Anabolic-Androgenic Steroids Revisited: Structural Biology, Receptor Signaling, and Mechanisms of Anabolic-Androgenic Dissociation.

Steroid hormones exert diverse and tissue-specific biological effects despite sharing a conserved tetracyclic scaffold. Among these, anabolic-androgenic steroids (AAS) present a longstanding paradox: structurally related compounds can elicit markedly different anabolic, androgenic, and cardiovascular outcomes. This narrative review integrates advances in steroid structural chemistry, androgen receptor (AR) biology, and intracellular signaling to elucidate the molecular mechanisms underlying anabolic-androgenic dissociation. We summarize classical genomic and emerging non-genomic modes of steroid action, emphasizing how receptor conformation, ligand-binding domain architecture, co-regulator recruitment, and signaling bias shape downstream biological responses. Particular focus is placed on the structure-activity relationships of endogenous and synthetic androgens, with C17-substitution chemistry highlighted as a central determinant of receptor affinity, metabolic stability, pharmacokinetics, and tissue selectivity. By linking molecular structure to receptor-level mechanisms, we contextualize the physiological and pathophysiological effects of major AAS classes used clinically and non-medically, including testosterone esters, 19-nor derivatives, 17α-alkylated steroids, heterocyclic compounds, and halogenated compounds. While much of the mechanistic evidence derives from preclinical models, the integrated framework presented here provides a coherent basis for interpreting divergent anabolic, androgenic, and cardiovascular effects observed in humans. Collectively, this review bridges fundamental steroid biology with applied physiology and sports medicine, offering mechanistic insight relevant to therapeutic development, anti-doping science, and risk assessment of supraphysiological androgen exposure.