Interaction of Human Chorionic Gonadotropin (hCG) and Asialo-hCG with Recombinant Human Thyrotropin Receptor.

hCG is a putative thyroid stimulator. The present studies were undertaken to examine its interaction and that of its desialylated variant asialo-hCG with recombinant human TSH (hTSH) receptor (hTSHr). To this end, we transfected a human thyroid carcinoma cell line (HTC) lacking endogenous TSHr with the full-length cDNA of the hTSHr. Unlike the wild type, the transfected cells, termed HTC-TSHr cells, were able to bind bovine TSH (bTSH) with high affinity and increase cAMP production in response to bTSH stimulation. Of the hCG forms, intact hCG displayed a weak activity to inhibit [125I] bTSH binding to HTC-TSHr cells, with 100 mg/L (2.6 x 10(-6) mol/L) producing maximally a 20% inhibition, whereas asialo-hCG achieved half-maximum binding inhibition at a concentration of 8 mg/L (2.3 x 10(-7) mol/L). The inhibitory constant (Ki) of asialo-hCG for recombinant hTSHr was calculated from saturation experiments in the presence of variable doses of bTSH and a fixed concentration of asialo-hCG to be approximately 8 x 10(-8) mol/L. The interaction of asialo-hCG with TSHr was further assessed by studies of the direct binding of the radioactively labeled hormone to both HTC and HTC-TSHr cells. [125I]Asialo-hCG binding to HTC-TSHr cells was 4.7%, compared to 1.5% in the wild-type cells lacking TSHr and was displaceable by bTSH (0.1-100 IU/L), indicating specific binding of the tracer to TSHr. Functionally, hCG (up to 100 mg/L; 2.6 x 10(-6) mol/L) proved unable to evoke any significant cAMP response over basal values in HTC-TSHr cells, as did asialo-hCG. Asialo-hCG, but not hCG, inhibited bTSH-stimulated adenylate cyclase activity in the cells in a dose-dependent manner. In conclusion, the present data show that intact hCG binds only weakly to HTC-TSHr cells and produces no significant cAMP stimulation, which is at variance with data obtained in FRTL-5 and Chinese hamster ovary-TSHr cells, but in good accord with previous findings in human thyroid membranes. Asialo-hCG, on the other hand, strongly binds to recombinant TSHr and inhibits the cAMP response to bTSH in HTC-TSHr cells, indicating that the desialylated hCG variant directly interacts with the receptor and truly is an antagonist of the hTSHr

BMI, Diet and Female Reproductive Factors as Risks for Thyroid Cancer: A Systematic Review

Background: Thyroid cancer incidence rates have been increasing worldwide but the reason behind this is unclear. Both the increasing use of diagnostic technologies allowing the detection of thyroid cancer and a true increase in thyroid cancer incidence have been proposed. This review assesses the role of body mass index (BMI), diet, and reproductive factors on the thyroid cancer trend. Methods: Epidemiologic studies of the selected risk factors up to June 2010 were reviewed and critically assessed. Results: Among the thirty-seven studies reviewed and despite variation in the risk estimates, most papers supported a small but positive association for BMI (risk estimate range: 1.1–2.3 in males and 1.0–7.4 in females.). Among specific dietary components, there was no consistent association of thyroid cancer risk with iodine intake through fortification (risk estimate range: 0.49–1.6) or fish consumption (risk estimate range 0.6–2.2), nor with diets high in cruciferous vegetables (risk estimate range 0.6–1.9). A small number of studies showed a consistent protective effect of diets high in non-cruciferous vegetable (risk estimate range: 0.71–0.92). Among reproductive factors (pregnancy, parity, number of live births, use of prescription hormones, menstrual cycle regularity, and menopausal status), none were consistently associated with higher thyroid cancer risk. Conclusions: BMI had the strongest link to thyroid cancer risk among those examined. Detailed examinations of populationleve

Design and baseline characteristics of the finerenone in reducing cardiovascular mortality and morbidity in diabetic kidney disease trial

Background: Among people with diabetes, those with kidney disease have exceptionally high rates of cardiovascular (CV) morbidity and mortality and progression of their underlying kidney disease. Finerenone is a novel, nonsteroidal, selective mineralocorticoid receptor antagonist that has shown to reduce albuminuria in type 2 diabetes (T2D) patients with chronic kidney disease (CKD) while revealing only a low risk of hyperkalemia. However, the effect of finerenone on CV and renal outcomes has not yet been investigated in long-term trials. Patients and Methods: The Finerenone in Reducing CV Mortality and Morbidity in Diabetic Kidney Disease (FIGARO-DKD) trial aims to assess the efficacy and safety of finerenone compared to placebo at reducing clinically important CV and renal outcomes in T2D patients with CKD. FIGARO-DKD is a randomized, double-blind, placebo-controlled, parallel-group, event-driven trial running in 47 countries with an expected duration of approximately 6 years. FIGARO-DKD randomized 7,437 patients with an estimated glomerular filtration rate >= 25 mL/min/1.73 m(2) and albuminuria (urinary albumin-to-creatinine ratio >= 30 to <= 5,000 mg/g). The study has at least 90% power to detect a 20% reduction in the risk of the primary outcome (overall two-sided significance level alpha = 0.05), the composite of time to first occurrence of CV death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for heart failure. Conclusions: FIGARO-DKD will determine whether an optimally treated cohort of T2D patients with CKD at high risk of CV and renal events will experience cardiorenal benefits with the addition of finerenone to their treatment regimen. Trial Registration: EudraCT number: 2015-000950-39; ClinicalTrials.gov identifier: NCT02545049