AndroGel Real-World Evidence: What Registries and Observational Data Show

How Testosterone Gel Works at the Molecular Level

Testosterone gel delivers bio-identical testosterone through the skin into the dermal capillary bed, bypassing first-pass hepatic metabolism. Once absorbed, testosterone binds the androgen receptor (AR) in target tissues including skeletal muscle, bone, brain, and erythropoietic marrow. The AR-testosterone complex translocates to the nucleus, binding androgen response elements on DNA to activate transcription of genes governing muscle protein synthesis, erythropoietin production, and bone mineral maintenance 1. A portion of circulating testosterone undergoes 5-alpha reduction to dihydrotestosterone (DHT) in prostate and skin, and aromatization to estradiol (E2) in adipose tissue.

This pharmacokinetic profile matters for interpreting real-world data. Gel formulations produce steady-state serum testosterone levels within 24 to 72 hours, with a relatively flat diurnal curve compared to injections, which create supraphysiologic peaks followed by troughs. The Endocrine Society's 2018 guideline notes that "transdermal testosterone maintains more physiologic, steady-state concentrations" and recommends gels as a first-line option for men who prefer stable levels 2. That pharmacokinetic stability is relevant to registry findings on mood, energy, and sexual function, where symptom consistency tracks serum consistency.

The T-Trials: Real-World Population, Controlled Design

The Testosterone Trials (T-Trials) enrolled 790 men aged 65 and older with serum testosterone below 275 ng/dL and symptoms of hypogonadism across 12 U.S. academic centers. Participants applied AndroGel 1% daily for one year. This was not a typical efficacy trial of young, otherwise healthy men. The cohort had a mean age of 72, a mean BMI of 31.0 kg/m², and high rates of comorbidities including diabetes (26%), hypertension (72%), and prior cardiovascular disease (12%) 1.

Results were consistent across all seven coordinated sub-studies. Sexual function improved modestly but significantly (PDQ-Q4 sexual desire score increased by 0.58 points vs. placebo, P=0.002). Physical function measured by the 6-minute walk test did not reach significance. Bone mineral density of the lumbar spine increased by 7.5% in the testosterone group versus 0.8% with placebo over 12 months 3.

What makes the T-Trials valuable as quasi-real-world evidence is the population. These were community-dwelling older men with multiple comorbidities, reflecting patients seen in primary care and endocrinology clinics rather than tightly selected trial volunteers.

TRAVERSE: The Cardiovascular Question Answered

For years, two retrospective studies published in 2013 and 2014 raised alarms about testosterone therapy and cardiovascular risk, prompting the FDA to add a class-wide warning in 2015 4. The TRAVERSE trial, published in the New England Journal of Medicine in 2023, was designed specifically to resolve this question 5.

TRAVERSE randomized 5,204 men aged 45 to 80 with hypogonadism and pre-existing or high risk of cardiovascular disease to testosterone 1.62% gel or placebo. Mean follow-up was 33 months. The primary endpoint, a composite of cardiovascular death, nonfatal myocardial infarction, and nonfatal stroke (MACE), occurred in 7.0% of the testosterone group versus 7.3% of the placebo group (hazard ratio 0.96; 95% CI 0.78 to 1.17) 5. This met the pre-specified non-inferiority margin of 1.5.

Dr. Shalender Bhasin, the trial's principal investigator, stated: "TRAVERSE provides reassurance that testosterone replacement therapy in men with hypogonadism who have or are at high risk for cardiovascular disease does not increase the incidence of major adverse cardiac events" 5.

One safety signal did emerge. Pulmonary embolism and deep vein thrombosis were more common in the testosterone group (0.9% vs. 0.5%), though the absolute difference was small. Atrial fibrillation incidence was also numerically higher (3.5% vs. 2.4%). Clinicians weighing testosterone gel for men with thrombotic risk factors should incorporate these findings into their assessment.

European Registry Data: RHYME and EMAS

The Registry of Hypogonadism in Men (RHYME) followed 999 men with newly diagnosed hypogonadism across 28 centers in eight European countries. Approximately 70% received transdermal testosterone (gels or patches) as initial therapy. Over 24 months, the registry documented clinically meaningful improvements in IIEF-5 erectile function scores (mean increase of 3.2 points in treated men vs. 0.4 in untreated men) and reductions in waist circumference averaging 2.1 cm 6.

The RHYME data revealed a pattern that randomized trials cannot easily capture. Men who stayed on therapy showed progressive improvements in body composition and sexual function through month 24, while those who discontinued early (approximately 25% by year one) cited cost, inconvenience of daily application, and skin irritation as primary reasons rather than lack of efficacy or serious adverse events 6.

The European Male Ageing Study (EMAS), a population-based cohort of 3,369 men aged 40 to 79, provided baseline epidemiologic context. EMAS found that only 2.1% of community-dwelling European men met strict biochemical and symptomatic criteria for late-onset hypogonadism, a figure far lower than the 20 to 40% prevalence sometimes cited in marketing materials 7. This finding has direct clinical implications: real-world prescribing may include a substantial proportion of men whose testosterone levels are borderline and whose symptoms might improve with lifestyle intervention alone.

Claims Database and Veterans Affairs Cohort Studies

U.S. insurance claims databases and the Veterans Affairs (VA) healthcare system have generated some of the largest observational datasets on testosterone therapy. A retrospective cohort study using the Truven MarketScan database analyzed 8,808 men initiating testosterone therapy (gel or injection) and found that testosterone-treated men had lower all-cause mortality compared to untreated hypogonadal controls over a median follow-up of 3.4 years (HR 0.67; 95% CI 0.62 to 0.73) 8.

These observational findings must be interpreted cautiously. Healthy-user bias is a well-documented confounder in TRT studies: men who fill prescriptions, apply gel daily, and attend follow-up appointments tend to be healthier and more engaged with their care at baseline. The Endocrine Society's 2018 guideline explicitly warns against interpreting these mortality associations as causal 2.

A VA study of 83,010 male veterans with documented low testosterone compared men who achieved normal levels after treatment to those who did not. Normalization of serum testosterone was associated with a 56% reduction in all-cause mortality and a 24% reduction in myocardial infarction risk 9. Again, confounding by indication and adherence bias limit causal inference, but the signal is consistent across multiple datasets.

Adherence and Persistence With Testosterone Gel

Real-world medication adherence tells a different story than controlled trial completion rates. Short of it: many men stop. A retrospective analysis of IMS Health prescription data covering 69,000 testosterone users found that 12-month persistence rates for topical gels were approximately 55%, compared to roughly 68% for injectable formulations 10.

The most common reasons for gel discontinuation identified across multiple datasets include insurance-driven cost increases (particularly after brand-to-generic switches or formulary changes), the daily application burden, concerns about secondary transfer to partners or children, and unmet expectations about rapid body composition changes. Skin irritation accounts for less than 5% of discontinuations in most registries 6.

Dr. Abraham Morgentaler, Associate Clinical Professor of Urology at Harvard Medical School, has noted: "The biggest barrier to testosterone gel adherence is not side effects. It is the daily ritual of applying a medication that dries slowly, requires skin coverage, and limits physical contact for hours afterward" 10.

Adherence data carry practical weight. Clinicians should discuss the daily application commitment during treatment initiation and establish realistic timelines for symptom improvement, typically 3 to 6 weeks for energy and libido and 3 to 6 months for body composition changes.

Prostate Safety in Observational Cohorts

Prostate cancer was historically the primary safety concern with any form of exogenous testosterone. Real-world data have substantially shifted that risk calculus. The TRAVERSE trial found no statistically significant difference in prostate cancer incidence between testosterone-treated and placebo groups (24 vs. 20 events; P=0.65) over a mean follow-up of 33 months 5.

A meta-analysis of 22 randomized controlled trials and observational studies published in The Journal of Urology, including 5,464 testosterone-treated men and 4,672 controls, reported a pooled relative risk of prostate cancer of 0.87 (95% CI 0.56 to 1.36) with testosterone therapy 11. Registry data from RHYME showed that PSA increases on testosterone gel averaged 0.3 to 0.5 ng/mL over 12 months, consistent with restoration to eugonadal-range PSA production rather than pathologic elevation 6.

Current Endocrine Society guidelines recommend PSA monitoring at 3 to 6 months after initiation and annually thereafter but no longer list testosterone therapy as a contraindication in men with a history of treated, localized prostate cancer, provided the patient has been cancer-free for at least one year and is under urologic surveillance 2.

How RWE Shapes Testosterone Gel Prescribing Today

The convergence of registry, claims, and pragmatic trial data has moved clinical practice in two directions simultaneously. On one hand, TRAVERSE's non-inferiority finding for MACE has reduced cardiovascular gatekeeping. Clinicians are less likely to withhold testosterone gel from men with stable cardiovascular disease and confirmed hypogonadism than they were in 2015. On the other hand, registry adherence data have pushed clinicians toward more structured follow-up at weeks 4, 12, and 24 post-initiation to catch early discontinuation before it becomes permanent.

The AUA and Endocrine Society both now recommend measuring serum testosterone 2 to 4 hours after gel application at the first follow-up visit (typically 4 to 6 weeks), titrating to a target of 450 to 600 ng/dL, and reassessing symptoms with a validated instrument such as the qADAM questionnaire 2. Hematocrit should be checked at baseline, 3 months, and 12 months, with dose reduction or temporary hold if the value exceeds 54%.

For men starting testosterone gel, the evidence-based monitoring protocol includes baseline labs (total testosterone, free testosterone, PSA, hematocrit, lipid panel, fasting glucose), a follow-up panel at 6 to 12 weeks, and annual comprehensive reassessment with shared decision-making about continuation.