How do androgen hormones affect genital development in males?
Executive summary
Androgens—chiefly testosterone and its more potent metabolite dihydrotestosterone (DHT)—drive the masculinization of internal and external genitalia by activating the androgen receptor in target tissues during a critical fetal window and again at puberty, with conversion enzymes, paracrine signaling and receptor sensitivity shaping the precise outcome [1] [2] [3]. Disruption at any step—hormone production, local conversion to DHT, receptor function, or timing—produces predictable changes from under‑virilized external genitalia to altered internal duct development, a fact illustrated by genetic syndromes and animal models while important molecular details remain incompletely mapped [4] [5] [6].
1. How androgens set the developmental program: timing, sources, and targets
Male genital development is orchestrated by testes that form under genetic control and then secrete hormones: Leydig cells produce testosterone early in fetal life (driven initially by hCG and later by fetal pituitary LH), while Sertoli cells produce Müllerian inhibiting substance (MIS/AMH) that prevents female tract formation—together these signals direct differentiation of male internal and external structures [7] [8] [4]. Testosterone circulates to Wolffian ducts, promoting their transformation into epididymis, vas deferens and seminal vesicles, while other androgens act locally to sculpt the external genitalia; this temporal coordination in a narrow embryonic window is essential because prenatal androgen effects are organizational and largely irreversible [7] [3] [4].
2. Two-androgen model and the role of DHT in external genital formation
The classic “two‑androgen” model holds that testosterone virilizes internal Wolffian derivatives while testosterone converted to DHT by 5α‑reductase in genital skin drives penis, scrotum and urethral masculinization; DHT binds the same androgen receptor with higher affinity and is therefore crucial for external genital morphogenesis [9] [2] [10]. Human clinical genetics reinforce this: 5α‑reductase deficiency reduces DHT synthesis and commonly yields incompletely masculinized external genitalia despite normal internal development, demonstrating the division of labor between testosterone and DHT [3] [4].
3. Receptor action, paracrine signaling and the limits of our molecular map
Androgens act through a single androgen receptor (AR) whose ligand‑activated complex modulates downstream gene programs in epithelial and mesenchymal tissues; tissue‑specific AR signaling and epithelial–mesenchymal interactions imply paracrine growth factors mediate many androgen effects, but the downstream molecular mechanisms remain incompletely defined despite robust models from mice and tissue recombination studies [3] [10] [5]. Clinical disorders such as complete or partial androgen insensitivity syndrome (CAIS/PAIS) show that even abundant circulating testosterone cannot masculinize tissues if AR function is defective, producing a spectrum from female external genitalia to partial virilization that underscores receptor centrality [6] [11].
4. Ancillary hormones and processes: Insl3, AMH, and the “backdoor” pathway
Androgens do not act alone: Insl3 from Leydig cells mediates testicular descent, and AMH from Sertoli cells prevents Müllerian structures, so defects in these hormones produce predictable anatomic outcomes alongside androgen defects [8] [7]. Recent research adds nuance: a “backdoor” pathway synthesizes potent androgens (e.g., androsterone) from placental progesterone without traversing circulating testosterone, suggesting alternative routes to masculinization in some contexts and complicating the simple two‑androgen narrative [9].
5. Clinical consequences, reversibility and developmental windows
Androgen action during embryogenesis produces permanent structural changes—prenatal deficits in androgen levels, local DHT synthesis, or AR function cannot be reversed postnatally, which explains congenital presentations like micropenis, hypospadias, cryptorchidism or ambiguous genitalia; by contrast, androgen effects at puberty (muscle, voice, secondary sexual traits) reflect activational, partly reversible processes [4] [12] [13]. Therapeutically, clinicians exploit this biology—for example, testosterone supplementation can help manage micropenis—yet outcomes depend on timing, dose and the specific defect in the androgen axis [12].
6. Competing perspectives and research gaps
Consensus across endocrinology and developmental biology supports the central role of androgens and AR in masculinization, but the field recognizes gaps: the detailed downstream gene networks, context‑dependent metabolism in tissues, and the quantitative thresholds of hormone/receptor activity that determine one phenotype versus another remain active areas of research, and experimental models (mice, marsupials) provide mechanistic insight that must be cautiously translated to humans [5] [9] [3]. Reports and reviews sometimes emphasize different aspects—clinical syndromes, enzymology, or paracrine signaling—so interpretations can reflect disciplinary focus; readers should note the limits of current molecular resolution even as the broad developmental role of androgens is well established [1] [10].