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Context: About 30% of patients with active acromegaly experience paradoxically increased growth hormone (GH) secretion during the diagnostic oral glucose tolerance test (OGTT). Endogenous glucose-dependent insulinotropic polypeptide (GIP) is implicated in this paradoxical secretion., Objective: We used the GIP receptor (GIPR) antagonist GIP(3-30)NH2 to test the hypothesis that GIP mediates this paradoxical response when GIPR is abundantly expressed in somatotropinomas., Methods: A total of 25 treatment-naive patients with acromegaly were enrolled. Each patient underwent one OGTT during simultaneous placebo infusion and one OGTT during a GIP(3-30)NH2 infusion. Blood samples were drawn at baseline and regularly after infusions to measure GH. We assessed pituitary adenoma size by magnetic resonance imaging and GIPR expression by immunohistochemistry on resected somatotropinomas. For mechanistic confirmation, we applied in vitro and ex vivo approaches. The main outcome measure was the effect of GIP(3-30)NH2 on paradoxical GH secretion during OGTT as a measure of GIP involvement., Results: In 4 of 7 patients with paradoxical GH secretion, GIP(3-30)NH2 infusion completely abolished the paradoxical response (P = .0003). Somatotrophs were available from 3 of 4 of these patients, all showing abundant GIPR expression. Adenoma size did not differ between patients with and without paradoxical GH secretion., Conclusion: Of 25 patients with acromegaly, 7 had paradoxical GH secretion during OGTT, and pharmaceutical GIPR blockade abolished this secretion in 4. Corresponding somatotroph adenomas abundantly expressed GIPR, suggesting a therapeutic target in this subpopulation of patients. In vitro and ex vivo analyses confirmed the role of GIP and the effects of the antagonist., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Endocrine Society.)

Objectives: We aimed to investigate potential associations between serum apolipoprotein levels in early pregnancy and the risk of gestational diabetes mellitus (GDM) and adverse pregnancy outcomes., Methods: This was an observational study of the population-based Odense Child Cohort. Pregnant women were followed from inclusion until childbirth. Apolipoprotein levels, including 12 apolipoproteins (ApoA-I, ApoA-II, ApoA-IV, ApoB, ApoC-I, ApoC-II, ApoC-III, ApoD, ApoE, ApoH, ApoJ, and ApoM) were measured by targeted proteomics using liquid chromatography mass spectrometry on late first trimester serum samples stored in a biobank. GDM was defined by WHO 2013 diagnostic criteria., Results: A total of 991 pregnant women were included, of which 415 (41.9%) were diagnosed with GDM. GDM was associated with increasing ApoB (adjusted OR: 1.26, P = 0.002) and ApoD levels (adjusted OR: 0.84, P = 0.021). ApoB levels in early pregnancy correlated significantly and positively with insulin resistance (r = 0.22, P < 0.001) and beta-cell function in 3rd trimester (r = 0.20, P < 0.001), whereas early pregnancy ApoD levels were inversely correlated with insulin resistance (r = -0.14, P < 0.001) and beta-cell function (r = -0.12, P < 0.001). Finally, high levels of ApoD was significantly associated with lower risk of large-for-gestational-age (LGA) infants (adjusted OR: 0.78, P = 0.041)., Conclusions: High levels of ApoB and low levels of ApoD in early pregnancy were independently associated with an increased risk of GDM, insulin resistance and LGA infants (low ApoD only), suggesting potential roles for future management of pregnancy outcomes., Competing Interests: Disclosures All authors report no conflicts of interest in the study presented here., (Copyright © 2025. Published by Elsevier Inc.)

Introduction: Myocardial dysfunction and the presence of calcified and non-calcified coronary plaques are predictors of cardiovascular disease. Masculinizing gender-affirming hormone therapy may increase cardiovascular risk, highlighting the need for prospective studies to evaluate cardiovascular outcomes during gender-affirming hormone therapy., Objectives: To evaluate changes in cardiac morphology, systolic and diastolic function, and development of coronary plaques after masculinizing gender-affirming hormone therapy., Methods: Prospective study including 47 transmasculine persons (gender-affirming hormone therapy-naïve, TransM&#95;TN, n = 15 and gender-affirming hormone therapy-ongoing, TransM&#95;TO, n = 32). Included persons were evaluated at study inclusion and after one year of masculinizing gender-affirming hormone therapy. At baseline, the median age of TransM&#95;TN was 22 years (interquartile range 19-28 years) and TransM&#95;TO 26 years (interquartile range 24-37 years) with a median gender-affirming hormone therapy duration of 4 years (interquartile range 2-5 years). Cardiac morphology including left ventricular wall thickness, volume, and mass, as well as left ventricular systolic and diastolic function was evaluated using echocardiography. Coronary artery calcifications and non-calcified coronary plaque were assessed using coronary computed tomography angiography. Paired and unpaired statistical analyses were performed within and between TransM&#95;TN and TransM&#95;TO groups., Results: In TransM&#95;TN, diastolic function decreased during follow-up with decreased septal and lateral left ventricular relaxation (14-11 cm/s, p = 0.04 and 18-15 cm/s, p = 0.02, respectively). No significant changes were observed in cardiac morphology, systolic function, or formation of coronary artery calcifications and non-calcified coronary plaque in TransM&#95;TN or TransM&#95;TO groups. At baseline, left ventricular end-diastolic internal diameter was significantly higher in TransM&#95;TO compared to TransM&#95;TN, 4.6 cm (interquartile range 4.3-5.0 cm) versus 4.4 cm (interquartile range 4.2-4.6 cm), p < 0.05. Other baseline cardiac outcomes were comparable between TransM&#95;TN and TransM&#95;TO., Conclusion: Diastolic function declined after the initiation of masculinizing gender-affirming hormone therapy and individuals on long-term masculinizing gender-affirming hormone therapy had larger left ventricular dimensions compared to individuals before gender-affirming hormone therapy initiation. Cardiac morphology, systolic function, and coronary plaque formation remained stable during masculinizing gender-affirming hormone therapy., (© 2025 The Author(s). Andrology published by John Wiley & Sons Ltd on behalf of American Society of Andrology and European Academy of Andrology.)

Aims: Women with previous gestational diabetes mellitus (GDM) have an increased risk for later development of type 2 diabetes. During pregnancy, GDM affects the cardio-metabolic protein profile; however, it is unknown how GDM affects the cardio-metabolic protein profile in the long term and if it is associated with type 2 diabetes after GDM. We hypothesise that the cardio-metabolic protein profile is affected long term and is associated with the development of type 2 diabetes after GDM., Materials and Methods: A case-control follow-up study based on the Odense GDM Follow-Up Study (OGFUS) cohort, which included women with previous GDM (n = 128) and matched controls without previous GDM (n = 70). Blood samples from a follow-up assessment 8-10 years after delivery were analysed using a 29-plex panel of apolipoproteins, transport and inflammation/immune proteins using multiple-reaction-monitoring mass spectrometry., Results: Apolipoprotein A-I, D and M were significantly lower in women with previous GDM compared to controls (all p < 0.001), while apolipoprotein L-I, H, vitamin D binding protein, CRP, vitronectin, transthyretin and complement factors 3 and B were significantly higher (p = 0.008, p < 0.001, p < 0.001, p < 0.001, p < 0.001, p = 0.005, respectively). All associations remained significant after adjustment for multiple testing except CRP, whereas apolipoprotein D, vitronectin and complement factors 3 and B were associated with the development of type 2 diabetes in women with previous GDM (p = 0.02, p = 0.001, p < 0.001, p = 0.004, respectively)., Conclusions: The cardio-metabolic protein profile 8-10 years after pregnancy is altered in women with previous GDM. Apolipoprotein D, vitronectin and complement factors 3 and B are candidate risk markers of type 2 diabetes after GDM pregnancy., (© 2025 The Author(s). Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)

Transgender identity is often associated with gender dysphoria and minority stress. Gender-affirming hormone treatment (GAHT) includes masculinising or feminising treatment and is expected to be lifelong in most cases. Sex and sex hormones have a differential effect on metabolism and CVD in cisgender people, and sex hormone replacement in hypogonadism is associated with higher vascular risk, especially in ageing individuals. Using narrative review methods, we present evidence regarding metabolic and cardiovascular outcomes during GAHT and propose recommendations for follow-up and monitoring of metabolic and cardiovascular risk markers during GAHT. Available data show no increased risk for type 2 diabetes in transgender cohorts, but masculinising GAHT increases lean body mass and feminising GAHT is associated with higher fat mass and insulin resistance. The risk of CVD is increased in transgender cohorts, especially during feminising GAHT. Masculinising GAHT is associated with a more adverse lipid profile, higher haematocrit and increased BP, while feminising GAHT is associated with pro-coagulant changes and lower HDL-cholesterol. Assigned male sex at birth, higher age at initiation of GAHT and use of cyproterone acetate are separate risk factors for adverse CVD markers. Metabolic and CVD outcomes may improve during gender-affirming care due to a reduction in minority stress, improved lifestyle and closer surveillance leading to optimised preventive medication (e.g. statins). GAHT should be individualised according to individual risk factors (i.e. drug, dose and form of administration); furthermore, doctors need to discuss lifestyle and preventive medications in order to modify metabolic and CVD risk during GAHT. Follow-up programmes must address the usual cardiovascular risk markers but should consider that biological age and sex may influence individual risk profiling including mental health, lifestyle and novel cardiovascular risk markers during GAHT., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Objective: Maternal thyroid autoimmunity and thyroid function in early pregnancy may impact fetal neurodevelopment. We aimed to investigate how thyroid autoimmunity and thyroid function in early pregnancy were associated with language acquisition in offspring at 12-36 months of age., Methods: This study was embedded in the prospective Odense child cohort. Mother-child dyads were excluded in case of maternal intake of thyroid medication during pregnancy. The parents completed MacArthur-Bates Communicative Development Inventories (MB-CDI) every third month to assess their offspring's productive vocabulary. All completed reports for each child were included in the analyses. Logistic growth curve models evaluated associations between MB-CDI scores and levels of maternal thyroid peroxidase antibodies (TPOAb), free thyroxine (FT4), and thyrotropin, respectively, measured in early pregnancy (median gestational week 12). All models were stratified by offspring sex and adjusted for maternal age, education, pre-pregnancy body mass index, parity, breastfeeding, and offspring age., Results: The study included 735 mother-child dyads. Children born to mothers with TPOAb ≥11 kIU/L, opposed to TPOAb <11 kIU/L, had a lower probability of producing words at age 18-36 months for girls (OR = 0.78, P < 0.001) and 33-36 months for boys (OR = 0.83, P < 0.001). The probability of producing words was higher in girls at 30-36 months of age with low-normal maternal FT4 vs high-normal FT4 (OR = 0.60, P < 0.001), and a similar trend was seen in boys. Results were ambiguous for thyrotropin., Conclusion: In women without known thyroid disease, TPOAb positivity in early pregnancy was negatively associated with productive vocabulary acquisition in girls and boys. This association was not mediated by a decreased thyroid function, as low-normal maternal FT4, unexpectedly, indicated better vocabulary acquisition. Our results support that maternal thyroid autoimmunity per se may affect fetal neurodevelopment.

Background: Preeclampsia shares numerous risk factors with cardiovascular diseases. Here, we aimed to assess the potential utility of high-sensitivity cardiac troponin I (hs-cTnI) values during pregnancy in predicting preeclampsia occurrence., Methods: This study measured hs-cTnI levels in 3721 blood samples of 2245 pregnant women from 4 international, prospective cohorts. Three analytical approaches were used: (1) a cross-sectional analysis of all women using a single blood sample, (2) a longitudinal analysis of hs-cTnI trajectories in women with multiple samples, and (3) analyses of prediction models incorporating hs-cTnI, maternal factors, and the sFlt-1 (soluble fms-like tyrosine kinase 1)/PlGF (placental growth factor) ratio., Results: Women with hs-cTnI levels in the upper quarter had higher odds ratios for preeclampsia occurrence compared with women with levels in the lower quarter. Associations were driven by preterm preeclampsia (odds ratio, 5.78 [95% CI, 2.73-12.26]) and remained significant when using hs-cTnI as a continuous variable adjusted for confounders. Between-trimester hs-cTnI trajectories were independent of subsequent preeclampsia occurrence. A prediction model incorporating a practical hs-cTnI level of detection cutoff (≥1.9 pg/mL) alongside maternal factors provided comparable performance with the sFlt-1/PlGF ratio. A comprehensive model including sFlt-1/PlGF, maternal factors, and hs-cTnI provided added value (cross-validated area under the receiver operator characteristic, 0.78 [95% CI, 0.73-0.82]) above the sFlt-1/PlGF ratio alone (cross-validated area under the receiver operator characteristic, 0.70 [95% CI, 0.65-0.76]; P =0.027). As assessed by likelihood ratio tests, the addition of hs-cTnI to each prediction model significantly improved the respective prediction model not incorporating hs-cTnI, particularly for preterm preeclampsia. Net reclassification improvement analyses indicated that incorporating hs-cTnI improved risk prediction predominantly by correctly reclassifying women with subsequent preeclampsia occurrence., Conclusions: These exploratory findings uncover a potential role for hs-cTnI as a complementary biomarker in the prediction of preeclampsia. After validation in prospective studies, hs-cTnI, alongside maternal factors, may either be considered as a substitute for angiogenic biomarkers in health care systems where they are sparce or unavailable, or as an enhancement to established prediction models using angiogenic markers., Competing Interests: Disclosures sFlt-1 and PlGF in OCC were initially measured in collaboration with BRAHMS GmbH at their facility in Hennigsdorf, Berlin. For this study, BRAHMS had no further involvement in collection or interpretation of data, writing of the report, or decision to submit the article for publication. S.B. has received research funding from Abbott, Abbott Diagnostics, Bayer, Boehringer Ingelheim, Siemens, and Thermo Fisher; honoraria for lectures from Abbott, Abbott Diagnostics, AstraZeneca, Bayer, Boehringer Ingelheim, Medtronic, Pfizer, Roche, Siemens Diagnostics, Siemens, and Thermo Fisher; and honoraria for advisory board memberships and consulting from Boehringer Ingelheim, Bayer, Novartis, Roche, and Thermo Fisher. T.Z. and S.B. are listed as coinventors of an international patent on the use of a computing device to estimate the probability of myocardial infarction (International Publication No. WO2022043229A1). T.Z. is a shareholder in ART.EMIS GmbH Hamburg. The other authors report no conflicts.

Objective: To investigate associations between maternal testosterone status and offspring birth anthropometrics., Design: Population-based prospective cohort study., Setting: University Hospital., Population: 1486 mother-child dyads from Odense Child Cohort., Methods: Maternal blood samples were collected at gestational weeks 27-30 and free testosterone (FT) levels were calculated using the Vermeulen equation from total testosterone (TT) analysed by mass spectrometry and sex hormone binding globulin. Associations between FT or TT levels and birth anthropometrics were analysed with multiple linear regression models according to offspring sex with adjustment for maternal age, parity, smoking and educational level. Analyses were repeated with polycystic ovary syndrome as exposure for offspring birth anthropometrics., Main Outcome Measures: Offspring birth weight (BW), birth length, abdominal and head circumferences., Results: Maternal mean (SD) age was 30.2 (4.5) years and pre-pregnancy body mass index was 23.5 (5.3) kg/m 2 . In boys (n = 787), higher FT was associated with lower birth weight (adjusted doubling constant = -65.53, P = 0.010), shorter birth length (adjusted doubling constant = -0.43, P < 0.001), and lower abdominal circumference (adjusted doubling constant = -0.39, P < 0.001); Higher TT was associated with lower abdominal circumference (adjusted doubling constant = -0.25, P = 0.028). In girls, no associations were found between maternal FT or TT and offspring anthropometrics., Conclusions: Higher maternal free testosterone exposure was linked to reduced birth weight, length and abdominal circumference in boys, whereas girls were not susceptible to maternal testosterone exposure., (© 2023 The Authors. BJOG: An International Journal of Obstetrics and Gynaecology published by John Wiley & Sons Ltd.)

Background: Polycystic ovary syndrome (PCOS) is the most prevalent, chronic endocrine-metabolic disorder of adolescents and young women (AYAs), affecting 5-10% of AYAs worldwide. There is no approved pharmacological therapy for PCOS. Standard off-label treatment with oral contraceptives (OCs) reverts neither the underlying pathophysiology nor the associated co-morbidities. Pilot studies have generated new insights into the pathogenesis of PCOS, leading to the development of a new treatment consisting of a fixed, low-dose combination of two so-called insulin sensitisers [pioglitazone (PIO), metformin (MET)] and one mixed anti-androgen and anti-mineralocorticoid also acting as an activator of brown adipose tissue [spironolactone (SPI)], within a single tablet (SPIOMET). The present trial will evaluate the efficacy, tolerability and safety of SPIOMET, on top of lifestyle measures, for the treatment of PCOS in AYAs., Methods: In this multicentre, randomised, double-blind, placebo-controlled, four-arm, parallel-group, phase II clinical trial, AYAs with PCOS will be recruited from 7 clinical centres across Europe. Intention is to randomise a total of 364 eligible patients into four arms (1:1:1:1): Placebo, PIO, SPI + PIO (SPIO) and SPI + PIO + MET (SPIOMET). Active treatment over 12 months will consist of lifestyle guidance plus the ingestion of one tablet daily (at dinner time); post-treatment follow-up will span 6 months. Primary endpoint is on- and post-treatment ovulation rate. Secondary endpoints are clinical features (hirsutism, menstrual regularity); endocrine-metabolic variables (androgens, lipids, insulin, inflammatory markers); epigenetic markers; imaging data (carotid intima-media thickness, body composition, abdominal fat partitioning, hepatic fat); safety profile; adherence, tolerability and acceptability of the medication; and quality of life in the study participants. Superiority (in this order) of SPIOMET, SPIO and PIO will be tested over placebo, and if present, subsequently the superiority of SPIOMET versus PIO, and if still present, finally versus SPIO., Discussion: The present study will be the first to evaluate-in a randomised, double-blind, placebo-controlled way-the efficacy, tolerability and safety of SPIOMET treatment for early PCOS, on top of a lifestyle intervention., Trial Registration: EudraCT 2021-003177-58. Registered on 22 December 2021. https://www.clinicaltrialsregister.eu/ctr-search/search?query=%092021-003177-58 ., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Background: Synthetic glucocorticoid exposure in late pregnancy may be associated with higher blood pressure in offspring. We hypothesized that endogenous cortisol in pregnancy relates to offspring blood pressure (OBP)., Objective: To investigate associations between maternal cortisol status in third trimester pregnancy and OBP., Methods: We included 1317 mother-child pairs from Odense Child Cohort, an observational prospective cohort. Serum (s-) cortisol and 24-hour urine (u-) cortisol and cortisone were assessed in gestational week 28. Offspring systolic blood pressure and diastolic blood pressure were measured at age 3, 18 months, and 3 and 5 years. Associations between maternal cortisol and OBP were examined by mixed effects linear models., Results: All significant associations between maternal cortisol and OBP were negative. In boys in pooled analyses, 1 nmol/L increase in maternal s-cortisol was associated with average decrease in systolic blood pressure (β=-0.003 mmHg [95% CI, -0.005 to -0.0003]) and diastolic blood pressure (β=-0.002 mmHg [95% CI, -0.004 to -0.0004]) after adjusting for confounders. At 3 months of age, higher maternal s-cortisol was significantly associated with lower systolic blood pressure (β=-0.01 mmHg [95% CI, -0.01 to -0.004]) and diastolic blood pressure (β=-0.010 mmHg [95% CI, -0.012 to -0.011]) in boys after adjusting for confounders, which remained significant after adjusting for potential intermediate factors., Conclusions: We found temporal sex dimorphic negative associations between maternal s-cortisol levels and OBP, with significant findings in boys. We conclude that physiological maternal cortisol is not a risk factor for higher blood pressure in offspring up to 5 years of age.

Fetal androgen exposure may be associated with autism spectrum disorder (ASD). We studied 1777 mother-child pairs in the prospective Odense Child Cohort. Prenatal androgen exposure was assessed by maternal 3rd trimester testosterone concentrations, maternal polycystic ovary syndrome (PCOS), and 3 months offspring anogenital distance. ASD traits were assessed at age 3 years with the ASD-symptom scale of the Child Behavior Checklist for ages 1½-5 years. Maternal testosterone was positively associated with traits of ASD in boys (p < 0.05). Maternal PCOS was associated with increased offspring ASD traits (p = 0.046), but became non-significant after excluding parental psychiatric diagnosis. Offspring anogenital distance was not linked to ASD traits. Higher prevalence of ASD in boys could be linked to higher susceptibility to fetal androgen exposure., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Objective: Active acromegaly is subject to sex differences in growth hormone (GH) and Insulin like growth factor 1 (IGF-I) patterns as well as clinical features but whether this also pertains to controlled disease is unclear., Design: In a cross-sectional, multi-centre study, 84 patients with acromegaly (F = 43, M = 41), who were considered controlled after surgery alone (n = 23) or during continued somatostatin receptor ligand (SRL) treatment (n = 61), were examined., Methods: Serum concentrations of GH, insulin, glucose and free fatty acid (FFA) were measured during an oral glucose tolerance test (OGTT) together with baseline serum IGF-I and completion of two HR-Qol questionnaires (acromegaly quality of life questionnaire [AcroQol] and Patient-assessed Acromegaly Symptom Questionnaire [PASQ])., Results: The mean age at the time of the study was 57 (±1.1) years and the majority of females (were postmenopausal. Females had significantly higher fasting GH but comparable IGF-I standard deviation scores (SDS). Using fasting GH < 1.0 µg/L as cut off, disease control was less prevalent in females (F: 56% vs. M: 83%, p = .007) whereas a comparable figure was observed using IGF-I SDS < 2 (F:79% vs. M:76%, p = .71). Compared with males, female patients showed impaired AcroQol physical score (p = .05), higher fasting FFA (p = .03) and insulin concentrations during the OGTT (p = .04)., Conclusion: In patients with acromegaly considered controlled, postmenopausal females exhibited higher GH levels than males despite comparable IGF-I levels, which also translated into impaired metabolic health and well-being. Our findings point to the relevance of including GH measurements in the assessment of disease control and suggest that disease-specific sex differences prevail after treatment., (© 2022 The Authors. Clinical Endocrinology published by John Wiley & Sons Ltd.)

Polycystic ovary syndrome (PCOS) is associated with insulin resistance. Few randomized controlled trials (RCT) compared myoinositol (MI) with metformin (MET) regarding insulin resistance in PCOS. This was an open-label six-month RCT in women with PCOS (n = 45) with interventions MI 4 g/day or MET 2 g/day. Primary outcome was the homeostasis model assessment of insulin resistance (HOMA-IR). Secondary outcomes were fasting glucose, weight, cycle length, lipids, testosterone, adverse effects, quality of life, and depression scores. Median age was 26 years. Body mass was index was 34.4 kg/m2. HOMA-IR was unchanged during MI (p = 0.31) and MET (p = 0.11) (MI vs. MET, p = 0.09). Median fasting glucose changed +0.2 mmol/L during MI (p < 0.001) and −0.1 mmol/L during MET (p = 0.04) (MI vs. MET p < 0.001). Median weight changed −2.3 kg during MI (p = 0.98) and −6.1 kg during MET (p < 0.001) (MI vs. MET, p = 0.02). Median cycle length decreased nine days during MI (p = 0.03) and 13 days during MET (p = 0.03) (MI vs. MET, p = 0.93). High-density lipoprotein (HDL) changed +0.1 mmol/L during MET (p = 0.04) (MI vs. MET, p = 0.07). All other blood parameters and scores of quality of life and depression remained unchanged during MI and MET (all p > 0.06) (MI vs. MET, all p > 0.27). Adverse effects appeared in four women during MI and 16 women during MET (MI vs. MET, p = 0.001). In conclusion, there was no effect on the metabolic outcomes during MI, but positive effects on fasting blood glucose, weight, and HDL during MET. The effect on cycle length was comparable during MI and MET. Adverse effects were less frequent during MI.

Background: Perfluoroalkyl substances (PFAS) are endocrine disrupting chemicals with elimination half-lives ranging from four to eight years. Experimental studies found PFAS able to interfere with thyroid hormone-binding proteins. During the first 20 weeks of gestation (GW), the fetus is reliant on placental transfer of maternal thyroid hormones, mainly free thyroxine (FT4). However, previous studies investigating associations between exposure to PFAS and thyroid hormone status mainly focused on blood samples from late pregnancy or umbilical cord with mixed findings., Objectives: To investigate associations between serum-PFAS concentrations and thyroid hormone status in early pregnancy as reflected by FT4 and thyroid-stimulating hormone (TSH)., Methods: In the Odense Child Cohort, a single-center study, we measured maternal pregnancy serum concentrations of five PFAS: perfluorohexane sulfonic acid (PFHxS), perfluorooctane sulfonic acid (PFOS), perfluorooctanoic acid (PFOA), perfluorononanoic acid (PFNA), perfluorodecanoic acid (PFDA); and FT4 and TSH in 1048 pregnant women at median GW 12 (25th, 75th percentile: 10, 15). Multivariate linear regression models were performed to estimate associations between PFAS exposure and thyroid hormone status., Results: A doubling in PFOS, PFOA, and PFNA concentrations was associated with an increment in FT4 concentration by 1.85% (95% CI: 0.66%, 3.05%), 1.29% (95% CI: 0.21%, 2.39%), and 1.70% (95% CI: 0.48%, 2.94%), respectively, in adjusted analyses. A statistically significant dose-response relationship was observed across exposure quartiles for PFOS, PFOA, and PFNA in the association with FT4. No association was found between concentrations of PFAS and TSH in adjusted analyses., Conclusion: Exposure to PFOS, PFOA, and PFNA was associated with higher FT4 concentrations in women during early pregnancy. The potential clinical implications of these findings remain to be clarified., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: Hypertension before and during early pregnancy has been associated with an increased risk of gestational diabetes mellitus (GDM) in retrospective analyses. We aimed to investigate the prospective blood pressure trackings in a population-based cohort of pregnant women, who were stratified according to their metabolic status in early third trimester., Methods: We recorded blood pressure longitudinally during pregnancy in 1230 women from the Odense Child Cohort, Denmark. Fasting glucose and insulin were measured at gestational weeks 28-30. Metabolic status was evaluated according to the WHO 2013 threshold for GDM (GDM-WHO: fasting plasma glucose ≥5.1 mmol/l), insulin and homeostatic model assessment of insulin resistance (HOMA-IR). Relationships between metabolic status in third trimester and blood pressure trajectories were evaluated with adjusted linear mixed models. Trajectory was defined as blood pressure records in pregnancy per 4 weeks interval., Results: Prevalence of GDM-WHO was 40% (498/1230). GDM-WHO was associated with 1.46 (0.22-2.70) mmHg higher SBP and 1.04 (0.07-2.01) mmHg higher DBP trajectories in the overall cohort. The associations were driven by differences in the overweight group, with 3.14 (1.05-5.25) mmHg higher SBP and 1.94 (0.42-3.47) mmHg higher DBP per 4 weeks in women with GDM-WHO compared with women without GDM-WHO. GDM-WHO was not associated with blood pressure in women with normal weight. Blood pressure trajectories were elevated across quartiles of insulin resistance., Conclusion: GDM-WHO is associated with higher blood pressure in pregnancy, and there appears to be a stronger effect in overweight women., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Introduction: Previous data suggested a link between maternal polycystic ovary syndrome (PCOS) and offspring attention deficit hyperactivity disorder (ADHD), which could be mediated by higher prenatal androgen exposure., Material and Methods: The study was part of the prospective Odense Child Cohort and included 1776 pregnant women, 165 (9%) with PCOS and 1607 (91%) controls. ADHD symptoms at 3 years of age were defined using the parent-reported questionnaire Child Behavior Checklist/1.5-5 (scores >90th centile of Danish national standard). Maternal blood samples were collected in the third trimester measuring total testosterone by mass spectrometry, sex hormone-binding globulin, and calculated free testosterone. Offspring anogenital distance was measured at 3 months of age. Regression models were performed with presence of ADHD symptoms as the dependent variable and adjusted for maternal age, body mass index, parity, smoking status, educational level, and parental psychiatric diagnoses., Results: ADHD symptoms were present in 105/937 (11%) boys and 72/839 (9%) girls. In boys, maternal PCOS was positively associated with ADHD symptoms (unadjusted odds ratio [OR] 1.91, 95% CI 1.07-3.43, p = 0.03, adjusted OR 2.20, 95% CI 1.20-4.02, p = 0.01), whereas maternal PCOS was not associated with ADHD symptoms in girls. Maternal total testosterone, free testosterone, and offspring anogenital distance were not associated with higher risk of ADHD symptoms in the offspring., Conclusions: Higher risk of ADHD in boys born of mothers with PCOS were not associated with maternal third-trimester testosterone levels or offspring anogenital distance., (© 2021 The Authors. Acta Obstetricia et Gynecologica Scandinavica published by John Wiley & Sons Ltd on behalf of Nordic Federation of Societies of Obstetrics and Gynecology (NFOG).)

Background: Parabens are added to personal care products as antimicrobial preservatives. They have been suggested to have endocrine disrupting abilities. Prenatal exposure to parabens has been associated with reproductive endpoints including reduced male anogenital distance (AGD, distance from anus to genitals), which is sensitive to prenatal anti-androgenic exposure., Objectives: To study the associations between maternal paraben concentrations in second trimester urine and AGD and reproductive hormone concentrations at 3 months of age in offspring., Methods: Pregnant women from Odense, Denmark were included in early pregnancy from 2010 to 12, and their children are being followed up. Fasting spot urine samples from 536 pregnant women were analyzed for methylparaben (MeP), ethyl-paraben (EtP), iso-propylparaben (i-PrP), n-propylparaben (n-PrP), n-butylparaben (n-BuP) and benzylparaben (BzP) by liquid chromatography tandem mass spectrometry and thereafter osmolarity adjusted. Three months after expected date of birth, AGD was measured in 452 children, and serum concentrations of follicle stimulating hormone (FSH), luteinizing (LH), testosterone, dehydroepiandrosterone-sulphate (DHEAS), androstenedione and 17-hydroxyprogesterone (17-OHP) were measured in 198 children. Maternal paraben exposure was categorized into tertiles or below and above level of detection, and sex-stratified multiple linear regression analyses were performed with AGD or reproductive hormones as outcomes., Results: Most pregnant women had low concentrations of parabens in urine, but 10% exceeded the threshold for adverse estrogenic effects. Higher maternal paraben exposure was associated with shorter AGD in male offspring and longer AGD in girls, although only significant for MeP in boys. In addition, FSH, LH, DHEAS, 17-OHP concentrations were lower in girls with high prenatal paraben exposure, whereas no consistent pattern was found in boys., Discussion: The endocrine disrupting abilities of parabens may affect humans at vulnerable time periods during development, which may have long term impact on reproductive function. This is the first study to find these associations in girls and our findings need confirmation., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)

Miscarriage is a common, complex trait affecting ~15% of clinically confirmed pregnancies. Here we present the results of large-scale genetic association analyses with 69,054 cases from five different ancestries for sporadic miscarriage, 750 cases of European ancestry for multiple (≥3) consecutive miscarriage, and up to 359,469 female controls. We identify one genome-wide significant association (rs146350366, minor allele frequency (MAF) 1.2%, P = 3.2 × 10 -8 , odds ratio (OR) = 1.4) for sporadic miscarriage in our European ancestry meta-analysis and three genome-wide significant associations for multiple consecutive miscarriage (rs7859844, MAF = 6.4%, P = 1.3 × 10 -8 , OR = 1.7; rs143445068, MAF = 0.8%, P = 5.2 × 10 -9 , OR = 3.4; rs183453668, MAF = 0.5%, P = 2.8 × 10 -8 , OR = 3.8). We further investigate the genetic architecture of miscarriage with biobank-scale Mendelian randomization, heritability, and genetic correlation analyses. Our results show that miscarriage etiopathogenesis is partly driven by genetic variation potentially related to placental biology, and illustrate the utility of large-scale biobank data for understanding this pregnancy complication.

Background: Perfluoroalkyl acids (PFAA) are repellants that cross the placental barrier, enabling interference with fetal programming. Maternal PFAA concentrations have been associated with offspring obesity and dyslipidemia in childhood and adulthood, but this association has not been studied in infancy., Objectives: We investigated associations between maternal PFAA concentrations and repeated markers of adiposity and lipid metabolism in infancy., Methods: In the prospective Odense Child Cohort, maternal pregnancy serum concentrations of five PFAA: Perfluorohexane sulfonic acid (PFHxS), perfluorooctane sulfonic acid (PFOS), perfluorooctanoic acid (PFOA), perfluorononanoic acid (PFNA), and perfluorodecanoic acid (PFDA) were measured in 649 women. Offspring were examined at birth ( n = 613 ) and at 3 months ( n = 602 ) and 18 months ( n = 503 ) of age. Total cholesterol, LDL, HDL, and triglyceride were evaluated at 3 months ( n = 262 ) and 18 months ( n = 198 ) of age. Mixed effects linear regression models estimated associations between PFAA and standardized (SDS) body mass index (BMI), ponderal index, and waist circumference. Associations between PFAA and body fat% (BF%) and plasma lipids SDS at 3 months and 18 months of age were investigated with linear regression models., Results: PFNA and PFDA were associated with higher BMI SDS [adjusted β = 0.26 ; 95% confidence interval (CI): 0.03, 0.49 and β = 0.58 ; 95% CI: - 0.03 , 1.19, respectively, for 1 -ng / mL increases] and ponderal index SDS ( β = 0.36 ; 95% CI: 0.13, 0.59 and β = 1.02 ; 95% CI: 0.40, 1.64, respectively) at 3 and 18 months of age (pooled) in girls. Corresponding estimates for boys were closer to the null but not significantly different from estimates for girls. In boys and girls (combined), PFNA and PFDA were associated with BF% at age 3 months (for 1 -ng / mL PFDA, β = 0.40 ; 95% CI: 0.04, 0.75), and PFDA was associated with total cholesterol SDS at 18 months ( β = 1.06 ; 95% CI: 0.08, 2.03) ( n = 83 )., Discussion: Prenatal PFAA were positively associated with longitudinal markers of adiposity and higher total cholesterol in infancy. These findings deserve attention in light of rising rates of childhood overweight conditions and dyslipidemia. https://doi.org/10.1289/EHP5184.

Background: Rapid human papillomavirus (HPV) DNA testing is an emerging cervical cancer screening strategy in resource-limited countries, yet it requires follow-up of women who test HPV positive., Objective: This study aimed to determine if one-way text messages improved attendance to a 14-month follow-up cervical cancer screening among HPV-positive women., Methods: This multicenter, parallel-group randomized controlled trial was conducted at 3 hospitals in Tanzania. Eligible participants were aged between 25 and 60 years, had tested positive to a rapid HPV test during a patient-initiated screening, had been informed of their HPV result, and had a private mobile phone with a valid number. Participants were randomly assigned in a 1:1 ratio to the intervention or control group through an incorporated algorithm in the text message system. The intervention group received one-way text messages, and the control group received no text messages. The primary outcome was attendance at a 14-month health provider-initiated follow-up screening. Participants were not blinded, but outcome assessors were. The analysis was based on intention to treat., Results: Between August 2015 and July 2017, 4080 women were screened for cervical cancer, of which 705 were included in this trial-358 women were allocated to the intervention group, and 347 women were allocated to the control group. Moreover, 16 women were excluded before the analysis because they developed cervical cancer or died (8 from each group). In the intervention group, 24.0% (84/350) women attended their follow-up screening, and in the control group, 23.8% (80/335) women attended their follow-up screening (risk ratio 1.02, 95% CI 0.79-1.33)., Conclusions: Attendance to a health provider-initiated follow-up cervical cancer screening among HPV-positive women was strikingly low, and one-way text messages did not improve the attendance rate. Implementation of rapid HPV testing as a primary screening method at the clinic level entails the challenge of ensuring a proper follow-up of women., Trial Registration: ClinicalTrials.gov NCT02509702; https://clinicaltrials.gov/ct2/show/NCT02509702., International Registered Report Identifier (irrid): RR2-10.2196/10.2196/15863., (©Ditte S Søndergaard Linde, Marianne S Andersen, Julius Mwaiselage, Rachel Manongi, Susanne K Kjaer, Vibeke Rasch. Originally published in the Journal of Medical Internet Research (http://www.jmir.org), 02.04.2020.)

Background: Fetal programming of the endocrine system may be affected by exposure to perfluoroalkyl substances (PFAAs), as they easily cross the placental barrier. In vitro studies suggest that PFAAs may disrupt steroidogenesis. "Mini puberty" refers to a transient surge in circulating androgens, androgen precursors, and gonadotropins in infant girls and boys within the first postnatal months. We hypothesize that prenatal PFAA exposure may decrease the concentrations of androgens in mini puberty., Objectives: To investigate associations between maternal serum PFAA concentrations in early pregnancy and serum concentrations of androgens, their precursors, and gonadotropins during mini puberty in infancy., Methods: In the prospective Odense Child Cohort, maternal pregnancy serum concentrations of five PFAAs: Perfluorohexane sulfonic acid (PFHxS), perfluorooctane sulfonic acid (PFOS), perfluorooctanoic acid (PFOA), perfluorononanoic acid (PFNA), and perfluorodecanoic acid (PFDA) were measured at median gestational week 12 (IQR: 10, 15) in 1628 women. Among these, offspring serum concentrations of dehydroepiandrosterone (DHEA), dehydroepiandrosterone-sulfate (DHEAS), androstenedione, 17-hydroxyprogesterone (17-OHP), testosterone, luteinizing (LH) and follicle stimulating hormones (FSH) were measured in 373 children (44% girls; 56% boys) at a mean age of 3.9 (±0.9 SD) months. Multivariate linear regression models were performed to estimate associations., Results: A two-fold increase in maternal PFDA concentration was associated with a reduction in DHEA concentration by -19.6% (95% CI: -32.9%, -3.8%) in girls. In girls, also, the androstenedione and DHEAS concentrations were decreased, albeit non-significantly (p < 0.11), with a two-fold increase in maternal PFDA concentration. In boys, no significant association was found between PFAAs and concentrations of androgens, their precursors, and gonadotropins during mini puberty., Conclusion: Prenatal PFDA exposure was associated with significantly lower serum DHEA concentrations and possibly also with lower androstenedione and DHEAS concentrations in female infants at mini puberty. The clinical significance of these findings remains to be elucidated., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Introduction: Vitamin D deficiency is common in pregnancy, especially in obese women. Lifestyle intervention could potentially result in higher levels of vitamin D. We therefore aimed to study the effect of lifestyle intervention during pregnancy on serum levels of 25-hydroxyvitamin D (25(OH)D)., Material and Methods: A total of 360 obese women were randomized before gestational age 14 weeks to lifestyle intervention (diet and exercise) or routine clinical follow up (controls). Clinical outcomes and levels of 25(OH)D were determined three times: At gestational age 12-15 weeks (baseline), gestational age 28-30 weeks and 6 months postpartum., Results: A total of 304 (84%) women completed the intervention study and 238 (66%) attended postpartum follow up. Vitamin D levels were similar in the two groups at baseline. At gestational age 28-30 weeks and 6 months postpartum, 25(OH)D levels were significantly higher in the intervention group than in controls (75.6 vs 66.8 nmol/L, P = 0.009) and (54.8 vs 43.1 nmol/L, P = 0.013), respectively. Concurrently, vitamin D deficiency (25-hydroxyvitamin D <50 nmol/L) was less frequent in the intervention group than in controls: 15 vs 25% (P = 0.038) at gestational age 28-30 and 45 vs 63% (P = 0.011) 6 months postpartum, respectively., Conclusions: Lifestyle intervention during pregnancy was associated with significantly increased vitamin D levels in late pregnancy and postpartum compared with controls., (© 2019 Nordic Federation of Societies of Obstetrics and Gynecology.)

Background: The impact of one-way SMS on health outcomes in Africa is unclear. We aimed to conduct a systematic review of one-way SMS randomised trials in Africa and a meta-analysis of their effect on healthcare appointments attendance and medicine adherence., Methods: PubMed, Embase, CENTRAL, The Global Health Library, ClinicalTrials.gov, ICTRP, and PACTR were searched for published and unpublished trials in Africa without language restriction (up to April 2018). Trials reporting effect estimates on healthcare appointment attendance and medicine adherence were assessed for risk of bias and included in meta-analyses using random-effects models. Other outcomes were reported descriptively. The protocol is registered in PROSPERO, ID:CRD42018081062., Results: We included 38 one-way SMS trials conducted in Africa within a broad range of clinical conditions. Eighteen trials were included in the meta-analyses, and four were assessed as overall low risk of bias. One-way SMS improved appointment attendance, OR:2·03; 95% CI:1·40-2·95 (12 trials, 6448 participants), but not medicine adherence, RR:1·10; 95% CI:0·98-1·23 (nine trials, 4213 participants). Subgroup analyses showed that one-way SMS had the highest impact on childhood immunization attendance, OR:3·69; 95% CI:1·67-8·13 (three trials, 1943 participants). There was no clear evidence of one-way SMS improving facility delivery, knowledge level (reproductive/antenatal health, hypertension), diabetes- and hypertension management., Conclusion: In an African setting, the clinical effect of one-way SMS is uncertain except for appointment attendance where the effect seems to vary depending on which clinical condition it is used in., Competing Interests: DSL, VR, MSA are currently conducting a trial in Tanzania assessing the effect of one-way SMS on attendance to cervical cancer screening follow-up appointment attendance. This does not alter our adherence to PLOS ONE policies on data sharing and materials. AL, MK and JK have no conflicts of interest.

Existing literature points to the possibility that cortisol could be one link between maternal adversity and poorer parenting quality, but most studies have examined salivary cortisol concentrations rather than hair cortisol concentrations. The current study examined hair cortisol concentration (HCC) during the third trimester of pregnancy as a mediator between maternal adversity indicators (childhood abuse, severe mental illness, symptomatic functioning) and maternal caregiving behavior at 4 months postpartum. Forty-four women participated in the study: 30 with severe mental disorders, and 14 nonclinical controls. HCC was assessed during the third trimester of pregnancy (HCC-P) and at 4 months postpartum (HCC-4M). Sexual, physical, and emotional abuse were assessed by the Adverse Childhood Experiences Study Questionnaire. Maternal disrupted interaction was reliably coded from mother-infant video interactions during a Still-Face Procedure. Mediation models indicated that maternal HCC-P and HCC-4M mediated associations between maternal psychopathology (severe mental illness, symptomatic functioning) and maternal disrupted interaction at 4 months. Maternal HCC at 4 months also mediated associations between experienced childhood abuse and overall disrupted interaction. Our findings indicate that HCC may be a potential early biomarker for future caregiving challenges among mothers with severe mental illness and histories of childhood abuse., (© 2019 Wiley Periodicals, Inc.)

Introduction: Low socioeconomic status (SES) may be associated with increased risk of polycystic ovary syndrome (PCOS) and vice versa. Possible associations between SES, obesity and ethnicity in PCOS are undetermined., Material and Methods: National register-based study including women with PCOS aged 25 years or above (PCOS Denmark and an embedded cohort; PCOS Odense University Hospital [OUH]) and one control population. PCOS Denmark (n = 13 891) included women with PCOS in the Danish National Patient Register. Women in PCOS OUH underwent clinical examination (n = 814). Three age-matched controls were included per patient (n = 41 584). The main outcome measure was SES (personal income, occupational status and education)., Results: The median (Q1; Q3) age of women in PCOS Denmark and controls was 33 (29; 39) years. Women with personal income in the lower tertile had a higher probability of a PCOS diagnosis than women in the high-income tertile (adjusted odds ratio [aOR] 1.5, 95% confidence interval [CI] 1.4-1.6). Women who were unemployed or on welfare payment (aOR 1.5, 95% CI 1.4-1.6), or who retired early (OR 1.8, 95% CI 1.7-2.0) had a higher probability of a PCOS diagnosis than women affiliated to the labor market. Women originating from the Middle East more often had PCOS (aOR 3.2, 95% CI 2.8-3.7) compared with women originating from Europe. In PCOS OUH, SES was lower in obese than in normal weight women., Conclusions: A diagnosis of PCOS was associated with lower SES. In PCOS, women of foreign origin and women with obesity more often had low SES., (© 2018 Nordic Federation of Societies of Obstetrics and Gynecology.)

Objective: To study effects of lifestyle intervention on metabolic and clinical outcomes in obese women fulfilling the World Health Organization (WHO) 2013 diagnostic criteria for gestational diabetes mellitus (GDM) in early gestation., Research Design and Methods: Secondary analysis of data from the Lifestyle in Pregnancy (LiP) study, a lifestyle randomized controlled trial in 304 pregnant women with BMI ≥30 kg/m 2 . Early GDM (week 12-15) was diagnosed according to modified WHO 2013 GDM criteria: fasting venous plasma glucose ≥5.1 mmol/L and/or 2-h capillary blood glucose (CBG) ≥8.5 mmol/L (75-g oral glucose tolerance test [OGTT]). Women with treated GDM fulfilling local Danish GDM criteria (2-h CBG ≥9.0 mmol/L) ( n = 16) and women with normal OGTT ( n = 198) were excluded., Results: Of 90 women with early GDM, 36 received lifestyle intervention and 54 standard care. All were Caucasian, and median age was 29 years (interquartile range 27-33) and BMI 34.5 kg/m 2 (32.3-38.1). All baseline characteristics were similar in the lifestyle intervention and standard care groups. At gestational week 28-30, the women in the lifestyle intervention group had significantly higher fasting total cholesterol and fasting LDL. All other metabolic parameters including measurements of glucose, insulin, and HOMA of insulin resistance were similar. There were more planned cesarean sections in the lifestyle intervention group (22.2 vs. 5.6%), but all other obstetric outcomes were similar., Conclusions: Lifestyle intervention in obese women fulfilling WHO 2013 GDM criteria in early pregnancy was not effective in improving obstetric or metabolic outcomes. Future studies should focus on interventions starting prepregnancy., (© 2018 by the American Diabetes Association.)

BackgroundAnogenital distance (AGD) has been suggested to represent a phenotypic signature reflecting in utero androgen action. However, it is not known whether an individual's AGD at birth correlates to the AGD later in life. We investigate correlations of AGD between 3 and 18 months of age and assess reproducibility of measurements.MethodsWe measured AGD from anus to scrotum (AGDas) and to penis (AGDap) in 407 boys, and to posterior fourchette (AGDaf) and clitoris (AGDac) in 282 girls. Each measure was repeated three times at 3 and 18 months of age, and some children were, furthermore, examined by two different examiners. We assessed age-related changes and reproducibility of measurements.ResultsAGD increased between the two examinations and correlated within the child. A large proportion of the observed variation in AGD was due to true differences between the children (AGDas: 62%, AGDap: 40%, AGDaf: 30%, AGDac: 21%), and measurement error due to between- and within-examiner variation was low.ConclusionsOur study showed that measures of AGD within a child correlated during infancy, especially in boys and particularly for AGD measured as the distance between anus and scrotum. A planned cohort follow-up through childhood and puberty will reveal whether AGD represents a phenotypic signature throughout life.

Background: Cervical cancer is a major health concern in Tanzania, caused by poor attendance for cervical cancer screening and follow-up of women at risk. Mobile telephone health interventions are proven effective tools to improve health behaviour in African countries. So far, no knowledge exists on how such interventions may perform in relation to cervical cancer screening in low-income settings. This study aims to assess the degree to which a Short Message Service (SMS) intervention can increase attendance at appointments among women who have tested positive for high-risk (HR) Human Papillomavirus (HPV) during cervical cancer screening., Methods/design: Connected2Care is a non-blinded, multicentre, parallel-group, randomised controlled trial. Tanzanian women testing positive to HR HPV at inclusion are randomly assigned in an allocation ratio of 1:1 to the SMS intervention or the control group (standard care). In a period of 10 months, the intervention group will receive 15 one-directional health educative text messages and SMS reminders for their appointment. The total sample size will be 700 with 350 women in each study arm. Primary outcome is attendance rate for follow-up. Secondary objectives are cost-effectiveness, measured through incremental ratios, and knowledge of cervical cancer by a 16-item true/false scale questionnaire at baseline and follow-up. Barriers against implementing the intervention will be assessed in a mixed-methods sub-population study., Discussion: This study may provide information on the potential effects, costs, and barriers in implementing an SMS intervention targeting a group of women who are followed up after testing positive for HR HPV and are, therefore, at increased risk of developing cervical cancer. This can guide decision-makers on the effective use of mobile technology in a low-income setting. Trial status: recruiting., Trial Registration: ClinicalTrials.gov, ID: NCT02509702 . Registered on 15 June 2015.

Colony-forming assays represent prospective methods, where cells isolated from enzymatically dissociated tissues or from tissue cultures are assessed for their proliferative capacity in vitro. Complex tissues such as the epithelial component of the skin (the epidermis) are characterized by a substantial cellular heterogeneity. Analysis of bulk populations of cells by colony-forming assays can consequently be convoluted by a number of factors that are not controlled for in population wide studies. It is therefore advantageous to refine in vitro growth assays by sub-fractionation of cells using flow cytometry. Using markers that define the spatial origin of epidermal cells, it is possible to interrogate the specific characteristics of subpopulations of cells based on their in vivo credentials. Here, we describe how to isolate, culture, and characterize keratinocytes from murine back and tail skin sorted by surface antigens associated with adult stem cell characteristics.

The skin forms a protective, water-impermeable barrier consisting of heavily crosslinked epithelial cells. However, the specific role of stem cells in sustaining this barrier remains a contentious issue. A detailed analysis of the interfollicular epidermis now proposes a model for how a composite of cells with different properties are involved in its maintenance.

Polycystic ovary syndrome (PCOS), the most common endocrine disease among premenopausal women, is caused by both genes and environment. We and others previously reported association between single nucleotide polymorphisms (SNPs) in the DENND1A gene and PCOS. We therefore sequenced the DENND1A gene in white patients with PCOS to identify possible alterations that may be implicated in the PCOS pathogenesis. Patients were referred with PCOS and/or hirsutism between 1998 and 2011 (n = 261). PCOS was diagnosed according to the Rotterdam criteria (n = 165). Sequence analysis was performed in 10 patients with PCOS. Additional patients (n = 251) and healthy female controls (n = 248) were included for SNP genotyping. Patients underwent clinical examination including Ferriman-Gallwey score (FG-score), biochemical analyses and transvaginal ultrasound. Mutation analysis was carried out by bidirectional sequencing. SNP genotyping was tested by allelic discrimination in real-time PCR in the additional patients and controls. Sequencing of the DENND1A gene identified eight SNPs; seven were not known to be associated with any diseases. One missense SNP was detected (rs189947178, A/C), potentially altering the structural conformation of the DENND1A protein. SNP genotyping of rs189947178 showed significantly more carriers among patients with PCOS and moderate hirsutism compared to controls. However, due to small sample size and lack of multiple regression analysis supporting an association between rs189947178 and FG-score or PCOS diagnosis, this could be a false positive finding. In conclusion, sequence analysis of the DENND1A gene of patients with PCOS did not identify alterations that alone could be responsible for the PCOS pathogenesis, but a missense SNP (rs189947178) was identified in one patient and significantly more carriers of rs189947178 were found among patients with PCOS and moderate hirsutism vs. controls. Additional studies with independent cohort are needed to confirm this due to the small sample size of this study.

Background: Polycystic ovary syndrome (PCOS) is often associated with an increased waist circumference and with lower cardio-respiratory fitness as a consequence of obesity, which may be improved by physical activity., Objective: To investigate the effect of high-intensity aerobic training combined with group counselling sessions on anthropometry and cardio-respiratory fitness in women with PCOS., Design: Seventeen sedentary, overweight women with PCOS were randomized in a cross-over design to 16 weeks of intervention: eight weeks high-intensity aerobic exercise was followed by eight weeks of group counselling (n = 8) or vice versa (n = 9). Fourteen of the women completed the tests., Main Outcome Measures: Waist circumference, body mass index and maximal aerobic capacity (VO(2max) ) were measured at baseline, cross-over and post-intervention., Results: There was a decrease in waist circumference (119.9 vs. 106.5 cm) and body mass index (34.9 vs. 34.4 kg/m(2) ) and an increase in VO(2max) (2554.9 vs. 2807.9 mL/min) during the intervention period (t = 16 weeks, n = 14), all p < 0.05. Weight loss tended to be highest in the group which started with group counselling (2.9 vs. 0.6 kg, t = 16 weeks, n = 14, p = 0.055)., Conclusion: Exercise in groups followed by counselling or vice versa had beneficial effects on waist circumference, weight, and VO(2max) in women with PCOS. Future studies should examine possible beneficial effects of combined group counselling and exercise on weight loss and adherence to exercise protocols among women with PCOS., (© 2013 The Authors Acta Obstetricia et Gynecologica Scandinavica © 2013 Nordic Federation of Societies of Obstetrics and Gynecology.)