Polycystic ovary syndrome (PCOS) : role of androgens and obesity on placental function and fetal development

Polycystic ovary syndrome (PCOS) is a common endocrine and metabolic disorder affecting women in childbearing age with a prevalence of up to 17.8%. The syndrome is characterized by hyperandrogenism, irregular cycles and polycystic ovaries. The etiology of PCOS is unclear, but it is thought to be multifactorial. There is a strong association between hyperinsulinemia and hyperandrogenism in PCOS, but the mechanisms behind their relationship with PCOS are not fully understood. Obesity and an aberrant metabolic profile is common in women with PCOS, and 50-70% of them are insulin resistant, which increase the risk of developing type 2 diabetes (T2D), independently of body mass index (BMI) and age. Women with PCOS have a reduced fertility rate, and when they become pregnant either by natural process or by assisted reproduction techniques, they are at higher risk of developing pregnancy complications including preeclampsia and gestational diabetes that worsen the prognosis of their own health and the health of the fetus. It is not well known if and how the intrauterine environment affects the fetus. In women with PCOS, a potential effect on the fetus can be hypothetically driven by direct exposure of high maternal androgens to the fetus or via dysregulation of placenta function. In both non-pregnant and pregnant women with PCOS, lifestyle modification including diet and physical exercise is the first line treatment. However, scarce information about treatment of pregnant women with PCOS to prevent the adverse outcomes is found in the literature. Acupuncture has been proposed as one treatment as has been shown to increase uterine artery blood flow in non-pregnant women. Importantly, acupuncture is usually reported to have less negative side-effects than pharmacological strategies. The overall aim of this thesis was to determine the role of androgens and obesity in pregnancy and whether acupuncture could modulate placenta function and fetal growth. First, in a crosssectional study, maternal blood and placental tissue were collected at delivery from 38 women with PCOS without pregnancy complications and 40 control pregnant women to investigate signal transducer and activator of transcription 3 (STAT-3) and mechanistic target of rapamycin (mTOR) signaling pathways in placenta. Second, in rats with prenatal androgenization (PNA), we evaluated markers of steroidogenesis, angiogenesis and sympathetic activity, and we tested the hypothesis that acupuncture with low-frequency electrical stimulation prevents any alteration in the expression of those markers. Thirdly, as women with PCOS are often overweight or obese, we investigated maternal growth and metabolism, placenta weight, placenta steroid receptor expression, and liver fat content from mice exposed to maternal androgen excess with or without diet-induced maternal obesity. Moreover, we performed a global proteomic analysis in placenta and fetal liver to find novel molecules that could be involved in the observed alterations. Pregnant women with PCOS display abnormal steroidogenic state, altered placenta gene expression of steroidogenic enzymes and molecules related to fetal growth as determined by the activation of STAT-3. Moreover, diet-induced maternal obesity and maternal androgen excess induced hepatic triglyceride accumulation and dysregulation of de novo lipogenesis in mothers. In proteomic analysis of placenta and fetal liver, we found a novel Catechol-OMethyltransferase (COMT) phosphorylation that was common in fetal liver and placenta. We also found altered gene expression of enzymes in the liver of female offspring suggesting that the sympathetic nervous system could play a role in the metabolic, reproductive or behavioral disturbances known in offspring of PCOS. These observations are supported by the finding that electroacupuncture given to pregnant dams exposed to testosterone increased systolic blood pressure, decreased fetal and placental growth and altered the expression of markers of angiogenesis, indicating an increased sympathetic nervous activity, contrary to our hypothesis. Besides pregnancy complications, it seems that molecular signatures might make women with PCOS more sensitive and vulnerable to metabolic challenges, which potentially can explain long-term health consequences in their offspring. Moreover, it seems that the sympathetic nervous system plays an important role for fetal development in androgenized dams

Antibiotic use and risk of colorectal cancer : a systematic review and dose-response meta-analysis

Background It is understudied whether the posed association of oral antibiotics with colorectal cancer (CRC) varies between antibiotic spectrums, colorectal continuum, and if a non-linear dose-dependent relationship is present. Design Three electronic databases and a trial platform were searched for all relevant studies, from inception until February 2020, without restrictions. Random-effects meta-analyses provided pooled effect-sizes (ES) with 95% confidence intervals (CI). Dose-response analyses modelling the relationship between number of days exposed to antibiotics and CRC risk were extended to non-linear multivariable random-effects models. Results Of 6483 identified publications ten were eligible, including 4.1 million individuals and over 73,550 CRC cases. The pooled CRC risk was increased among individuals who ever-used antibiotics (ES = 1.17, 95%CI 1.05-1.30), particularly for broad-spectrum antibiotics (ES = 1.70, 95%CI 1.26-2.30), but not for narrow-spectrum antibiotic (ES = 1.11, 95% 0.93-1.32). The dose-response analysis did not provide strong evidence of any particular dose-response association, and the risk patterns were rather similar for colon and rectal cancer. Discussion The antibiotic use associated CRC risk seemingly differs between broad- and narrow-spectrum antibiotics, and possibly within the colorectal continuum. It remains unclear whether this association is causal, requiring more mechanistic studies and further clarification of drug-microbiome interactions

Increases in norepinephrine release and ovarian cyst formation during ageing in the rat

<p>Abstract</p> <p>Background</p> <p>Depletion of ovarian follicles is associated with the end of reproductive function in ageing females. Recently, it has been described that this process parallels increases in the concentration of norepinephrine (NE) in the rat ovary. In sexually mature rats, experimentally-induced increases in the sympathetic tone of the ovary is causally related to ovarian cyst formation and deranged follicular development. Thus, there is a possibility that increased ovarian NE concentrations represent changes in the activity of sympathetic nerves, which consequently participate in the process of ovarian cyst formation observed during ageing in the human and experimental animal models.</p> <p>Methods</p> <p>Sprague-Dawley rats between 6 and 14 months old were used to analyse the capacity of the ovary to release ³H-NE recently incorporated under transmural depolarisation in relation to changes in the ovarian follicular population. Morphometric analysis of ovarian follicles and real time PCR for Bcl2 and Bax mRNA were used to assess follicular atresia.</p> <p>Results</p> <p>From 8 months old, the induced release of recently incorporated ³H-norepinephrine (³H-NE) from the ovary and ovarian NE concentrations increased, reaching their peak values at 12 months old and remained elevated up to 14 months old. Increases in sympathetic nerve activity paralleled changes in the follicular population, as well as disappearance of the corpus luteum. In contrast, luteinised follicles, precystic follicles, and cystic follicles increased. During this period, the relationship between Bax and Bcl2 mRNAs (the proapoptotic/antiapoptotic signals) increased, suggesting atresia as the principal mechanism contributing to the decreased follicular population. When NE tone was increased, the mRNA ratio favoured Bcl2 to Bax and antiapoptotic signals dominated this period of development. Thus, these changing ratios could be responsible for the increase in luteinised follicles, as well as precystic and cystic follicles.</p> <p>Conclusion</p> <p>These data suggest that the ageing process in the ovary of the Sprague-Dawley rat is accompanied by an increased sympathetic tone of the ovary. Consequently, this sympathetic change could be related to a neuroendocrine-driven formation of a polycystic condition similar to that observed in the sympathetic-activated adult ovary.</p

Paternal diabetes programs sex-dependent placental alterations and fetal overgrowth

The aim of this study was to evaluate the paternal programming of sex-dependent alterations in fetoplacental growth and placental lipid metabolism regulated by peroxisome proliferator-activated receptor (PPAR) target genes in F1 diabetic males born from F0 pregestational diabetic rats. F1 control and diabetic male rats were mated with control female rats. On day 21 of gestation, F2 male and female fetoplacental growth, placental lipid levels, and protein and mRNA levels of genes involved in lipid metabolism and transport were evaluated. Fetal but not placental weight was increased in the diabetic group. Triglyceride, cholesterol and free fatty acid levels were increased in placentas of male fetuses from the diabetic group. The mRNA levels of Pparα and Pparγ coactivator 1α (Pgc-1α) were increased only in placentas of male fetuses from the diabetic group. Protein levels of PPARα and PGC-1α were decreased only in placentas of male fetuses from the diabetic group. No differences were found in Pparγ mRNA and protein levels in placentas from the diabetic group. The mRNA levels of genes involved in lipid synthesis showed no differences between groups, whereas the mRNA levels of genes involved in lipid oxidation and transport were increased only in placentas of male fetuses from the diabetic group. In conclusion, paternal diabetes programs fetal overgrowth and sex-dependent effects on the regulation of lipid metabolism in the placenta, where only placentas of male fetuses show an increase in lipid accumulation and mRNA expression of enzymes involved in lipid oxidation and transport pathways.Fil: Fornes, Daiana. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Centro de Estudios Farmacológicos y Botánicos. Universidad de Buenos Aires. Facultad de Medicina. Centro de Estudios Farmacológicos y Botánicos; ArgentinaFil: Heinecke, Maria Florencia. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Centro de Estudios Farmacológicos y Botánicos. Universidad de Buenos Aires. Facultad de Medicina. Centro de Estudios Farmacológicos y Botánicos; ArgentinaFil: Gatti, Cintia Romina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Centro de Estudios Farmacológicos y Botánicos. Universidad de Buenos Aires. Facultad de Medicina. Centro de Estudios Farmacológicos y Botánicos; ArgentinaFil: Roberti, Sabrina Lorena. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Centro de Estudios Farmacológicos y Botánicos. Universidad de Buenos Aires. Facultad de Medicina. Centro de Estudios Farmacológicos y Botánicos; ArgentinaFil: White, Verónica. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Centro de Estudios Farmacológicos y Botánicos. Universidad de Buenos Aires. Facultad de Medicina. Centro de Estudios Farmacológicos y Botánicos; ArgentinaFil: Jawerbaum, Alicia Sandra. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Centro de Estudios Farmacológicos y Botánicos. Universidad de Buenos Aires. Facultad de Medicina. Centro de Estudios Farmacológicos y Botánicos; ArgentinaFil: Capobianco, Evangelina Lorena. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Centro de Estudios Farmacológicos y Botánicos. Universidad de Buenos Aires. Facultad de Medicina. Centro de Estudios Farmacológicos y Botánicos; Argentin

The activation of peroxisome proliferator activated receptros (PPARs) as the regulator of lipid metabolism in the placenta of patients with diabetes

Dadas las alteraciones metabólicas inducidas por la diabetes materna y la capacidad de los receptores nucleares PPAR de regular el metabolismo lipídico, se propuso como objetivo evaluar los niveles de lípidos y PPAR en la placenta de pacientes sanas y con diabetes tipo 2, y determinar si la activación de los PPAR regula los niveles y peroxidación lipídica en dichos tejidos. Metodología: las placentas se obtuvieron luego del alumbramiento, se determinaron los niveles de lípidos mediante cromatografía, los niveles de PPAR mediante Western blot y la peroxidación lipídica mediante la cuantificación de TBARS. Resultados: se evidenciaron mayores niveles de lípidos y menores niveles de PPAR_ y PPARaen placenta de pacientes diabéticas en relación con el control (P<0,05). Los agonistas de PPAR_ redujeron la masa lipídica en la placenta de pacientes sanas y diabéticas, mientras que la activación de PPARb la redujo sólo en la placenta de pacientes sanas. Al activar PPARaaumenta la masa lipídica y la expresión de la enzima de síntesis de ácidos grasos FASN (P<0,05). La peroxidación lipídica, incrementada en placenta de pacientes diabéticas (P<0,001), se reguló negativamente al activar los tres isotipos de los PPAR (P<0,05). Conclusión: se identificaron en este estudio noveles funciones de los PPAR en la placenta humana, relevantes en la regulación del metabolismo lipídico y la lipoperoxidación. La diabetes tipo 2 induce a nivel placentario alteraciones en los niveles y función de los PPAR vinculadas a las importantes anomalías en el metabolismo lipídico y un estado prooxidante inducidas por esta patología.Due to the metabolic alterations induced by maternal diabetes and the capacity of nuclear receptors PPARs to regulate lipid metabolism the aim of this study was to evaluate the concentrations of lipids and PPARs in the placenta from healthy and type 2 diabetic patients and to determine whether PPARs activation regulate lipid concentrations and peroxidation in these tissues. Methods: Placentas were obtained after delivery, lipid levels were determined by chromatography, concentrations of PPARs isotypes were evaluated by Western blot and the lipid peroxidation determined by TBARS quantification. Results: There are higher levels of lipids and lower concentrations of PPAR_ and PPARa in the placenta from diabetic patients when compared to controls (P<0.05). PPAR_ agonists decreased the lipid mass in the placenta from healthy and diabetic patients, while PPARb activation decreased the lipid mass only in the placenta from healthy patients. When PPARa was activated, the lipid mass and the expression of the fatty acid synthase enzyme (FASN) were increased. Lipid peroxidation, increased in the placenta from diabetic patients (P<0.001), was negatively regulated when the three PPARs were activated (P<0.05). Conclusion: We identified in this work novel PPAR functions in the human placenta as relevant regulators of lipid metabolism and peroxidation. Type 2 diabetes induced in the placenta alterations in PPARs expression and function, related to the important anomalies in lipid metabolism and the pro-oxidative state induced by this pathology.Fil: Capobianco, Evangelina Lorena. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Centro de Estudios Farmacológicos y Botánicos; Argentina. Universidad de Buenos Aires. Facultad de Medicina; ArgentinaFil: Martinez, Nora Alicia. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Centro de Estudios Farmacológicos y Botánicos; Argentina. Universidad de Buenos Aires. Facultad de Medicina; ArgentinaFil: Fornes, Daiana. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Centro de Estudios Farmacológicos y Botánicos; Argentina. Universidad de Buenos Aires. Facultad de Medicina; ArgentinaFil: Higa, Romina Daniela. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Centro de Estudios Farmacológicos y Botánicos; Argentina. Universidad de Buenos Aires. Facultad de Medicina; ArgentinaFil: Kurtz, Melisa Lidia Amelia. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Centro de Estudios Farmacológicos y Botánicos; Argentina. Universidad de Buenos Aires. Facultad de Medicina; ArgentinaFil: Di Marco, Ingrid. Hospital Materno-Infantil Ramón Sardá; ArgentinaFil: Basualdo, María Natalia. Hospital Materno-Infantil Ramón Sardá; ArgentinaFil: Faingold, Cristina. Hospital César Milstein; ArgentinaFil: Jawerbaum, Alicia Sandra. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Centro de Estudios Farmacológicos y Botánicos; Argentina. Universidad de Buenos Aires. Facultad de Medicina; Argentin

Association of Polyphenols Consumption with Risk for Gestational Diabetes Mellitus and Preeclampsia: A Systematic Review and Meta-Analysis

Gestational Diabetes Mellitus (GDM) and preeclampsia (PE) affects 6&ndash;25% of pregnancies and are characterized by an imbalance in natural prooxidant/antioxidant mechanisms. Due to their antioxidant and anti-inflammatory properties, polyphenols consumption during the pregnancy might exert positive effects by preventing GDM and PE development. However, this association remains inconclusive. This systematic review and metanalysis is aimed to analyze the association between polyphenol-rich food consumption during pregnancy and the risk of GDM and PE. A systematic search in MEDLINE, EMBASE, and Web of Science (Clarivate Analytics, London, United Kingdom) for articles dated between 1 January 1980 and July 2022 was undertaken to identify randomized controlled trials and observational studies evaluating polyphenol-rich food consumption and the risk of GDM and PE. The Newcastle-Ottawa Scale was used to evaluate the quality of these included studies. Twelve studies were included, of which eight articles evaluated GDM and four studied PE. A total of 3785 women presented with GDM (2.33%). No association between polyphenol consumption and GDM was found (ES = 0.85, 95% CI 0.71&ndash;1.01). When total polyphenol intake was considered, a lower likelihood to develop GDM was noted (ES = 0.78, 95% CI 0.69&ndash;0.89). Furthermore, polyphenol consumption was not associated with PE development (ES = 0.90, 95% CI 0.57&ndash;1.41). In conclusion, for both outcomes, pooled analyses showed no association with polyphenol-rich food consumption during pregnancy. Therefore, association of polyphenol intake with a decreased risk of GDM and PE remains inconclusive

Diets enriched in PUFAs at an early postimplantation stage prevent embryo resorptions and impaired mTOR signaling in the decidua from diabetic rats

Maternal diabetes increases the risk of embryo resorptions and impairs embryo development. Decidualization is crucial for embryo development and regulated by mTOR signaling. However, little is known about how maternal diabetes affects the decidua at early postimplantation stages and whether dietary treatments enriched in polyunsaturated fatty acids (PUFAs) can prevent decidual alterations. Here, we determined resorption rates, decidual mTOR pathways and markers of decidual function and remodeling in diabetic rats fed or not with diets enriched in PUFAs exclusively during the early postimplantation period. Pregestational streptozotocin-induced diabetic Albino Wistar rats and controls were fed or not with diets enriched in 6% sunflower oil or 6% chia oil (enriched in n-6 or n-3 PUFAs, respectively) on days 7, 8 and 9 of pregnancy and evaluated on day 9 of pregnancy. Maternal diabetes induced an 11-fold increase in embryo resorptions, which was prevented by both PUFAs-enriched diets despite no changes in maternal glycemia. The activity of mTOR pathway was decreased in the decidua from diabetic rats, an alteration prevented by the PUFAs-enriched diets. PUFAs-enriched diets prevented increased expression of Foxo1 (a negative regulator of mTOR) and reduced expression of miR-21 (a negative regulator of Foxo1). These diets also prevented reduced markers of decidual function (leukemia inhibitory factor and IGFBP1 expression and MMPs activity) in diabetic rat decidua. We identified the early post implantation as a crucial stage for pregnancy success, in which dietary PUFAs can protect diabetic pregnancies from embryo resorptions, decidual mTOR signaling impairments, and altered markers of decidual function and remodeling.Fil: Roberti, Sabrina Lorena. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Centro de Estudios Farmacológicos y Botánicos. Universidad de Buenos Aires. Facultad de Medicina. Centro de Estudios Farmacológicos y Botánicos; ArgentinaFil: Gatti, Cintia Romina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Centro de Estudios Farmacológicos y Botánicos. Universidad de Buenos Aires. Facultad de Medicina. Centro de Estudios Farmacológicos y Botánicos; ArgentinaFil: Fornes, Daiana. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Centro de Estudios Farmacológicos y Botánicos. Universidad de Buenos Aires. Facultad de Medicina. Centro de Estudios Farmacológicos y Botánicos; ArgentinaFil: Higa, Romina Daniela. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Centro de Estudios Farmacológicos y Botánicos. Universidad de Buenos Aires. Facultad de Medicina. Centro de Estudios Farmacológicos y Botánicos; ArgentinaFil: Jawerbaum, Alicia Sandra. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Centro de Estudios Farmacológicos y Botánicos. Universidad de Buenos Aires. Facultad de Medicina. Centro de Estudios Farmacológicos y Botánicos; Argentin

Association between menopausal hormone therapy use and mortality risk: a Swedish population-based matched cohort study

Background The net effect of menopausal hormone therapy on the risk of death is understudied, and current evidence is conflicting. Our aim was to investigate the association between menopausal hormones and risk of all-cause, cardiovascular, and cancer-specific mortality, based on the Swedish Prescribed Drug Registry and National Patient Registry. Methods This Swedish population-based matched cohort study included all women, 40 years or older, who had received at least one prescription of systemic menopausal hormone therapy between 2005-2014 (n = 290,186), group level matched 1:3 to non-users (n = 870,165). Multivariable conditional logistic regression models estimated the relative risk of all-cause and cause-specific mortality, adjusting for several clinical factors and comorbidities. Results Ever-use of menopausal hormones was associated with a slightly lower overall odds of all-cause (OR = 0.97, 95%CI 0.95-0.98) and cardiovascular (OR = 0.97, 95%CI 0.95-0.99) mortality, whilst 30% lower overall odds of cancer-related mortality (OR = 0.70, 95%CI 0.68-0.72) was shown. The odds of all-cause and cancer-related mortality were consistently reduced among women who began menopausal hormone therapy = 70 years. Among current users, oestrogen-only therapy was associated with higher odds of all-cause (OR = 1.48, 95%CI 1.44-1.52) and cardiovascular mortality (OR = 1.24, 95%CI 1.20-1.28), whereas past use of oestrogen-only therapy suggested lower odds of mortality. Conclusions Our generalisable data suggest that early menopausal hormone treatment initiation does not increase the odds of mortality. However, the role of oestrogens in particularly cardiovascular mortality remains to be investigated