Insulin-sensitizing agents for infertility treatment in woman with polycystic ovary syndrome: a narrative review of current clinical practice.

PURPOSE: Polycystic ovary syndrome (PCOS) is an endocrine, metabolic, and reproductive disorder which, according to the Rotterdam criteria, affects up to 24% of women of childbearing age. Although the prevalence of infertility in this subpopulation of women is high, the optimal treatment has not been fully established yet. Insulin resistance is considered to be an important mechanism involved in the development of PCOS; hence, the aim of this narrative review is to present an overview of the current pharmacological insulin-sensitizing treatment modalities for infertile women with PCOS. METHODS: A MEDLINE and PubMed search for the years 1990-2023 was performed using a combination of keywords. Clinical trials with insulin sensitizers used for infertility treatment as well as analyses of systematic reviews and meta-analyses were evaluated. When deemed necessary, additional articles referenced in the retrieved papers were included in this narrative review. RESULTS: Several insulin-sensitizing compounds and various therapeutical protocols are available for infertility treatment of women with PCOS. Metformin is the most common adjuvant medication to induce ovulation in infertile women with PCOS and is more frequently administered in combination with clomiphene citrate than on its own. Recently, inositol and glucagon-like peptide-1 (GLP-1) receptor agonists have emerged as possible options for infertility treatment in PCOS. CONCLUSION: The future of medical treatment of PCOS women with infertility lies in a personalized pharmacological approach, which involves various compounds with different mechanisms of action that could modify ovarian function and endometrial receptivity, ultimately leading to better overall reproductive outcomes in these women.

Association Between Endothelial Nitric Oxide Synthase (eNOS) -786 T/C and 27-bp VNTR 4b/a Polymorphisms and Preeclampsia Development.

The aim of the present study was to analyze the distribution of genotypes and haplotypes of functional eNOS gene polymorphisms in the promoter (-786 T/C), intron 4 (VNTR4b/a) and exon 7 (894 G/T), in Serbian population of pregnant women, and establish a possible association between these polymorphisms and preeclampsia development. DNA was isolated from venous blood samples of 50 heathy pregnant women and 50 preeclampsia patients. Polymerase Chain Reaction/Restriction Fragment Length Polymorphism (PCR/RFLP) technique, with appropriate sets of primers and specific restriction enzymes, was used to determine polymorphisms in eNOS gene. Statistical analysis was done using the SPSS and HAPLOVIEW software packages. eNOS -786 T/C polymorphism was significantly associated with preeclampsia (P = 0.006). Homozygotes for the VNTR polymorphism had also an elevated risk of developing preeclampsia (OR=7.68, 95%CI (0.89-65.98)), especially the mild (OR=9.33, 95%CI (0.98-88.57)) and late form (OR=8.52, 95%CI (0.90-80.58)). The 894 G/T polymorphism was not associated with preeclampsia. "G-C-b" and "T-4a-T" haplotypes were more frequent in preeclampsia, though without reaching statistical significance. -786 T/C and VNTR 4b/a eNOS gene polymorphisms were associated with preeclampsia risk in Serbian patients.

VAL158MET catechol O-methyltransferase polymorphism contributes to the development of preeclampsia.

Objectives: Establishment of association between: (a) Val158Met COMT (G1947A) polymorphism and preeclampsia; (b) cytokines gene expression and COMT genotypes. Methods: 50 preeclampsia and 50 healthy pregnant women were enrolled. COMT genotyping was done by PCR/RFLP. TNF-α, IL-1ß, and IL-6 mRNA levels were determined by Real-time PCR. Results: Variant (AA) homozygotes carried 3.7-fold increased preeclampsia odds, especially for severe (OR = 9.0, 95%CI (2.09-38.799)) and early forms (OR = 6.6, 95%CI (1.62-26.87)). AA homozygotes with PE had higher TNF-α levels compared to controls (P = 0.012). Conclusions: Val158Met COMT polymorphism increases preeclampsia risk. TNF-α expression and Val158Met COMT polymorphism have concomitant roles in PE pathogenesis.

Glutathione-S-transferase M1 polymorphism and pro-inflammatory cytokines tumour necrosis factor-α and interleukin-1ß are associated with preeclampsia in Serbian women.

PROBLEM: Preeclampsia has a multifactorial origin with genetic, immunological, and environmental factors described as main contributors to its onset. This study aimed to investigate glutathione-S-transferase M1 (GSTM1) and glutathione-S-transferase T1 (GSTT1) gene polymorphisms, the expression of pro-inflammatory cytokines (TNF-α, IL-1ß, IL-6), and the potential relationship between GST polymorphisms and cytokine expression levels in preeclampsia and uncomplicated pregnancy. METHOD OF STUDY: This prospective case-control study included 50 women with preeclampsia and 50 healthy pregnant women. DNA and RNA were extracted from women leukocytes. Deletion polymorphisms were analyzed by PCR, while cytokine mRNA expression was analyzed by real-time PCR. RESULTS: GSTM1 null genotype with present GSTT1 increased the risk for preeclampsia development. Deletion of GSTT1 without deletion of GSTM1 increased the risk for early preeclampsia. Relative mRNA expression of TNF-α was significantly higher in preeclampsia compared to healthy pregnant women (P = 0.006). Expression of IL-1ß was significantly higher in severe and late preeclampsia compared to the control group (P = 0.005, P = 0.007, respectively). A significant positive correlation between TNF-α and IL-1ß was observed (Spearman's ρ = 0.312, P = 0.028) and between IL-1ß and IL-6, in preeclampsia group (Spearman's ρ = 0.296, P = 0.037). IL-1ß was significantly increased in patients with GSTT1 null genotype (P = 0.015) while IL-6 was increased in patients with GSTM1 null genotype (P = 0.015). CONCLUSIONS: GSTM1 null genotype represents a risk factor for preeclampsia development, while GSTT1 null genotype favors early preeclampsia. Preeclampsia is also associated with increased expression of pro-inflammatory cytokines, predominantly TNF-α and IL-1ß.

Maternal glycoregulation in pregnancies complicated by diabetes mellitus in the prediction of fetal echography findings and perinatal outcomes.

AIM: We aimed to determine maternal hemoglobin A1c (HbA1c) levels and pregestational body mass index (BMI) as the predictors of glycemic control and its importance for fetal echography findings and perinatal outcomes in pregnancies complicated by diabetes mellitus (DM). METHODS: Our intention was to evaluate how BMI and HbA1c levels might be used to predict fetal interventricular septum (IVS) thickness, atrioventricular inflow early diastole (E)/ atrial systole (A) velocity ratio, and perinatal outcomes. Patients in the 38th gestational week were divided into three groups according to their insulin therapy: (i) patients with gestational diabetes mellitus (GDM) treated only with dietary changes (GDM group, n = 32); (ii) patients with GDM treated with insulin therapy (DM2 group, n = 27); and (iii) patients with type 1 DM (DM1 group, n = 22). RESULTS: In the DM1 group, we found statistically significant correlations between BMI and IVS thickness (P = 0.036), HbA1c and IVS thickness, as well as the mitral E/A velocity ratio (P = 0.013 vs P = 0.007). In this group, HbA1c showed a statistically significant correlation to neonatal birth weight (P = 0.037) and BMI influenced on appearance respiratory distress syndrome in neonates in DM1 group (P = 0.027). The values of HbA1c predict neonatal respiratory distress syndrome in DM2 and GDM groups (P = 0.036). CONCLUSION: As good predictors of maternal glycoregulation, BMI and HbA1c levels determine fetal echography findings as well as neonatal outcomes in pregnancies complicated by DM.

Fetal and maternal plasma homocysteine levels during the second half of uncomplicated pregnancy.

OBJECTIVE: To measure fetal and maternal plasma homocysteine (Hcy) concentrations in uncomplicated pregnancies. METHODS: Paired maternal venous and fetal umbilical cord blood (n = 81) samples were evaluated for plasma Hcy and vitamin B12 levels, in addition to eight neonatal umbilical cord blood samples obtained immediately following delivery. RESULTS: Both fetal and maternal Hcy concentrations were positively correlated with advancing gestational age (ρ = 0.44, p < 0.0001; and ρ = 0.27, p < 0.05, respectively). Fetal plasma Hcy concentrations [2.2 µmol/l (IQR: 2.0-3.2)] were significantly lower than both neonatal umbilical vein [5.0 µmol/l (IQR: 4.4-6.5); p < 0.001] and maternal plasma Hcy levels [4.4 µmo/l (IQR: 3.4-5.4); p < 0.001]. In addition, Hcy values at term were higher in the umbilical vein compared with the umbilical artery [5.0 µmol/l (IQR: 3.4-5.4) versus 4.2 µmol/l (IQR: 3.7-5.5), respectively; p = 0.016]. Significant correlation was noted and between fetal and maternal Hcy levels (ρ = 0.50, p < 0.0001), while fetal Hcy was negatively correlated with maternal B12 concentrations (ρ = -0.32, p < 0.001). CONCLUSIONS: Fetal Hcy levels were significantly lower than maternal and neonatal levels and correlated with gestational age across the second half of pregnancy.

Perinatal Outcomes of Pregnancies Conceived by Assisted Reproductive Technologies.

INTRODUCTION: Recent epidemiological studies showed significantly higher incidence of perinatal complications in newborns and women after the use of assisted reproductive technologies (ART). Multiple pregnancies are more frequent after the use of ART. Singleton pregnancies following ART are more prone to preterm birth, low and very low birth weight (LBW and VLBW), small for gestational age (SGA) and perinatal mortality. ObjectiveThe aim of this study was to summarize the results of relevant articles and to evaluate whether the mode of conception is the determining factor for different pregnancy outcomes after assisted and natural conceptions. Methods Eleven studies were included in this review. The following outcomes were observed: preterm and very preterm birth, SGA, LBW, VLBW, perinatal mortality, admission to neonatal intensive care unit (NICU), and Apgar score (As) ≤7 at fifth minute. Qualitative analysis nd quantitative assessment were performed. Results For singletons, odds ratios were 1.794 (95% confidence interval 1.660-1.939) for preterm birth, 1.649 (1.301-2.089) for LBW, 1.265 (1.048-1.527) for SGA. Admission to NICU, As≤7 at fifth minute and perinatal mortality showed significantly different frequency after assisted conception. Summary of results for twin gestations showed no significant difference between ART and spontaneous conception for preterm birth (32-36 weeks), very preterm birth (<32 weeks), LBW and VLBW. Conclusion Analyzed studies showed that infants from ART have significantly worse perinatal outcome compared with natural conception. More observational studies should be conducted in order to establish

Nutrition in pregnancy: basic principles and recommendations.

Healthy diet in pregnancy should guarantee proper fetal growth and development, maintain (and promote) maternal health and enable lactation. Nutritional counseling and interventions need to be an integral part of antenatal care and continue during pregnancy in order to reduce the risk of maternal, fetal and neonatal complications, as well as the short- and long-term adverse outcomes. Adverse pregnancy outcomes are more common in women who begin the gestation as undernourished or obese in comparison to pregnant women whose weight is within normal ranges. Increased nutritional and energy needs in pregnancy are met through numerous metabolic adaptations; pregnancy is successfully achieved within wide range of variations in energy supply and weight gain. However, if nutrient restriction exceeds the limits of adaptive responses, evidence indicates that fetus will develop the alternative metabolic competence that might emerge as a disease (type 2 diabetes, hypertension, coronary heart disease and stroke) in adult life.

Is the rate of congenital heart defects detected by fetal echocardiography among pregnancies conceived by in vitro fertilization really increased?: a case-historical control study.

OBJECTIVE: We investigated the prenatal prevalence of congenital heart defects (CHDs) among in vitro fertilization (IVF) pregnancies at a referral program in the United States. METHODS: Study patients were referred for fetal echocardiography between April 1, 2006, and May 1, 2009, due to IVF. An IVF pregnancy was defined as a patient who conceived with IVF with or without intracytoplasmic sperm injection. Congenital heart defect odds relative to historical data were calculated by standard methods. P < .05 was considered statistically significant. RESULTS: During the study period, we performed fetal echocardiography on 749 consecutive IVF pregnancies. Overall, the frequency of CHDs was 1.1% (95% confidence interval, 0.3%-1.8%) per pregnancy. Compared to earlier historical population data, IVF pregnancies had a significantly higher risk of CHDs (odds ratios, 7.3 [3.6-14.7] and 2.9 [1.4-5.9], respectively). However, compared to more contemporary population data, there was no difference in the CHD risk between IVF gestations and naturally conceived pregnancies. Further analysis indicated that IVF twin pregnancies were as much as 12.5 (4.6-33.5) times as likely to have CHDs compared to a general population. CONCLUSIONS: In this study population, the frequency of CHDs in IVF pregnancies was higher than early historical population data; however, it was similar to that of a more contemporary general population. Further analysis showed that this increase was mainly driven by IVF twin gestations. Previous reports of increased CHD risk in pregnancies conceived via IVF may have been due, in part, to an increased frequency of higher-order pregnancies seen among these patients.

The role of antioxidant vitamins in hypertensive disorders of pregnancy.

Preeclampsia (PE) is an important and a leading cause of both maternal morbidity and adverse perinatal outcomes. Despite progress in perinatal medicine for patients with an established diagnosis of PE, a therapeutic approach other than termination of pregnancy was unsuccessful. Women predisposed to PE begin pregnancy with a certain degree of endothelial dysfunction, a lesion that precedes shallow placentation. The proposed sequence of events comprises endothelial dysfunction, defective trophoblast invasion, and consequential impaired placental perfusion, immune maladaptation and inflammation. The possible link between these could be oxidative stress by excessive production of reactive oxygen species coupled with inadequate or overwhelmed antioxidant defense mechanisms. These defense mechanisms, involving antioxidant vitamins and enzyme systems, may restrain the extent of damage caused by oxidative stress. Markers of oxidative stress in women with established PE were confirmed. Accordingly, these findings support an expected beneficial effect of antioxidant therapy in the prevention of PE and other pregnancy-related disorders. Numerous studies have been carried out in order to investigate this possible and simple prophylactic and/or therapeutic approach in prevention of oxidative stress and eventual reduction of PE and its perinatal complications. In this review the role of vitamin antioxidants in prevention and treatment of PE is discussed. Despite the logic behind using antioxidant vitamins, the data, thus far, are at best conflicting.

Micronutrients in women's reproductive health: I. Vitamins.

Proper nutritional status of women before, during, and after pregnancy is an important element of reproductive health. It maintains maternal health and reduces the risk of adverse pregnancy outcome, birth defects and chronic disease in children later in postnatal life. Pregnancy creates a special metabolic demand for high-quality nutrients. With careful food selection, it is possible to obtain most of the recommended levels of nutrients. Apart from the dietary intake, nutrition is highly dependant on economic status, social and cultural environment, and personal habits of the mother. Nutritional imbalance could cause detrimental effects to the pregnant woman, influence pregnancy outcome, and impair breast milk composition. Despite the extensive research, we still do not have a complete understanding how nutritional status of the mother influences her health as well as fetal growth and development. It is well known that fetal growth and development is strongly linked with maternal supply of essential nutrients, e.g. vitamins. The exact role of the variety of micronutrients in fetal growth and development has yet to be explored in detail. It is estimated that up to 30% of pregnant women suffer from a vitamin deficiency. Without supplementation, about 75% would show a deficit of at least one vitamin. Moreover, multivitamin deficit combinations often co-exist, and subclinical depletations are probably common; consequences could be severe. Studies carried on in developing countries have shown that improving micronutrient intake in deficient women can reduce maternal morbidity and mortality. Also, proper maternal intake of important micronutrients directly enhances the quality of breast milk. To meet the increasing demands during pregnancy and the breastfeeding period women should not be dependent only upon the dietary intake: adequate reserve is essential for the successful pregnancy outcome.

Micronutrients in women's reproductive health: II. Minerals and trace elements.

It is widely accepted that micronutrients have a major function in many periods of women's life, particularly during pregnancy and lactation. Inadequate stores or intake of micronutrients might have adverse effects both to the mother (hypertension, anemia, complications of labor) and the fetus (congenital malformations, pre-term delivery, intrauterine growth retardation). The effect of improper nutrition is influenced by gestational age, severity of deficiency, or both. Generally, the daily requirements in minerals and trace elements are easily met in women having a balanced diet. Such diet during pregnancy should provide the recommended daily allowance of all nutrients except elemental iron. Consequently, deficiency states are supposed to be rare in developed countries, and supplementation should be made on an individual basis. On the other hand, nutritional deficiencies during pregnancy might be difficult to detect. Studies from developing countries where micronutrient malnutrition is common during pregnancy gave us strong evidence that supplementation of certain trace elements and minerals could prevent some of the most severe adverse pregnancy outcomes. While some micronutrients have been studied extensively (e.g. calcium, iron, zinc, iodine), much less is known about others. It has been shown that multiple micronutrient deficiencies, rather than single deficiencies, are common. Our knowledge about the significance of interactions between micronutrients in relation to pregnancy outcome is limited. The role of these interactions in improving pregnancy outcome need to be investigated more precisely. According to the summarized data, the potential benefits of routine supplementation seem to outweigh any potential adverse reaction that can be attributed to their consumption.