bluuebunny/crossref_metadata_2025_split huggingface dataset:
Early Phenotypes in Girls at Risk for PCOS Replicate Metabolic and Reproductive Subtypes: An Unsupervised Clustering Analysis
Authors: Torchen Laura Christine , Sisk Ryan , Ratnam Sarayu , Dunaif Andrea Elizabeth 
Published: May 2021

Abstract
Both daughters of women with PCOS (PCOS-d) and overweight girls (OW-g) are proposed to be at increased risk of PCOS because they have peripubertal increases in testosterone (T) levels, a cardinal feature of PCOS. We are testing this hypothesis by performing longitudinal studies in these girls after menarche. In adult women with PCOS, we have recently identified reproductive and metabolic subtypes using unsupervised cluster analyses. These subtypes were associated with novel PCOS susceptibility genetic loci suggesting that the subtypes reflect biologically discrete entities. We performed similar analyses in our cohort of early postmenarchal PCOS-d and OW-g to test the hypothesis that these subtypes are present in girls at risk for PCOS.
Fifteen PCOS-d and 10 OW-g aged 11-16 years and with postmenarchal age less than 2 years were studied. Mothers of PCOS-d fulfilled NIH criteria for PCOS, mothers of OW-g were reproductively normal with no history of irregular menses or clinical hyperandrogenism. OW-g had a BMI above the 85th percentile for age. There was no BMI inclusion criterion for PCOS-d; four PCOS-d had a BMI above the 85th percentile. The girls were of comparable age, post-menarchal age and BMI z score. A fasting morning blood sample was drawn for T, SHBG, DHEAS, glucose and insulin. Leuprolide 10 mcg/kg SC was administered. LH and FSH levels were measured at baseline, 30 min, and 60 min following leuprolide.
Unsupervised hierarchical cluster analysis adjusted for age was performed on quantitative traits including BMI, T, fasting insulin, fasting glucose, DHEAS, SHBG, and LH and FSH. These are the same quantitative traits used for clustering in adult PCOS. The clustering revealed 2 distinct PCOS subtypes: a reproductive group (41%), characterized by higher SHBG levels, LH and FSH with relatively low BMI and insulin levels, and a metabolic group (41%), characterized by higher BMI and insulin levels and lower SHBG, LH, and FSH. Jaccard coefficients indicated cluster stability (0.70 reproductive, 0.69 metabolic). There was a significant difference in the distribution of the two subgroups in PCOS-d and OW-g: PCOS-d 60% reproductive, 13% metabolic, 27% indeterminate; OW-g 25% reproductive, 50% metabolic, 25% indeterminate (Chi Sq P=0.05).
We found that early postmenarchal PCOS-d and OW-g demonstrate reproductive and metabolic subtypes similar to those identified in adult women with PCOS. The majority of PCOS-d had the reproductive subtype. These findings suggest that this subtype, which is characterized by disordered gonadotropin secretion, is an early harbinger of PCOS. Longitudinal studies are ongoing to test this hypothesis.
Mechanisms Involved in Intrauterine Growth Restriction in Patients With Polycystic Ovary Syndrome: Primary and Secondary Prevention of Metabolic Syndrome and Cancer Risk in the Adult Life of Offspring
Authors: Mugnolo Domingo , Giraldo Erica , Lana Maria Perez , Campeni Susana Beatriz 
Published: May 2021

Abstract
Polycystic ovary syndrome (PCOS) is one of the most common hormonal disorders that affects between 5- 10% of women of reproductive age. It is currently considered a complex and multifactorial disease with metabolic, cardiovascular implications and represents per se an increased cancer risk. PATIENTS with PCOS routinely have menstrual disorders, hyperandrogenism, infertility and reproductive complications such as recurrent abortions, gestational diabetes, intrauterine growth restriction, pregnancy induced hypertension that give rise to underweight newborns and condition metabolic diseases to adult life and increased risk of cancer, especially breast and endometrial cancer. Insulin resistance and hyperandrogenism are the most important etiopathogenic factors in PCOS. On the other hand, subjects exposed to an adverse microenvironment in the intrauterine stage develop compensating responses to survive, a process called fetal programming. Prenatal exposure to androgens and/or insulin resistance may act as fetal programming factors and cause restriction of intrauterine growth, obesity and insulin resistance in offspring. Newborn may have an increased risk of metabolic syndrome, increased incidence of hypertensive, type 2 diabetes, heart disease and cerebrovascular disease. Prevention of these complications will be achieved if women with Polycystic Ovary Syndrome are treated appropriately throughout their lives, but especially before and during their pregnancy. Only in this way can the risk of them be reduced, representing a better quality and greater life expectancy.
A Re-Examination of the oCRH Stimulation Test for the Diagnosis of Ectopic ACTH Secretion
Authors: Newman Andrew Joseph , McGlotten Raven , Nieman Lynnette K 
Published: May 2021

Abstract
Background: Previous studies of the oCRH test for the differential diagnosis of ACTH-dependent Cushing’s syndrome gave imprecise point estimates of specificity because of small numbers (n&lt;20) of patients with ectopic ACTH secretion (EAS). We examined a large EAS population to re-assess the test’s performance and whether benign tumors were associated with a positive response (i.e. Cushing’s disease (CD). Methods: We evaluated 103 EAS patients, including 58 females, with median age of 38 years (range 10 - 83); 99 had surgically-proven tumors and four had biochemical testing consistent with EAS. ACTH and cortisol were measured 5 and 0 minutes before and 15, 30 and 45 minutes after administration of oCRH, 1 ug/kg up to 100 ug, iv. Previous criteria were used to determine EAS responses: mean ACTH increase of &lt;34% at 15 and 30 min or mean cortisol increase of &lt;20% at 30 and 45 min. Mean responses and UFC (expressed as fold increase above upper limit of normal, ULN) were compared with t-tests; a p-value of &lt; 0.05 was considered significant. Results: Tumor types included NET (pulmonary n=67; with 4 spindle type and 5 tumorlets, thymic n=9, pancreas n=7, appendix n=1, prostate n=1), SCLC (N=3), pheochromocytoma/paraganglioma (n=3/1), metastatic without known primary (n=3), teratoma with corticotroph elements (n=1) and occult (n=4). 23 patients had “CD” responses that were significantly higher than those of non-responders: 11 with ACTH (mean+SD: 83.7 + 49.8% vs 1.2 + 18.8%, p=00025), 15 with cortisol (mean+SD: 34.7 + 8.9% vs -1.7 + 14.2%, p&lt; 0.00001). Three patients responded to both ACTH and cortisol. Among the ACTH (only) responders, 6 had cortisol increases of &lt; 10% (range 0-2-8.5%); a similar discordant response was seen among cortisol (only) responders, of whom 7 had ACTH increases of &lt;20% (range -18 - 13.4%). 70% of responders, including 3 with both ACTH and cortisol responses, had pulmonary NET (n=13), spindle cell NET (n=2) or tumorlets (n=4). Other responders had thymic NET (n=3), appendiceal NET n=1, teratoma (n=1) or were occult (n=2). The patient with corticotroph elements in a teratoma had an ACTH response only. UFC fold-increases above ULN were similar in responders and non-responders (20.20 + 26.9 xULN vs 31.4 + 38.4 xULN, p =0.21). Four of 10 patients with UFC cyclicity responded to CRH. Conclusions: Among patients with EAS the rate of false positive responses to CRH was similar to that of initial reports, 11–15%, and was associated with hormonal cyclicity and presence of a thymic carcinoid. The marked discordance of ACTH and cortisol responses may result from reduced sensitivity to ACTH, less biologically active ACTH, or autonomous cortisol release.
Sleep Characteristics Among Women With and Without PCOS
Authors: Oppermann Karen , Hemkemeier Stéfanie Zamboni Perozzo , Reichert Ana Victoria , Weber Lais , Rinaldi Laura 
Published: May 2021

Abstract
Clinical studies indicate that sleep disorders, including obstructive sleep apnea (OSA) and excessive daytime sleepiness, occur more frequently among women with PCOS compared to comparison groups without the syndrome. The presence of OSA in PCOS is associated with worsening of metabolic parameters. There is some evidence that obesity directly contributes to OSA among women with PCOS, although, it does not fully account for findings from community-and clinic-based studies. Questionnaires are used as screening for sleep disorders. The objective was to verify the quality of sleep, the prevalence of OSA and daytime sleepness among women with PCOS compared to control group. The sample size calculation was based on estimates bad quality of sleep among women with PCOS in 80% and among control women in 45% (1). The sample with 58 women, 29 each group, had a power of 80%, with a significance level of 0.05. This is a cross sectional study with 29 patients with PCOS and 31 controls from Gynecology Endocrinology Ambulatory of São Vicente de Paulo Hospital, Passo Fundo, RS, Brazil, who consulted between January 2017 and March 2020. Women with PCOS by Rotterdam criteria and controls were under 40 years old and no pregnant. Controls women had regular cycles, no history of PCOS or hirsutism and had normal ovaries on transvaginal ultrasound. Age, BMI, blood pressure (BP), waist circumference (WC) were measured. It was applied the validated questionnaires of Pittsburgh Sleep Quality Index, to classify in good and bad sleep quality; Epworth Sleepiness Scale for daytime sleepiness and Berlim Questionnaire for evaluate sleep apnea risk. The mean of age was 30.6 ± 5.9, PCOS 29.1± 6.7 versus 32.3±4.7, p=0.06. The group of PCOS women was heavier (BMI 32.4±6.1versus 28.0 ± 5.3, p=0.04) and presented higher WC (101.3±16.1 versus 91.6 ±14cm, p=0.03). The mean of BP was similar between the groups. The prevalence of bad sleep quality was 53.6% for women with PCOS and 63.1% for controls (p=0.29). The daytime sleepiness was present in 14,5% of the women with PCOS and 35.7% of controls (p=0,061) and the sleep apnea risk was 32.1% for women with PCOS and 21.4% for controls (p=0.27). The association of risk of OSA was verified with robust multivariate Poisson. The prevalence ratio (PR) of BMI ≥ 30 was 1.820 (CI 1.281-2.587) p&lt;0.001, BMI ≥ 25 1.549 (IC 1.067- 2.250) p=0.02, adjusted for age, WC and PCOS diagnosis. In conclusion, there was no difference in prevalence of quality of sleep, OSA risk or daytime sleepiness between women with PCOS and controls. The risk of OSA was higher in obese women independently of age, abdominal circumference and PCOS diagnosis.
Reference: (1) Fernandez et al., Nature and Science of Sleep 2018; 10: 45–64.
ANGPTL3 Levels in Healthy and Mild Preeclamptic Pregnant Women
Authors: Garces Maria F , Franco - Vega Roberto , Maldonado - Acosta Luis M , Castro - Pinzón Andres , Eslava-Schmalbach Javier , Parada - Banos Arturo J , Angel–Müller Edith , Nogueiras Rubén , Dieguez Carlos , Castaño Justo , Ruiz–Parra Ariel I , Caminos Jorge Eduardo 
Published: May 2021

Abstract
Introduction: Throughout normal pregnancy, different metabolic and hormonal adaptations are presented, among others, significant modifications in the profile of lipids and lipoprotein metabolism. On the other hands, Angiopoietin-like protein 3 (ANGPTL3) are involved in the regulation of triglyceride metabolism in the fed state by inhibiting the enzyme lipoprotein lipase in oxidative tissues. Objective: Thus, the objective of this study was to determine the profile of serum ANGPTL3 levels during three periods of gestation and three months after delivery. Design, setting and Participants: Serum ANGPTL3 levels were analyzed by ELISA, throughout pregnancy in a case-control study nested within a longitudinal prospective cohort of healthy pregnant (n = 52) and mild preeclamptic women (n = 20), women in the third month postpartum (n = 20) and healthy non-pregnant women (n = 20). The results obtained were correlated with biochemical, hormonal, and anthropometric variables. Results: A significant reduction in ANGPTL3 levels was observed from the first to the third trimesters of pregnancy in healthy and preeclamptic pregnant women when compared with healthy non-pregnant and postpartum women (p&lt;0.01). There were no significant differences in serum ANGPTL3 levels between normal and preeclamptic women. Serum ANGPTL3 levels were positively correlated with triglyceride, very-low-density lipoprotein cholesterol, and total cholesterol levels in healthy non-pregnant (p&lt;0.05); whereas there were no significant correlations between ANGPTL3 with the same variables in healthy and preeclamptic pregnant women. Besides, there were no significant correlations between serum ANGPTL3 with body mass index, high-density lipoprotein cholesterol, glucose, insulin, leptin or HOMA-IR in the study groups described above. Conclusions: The results of the present study show for the first time that ANGPTL3 could be playing a fundamental role in the homeostasis of lipid metabolism throughout gestation. Thus, low levels of ANGPTL3 during pregnancy might favor the accumulation of lipid in oxidative tissues as a deposit of maternal energy source, while preserving glucose and amino acids for the fetus.
BMP6 Mediates BMP2-Increased Human Trophoblast Invasion
Authors: Deng Jianye , Li Yan 
Published: May 2021

Abstract
TGF-β superfamily proteins play divergent roles in regulating human extravillous trophoblast (EVT) invasion and their coordinated effects are essential for adequate placentation during pregnancy 1. Bone morphogenetic protein 2 (BMP2), which belongs to the BMP subfamily of TGF-β superfamily, has been shown to promote human EVT invasion and the acquisition of endothelial-like phenotype 2,3. It has been reported that BMP2 promotes EVT invasion by up-regulating Activin A, a growth factor which also belongs to TGF-β superfamily. However, whether BMP6 mediates the pro-invasive effect of BMP2 has yet to be determined. Herein, we firstly treated immortalized trophoblast cells (HTR8/SVneo) with recombinant BMP2 protein for 6 and 24 hrs, and our bulk-RNA sequencing results demonstrated significantly increased BMP6 mRNA levels after BMP2 treatment. Furthermore, we confirmed the up-regulatory effects of BMP2 on BMP6 mRNA and protein levels in both HTR8/SVneo and primary EVTs isolated from first-trimester villi. Notably, siRNA-mediated down-regulation of BMP6 significantly attenuated both basal and BMP2-induced cell invasion in HTR8/SVneo cells as measured by Matrigel-coated transwell invasion assay. In summary, our results firstly demonstrated the up-regulatory effect of BMP2 on BMP6 expression in human trophoblasts and identified the mediation role of BMP6 in BMP2-promoted EVT invasion, suggesting the interplay between BMP subfamily members during EVT invasion regulation. Our ongoing research focusing the underlying molecular mechanisms and signaling pathways could further benefit the advancement of diagnostic and therapeutic strategies for EVT invasion dysregulation-related pregnancy disorders, e.g., pre-eclampsia. Reference: (1) Li Yan et al., Trends Endocrinol Metab 2021 18: S1043-2760(20)30266-6. (2) Hong-Jin Zhao et al., FASEB J 2020;34(2):3151-3164. (3) Hong-Jin Zhao et al., Cell Death Dis 2018;9(2):174.
Effects of Dexamethasone on Offspring Survival and Intrauterine Growth Restriction
Authors: El Habbal Noura , Mulcahy Molly C , Redd JeAnna R , Bridges Dave 
Published: May 2021

Abstract
The placenta is the primary organ responsible for deactivating maternal glucocorticoids and reducing fetal exposure. Glucocorticoid use during pregnancy is a common treatment for asthma, allergies, and COVID-19. Several studies have reported adverse effects including intrauterine growth restriction as a result of glucocorticoid exposure, yet little is known about the mechanisms by which short and long-term maternal glucocorticoid exposures affect placental biology and fetal development. To better understand the role of glucocorticoids on placental and fetal outcomes, we used a mouse model exposed to the synthetic glucocorticoid, dexamethasone (Dex), prior to and throughout gestation. We conducted a randomized controlled trial in mice with a treatment arm of Dex exposure and water exposure as control. Virgin C57Bl/6J female mice were single-housed at 11 weeks of age, and Dex was introduced in the drinking water as a 1mg/kg/day dose. After one week of treatment, mice were bred with age-matched virgin males. Dam body composition, food, and water intake were monitored weekly. Maternal insulin sensitivity, pup survival rate, litter size, and pup birth weight at postnatal day (PND) 0.5 were also assessed. Dams treated with Dex lost significant lean mass after one week of treatment. Dex treatment did not appear to affect the dams’ ability to get pregnant, as both groups carried pups to term with similar lengths of gestation (p=0.838). Water and Dex-treated dams gained comparable weight during the first and second trimesters of pregnancy, however, the Dex group gained less lean mass than the water group during the third trimester. At PND0.5, Dex dams had fewer pups with a 40% reduction in litter size (p=0.01) and lighter pups with a 37% reduction in offspring weight (p&lt;0.001), indicating substantial intrauterine growth restriction. All pups of Dex-treated dams died by PND1. Attempts to rescue pups of Dex-dams by cross-fostering with water-treated nursing dams or by feeding the pups 10% glucose at PND0.5 failed by PND1. These results demonstrate a novel finding regarding the chronic use of glucocorticoids before and during conception and pregnancy. The reduction in both pup weight and late-pregnancy maternal weight gain suggests potential growth restriction or placental insufficiency. Further molecular studies during multiple time points of gestation will help elucidate the mechanisms at play.
Effects of Peripartal Sertraline on Maternal Calcium Metabolism and Maternal Bone Health
Authors: Sheftel Celeste M , Sartori Luma C , Manuel Robbie S J , Fricke Hannah P , Charles Julia F , Hernandez Laura L 
Published: May 2021

Abstract
Lactation taxes mothers’ bone health, causing them to lose up to 10% of their bone mass for milk calcium. Selective serotonin reuptake inhibitor antidepressants (SSRIs) are commonly used during pregnancy and lactation but independently decrease bone mass. We previously demonstrated that both maternal and offspring bone densities were compromised by maternal treatment with the SSRI fluoxetine throughout pregnancy and lactation.
In this study, we examined whether sertraline similarly affect maternal and offspring bone. Female C57BL/6 dams (n=23/group) were treated with sertraline (10 mg/kg/d) or a vehicle (DMSO) for 41 d (E0-lactation(L) 21). Pups were euthanized at weaning (L21). Dams were euthanized at peak lactation (L10, n=4/group), weaning (L21, n=9/group) or 3 mo post-weaning (n=10/group) for analysis.
Sertraline treatment did not affect dams’ weight gain during pregnancy or lactation and did not impact milk production/consumption, measured by weigh-suckle-weigh. Unlike fluoxetine, which increases circulating calcium, sertraline treatment reduced serum calcium concentration at L21 compared with control (p&lt;0.05). Mammary calcium genes were not altered at L10, but at L21 we observed decreased mammary expression of the calcium transporters Orai1, Spca1, Spca2, and Serca2 (p&lt;0.05), and a tendency for decreased Pthlh (a calcium-regulating peptide; p=0.08). In the intestinal duodenum, Calb1 (a cytosolic calcium trafficking protein) expression was increased at L10 and L21 (p&lt;0.05), and the calcium transporters Trpv6, Pmca1 and Spca2 were increased by L21 (p&lt;0.05). Sertraline treatment did not affect L21 calcium concentration in either tissue, although the mammary gland calcium was 3.5 times that of the duodenum.
Previously, we reported that circulating markers of bone formation (P1NP) or bone resorption (CTX) were unchanged in sertraline-treated dams at L21. This is unlike fluoxetine, which decreased P1NP without altering CTX. Furthermore, compared with control, sertraline treatment did not alter expression of bone resorption or formation genes (e.g. Trap, Rank/RankL, Alp, Runx2) in maternal femoral bone at L21 or 3 mo post-weaning.
Interestingly, in utero exposure to sertraline reduced litter size (5.4 vs 6.8 pups/dam, p&lt;0.01) and increased pup mortality (20% vs 5% dead pups/litter, p&lt;0.01) during the first 24 hours postpartum compared with controls, but did not affect length of gestation or live birth rate. Exposure to sertraline during lactation did not alter weight gain in the surviving offspring, nor did it alter circulating calcium in the pups at weaning, suggesting an adequate supply of calcium in the milk from the dam.
These data suggest that, compared with high-dose fluoxetine, low-dose peripartal sertraline has a milder impact on maternal bone and may reduce mammary calcium but could induce a failure to thrive in the offspring.
Aromatase Inhibitors in Erectile Dysfunction
Authors: Singh Santosh 
Published: May 2021

Abstract
Hyperestrogenism may cause erectile dysfunction(ED) by impeding normal penile development,increasing venous vascular permeability and leakage(via VEGF) and by inhibiting testosterone(T)production. Estrogen excess can impair spermatogenesis and may increase the risk of estrogen-sensitive cancers(viz.breast cancer)[1,2]Weekly and biweekly letrozole(2.5 mg),an aromatase inhibitor,has been reported to normalize serum T in males with obesity related hypogonadism and poor sperm quality,respectively.[3,4]A 40-year old insulin requiring,normotensive,obese(BMI-26.9),diabetic(12 years duration) was evaluated for ED.T was 187 ng/dl and estradiol(E2) was 69 pg/ml(normal-11-44 pg/ml) with normal LH and prolactin levels. There was normalization of T(increased to 487 ng/dl) with 2.5 mg letrozole every 3 weeks. Another patient,55 year old male, insulin requiring,hypertensive,obese(BMI-28.8),diabetic(21 years duration) had normalization of T(401 ng/dl) with baseline low T(224.4 ng/dl) and normal E2(33 pg/ml) with T-E2 ratio of less than 10,with weekly 2.5 mg letrozole. There was one kg weight gain and 0.2 ng/ml increase in PSA in two years. These cases highlight the significance of estimating both T and E2 in the evaluation of ED. Moreover,it also highlights the efficacy and safety of weekly and even every 3-week 2.5 mg letrozole therapy.
References: 1. .Schulster M,Bernie AM,Ramasamy R:The role of estradiol in male reproductive function.Asian Journal of Andrology,2016,18(3),435-440. 2. Goldfrank LR and Flomenbaum N:Goldfrank’s Toxicologic Emergencies,McGraw- Hill Professional,2006,p443. 3.Loves S,Ruinemans-Koerts,de Boer H:Letrozole once a week normalizes serum testosterone in obesity-related male hypogonadism. Eur J Endocrinol,2008,158,741-747.4. Singh SK:Aromatase inhibitors in male sex. Indian J Endocrinol Metab,2013,17,S259-261.