Implantation and Decidualization in PCOS: Unraveling the Complexities of Pregnancy

Abstract

Polycystic Ovary Syndrome (PCOS) is a prevalent endocrine disorder in women of reproductive age, affecting 5-15% globally with a large proportion undiagnosed. This review explores the multifaceted nature of PCOS and its impact on pregnancy, including challenges in fertility due to hormonal imbalances and insulin resistance. Despite restoring ovulation pharmacologically, women with PCOS face lower pregnancy rates and higher risks of implantation failure and miscarriage. Our review focuses on the complexities of hormonal and metabolic imbalances that impair endometrial receptivity and decidualization in PCOS. Disrupted estrogen signaling, reduced integrity of endometrial epithelial tight junctions, and insulin resistance impair the window of endometrial receptivity. Furthermore, progesterone resistance adversely affects decidualization. Our review also examines the roles of various immune cells and inflammatory processes in the endometrium, contributing to the condition's reproductive challenges. Lastly, we discuss the use of rodent models in understanding PCOS, particularly those induced by hormonal interventions, offering insights into the syndrome's impact on pregnancy and potential treatments. This comprehensive review underscores the need for advanced understanding and treatment strategies to address the reproductive complications associated with PCOS, emphasizing its intricate interplay of hormonal, metabolic, and immune factors.

Keywords: PCOS; animal model; decidualization; implantation; pregnancy.

Figure 1

Diagram of the intricate signaling pathways involved in embryo implantation. In PCOS, abnormal expression of ESR1 increases Ki-67 expression in the endometrial epithelium and stroma, leading to decreased endometrial receptivity. LIF triggers the activation of JAK which in turn activates signal transducer and activator of STAT3 through phosphorylation. The role of the LIF-STAT3 pathway is characterized by inactivation in PCOS, which leads to the production of Ltf and Muc1, suggesting that the endometrium is in a non-receptive state. The dysregulation of the Wnt/β-catenin/Msx1 pathway impairs endometrial receptivity in PCOS and Msx1 is increased. Insulin resistance contributes to progesterone resistance and exacerbates issues with endometrial functionality. The abnormal expression of Ihh signaling in PCOS is depicted as a key factor affecting endometrial receptivity. Elevated androgen levels impact the integrity of tight junctions in the endometrial epithelium by decreasing Cldn4 and Cldn1. Insulin resistance impairs endometrial receptivity in PCOS, leading to mitochondrial dysfunction. A: Androgen; P4: Progesterone; E2: Estrogen; In: Insulin; P: phosphorylation.

Figure 2

Schematic illustration of the molecular signaling pathways involved in the transformation of stromal fibroblast cells to epithelioid-like decidual cells. The decidual reaction is initiated via a complex interplay of progesterone, estrogen, cAMP, and androgen. Androgen hormone, P4, and E2 cross the cell membrane and translocate into the nucleus to bind to their respective associated receptors. Within the nucleus, the expression of both PGR and ESR1 is mediated by cAMP signaling via a G-protein coupled receptor. PGR regulates downstream expression of HAND2, FOXO1, HOXA10, and BMP2. PLZF, another component of the signaling cascade governing cell motility, is activated by both AR and PGR. The AR receptor is regulated via the co-regulator MAGEA11 and controls expression of KLF9, KFL12, and PLZF. Estrogen signaling via ESR1 controls downstream expression of WNT4 via MED1, a subunit of the mediator coactivator complex. WNT4 plays a crucial role in decidualization through binding to a seven-pass transmembrane Frizzled receptor and activating the B-catenin pathway. A: androgen; P4: progesterone; E2: estrogen.