Pregnenolone

Pregnenolone is the "mother of all steroid hormones" — synthesized from cholesterol via CYP11A1 (P450scc), it is the first step in steroidogenesis and the precursor to DHEA, progesterone, cortisol, testosterone, and estradiol. Critically relevant to TRT because exogenous testosterone suppresses the entire steroidogenic cascade upstream, potentially depleting pregnenolone and its neurosteroid metabolites (allopregnanolone, pregnenolone sulfate). Many men on TRT report "emotional blunting" or cognitive fog that resolves with pregnenolone supplementation — hypothesized to be from neurosteroid depletion. Pregnenolone sulfate is a potent positive allosteric modulator of NMDA receptors and negative modulator of GABA-A receptors, enhancing memory consolidation and cognitive flexibility. Phase II trials show promise for schizophrenia negative symptoms (Marx et al., 2009) and cannabis use disorder. OTC in the US; the most upstream point of intervention in the steroid cascade.