Language

English

Publication Date

6-30-2026

Journal

Translational Andrology and Urology

DOI

10.21037/tau-2026-0182

PMID

42436779

PMCID

PMC13355247

PubMedCentral® Posted Date

5-15-2026

PubMedCentral® Full Text Version

Post-print

Abstract

Background: The preferred treatment for hypogonadism, testosterone replacement therapy (TRT), has a varying efficacy that is currently not fully understood. This observation may be explained by polymorphism of the androgen receptor (AR), a ligand-binding transcription factor whose polyglutamine tract length affects various health conditions and androgen sensitivity. It has been theorized that this polymorphism may also affect the severity of hypogonadism. This study sought to determine a correlation between hypogonadism severity, TRT efficacy, and number of CAG trinucleotide repeats in the AR gene.

Methods: One hundred sixty-two males presenting to a single institution with symptoms of hypogonadism were recruited for this observational study. Patient Health Questionnaire-9 (PHQ-9) and International Index of Erectile Function (IIEF-15) surveys were taken upon initial visit. Patients' baseline and follow-up testosterone (T) levels were measured before and after starting TRT, respectively. CAG repeat length was determined via polymerase chain reaction (PCR) followed by Sanger sequencing. Linear regression and t-test (RStudio) were performed.

Results: Average patient age was 52 years. Average number of CAG repeats found was 22±3.1, which is within the normal range as described by current literature. A very loose, but statistically significant correlation (R2=0.0631, P=0.02) was found between T levels following TRT and CAG repeat number, which increased when type 2 diabetes and erectile dysfunction (ED) were added as predictors (R2=0.178, adjusted R2=0.143, P=0.002). Additionally, patients who presented with hypogonadal symptoms and a baseline T value above 300 ng/dL demonstrated a higher average CAG repeat length than those below 300 (P=0.02). Patients who required higher T levels (>700 ng/dL) for symptomatic improvement demonstrated a higher average CAG repeat length than those who were at lower T levels, though this did not reach statistical significance (P=0.11).

Conclusions: These data suggest that CAG repeat length may serve as an accurate measure of TRT efficacy and hypogonadism severity. Patients with longer CAG repeat lengths may, therefore, exhibit hypogonadal symptoms despite seemingly eugonadal T levels and require more exogenous T to effectively treat symptoms. More research with a larger sample size and further analysis is warranted to fully explore the relationship between CAG repeat length and hypogonadism.

Keywords

Hypogonadism, CAG repeats, androgen receptor (AR), testosterone replacement therapy (TRT)

Published Open-Access

yes

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