The endoplasmic reticulum (ER), comprises 60% of the total cell membrane and interacts directly or indirectly with several cell organelles i.e., Golgi bodies, mitochondria and proteasomes. The ER is usually associated with large numbers of attached ribosomes. During evolution, ER developed as the specific cellular site of synthesis, folding, modification and trafficking of secretory and cell-surface proteins. The ER is also the major intracellular calcium storage compartment that maintains cellular calcium homeostasis. During the production of functionally effective proteins, several ER-specific molecular steps sense quantity and quality of synthesized proteins as well as proper folding into their native structures. During this process, excess accumulation of unfolded/misfolded proteins in the ER lumen results in ER stress, the homeostatic coping mechanism that activates an ER-specific adaptation program, (the unfolded protein response; UPR) to increase ER-associated degradation of structurally and/or functionally defective proteins, thus sustaining ER homeostasis. Impaired ER homeostasis results in aberrant cellular responses, contributing to the pathogenesis of various diseases. Both female and male reproductive tissues undergo highly dynamic cellular, molecular and genetic changes such as oogenesis and spermatogenesis starting in prenatal life, mainly controlled by sex-steroids but also cytokines and growth factors throughout reproductive life. These reproductive changes require ER to provide extensive protein synthesis, folding, maturation and then their trafficking to appropriate cellular location as well as destroying unfolded/misfolded proteins via activating ER-associated degradation mediated proteasomes. Many studies have now shown roles for ER stress/UPR signaling cascades in the endometrial menstrual cycle, ovarian folliculogenesis and oocyte maturation, spermatogenesis, fertilization, pre-implantation embryo development and pregnancy and parturition. Conversely, the contribution of impaired ER homeostasis by severe/prolong ER stress-mediated UPR signaling pathways to several reproductive tissue pathologies including endometriosis, cancers, recurrent pregnancy loss and pregnancy complications associated with pre-term birth have been reported. This review focuses on ER stress and UPR signaling mechanisms, and their potential roles in female and male reproductive physiopathology involving in menstrual cycle changes, gametogenesis, preimplantation embryo development, implantation and placentation, labor, endometriosis, pregnancy complications and preterm birth as well as reproductive system tumorigenesis.

Significance: Preterm birth (PTB) is the leading cause of neonatal morbidity and mortality. The genetics and molecular characteristics of PTB remain unclear. FKBP51 is an important mediator of the stress response and is implicated in the etiology of stress-related disorders. By combining studies in humans and Fkbp5 ^−/− mice, we show that maternal stress up-regulates FKBP51 levels and enhances binding of FKBP51 to progesterone receptors. FKBP51 binding to progesterone receptors reduces progesterone receptor activity by causing functional progesterone withdrawal that induces PTB. In contrast, Fkbp5 ^−/− mice are resistant to maternal stress–induced PTB and exhibit prolonged gestation. These findings provide molecular insights into stress-related PTB, indicating the importance of the potential use of inhibitor(s) against FKBP51 to treat PTB in future studies.

Progestin-only long-acting reversible-contraceptive (pLARC)-exposed endometria displays decidualized human endometrial stromal cells (HESCs) and hyperdilated thin-walled fragile microvessels. The combination of fragile microvessels and enhanced tissue factor levels in decidualized HESCs generates excess thrombin, which contributes to abnormal uterine bleeding (AUB) by inducing inflammation, aberrant angiogenesis, and proteolysis. The- zinc finger and BTB domain containing 16 (ZBTB16) has been reported as an essential regulator of decidualization. Microarray studies have demonstrated that ZBTB16 levels are induced by medroxyprogesterone acetate (MPA) and etonogestrel (ETO) in cultured HESCs. We hypothesized that pLARC-induced ZBTB16 expression contributes to HESC decidualization, whereas prolonged enhancement of ZBTB16 levels triggers an inflammatory milieu by inducing pro-inflammatory gene expression and tissue-factor-mediated thrombin generation in decidualized HESCs. Thus, ZBTB16 immunostaining was performed in paired endometria from pre- and post-depo-MPA (DMPA)-administrated women and oophorectomized guinea pigs exposed to the vehicle, estradiol (E₂), MPA, or E₂ + MPA. The effect of progestins including MPA, ETO, and levonorgestrel (LNG) and estradiol + MPA + cyclic-AMP (E₂ + MPA + cAMP) on ZBTB16 levels were measured in HESC cultures by qPCR and immunoblotting. The regulation of ZBTB16 levels by MPA was evaluated in glucocorticoid-receptor-silenced HESC cultures. ZBTB16 was overexpressed in cultured HESCs for 72 h followed by a ± 1 IU/mL thrombin treatment for 6 h. DMPA administration in women and MPA treatment in guinea pigs enhanced ZBTB16 immunostaining in endometrial stromal and glandular epithelial cells. The in vitro findings indicated that: (1) ZBTB16 levels were significantly elevated by all progestin treatments; (2) MPA exerted the greatest effect on ZBTB16 levels; (3) MPA-induced ZBTB16 expression was inhibited in glucocorticoid-receptor-silenced HESCs. Moreover, ZBTB16 overexpression in HESCs significantly enhanced prolactin (PRL), insulin-like growth factor binding protein 1 (IGFBP1), and tissue factor (F3) levels. Thrombin-induced interleukin 8 (IL-8) and prostaglandin-endoperoxide synthase 2 (PTGS2) mRNA levels in control-vector-transfected HESCs were further increased by ZBTB16 overexpression. In conclusion, these results supported that ZBTB16 is enhanced during decidualization, and long-term induction of ZBTB16 expression by pLARCs contributes to thrombin generation through enhancing tissue factor expression and inflammation by enhancing IL-8 and PTGS2 levels in decidualized HESCs.

Prenatal stress (PNS) impairs offspring ovarian development by exerting negative long-term effects on postnatal ovarian function and folliculogenesis. FKBP51 is a stress-responsive protein that inhibits glucocorticoid and progesterone receptors. We hypothesize that FKBP51 contributes to impaired ovarian development and folliculogenesis induced by PNS. Timed-pregnant Fkbp5^+/+ (wild-type) and Fkbp5^−/− (knockout) mice were randomly assigned to either the undisturbed (nonstress) or PNS group, with exposure to maternal restraint stress from embryonic days 8 to 18. Ovaries from the offspring were harvested and stained, and follicles were counted according to their stages. Ovarian expressions of FKBP51 were evaluated by immunohistochemistry and Fkbp5 and steroidogenic enzymes were evaluated by qPCR. Compared to controls, Fkbp5^+/+ PNS offspring had increased peripubertal primordial follicle atresia and fewer total follicles in the adult and middle-aged groups. In adult Fkbp5^+/+ offspring, PNS elevated FKBP51 levels in granulosa cells of primary to tertiary follicles. Our results suggest that PNS administration increased FKBP51 levels, depleted the ovarian reserve, and dysregulated ovarian steroid synthesis. However, these PNS effects were tolerated in Fkbp5^−/− mice, supporting the conclusion that FKBP51 contributes to reduced ovarian reserve induced by PNS.