Progesterone Beyond Pituitary Suppression in Assisted Reproduction: Peripheral Signalling, Gamete Biology,...

Progesterone is indispensable to assisted reproduction, yet the phrase "progesterone effect" collapses non-equivalent biological processes. Classical progesterone receptors (PGR-A and PGR-B), progestin and adipoQ receptor-family proteins, progesterone receptor membrane components 1 and 2 (PGRMC1/2), and an unresolved proximal sensor upstream of sperm CatSper operate over different timescales and with unequal evidence for direct ligand binding. In the ovary, PGRMC-associated complexes regulate granulosa-cell survival, mitosis and oocyte competence, although much causal evidence is non-human. In sperm, progesterone-evoked CatSper activation is robust, whereas the influential ABHD2 hydrolase model was challenged by human data in 2026. In endometrium, receptivity emerges from temporally ordered PGR-dependent epithelial-stromal, immune, metabolic and vascular programmes; "progesterone resistance" is therefore better treated as a family of molecular states than as a single diagnosis. Oral, vaginal, subcutaneous and intramuscular regimens generate different systemic and uterine exposures, and serum progesterone is an exposure marker rather than a direct assay of tissue response. We integrate these levels into an exposure-target engagement-tissue state-outcome framework. This framework explains why universal serum thresholds and unselected rescue strategies remain uncertain and defines the experiments and trials needed for mechanism-informed luteal support and frozen embryo transfer.