Progesterone Beyond Pituitary Suppression in Assisted Reproduction: Peripheral Signalling, Gamete Biology, Endometrial Competence and Precision Therapeutic Use

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.