(in alphabetischer Reihenfolge der Presenting Authors)

(in alphabetischer Reihenfolge der Presenting Authors)

Key words disorders of sex development (DSD) - gender development - psychosocial development - clinical management

Background: Women with polycystic ovary syndrome (PCOS) frequently suffer from metabolic disturbances, in particular from insulin resistance. Accumulating evidence suggests that vitamin D deficiency may contribute to the development of insulin resistance. Hence, we aimed to examine the effect of vitamin D supplementation on metabolic and endocrine parameters in PCOS women. Methods: Fifty-seven PCOS women were included in the study. PCOS women received 20,000 IU cholecalciferol weekly for 24 weeks. Anthropometric measures, oral glucose tolerance test, and blood analyses of endocrine parameters were performed at baseline and after 12 weeks (V2) and 24 weeks (V3). Results: Forty-six PCOS women finished the study. 25-hydroxyvitamin D [25(OH)D] levels significantly increased from 28.0±11.0 ng/ml at baseline to 51.3±17.3 and 52.4±21.5 at V2 and V3, respectively ( p <0.001). We observed a significant decrease of fasting and stimulated glucose (V3, p <0.05) and C-peptide levels (V2 and 3, p <0.001) after vitamin D treatment. Moreover, triglyceride and estradiol levels significantly decreased at V3 ( p =0.001) and V2 ( p =0.022), respectively, whereas total cholesterol (V2, p =0.008) and LDL cholesterol levels (V2, p =0.005; V3, p =0.026) significantly increased after vitamin D treatment. There were no changes in androgens. At V2, 14 out of 46 PCOS women previously affected by menstrual disturbances (30.4%) reported improvement of menstrual frequency; at V3, 23 out of 46 women (50.0%), who were oligo- or amenorrheic at baseline reported improvement. Discussion: Our results suggest that vitamin D treatment might improve glucose metabolism and menstrual frequency in PCOS women. Further randomized controlled trails are warranted to confirm our findings.

Esophageal adenocarcinoma develops in the setting of gastroesophageal reflux and columnar metaplasia in distal esophagus. Columnar metaplasia arising in gastroesophageal reflux models has developed in rat; however, gastroesophageal reflux models in mice have not been well-characterized.One hundred thirty-five C57Bl/6J mice aged 8 weeks old were divided into the following operations: esophagogastrojejunostomy (side-to-side) (EGJ), esophageal separation and esophagojejunostomy (end-to-side) (EJ), and EJ and gastrectomy (end-to-side) (EJ/TG). The animals were euthanized after 40 weeks and the histology of the junction was examined. Immunohistochemistry for p53, PDX-1, and CDX-2 was performed.Metaplasia developed in 15/33 (45.5%) of EGJ, 0/38 (0%) of EJ, and 6/39 (15.4%) of EJ/TG (P < .05) and dysplasia developed 7/33 (21.2%) of EGJ, 0% of EJ, and 1/39 (2.6%) of EJ/TG. p53 was positive in all of the dysplastic regions, 12/15 (80%) metaplasias in the EGJ model, and 1/6 (16.7%) metaplasia in the EJ/TG model. CDX-2 was positive in all cases of metaplasias, but decreased in some cases of dysplasia. PDX-1 was positive in 7/8 (88%) cases of dysplasia and in 15/21 (71%) cases of metaplasia (P < .05).The EGJ model, which causes reflux of gastric acid and duodenal content, developed metaplasia and dysplasia most frequently. No metaplasia developed in the EJ model in which gastric juice and duodenal content mixed before reflux. Thus, duodenal contents alone can induce columnar metaplasia and dysplasia; however, the combination of gastric acid with duodenal content reflux can cause metaplasia and dysplasia more efficiently.

BACKGROUND Women with polycystic ovary syndrome (PCOS) frequently suffer from metabolic disturbances. Lipid accumulation product (LAP) is an emerging cardiovascular risk factor. We aimed to investigate the association of LAP with impaired glucose tolerance (IGT) in PCOS and control women. METHODS The LAP was calculated as [waist circumference (centimeters) - 58] × [triglycerides (millimoles per liter)] in 392 PCOS and 140 body mass index (BMI)-matched control women within the same age range. Metabolic, endocrine, and anthropometric measurements and oral glucose tolerance tests were performed. RESULTS PCOS women had significantly higher LAP levels than control women in age-adjusted analyses [22.2 (10.9-46.2) and 18.2 (10.7-36.3), respectively, P = 0.001). In PCOS and control women, age, BMI, blood pressure, fasting and stimulated glucose, fasting and stimulated insulin, and free testosterone progressively increased, whereas SHBG decreased across LAP quartiles. In PCOS and control women, receiver operating characteristic curve analysis revealed that the best cutoff value for LAP to define the presence of IGT was 44.1 and 41.8, respectively [sensitivity 79.5%, specificity 80.5%, and area under the curve (AUC) 0.86 and sensitivity 82.3%, specificity 90.5%, and AUC 0.86, respectively]. In PCOS and control women, receiver operating characteristic curve analyses for BMI (0.77 and 0.54, respectively) and waist circumference (0.80 and 0.72, respectively) to define IGT revealed lower AUC. Odds ratios for IGT for PCOS women in the highest LAP, BMI, and waist-to-hip ratio quartile were 41.81 (5.52-316.54), 10.24 (2.94-35.63), and 18.45 (4.19-81.30), respectively, when compared with PCOS women in the lowest LAP, BMI, and WHR quartile, respectively. CONCLUSION LAP is an easily obtainable and cheap marker associated with IGT in PCOS and control women.

Objective: Given its role in converting testosterone to dihydrotestosterone and cortisol to dihydrocortisol, 5 alpha-reductase may be important in the pathophysiology of the polycystic ovary syndrome (PCOS). Increased activity of this enzyme has already been demonstrated in ovaries of affected women, and might be caused by genetic alterations. The aim of this study was to analyze representative genetic variants of both isoforms of 5 alpha-reductase with regard to PCOS parameters in lean and obese women.Study design: We analyzed one single nucleotide polymorphism (SNP) (rs523349) of the isoform 2 (SRD5A2) and one haplotype of the isoform 1 (SRD5A1), consisting of the two SNPs rs39848 and rs3797179, in 249 women with PCOS and 226 healthy women using a 5'-exonuclease-assay. The genotypes were associated with anthropometric, metabolic and hormonal as well as functional tests in these women.Results: In the investigated haplotype of SRD5A1, the TA variant was associated with an increased frequency of PCOS (P=0.022) and an increased Ferriman-Gallwey Score (hirsutism) (P= 0.016) in women with normal weight. The G allele at the examined position of the SRD5A2 showed a decreased frequency of PCOS (P= 0.03) in women with normal weight.Conclusion: One of the keys in the development of the PCOS is hyperandrogenism, which might be caused by an increased 5 alpha-reductase activity, as it is often seen in obesity. This mechanism might therefore be of importance in lean PCOS patients and contribute to the clinical findings. (C) 2011 Elsevier Ireland Ltd. All rights reserved.

The relationship between alcohol and adiposity has been conflicting. There is a widespread belief that drinking beer promotes abdominal fat ("beer belly") and that wine has little or no such effect. This chapter reviews the epidemiological evidence in population studies on the influence of the type of alcohol on adiposity measures including body weight and central adiposity. The association between alcohol and adiposity appears to be greater for abdominal adiposity (waist circumference and waist-to-hip-ratio) than for general adiposity (body mass index). Overall, evidence from cross-sectional and prospective studies supports the concept that alcohol, in particular beer and spirits, is a risk factor for obesity, as one might expect if the energy derived from alcohol consumption was added to the usual dietary calorie intake. There is no convincing evidence that wine is protective against abdominal fat deposition.

Aims Accumulating evidence suggests that androgen deficiency is associated with cardiovascular disease. We aimed at evaluating whether total testosterone (TT) and free testosterone (FT) are associated with specific cardiovascular events.Methods and results We measured TT and sex-hormone-binding globulin levels in 2078 men who were routinely referred for coronary angiography between 1997 and 2000. Free testosterone was calculated according to Vermeulen. Main outcome measures were Cox proportional hazard ratios (HRs) for sudden cardiac death, fatal myocardial infarction, death from congestive heart failure (CHF), as well as other cardiac deaths according to quartiles of TT and FT. The median follow-up time was 7.7 years. Multivariable adjusted HRs (with 95% confidence intervals) in the fourth compared with the first FT quartile and per 1 SD increase in FT for CHF mortality were 0.38 (0.17-0.87) and 0.37 (0.15-0.89), respectively. We observed no independent significant association of FT with sudden cardiac death, fatal myocardial infarction, or other cardiac death. There was no independent association of TT levels with cardiovascular events or cardiac disease.Conclusion Low levels of FT are independently associated with increased CHF mortality.

Lipid accumulation product (LAP) is an emerging cardiovascular risk factor, which is calculated from waist circumference (WC) and triglyceride (TG) levels. The aim of this study was to elucidate the relationship between LAP and cardiovascular mortality as well as the presence of type 2 diabetes with respect to gender‐specific differences. We determined WC and fasting TG levels and the cardiovascular and metabolic phenotypes coronary artery disease (CAD), hypertension, metabolic syndrome, and diabetes mellitus in 2,279 men and 875 postmenopausal women who were routinely referred to coronary angiography. The LAP was calculated as (WC (cm) — 65) × (TG (mmol/l)) for men and as (WC (cm) — 58) × (TG (mmol/l)) for women. LAP levels were independently associated with congestive heart failure mortality in all postmenopausal women and with all‐cause mortality in diabetic postmenopausal women but not in men. Multivariable‐adjusted hazard ratios (with 95% confidence intervals) for all‐cause, cardiovascular, and congestive heart failure mortality in the third compared to the first LAP tertile were 4.28 (1.94–9.44; P < 0.001), 3.47 (1.28–9.40; P = 0.015), and 10.77 (1.21–95.88; P = 0.033), respectively, in normal weight postmenopausal women, whereas no significant associations were found in men. LAP levels were highly associated with type 2 diabetes in all subjects, postmenopausal women, and men. High LAP values are predictive of mortality independently of other cardiovascular risk factors in normal weight and diabetic postmenopausal women but not in men. Type 2 diabetes (T2DM) was highly associated with LAP in women and men. Our study validates an inexpensive and simple risk profiling that may allow identifying postmenopausal women at high cardiovascular risk.

OBJECTIVE Hyperandrogenemia is associated with cardiovascular risk factors in women but evidence about the relationship of testosterone levels with mortality is sparse. We aimed to evaluate whether total testosterone (TT), free testosterone (FT), and sex hormone–binding globulin (SHBG) are associated with all-cause and cardiovascular mortality in a cohort of postmenopausal women. RESEARCH DESIGN AND METHODS We measured TT and SHBG levels in 875 postmenopausal women who were referred for coronary angiography (during 1997–2000). FT was calculated according to the Vermeulen method. The main outcome measures were Cox proportional hazard ratios (HRs) for mortality from all causes and from cardiovascular causes. RESULTS After a median follow-up time of 7.7 years, 179 women (20.5%) had died. There were 101 deaths due to cardiovascular disease (56.4% of all deaths). We found no association of FT, TT, and SHBG levels with mortality in all postmenopausal women. In postmenopausal diabetic women, multivariable-adjusted HRs (with 95% CIs) in the fourth compared with the first FT quartile for all-cause and cardiovascular mortality were 0.38 (0.08–0.90), P = 0.025, and 0.28 (0.08–0.90), P = 0.032, respectively. We found no association of TT and SHBG with mortality in diabetic postmenopausal women. CONCLUSIONS In postmenopausal diabetic women referred for coronary angiography, low FT levels are independently associated with increased all-cause and cardiovascular mortality.

INTRODUCTION:Women with polycystic ovary syndrome (PCOS) frequently suffer from metabolic disturbances including insulin resistance (IR), which might be related to vitamin D metabolism. We aimed to investigate the association of polymorphisms in the vitamin D receptor (VDR) gene as well as vitamin D level-associated genes with metabolic and endocrine parameters in PCOS women. Moreover, we examined whether there are associations with PCOS susceptibility. METHODS:Metabolic, endocrine, and anthropometric measurements and oral glucose tolerance tests were performed in 545 PCOS and 145 control women. Genotyping of VDR (Cdx2, Bsm-I, Fok-I, Apa-I, and Taq-I), GC, DHCR7, and CYP2R1 polymorphisms was performed. RESULTS:25-Hydroxyvitamin D (25(OH)D) levels showed significant negative correlation with IR and positive correlation with insulin sensitivity (P<0.05 for all) in PCOS women. In PCOS women, the VDR Cdx2 'AA' genotype was associated with lower fasting insulin (P=0.039) and homeostatic model assessment-IR (P=0.041) and higher quantitative insulin-sensitivity check index (P=0.012) and MATSUDA index (P=0.003). The VDR Apa-I 'AA' genotype was associated with lower testosterone (P=0.028) levels. In PCOS women, 170 women (31.2%) presented with 25(OH)D levels <20 ng/ml. PCOS women carrying the GC 'GG' genotype and the DHCR7 'GG' genotype had a significantly higher risk for 25(OH)D levels <20 ng/ml (OR 2.53 (1.27-5.06), P=0.009, and OR 2.66 (1.08-6.55), P=0.033 respectively) compared with PCOS women carrying the GC 'TT' genotype and DHCR 'TT' genotype in multivariate analyses. We observed no association of genetic variations and PCOS susceptibility. CONCLUSION:VDR and vitamin D level-related variants are associated with metabolic and endocrine parameters including 25(OH)D levels in PCOS women.

The male reproductive tract has been identified as a target tissue for vitamin D, and previous data suggest an association of 25-hydroxyvitamin D [25(OH)D] with testosterone levels in men. We therefore aimed to evaluate whether vitamin D supplementation influences testosterone levels in men. Healthy overweight men undergoing a weight reduction program who participated in a randomized controlled trial were analyzed for testosterone levels. The entire study included 200 nondiabetic subjects, of whom 165 participants (54 men) completed the trial. Participants received either 83 μg (3,332 IU) vitamin D daily for 1 year (n = 31) or placebo (n =2 3). Initial 25(OH)D concentrations were in the deficiency range (< 50 nmol/l) and testosterone values were at the lower end of the reference range (9.09-55.28 nmol/l for males aged 20-49 years) in both groups. Mean circulating 25(OH)D concentrations increased significantly by 53.5 nmol/l in the vitamin D group, but remained almost constant in the placebo group. Compared to baseline values, a significant increase in total testosterone levels (from 10.7 ± 3.9 nmol/l to 13.4 ± 4.7 nmol/l; p < 0.001), bioactive testosterone (from 5.21 ± 1.87 nmol/l to 6.25 ± 2.01 nmol/l; p = 0.001), and free testosterone levels (from 0.222 ± 0.080 nmol/l to 0.267 ± 0.087 nmol/l; p = 0.001) were observed in the vitamin D supplemented group. By contrast, there was no significant change in any testosterone measure in the placebo group. Our results suggest that vitamin D supplementation might increase testosterone levels. Further randomized controlled trials are warranted to confirm this hypothesis.

Summary Objective Studies in rodents indicate a role of vitamin D in male reproduction, but the relationship between vitamin D and androgen levels in men is largely unexplored. We aimed to investigate the association of 25‐hydroxyvitamin D [25(OH)D] levels with testosterone, free androgen index (FAI) and SHBG. Moreover, we examined whether androgen levels show a similar seasonal variation to 25(OH)D. Design In this cross‐sectional study, 25(OH)D, testosterone and SHBG levels were assessed by immunoassay in 2299 men who were routinely referred for coronary angiography (1997–2000). Measurements Main outcome measures were associations of 25(OH)D levels with testosterone, SHBG and FAI. FAI was calculated as testosterone (nmol/l)/SHBG (nmol/l) × 100. Results Men with sufficient 25(OH)D levels (≥30 μg/l) had significantly higher levels of testosterone and FAI and significantly lower levels of SHBG when compared to 25(OH)D insufficient (20–29·9 μg/l) and 25(OH)D‐deficient (<20 μg/l) men ( P < 0·05 for all). In linear regression analyses adjusted for possible confounders, we found significant associations of 25(OH)D levels with testosterone, FAI and SHBG levels ( P < 0·05 for all). 25(OH)D, testosterone and FAI levels followed a similar seasonal pattern with a nadir in March (12·2 μg/l, 15·9 nmol/l and 40·8, respectively) and peak levels in August (23·4 μg/l, 18·7 nmol/l and 49·7, respectively) ( P < 0·05 for all). Conclusion Androgen levels and 25(OH)D levels are associated in men and reveal a concordant seasonal variation. Randomized controlled trials are warranted to evaluate the effect of vitamin D supplementation on androgen levels.

Objective  Accumulating evidence suggests that sex steroids are associated with various chronic diseases. We aimed at evaluating whether total testosterone (TT), free testosterone (FT) and sex hormone–binding globulin (SHBG) are associated with all‐cause mortality and specific fatal events.