Excessive Pregestational Weight and Maternal Obstetric Complications: The Role of Adipokines.

There is a high frequency of overweight and obesity in women of reproductive age. Women who start pregnancy with overweight or obesity have an increased risk of developing maternal obstetric complications such as gestational hypertension, pre-eclampsia, gestational diabetes mellitus, postpartum hemorrhage, and requiring C-section to resolve the pregnancy with a higher risk of C-section surgical site infection. Excessive weight in pregnancy is characterized by dysregulation of adipokines, the functions of which partly explain the predisposition of pregnant women with overweight or obesity to these maternal obstetric complications. This review compiles, organizes, and analyzes the most recent studies on adipokines in pregnant women with excess weight and the potential pathophysiological mechanisms favoring the development of maternal pregnancy complications.

New Insights into Adipokines in Gestational Diabetes Mellitus.

Gestational diabetes mellitus (GDM) is the most common metabolic disorder of pregnancy and has considerable short- and long-term consequences for the health of both the mother and the newborn. Within its pathophysiology, genetic, nutritional, epigenetic, immunological, and hormonal components have been described. Within the last two items, it is known that different hormones and cytokines secreted by adipose tissue, known collectively as adipokines, are involved in the metabolic alterations underlying GDM. Although the maternal circulating profile of adipokines in GDM has been extensively studied, and there are excellent reviews on the subject, it is in recent years that more progress has been made in the study of their expression in visceral adipose tissue (VAT), subcutaneous adipose tissue (SAT), placenta, and their concentrations in the umbilical circulation. Thus, this review compiles and organizes the most recent findings on the maternal and umbilical circulating profile and the levels of expression of adipokines in VAT, SAT, and placenta in GDM.

The Genomic Landscape of Corticotroph Tumors: From Silent Adenomas to ACTH-Secreting Carcinomas.

Corticotroph cells give rise to aggressive and rare pituitary neoplasms comprising ACTH-producing adenomas resulting in Cushing disease (CD), clinically silent ACTH adenomas (SCA), Crooke cell adenomas (CCA) and ACTH-producing carcinomas (CA). The molecular pathogenesis of these tumors is still poorly understood. To better understand the genomic landscape of all the lesions of the corticotroph lineage, we sequenced the whole exome of three SCA, one CCA, four ACTH-secreting PA causing CD, one corticotrophinoma occurring in a CD patient who developed Nelson syndrome after adrenalectomy and one patient with an ACTH-producing CA. The ACTH-producing CA was the lesion with the highest number of single nucleotide variants (SNV) in genes such as USP8, TP53, AURKA, EGFR, HSD3B1 and CDKN1A. The USP8 variant was found only in the ACTH-CA and in the corticotrophinoma occurring in a patient with Nelson syndrome. In CCA, SNV in TP53, EGFR, HSD3B1 and CDKN1A SNV were present. HSD3B1 and CDKN1A SNVs were present in all three SCA, whereas in two of these tumors SNV in TP53, AURKA and EGFR were found. None of the analyzed tumors showed SNV in USP48, BRAF, BRG1 or CABLES1. The amplification of 17q12 was found in all tumors, except for the ACTH-producing carcinoma. The four clinically functioning ACTH adenomas and the ACTH-CA shared the amplification of 10q11.22 and showed more copy-number variation (CNV) gains and single-nucleotide variations than the nonfunctioning tumors.

Epigenetic Alterations Related to Gestational Diabetes Mellitus.

Gestational diabetes mellitus (GDM) is the most common metabolic complication in pregnancy, which affects the future health of both the mother and the newborn. Its pathophysiology involves nutritional, hormonal, immunological, genetic and epigenetic factors. Among the latter, it has been observed that alterations in DNA (deoxyribonucleic acid) methylation patterns and in the levels of certain micro RNAs, whether in placenta or adipose tissue, are related to well-known characteristics of the disease, such as hyperglycemia, insulin resistance, inflammation and excessive placental growth. Furthermore, epigenetic alterations of gestational diabetes mellitus are observable in maternal blood, although their pathophysiological roles are completely unknown. Despite this, it has not been possible to determine the causes of the epigenetic characteristics of GDM, highlighting the need for integral and longitudinal studies. Based on this, this article summarizes the most relevant and recent studies on epigenetic alterations in placenta, adipose tissue and maternal blood associated with GDM in order to provide the reader with a general overview of the subject and indicate future research topics.

Immune tolerance at the maternal-placental interface in healthy pregnancy and pre-eclampsia.

AIM: The objective of this review is to describe the immunological mechanisms which facilitate maternal tolerance at the maternal-placental interface, and to discuss how these mechanisms are disrupted in pre-eclampsia. METHODS: A literature review was performed based on the analysis of papers available on PubMed. The most important and relevant studies regarding the immunological mechanisms which facilitate maternal tolerance in healthy pregnancy and pre-eclampsia are presented in this article. RESULTS: The maternal-placental interface is the site where the immune tolerance begins and develops. Within the innate immunity, natural killer cells, macrophages and dendritic cells play a pivotal role in tolerance through regulation of inflammation. On the other hand, within the adaptive immunity, the correct increase of regulatory T cells is crucial for ensuring immune tolerance toward placental cells. Disturbances in maternal tolerance can lead to the appearance of pregnancy complications such as pre-eclampsia, which has a considerable impact on perinatal morbidity and mortality. CONCLUSION: Our partial knowledge of immunological mechanisms involved in tolerance at the maternal-placental interface indicates that pre-eclampsia is characterized by alterations of this maternal immune tolerance, which could represent the origin of the disease.

Placental Proinflammatory State and Maternal Endothelial Dysfunction in Preeclampsia.

OBJECTIVE: To evaluate the placental and decidual gene expression and maternal and umbilical serum concentrations of tumor necrosis factor alpha, interleukin 6 (IL-6), IL-8, IL-10, IL-1 receptor antagonist (IL-1RA), intercellular adhesion molecule-1 and vascular cell adhesion molecule-1 (VCAM-1), along with the proinflammatory/anti-inflammatory cytokine ratios in women with preeclampsia (PE) vs. women with normal pregnancy (NP), and to analyze PE classified as early- (EO) and late-onset (LO). METHODS: This cross-sectional study was performed with 50 women with PE (EO n = 30, LO n = 20) and 50 women with NP. Tissue gene expression levels were measured by real-time RT-PCR. Cytokines and adhesion molecules serum concentrations were measured by immunoassays. RESULTS: In PE, placental expression of IL-10 and IL-1RA was lower, while placental IL-8/IL-1RA ratio and maternal concentrations of VCAM-1 were higher vs. NP. In EO, placental expression of IL-10 was lower, while placental IL-8/IL-10 and IL-8/IL-1RA ratios were higher than LO and NP. Maternal concentrations of IL-6 were higher in LO than EO and NP. Throughout PE, maternal VCAM-1 concentrations were higher vs. NP. No significant differences were observed in the decidual expression and umbilical concentrations of the markers between the groups. CONCLUSION: PE associates with a proinflammatory placental state; however, EO associates with a proinflammatory placental state, while LO associates with systemic maternal inflammation. Both subtypes associated with maternal endothelial dysfunction.

Deregulated microRNAs and Adiponectin in Postmenopausal Women with Breast Cancer.

BACKGROUND: Obesity is a risk factor for breast cancer (BC). Some mechanisms through which obesity can lead to cancer development are insulin-like growth factors (IGFs), adipokines, and microRNAs (miRs). The objective of the study was to determine whether miR-17-5p, miR-195-5p, and miR-221-3p expressions were deregulated in serum samples of obese and nonobese postmenopausal women with BC. In addition, insulin, adiponectin, leptin and IGFs were analyzed. METHODS: Fifty postmenopausal women with newly diagnosed BC and 50 postmenopausal healthy women were evaluated. Differences in miRs between BC and healthy cases and between obese and lean participants were analyzed. Receiver operating characteristic curves for miRs for discriminating patients with or without BC were established, and relationships between the miRs, adipokines, and breast tumor characteristics were also investigated. RESULTS: miR-17-5p and miR-195-5p were higher in patients with BC in comparison to the controls, while miR-221-3p and adiponectin were significantly lower. Increased levels of miR-195-5p allowed the differentiation of BC from controls with a sensitivity of 83.3 and a specificity of 78.3%, and were associated with lobular and poorly differentiated cancer. There was no difference in miRs levels between obese and lean groups. CONCLUSIONS: Circulating miRs and adiponectin were deregulated in postmenopausal women with BC.

Similar to Adiponectin, Serum Levels of Osteocalcin are Associated with Mammographic Breast Density in Postmenopausal Women.

OBJECTIVE: Breast cancer is the most common type of cancer in Canadian women and worldwide. Mammographic density is a well-established breast cancer risk. Recent evidence suggested inverse correlations among adiponectin, osteocalcin, and the risk developing breast cancer. The objective of the study was to evaluate the relationship between breast density and adiponectin and osteocalcin concentrations. METHODS: A cross-sectional study was performed in 239 women, age range 40 to 60. Mammographic density, serum adiponectin, and osteocalcin levels were measured. According to the Wolfe method, participants were divided into those with low-risk and high-risk pattern mammograms. RESULTS: The study population included 107 premenopausal and 132 postmenopausal women. Parameters were no different between women with low-risk and high-risk patterns. In obese postmenopausal women, the high-risk pattern mammogram group had significantly higher values of adiponectin and osteocalcin compared with the low-risk pattern group. Multiple linear regression analyses showed that adiponectin and osteocalcin levels were associated with high-risk pattern mammograms. CONCLUSION: Adiponectin and osteocalcin levels were directly associated with high-risk pattern mammograms in obese postmenopausal women. These results do not support the use of adipokines as biomarkers; nevertheless, the most important factor is to assess the risk through breast density.

[Perinatal complications and serotonin level (5-HT) associated with low birth weight]. / Complicaciones perinatales y concentración de serotonina (5-HT) en recién nacidos asociadas con bajo peso al nacimiento.

BACKGROUND: Studies in human and in experimental models suggest that interaction among the adverse prenatal and postnatal environment increases susceptibility for chronic diseases. This environment could induce changes in the metabolism balance. OBJECTIVE: To analyze how the low birth weight (LBW) influences on the perinatal complications and serotonin serum concentration associated with the possible changes in the alimentary behavior. MATERIAL AND METHODS: A prospective, longitudinal and descriptive study was made during 6 months of the obstetric events to know the frequency and complications of LBW. To evaluate if these complications could have some relationship with the serotonin concentration we measured through their metabolite 5-hidroxitriptamina (5-HT) and the possible chronic illnesses of the adult life. RESULTS: From 1,418 obstetric events attended during the study period, 506 patients with viable pregnancies and met the inclusion criteria were included, 26.8% had LBW and the immediate clinical complications were presented in 52.2% of them and serum concentration 5-HT of 362.2 ± 21.8 vs 82.1 ± 13.6 ng/mL. CONCLUSION: Low birth weight, besides causing perinatal complica- tions, also conditions permanent changes in the expression of satiety neurotransmitters and some tissues, that alter the regulation mechanisms to maintain the energy balance leading to metabolic stability, which is needed to the proper endocrine functioning in the adult life of these individuals.

[Clinical implications of basic research in preeclampsia: immunological tolerance]. / Implicaciones clínicas de la investigación básica de la preeclampsia: tolerancia inmunológica.

Preeclampsia is one of the main causes of maternal and perinatal mortality in the world; however, the pathophysiologic pathways haven't been clearly elucidated. It is thought to result from a breakdown of maternal tolerance to paternal antigens in placenta that start an immune response against the trophoblast inducing a defective placentation and a hipoxic/isquemic environment which in turn triggers a systemic inflamatory response. This review gives an overview of the mechanims involved in maternal tolerance, how these are disrupted in preeclampsia, and how they contribute to the inflamatory response.

[Commentary on the Nobel Prize that has been granted in Medicine-Physiology, Chemistry and Physics to noteable investigators]. / Comentario sobre los Premios Nobel de Medicina-Fisiología, Química y Física otorgados a investigadoras notables.

The Nobel Prize was established by Alfred Nobel in 1901 to award people who have made outstanding achievements in physics, chemistry and medicine. So far, from 852 laureates, 45 have been female. Marie Curie was the first woman to receive the Nobel Prize in 1903 for physics and eight years later also for chemistry It is remarkable that her daughter Irene and her husband also received the Nobel Prize for chemistry in 1935. Other two married couples, Cori and Moser, have also been awarded the Nobel Prize. The present commentary attempts to show the female participation in the progress of scientific activities.

[Convenience clinic redefine polycystic ovary syndrome (Stein-Leventhal)]. / Conveniencia clínica de redefinir al síndrome de poliquistosis ovárica (Stein-Leventhal).

In 1935 during a medical meeting behalf in New Orleans was presents a study that included seven cases of women that suffered menstrual dysfunctions, hirsutism and sterility, for laparotomy the description of the ovaries had a pearly white color and it was hypertrophic, the cuneiform resection in both ovaries resulted in correction of the menstrual dysfunction and two of them got pregnancy later on, receiving the name of polycystic ovary syndrome (PCOS). The technological advance facilitates the hormonal analyses demonstrating the hyperandrogenism existence and the mechanism of the anovulation, the PCOS showed to be heterogeneous, reason why it was hindered to define it, this advanced the current trend to question the existence of the PCOS and to accept the convenience, either to change the name or to redefine it, leaving it as a simple syndrome with several phenotypes. The endocrine component includes abnormal secretion of insulin and consequently outlying resistance to this hormone, likewise is hyperandrogenism, dislipoproteinemia and obesity. The hormonal exams are unnecessary for the diagnostic and treatment; it is convenient to demonstrate for sonography the ovarian growth. Other dysfunctions like the congenital suprarenal hyperplasia, hyperprolactinemia and hypotiroidism should be discarded. The treatment should be individualized with relationship to the reason of the consultation and the patients age. It has not been demonstrated that the sensibilitizers use to the insulin avoids long term cardiovascular illness and diabetes. Therefore, the phenotype is heterogeneous with a fickle metabolic component and for it has arisen the restlessness of a better definition of the SPO.

[Efficacy and adverse effects of oral antidiabetic agents]. / Eficacia y efectos adversos de los antidiabéticos orales.

The management of type 2 diabetes is still a challenge and a conundrum for treatment intensity and choice of pharmaceutical agent. There is also uncertainty about possible cardiovascular adverse effects.

Differential Expression of FXR and Genes Involved in Inflammation and lipid Metabolism Indicate Adipose Tissue Dysfunction in Gestational Diabetes.

BACKGROUND: Gestational diabetes mellitus (GDM) is the most frequent metabolic alteration in pregnancy. Several abnormalities in visceral adipose tissue (VAT) have been described as part of its pathophysiology including hypertrophy, inflammation and altered lipid metabolism. Farnesoid X receptor (FXR) is involved in adipocyte physiology and inflammation, so its expression may correlate with the expression of tumor necrosis factor-alpha (TNF-α), interleukin-10 (IL-10), lipoprotein lipase (LPL), and two fatty acid transporters (SLC27A2, and SLC27A4). AIM: To compare the FXR, LPL, SLC27A2, SLC27A4, TNF-α, and IL-10 mRNA expression in VAT between women with GDM and healthy pregnant (HP) women. Secondarily, to evaluate the potential correlation between these expression levels. MATERIALS AND METHODS: Cross-sectional study of 50 GDM and 50 HP women. Conventional biochemical tests were performed and relative mRNA expression in VAT was measured by RT-qPCR. RESULTS: Gene expression levels of FXR and IL-10 were lower, whereas those of LPL, as well as the TNF-α/IL-10 ratio, were higher in women with GDM compared to HP. Pre-pregnancy BMI was the main significant independent variable for FXR levels in VAT from women with GDM. In all women, LPL expression levels correlated positively with those of SLC27A2. Only in women with GDM, IL-10 expression levels correlated negatively with those of SLC27A2, and SLC27A4. CONCLUSIONS: GDM is associated with decreased expression of FXR and IL-10 and increased expression of LPL, as well as a higher TNF/IL-10 ratio in VAT. These results suggest increased lipid storage and pro-inflammatory state indicating VAT dysfunction in this metabolic disorder.

Gestational Weight Gain Is Associated with the Expression of Genes Involved in Inflammation in Maternal Visceral Adipose Tissue and Offspring Anthropometric Measures.

BACKGROUND: Adequate gestational weight gain (GWG) is essential for maternal and fetal health. GWG may be a sign of higher visceral adipose tissue (VAT) accretion. A higher proportion of VAT is associated with an inflammatory process that may play a role in the fetal programming of obesity. This study aimed to (1) compare the expression of genes involved in inflammatory responses (TLR2, TLR4, NFκB, IKKß, IL-1RA, IL-1ß, IL-6, IL-10, TNF-α) in the VAT of pregnant women according to GWG and (2) explore whether VAT inflammation and GWG are related to offspring anthropometric measures. MATERIAL AND METHODS: 50 women scheduled for cesarean section who delivered term infants were included in the study. We collected maternal omental VAT, and the expression of genes was examined with RT-qPCR. RESULTS: Women with excessive and with adequate GWG had significantly higher expressions of most inflammatory genes than women with insufficient GWG. Neonates from mothers with excessive GWG had greater birth weight and chest circumference than those from mothers with insufficient GWG. GWG was positively correlated with fetal birth weight. CONCLUSIONS: The VAT expression of most genes associated with inflammatory pathways was higher in excessive and adequate GWG than in pregnant women with insufficient GWG. Moreover, GWG was found to be positively associated with newborn weight.

Role of Oxidative Stress and Inflammation in Gestational Diabetes Mellitus.

Gestational diabetes mellitus (GDM) is one of the most common pregnancy complications. It is related to several gestational and fetal adverse outcomes. Moreover, women with GDM and their infants have a high risk of developing type 2 diabetes in the future. The pathogenesis of GDM is not completely understood; nevertheless, two factors that contribute to its development are oxidative stress and inflammation. Oxidative stress and inflammation are related; reactive oxygen species (ROS) production can activate inflammatory cells and enhance the production of inflammatory mediators. Inflammation, in turn, leads to an increased ROS release, causing a vicious circle to ensue. Inflammatory responses can be achieved via the activation of the NF-κB signaling pathway. Herein, we review the English literature regarding oxidative stress and inflammation evaluated simultaneously in the same population, attempting to identify mechanisms through which these factors contribute to the development of GDM. Furthermore, the modulation of oxidative stress and inflammation by different therapies used in women with GDM and in cell models of GDM is included in the review. Probiotics and nutrient supplementations have been shown to reduce biomarkers of inflammation and oxidative stress in vitro and in women with GDM.

Hirsutism and Polycystic Ovarian Morphology are the Most Frequent Components of Polycystic Ovary Syndrome in Women with Type 1 Diabetes.

BACKGROUND: Polycystic ovarian syndrome (PCOS) is one of the most common endocrine disorders in women of reproductive age. In Mexico, its prevalence in patients with type 1 diabetes (T1D) is unknown. AIM: To evaluate the clinical and biochemical characteristics of patients with T1D with and without PCOS. METHODS: A cross-sectional study was conducted to evaluate women of reproductive age with T1D for the diagnosis of PCOS using the criteria of the European Society for Human Reproduction and Embryology/American Society for Reproductive Medicine. Clinical information was obtained from clinical records, and we recorded anthropometric variables and performed a laboratory test during the follicular phase. The estimated glucose disposal rate and visceral adiposity index were also calculated to assess insulin resistance. Subsequently, participants were evaluated based on the presence or absence of PCOS. RESULTS: Thirty-nine percent of patients with T1D had PCOS. The most frequent components of PCOS were polycystic ovary morphology (58.5%), clinical hyperandrogenism (41.5%), oligomenorrhea (29.2%), and biochemical hyperandrogenism (19.5%). Patients with PCOS used more insulin per day (1.04 ± 0.33 vs. 0.71 ± 0.29 IU/kg/d, p = 0.003), had lower fasting glucose (116.4 ± 59.79 vs. 161.16 ± 63.9 mg/dl, p = 0.029) and higher right ovarian volume (11.36 [8.64-15.89] vs. 6.9 [5.55-8.77] cm3, p = 0.005) and Ferriman-Gallwey scores (9.06 ± 2.05 vs. 7.12 ± 3.15 points, p = 0.035) compared to patients without PCOS. The frequency of insulin resistance and metabolic syndrome in women with PCOS was 37.5 and 18.8%, respectively. CONCLUSION: PCOS is a very heterogeneous entity, with a high frequency in women with T1D.

Women with gestational diabetes develop glucose intolerance with high frequency within one year postpartum.

OBJECTIVE: To investigate the incidence of glucose intolerance postpartum in women with gestational diabetes (GDM) and assess body weight, cholesterol and triglyceride concentrations after delivery. METHODS: This was a study of an initial cohort of 100 women with GDM who were tested at 6 weeks, 6 months, and 1 year postpartum. Postpartum evaluations were glucose tolerance, weight and cholesterol and triglycerides. RESULTS: Impaired fasting glucose (IFG) and/or impaired glucose tolerance (IGT) was present in 36.5% of 52 participants who were assessed at 6 weeks postpartum and diabetes in 17.3%; the remaining 48 women failed to return for the 3 evaluations. By 6 months, IFG/IGT was demonstrated in 55.8% and diabetes in 32.7% of the women. At 1 year, 46.2% exhibited IFG/IGT and 48% diabetes. Moreover, the weight was higher in those women who presented IFG/IGT (75.5 ± 15.2 kg, mean ± SD) and diabetes (79.0 ± 16.2 kg) compared with those who had normal glucose tolerance (65.3 ± 14.5 kg; p < 0.05). In addition, triglycerides were higher in mothers with glucose intolerance (181.3 ± 85.9 mg/dl in IFG/IGT and 230.9 ± 90.9 mg/dl in diabetes) than in women with normal glycemia (147.8 ± 11.2 mg/dl; p < 0.05). CONCLUSION: We demonstrated an increased incidence of women exhibiting glucose intolerance within 1 year postpartum, mainly in those who remained obese.

[The treatment of hypercholesterolemia is in a crossroad]. / El tratamiento del colesterol alterado en una encrucijada terapéutica.

In order to correct the high level of cholesterol in blood is necessary to improve the life style which includes proper nutrition and physical exercise, but frequently is added some medication. The initial medication that is used is a stantin which decreases total cholesterol and low density cholesterol associated with increment in high density cholesterol in order to prevent cardiovascular involvement. It is frequent the addition of other medicaments, such as niacin or ezetemiba to achieve a greater effect on cholesterol disorders. The effectively of anti-cholesterol elevation should be evaluated by the occurrence of cardiovascular events, instead of the improvement in biochemist markers.

Association between Galectin Levels and Neurodegenerative Diseases: Systematic Review and Meta-Analysis.

Galectins are a family of proteins with an affinity for ß-galactosides that have roles in neuroprotection and neuroinflammation. Several studies indicate that patients with neurodegenerative diseases have alterations in the concentration of galectins in their blood and brain. However, the results of the studies are contradictory; hence, a meta-analysis is performed to clarify whether patients with neurodegenerative diseases have elevated galectin levels compared to healthy individuals. Related publications are obtained from the databases: PubMed, Central-Conchrane, Web of Science database, OVID-EMBASE, Scope, and EBSCO host until February 2022. A pooled standard mean difference (SMD) with a 95% confidence interval (CI) is calculated by fixed-effect or random-effect model analysis. In total, 17 articles are included in the meta-analysis with a total of 905 patients. Patients with neurodegenerative diseases present a higher level of galectin expression compared to healthy individuals (MDS = 0.70, 95% CI 0.28-1.13, p = 0.001). In the subgroup analysis by galectin type, a higher galectin-3 expression is observed in patients with neurodegenerative diseases. Patients with Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALD), and Parkinson's disease (PD) expressed higher levels of galectin-3. Patients with multiple sclerosis (MS) have higher levels of galectin-9. In conclusion, our meta-analysis shows that patients with neurovegetative diseases have higher galectin levels compared to healthy individuals. Galectin levels are associated with the type of disease, sample, detection technique, and region of origin of the patients.