Aromatase inhibitors as endocrine modulators: From breast cancer therapy to male off-label use and doping practice

Aromatase inhibitors (AIs) suppress estrogen biosynthesis by blocking the conversion of androgens to estrogens. Although they are established endocrine therapies in postmenopausal breast cancer, their mechanism has led to off-label and non-medical use in men, including performance-enhancing drug practices, post-cycle therapy, supplement-related contexts, and attempts to manipulate the testosterone-estradiol balance. This review summarizes the pharmacology of clinically approved and non-approved aromatase-inhibiting compounds and evaluates their endocrine and health-related consequences in male populations. Across clinical and experimental studies, aromatase inhibition generally reduced estradiol and increased gonadotropins and testosterone. Responses were heterogeneous and influenced by baseline endocrine status, clinical context, treatment protocol, and analytical methodology. Group-level summaries may obscure substantial interindividual variability. Most studies did not systematically evaluate men with prior anabolic-androgenic steroid exposure, despite the relevance of this subgroup to performance-enhancing drug use and post-cycle endocrine recovery. AI-induced testosterone increases appeared to develop rapidly, reach an apparent ceiling, and generally reverse after discontinuation. However, biochemical increases in testosterone did not consistently translate into improved sexual function, physical performance, or broader patient-reported benefit. In adolescent boys, aromatase inhibition may delay skeletal maturation, but the long-term endocrine, skeletal, and developmental consequences of estrogen deprivation remain incompletely defined. The available evidence supports a cautious, indication-specific view of AI use in men. AIs should not be regarded as general testosterone-restoring or performance-enhancing agents. Better phenotyping and mass-spectrometric steroid profiling are needed to clarify clinically relevant subgroups and health risks.