To study the cardiometabolic profile characteristics and compare the prevalence of cardiovascular (CV) risk factors between women with different polycystic ovary syndrome (PCOS) phenotypes.
A ...cross-sectional multicenter study analyzing 2,288 well phenotyped women with PCOS.
Specialized reproductive outpatient clinic.
Women of reproductive age (18–45 years) diagnosed with PCOS.
Women suspected of oligo- or anovulation underwent a standardized screening consisting of a systematic medical and reproductive history taking, anthropometric measurements, and transvaginal ultrasonography followed by an extensive endocrinologic/metabolic evaluation.
Differences in cardiometabolic profile characteristics and CV risk factor prevalence between women with different PCOS phenotypes, i.e., obesity/overweight, hypertension, insulin resistance, dyslipidemia, and metabolic syndrome.
Women with hyperandrogenic PCOS (n = 1,219; 53.3% of total) presented with a worse cardiometabolic profile and a higher prevalence of CV risk factors, such as obesity and overweight, insulin resistance, and metabolic syndrome, compared with women with nonhyperandrogenic PCOS. In women with nonhyperandrogenic PCOS overweight/obesity (28.5%) and dyslipidemia (low-density lipoprotein cholesterol ≥3.0 mmol/L; 52.2%) were highly prevalent.
Women with hyperandrogenic PCOS have a worse cardiometabolic profile and higher prevalence of CV risk factors compared with women with nonhyperandrogenic PCOS. However, all women with PCOS should be screened for the presence of CV risk factors, since the frequently found derangements at a young age imply an elevated risk for the development of CV disease later in life.
Context:
Anti-Müllerian hormone (AMH) is an accurate marker of ovarian reserve. However, sufficiently large sets of normative data from infancy to the end of reproductive life are scarce.
Objective:
...This study was an assessment of serum AMH levels in healthy females.
Subjects:
In 804 healthy females ranging from infancy until the end of the reproductive period, serum AMH levels were measured with an enzyme-linked immunometric assay. All adults had regular menstrual cycles. The majority was proven fertile and none of them had used oral contraceptive pills prior to study inclusion.
Results:
In the total cohort, AMH was inversely correlated with age (r = −0.24; P < 0.001). The age at which the maximum AMH value was attained was at 15.8 yr. In girls younger than 15.8 yr, serum AMH and age were positively correlated (r = +0.18; P = 0.007). Thereafter AMH levels remained stable (r = −0.33; P = 0.66), whereas from the age of 25.0 yr onward, an inverse correlation between AMH and age (r = −0.47; P < 0.001) was observed. At any given age, considerable interindividual differences in serum AMH levels were observed.
Conclusion:
During infancy AMH levels increase, whereas during adolescence, a plateau until the age of 25 yr was observed. From the age of 25 yr onward, serum AMH levels correlate inversely with age, implying that AMH is applicable as a marker of ovarian reserve only in women of 25 yr old and older. Our nomogram may facilitate counseling women on their reproductive potential.
Context: Thyroid hormones are essential for neurodevelopment from early pregnancy onward. Yet population-based data on the association between maternal thyroid function in early pregnancy and ...children’s cognitive development are sparse.
Objective: Our objective was to study associations of maternal hypothyroxinemia and of early pregnancy maternal TSH and free T4 (FT4) levels across the entire range with cognitive functioning in early childhood.
Design and Setting: We conducted a population-based cohort in The Netherlands.
Participants: Participants included 3659 children and their mothers.
Main Measures: In pregnant women with normal TSH levels at 13 wk gestation (sd = 1.7), mild and severe maternal hypothyroxinemia were defined as FT4 concentrations below the 10th and 5th percentile, respectively. Children’s expressive vocabulary at 18 months was reported by mothers using the MacArthur Communicative Development Inventory. At 30 months, mothers completed the Language Development Survey and the Parent Report of Children’s Abilities measuring verbal and nonverbal cognitive functioning.
Results: Maternal TSH was not related to the cognitive outcomes. An increase in maternal FT4 predicted a lower risk of expressive language delay at 30 months only. However, both mild and severe maternal hypothyroxinemia was associated with a higher risk of expressive language delay across all ages odds ratio (OR) = 1.44; 95% confidence interval (CI) = 1.09–1.91; P = 0.010 and OR = 1.80; 95% CI = 1.24–2.61; P = 0.002, respectively. Severe maternal hypothyroxinemia also predicted a higher risk of nonverbal cognitive delay (OR = 2.03; 95% CI = 1.22–3.39; P = 0.007).
Conclusions: Maternal hypothyroxinemia is a risk factor for cognitive delay in early childhood.
Maternal hypothyroxinemia during early pregnancy is a determinant of verbal and nonverbal cognitive functioning in early childhood.
STUDY QUESTION
Are differences in androgen levels among women with various forms of ovarian dysfunction associated with cardiometabolic abnormalities?
SUMMARY ANSWER
Androgen levels differed ...substantially between women with and without ovarian dysfunction, and increased androgen levels were associated with impaired cardiometabolic features in all women irrespective of their clinical condition.
WHAT IS KNOWN ALREADY
Sex steroid hormones play important roles in the development of cardiovascular diseases (CVD). Extremes of low as well as high androgen levels have been associated with increased CVD risk in both men and women.
STUDY DESIGN, SIZE, DURATION
This cross-sectional study included 680 women with polycystic ovary syndrome (PCOS), premature ovarian insufficiency (POI), natural post-menopausal women (NM), or regular menstrual cycles (RC) (170 women per group).
PARTICIPANTS/MATERIALS, SETTING, METHODS
Measurements of serum testosterone, androstenedione and dehydroepiandrosterone sulfate were performed using liquid chromatography-tandem mass spectrometry. Assessments were taken of body mass index (BMI), blood pressure, lipid profiles, glucose, insulin and SHBG, and the bioactive fraction of circulating testosterone was calculated using the free androgen index (FAI).
MAIN RESULTS AND THE ROLE OF CHANCE
PCOS women were hyperandrogenic median FAI = 4.9 (IQR 3.6–7.4), and POI women were hypoandrogenic FAI = 1.2 (0.8–1.7), compared with RC women FAI = 1.7 (1.1–2.8), after adjustment for age, ethnicity, smoking and BMI (P < 0.001). After adjustment for age, there were no significant differences in androgens between POI and NM (P = 0.15) women and between NM and RC (P = 0.27) women, the latter indicating that chronological aging rather than ovarian aging influences the differences between pre- and post-menopausal women. A high FAI was associated with elevated triglycerides (β log FAI for PCOS: 0.45, P < 0.001, POI: 0.25, P < 0.001, NM: 0.20, P = 0.002), insulin (β log FAI for PCOS: 0.77, POI: 0.44, NM: 0.40, all P < 0.001), HOMA-IR (β log FAI for PCOS: 0.82, POI: 0.46, NM: 0.47, all P < 0.001) and mean arterial pressure (β log FAI for PCOS: 0.05, P = 0.002, POI: 0.07, P < 0.001, NM: 0.04, P = 0.04) in all women; with increased glucose (β log FAI for PCOS: 0.05, P = 0.003, NM: 0.07, P < 0.001) and decreased high-density lipoprotein (β log FAI for PCOS: −0.23, P < 0.001, NM: −0.09, P = 0.03) in PCOS and NM women; and with increased low-density lipoprotein (β log FAI for POI: 0.083, P = 0.041) in POI women. Adjustment for BMI attenuated the observed associations. Associations between FAI and cardiometabolic features were the strongest in PCOS women, even after adjustment for BMI.
LIMITATIONS, REASONS FOR CAUTION
Associations between androgen levels and cardiometabolic features were assessed in PCOS, POI and NM women only, due to a lack of available data in RC women. Due to the cross-sectional design of the current study, the potential associations between androgen levels and actual future cardiovascular events could not be assessed.
WIDER IMPLICATIONS OF THE FINDINGS
This study affirms the potent effect of androgens on cardiometabolic features, indicating that androgens should indeed be regarded as important denominators of women's health. Future research regarding the role of androgens in the development of CVD and potential modulatory effects of BMI is required.
STUDY FUNDING/COMPETING INTEREST(S)
N.M.P.D. is supported by the Dutch Heart Foundation (grant number 2013T083). L.J. and O.H.F. work in ErasmusAGE, a center for aging research across the life course, funded by Nestlé Nutrition (Nestec Ltd), Metagenics Inc. and AXA. M.K. is supported by the AXA Research Fund. Nestlé Nutrition (Nestec Ltd), Metagenics Inc. and AXA had no role in the design and conduct of the study; the collection, management, analysis and interpretation of the data; or the preparation, review or approval of the manuscript. J.S.E.L. has received fees and grant support from the following companies (in alphabetical order): Ferring, Merck-Serono, Merck Sharpe & Dome, Organon, Schering Plough and Serono. In the last 5 years, B.C.J.M.F. has received fees and grant support from the following companies (in alphabetic order); Actavis, COGI, Euroscreen, Ferring, Finox, Genovum, Gedeon-Richter, Merck-Serono, OvaScience, Pantharei Bioscience, PregLem, Roche, Uteron and Watson laboratories. With regard to potential conflicts of interest, there is nothing further to disclose.
Although the consequences of severe iodine deficiency are beyond doubt, the effects of mild to moderate iodine deficiency in pregnancy on child neurodevelopment are less well established.
To study ...the association between maternal iodine status during pregnancy and child IQ and identify vulnerable time windows of exposure to suboptimal iodine availability.
Meta-analysis of individual participant data from three prospective population-based birth cohorts: Generation R (Netherlands), INMA (Spain), and ALSPAC (United Kingdom); pregnant women were enrolled between 2002 and 2006, 2003 and 2008, and 1990 and 1992, respectively.
General community.
6180 mother-child pairs with measures of urinary iodine and creatinine concentrations in pregnancy and child IQ. Exclusion criteria were multiple pregnancies, fertility treatment, medication affecting the thyroid, and preexisting thyroid disease.
Child nonverbal and verbal IQ assessed at 1.5 to 8 years of age.
There was a positive curvilinear association of urinary iodine/creatinine ratio (UI/Creat) with mean verbal IQ only. UI/Creat <150 µg/g was not associated with lower nonverbal IQ (-0.6 point; 95% CI: -1.7 to 0.4 points; P = 0.246) or lower verbal IQ (-0.6 point; 95% CI: -1.3 to 0.1 points; P = 0.082). Stratified analyses showed that the association of UI/Creat with verbal IQ was only present up to 14 weeks of gestation.
Fetal brain development is vulnerable to mild to moderate iodine deficiency, particularly in the first trimester. Our results show that potential randomized controlled trials investigating the effect of iodine supplementation in women with mild to moderate iodine deficiency on child neurodevelopment should begin supplementation not later than the first trimester.
Identifying subjects with cystic fibrosis (CF) who may benefit from cystic fibrosis transmembrane conductance regulator (CFTR)-modulating drugs is time-consuming, costly, and especially challenging ...for individuals with rare uncharacterized CFTR mutations. We studied CFTR function and responses to two drugs-the prototypical CFTR potentiator VX-770 (ivacaftor/KALYDECO) and the CFTR corrector VX-809 (lumacaftor)-in organoid cultures derived from the rectal epithelia of subjects with CF, who expressed a broad range of CFTR mutations. We observed that CFTR residual function and responses to drug therapy depended on both the CFTR mutation and the genetic background of the subjects. In vitro drug responses in rectal organoids positively correlated with published outcome data from clinical trials with VX-809 and VX-770, allowing us to predict from preclinical data the potential for CF patients carrying rare CFTR mutations to respond to drug therapy. We demonstrated proof of principle by selecting two subjects expressing an uncharacterized rare CFTR genotype (G1249R/F508del) who showed clinical responses to treatment with ivacaftor and one subject (F508del/R347P) who showed a limited response to drug therapy both in vitro and in vivo. These data suggest that in vitro measurements of CFTR function in patient-derived rectal organoids may be useful for identifying subjects who would benefit from CFTR-correcting treatment, independent of their CFTR mutation.
Highlights • Hair glucocorticoids (cortisol and cortisone) are increasingly used to evaluate long-term HPA axis activity in relation to somatic and psychological health, but are subject to ...‘wash-out’: the gradual decrease of glucocorticoid content along the hair shaft. • We hypothesized that wash-out of hair glucocorticoids may in part be caused by ultraviolet (UV) radiation present in natural sunlight. • In our experiments, hair cortisol and cortisone were decreased after exposure to a high amount of artificial UV radiation, but also after 40 h of natural sunlight exposure. • Sunlight exposure should be considered as a potential confounder in studies investigating hair glucocorticoids.
Flavonoids receive considerable attention in the literature, specifically because of their biological and physiological importance. This review focuses on separation and detection methods for ...flavonoids and their application to plants, food, drinks and biological fluids. The topics that will be discussed are sample treatment, column liquid chromatography (LC), but also methods such as gas chromatography (GC), capillary electrophoresis (CE) and thin-layer chromatography (TLC), various detection methods and structural characterization. Because of the increasing interest in structure elucidation of flavonoids, special attention will be devoted to the use of tandem-mass spectrometric (MS/MS) techniques for the characterization of several important sub-classes, and to the potential of combined diode-array UV (DAD UV), tandem-MS and nuclear magnetic resonance (NMR) detection for unambiguous identification. Emphasis will be on recent developments and trends.
Vitamin B1 and B6 have recently been included in the Dutch clinical guidelines for the general practitioner in the differential diagnosis of dementia. To keep up with the sharp rise in the number of ...requests, an LC–MS/MS method using stable isotopes as internal standards was developed. The active vitamers thiamine pyrophosphate (TPP) and pyridoxal-5′-phosphate (PLP) in whole blood are simultaneously measured with a short run time of 2min. Whole blood is mixed with internal standard solution containing both TPP-d3 and PLP-d3, followed by deproteinization with a trichloroacetic acid (TCA) solution. A UPLC–MS/MS system from Waters™ was used for chromatographic separation and subsequent detection by electrospray ionization in the positive mode with mass transitions of 425.1>121.85 for TPP and 247.9>149.9 for PLP. The method is linear across the range of 12–4870 nmol/L for TPP and 6–4850 nmol/L for PLP. The mean intra-assay and inter-assay precision are 3.5% and 7.6% respectively for TPP and 3.4% and 6.1% for PLP. The relative matrix effect (TPP 97%, PLP 93%), recovery (TPP 99%, PLP 94%) and lower limit of quantification (TPP 12 nmol/L, PLP 6 nmol/L) meet the applied acceptance criteria. The comparison of the new LC-ESI–MS/MS method for TPP with our current HPLC-Fluorescence method for total thiamine yields the following equation: TPP LC–MS/MS=0.97×total thiamine HPLC – 10.61 (r2=0.94). The comparison of the new LC-ESI–MS/MS method for PLP with our current LC-ESI–MS/MS method results in PLP LC–MS/MS new=1.01×PLP LC–MS/MS old – 1.58 (r2=0.99). In conclusion, this LC–MS/MS based assay is characterized by simple sample processing with a short run time and comparison with the current methods is excellent. The new LC–MS/MS method is a convenient method to determine TPP and PLP in whole blood for both clinical routine and research applications.
Up to 7% of term and late-preterm neonates in high-income countries receive antibiotics during the first 3 days of life because of suspected early-onset sepsis. The prevalence of culture-proven ...early-onset sepsis is 0·1% or less in high-income countries, suggesting substantial overtreatment. We assess whether procalcitonin-guided decision making for suspected early-onset sepsis can safely reduce the duration of antibiotic treatment.
We did this randomised controlled intervention trial in Dutch (n=11), Swiss (n=4), Canadian (n=2), and Czech (n=1) hospitals. Neonates of gestational age 34 weeks or older, with suspected early-onset sepsis requiring antibiotic treatment were stratified into four risk categories by their treating physicians and randomly assigned 1:1 using a computer-generated list stratified per centre to procalcitonin-guided decision making or standard care-based antibiotic treatment. Neonates who underwent surgery within the first week of life or had major congenital malformations that would have required hospital admission were excluded. Only principal investigators were masked for group assignment. Co-primary outcomes were non-inferiority for re-infection or death in the first month of life (margin 2·0%) and superiority for duration of antibiotic therapy. Intention-to-treat and per-protocol analyses were done. This trial was registered with ClinicalTrials.gov, number NCT00854932.
Between May 21, 2009, and Feb 14, 2015, we screened 2440 neonates with suspected early-onset sepsis. 622 infants were excluded due to lack of parental consent, 93 were ineligible for reasons unknown (68), congenital malformation (22), or surgery in the first week of life (3). 14 neonates were excluded as 100% data monitoring or retrieval was not feasible, and one neonate was excluded because their procalcitonin measurements could not be taken. 1710 neonates were enrolled and randomly assigned to either procalcitonin-guided therapy (n=866) or standard therapy (n=844). 1408 neonates underwent per-protocol analysis (745 in the procalcitonin group and 663 standard group). For the procalcitonin group, the duration of antibiotic therapy was reduced (intention to treat: 55·1 vs 65·0 h, p<0·0001; per protocol: 51·8 vs 64·0 h; p<0·0001). No sepsis-related deaths occurred, and 9 (<1%) of 1710 neonates had possible re-infection. The risk difference for non-inferiority was 0·1% (95% CI −4·6 to 4·8) in the intention-to-treat analysis (5 0·6% of 866 neonates in the procalcitonin group vs 4 0·5% of 844 neonates in the standard group) and 0·1% (−5·2 to 5·3) in the per-protocol analysis (5 0·7% of 745 neonates in the procalcitonin group vs 4 0·6% of 663 neonates in the standard group).
Procalcitonin-guided decision making was superior to standard care in reducing antibiotic therapy in neonates with suspected early-onset sepsis. Non-inferiority for re-infection or death could not be shown due to the low occurrence of re-infections and absence of study-related death.
The Thrasher Foundation, the NutsOhra Foundation, the Sophia Foundation for Scientific research.
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