Effects of sex hormone treatment on the metabolic syndrome in transgender individuals : focus on metabolic cytokines

Context: Hormonal treatment in transgender persons affects many components of the metabolic syndrome (MS). Objective: To determine the role of direct hormonal effects, changes in metabolic cytokines, and body composition on metabolic outcomes. Design, Setting, and Participants: 24 transwomen and 45 transmen from the European Network for the Investigation of Gender Incongruence were investigated at baseline and after 12 months of hormonal therapy. Outcome Measures: Best predictors for changes in components of MS, applying least absolute shrinkage and selection operator regression. Results: In transwomen, a decrease in triglyceride levels was best explained by a decrease in fat mass and an increase in fibroblast growth factor 21 (FGF-21); the decrease in total and low-density lipoprotein cholesterol levels was principally due to a decrease in resistin. A decrease in high-density lipoprotein cholesterol depended on an inverse association with fat mass. In contrast, in transmen, an increase in low-density lipoprotein cholesterol was predicted by a decrease in FGF-21 and an increase in the waist/hip ratio; a decrease in the high-density lipoprotein/total cholesterol ratio depended on a decline in adiponectin levels. In transwomen, worsened insulin resistance and increased early insulin response seemed to be due to a direct treatment effect; however, improvements in hepatic insulin sensitivity in transmen were best predicted by a positive association with chemerin, resistin, and FGF-21 and were inversely related to changes in the waist/hip ratio and leptin and adipocyte fatty acid-binding protein levels. Conclusions: The effects of hormonal therapy on different components of the MS are sex-specific and involve a complex interplay of direct hormonal effects, changes in body composition, and metabolic cytokine secretion

Shorter telomeres associated with high doses of glucocorticoids: the link to increased mortality?

Objective: Patients with non-functioning pituitary adenomas exhibit high morbidity and mortality rates. Growth hormone deficiency and high doses of glucocorticoid substitution therapy have been identified as corresponding risk factors. Interestingly, high levels of endogenous cortisol in, e.g., patients with post-traumatic stress disorder or patients with Cushing's disease have been linked to shorter telomere length. Telomeres are noncoding DNA regions located at the end of chromosomes consisting of repetitive DNA sequences which shorten with aging and hereby determine cell survival. Therefore, telomere length can serve as a predictor for the onset of disease and mortality in some endocrine disorders (e.g., Cushing's disease). Design/methods: Here, we examine telomere length from blood in patients (n=115) with non-functioning pituitary adenomas (NFPA) in a cross-sectional case-control (n= 106, age-, gender-matched) study using qPCR. Linear regression models were used to identify independent predictors of telomere length. Results: We show that patients with NFPA exhibited shorter telomeres than controls. No significant association of indices of growth hormone deficiency (IGF-1-level-SDS, years of unsubstituted growth hormone deficiency etc.) with telomere length was detected. Interestingly, linear regression analysis showed that hydrocortisone replacement dosage in patients with adrenal insufficiency (n=52) was a significant predictor for shorter telomere length (beta=0.377;P=0.018) independent of potential confounders (gender, age, BMI, arterial hypertension, systolic blood pressure, number of antihypertensive drugs, total leukocyte count, waist-to-hip ratio, waist circumference, diabetes mellitus type 2, HbA1c, current statin use). Median split analysis revealed that higher hydrocortisone intake (>20 mg) was associated with significantly shorter telomeres. Conclusion: These observations strengthen the importance of adjusted glucocorticoid treatment in NFPA patients with respect to morbidity and mortality rates

Hypoxia and the hypoxia inducible factor 1α activate protein kinase A by repressing RII beta subunit transcription

Overactivation of the cAMP signal transduction pathway plays a central role in the pathogenesis of endocrine tumors. Genetic aberrations leading to increased intracellular cAMP or directly affecting PKA subunit expression have been identified in inherited and sporadic endocrine tumors, but are rare indicating the presence of nongenomic pathological PKA activation. In the present study, we examined the impact of hypoxia on PKA activation using human growth hormone (GH)-secreting pituitary tumors as a model of an endocrine disease displaying PKA-CREB overactivation. We show that hypoxia activates PKA and enhances CREB transcriptional activity and subsequently GH oversecretion. This is due to a previously uncharacterized ability of HIF-1α to suppress the transcription of the PKA regulatory subunit 2B (PRKAR2B) by sequestering Sp1 from the PRKAR2B promoter. The present study reveals a novel mechanism through which the transcription factor HIF-1α transduces environmental signals directly onto PKA activity, without affecting intracellular cAMP concentrations. By identifying a point of interaction between the cellular microenvironment and intracellular enzyme activation, neoplastic, and nonneoplastic diseases involving overactivated PKA pathway may be more efficiently targeted

Association of dietary intake of milk and dairy products with blood concentrations of insulin-like growth factor 1 (IGF-1) in Bavarian adults

PURPOSE Circulating IGF-1 concentrations have been associated with higher cancer risk, particularly prostate, breast and colorectal cancer. There is evidence from observational and intervention studies that milk and dairy products intake is associated with higher IGF-1 concentrations, but results were not always consistent. The purpose of this study was to examine the relationship between dairy intake and circulating IGF-1 concentrations in participants of the Second Bavarian Food Consumption Survey, thereby providing data for a German population for the first time. METHODS In this cross-sectional study of 526 men and women aged 18-80 years, in contrast to most previous investigations, dietary intake was assessed with a more detailed instrument than food frequency questionnaires (FFQs), i.e., by three 24-h dietary recalls conducted on random days close in time to the blood collection. Circulating IGF-1 concentrations were measured in blood samples. Multivariable linear regression models were used to examine the association of dairy intake with IGF-1 concentrations. RESULTS Each 400 g increment in daily dairy intake was associated with 16.8 µg/L (95% CI 6.9, 26.7) higher IGF-1 concentrations. Each 200 g increment in milk per day was associated with 10.0 µg/L (95% CI 4.2, 15.8) higher IGF-1. In contrast, we observed no association between cheese or yogurt intake and IGF-1 concentrations. CONCLUSIONS Our findings are in line with most previous investigations and support the hypothesis that dairy and milk intake are associated with higher IGF-1 concentrations

Adjusted Troponin I for Improved Evaluation of Patients with Chest Pain

The use of cardiac troponins (cTn) is the gold standard for diagnosing myocardial infarction. Independent of myocardial infarction (MI), however, sex, age and kidney function affect cTn levels. Here we developed a method to adjust cTnI levels for age, sex, and renal function, maintaining a unified cut-off value such as the 99th percentile. A total of 4587 individuals enrolled in a prospective longitudinal study were used to develop a model for adjustment of cTn. cTnI levels correlated with age and estimated glomerular filtration rate (eGFR) in males/females with r(age) = 0.436/0.518 and with (r)(eGFR) = -0.142/-0.207. For adjustment, these variables served as covariates in a linear regression model with cTnl as dependent variable. This adjustment model was then applied to a real-world cohort of 1789 patients with suspected acute MI (AMI) (N = 407). Adjusting cTnI showed no relevant loss of diagnostic information, as evidenced by comparable areas under the receiver operator characteristic curves, to identify AMI in males and females for adjusted and unadjusted cTnI. In specific patients groups such as in elderly females, adjusting cTnI improved specificity for AMI compared with unadjusted cTnI. Specificity was also improved in patients with renal dysfunction by using the adjusted cTnI values. Thus, the adjustments improved the diagnostic ability of cTnI to identify AMI in elderly patients and in patients with renal dysfunction. Interpretation of cTnI values in complex emergency cases is facilitated by our method, which maintains a single diagnostic cut-off value in all patients

Adjusted Troponin I for Improved Evaluation of Patients with Chest Pain

The use of cardiac troponins (cTn) is the gold standard for diagnosing myocardial infarction. Independent of myocardial infarction (MI), however, sex, age and kidney function affect cTn levels. Here we developed a method to adjust cTnI levels for age, sex, and renal function, maintaining a unified cut-off value such as the 99th percentile. A total of 4587 individuals enrolled in a prospective longitudinal study were used to develop a model for adjustment of cTn. cTnI levels correlated with age and estimated glomerular filtration rate (eGFR) in males/females with r(age) = 0.436/0.518 and with (r)(eGFR) = -0.142/-0.207. For adjustment, these variables served as covariates in a linear regression model with cTnl as dependent variable. This adjustment model was then applied to a real-world cohort of 1789 patients with suspected acute MI (AMI) (N = 407). Adjusting cTnI showed no relevant loss of diagnostic information, as evidenced by comparable areas under the receiver operator characteristic curves, to identify AMI in males and females for adjusted and unadjusted cTnI. In specific patients groups such as in elderly females, adjusting cTnI improved specificity for AMI compared with unadjusted cTnI. Specificity was also improved in patients with renal dysfunction by using the adjusted cTnI values. Thus, the adjustments improved the diagnostic ability of cTnI to identify AMI in elderly patients and in patients with renal dysfunction. Interpretation of cTnI values in complex emergency cases is facilitated by our method, which maintains a single diagnostic cut-off value in all patients