In women with endometrial hyperplasia, progesterone is not made and the lining of the uterus does not shed itself as a result of missed ovulation 4. The endometrium continues to grow in response to the rise in production of estrogen. When the cells of the endometrium get crowded abnormally (causing hyperplasia), it may lead to uterine cancer 5.
Polycystic ovary syndrome (PCOS) is a state of altered steroid hormone production and activity. Chronic estrogen exposure or lack of progesterone due to ovarian dysfunction can result in endometrial hyperplasia and carcinoma. A key contributor to our understanding of progesterone as a critical regulator for normal uterine function has been the elucidation of progesterone receptor (PR) expression, regulation, and signaling pathways. Several human studies indicate that PR-mediated signaling pathways in the nucleus are associated with progesterone resistance in women with PCOS. The aim of this review is to provide an overview of endometrial progesterone resistance in women with PCOS; to present the PR structure, its different isoforms, and their expression in the endometrium; to illustrate the possible regulation of PR and PR-mediated signaling in progesterone resistance in women with PCOS; and to discuss current clinical treatments for atypical endometrial hyperplasia and endometrial carcinoma in women with PCOS and accompanying progesterone resistance. Polycystic ovary syndrome: a multifactorial diseasePolycystic ovary syndrome (PCOS) is a heterogeneous hormone-imbalance disorder that occurs in approximately 4% or 18% of reproductive-aged women worldwide.
Although PCOS is usually diagnosed during the early reproductive years, the precise etiology and pathogenesis of PCOS remain uncertain. The main clinical complications of this disease include hyperandrogenism, chronic oligo/anovulation, polycystic ovaries, insulin resistance, and type 2 diabetes mellitus ,. Because the signs and symptoms of PCOS can vary among individuals, and because no single factor is likely to explain the constellation of abnormalities in this syndrome, it is often difficult to accurately diagnose women with PCOS.
According to the Rotterdam criteria provided by the American Society for Reproductive Medicine and the European Society for Human Reproduction and Embryology , at least two of the following diagnostic criteria should be met: oligo/anovulation; clinical signs of hyperandrogenism (e.g., hirsutism and acne) and/or biochemical measurements; or enhanced polycystic ovaries and/or multiple discrete follicles in diameter in one ovary as detected by ultrasonography. In addition, other androgen excess disorders and specific etiologies such as congenital adrenal hyperplasia, Cushing’s syndrome, thyroid hormone abnormalities, hyperprolactinemia, and ovarian/adrenal tumors need to be excluded.In clinical practice, 75% of women with PCOS suffer from anovulation infertility and 50% of them experience recurrent pregnancy loss.
It is, however, not clear whether these defects are caused by uterine dysfunction itself or by the interrupted interaction between uterine cells and the developing embryo. Additionally, the chronic anovulation seen in PCOS implies prolonged estrogen excess or lack of progesterone and results in atypical endometrial hyperplasia, which is the precursor of endometrial carcinoma ,. Indeed, young women with PCOS-induced endometrial hyperplasia are more likely than non-PCOS women to develop endometrial carcinoma. Therefore, it is important to understand the mechanisms and consequences behind the pathophysiological changes in the endometrium in women with PCOS in order to develop effective treatments to prevent the development of endometrial carcinoma.This review focuses on progesterone activity in the endometrium and the structural characteristics of human progesterone receptor (PR) isoforms.
The review further compares PR isoform expression and regulation in women with PCOS in relation to the clinical consequences of progesterone resistance. We also discuss the principal therapeutic treatments that have been used to improve progesterone sensitivity in women with PCOS. The general structure of human progesterone receptors. The PR protein consists of four structurally and functionally distinct domains: the N-terminal transactivation domain (NTD), the DNA binding domain (DBD), a small hinge region, and the C-terminal ligand-binding domain (LBD).
The LBD shares the greatest degree of homology among the different human PR isoforms. In addition to hPRA and hPRB, hPRC lacks the first of two zinc fingers and be defective in DNA binding, whereas hPRM lacks both NTD and DBD. The structure of both hPRC and hPRM predicts extra-nuclear localization. HPRS contains only LBD and may be involved in the progesterone-induced nuclear translocation. HPR, human progesterone receptor; aa, amino acids; AF, activation function. Progesterone receptors mediate genomic and non-genomic actions in human endometrium.
Uterine responsiveness to progesterone is dependent on nuclear PRA/B. Progesterone also acts through different membrane-bound PRs that mediate non-genomic activities. In addition to progesterone, nuclear PRA/B has been shown to be under estrogenic control in human and animal uteri. Although the non-genomic effects of membrane-bound PRs in the endometrium are unclear, several studies have suggested that the PRA/B-regulated genes are involved in the regulation of endometrial proliferation. PRA/B, progesterone receptor isoforms A and B. Both PRA and PRB can either homodimerize or heterodimerize in vivo, and the relative expression of the two isoforms varies dramatically in different tissues, cell types, physiological states, and in diseases ,. To date, there is no evidence of distinct nuclear PR isoform expression linked to human endometrial function in vivo.
Thus, one should keep in mind that the relative contribution of PRA and PRB might contribute to the diverse and indispensable actions of progesterone in cellular events in humans. Furthermore, nuclear PRs exist in additional isoforms each with varying intracellular domains (Figure ). Although PRC, PRM, and PRS have been identified in human myometrial cells in vitro, , the essential role of these PR isoforms in the uterus in vivo is unknown.Progesterone also acts through different membrane-bound PRs that mediate non-genomic activities (Figure ). Although the membrane-bound PRs appear to be expressed and regulated in normal human endometrium in a cycle-dependent manner.