Endometriosis is one of the most common disorders that causes infertility in women. Iron is overloaded in endometriosis peritoneal fluid (PF), with harmful effects on early embryo development. However, the mechanism by which endometriosis peritoneal fluid affects embryonic development remains unclear. Hence, this study investigated the effect of iron overload on mouse embryos and elucidated the molecular mechanism. Iron overload in endometriosis PF disrupted blastocyst formation, decreased GPX4 expression and induced lipid peroxidation, suggesting that iron overload causes embryotoxicity and induces ferroptosis. Moreover, mitochondrial damage occurs in iron overload-treated embryos, presenting as decreased ATP levels, increased ROS levels and MMP hyperpolarization. The cytotoxicity of iron overload is attenuated by the ferroptosis inhibitor Fer-1. Furthermore, Smart-seq analysis revealed that HMOX1 is upregulated in embryo ferroptosis and that HMOX1 suppresses ferroptosis by maintaining mitochondrial function. This study provides new insight into the mechanism of endometriosis infertility and a potential target for future endometriosis infertility treatment efforts.

Estrogen plays a prominent role in regulating and coordinating energy homeostasis throughout the growth, development, reproduction, and aging of women. Estrogen receptors (ERs) are widely expressed in the brain and nearly all tissues of the body. Within the brain, central estrogen via ER regulates appetite and energy expenditure and maintains cell glucose metabolism, including glucose transport, aerobic glycolysis, and mitochondrial function. In the whole body, estrogen has shown beneficial effects on weight control, fat distribution, glucose and insulin resistance, and adipokine secretion. As demonstrated by multiple in vitro and in vivo studies, menopause-related decline of circulating estrogen may induce the disturbance of metabolic signals and a significant decrease in bioenergetics, which could trigger an increased incidence of late-onset Alzheimer’s disease, type 2 diabetes mellitus, hypertension, and cardiovascular diseases in postmenopausal women. In this article, we have systematically reviewed the role of estrogen and ERs in body composition and lipid/glucose profile variation occurring with menopause, which may provide a better insight into the efficacy of hormone therapy in maintaining energy metabolic homeostasis and hold a clue for development of novel therapeutic approaches for target tissue diseases.

We and others have previously shown that abnormal pelvic environment plays an important role in the unexplained infertility of endometriosis. However, whether iron overload caused by ectopic periodic bleeding found in patients with endometriosis participates in endometriosis-associated reproductive failure is unknown. This study aimed to investigate effects of iron at level relevant to pelvic iron overload on the development of preimplantation mouse embryo. Two-cell embryos were collected, and cultured to blastocysts in G1/G2 medium supplemented with iron alone or in combination with iron chelator. The development rates, ATP level, mitochondrial membrane potential (MMP), reactive oxygen species level (ROS), and apoptotic and ferroptotic indices were compared between control and iron treatments across each specific developmental stage. Prolonged exposure to iron remarkably impaired early embryo development in vitro by hampering blastocyst formation (P < 0.001), which could be partly restored by iron chelator (P < 0.001). The arrest of embryo development was linked with iron-initiated mitochondrial dysfunction with reduction of ATP generation and MMP (P < 0.05 and P < 0.001, respectively). Impaired mitochondria altered ROS accumulation post-iron exposure at morula stage and blastocyst stage (P < 0.05). Moreover, Iron-exposed blastocyst stage embryos showed higher apoptotic and ferroptotic rates (P < 0.001 and P < 0.05, respectively). Our results highlight that pathologically relevant level of iron compromises preimplantation mouse embryo development by disrupting mitochondrial function and triggering both apoptosis and ferroptosis, which implicates that excess iron found in peritoneal fluid of women with endometriosis likely participates in endometriosis-associated reproductive failure.

During the in vitro fertilization treatment, human chorionic gonadotrophin (hCG) is routinely used as a substitute for the natural endogenous LH surge during the final stage of oocyte maturation. However, it does not provide the FSH surge observed in the mid‐cycle of the natural cycle. To date, whether the FSH surge can improve oocyte quality and pregnancy outcomes remains unknown. Randomized controlled trials comparing the following four trigger methods to conventional hCG were examined: GnRH agonist (GnRHa), kisspeptin, GnRHa plus hCG (dual trigger), and FSH plus hCG (FSH co‐trigger). The results showed that the use of dual triggers was associated with a significantly higher number of retrieved cumulus‐oocyte complexes (COCs) (weighted mean difference [WMD] 1.625, 95% CI 0.684‐2.565), retrieved mature oocytes (WMD 0.986, 95% CI 0.426‐1.545) and fertilized (2PN) oocytes (WMD 0.792, 95% CI 0.083‐1.501), compared with the use of hCG. However, there was no significant difference between the two groups in terms of pregnancy rate. The FSH co‐trigger resulted in significantly higher rates of 2PN oocytes retrieved than the hCG trigger (WMD 0.077, 95% CI 0.028‐0.126). Notably, the risk of OHSS did not differ among the three treatment groups compared to that of the hCG group. This review protocol was registered with PROSPERO (CRD 42020194201).

Infertility is a social and medical problem around the world and the incidence continues to rise. Thin endometrium (TE) is a great challenge of infertility treatment, even by in vitro fertilization and embryo transfer. It is widely believed that TE impairs endometrium receptivity. However, only a few studies have explained the molecular mechanism. Herein, in order to reveal the possible mechanism, we sampled endometrium from a TE patient and a control volunteer and got a transcriptomic atlas of 18 775 individual cells which was constructed using single‐cell RNA sequencing, and seven cell types have been identified. The cells were acquired during proliferative and secretory phases, respectively. The proportion of epithelial cells and stromal cells showed a significant difference between the TE group and the control group. In addition, differential expressed genes (DEGs) in diverse cell types were revealed, the enriched pathways of DEGs were found closely related to the protein synthesis in TE of both proliferative and secretory phases. Some DEGs can influence cell‐type ratio and impaired endometrial receptivity in TE. Furthermore, divergent expression of estrogen receptors 1 and progesterone receptors in stromal and epithelial cells were compared in the TE sample from the control. The cellular and molecular heterogeneity found in this study provided valuable information for disclosing the mechanisms of impaired receptivity in TE.

Evaluation of tubal patency is one of the vital steps in the process of female infertility management. Hysterosalpingo-contrast Sonography (HyCoSy) has become the first-line recommendation for evaluating tubal patency. However, there remain some controversies and dilemmas relevant to the evaluation of tubal patency by HyCosy, with no effective solution has been proposed or no consensus has been reached. Herein, combined with previous research and clinical experience, we conclude and analyze these controversies and dilemmas, aiming at offering our perspective on the opportunities and challenges which are faced by HyCosy.