Clomiphene Citrate in off-Label Post-Cycle Therapy: Mechanisms, Efficacy and Diagnostic Challenges in Endocrine...

Anabolic steroid-induced hypogonadism (ASIH) is a disorder resulting from prolonged suppression of the hypothalamic-pituitary-gonadal axis, frequently observed in anabolic-androgenic steroid (AAS) users after cessation. Despite its growing prevalence, no standardized treatment exists, and post-cycle therapy is often pursued through unsupervised use of selective oestrogen receptor modulators including clomiphene citrate (CC), human chorionic gonadotropin, and aromatase inhibitors. CC is the most commonly employed off-label medication in ASIH, yet its clinical efficacy, safety and optimal monitoring strategies remain poorly defined. CC antagonizes oestrogen receptors, reducing negative feedback on the hypothalamic-pituitary axis, thereby increasing gonadotropin secretion, stimulating endogenous testosterone production, and preserving spermatogenesis. Clinical studies consistently show improvements in hormonal parameters across different types of study participants, although symptomatic recovery varies and concerns remain regarding adverse metabolic and long-term efficacy. Monitoring is further complicated by the limited specificity of immunoassays, with mass spectrometry offering superior reliability for assessing hormonal recovery and detecting residual AAS metabolites. Emerging approaches, including kisspeptin analogues, the enclomiphene isomer, and genotype-guided interventions, suggest potential future directions but lack validation in ASIH populations. This narrative review synthesizes current evidence on CC in post-cycle therapy and highlights key challenges in defining safe and standardized approaches to endocrine recovery following AAS use.