Progesterone

Progesterone is a steroid hormone produced naturally in the body, classified as a progestogen, and it plays a central role in the menstrual cycle, pregnancy, and embryonic development across many species. As the primary progestogen, it serves multiple functions: it acts as a key intermediate in the synthesis of other steroids, including sex hormones and corticosteroids, and it functions as a neurosteroid in the brain. Beyond its natural roles, progesterone is also used medically—often combined with estrogen—for contraception, lowering the risk of uterine or cervical cancer, hormone replacement therapy, and feminizing hormone therapy.

Progesterone is the most significant progestogen in the body. It strongly activates the nuclear progesterone receptor, which influences ribosomal transcription and is crucial for regulating female reproduction. It also activates membrane progesterone receptors, which affect processes like oocyte maturation, labor, and sperm motility, though their exact roles are still being clarified. Additionally, progesterone binds to PGRMC1, impacting tumor progression, metabolism, and nerve cell survival. It acts as an antagonist of the sigma σ1 receptor, a negative allosteric modulator of nicotinic acetylcholine receptors, and a potent antagonist of the mineralocorticoid receptor—blocking it more effectively than aldosterone or glucocorticoids, leading to antimineralocorticoid effects like natriuresis at normal levels. Progesterone also partially activates the glucocorticoid receptor, but with much lower potency than cortisol. Through its neurosteroid metabolites, such as allopregnanolone, it indirectly enhances GABAA receptor activity. Some metabolites, like 5β-dihydroprogesterone, weakly activate the pregnane X receptor, which induces liver enzymes like CYP3A4, especially during pregnancy when progesterone levels are high; perimenopausal women show greater CYP3A4 activity than men or postmenopausal women, likely due to their higher progesterone levels. Progesterone also modulates CatSper channels in sperm, guiding them toward eggs via chemotaxis, a mechanism that could be targeted for male contraception.

Progesterone’s effects are often amplified by estrogen, which upregulates progesterone receptors—for instance, in breast tissue, enabling lobuloalveolar development. High progesterone levels reduce aldosterone’s sodium-retaining effect, causing natriuresis and lowering extracellular fluid volume. When progesterone drops, a compensatory rise in aldosterone temporarily increases sodium retention and fluid volume. During fetal development, placental progesterone can be converted into 5α-dihydrotestosterone via both the testosterone pathway and the androgen backdoor pathway, contributing to male genitalia formation and sexual differentiation.

In the reproductive system, progesterone influences human sperm through non-genomic signaling as they travel through the female tract, triggering calcium transients and oscillations that may regulate motility. Produced by the ovaries, it is often called the "hormone of pregnancy" due to its roles in fetal development: it transforms the endometrium into a secretory state for implantation, thickens cervical mucus to block sperm, and counteracts estrogen’s growth effects in endometrial cells. If pregnancy does not occur, progesterone levels fall, leading to menstruation—normal menstrual bleeding is withdrawal bleeding from progesterone. Without ovulation and corpus luteum formation, progesterone levels remain low.