The pregnenolone sulfate test is a specific blood test that measures levels of pregnenolone sulfate, a neuroactive steroid and essential metabolite involved in the production of steroid hormones. It assesses adrenal and gonadal function, investigates enzyme deficiencies related to steroid production, and evaluates neurosteroid imbalances that can influence mood, cognition, and neurological health. This test is commonly used to diagnose congenital adrenal hyperplasia (CAH), rare enzyme deficiencies, and conditions affecting central nervous system function or hormone regulation.
Pregnenolone sulfate is the sulfated form of pregnenolone, mainly produced in the adrenal glands, central nervous system, and gonads from cholesterol through a mitochondrial cytochrome P450 side-chain cleavage enzyme (P450scc). Sulfotransferase enzymes, primarily SULT2A1, facilitate the conversion of pregnenolone into pregnenolone sulfate. This sulfated metabolite is more water-soluble and can exist at higher concentrations in the plasma than free pregnenolone, acting as both a storage form and a regulator of steroid hormone availability.
Functionally, pregnenolone sulfate is known for its modulatory effects on the central nervous system. It interacts with several neurotransmitter systems, including gamma-aminobutyric acid (GABA), N-methyl-D-aspartate (NMDA), and sigma-1 receptors. Through these interactions, pregnenolone sulfate has been linked to regulating memory, mood, learning processes, and neuroprotection. It acts as a negative allosteric modulator of GABA-A receptors and as a positive modulator of NMDA receptors, thereby influencing the balance between excitatory and inhibitory signals in the brain. Changes in its levels have been associated with neurological disorders such as epilepsy, depression, schizophrenia, and cognitive decline.
As a key intermediate in steroidogenesis, pregnenolone sulfate provides insights into the activity of enzymes such as 3β-hydroxysteroid dehydrogenase (3β-HSD), 17α-hydroxylase, and 21-hydroxylase. Abnormal levels can indicate enzymatic blocks in steroid synthesis pathways, such as in various forms of congenital adrenal hyperplasia or steroidogenic disorders that impair adrenal and gonadal hormone production. Because pregnenolone is an upstream precursor of glucocorticoids, mineralocorticoids, androgens, and estrogens, its sulfated form serves as an essential marker for identifying upstream dysfunctions before downstream metabolites are affected.
Testing pregnenolone sulfate levels is also helpful in examining the role of neurosteroids in psychiatric and neurodegenerative disorders. Additionally, because this steroid exhibits diurnal variation and is influenced by stress, sleep, and metabolic states, measuring it can facilitate broader research into endocrine–neurochemical interactions and their overall effects.
Last updated: 29/06/2025
