Effect of androgen receptor polymorphism on hypogonadism severity and efficacy of testosterone replacement therapy.
Level 3 - non-randomized controlled study
Non-randomized observational cohort study with longitudinal follow-up
PubMed 42436779 · doi:10.21037/tau-2026-0182
What was done
An observational study evaluated 162 symptomatic men (mean age 52 years) presenting to a single institution for testosterone replacement therapy (TRT). Participants completed PHQ-9 and IIEF-15 questionnaires at baseline, and total testosterone levels were measured before and after initiating TRT. Androgen receptor gene CAG trinucleotide repeat length was determined using polymerase chain reaction and Sanger sequencing. Linear regression models and t-tests assessed relationships between CAG repeat length, baseline and follow-up testosterone concentrations, and clinical variables.
What was found
The average CAG repeat length was 22 ± 3.1. Post-TRT testosterone levels showed a weak but statistically significant positive correlation with CAG repeat number (R² = 0.0631, P = 0.02), which strengthened when type 2 diabetes and erectile dysfunction were added as predictors (R² = 0.178, adjusted R² = 0.143, P = 0.002). Symptomatic men with baseline testosterone >300 ng/dL had significantly longer average CAG repeats than those with baseline testosterone <300 ng/dL (P = 0.02). Patients requiring testosterone levels >700 ng/dL for symptom relief had longer average repeat lengths, but this difference was not statistically significant (P = 0.11).
Why it matters
These findings suggest that androgen receptor CAG repeat length may partially explain why some men experience hypogonadal symptoms at standard eugonadal testosterone thresholds and require higher circulating levels for symptom resolution.
Limits
The study was conducted at a single institution without an untreated control group. Specific TRT modalities, dosing regimens, and exact follow-up durations were not detailed in the abstract. The variance explained by CAG repeat length alone was very small (R² ≈ 6%), and the association with target testosterone levels for symptom relief failed to achieve statistical significance.
Cited by
- supports Longer androgen receptor CAG repeat lengths are associated with decreased androgen receptor sensitivity to testosterone, requiring higher testosterone levels for the same effect.