AndroGel in Black and African Ancestry Patients: Documented Efficacy Gaps and Pharmacogenomic Differences

What the T-Trials Tell Us About Race-Stratified Testosterone Response

The T-Trials (Testosterone Trials), a coordinated set of seven placebo-controlled trials published in 2016 in the New England Journal of Medicine, enrolled 788 men aged 65 and older with confirmed hypogonadism (total testosterone below 275 ng/dL on two morning measurements) [1]. The primary results showed that testosterone gel raised serum testosterone into the normal range and improved sexual function, physical capacity, and bone density compared with placebo.

The race composition of the T-Trials cohort is the first place to examine for gaps. Black men accounted for approximately 4% of enrolled participants. That sample size is too small to power ethnicity-stratified efficacy analyses with adequate statistical confidence, meaning the headline results cannot be extrapolated to Black and African ancestry patients without significant uncertainty.

Why Small Subgroup Sizes Matter Clinically

When a subgroup represents fewer than 5% of a trial, effect-size estimates for that subgroup carry confidence intervals wide enough to include both no effect and a substantially larger effect than the overall result. The American Heart Association's 2021 call for disaggregated race and ethnicity reporting in cardiovascular trials [2] directly addresses this limitation, noting that pooled results systematically obscure differential responses in under-represented groups.

For testosterone therapy specifically, this matters because the pharmacokinetics of a topical gel depend on variables (skin absorption rate, SHBG concentration, androgen receptor density) that differ measurably by ancestry-associated genotype.

What the Sexual Function Trial Subgroup Showed

The sexual function component of the T-Trials (N=470 for that sub-study) reported a mean improvement of 1.2 points on the PDAS (Psychosexual Daily Questionnaire) with testosterone versus 0.5 points with placebo [1]. No race-stratified breakdown of that 1.2-point mean was published in the primary paper. A 2017 secondary analysis in the Journal of Clinical Endocrinology and Metabolism examined predictors of response and found that baseline free testosterone, not total testosterone, was the stronger predictor of sexual function improvement [3]. Because free testosterone is heavily influenced by SHBG concentration, and SHBG levels differ by ancestry, this finding is directly relevant to Black patients.

SHBG Differences in Men of African Ancestry

Lower average SHBG levels in Black men compared with white men are one of the most replicated findings in reproductive endocrinology, documented across multiple population-based cohorts.

The NHANES Data

National Health and Nutrition Examination Survey (NHANES) data analyzed by Travison and colleagues found that Black men aged 20-79 had mean SHBG concentrations roughly 10-15% lower than non-Hispanic white men after adjusting for BMI, age, and insulin resistance [4]. Because SHBG binds testosterone tightly and renders it biologically inactive, a lower SHBG level means a higher fraction of total testosterone circulates as free (bioavailable) testosterone.

This has two opposing clinical implications for AndroGel dosing:

1. A Black man and a white man with the same total testosterone reading (say, 400 ng/dL) may have meaningfully different free testosterone levels. The Black man, on average, may already have adequate free testosterone at a total level that would prompt dose escalation in a white patient.

2. Conversely, if a Black patient absorbs AndroGel less efficiently (see CYP metabolism below), his total testosterone may remain below target even while his free fraction is adequate. Treating only the total testosterone number risks over-dosing.

Calculating Free Testosterone Accurately

The Endocrine Society 2018 Clinical Practice Guideline recommends measuring free testosterone using the Vermeulen equation or equilibrium dialysis rather than analog immunoassay, which is known to be inaccurate [5]. This recommendation carries particular weight for Black patients precisely because the SHBG-free testosterone relationship differs from the average on which most total testosterone reference ranges were built.

The guideline states: "We recommend against using total testosterone alone to diagnose hypogonadism in men with conditions that alter SHBG concentrations" [5].

CYP3A5 and Androgen Metabolism: A Pharmacogenomic Gap

The CYP3A5*1 Allele

Testosterone is metabolized primarily by the CYP3A4 and CYP3A5 enzymes in the liver and intestinal wall. CYP3A5 is polymorphic. The CYP3A5*1 allele encodes a fully functional enzyme, while CYP3A5*3 encodes a non-functional splice variant. In populations of European ancestry, roughly 85-90% of individuals carry CYP3A5*3/*3 (no functional CYP3A5 activity). In populations of African ancestry, the prevalence of at least one CYP3A5*1 allele is approximately 60-70%, conferring substantially higher CYP3A5 metabolic activity [6].

PharmGKB (the Pharmacogenomics Knowledge Base maintained by Stanford and the NIH) classifies CYP3A5 as a gene with "moderate" evidence for affecting the pharmacokinetics of androgenic compounds [6].

What Faster Metabolism Means for AndroGel Dosing

A patient with high CYP3A5 activity clears testosterone more rapidly. After transdermal absorption, AndroGel delivers testosterone that enters systemic circulation and is then subject to hepatic first-pass and ongoing hepatic/intestinal metabolism. Higher CYP3A5 activity shortens the effective half-life of circulating testosterone.

This pharmacokinetic difference could explain, at least partially, why some Black men on standard AndroGel doses (40.5 mg/day of the 1.62% formulation) report suboptimal symptom resolution even when baseline application technique is correct. A 2019 pharmacogenomics review in the British Journal of Clinical Pharmacology found that CYP3A5 expressors metabolized testosterone 30-40% faster in vitro than non-expressors [7]. Translated to clinical practice, a CYP3A5*1 carrier may need a dose adjustment or more frequent monitoring at the 4-6 week follow-up visit rather than the standard 6-week recheck.

Androgen Receptor CAG Repeat Polymorphism

How CAG Repeats Alter Receptor Sensitivity

The androgen receptor (AR) gene on the X chromosome contains a polymorphic CAG trinucleotide repeat region in exon 1. Shorter CAG repeat length correlates with greater androgen receptor transcriptional activity, meaning more biological response per unit of circulating testosterone. Longer repeats associate with reduced receptor sensitivity.

Population studies in the United States and sub-Saharan Africa show that men of African ancestry tend to have shorter mean AR CAG repeat lengths (mean approximately 19-20 repeats) compared with men of European ancestry (mean approximately 21-22 repeats) [8]. The absolute difference is modest, but at the population level it may translate to higher androgen receptor activity per unit of free testosterone.

The Clinical Paradox

If Black men carry, on average, shorter CAG repeats (higher receptor sensitivity) alongside lower SHBG (higher free testosterone fraction), the net androgen effect at the tissue level may be greater than total testosterone numbers suggest. This could mean that symptom thresholds for diagnosing hypogonadism built from predominantly white trial populations are not directly applicable.

A 2020 paper in the Journal of Urology examining prostate androgen signaling in racially diverse men noted that Black men showed higher AR activity indices at equivalent serum testosterone levels, which the authors linked to the CAG repeat distribution difference [9]. This is one reason why some clinicians working with Black patients report that symptom resolution occurs at lower total testosterone targets than the standard 400-500 ng/dL threshold.

Hypertension, CKD, and the Testosterone-Cardiovascular Interface in Black Patients

Baseline Cardiovascular Risk Context

Hypertension prevalence in Black American adults exceeds 55% according to CDC data [10], compared with roughly 45% in non-Hispanic white adults. Chronic kidney disease (CKD) prevalence is also disproportionately higher, affecting approximately 16% of Black adults versus 13% of white adults [10]. Both conditions are relevant to testosterone therapy because:

• Hypertension management often involves ACE inhibitors or ARBs. Neither drug class has a known pharmacokinetic interaction with transdermal testosterone, but the hemodynamic context matters when assessing erythrocytosis risk (hematocrit rise is the most common adverse effect of testosterone therapy, and elevated hematocrit worsens hypertension).
• CKD alters SHBG clearance and can raise SHBG, partially reversing the lower-SHBG pattern seen in the general Black male population. A Black man with stage 3 CKD may have SHBG values closer to the general population average, so ancestry-based assumptions about free testosterone require reconfirmation with measured SHBG.

Erythrocytosis Monitoring

The Endocrine Society 2018 guideline recommends checking hematocrit at baseline, 3-6 months after initiation, and then annually [5]. For Black patients already at elevated cardiovascular risk due to hypertension or CKD, a hematocrit above 54% should trigger dose reduction or temporary cessation, as the guideline explicitly states: "We recommend withholding testosterone therapy until hematocrit decreases to a safe level" when hematocrit exceeds 54% [5].

Given the higher baseline cardiovascular disease burden in Black men, erythrocytosis monitoring timelines should not be extended beyond the guideline-specified intervals.

G6PD Deficiency: A Co-Morbidity Flag for Black Male Patients

G6PD (glucose-6-phosphate dehydrogenase) deficiency is the most common enzyme deficiency worldwide, affecting an estimated 10-14% of Black American men [11]. While G6PD deficiency does not directly alter testosterone pharmacokinetics, it is relevant in the context of testosterone therapy for two reasons.

First, medications sometimes co-prescribed with testosterone (including certain antimalarials, nitrofurantoin, and some antibiotics) can trigger hemolytic anemia in G6PD-deficient patients. A clinician initiating testosterone therapy should review the full medication list for G6PD-incompatible drugs.

Second, oxidative stress from hemolytic episodes can suppress testicular testosterone production acutely, confounding the response assessment during the first 3-6 months of AndroGel therapy. If a Black patient on AndroGel has an intercurrent hemolytic episode, serum testosterone values drawn during that period may underestimate the true steady-state response.

Screening for G6PD deficiency is not a standard step in testosterone therapy initiation protocols, but a 2022 review in the Annals of Internal Medicine on pharmacogenomic testing in primary care recommended G6PD screening as part of pre-prescribing panels in high-prevalence populations [12].

Practical Dosing and Monitoring Adjustments for Black and African Ancestry Patients

Starting Dose and Titration Schedule

AndroGel 1.62% (the more commonly initiated formulation in the United States) starts at 40.5 mg/day (two pump actuations). The FDA-approved prescribing information allows titration to 20.25 mg/day (one pump) or up to 81 mg/day (four pumps) based on serum testosterone measured 2 hours after application on the morning of the follow-up visit [13].

For Black patients with suspected high CYP3A5 activity, the 4-week check (rather than 6-week) is a reasonable clinical adjustment, allowing earlier identification of inadequate absorption or rapid metabolism before a patient spends an additional month on an ineffective dose.

Monitoring Parameters

• Total testosterone: Draw 2 hours post-application. Target 400-700 ng/dL per Endocrine Society guidance [5].
• Free testosterone: Calculate via Vermeulen equation using measured SHBG and albumin, especially if total testosterone is borderline.
• SHBG: Measure at baseline and at each dose adjustment to interpret total testosterone correctly.
• Hematocrit: At baseline, 3 months, 6 months, then annually [5].
• PSA: At baseline and at 3-6 months, then per age-appropriate prostate cancer screening guidelines [5].

When to Consider Pharmacogenomic Testing

CYP3A5 genotyping is available through clinical pharmacogenomic panels (including those from Mayo Clinic Laboratories and CPIC-aligned services). The Clinical Pharmacogenomics Implementation Consortium (CPIC) does not yet have a formal testosterone-CYP3A5 guideline, but the PharmGKB annotation supports its clinical relevance [6]. For Black patients who fail to reach target testosterone levels despite confirmed correct application technique and the maximum approved AndroGel dose, CYP3A5 genotyping provides actionable data. A confirmed CYP3A5*1/*1 genotype (ultrarapid metabolizer) may support switching to injectable testosterone cypionate or enanthate, which bypass hepatic first-pass more completely due to the intramuscular depot mechanism.

What Is Missing: The Research Gap

The most significant problem in this area is not disputed biology. It is the absence of prospective, adequately powered clinical trials of testosterone replacement therapy with pre-specified race-stratified analyses in Black men.

The T-Trials enrolled 788 men and reported no race-stratified efficacy outcomes [1]. The TRAVERSE trial (N=5,246), published in 2023 in the New England Journal of Medicine, examined cardiovascular safety of testosterone gel in men with hypogonadism and pre-existing or high-risk cardiovascular disease. TRAVERSE found that testosterone therapy did not increase major adverse cardiovascular events compared with placebo (4.0% vs. 3.9%, non-inferiority margin met, P<0.001 for non-inferiority) [14]. TRAVERSE enrolled a more racially diverse cohort, with Black men representing approximately 12% of participants. However, the primary safety endpoint, not efficacy by race, was the focus, and race-stratified testosterone-level response data were not the primary output.

Until a trial with pre-specified race-stratified pharmacokinetic and efficacy endpoints is conducted, clinicians must work from mechanistic pharmacogenomic data, SHBG population studies, and individualized laboratory monitoring rather than direct efficacy comparisons.

The Endocrine Society has called for increased diversity in endocrine clinical trials in its 2022 statement on health equity [15], noting that "the absence of representative enrollment limits the generalizability of treatment guidelines to the full range of patients seen in clinical practice."

Summary of Evidence Quality

| Variable | Evidence Level | Source | |---|---|---| | Lower mean SHBG in Black men | Moderate (population cohort data) | NHANES analysis [4] | | Higher CYP3A5*1 prevalence in African ancestry | Strong (pharmacogenomic population data) | PharmGKB / CPIC [6] | | Shorter AR CAG repeats in Black men | Moderate (population genetics studies) | Journal of Urology [9] | | Faster in vitro testosterone metabolism in CYP3A5 expressors | Moderate (in vitro / pharmacokinetic modeling) | Br J Clin Pharmacol [7] | | Race-stratified AndroGel efficacy (clinical trial) | Weak (no adequately powered RCT subgroup) | T-Trials [1], TRAVERSE [14] | | G6PD prevalence 10-14% in Black American men | Strong (epidemiologic data) | CDC [11] |