Mathis Grossmann

Description:Background: Current first-line therapy for hyponatremia, fluid restriction (FR), is often unsuccessful. Tolvaptan, an arginine vasopressin V2-receptor antagonist, is effective however concerns about plasma sodium (pNa) overcorrection risk have limited uptake. Objective: To compare the efficacy of tolvaptan and fluid restriction, with a pre-specified protocol for dextrose 5% intervention if sodium correction targets were exceeded. Methods: Open-label randomized trial. Methods: Single centre tertiary hospital Austin Health in Melbourne, Australia. Methods: 54 hospitalized patients with pNa 115-130mmol/L (mean 124mmol/L) meeting criteria for syndrome of inappropriate antidiuresis (SIAD). Methods: Tolvaptan 7.5mg oral daily or FR <1000ml/day (1:1) for 3 days, with daily titration according to pNa response. Methods: Plasma sodium change from Day 1 to 4; requirement for IV 5% dextrose to prevent or treat overcorrection; symptom measures; length of hospital stay. Results: Plasma sodium concentrations increased more in the tolvaptan group, compared to FR, over 3 days (p.overall<0.001). The mean adjusted difference in pNa between groups at Days 2, 3 and 4 was 3.2 (95%CI 1.6-4.7), 3.5 (95%CI 1.9-5.2), and 2.5mmol/L (95%CI 0.8-4.2), respectively. Five tolvaptan recipients (19%) required dextrose 5% to treat rapid sodium rise. With this intervention, no patient had sodium rise >10mmol/L at 24 hours. There was no difference in length of stay or symptoms. Conclusions: Tolvaptan was superior to FR at raising pNa over 3 days. However, intervention was required to prevent overcorrection in some, with no benefit in secondary outcomes. This is the first prospectively-validated protocol to detect and prevent tolvaptan-related overcorrection.

Description:Objective: We have shown that men aged 50 years+ at high risk of type 2 diabetes treated with testosterone together with a lifestyle program reduced the risk of type 2 diabetes at 2 years by 40% compared to a lifestyle program alone. To develop a personalized approach to treatment, we aimed to explore a prognostic model for incident type 2 diabetes at 2 years and investigate biomarkers predictive of the testosterone effect. Methods: Model development in 783 men with impaired glucose tolerance but not type 2 diabetes from Testosterone for Prevention of Type 2 Diabetes; a multicenter, 2-year trial of Testosterone vs placebo. External validation performed in 236 men from the Examining Outcomes in Chronic Disease in the 45 and Up Study (EXTEND-45, n = 267 357). Methods: Type 2 diabetes at 2 years defined as 2-h fasting glucose by oral glucose tolerance test (OGTT) ≥11.1 mmol/L. Risk factors, including predictive biomarkers of testosterone treatment, were assessed using penalized logistic regression. Results: Baseline HbA1c and 2-h OGTT glucose were dominant predictors, together with testosterone, age, and an interaction between testosterone and HbA1c (P = .035, greater benefit with HbA1c ≥ 5.6%, 38 mmol/mol). The final model identified men who developed type 2 diabetes, with C-statistics 0.827 in development and 0.798 in validation. After recalibration, the model accurately predicted a participant's absolute risk of type 2 diabetes. Conclusions: Baseline HbA1c and 2-h OGTT glucose predict incident type 2 diabetes at 2 years in high-risk men, with risk modified independently by testosterone treatment. Men with HbA1c ≥ 5.6% (38 mmol/mol) benefit most from testosterone treatment, beyond a lifestyle program.

Description:Background: The combined effects of testosterone treatment and lifestyle intervention on sexual function in men at high risk of type 2 diabetes are unclear. Objective: To assess the effect of testosterone treatment with a lifestyle intervention in men aged 50 to 74 years at high risk of, or newly diagnosed with, type 2 diabetes (via oral glucose tolerance test). Methods: A secondary analysis of the Testosterone for the Prevention of Type 2 Diabetes trial, a double-blind, placebo-controlled trial conducted across 6 Australian centers. Methods: Intramuscular testosterone undecanoate (1000 mg) or placebo, 3 monthly for 2 years alongside a community-based lifestyle program. Results: Sexual function measured using the International Index of Erectile Function (IIEF)-15 questionnaire. Results: Of 1007 participants, 792 (79%) had complete International Index of Erectile Function-15 data. Baseline domain scores were inversely related to age and waist circumference, but unrelated to serum testosterone or estradiol levels. Testosterone treatment improved all 5 International Index of Erectile Function-15 domain scores, with stronger effects on sexual desire and orgasmic function in older men, and sexual desire in men with higher depression scores. Testosterone had no impact on depression. Independent of treatment, reductions in waist circumference were associated with improved erectile function, and reductions in depression scores correlated with better sexual function. Clinically significant improvement in erectile function and sexual desire occurred in 3% and 10% of men, respectively, and was inversely related to baseline function. Clinically significant improvement improvements in erectile function and sexual desire were greater in younger and older men respectively. Conclusions: Testosterone treatment enhanced sexual desire and, to a lesser extent, erectile function, particularly in older men and those with higher waist circumference or depressive symptoms. Reduced waist circumference and depression independently improved sexual function.

Description:Background: Survival of patients with prostate and breast cancer, the commonest cancer in men and women, respectively, has markedly improved with advances in early diagnosis, treatment and multi-disciplinary care by the oncology and surgical community. However, the use of increasingly potent endocrine therapies may cause bone loss, resulting in secondary osteoporosis. Methods: This review summarises the current management of cancer treatment-induced bone loss in this group of patients at high risk of osteoporotic fractures with their attendant morbidity and mortality. Conclusions: Bone health is an increasingly important part of cancer survivorship. Radiation and medical oncologists, urologists, bone health experts, general practitioners, healthcare professional bodies and bone health and cancer consumer organisations should increase awareness of the potential adverse effect of endocrine therapy on bone health. While this should never delay cancer treatment, bone health should be part of routine care for men and women receiving endocrine therapy for prostate and breast cancer.