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* Steroid 5a-reductases (5aRs) catalyze the irreversible, NADPH-dependent reduction of A*-3-ketosteroids. This process regulates major steroid signaling pathways, including neurosteroid biosynthesis, androgen activation, and glucocorticoid metabolism. By governing these processes, 5aRs influence GABAergic and dopaminergic neurotransmission, and behavioral responses to stress and reward. Although the two principal isoenzymes, 5aR1 and 5aR2, have overlapping functions, they are increasingly recognized as functionally distinct. 5aR1 supports constitutive neurosteroid synthesis in several brain regions. Conversely, 5aR2, long known for converting testosterone to dihydrotestosterone during male sexual differentiation, has emerged as the enzyme that mediates rapid allopregnanolone production in the prefrontal cortex of males during acute stress.
Figure 2. Catalytic functions of 5a-reductase (5aR). (A) Under conditions of reduced 5aR activity, testosterone (TEST) remains the primary activator of androgen receptors (AR), while corticosterone in rodents and cortisol in humans (CORT) activate glucocorticoid receptors (GR). Conversion of progesterone (PROG) to dihydroprogesterone (DHP) and subsequently to allopregnanolone (AP) is limited. (B) When 5aR activity is intact, TEST is converted to the more potent AR agonist dihydrotestosterone (DHT), which can be further metabolized to 5a-androstane-3a,17B-diol (3a-DIOL). PROG is converted to DHP, promoting AP synthesis. Together, 3a-DIOL and AP act as positive allosteric modulators of GABA-A receptors. In parallel, conversion of CORT to dihydrocorticosterone (DHB) or dihydrocortisol (DHF) alters GR activation, thereby reducing the impact of hypothalamic-pituitary—adrenal (HPA) axis signaling on neuronal function. Adapted from Servier Medical Art (SMART - Servier Medical ART).
Steroid Sa-reductases in the brain: From neurosteroidogenesis to therapeutic implications
Giulia Braccagni, Caterina Branca, Marco Bortolato
Taken together, the available evidence argues against viewing 5a-reduction solely as a peripheral, androgen-activating process. Instead, brain 5aR1 and 5aR2 should be regarded as functionally distinct contributors to neurosteroidogenesis whose roles vary by cell type, circuit, and sex. The tonic/phasic framework should be regarded as a working hypothesis rather than a settled conclusion; from this perspective, its main value lies in organizing a fragmented literature and identifying the gaps that must be closed before it can be properly tested. What is already apparent, however, is that the two isoenzymes are not functionally redundant. We fully expect that resolving their distinct, sex-dependent contributions will prove essential to understanding how neurosteroidogenic capacity shapes vulnerability and resilience across stress-related disorders.
Figure 2. Catalytic functions of 5a-reductase (5aR). (A) Under conditions of reduced 5aR activity, testosterone (TEST) remains the primary activator of androgen receptors (AR), while corticosterone in rodents and cortisol in humans (CORT) activate glucocorticoid receptors (GR). Conversion of progesterone (PROG) to dihydroprogesterone (DHP) and subsequently to allopregnanolone (AP) is limited. (B) When 5aR activity is intact, TEST is converted to the more potent AR agonist dihydrotestosterone (DHT), which can be further metabolized to 5a-androstane-3a,17B-diol (3a-DIOL). PROG is converted to DHP, promoting AP synthesis. Together, 3a-DIOL and AP act as positive allosteric modulators of GABA-A receptors. In parallel, conversion of CORT to dihydrocorticosterone (DHB) or dihydrocortisol (DHF) alters GR activation, thereby reducing the impact of hypothalamic-pituitary—adrenal (HPA) axis signaling on neuronal function. Adapted from Servier Medical Art (SMART - Servier Medical ART).
Steroid Sa-reductases in the brain: From neurosteroidogenesis to therapeutic implications
Giulia Braccagni, Caterina Branca, Marco Bortolato
Taken together, the available evidence argues against viewing 5a-reduction solely as a peripheral, androgen-activating process. Instead, brain 5aR1 and 5aR2 should be regarded as functionally distinct contributors to neurosteroidogenesis whose roles vary by cell type, circuit, and sex. The tonic/phasic framework should be regarded as a working hypothesis rather than a settled conclusion; from this perspective, its main value lies in organizing a fragmented literature and identifying the gaps that must be closed before it can be properly tested. What is already apparent, however, is that the two isoenzymes are not functionally redundant. We fully expect that resolving their distinct, sex-dependent contributions will prove essential to understanding how neurosteroidogenic capacity shapes vulnerability and resilience across stress-related disorders.
