Abstract
Estrogen and progesterone and their signaling mechanisms are tightly regulated to maintain a normal menstrual cycle and to support a successful pregnancy. The imbalance of estrogen and progesterone disrupts their complex regulatory mechanisms, leading to estrogen dominance and progesterone resistance. Gynecological diseases are heavily associated with dysregulated steroid hormones and can induce chronic pelvic pain, dysmenorrhea, dyspareunia, heavy bleeding, and infertility, which substantially impact the quality of women’s lives. Because the menstrual cycle repeatably occurs during reproductive ages with dynamic changes and remodeling of reproductive-related tissues, these alterations can accumulate and induce chronic and recurrent conditions. This review focuses on faulty progesterone signaling mechanisms and cellular responses to progesterone in endometriosis, adenomyosis, leiomyoma (uterine fibroids), polycystic ovary syndrome (PCOS), and endometrial hyperplasia. We also summarize the association with gene mutations and steroid hormone regulation in disease progression as well as current hormonal therapies and the clinical consequences of progesterone resistance.
Highlights
Can directly bind to PRA, ARID1A is essential for normal endometrial functions and reduced ARID1A expression can alter progesterone receptors (PGR) signaling leading to progesterone resistance in the endometrium with endometriosis [125]
Increased collagen expression by miR-29b is not sufficient for the transformation from myometrial cells to leiomyoma cells, 17β-estradiol and progesterone decrease miR-29b and increase multiple collagen expressions. These results suggest that miR-29R is one of the critical factors to produce extracellular matrix (ECM) accumulation regulated by steroid hormones in leiomyoma
polycystic ovary syndrome (PCOS) when the endometrium is subject to prolonged estrogen exposure that is unopposed to subsequent progesterone signaling due to insufficient hormone production or PGR
Summary
Female mice with ablation of Pgr (PGRKO) clearly show complete sterility with multiple abnormalities in reproductive functions: ovulation failure, hyperplastic uterine response to estrogen and progesterone, decidualization failure, disruption of mammary gland development, and a lack of sexual behavior [2]. The endometrium is sensitive to environmental cues (including endocrine-disrupting exposure), inflammatory signals, and other unknown factors which alter and dysregulate hormone-derived endometrial cellular functions. These lead to changes in downstream gene expression and epigenetic marks which further complicate endometrial tissue regulation by establishing a hormone-insensitive environment [12,16,17,18,19]. We focus on summarizing the established and putative gene mutations and misregulation of steroid hormone signaling in disease progression, as well as current hormonal therapies and the clinical consequences of progesterone resistance (Table 1)
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