The progesterone receptor (PR), also known as NR3C3, is a protein found inside cells. It is activated by the steroid hormone progesterone.
In humans, PR is encoded by a single PGR gene residing on chromosome 11 has two isoforms, PR-A and PR-B, which differ in their molecular weight, PR-B is the positive regulator of the effects of progesterone, while PR-A serves to antagonize the effects of PR-B.
Progesterone is necessary to induce progesterone receptors. When there is no binding hormone, the carboxyl terminal inhibits transcription. Binding to a hormone induces a structural change that eliminates inhibitory action. Progesterone antagonists prevent reconfiguration.
After progesterone binds to the receptor, a restructuring takes place, the complex enters the nucleus and binds to DNA. There transcription takes place, resulting in the formation of messenger RNA that is translated by ribosomes to produce specific proteins.
In common with other steroid receptors, the progesterone receptor has an N-terminal regulatory domain, a DNA binding domain, a hinge section, and a C-terminal ligand binding domain. A special transcription activation function is present in the progesterone-B receptor at the amino acid terminal. This segment is not present in the A-receptor.
As demonstrated in progesterone receptor-deficient mice, the physiological effects of progesterone depend entirely on the presence of the human progesterone receptor (hPR), a member of the steroid receptor-receptor nuclear superfamily.
PR-B contributes to epithelial cell proliferation, rather than inhibiting it, both in response to estrogen alone and in the presence of progesterone and estrogen. These results suggest that in the uterus, PR-A isoform is necessary to oppose estrogen-induced proliferation as well as PR-B-dependent proliferation.
Progesterone receptors are identified in normal arachnoid tissue, while normal adult meninges express low levels of progesterone receptors. They are expressed in meningiomas, in which they are functional.
The progesterone receptor (PR) belongs to the superfamily of steroid receptors and mediates the action of progesterone on their target tissues. In the mammary gland, in particular, PR expression is limited to the compartment of light epithelial cells.
-Stimulators and inhibitors:
Six variable sites have been identified, including four polymorphisms. It is currently unknown which polymorphisms of this receptor are significant for cancer.
Agonists: Endogenous progestogens (e.g., progesterone)
Synthetic progestins (eg, norethisterone, levonorgestrel, medroxyprogesterone acetate, megestrol acetate, dydrogesterone, drospirenone)
Selective progesterone receptor modulators (e.g., ulipristone acetate, telapristone acetate, vilaprisan, asoprisnil, asoprisnil ecamate)
Antiprogestagens (eg, mifepristone, aglepristone, onapristone, lonapristine, lilopristone, toripristone).
-Receptor of membrane progesterone:
Membrane progesterone receptors (MPR) are a group of cell surface receptors and membrane steroid receptors belonging to the family of progestin receptors that bind to endogenous progesterone and neurosteroid progesterone, as well as neurosteroid alopregnanolone.
Unlike the progesterone receptor (PR), a nuclear receptor that mediates its effects through genomic mechanisms, mPRs are cell-surface receptors that rapidly alter cell signaling through modulation of intracellular signaling cascades.
MPRs are involved in important physiological functions in the male and female reproductive tracts, liver, neuroendocrine tissues and immune system, as well as in breast and ovarian cancer.
MPRs appear to be involved in the neuroprotective and antigonadotropic effects of progesterone and alopregnanolone. The active metabolites of progesterone 5α-dihydroprogesterone, also a progestin, and alopregnanolone, which are positive modulators of the GABA receptor, have been found to rapidly influence the sexual receptivity and behavior of mice, actions that depend on GABA receptors.
Progesterone is involved in regulating the growth of different types of tumors, in part because of its interactions with their intracellular (RP) receptors. MPR has also been found in cancer cells and tissues. Their roles in the process are unclear, but it has been suggested that at least this steroid hormone may inhibit the tumor progression.
Recently, it has been reported that progesterone membrane receptors (mPRs) are expressed in ovarian and breast cancer cells, and that progesterone may exert some actions through these receptors in both cell lines and breast tumor tissues.
In the case of ovarian cancer, transcripts of two of the three mPRs, α and β, were differentially expressed in ovarian cystadenomas, borderline tumors, and carcinomas: while the expression of mPRγ was significantly higher in endometrioid and clear cell carcinomas, which are closely related tumors.
Recent studies suggest that some actions of progesterone in astrocytoma cells (the most common and malignant human brain tumors) may also be mediated by mPRs. Recently, it has also been discovered that mPRα and mPRβ are clearly expressed in the mRNA and protein levels in astrocytoma cells, while mPRγ was barely expressed in these cells.
-Selective progesterone receptor modulator:
A selective progesterone receptor modulator (SPRM) is an agent that acts on the progesterone receptor (PR), the biological target of progestogens such as progesterone. One characteristic that distinguishes these substances from complete receptor agonists (e.g., progesterone, progestins) and complete antagonists (e.g., aglepristone) is that their action differs in different tissues, i.e., agonist in some tissues while antagonist in others.
This mixed profile of action leads to tissue-specific stimulation or inhibition, further increasing the potential to dissociate undesirable adverse effects from the development of synthetic PR modulator drugs.
G-protein coupled receptor
It has been proven that the activity of progesterone was not only mediated by the transcription factor, but also by a receptor attached to the G protein attached to the membrane. When the receptor is activated, it blocks adenyl cyclase, leading to a decrease in biosynthesis of the second cAMP intracellular messenger.
Currently the use of SPMRs has been approved for emergency contraception (ulipristal acetate) and termination of pregnancy (mifepristone in association with prostaglandins). The use of these compounds is being developed in a number of other gynecological applications such as estrogen-free contraception, treatment of uterine leiomyomas, and eventually, treatment of endometriosis.