Progesterone is an endogenous steroid and progestogen sex hormone involved in the menstrual cycle, pregnancy, and embryogenesis of humans and other species. It belongs to a group of steroid hormones called the progestogens and is the major progestogen in the body. Progesterone has a variety of important functions in the body. It is also a crucial metabolic i
This article is about progesterone as a hormone. For its use as a medication, see progesterone (medication).Chemical compound
Progesterone (/proʊˈdʒɛstəroʊn/ ⓘ; P4) is an endogenous steroid and progestogen sex hormone involved in the menstrual cycle, pregnancy, and embryogenesis of humans and other species.[3][13] It belongs to a group of steroid hormones called the progestogens[13] and is the major progestogen in the body. Progesterone has a variety of important functions in the body. It is also a crucial metabolic intermediate in the production of other endogenous steroids, including the sex hormones and the corticosteroids, and plays an important role in brain function as a neurosteroid.[14]
In addition to its role as a natural hormone, progesterone is also used as a medication, such as in combination with estrogen for contraception, to reduce the risk of uterine or cervical cancer, in hormone replacement therapy, and in feminizing hormone therapy.[15] It was first prescribed in 1934.[16]
Biological activity
See also: Pharmacodynamics of progesterone § Mechanism of actionProgesterone is the most important progestogen in the body. As a potent agonist of the nuclear progesterone receptor (nPR) (with an affinity of KD = 1 nM), the resulting effects on ribosomal transcription play a major role in regulation of female reproduction.[13][17] In addition, progesterone is an agonist of the more recently discovered membrane progesterone receptors (mPRs),[18] of which the expression has regulation effects in reproduction function (oocyte maturation, labor, and sperm motility) and cancer, although additional research is required to further define the roles.[19] It also functions as a ligand of the PGRMC1 (progesterone receptor membrane component 1) which impacts tumor progression, metabolic regulation, and viability control of nerve cells.[20][21][22] Moreover, progesterone is also known to be an antagonist of the sigma σ1 receptor,[23][24] a negative allosteric modulator of nicotinic acetylcholine receptors,[14] and a potent antagonist of the mineralocorticoid receptor (MR).[25] Progesterone prevents MR activation by binding to this receptor with an affinity exceeding even those of aldosterone, and glucocorticoids such as cortisol and corticosterone,[25] and it produces antimineralocorticoid effects, such as natriuresis, at physiological concentrations.[26] Progesterone also binds to, and behaves as a partial agonist of, the glucocorticoid receptor (GR), albeit with very low potency (EC50 >100-fold less relative to cortisol).[27][28]
Through its neurosteroid active metabolites, such as 5α-dihydroprogesterone and allopregnanolone, progesterone acts indirectly as a positive allosteric modulator of the GABAA receptor.[29]
Progesterone and some of its metabolites, such as 5β-dihydroprogesterone, are agonists of the pregnane X receptor (PXR),[30] albeit weakly so (EC50 >10 μM).[31] In accordance, progesterone induces several hepatic cytochrome P450 enzymes,[32] such as CYP3A4,[33][34] especially during pregnancy when concentrations are much higher than usual.[35] Perimenopausal women have been found to have greater CYP3A4 activity relative to men and postmenopausal women, and it has been inferred that this may be due to the higher progesterone levels present in perimenopausal women.[33]
Progesterone modulates the activity of CatSper (cation channels of sperm) voltage-gated Ca2+ channels. Since eggs release progesterone, sperm may use progesterone as a homing signal to swim toward eggs (chemotaxis). As a result, it has been suggested that substances that block the progesterone binding site on CatSper channels could potentially be used in male contraception.[36][37]
Biological function
Hormonal interactions
Progesterone has a number of physiological effects that are amplified in the presence of estrogens. Estrogens through estrogen receptors (ERs) induce or upregulate the expression of the PR.[39] One example of this is in breast tissue, where estrogens allow progesterone to mediate lobuloalveolar development.[40][41][42]
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) due to the compensatory increase in aldosterone production, which combats the blockade of the mineralocorticoid receptor by the previously elevated level of progesterone.[43]
Early sexual differentiation
Placental progesterone can be converted into 5α-dihydrotestosterone (DHT), a potent androgen that is responsible for the development of male genitalia.[44] This can be done both by conversion into testosterone, which is then converted to DHT, and via the androgen backdoor pathway, which is particularly important for fetal development.[45] Progesterone is the precursor for both pathways and therefore plays a key role in sexual differentiation.[46][47]
Reproductive system
Progesterone has key effects via non-genomic signalling on human sperm as they migrate through the female reproductive tract before fertilization occurs, though the receptor(s) as yet remain unidentified.[48] Detailed characterisation of the events occurring in sperm in response to progesterone has elucidated certain events including intracellular calcium transients and maintained changes,[49] slow calcium oscillations,[50] now thought to possibly regulate motility.[51] It is produced by the ovaries.[52] Progesterone has also been shown to demonstrate effects on octopus spermatozoa.[53]
Progesterone is sometimes called the "hormone of pregnancy",[54] and it has many roles relating to the development of the fetus:
- Progesterone converts the endometrium to its secretory stage to prepare the uterus for implantation. At the same time progesterone affects the vaginal epithelium and cervical mucus, making it thick and impenetrable to sperm. Progesterone is anti-mitogenic in endometrial epithelial cells, and as such, mitigates the tropic effects of estrogen.[55] If pregnancy does not occur, progesterone levels will decrease, leading to menstruation. Normal menstrual bleeding is progesterone-withdrawal bleeding. If ovulation does not occur, and the corpus luteum does not develop, levels of progesterone may be low, leading to anovulatory dysfunctional uterine bleeding.
- During implantation and gestation, progesterone appears to decrease the maternal immune response to allow for the acceptance of the pregnancy.[56]
- Progesterone decreases contractility of the uterine smooth muscle.[54] This effect contributes to prevention of preterm labor.[56] Studies have shown that in individuals who are pregnant with a single fetus, asymptomatic in the prenatal stage, and at a high risk of giving pre-term birth spontaneously, vaginal progesterone medication has been found to be effective in preventing spontaneous pre-term birth. Individuals who are at a high risk of giving pre-term birth spontaneously are those who have a short cervix of less than 25 mm or have previously given pre-term birth spontaneously. Although pre-term births are generally considered to be less than 37 weeks, these studies found that vaginal progesterone is associated with fewer pre-term births of less than 34 weeks.[57]
- A drop in progesterone levels is possibly one step that facilitates the onset of labor.[citation needed]
- In addition, progesterone inhibits lactation during pregnancy. The fall in progesterone levels following delivery is one of the triggers for milk production.[citation needed]
The fetus metabolizes placental progesterone in the production of adrenal steroids.[45]
