular outcomes for all testosterone products."^[5] From the blood pressure studies, FDA required product-specific blood pressure information where studies were complete and "a new warning about increased blood pressure for testosterone products which currently do not have such a warning in their labeling."^[5] The AndroGel 1.62% label on DailyMed, revised 07/2025, reflects this: its boxed warning concerns secondary exposure of children, its Limitations of Use state that "Safety and efficacy of AndroGel 1.62% in men with “age-related hypogonadism” (also referred to as “late-onset hypogonadism”) have not been established", and section 5.5 warns that the product "can increase blood pressure, which can increase cardiovascular risk over time."^[9]

FDA then convened an Expert Panel on Testosterone Replacement Therapy for Men on 10 December 2025 and opened docket FDA-2025-N-6743 for public comment through 9 February 2026, noting that "any potential new indications will be based on rigorous scientific evidence and comprehensive risk-benefit analysis."^[16] On 20 April 2026 the agency published a notice stating that its preliminary literature review "suggests that TRT may be safe and effective in treating low libido in men with decreased libido associated with idiopathic hypogonadism" and inviting holders of approved testosterone NDAs to contact FDA about a supplemental application; the same notice restates that approved products are indicated for primary and hypogonadotropic hypogonadism and "bear a limitation of use in the labeling to note that safety and efficacy of TRT in men with “age-related hypogonadism” have not been established."^[17]

As of 8 November 2026, that page is FDA's most recent statement on the class labeling, and it describes a request to sponsors rather than an approved label.^[4] The AndroGel 1.62% prescribing information published on DailyMed is dated 07/2025 and still carries the age-related hypogonadism limitation of use.^[9] A practice reading a testosterone label should therefore expect the limitation of use to remain in the published label of any given product until that product's sponsor submits and FDA approves the revised labeling.^[4][9]

Schedule III status governs every prescription and dispensing record

Testosterone is listed at 21 CFR 1308.13(f), the Schedule III anabolic steroid paragraph, which covers "any substance meeting the definition of anabolic steroid as set forth in § 1300.01 of this chapter, including any material, compound, mixture or preparation containing any quantity of the following substances, including its salts, esters and ethers", with "(84) testosterone (17β-hydroxyandrost-4-en-3-one)" among the 86 named substances under DEA code 4000.^[6] The statutory definition at 21 U.S.C. 802(41)(A) reaches "any drug or hormonal substance, chemically and pharmacologically related to testosterone (other than estrogens, progestins, corticosteroids, and dehydroepiandrosterone)".^[18] Every testosterone ester a compounding pharmacy might use, and every compounded preparation containing one, is inside the schedule.^[6]

For dispensing, 21 U.S.C. 829(b) provides that a Schedule III prescription drug may not be dispensed "without a written or oral prescription in conformity with section 503(b)" of the Food, Drug, and Cosmetic Act, and that "Such prescriptions may not be filled or refilled more than six months after the date thereof or be refilled more than five times after the date of the prescription unless renewed by the practitioner."^[19] Under 21 CFR 1306.04(a), a controlled substance prescription "must be issued for a legitimate medical purpose by an individual practitioner acting in the usual course of his professional practice", and "a corresponding responsibility rests with the pharmacist who fills the prescription."^[20] The AndroGel label itself records the status in section 9.1: the product "contains testosterone, a Schedule III controlled substance in the Controlled Substances Act."^[9]

What a practice would document, as the guideline describes it

Read together, the Endocrine Society recommendations and Table 9 describe a chart that contains the following items, each of which maps to a guideline statement rather than to a product.^[1]

• Symptoms and signs consistent with testosterone deficiency, recorded before any laboratory order (Recommendation 1.1).
• Two fasting morning total testosterone measurements on an accurate assay, with a free testosterone value where total testosterone is borderline or SHBG is altered (Recommendations 1.1 and text).
• Luteinizing hormone and follicle-stimulating hormone to distinguish primary from secondary hypogonadism, and the evaluation of cause (Recommendations 1.3 and 1.4).
• The Recommendation 2.2 checklist: PSA, hematocrit, prostate examination, sleep apnea, lower urinary tract symptoms, heart failure, recent myocardial infarction or stroke, thrombophilia, and fertility plans.
• Follow-up at 3 to 12 months and then annually, with testosterone and hematocrit at 3 to 6 months, PSA and digital rectal examination at 3 to 12 months, and the Recommendation 3.2 referral thresholds applied in the first year.
• For Schedule III dispensing, a patient-specific prescription issued for a legitimate medical purpose, with the six-month and five-refill limits of 21 U.S.C. 829(b) tracked by the dispensing pharmacy.

Compounded hormone preparations reach a practice working with ExaVeyra through a licensed 503A pharmacy partner on a patient-specific prescription, and the partner dispenses testosterone and any other controlled substance under its own DEA registration.^[19][20] Whether a patient meets a guideline definition of hypogonadism, which product is prescribed, and how the patient is monitored are decisions for the prescribing practitioner, documented against the guideline the practice has chosen to follow.^[1][2]

This article summarizes published clinical practice guidelines, trial reports and federal regulation for licensed practitioner education. It is not legal advice, medical advice, or regulatory guidance, and it does not establish that any particular product or practice is compliant. Confirm current federal and state obligations with qualified counsel.