Honest Criticisms and Limitations of the Testosterone Trials (T-Trials) Trial

At a glance

Parameter	Detail
N	790 men aged 65+ with low testosterone (<275 ng/dL)
Intervention	Transdermal testosterone gel (AndroGel 1.62%), dose-titrated to mid-normal range
Comparator	Placebo gel
Duration	12 months
Primary endpoints	Sexual function (PDQ-Q4), physical function (6-minute walk), vitality (FACIT-Fatigue)
Key result	Significant improvement in sexual function and walking distance; modest vitality gains

Trial Architecture: What Was Actually Tested

The Testosterone Trials were coordinated across 12 U.S. academic medical centers from 2010 to 2014. The study enrolled men 65 years or older who had a serum testosterone below 275 ng/dL on two morning draws and who reported symptoms consistent with one of three functional domains: sexual dysfunction, reduced vitality, or limited physical mobility.

The design was unusual. Rather than a single primary endpoint, the T-Trials comprised seven nested sub-trials (Sexual Function, Physical Function, Vitality, Cognitive Function, Anemia, Bone, and Cardiovascular). The first three were powered as co-primary endpoints in the initial NEJM publication. The remaining four reported separately.

This architecture matters for interpretation. Each sub-trial had its own inclusion criteria layered on top of the common testosterone threshold, creating overlapping but non-identical cohorts within the 790 participants.

Enrollment Biases and Who Was Excluded

The HealthRX.com Enrollment Bias Framework for the T-Trials

We identify five categories of selection pressure that shaped who entered this trial and, by extension, who the results apply to:

1. Age floor without ceiling pressure. All participants were 65+, but the mean age was 72. Men in their late 50s and early 60s, who represent the largest TRT-prescribing demographic in clinical practice, were entirely absent.

2. Testosterone threshold artifact. The <275 ng/dL cutoff on two morning samples excluded men with borderline values (275-350 ng/dL) who may be symptomatic. The Endocrine Society guidelines later set their threshold at <300 ng/dL, meaning the T-Trials population was slightly more hypogonadal than the guideline-defined group.

3. Cardiovascular exclusion. Men with recent MI, stroke, or uncontrolled heart failure were excluded. This creates a survivorship bias: the enrolled cohort was healthier than the average 72-year-old man with low testosterone. Post-hoc cardiovascular findings from this trial cannot be projected onto higher-risk patients.

4. BMI and comorbidity filtering. Although obesity was common (mean BMI ~30), men with severe obesity (BMI >40) or uncontrolled diabetes (A1c >8%) were generally excluded by site investigators during screening, though no hard protocol cutoff existed for BMI.

5. Volunteerism bias. Recruitment required motivation to attend 9+ clinic visits over 12 months. Men with depression, cognitive decline, or limited mobility (the very populations who might benefit most from TRT) were underrepresented.

Duration: Twelve Months Is Not Long Enough

The T-Trials lasted one year. For a therapy many clinicians prescribe indefinitely, this constrains interpretation in three ways.

First, prostate safety. The FDA label for testosterone products warns about prostate monitoring. Twelve months is insufficient to detect clinically meaningful changes in prostate cancer incidence, which typically requires 3-5 years of observation.

Second, cardiovascular risk. The subsequent TRAVERSE trial (2023, N=5,246) was specifically designed to address the cardiovascular question with a median follow-up of 33 months. TRAVERSE found non-inferiority but a signal for increased atrial fibrillation and pulmonary embolism. The T-Trials' 12-month window was too narrow to detect these events with statistical confidence.

Third, durability of benefit. The T-Trials publication showed sexual function improvements were maximal at 3 months and sustained at 12 months. Whether these gains persist at 24 or 36 months, or whether tachyphylaxis occurs, remains unknown from this dataset.

Statistical Design Caveats

Multiple Co-Primary Endpoints Without Multiplicity Adjustment

The three co-primary endpoints (sexual function, physical function, vitality) were evaluated at alpha = 0.05 each, without formal correction for multiple comparisons. The investigators justified this by noting the endpoints were pre-specified and that each addressed a distinct clinical domain. Critics pointed out that with three bites at the apple, the family-wise error rate approached 14%.

Effect Sizes in Context

The walking distance improvement of 6.3 meters fell well below the accepted minimal clinically important difference for the 6-minute walk test. The vitality score similarly did not reach established MCID thresholds. Only sexual function showed an effect size that most participants would notice subjectively, as reported in the original T-Trials results.

Responder Analysis Was Post-Hoc

The publication reports mean changes but does not include pre-specified responder analyses. How many individual men experienced meaningful improvement versus how many showed no change is unclear from the primary report. Subsequent sub-analyses addressed this partially, but without the statistical rigor of a pre-specified threshold.

Generalizability Gaps

The enrolled population was 88% white, drawn exclusively from U.S. academic centers. Racial and ethnic minorities, who may have different testosterone-symptom relationships and different baseline cardiovascular risk profiles, were underrepresented.

The intervention (AndroGel 1.62%) represents one specific delivery system. Injections (testosterone cypionate or enanthate), which account for the majority of TRT prescriptions by volume, were not studied. Pharmacokinetic differences between gels and injections (steady-state vs. peaks and troughs) may produce different symptomatic and safety profiles.

Men with known causes of hypogonadism (pituitary tumors, Klinefelter syndrome, prior orchidectomy) were excluded. The trial specifically targeted "age-related" low testosterone, sometimes called "late-onset hypogonadism," a category whose validity as a distinct clinical entity remains debated in European Association of Urology guidelines.

Conflict of Interest and Funding

The T-Trials were funded by the National Institute on Aging, with testosterone gel provided by AbbVie (manufacturer of AndroGel). AbbVie had no role in study design, data collection, or analysis according to the published disclosures.

However, several investigators disclosed consulting fees or grants from AbbVie and other testosterone manufacturers. Letters to the editor in NEJM following publication raised the concern that the trial's framing emphasized the positive sexual function result while the null physical function and borderline vitality findings received comparatively less attention in the abstract and conclusions.

The NIA funding insulates the T-Trials from the most common criticism of industry-sponsored TRT research, but the product supply relationship and individual investigator conflicts warranted transparency, which the authors did provide in supplementary materials.

What Subsequent Commentary Identified

Post-publication letters and editorials raised several additional points:

The accompanying NEJM editorial noted that the trial was "not designed or powered to assess the long-term risks" and cautioned against interpreting the results as evidence that TRT is safe.

A 2017 sub-study from the T-Trials (the Cardiovascular Trial) found that testosterone increased coronary artery plaque volume measured by CT angiography. This finding, published in JAMA, introduced uncertainty about cardiovascular safety that the 12-month primary endpoints could not address.

The bone density sub-trial showed improvements in volumetric BMD, but without fracture endpoints. Whether the BMD gains translate to fracture prevention in this population remains speculative.

What This Means for Clinical Practice

The T-Trials remain the most rigorous evidence that testosterone gel improves sexual function in older hypogonadal men over 12 months. That finding is real. But prescribers should understand what the trial did not establish: long-term safety, benefit in men under 65, benefit from injectable formulations, clinically meaningful improvements in physical function or energy, and applicability to racially diverse populations.

The trial is best understood as proof-of-concept for symptomatic relief in a carefully selected population, not as a blanket endorsement of TRT in aging men with borderline testosterone levels.

Frequently asked questions

›How many men were screened versus enrolled in the T-Trials?

Approximately 51,085 men were assessed for eligibility through initial contact. Of these, 790 were randomized. The large screening-to-enrollment ratio reflects the strict testosterone threshold and symptom requirements, which limits generalizability to broader clinical populations.

›Did the T-Trials prove testosterone is safe for older men?

No. The trial was not powered for safety outcomes. With 790 participants over 12 months, it could not reliably detect differences in cardiovascular events, prostate cancer, or thromboembolic disease. The subsequent TRAVERSE trial (N=5,246, median 33 months) was designed specifically for cardiovascular safety.

›Why did the physical function endpoint fail to reach clinical significance?

The 6-minute walk distance improved by only 6.3 meters, well below the 20-30 meter MCID for this test. The enrolled men had only moderate mobility limitations at baseline, creating a potential ceiling effect. Men with more severe physical impairment might have shown larger gains.

›Were the T-Trials funded by a testosterone manufacturer?

The primary funder was the National Institute on Aging (NIA). AbbVie supplied the testosterone gel and placebo but did not participate in study design, data analysis, or manuscript preparation. Individual investigators disclosed consulting relationships with AbbVie and other companies.

›Can T-Trials results be applied to men aged 50-64?

Not directly. All participants were 65 or older (mean age 72). Younger hypogonadal men may have different risk-benefit profiles, different causes of low testosterone, and different responses to supplementation. No extrapolation to younger men is supported by this data.

›What happened to participants after the 12-month trial ended?

The T-Trials did not include an extension phase. Participants returned to their usual care. No systematic follow-up data on symptom durability or late adverse events have been published from this cohort beyond the 12-month window.

›Did the coronary plaque finding from the cardiovascular sub-trial change prescribing guidelines?

The 2017 finding of increased non-calcified coronary plaque volume raised concerns but did not definitively change guidelines. The Endocrine Society's 2018 guidelines noted it as an area of uncertainty. The TRAVERSE trial's later non-inferiority finding on MACE partially reassured clinicians, though the atrial fibrillation signal introduced new caution.

›How does the T-Trials' testosterone threshold compare to current diagnostic criteria?

The T-Trials used <275 ng/dL on two morning samples. The 2018 Endocrine Society guideline uses <300 ng/dL. This means the T-Trials cohort was slightly more definitively hypogonadal than the current guideline threshold would require, potentially selecting for men more likely to respond.

›Were patient-reported outcomes validated in this age group before the trial?

The PDQ (Psychosexual Daily Questionnaire) had been validated in younger populations with erectile dysfunction. Its performance characteristics in men over 65 with age-related hypogonadism were less established at trial inception, though the T-Trials data itself contributed to validation in this demographic.

›What is the biggest unresolved question from the T-Trials?

Whether the symptomatic benefits persist beyond 12 months and whether they justify the uncertain long-term cardiovascular and prostate risks. The trial demonstrated short-term efficacy for sexual function but left the risk-benefit ratio for indefinite use unanswered.

References

1. Snyder PJ, Bhasin S, Cunningham GR, et al. Effects of Testosterone Treatment in Older Men. N Engl J Med. 2016;374(7):611-624. https://pubmed.ncbi.nlm.nih.gov/26886521/

2. Budoff MJ, Ellenberg SS, Lewis CE, et al. Testosterone Treatment and Coronary Artery Plaque Volume in Older Men With Low Testosterone. JAMA. 2017;317(7):708-716. https://pubmed.ncbi.nlm.nih.gov/28241244/

3. 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(5):1715-1744. https://pubmed.ncbi.nlm.nih.gov/29562364/

4. Lincoff AM, Bhasin S, Flevaris P, et al. Cardiovascular Safety of Testosterone-Replacement Therapy. N Engl J Med. 2023;389(2):107-117. https://pubmed.ncbi.nlm.nih.gov/37334136/

5. FDA. AndroGel (testosterone gel) 1.62% Prescribing Information. 2018. https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/021229s052lbl.pdf