Progesterone

Progesterone is a naturally occurring steroid and progestogen sex hormone that plays a key role in the menstrual cycle, pregnancy, and the development of embryos in humans and other animals. It is the body's primary progestogen, a category of steroid hormones. Beyond its reproductive functions, progesterone serves as a crucial metabolic building block for making other steroids, including sex hormones and corticosteroids, and it also acts as a neurosteroid in the brain. As a medication, it has been prescribed since 1934, often combined with estrogen for contraception, to lower the risk of uterine or cervical cancer, in hormone replacement therapy, and in feminizing hormone therapy.

Biologically, progesterone is the most significant progestogen. It works by strongly activating the nuclear progesterone receptor (nPR), which influences ribosomal transcription and is central to regulating female reproduction. It also activates membrane progesterone receptors (mPRs), which affect reproduction processes like oocyte maturation, labor, and sperm motility, as well as cancer, though these roles are not fully understood. Progesterone binds to PGRMC1, impacting tumor progression, metabolism, and nerve cell survival. Additionally, it blocks the sigma σ1 receptor, negatively modulates nicotinic acetylcholine receptors, and strongly blocks the mineralocorticoid receptor (MR)—even more effectively than aldosterone or glucocorticoids like cortisol—leading to antimineralocorticoid effects such as sodium loss (natriuresis) at normal levels. It also weakly activates the glucocorticoid receptor (GR) as a partial agonist. Through its neurosteroid metabolites, such as 5α-dihydroprogesterone and allopregnanolone, it indirectly enhances GABAA receptor activity. Progesterone and some metabolites, like 5β-dihydroprogesterone, weakly activate the pregnane X receptor (PXR), which induces liver enzymes like CYP3A4, especially during pregnancy when progesterone levels are high; perimenopausal women show higher CYP3A4 activity than men or postmenopausal women, likely due to their elevated progesterone. Progesterone also modulates CatSper channels in sperm, guiding them toward eggs via chemotaxis, suggesting that blocking this site could lead to male contraception.

In terms of biological function, progesterone’s effects are often amplified by estrogens, which increase progesterone receptor expression—for example, in breast tissue where estrogens enable progesterone to drive lobuloalveolar development. High progesterone levels strongly reduce aldosterone’s sodium-retaining effect, causing natriuresis and lowering extracellular fluid volume. When progesterone drops, a temporary increase in sodium retention occurs due to a compensatory rise in aldosterone. During fetal development, placental progesterone can be converted into 5α-dihydrotestosterone (DHT), a potent androgen responsible for male genitalia formation, either via testosterone or the androgen backdoor pathway, making progesterone a precursor for sexual differentiation.

In the reproductive system, progesterone acts on human sperm through non-genomic signaling as they travel through the female tract before fertilization, though the exact receptor is unknown. It triggers calcium changes in sperm that may regulate motility. Produced by the ovaries, progesterone is often called the "hormone of pregnancy" due to its many fetal roles: it transforms the endometrium into its secretory stage 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 (a progesterone-withdrawal bleed). Without ovulation and corpus luteum formation, progesterone levels remain low.