What Do We Know about Classical and Non-Classical Progesterone Receptors in the Human Female Reproductive Tract? A Review

Abstract

The progesterone hormone regulates the human menstrual cycle, pregnancy, and parturition by its action via the different progesterone receptors and signaling pathways in the female reproductive tract. Progesterone actions can be exerted through classical and non-classical receptors, or even a combination of both. The former are nuclear receptors whose activation leads to transcriptional activity regulation and thus in turn leads to slower but long-lasting responses. The latter are composed of progesterone receptors membrane components (PGRMC) and membrane progestin receptors (mPRs). These receptors rapidly activate the appropriate intracellular signal transduction pathways, and they can subsequently initiate specific cell responses or even modulate genomic cell responses. This review covers our current knowledge on the mechanisms of action and the relevance of classical and non-classical progesterone receptors in female reproductive tissues ranging from the ovary and uterus to the cervix, and it exposes their crucial role in female infertility.

Membrane Progesterone Receptors (mPRs, PAQRs): Review of Structural and Signaling Characteristics

“…The widespread distribution of mPRs in reproductive tissues, their hormonal regulation, changes in mPR expression during the reproductive cycle, critical mPR functions in different reproductive tissues, and their potential involvement in reproductive tissue cancers have been the subjects of several recent extensive reviews [ 8 , 9 , 13 , 14 , 15 , 16 , 17 , 18 ], so they are not discussed further here. Nevertheless, several controversies over the structural characteristics, membrane topology, and signal transduction of mPRs have not been completely resolved [ 2 , 19 , 20 ].…”

Progesterone Resistance in Endometriosis

“…In the nucleus, PGR dimerises to form homodimers (AA, BB) or heterodimers (AB), and binds to the progesterone response element sequence in the target gene. [14][15][16][17][18][19] A third variant of PGR, PGR-C isoform (60 kDa), has also been described in humans (Figures 1 and 2). PGR-C also can form heterodimers with PGR-A and PGR-B and regulates their transcriptional activity.…”

“…Interested readers may be referred to the comprehensive review articles that covered different aspects of PGR in mammalian cells and specifically in endometrium. 11,[14][15][16][17][18][19] Classical Progesterone Receptors There are two main isoforms of classical PGR: PGR-A (94 kDa) and PGR-B (120 kDa). Both are transcribed from the same gene, but by two different promoters.…”

“…Unbound PGR in cytoplasm are complexed with chaperone proteins. [14][15][16][17][18][19] Several lines of evidence suggests that PGR-A is functionally distinct from PGR-B, and thus tissue-specific distribution patterns of PGR-A and PGR-B result in the observed diversity of progesteronemediated actions.…”

“…14,19,23 Non-classical Progesterone Receptors receptor membrane component (PGRMC) family, both having several subtypes. 8,11,16,19,24 There is evidence to suggest that both types of non-classical PGRs may interact to mediate their actions in target cells. The physiological significance of non-classical PGRs in the uterus is not clear.…”