Beyond Testosterone: The Androgen Receptor Exon-1 CAG Repeat from Molecular Mechanism and Kennedy Disease to Compensated Androgen Resistance and Precision Endocrinology

The biological effect of testosterone cannot be inferred from its circulating concentration alone. Androgen action is determined jointly by ligand availability, tissue steroid metabolism, androgen-receptor (AR) abundance and function, coregulatory context, and hypothalamic-pituitary-testicicular feedback. A polymorphic CAG repeat in exon 1 of the X-linked AR gene encodes a variable polyglutamine tract in the intrinsically disordered N-terminal transactivation domain. Pathogenic expansion causes spinal and bulbar muscular atrophy (SBMA; Kennedy disease), in which partial androgen insensitivity coexists with an androgen-dependent toxic gain of function. Within the non-SBMA range, longer repeats usually—but not invariably—reduce AR-mediated transcription in experimental systems and may shift the relationship between serum testosterone and androgen-responsive phenotypes. This critical translational review integrates the molecular biochemistry, historical discovery, population diversity, endocrine compensation, organ-specific phenotypes, and pharmacogenetics of the AR CAG repeat. The evidence supports a graded, tissue-dependent effect rather than a universal molecular switch. SBMA provides compelling proof that long polyglutamine tracts impair aspects of canonical AR action, but its neurodegeneration reflects additional ligand-dependent proteotoxic mechanisms and cannot be extrapolated linearly to ordinary alleles. In population cohorts, longer common-range repeats are often accompanied by modestly higher total and free testosterone and sometimes higher estradiol, consistent with a shifted feedback set point. High luteinizing hormone is not obligatory. Phenotypic associations involving fertility, sexuality, body composition, metabolism, bone, mood, prostate, and cardiovascular traits are heterogeneous, whereas differential prostate and erythropoietic responses during testosterone therapy provide comparatively coherent pharmacogenetic signals. AR CAG length should therefore be considered a quantitative modifier of androgen action. A continuous CAG-by-testosterone response surface spanning 15-35 repeats is proposed as a transparent framework.