OBJECTIVEThe aim of the study was to investigate are there associations between common female sex-specific health conditions (oligo/amenorrhea, hyperandrogenism, menopause and polycystic ovary ...syndrome PCOS) and high-sensitivity troponin-T (hs-TnT) levels.METHODSCross-sectional and longitudinal analyses of a general population-based prospective cohort study were performed. The hs-TnT levels of 3146 women aged 46 were measured using an Elecsys® Troponin T high-sensitivity assay. Median hs-TnT levels and 25 and 75 percentiles of the cases and controls were compared. Also, a logistic regression analysis using a binary outcome - undetectable hs-TnT (< 3.0 ng/L) versus detectable hs-TnT (≥ 3.0 ng/L) - was performed.RESULTSWomen with oligo/amenorrhea at age 31 had significantly higher hs-TnT levels at age 46 than women without oligo/amenorrhea (4.06 3.59; 4.86 vs 3.98 3.44; 4.71 ng/L, p = .042). Menopausal women had significantly higher hs-TnT levels than premenopausal women (4.15 3.54; 4.91 vs 3.95 3.45; 4.68 ng/L, p = .012) at age 46. Women with PCOS or hyperandrogenism had comparable hs-TnT levels with their controls. In the adjusted logistic regression analysis, oligo/amenorrhea (odds ratio OR = 1.52 0.90-2.57), hyperandrogenism (OR = 1.20 0.75-1.92), PCOS (OR = 1.51 0.81-2.84) and menopause (OR = 1.05 0.63-1.74) were not significantly associated with detectable hs-TnT.CONCLUSIONSThis study was the first to investigate how oligo/amenorrhea, hyperandrogenism, PCOS and menopause are associated with hs-TnT. Although women with oligo/amenorrhea and menopause had higher hs-TnT levels than women without these conditions, the difference was small. Larger studies are required to better understand the effects of oligo/amenorrhea on cardiovascular health.
To date, little is known about differences in the knowledge, diagnosis making and treatment strategies of health care providers regarding polycystic ovary syndrome (PCOS) across different disciplines ...in countries with similar health care systems. To inform guideline translation, we aimed to study physician reported awareness, diagnosis and management of PCOS and to explore differences between medical disciplines in the Nordic countries and Estonia.
This cross-sectional survey was conducted among 382 endocrinologists and obstetrician-gynaecologists in the Nordic countries and Estonia in 2015-2016. Of the participating physicians, 43% resided in Finland, 18% in Denmark, 16% in Norway, 13% in Estonia, and 10% in Sweden or Iceland, and 75% were obstetrician-gynaecologists. Multivariable logistic regression models were run to identify health care provider characteristics for awareness, diagnosis and treatment of PCOS.
Clinical features, lifestyle management and comorbidity were commonly recognized in women with PCOS, while impairment in psychosocial wellbeing was not well acknowledged. Over two-thirds of the physicians used the Rotterdam diagnostic criteria for PCOS. Medical endocrinologists more often recommended lifestyle management (OR = 3.6, CI 1.6-8.1) or metformin (OR = 5.0, CI 2.5-10.2), but less frequently OCP (OR = 0.5, CI 0.2-0.9) for non-fertility concerns than general obstetrician-gynaecologists. The physicians aged <35 years were 2.2 times (95% CI 1.1-4.3) more likely than older physicians to recommend lifestyle management for patients with PCOS for fertility concerns. Physicians aged 46-55 years were less likely to recommend oral contraceptive pills (OCP) for patients with PCOS than physicians aged >56 (adjusted odds ratio (OR) = 0.4, 95% CI 0.2-0.8).
Despite well-organized healthcare, awareness, diagnosis and management of PCOS is suboptimal, especially in relation to psychosocial comorbidities, among physicians in the Nordic countries and Estonia. Physicians need more education on PCOS and evidence-based information on Rotterdam diagnostic criteria, psychosocial features and treatment of PCOS, with the recently published international PCOS guideline well needed and welcomed.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Objective To learn whether metformin treatment affects oxidative stress as measured by serum concentrations of 8-hydroxy-2′-deoxyguanosine (8-OHdG). Design Double-blind, randomized, ...placebo-controlled trial. Setting University outpatient clinic. Patient(s) The study cohort consisted of 50 obese women (body mass index BMI ≥27 kg/m2 ) and 60 nonobese patients (BMI <27 kg/m2 ), mean age was 27.7 ± 4.0 SD years. Intervention(s) Randomization to receive metformin or placebo for 3 months. Main Outcome Measure(s) Serum levels of 8-OHdG before and after medical treatment. Result(s) The levels of 8-OHdG were equal at baseline in the placebo and metformin groups. Obese women had higher baseline serum concentrations of 8-OHdG. Levels of 8-OHdG were statistically significantly reduced with metformin treatment, especially in obese patients with polycystic ovary syndrome. This study was a secondary subanalysis of a previously conducted prospective multicenter, randomized, placebo-controlled study on the effects of metformin on miscarriage, pregnancy, and miscarriage rates. Conclusion(s) Metformin treatment, compared with placebo, statistically significantly decreased 8-OHdG levels in women with polycystic ovary syndrome. Clinical Trial Registration Number NCT00994812.
Aims
Atorvastatin is known to both inhibit and induce the cytochrome P450 3A4 (CYP3A4) enzyme in vitro. Some clinical studies indicate that atorvastatin inhibits CYP3A4 but there are no ...well‐controlled longer term studies that could evaluate the inducing effect of atorvastatin. We aimed to determine if atorvastatin induces or inhibits CYP3A4 activity as measured by the 4β‐hydroxycholesterol to cholesterol ratio (4βHC : C).
Methods
In this randomized, double‐blind, placebo‐controlled 6 month study we evaluated the effects of atorvastatin 20 mg day−1 (n = 15) and placebo (n = 14) on oxysterol concentrations and determined if atorvastatin induces or inhibits CYP3A4 activity as assessed by the 4βHC : C index. The respective 25‐hydroxycholesterol and 5α,6α‐epoxycholesterol ratios were used as negative controls.
Results
Treatment with atorvastatin decreased 4βHC and 5α,6α‐epoxycholesterol concentrations by 40% and 23%, respectively. The mean 4βHC : C ratio decreased by 13% (0.214 ± 0.04 to 0.182 ± 0.04, P = 0.024, 95% confidence interval (CI) of the difference –0.0595, –0.00483) in the atorvastatin group while no significant change occurred in the placebo group. The difference in change of 4βHC : C between study arms was statistically significant (atorvastatin –0.032, placebo 0.0055, P = 0.020, 95% CI of the difference –0.069, –0.0067). The ratios of 25‐hydroxycholesterol and 5α,6α‐epoxycholesterol to cholesterol did not change.
Conclusions
The results establish atorvastatin as an inhibitor of CYP3A4 activity. Furthermore, 4βHC : C is a useful index of CYP3A4 activity, including the conditions with altered cholesterol concentrations.
STUDY QUESTION
Is it necessary to monitor lipid profiles in all young women with polycystic ovary syndrome (PCOS)?
SUMMARY ANSWER
Lipid profiling is required when women with PCOS develop type 2 ...diabetes (T2D) or hypertension, but rarely changes clinical care before the age of 35 years.
WHAT IS KNOWN ALREADY
PCOS consensus statements and guidelines recommend that women with PCOS should be screened for dyslipidaemia every second year or annually.
STUDY DESIGN, SIZE, DURATION
Women from Denmark, Norway, Finland and Sweden, who had participated in research projects or clinical trials or in whom lipid profiles had been determined routinely as part of clinical care since 2000 were included.
PARTICIPANTS/MATERIALS, SETTING, METHODS
One thousand three hundred and twenty-seven women with PCOS (Rotterdam criteria) were included. Based on individual cardiovascular risk score and lipid levels, treatment level was guided by the European Society of Cardiology and the European Atherosclerosis Society Task Force for the management of dyslipidaemias. Change in clinical care was defined as need to (i) immediately start statin treatment or (ii) consider statin treatment if life-style intervention fails.
MAIN RESULTS AND THE ROLE OF CHANCE
All in all, 74 (5.6%) women with PCOS should immediately start statin treatment, and statin treatment should be considered in 33 women (2.5%). Among women with T2D, 27/28 (96.4%) should initiate statin treatment and the corresponding number for women with hypertension was 42/57 (73.7%). In PCOS women who had not yet developed T2D or hypertension, lipid profiling only changed clinical care in 28 (2.3%). This number was further reduced to 12 (1.2%) in women below the age of 35 years, and to zero in normal-weight women below the age of 35 years.
LIMITATIONS, REASONS FOR CAUTION
Findings can only be generalized to countries with low cardiovascular mortality rates.
WIDER IMPLICATIONS OF THE FINDINGS
Lipid profiling is required when women with PCOS develop T2D or hypertension. However, lipid profiling rarely changes the clinical care of low risk PCOS patients before the age of 35, especially in the normal-weight women.
STUDY FUNDING/COMPETING INTEREST(S)
The Academy of Finland, Sigrid Juselius Foundation and the Nordic Federation of Obstetrics and Gynecology. There are no conflicts of interest to be declared.
Abstract
Ceramides contribute to the development of type 2 diabetes but it is uncertain whether they predict gestational diabetes (GDM). In this multicentre case–control study including 1040 women ...with GDM and 958 non-diabetic controls, early pregnancy (mean 10.7 gestational weeks) concentrations of four ceramides—Cer(d18:1/16:0), Cer(d18:1/18:0), Cer(d18:1/24:0) and Cer(d18:1/24:1)—were determined by a validated mass-spectrometric method from biobanked serum samples. Traditional lipids including total cholesterol, LDL, HDL and triglycerides were measured. Logistic and linear regression and the LASSO logistic regression were used to analyse lipids and clinical risk factors in the prediction of GDM. The concentrations of four targeted ceramides and total cholesterol, LDL and triglycerides were higher and HDL was lower among women with subsequent GDM than among controls. After adjustments, Cer(d18:1/24:0), triglycerides and LDL were independent predictors of GDM, women in their highest quartile had 1.44-fold (95% CI 1.07–1.95), 2.17-fold (95% CI 1.57–3.00) and 1.63-fold (95% CI 1.19–2.24) odds for GDM when compared to their lowest quartiles, respectively. In the LASSO regression modelling ceramides did not appear to markedly improve the predictive performance for GDM alongside with clinical risk factors and triglycerides. However, their adverse alterations highlight the extent of metabolic disturbances involved in GDM.
Müllerian aplasia (MA) is a congenital disorder of the female reproductive tract with absence of uterus and vagina with paramount impact on a woman's life. Despite intense research, no major genes ...have been found to explain the complex genetic etiology.
We have used several genetic methods to study 112 patients with MA. aCGH identified CNVs in 8/50 patients (16%), including 16p11.2 and 17q12 deletions previously associated with MA. Subsequently, another four patients were shown to carry the ~0.53 Mb deletion in 16p11.2. More importantly, sequencing of TBX6, residing within 16p11.2, revealed two patients carrying a splice site mutation. Two previously reported TBX6 variants in exon 4 and 6 were shown to have a significantly higher frequency in patients (8% and 5%, respectively) than in controls (2% each). We also sequenced LHX1 and found three apparently pathogenic missense variants in 5/112 patients. Altogether, we identified either CNVs or variations in TBX6 or LHX1 in 30/112 (26.8%) MA patients. CNVs were found in 12/112 (10.7%), patients, novel variants in TBX6 or LHX1 in 7/112 (6.3%), and rare variants in TBX6 in 15/112 (13.4%) patients. Furthermore, four of our patients (4/112, 3.6%) were shown to carry variants in both TBX6 and LHX1 or a CNV in combination with TBX6 variants lending support to the complex genetic etiology of MA.
We have identified TBX6 as a new gene associated with MA. Our results also support the relevance of LHX1 and CNVs in the development of this congenital malformation.
Hormonal contraception is commonly used worldwide, but its systemic effects across lipoprotein subclasses, fatty acids, circulating metabolites and cytokines remain poorly understood.
A comprehensive ...molecular profile (75 metabolic measures and 37 cytokines) was measured for up to 5841 women (age range 24-49 years) from three population-based cohorts. Women using combined oral contraceptive pills (COCPs) or progestin-only contraceptives (POCs) were compared with those who did not use hormonal contraception. Metabolomics profiles were reassessed for 869 women after 6 years to uncover the metabolic effects of starting, stopping and persistently using hormonal contraception.
The comprehensive molecular profiling allowed multiple new findings on the metabolic associations with the use of COCPs. They were positively associated with lipoprotein subclasses, including all high-density lipoprotein (HDL) subclasses. The associations with fatty acids and amino acids were strong and variable in direction. COCP use was negatively associated with albumin and positively associated with creatinine and inflammatory markers, including glycoprotein acetyls and several growth factors and interleukins. Our findings also confirmed previous results e.g. for increased circulating triglycerides and HDL cholesterol. Starting COCPs caused similar metabolic changes to those observed cross-sectionally: the changes were maintained in consistent users and normalized in those who stopped using. In contrast, POCs were only weakly associated with metabolic and inflammatory markers. Results were consistent across all cohorts and for different COCP preparations and different types of POC delivery.
Use of COCPs causes widespread metabolic and inflammatory effects. However, persistent use does not appear to accumulate the effects over time and the metabolic perturbations are reversed upon discontinuation. POCs have little effect on systemic metabolism and inflammation.
Infertility and fecundability problems have been linked with lower 25-hydroxyvitamin D (25(OH)D) concentrations, but studies conducted with small, heterogenous or selected populations have shown ...inconsistent results.
This study included women at age 31 from prospective population-based Northern Finland Birth Cohort 1966. Serum 25(OH)D concentrations were evaluated between women with or without previous infertility examinations or treatments (infertility group,
= 375, reference group,
= 2051) and time to pregnancy (TTP) of over 12 months (decreased fecundability group,
= 338) with a wide range of confounders. Furthermore, 25(OH)D concentrations were also compared among reproductive outcomes.
The mean 25(OH)D concentration was lower and 25(OH)D < 30 nmol/L was more frequent in women with a history of infertility compared to reference group. Moreover, 25(OH)D > 75 nmol/L was more frequent in the reference group. The mean 25(OH)D concentration was lower in women who had had multiple miscarriages. Both history of infertility (β = -2.7, 95% confidence interval (CI) -4.6, -0.7) and decreased fecundability associated with lower 25(OH)D concentration (β = -4.1, 95% CI -7.4, -0.8) after adjustments. In conclusion, this population-based study demonstrated that previous infertility and decreased fecundability were associated with lower 25(OH)D.
Metformin, a biguanide antihyperglycemic drug, has been shown to improve ovarian function and glucose metabolism in women with polycystic ovary syndrome (PCOS), but results concerning its effects on ...insulin sensitivity are controversial. Oral contraceptive pills are commonly used in the treatment of PCOS; but, like metformin, their influence on insulin sensitivity is not well known. We randomized 32 obese (body mass index > 27 kg/m2) women with PCOS, either to metformin (500 mg x 2 daily for 3 months, then 1,000 mg x 2 daily for 3 months) or to ethinyl estradiol (35 microg)-cyproterone acetate (2 mg) oral contraceptive pills (Diane Nova) for 6 months. Metformin significantly decreased the waist-to-hip ratio, serum testosterone, fasting free fatty acid, and insulin concentrations and improved oxidative glucose utilization and menstrual cyclicity, with slight (but nonsignificant) improvements in insulin hepatic extraction and insulin sensitivity. Diane Nova significantly decreased serum testosterone and increased serum sex hormone-binding globulin concentrations and glucose area under the curve during oral glucose tolerance test. It is concluded that metformin, probably by way of its effect on adipose tissue, leads to reduction of hyperinsulinemia and concomitant improvement in the menstrual pattern; and therefore, it offers a useful alternative treatment for obese, anovulatory women with PCOS. Despite slight worsening of glucose tolerance, Diane Nova is an efficient treatment for women with hyperandrogenism and hirsutism.
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