Progesterone receptor: nootropics and compounds | sci-wiki

Megestrol Acetate

Megestrol acetate is a synthetic progestin, a man-made form of the hormone progesterone, used chiefly as an appetite stimulant and as a hormonal treatment in certain cancers. It is prescribed to counter severe appetite loss and wasting, the anorexia-cachexia syndrome, in people with cancer or AIDS, and it has been used as a second-line therapy for breast and endometrial cancer [1][2]. Systematic reviews find that it reliably increases appetite and body weight but does not clearly improve quality of life or survival and raises the risk of certain side effects [1][2].

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Hormone

Progesterone

Progesterone (P4; pregn-4-ene-3,20-dione) is an endogenous pregnane steroid hormone best known for its reproductive roles and is the prototypical neuroactive precursor within the neurosteroid system. Although the parent hormone signals principally through classical nuclear progesterone receptors and through membrane-associated receptors such as PGRMC1 and the mPR/PAQR family, most of its rapid effects on neuronal excitability arise only after sequential metabolism to 5-alpha-dihydroprogesterone and then to allopregnanolone, one of the most potent endogenous positive allosteric modulators of the GABA-A receptor (the brain's principal inhibitory chloride channel). Progesterone and its metabolites are synthesized within the nervous system itself, where they regulate myelination, neuronal survival, neuroinflammation, and inhibitory tone. It has been studied extensively as a neuroprotective agent, with strong preclinical support but negative large-scale human trials in acute traumatic brain injury.

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Neurosteroid

5α-Dihydroprogesterone

5α-Dihydroprogesterone (5α-DHP) is an endogenous neurosteroid and progestogen formed when the enzyme 5α-reductase reduces progesterone at the A-ring of the steroid nucleus, yielding 5α-pregnane-3,20-dione. It occupies the committed first step of the principal neurosteroid pathway, standing between progesterone and allopregnanolone (its 3α-hydroxylated metabolite and one of the most potent naturally occurring positive modulators of the GABA-A receptor, the brain's main inhibitory ion channel). Unlike allopregnanolone, 5α-DHP is itself a high-affinity agonist of the classical (nuclear) progesterone receptor, driving progesterone-responsive gene transcription; in horses it is a fully biopotent progesterone receptor agonist that sustains the second half of pregnancy after circulating progesterone becomes undetectable. It is synthesized in situ within neurons and glia of the central and peripheral nervous systems, where its production rises after nerve injury and falls under chronic stress.

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Hormone

6-Ketoprogesterone

6-Ketoprogesterone (systematic name pregn-4-ene-3,6,20-trione) is a synthetic oxidised derivative and minor oxidative metabolite of progesterone in which an additional ketone (a carbonyl group) is introduced at the sixth carbon of the steroid B-ring. First isolated from perfused human placentae in 1956 and characterised pharmacologically in Japan in 1958, it is notable for having lost the classical progestational activity of its parent hormone while retaining a weaker, progesterone-like depressant action on the central nervous system. Today it exists chiefly as a pharmacopeial reference standard (a purified compound used to calibrate analytical assays), as a mechanistic probe for the C6 oxidation of progesterone, and as a metabolic curiosity of pregnancy endocrinology. Its status as a genuinely endogenous neurosteroid remains uncertain, so it is treated conservatively as non-endogenous.

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