In this retrospective study, we investigated multiple glucose metabolism parameters in patients undergoing ART with RPL and/or RIF. We found the simple RPL group and the simple RIF group had significantly higher 2hPG than the control group. Patients with RPL history, no matter with or without RIF history, had significantly higher FINS, HOMA-IR and HOMA-β, while the FINS, AUCI, HOMA-IR and HOMA-β of the simple RIF group were at the lowest level. The incidences of insulin resistance were significantly higher in the simple RPL group and complicated group. After adjusted for age and WHR, FINS and HOMA-β were of the lowest level in the simple RIF group were the highest level in the simple RPL group. In the simple RIF group, the FINS tended to increase with times of implantation failure among those patients with six or fewer times implantation failure history, while those with more than six times implantation failure history have a significantly lower level of FINS, and similar tendencies were observed in HOMA-IR and HOMA-β but without significance.
The relationship between IR and idiopathic RPL is controversial. Studies revealed that patients with RPL have a significantly increased prevalence of IR than the fertile controls[13, 14, 21]. Other clinical investigations showed that IR may be the risk factor for early-stage embryonic miscarriage of PCOS patients[22–24]. Metformin, a sensitizer of insulin, has been reported to be contributive to the reduction of IR and reduction of miscarriage rate[22, 24]. However, Diejomaoh et al demonstrated that insulin resistance was not significantly associated with the recurrent spontaneous abortion of unknown aetiology. Abnormal glucose levels may be also involved in the etiology of RPL. Diabetic women with good metabolic control were less likely than nondiabetic women to occur the loss of pregnancy, but diabetic women with elevated blood glucose and glycosylated hemoglobin levels in the first trimester have a significantly increased risk of having a spontaneous abortion. Zolghadri et al found that patients with RSA were found to have an abnormal glucose tolerance test result compared with patients in the normal pregnancy group. Romero et al demonstrated a glycemic control marker serum fructosamine was increased in women with RPL. The results of our study was consistent with the above mentioned reports that IR was related to RPL.
Few studies involve the relation between IR and RIF directly. Studies found that ART outcomes such as implantation rate, pregnancy rate, and live birth rate were impaired in IR patients with PCOS[16–18], or even in IR patients without PCOS. Chang et al found that the effects of hyperinsulinemia on endometrial function and implantation process maybe underlie the significant decrease in ART outcomes in IR patients with PCOS.
The hypothesized reasons of IR on ART failure in both RIF and RPL were that IR may be related to the decreased oocyte quality[30, 31], poor embryonic development[32, 33] and decreased endometrial receptivity[34–36].
As an important part of endometrial receptivity, the endometrial decidual process is fundamental for functional fetomaternal interface formation. It maintains tissue homeostasis in the process of endovascular trophoblast invasion and provides tissue resistance to stress signals, including protection against oxidative cell death. Abnormal endometrial decidualization leads to abnormal implantation/placentation and ultimately to clinical disease such as abortion. Frolova et al demonstrated lower glucose availability leads to lower decidualization marker expression, abnormal glucose metabolism leads to inefficient decidualization both in vitro and in vivo. That may be an important cause of incomplete embryo implantation and miscarriages. IR and hyperinsulinemia may influence decidualization by multiple factors like prokineticin 1, forkhead-O1, insulin-like growth factor binding protein-1, hox gene A10 and endometrial protein PP14. A study conducted by Hu et al on pregnant rats demonstrated that insulin resistance induced damage mediated by mitochondria as well as the subsequent imbalance of oxidative stress responses in the gravid uterus. Oocyte quality is another key factor of female fertility, studies have suggested that a changed maternal metabolic environment leads to an abnormal follicular fluid microenvironment, and afterwards poor oocyte and embryo quality. Another study found ascending level of insulin coexisted with ascending C-reactive protein level in follicular fluid implying the status of inflammation and increased oxidative stress, which was associated with declined developmental potential in the oocyte. Ou et al studied an insulin-resistant mouse model, finding that IR contributed to oxidative stress and damaged mitochondrial function in mouse oocytes, which may disturb the accurate transmission of mtDNA in intergeneration. Therefore, it resulted in poor oocyte quality and detrimental embryonic development of insulin-resistant mice[33, 45].
In the present study, the FINS levels of the simple RIF group had a significant decline with more than six times implantation failure history, and similar tendencies were observed in HOMA-IR and HOMA-β. This finding may indicate a dysfunction of the pancreatic β cells, which has been less studied. Only a few studies have reported the loss function of the pancreatic β cells were due to abnormal DNA methylation of CD4 T cells, T-reg cells, or NK cells in latent autoimmune diabetes in adults, and this abnormal glucose metabolism finally has adverse effects on pregnancy. The autoimmune thyroid disease and autoimmune diabetes usually exist in the same individual due to a strongly shared genetic susceptibility. Alecsandru et al studied patients with RIF or RPL in ART. All the patients had a normal metabolic state before ART under the indices of HbA1c, fasting glucose and insulin level. Eighty-five percent of these patients had thyroid autoimmune disease and a family history of diabetes mellitus (100%), and 70% had a low level of 2 hours’ insulin secretion after OGTT. They deduced patients with agnogenic RPL or RIF with thyroid autoimmune disorders, family history of diabetes mellitus and abnormal insulin response after glucose load could be taken as the same subset of patients. Thus, we can also suppose that insulin secretion impairment may be related to RIF.
Being a retrospective study, a well-designed prospective study would be necessary to clarify the role of IR in RPL and RIF.