Gonadal status and outcome of bariatric surgery in obese men.

BACKGROUND: Obesity-related hypogonadotrophic hypogonadism (OrHH) occurs in over 40% of morbidly obese men. Obesity-related hypogonadotrophic hypogonadism may reduce the beneficial effects of bariatric surgery. OBJECTIVE: To assess the impact of OrHH on the outcome of bariatric surgery in men. PATIENTS AND METHODS: Observational study with measurement of serum gonadal hormones, and assessment of body composition, glucose, lipid and bone metabolism during the first year after bariatric surgery in 13 men with OrHH (free testosterone (free T) <225 pmol/l) and 11 age-matched eugonadal morbidly obese men (free T > 225 pmol/l). RESULTS: Serum free T was inversely related to body weight (R = -0·65, P < 0·0001) and rose gradually after bariatric surgery, in eugonadal as well as in OrHH men, by 30 pmol/l for every 10 kg loss of weight. In three patients, serum free T remained within the hypogonadal range despite substantial weight loss. Gonadal hormone status prior to surgery did not affect the 1-year outcome of surgery. CONCLUSION: Obesity-related hypogonadotrophic hypogonadism is a reversible condition in the majority of obese men. It does not reduce the efficacy of bariatric surgery. Preoperative weight-adjusted normal values are recommended to avoid an incorrect diagnosis of hypogonadism in obese men.

Cohort profile: the 'Biomarkers of heterogeneity in type 1 diabetes' study-a national prospective cohort study of clinical and metabolic phenotyping of individuals with long-standing type 1 diabetes in the Netherlands.

PURPOSE: The 'Biomarkers of heterogeneity in type 1 diabetes' study cohort was set up to identify genetic, physiological and psychosocial factors explaining the observed heterogeneity in disease progression and the development of complications in people with long-standing type 1 diabetes (T1D). PARTICIPANTS: Data and samples were collected in two subsets. A prospective cohort of 611 participants aged ≥16 years with ≥5 years T1D duration from four Dutch Diabetes clinics between 2016 and 2021 (median age 32 years; median diabetes duration 12 years; 59% female; mean glycated haemoglobin (HbA1c) 61 mmol/mol (7.7%); 61% on insulin pump; 23% on continuous glucose monitoring (CGM)). Physical assessments were performed, blood and urine samples were collected, and participants completed questionnaires. A subgroup of participants underwent mixed-meal tolerance tests (MMTTs) at baseline (n=169) and at 1-year follow-up (n=104). Genetic data and linkage to medical and administrative records were also available. A second cross-sectional cohort included participants with ≥35 years of T1D duration (currently n=160; median age 64 years; median diabetes duration 45 years; 45% female; mean HbA1c 58 mmol/mol (7.4%); 51% on insulin pump; 83% on CGM), recruited from five centres and measurements, samples and 5-year retrospective data were collected. FINDINGS TO DATE: Stimulated residual C-peptide was detectable in an additional 10% of individuals compared with fasting residual C-peptide secretion. MMTT measurements at 90 min and 120 min showed good concordance with the MMTT total area under the curve. An overall decrease of C-peptide at 1-year follow-up was observed. Fasting residual C-peptide secretion is associated with a decreased risk of impaired awareness of hypoglycaemia. FUTURE PLANS: Research groups are invited to consider the use of these data and the sample collection. Future work will include additional hormones, beta-cell-directed autoimmunity, specific immune markers, microRNAs, metabolomics and gene expression data, combined with glucometrics, anthropometric and clinical data, and additional markers of residual beta-cell function. TRIAL REGISTRATION NUMBER: NCT04977635.

High-Dose, Diazoxide-Mediated Insulin Suppression Boosts Weight Loss Induced by Lifestyle Intervention.

Context: Obesity-related hyperinsulinism may impede lifestyle-initiated weight loss. Objective: Proof-of-concept study to investigate the amplifying effects of diazoxide (DZX)-mediated insulin suppression on lifestyle-induced weight loss in nondiabetic, hyperinsulinemic, obese men. Design: Twelve-month study comprising an initial 6-month, double-blind trial, followed by a partially de-blinded 6-month extension in men with obesity with a body mass index of 30 to 37.5 kg/m2 and a fasting serum C-peptide level >1.00 nM. Patients were randomized into three treatment groups: DZX + placebo (DZX + PL), DZX + metformin (DZX + MTF), and double PL (PL + PL). Results: At 6 months, DZX treatment was associated with a 6.1-kg PL-subtracted decline in fat mass (FM), and at 12 months, FM had decreased by a total of 15.7 ± 2.5 kg. Twelve months of DZX treatment was also associated with a significant decline in systolic (-6.6%) and diastolic (-8.6%) blood pressure and low-density lipoprotein-cholesterol (-18%) and triglycerides (-43%) and a 39% rise in high-density lipoprotein-cholesterol. These effects were achieved at the cost of a small rise in fasting glucose (95% CI: 0.2 to 1.0 mM) and hemoglobin A1c (95% CI: -0.08% to 0.44%). There were no differences between DZX monotherapy and the combination of DZX + MTF. Conclusion: High-dose DZX treatment of 1 year resulted in a substantial decrease in FM, blood pressure, and lipid levels at the cost of a small rise in blood glucose levels.

Effects of Diazoxide-Mediated Insulin Suppression on Glucose and Lipid Metabolism in Nondiabetic Obese Men.

Context: It has been suggested that stimulation of lipolysis by diazoxide (DZX)-mediated insulin suppression may be useful in treating obesity. However, the optimal dose to promote lipolysis without causing hyperglycemia is unknown. Objective: To assess the effects of DZX in nondiabetic obese men on lipid and glucose metabolism. Design: Double-blind, placebo (PL)-controlled, 6-month trial in men with a body mass index of 30 to 37.5 kg/m2 treated with a combination of caloric restriction, a standardized exercise program, and DZX or PL dose escalation. Results: The mean maximal tolerated dose of DZX was 422 ± 44 mg/d (range, 200 to 700 mg/d). Dose-limiting events were edema (n = 11), hyperglycemia (n = 6), and nausea (n = 2). After dose reduction to a level free of clinical side effects, DZX treatment was associated with a markedly greater decrease in fasting insulin levels than PL (-72.3 ± 3.5% vs -23.0 ± 12.6%; P < 0.001) and a significant improvement of blood pressure and plasma lipid levels. The decline in insulin levels occurred at the cost of a small increase in plasma glucose (0.6 ± 0.2 mmol/L vs -0.1 ± 0.1 mmol/L; P = 0.04) and hemoglobin A1C (0.2 ± 0.1% vs 0.0 ± 0.1%; P = 0.17). Conclusion: In nondiabetic obese men, insulin levels can be reduced up to 70% without major metabolic side effects. The marked intersubject variation in maximal tolerated dose indicates that DZX dose titration needs to be individualized.

Somatic and psychological effects of low-dose aromatase inhibition in men with obesity-related hypogonadotropic hypotestosteronemia.

INTRODUCTION: Reduced testosterone levels are frequently observed in obese men. Increased aromatase activity may be an etiological factor. OBJECTIVE: In this study, we evaluate the clinical effects of aromatase inhibition in obesity-related hypogonadotropic hypotestosteronemia (OrHH). METHODS: Double-blind, placebo-controlled, 6-month trial in 42 obese men with a BMI >35 kg/m(2), and a serum total testosterone <10 nmol/l. All patients started on one tablet of 2.5 mg/week, with subsequent dose escalation every month until a serum total testosterone of 20 nmol/l was reached. ENDPOINTS: Psychological function, body composition, exercise capacity, and glucose, lipid, and bone metabolism. RESULTS: Thirty-nine patients completed the study according to protocol. Letrozole decreased serum estradiol from 119.1±10.1 to 59.2±6.1 pmol/l (P<0.001), and increased serum LH from 3.3±0.3 to 8.8±0.9 U/l (P<0.0001) and serum total testosterone from 8.6±0.7 to 21.5±1.3 nmol/l (P<0.0001). Significant effects on the predefined endpoints were not observed. CONCLUSION: Despite a marked rise in serum testosterone, low-dose aromatase inhibition had no somatic or psychological effects in men with OrHH.

Letrozole once a week normalizes serum testosterone in obesity-related male hypogonadism.

OBJECTIVE: Isolated hypogonadotropic hypogonadism (IHH) is frequently observed in severely obese men, probably as a result of increased estradiol (E(2)) production and E(2)-mediated negative feedback on pituitary LH secretion. Aromatase inhibitors can reverse this process. This study evaluates whether letrozole once a week can normalize serum testosterone in severely obese men and maintain its long term effect. DESIGN: Open, uncontrolled 6-month pilot study in 12 severely obese men (body mass index>35.0 kg/m(2)) with obesity-related IHH and free testosterone levels <225 pmol/l, treated with 2.5 mg letrozole once a week for 6 months. RESULTS: Six weeks of treatment reduced total E(2) from 123+/-11 to 58+/-7 pmol/l (P<0.001, mean+/-s.e.m.), and increased serum LH from 4.4+/-0.6 to 11.1+/-1.5 U/l (P<0.001). Total testosterone rose from 5.9+/-0.5 to 19.6+/-1.4 nmol/l (P<0.001), and free testosterone from 163+/-13 to 604+/-50 pmol/l (P<0.001). Total testosterone rose to within the normal range in all subjects, whereas free testosterone rose to supraphysiological levels in 7 out of 12 men. The testosterone and E(2) levels were stable throughout the week and during the 6-month treatment period. CONCLUSION: Letrozole 2.5 mg once a week produced a sustained normalization of serum total testosterone in obese men with IHH. However, free testosterone frequently rose to supraphysiological levels. Therefore, a starting dose <2.5 mg once a week is recommended.

Familial Aggregation of Non-Hodgkin's Lymphoma (NHL). A Case Report.

A family is reported in which three male siblings of Asian descent developed non-Hodgkin's lymphoma (NHL). Case 1 was diagnosed with indolent follicular lymphoma stage IIIA at age 45. Case 2 presented with large B-cell lymphoma stage IIB at age 56. Chromosomal investigation of the peripheral blood did not show abnormalities. Chemotherapy induced a complete remission. However, after a period of nearly ten years he developed acute myeloid leukaemia. Case 3 developed large B-cell lymphoma stage IVA at age 52. Cytogenetic analysis in peripheral blood was normal. Shared genetic and environmental risk factors remain to be identified in this family. Familial aggregation of NHL is uncommon. In some families, various forms of immunodeficiency have been found. In addition to coincidental clustering of cases, and rare cases explained by known tumour syndromes such as Li-Fraumeni (like) syndrome, other familial cases may share as yet unknown genetic and/or environmental risk factors.