Inflammatory and Anti-Inflammatory Parameters in PCOS Patients Depending on Body Mass Index: A Case-Control Study.

BACKGROUND: it has been suggested that chronic low-grade inflammation plays an important role in the pathogenesis of polycystic ovary syndrome (PCOS). According to previous studies, it remains unclear which cytokines influence the development of this syndrome and whether their increase is associated with the presence of excess weight/obesity or is an independent factor. The aim of our research was to determine the parameters of chronic inflammation in women with PCOS in comparison with healthy women in the normal weight and the overweight subgroups. METHODS: This case-control study included 44 patients with PCOS (19 women with a body mass index (BMI) < 25 kg/m² and 25 women with a BMI ≥ 25 kg/m²) and 45 women without symptoms of PCOS (22 women with a BMI < 25 kg/m² and 23 women with a BMI ≥ 25 kg/m²). Thirty-two cytokines were analyzed in the plasma of the participants using Immunology multiplex assay HCYTA-60K-PX48 (Merck Life Science, LLC, Germany). RESULTS: Cytokines: interleukin-1 receptor antagonist (IL-1 RA), IL-2, IL-6, IL-17 E, IL-17 A, IL-18, and macrophage inflammatory protein-1 alpha (MIP-1 α) were increased in women with PCOS compared to controls, both in lean and overweight/obese subgroups (p < 0.05). Moreover, only lean women with PCOS had higher levels of IL-1 alpha, IL-4, IL-9, IL-12, IL-13, IL-15, tumor necrosis factor (TNF- α) alpha and beta, soluble CD40 and its ligand (SCD40L), fractalkine (FKN), monocyte-chemotactic protein 3 (MCP-3), and MIP-1 ß compared to the control group (p < 0.05). IL-22 was increased in the combined group of women with PCOS (lean and overweight/obese) compared to the control group (p = 0.012). CONCLUSION: Chronic low-grade inflammation is an independent factor affecting the occurrence of PCOS and does not depend on the presence of excess weight/obesity. For the first time, we obtained data on the increase in such inflammatory parameters as IL-9, MCP-3, and MIP-1α in women with PCOS.

Association of Common Genetic Risk Variants With Gestational Diabetes Mellitus and Their Role in GDM Prediction.

Objective: We aimed to explore the associations between common genetic risk variants with gestational diabetes mellitus (GDM) risk in Russian women and to assess their utility in the identification of GDM cases. Methods: We conducted a case-control study including 1,142 pregnant women (688 GDM cases and 454 controls) enrolled at Almazov National Medical Research Centre. The International Association of Diabetes and Pregnancy Study Groups criteria were used to diagnose GDM. A total of 11 single- nucleotide polymorphisms (SNPs), including those in HKDC1 (rs10762264), GCK (rs1799884), MTNR1B (rs10830963 and rs1387153), TCF7L2 (rs7903146 and rs12255372), KCNJ11 (rs5219), IGF2BP2 (rs4402960), IRS1 (rs1801278), FTO (rs9939609), and CDKAL1 (rs7754840) were genotyped using Taqman assays. A logistic regression model was used to calculate odds ratios (ORs) and their confidence intervals (CIs). A simple-count genetic risk score (GRS) was calculated using 6 SNPs. The area under the receiver operating characteristic curve (c-statistic) was calculated for the logistic regression model predicting the risk of GDM using clinical covariates, SNPs that had shown a significant association with GDM in our study, GRS, and their combinations. Results: Two variants in MTNR1B (rs1387153 and rs10830963) demonstrated a significant association with an increased risk of GDM. The association remained significant after adjustment for age, pre-gestational BMI, arterial hypertension, GDM in history, impaired glucose tolerance, polycystic ovary syndrome, family history of diabetes, and parity (P = 0.001 and P < 0.001, respectively). After being conditioned by each other, the effect of rs1387153 on GDM predisposition weakened while the effect of rs10830963 remained significant (P = 0.004). The risk of GDM was predicted by clinical variables (c-statistic 0.712, 95 % CI: 0.675 - 0.749), and the accuracy of prediction was modestly improved by adding GRS to the model (0.719, 95 % CI 0.682 - 0.755), and more by adding only rs10830963 (0.729, 95 % CI 0.693 - 0.764). Conclusion: Among 11 SNPs associated with T2D and/or GDM in other populations, we confirmed significant association with GDM for two variants in MTNR1B in Russian women. However, these variants showed limited value in the identification of GDM cases.

"All-In-One" Genetic Tool Assessing Endometrial Receptivity for Personalized Screening of Female Sex Steroid Hormones.

Endometrium is the uterine lining that undergoes hundreds of cycles of proliferation, differentiation, and desquamation throughout a woman's reproductive life. Recently, much attention is paid to the appropriate endometrial functioning, as decreased endometrial receptivity is stated to be one of the concerns heavily influencing successes of embryo implantation rates and the efficacy of in vitro fertilization (IVF) treatment. In order to acquire and maintain the desired endometrial receptivity during IVF cycles, luteal phase support by various progestagens or other hormonal combinations is generally recommended. However, today, the selection of the specific hormonal therapy during IVF seems to be empirical, mainly due to a lack of appropriate tools for personalized approach. Here, we designed the genetic tool for patient-specific optimization of hormonal supplementation schemes required for the maintenance of endometrial receptivity during luteal phase. We optimized and characterized in vitro endometrial stromal cell (ESC) decidualization model as the adequate physiological reflection of endometrial sensitivity to steroid hormones. Based on the whole transcriptome RNA sequencing and the corresponding bioinformatics, we proposed that activation of the decidual prolactin (PRL) promoter containing ancient transposons MER20 and MER39 may reflect functioning of the core decidual regulatory network. Furthermore, we cloned the sequence of decidual PRL promoter containing MER20 and part of MER39 into the expression vector to estimate the effectiveness of ESC decidual response and verified sensitivity of the designed system. We additionally confirmed specificity of the generated tool using human diploid fibroblasts and adipose-derived human mesenchymal stem cells. Finally, we demonstrated the possibility to apply our tool for personalized hormone screening by comparing the effects of natural progesterone and three synthetic analogs (medroxyprogesterone 17-acetate, 17α-hydroxyprogesterone caproate, dydrogesterone) on decidualization of six ESC lines obtained from patients planning to undergo the IVF procedure. To sum up, we developed the "all-in-one" genetic tool based on the MER20/MER39 expression cassette that provides the ability to predict the most appropriate hormonal cocktail for endometrial receptivity maintenance specifically and safely for the patient, and thus to define the personal treatment strategy prior to the IVF procedure.