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.

Keywords: female infertility; human; progesterone; progesterone receptor; reproduction.

Figure 2

Graphic representation showing the subcellular localization and biological processes for classical (left) and non-classical (right) PGR in the cell and their interaction with proteins. ER = endoplasmic reticulum. Created with BioRender.com [47].

Figure 1

Representation of the classical PGR gene found in chromosome 11, and as of the protein domains of PGR isoforms A, B, and C. In response to estrogen binding to ERE, the PGR gene codifies for the distinct isoforms by the influence of different promoters. ERE = estrogen response elements. AF = activation function domain. ID = inhibitory domain. DBD = DNA-binding domain. LBD = ligand-binding domain. NH₂ = amino terminal region. COOH = carboxyl terminal region.

Figure 3

Schematic representation of the non-classical PGR genes and their localization in chromosomes. PGRMC1 and PGRMC2 comprise a single N-terminal transmembrane domain (TM) and a cytochrome (Cyt) b5 domain. The interaction sites for SH2 and SH3 domains revealed the presence of three binding sites for the Src homology domains. mPRα, β, and γ were proposed as being classical membrane G protein-coupled receptors with the typical 7 TM domain structure and the N-terminus facing the extracellular space. This assumption was challenged by placing an extended group of mPRs (α, β, γ, ɗ, and ɛ) with predicted 8 TM topology. NH₂ = amino terminal region. COOH = carboxyl terminal region.