Progesterone is an endogenous steroid and progestogen sex hormone involved in the menstrual cycle, pregnancy, and embryogenesis of humans and different species. It belongs to a bunch of steroid hormones known as the progestogens, and is the major progestogen in the body. Progesterone has a wide range of important functions in the body. It is also an important metabolic intermediate in the production of other endogenous steroids, including the sex hormones and the corticosteroids, and plays a crucial role in brain perform as a neurosteroid.
Progesterone is the most important progestogen in the body, the result of its action as a potent agonist of the nuclear progesterone receptor (nPR) (with an affinity of KD = 1 nM). Additionally, progesterone is an agonist of the more recently discovered membrane progesterone receptors (mPRs), similarly as a matter of PGRMC1 (progesterone receptor membrane component 1). Moreover, progesterone is also known to be an antagonist of the sigma σ1 receptor, a negative allosteric modulator of nicotinic acetylcholine receptors, and a potent antagonist of the mineralocorticoid receptor (MR).Progesterone prevents MR activation by binding to this receptor with an affinity exceeding even those of aldosterone and glucocorticoids similar to cortisol and corticosterone, and produces antimineralocorticoid effects, such as natriuresis, at physiological concentrations. In addition, progesterone binds to and behaves as a partial agonist of the glucocorticoid receptor (GR), albeit with very low potency. Progesterone, through its neurosteroid active metabolites similar to 5α-dihydroprogesterone and allopregnanolone, acts indirectly as a positive allosteric modulator of the GABAA receptor.
Progesterone and some of its metabolites, such as 5β-dihydroprogesterone, are agonists of the pregnane X receptor (PXR), albeit weakly so (EC50 >10 µM). In accordance, progesterone induces several hepatic cytochrome P450 enzymes, such as CYP3A4, especially during pregnancy when concentrations are much higher than usual. Perimenopausal women have been found to have higher CYP3A4 activity relative to men and postmenopausal women, and it's been inferred that this could be due to the higher progesterone levels present in perimenopausal women.
Progesterone modulates the activity of CatSper (cation channels of sperm) voltage-gated Ca2+ channels. Since eggs unleash progesterone, sperm could use progesterone as a homing signal to swim toward eggs (chemotaxis). In consequence, it has been instructed that substances that block the progesterone binding site on CatSper channels could potentially be used in male contraception.
Progesterone includes a wide range of physiological effects that are amplified in the presence of estrogens. Estrogens through estrogen receptors (ERs) induce or upregulate the expression of the PR. One example of this can be breast tissue, where estrogens allow progesterone to mediate lobuloalveolar development.
Elevated levels of progesterone potently reduce the sodium-retaining activity of aldosterone, resulting in natriuresis and a reduction in extracellular fluid volume. Progesterone withdrawal, on the other hand, is associated with a temporary increase in sodium retention (reduced natriuresis, with an increase in extracellular fluid volume) because of the compensatory increase in aldosterone production that combats the blockade of the mineralocorticoid receptor by the previously elevated level of progesterone.
Progesterone has key effects via non-genomic signalling on human sperm as they migrate through the female tract before fertilization happens, although the receptors so far stay unidentified. Detailed characterisation of the events occurring in sperm in response to progesterone has elucidated certain events including intracellular calcium transients and maintained changes, slow calcium oscillations, now thought to possibly regulate motility. It is created by the ovaries. Progesterone has also been shown to demonstrate effects on octopus spermatozoa.
In mammals, progesterone, like all different kinds of steroid hormones, is synthesized from pregnenolone, which itself is derived from cholesterol. Cholesterol undergoes double oxidation to provide 22R-hydroxycholesterol and then 20α,22R-dihydroxycholesterol. This vicinal diol is then further oxidized with loss of the side chain starting at position C22 to produce pregnenolone. This reaction is catalyzed by cytochrome P450scc.The conversion of pregnenolone to progesterone takes place in two steps. First, the 3β-hydroxyl group is oxidized to a keto group and second, the double bond is moved to C4, from C5 through a keto/enol tautomerization reaction. This reaction is catalyzed by 3β-hydroxysteroid dehydrogenase/δ5-4-isomerase. Progesterone successively is that the precursor of the mineralocorticoid aldosterone, and after conversion to 17α-hydroxyprogesterone, of cortisol and androstenedione. Androstenedione is born-again to androgen, estrone, and estrogen. Pregnenolone and progestogen also can be synthesized by yeast. around thirty mg of progestogen is secreted from the ovaries per day in girls, whereas the adrenal glands manufacture concerning one mg of progestogen per day.
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