The Pregnenolone Steal Effect is a hypothetical but clinically relevant model suggesting that chronic, sustained activation of the Hypothalamic-Pituitary-Adrenal (HPA) axis due to persistent psychological or physiological stress diverts the common steroid precursor, pregnenolone, away from the synthesis of sex hormones. This metabolic diversion prioritizes the production of cortisol to manage the stress response, thereby ‘stealing’ pregnenolone that would otherwise be converted into DHEA, progesterone, and ultimately testosterone and estrogen. This results in a relative deficiency of sex and neurosteroids.
Origin
This concept originates from the field of steroid biochemistry and clinical endocrinology, based on the well-established cascade of steroidogenesis within the adrenal glands and gonads. The term ‘steal’ is used metaphorically to describe the metabolic flux shift caused by the overwhelming demand for cortisol. While the exact degree of the effect is debated, it provides a valuable framework for explaining stress-induced sex hormone deficiency.
Mechanism
The mechanism is centered on the enzyme Cytochrome P450 side-chain cleavage enzyme (P450scc), which converts cholesterol to pregnenolone, the starting point for all steroid hormones. Under chronic stress, the signal from the pituitary gland—Adrenocorticotropic Hormone (ACTH)—drives the adrenal cortex to rapidly convert pregnenolone primarily down the pathway leading to cortisol via 17-hydroxypregnenolone. This accelerated flux effectively limits the availability of pregnenolone for the other downstream pathways, resulting in a measurable reduction in DHEA and progesterone production.
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