Progesterone

Lore & Background

Progesterone is the most important progestogen in the body, acting as a potent agonist of the nuclear progesterone receptor (nPR) with an affinity of KD = 1 nM, which plays a major role in regulation of female reproduction. It also acts as an agonist of membrane progesterone receptors (mPRs) and binds to PGRMC1, impacting tumor progression, metabolic regulation, and nerve cell viability. Additionally, progesterone is an antagonist of the sigma σ1 receptor, a negative allosteric modulator of nicotinic acetylcholine receptors, and a potent antagonist of the mineralocorticoid receptor (MR), producing antimineralocorticoid effects such as natriuresis at physiological concentrations.

Reader's Guide

Progesterone is essential for female reproductive function, converting the endometrium to its secretory stage for implantation, decreasing uterine contractility to prevent preterm labor, and inhibiting lactation during pregnancy. It also plays a role in breast development, mediating lobuloalveolar maturation during pregnancy via RANKL. Beyond reproduction, progesterone modulates CatSper channels in sperm, potentially guiding sperm toward eggs via chemotaxis. As a medication, it is used in combination with estrogen for contraception, to reduce the risk of uterine or cervical cancer, in hormone replacement therapy, and in feminizing hormone therapy. Its neurosteroid metabolites, such as allopregnanolone, act as positive allosteric modulators of the GABAA receptor, influencing brain function.

Did You Know?

• Progesterone is an antagonist of the mineralocorticoid receptor with an affinity exceeding that of aldosterone.
• Progesterone induces hepatic cytochrome P450 enzymes such as CYP3A4, especially during pregnancy.
• Sperm may use progesterone as a homing signal to swim toward eggs via CatSper channels.
• Progesterone is converted into 5α-dihydrotestosterone via the androgen backdoor pathway, contributing to fetal sexual differentiation.