{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nSRD5A2 encodes the steroid 5α‐reductase type II enzyme, which catalyzes the conversion of testosterone into the more potent androgen dihydrotestosterone (DHT). This reaction is essential for normal male sexual differentiation, proper prostate development, and the formation of external genitalia. In fetal life, tightly regulated SRD5A2 activity contributes to urethral morphogenesis and penile formation, while the recent discovery of additional isozymes underscores the complexity of androgen metabolism in various tissues."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "6"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nDefects in SRD5A2—whether through deleterious mutations or decreased enzyme activity—can markedly reduce DHT production, leading to disorders of sexual development. Such impairments have been implicated in conditions characterized by ambiguous genitalia, hypospadias, micropenis, and other 46,XY differentiation disorders. Rapid and precise molecular analyses in affected individuals are therefore critical for optimal clinical management and appropriate sex assignment."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "7", "end_ref": "11"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nA multitude of population‐based studies have scrutinized common SRD5A2 polymorphisms—including variants such as V89L and A49T—to determine their influence on enzyme kinetics, circulating androgen levels, and the risk for hormone‐dependent disorders. Variations in SRD5A2 have been associated with differential risks of prostate cancer, benign prostatic hyperplasia, polycystic ovary syndrome, as well as breast, ovarian, and endometrial pathologies. Ethnic differences in allele frequencies help explain some of the observed disparities in disease prevalence, and analyses integrating SRD5A2 with other hormone‐regulating genes support a polygenic model underlying these conditions."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "12", "end_ref": "40"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nRecent structural and mechanistic studies have revealed that SRD5A2 possesses a unique seven‐transmembrane topology and harbors a largely enclosed catalytic cavity that accommodates both its cofactor and inhibitors such as finasteride. These insights not only elucidate the fundamental catalytic mechanism and the impact of pathogenic mutations on enzyme activity but also support the rationale behind therapeutic interventions targeting DHT synthesis in conditions like benign prostatic hyperplasia and prostate cancer. Epigenetic alterations—such as aberrant methylation of the SRD5A2 promoter region—are also emerging as potential biomarkers in other malignancies, further underlining the enzyme’s clinical significance."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "6"}, {"type": "fg_f", "ref": "35"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Lynn N Thomas, C B Lazier, R Gupta, et al. 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