Homeostatic Model Assessment for Insulin Resistance Is Associated With Late Miscarriage in Non-Dyslipidemic Women Undergoing Fresh IVF/ICSI Embryo Transfer.
Frontiers in endocrinology
Objective:To evaluate the associations between homeostatic model assessment for insulin resistance (HOMA-IR) and pregnancy outcomes in non-dyslipidemic infertile women undergoing fertilization/intracytoplasmic sperm injection-embryo transfer (IVF/ICSI-ET). Materials and Methods:This is a retrospective study involving 3,615 non-dyslipidemic infertile women who attend to the Reproductive Medicine Center of Xiangya Hospital, Central South University (CSU) between January 2014 and October 2021. Eligible participants were divided into three groups according to the quartiles of HOMA-IR: Group 1 (HOMA-IR <1.46), Group 2 (1.46 to <2.71) and Group 3 (HOMA-IR ≥2.71). Baseline data, clinical characteristics during the assisted reproductive technology (ART) procedure, pregnancy, and neonatal outcomes were compared among the three groups. Subgroup analysis based on presence or absence of the polycystic ovary syndrome (PCOS) status was also performed to analyze the effects of HOMA-IR among non-PCOS populations. Results:The late miscarriage rate and percentage of macrosomia increased with the HOMA-IR group (for late miscarriage rate: 2.23% vs. 3.04% vs. 7.35%, P<0.001; for macrosomia: 0.21% vs. 1.70% vs. 3.23%, P=0.002). Increased HOMA-IR (HOMA-IR≥2.71) was positively associated with late miscarriage (crude OR 3.50, 95% CI 1.64-7.47, P=0.001; adjusted OR 3.56, 95% CI 1.56-8.15, P=0.003). In the subgroup analysis, there were 3,165 participants in the non-PCOS group and 450 were assigned to the PCOS group. Late miscarriage rate increased with the HOMA-IR group among non-PCOS populations (2.20% vs. 3.03% vs. 7.67%, P<0.001). Late miscarriage rate of PCOS women were comparable among the three HOMA-IR groups (2.50% vs. 3.06% vs. 5.71%, P=0.634). Among non-PCOS women, increased HOMA-IR (HOMA-IR≥2.71) was positively associated with late miscarriage (crude OR 3.71, 95% CI 1.66-8.30, P=0.001; adjusted OR 3.82, 95% CI 1.59-9.17, P=0.003). Conclusions:Late miscarriage rate and prevalence of macrosomia increased with the HOMA-IR index. Preconception HOMA-IR is an independent risk factor for late miscarriage in normolipidemic women undergoing IVF/ICSI-ET. Controlling insulin resistance before ART might prevent the occurrence of late miscarriage and macrosomia.
10.3389/fendo.2022.880518
Advances in the study of the correlation between insulin resistance and infertility.
Frontiers in endocrinology
This is a narrative review of the progress of research on the correlation between insulin resistance and infertility. Insulin resistance (IR) is not only involved in the development of various metabolic diseases, but also affects female reproductive function, and to some extent is closely related to female infertility. IR may increase the risk of female infertility by activating oxidative stress, interfering with energy metabolism, affecting oocyte development, embryo quality and endometrial tolerance, affecting hormone secretion and embryo implantation, as well as affecting assisted conception outcomes in infertile populations and reducing the success rate of assisted reproductive technology treatment in infertile populations. In addition, IR is closely associated with spontaneous abortion, gestational diabetes and other adverse pregnancies, and if not corrected in time, may increase the risk of obesity and metabolic diseases in the offspring in the long term. This article provides a review of the relationship between IR and infertility to provide new ideas for the treatment of infertility.
10.3389/fendo.2024.1288326
Hyperandrogenism and insulin resistance-induced fetal loss: evidence for placental mitochondrial abnormalities and elevated reactive oxygen species production in pregnant rats that mimic the clinical features of polycystic ovary syndrome.
Zhang Yuehui,Zhao Wei,Xu Hongfei,Hu Min,Guo Xiaozhu,Jia Wenyan,Liu Guoqi,Li Juan,Cui Peng,Lager Susanne,Sferruzzi-Perri Amanda Nancy,Li Wei,Wu Xiao-Ke,Han Yanhua,Brännström Mats,Shao Linus R,Billig Håkan
The Journal of physiology
KEY POINTS:Women with polycystic ovary syndrome (PCOS) commonly suffer from miscarriage, but the underlying mechanisms remain unknown. Herein, pregnant rats chronically treated with 5α-dihydrotestosterone (DHT) and insulin exhibited hyperandrogenism and insulin resistance, as well as increased fetal loss, and these features are strikingly similar to those observed in pregnant PCOS patients. Fetal loss in our DHT+insulin-treated pregnant rats was associated with mitochondrial dysfunction, disturbed superoxide dismutase 1 and Keap1/Nrf2 antioxidant responses, over-production of reactive oxygen species (ROS) and impaired formation of the placenta. Chronic treatment of pregnant rats with DHT or insulin alone indicated that DHT triggered many of the molecular pathways leading to placental abnormalities and fetal loss, whereas insulin often exerted distinct effects on placental gene expression compared to co-treatment with DHT and insulin. Treatment of DHT+insulin-treated pregnant rats with the antioxidant N-acetylcysteine improved fetal survival but was deleterious in normal pregnant rats. Our results provide insight into the fetal loss associated with hyperandrogenism and insulin resistance in women and suggest that physiological levels of ROS are required for normal placental formation and fetal survival during pregnancy. ABSTRACT:Women with polycystic ovary syndrome (PCOS) commonly suffer from miscarriage, but the underlying mechanism of PCOS-induced fetal loss during pregnancy remains obscure and specific therapies are lacking. We used pregnant rats treated with 5α-dihydrotestosterone (DHT) and insulin to investigate the impact of hyperandrogenism and insulin resistance on fetal survival and to determine the molecular link between PCOS conditions and placental dysfunction during pregnancy. Our study shows that pregnant rats chronically treated with a combination of DHT and insulin exhibited endocrine aberrations such as hyperandrogenism and insulin resistance that are strikingly similar to those in pregnant PCOS patients. Of pathophysiological significance, DHT+insulin-treated pregnant rats had greater fetal loss and subsequently decreased litter sizes compared to normal pregnant rats. This negative effect was accompanied by impaired trophoblast differentiation, increased glycogen accumulation, and decreased angiogenesis in the placenta. Mechanistically, we report that over-production of reactive oxygen species (ROS) in the placenta, mitochondrial dysfunction, and disturbed superoxide dismutase 1 (SOD1) and Keap1/Nrf2 antioxidant responses constitute important contributors to fetal loss in DHT+insulin-treated pregnant rats. Many of the molecular pathways leading to placental abnormalities and fetal loss in DHT+insulin treatment were also seen in pregnant rats treated with DHT alone, whereas pregnant rats treated with insulin alone often exerted distinct effects on placental gene expression compared to insulin treatment in combination with DHT. We also found that treatment with the antioxidant N-acetylcysteine (NAC) improved fetal survival in DHT+insulin-treated pregnant rats, an effect related to changes in Keap1/Nrf2 and nuclear factor-κB signalling. However, NAC administration resulted in fetal loss in normal pregnant rats, most likely due to PCOS-like endocrine abnormality induced by the treatment. Our results suggest that the deleterious effects of hyperandrogenism and insulin resistance on fetal survival are related to a constellation of mitochondria-ROS-SOD1/Nrf2 changes in the placenta. Our findings also suggest that physiological levels of ROS are required for normal placental formation and fetal survival during pregnancy.
10.1113/JP277879
Endometrial function in women with polycystic ovary syndrome: a comprehensive review.
Palomba Stefano,Piltonen Terhi T,Giudice Linda C
Human reproduction update
BACKGROUND:Polycystic ovary syndrome (PCOS) is the most common cause of anovulatory infertility. An endometrial component has been suggested to contribute to subfertility and poor reproductive outcomes in affected women. OBJECTIVE AND RATIONALE:The aim of this review was to determine whether there is sufficient evidence to support that endometrial function is altered in women with PCOS, whether clinical features of PCOS affect the endometrium, and whether there are evidence-based interventions to improve endometrial dysfunction in PCOS women. SEARCH METHODS:An extensive literature search was performed from 1970 up to July 2020 using PubMed and Web of Science without language restriction. The search included all titles and abstracts assessing a relationship between PCOS and endometrial function, the role played by clinical and biochemical/hormonal factors related to PCOS and endometrial function, and the potential interventions aimed to improve endometrial function in women with PCOS. All published papers were included if considered relevant. Studies having a specific topic/hypothesis regarding endometrial cancer/hyperplasia in women with PCOS were excluded from the analysis. OUTCOMES:Experimental and clinical data suggest that the endometrium differs in women with PCOS when compared to healthy controls. Clinical characteristics related to the syndrome, alone and/or in combination, may contribute to dysregulation of endometrial expression of sex hormone receptors and co-receptors, increase endometrial insulin-resistance with impaired glucose transport and utilization, and result in chronic low-grade inflammation, immune dysfunction, altered uterine vascularity, abnormal endometrial gene expression and cellular abnormalities in women with PCOS. Among several interventions to improve endometrial function in women with PCOS, to date, only lifestyle modification, metformin and bariatric surgery have the highest scientific evidence for clinical benefit. WIDER IMPLICATIONS:Endometrial dysfunction and abnormal trophoblast invasion and placentation in PCOS women can predispose to miscarriage and pregnancy complications. Thus, patients and their health care providers should advise about these risks. Although currently no intervention can be universally recommended to reverse endometrial dysfunction in PCOS women, lifestyle modifications and metformin may improve underlying endometrial dysfunction and pregnancy outcomes in obese and/or insulin resistant patients. Bariatric surgery has shown its efficacy in severely obese PCOS patients, but a careful evaluation of the benefit/risk ratio is warranted. Large scale randomized controlled clinical trials should address these possibilities.
10.1093/humupd/dmaa051
Insulin Resistance is a Risk Factor for Early Miscarriage and Macrosomia in Patients With Polycystic Ovary Syndrome From the First Embryo Transfer Cycle: A Retrospective Cohort Study.
Frontiers in endocrinology
Objective:The objective of the study was to explore the effect of insulin resistance on pregnancy outcomes in patients with polycystic ovary syndrome (PCOS) from the first embryo transfer cycle. Design:This was a single-center, retrospective, observational cohort study. Patients:Included in the study were women with PCOS for the first embryo transfer. Main Outcome Measures:Early miscarriage rate and macrosomia rate were the main outcome measures. Results:With increased HOMA-IR, the early miscarriage rate (7.14, 13.21, and 16.22%, respectively; = 0.039), macrosomia rate (5.78, 11.79, and 17.58%, respectively; = 0.026) and the incidence of gestational diabetes (GDM) (10.00, 14.50, and 25.67% respectively; = 0.002) significantly increased, while the live birth rate markedly decreased (63.03, 55.27, and 47.88%, respectively; = 0.004). No significant difference was found in clinical pregnancy rate, late miscarriage rate, low birthweight rate and baby gender ratio (all 0.05). After adjusting for confounding factors, HOMA-IR was an independent risk factor of early miscarriage rate and macrosomia rate. Conclusion:Insulin resistance is an independent risk factor for early miscarriage and macrosomia in PCOS patients during the first embryo transfer cycle. It is essential to give more attention before and after pregnancy for PCOS women with high HOMA-IR.
10.3389/fendo.2022.853473
Chronic Low Grade Inflammation in Pathogenesis of PCOS.
Rudnicka Ewa,Suchta Katarzyna,Grymowicz Monika,Calik-Ksepka Anna,Smolarczyk Katarzyna,Duszewska Anna M,Smolarczyk Roman,Meczekalski Blazej
International journal of molecular sciences
Polycystic ovary syndrome (PCOS) is a one of the most common endocrine disorders, with a prevalence rate of 5-10% in reproductive aged women. It's characterized by (1) chronic anovulation, (2) biochemical and/or clinical hyperandrogenism, and (3) polycystic ovarian morphology. PCOS has significant clinical implications and can lead to health problems related to the accumulation of adipose tissue, such as obesity, insulin resistance, metabolic syndrome, and type 2 diabetes. There is also evidence that PCOS patients are at higher risk of cardiovascular diseases, atherosclerosis, and high blood pressure. Several studies have reported the association between polycystic ovary syndrome (PCOS) and low-grade chronic inflammation. According to known data, inflammatory markers or their gene markers are higher in PCOS patients. Correlations have been found between increased levels of C-reactive protein (CRP), interleukin 18 (IL-18), tumor necrosis factor (TNF-α), interleukin 6 (IL-6), white blood cell count (WBC), monocyte chemoattractant protein-1 (MCP-1) and macrophage inflammatory protein-1α (MIP-1α) in the PCOS women compared with age- and BMI-matched controls. Women with PCOS present also elevated levels of AGEs and increased RAGE (receptor for advanced glycation end products) expression. This chronic inflammatory state is aggravating by obesity and hyperinsulinemia. There are studies describing mutual impact of hyperinsulinemia and obesity, hyperandrogenism, and inflammatory state. Endothelial cell dysfunction may be also triggered by inflammatory cytokines. Many factors involved in oxidative stress, inflammation, and thrombosis were proposed as cardiovascular risk markers showing the endothelial cell damage in PCOS. Those markers include asymmetric dimethylarginine (ADMA), C-reactive protein (CRP), homocysteine, plasminogen activator inhibitor-I (PAI-I), PAI-I activity, vascular endothelial growth factor (VEGF) etc. It was also proposed that the uterine hyperinflammatory state in polycystic ovary syndrome may be responsible for significant pregnancy complications ranging from miscarriage to placental insufficiency. In this review, we discuss the most importance evidence concerning the role of the process of chronic inflammation in pathogenesis of PCOS.
10.3390/ijms22073789
Polycystic ovary syndrome.
The lancet. Diabetes & endocrinology
Polycystic ovary syndrome (PCOS) affects 5-18% of women, and is a reproductive, metabolic, and psychological condition with impacts across the lifespan. The cause is complex, and includes genetic and epigenetic susceptibility, hypothalamic and ovarian dysfunction, excess androgen exposure, insulin resistance, and adiposity-related mechanisms. Diagnosis is recommended based on the 2003 Rotterdam criteria and confirmed with two of three criteria: hyperandrogenism (clinical or biochemical), irregular cycles, and polycystic ovary morphology. In adolescents, both the criteria of hyperandrogenism and irregular cycles are needed, and ovarian morphology is not included due to poor specificity. The diagnostic criteria generates four phenotypes, and clinical features are heterogeneous, with manifestations typically arising in childhood and then evolving across adolescent and adult life. Treatment involves a combination of lifestyle alterations and medical management. Lifestyle optimisation includes a healthy balanced diet and regular exercise to prevent excess weight gain, limit PCOS complications and target weight reduction when needed. Medical management options include metformin to improve insulin resistance and metabolic features, combined oral contraceptive pill for menstrual cycle regulation and hyperandrogenism, and if needed, anti-androgens for refractory hyperandrogenism. In this Review, we provide an update on the pathophysiology, diagnosis, and clinical features of PCOS, and discuss the needs and priorities of those with PCOS, including lifestyle, and medical and infertility treatment. Further we discuss the status of international evidence-based guidelines (EBG) and translation, to support patient self management, healthcare provision, and to set research priorities.
10.1016/S2213-8587(22)00163-2
Insulin resistance in women with recurrent miscarriage: a systematic review and meta-analysis.
BMC pregnancy and childbirth
PURPOSE:This review aimed to investigate the association of insulin resistance (IR) in women with recurrent pregnancy loss compared to women with normal pregnancy history. METHODS:PubMed, EMBASE, the Web of Science and Google Scholar databases were accessed to collect published observational studies that compared IR of recurrent pregnancy loss women with healthy women until the 6 of October 2022. Outcomes assessed in this review and meta-analysis included fasting blood glucose, fasting plasma insulin, homeostasis model assessment for IR, glucose to insulin ratio. Mean differences, odds ratios with 95% confidence interval were pooled using the fixed or random effect models. Sensitivity analyses were performed to validate the robustness of the results. Review Manager version 5.4.1 and Stata version 8.0 were used. RESULTS:A total of nineteen studies involving 4453 individuals were included. Recurrent pregnancy loss patients presented significantly higher fasting blood glucose, fasting plasma insulin, homeostasis model assessment for IR, and lower glucose to insulin ratios. Additionally, recurrent pregnancy loss patients had higher rates of IR as defined by abnormal fasting plasma insulin, homeostasis model assessment for IR, and glucose to insulin ratio. Sensitivity analyses validated the robustness of the results. CONCLUSION:In the current review, we show that recurrent pregnancy loss is associated with a higher degree of IR and highlight the importance of screening and treatment of IR.
10.1186/s12884-022-05256-z