Excess weight, weight gain, and prostate cancer risk and prognosis: the PROCA-life study.

BACKGROUND: Studies of excess weight and weight changes throughout adult life for prostate cancer (PCa) risk and prognosis have shown inconsistent results. METHODS: In a population-based cohort, the Prostate Cancer Study throughout life (PROCA-life), 16,960 healthy men from the prospective cohort Tromsø Study (1994-2016) were included. Body mass index (BMI) and weight were measured at all four attendings, and weight change was calculated as the difference between the first and last of either Tromsø4, Tromsø5 or Tromsø6. Overall, 904 men developed PCa during 16 years of follow-up, and Poisson regression with fractional polynomials was used to investigate trends in incidence. Cox proportional hazard and logistic regression models were used to study associations between measurements of BMI and weight change and PCa risk, severity, and mortality. RESULTS: At study entry, 46% of the participants (median age 44 years) were overweight, and 14% were obese (BMI > 30 kg/m2). We observed a 127% increase in overall age adjusted PCa incidence in the cohort during 1995 through 2019. No overall associations between BMI or weight change and PCa risk were observed. However, in sub-group analysis, weight gain among obese men was associated with a three-fold higher PCa risk (HR 3.03, 95% CI 1.39-6.58) compared with obese men with stable weight. Overweight was associated with lower risk of metastatic cancer (OR 0.48, 95% CI 0.30-0.75) at diagnosis. Men with obesity had higher risk of PCa-specific death (HR 1.72, 95% CI 1.03-2.88), while nonsmoking obese PCa cases had two times higher PCa-specific mortality compared with normal weighted PCa cases (HR 2.10, 95% CI 1.11-3.70). INTERPRETATION: In our cohort, weight gain among obese men was associated with higher risk of PCa, and obesity was associated with higher PCa-specific mortality, especially among nonsmokers. The relationship between weight and risk for PCa remains complicated, and future studies are needed to determine clinical implications.

Plasma free tissue factor pathway inhibitor (TFPI) levels and TF-induced thrombin generation ex vivo in men with low testosterone levels.

Low testosterone levels in men have been associated with cardiovascular risk factors, some prothrombotic factors, and lately also an increased risk of both cardiovascular disease and all-cause mortality. Experimental studies have shown increased synthesis and release of tissue factor pathway inhibitor (TFPI) by physiological levels of testosterone in endothelial cells. Our hypothesis was that elderly men with low testosterone levels would have lower plasma levels of plasma free TFPI with subsequent increased thrombin generation. Elderly men with low (n = 37) and normal (n = 41) testosterone levels were recruited from a general population, and tissue factor (TF)-induced thrombin generation ex vivo and plasma free TFPI Ag were measured. Elderly men with low testosterone levels had lower plasma free TFPI Ag (10.9 +/- 2.3 ng/ml vs. 12.3 +/- 3.0 ng/ml, p = 0.027) and shorter initiation phase of TF-induced coagulation assessed by lag-time (5.1 +/- 1.0 min vs. 5.7 +/- 1.3, p = 0.039). The differences between groups remained significant and were strengthened after adjustment for waist circumference and other cardiovascular risk factors. Lag-time increased linearly across quartiles of plasma free TFPI Ag (p<0.001). Multiple regression analysis revealed that total and free testosterone were independent predictors of plasma free TFPI Ag. Our findings suggest that low testosterone levels in elderly men is associated with low plasma free TFPI Ag and subsequent shortened initiation phase of TF-induced coagulation.

Low serum testosterone in men is inversely associated with non-fasting serum triglycerides: the Tromsø study.

OBJECTIVE: To study the relationships between endogenous testosterone, sex hormone-binding globulin (SHBG) and serum lipids in non-fasting men. METHODS: We performed a cross-sectional study in 1274 men without known cardiovascular disease who participated in a population-based study, the 1994/1995 Tromsø study. Anthropometric characteristics were measured and questionnaires regarding lifestyle and medical history were completed. Non-fasting blood samples were drawn between 08.00 and 16.00h, and total testosterone, SHBG, triglycerides (TG), total cholesterol (TC) and high-density lipoprotein (HDL) were analyzed. RESULTS: In stratified analyses based on sampling time, a linear increase in serum TG levels was found in men with total testosterone levels below the 50th percentile during the day (p for trend=0.004). In contrast, serum triglycerides did not change during the day in men with testosterone levels above the 50th percentile. In regression analyses, total testosterone and SHBG were inversely and independently associated with TG (p<0.001 and p<0.001 respectively), and positively and independently associated with HDL (p=0.005 and p<0.001, respectively). Men with an unfavorable lipid profile (HDL <0.90 and TG >1.8) had significantly lower levels of total testosterone and SHBG (p=0.004 and p<0.001, respectively) in age and BMI adjusted analyses, compared to men with a normal lipid profile. CONCLUSIONS: Low serum total testosterone was associated with a linear increase in serum TG during the day, and was independently associated with an unfavorable lipid profile. Our findings may indicate that low total testosterone is associated with impaired TG metabolism in men.

Postprandial triglyceride metabolism in elderly men with subnormal testosterone levels.

AIM: To investigate the level of postprandial triglycerides (TG)s in elderly men with subnormal testosterone level (< or = 11.0 nmol/L) compared to men with normal testosterone level (> 11.0 nmol/L). METHODS: Thirty-seven men with subnormal and 41 men with normal testosterone aged 60-80 years underwent an oral fat load and TG levels were measured fasting and 2, 4, 6 and 8 h afterwards. RESULTS: Men with subnormal testosterone had significantly higher body mass index (BMI) and waist circumference (P < 0.001) than men with normal testosterone. They had significantly higher area under curve (AUC, P = 0.037), incremental area under curve (AUCi, P = 0.035) and TG response (TGR, P = 0.014) for serum-TG and significantly higher AUC (P = 0.023), AUCi (P = 0.023) and TGR (P = 0.014) for chylomicron-TG compared to men with normal testosterone level. Adjusting for waist circumference erased the significant differences between the groups in postprandial triglyceridemia. CONCLUSION: Men with subnormal testosterone have increased postprandial TG levels indicating an impaired metabolism of postprandial TG-rich lipoproteins (TRL), which may add to an unfavourable lipid profile and promote development of atherosclerosis.

Impact of long-term testosterone treatment on plasma levels of free TFPI and TF-induced thrombin generation ex vivo in elderly men with low testosterone levels.

Men have a higher incidence of cardiovascular disease (CVD) than women of similar age, and it has been suggested that testosterone may influence the development of CVD. Recently, we demonstrated that elderly men with low testosterone levels had lower plasma levels of free tissue factor pathway inhibitor (TFPI) Ag associated with shortened tissue factor (TF)-induced coagulation initiation in a population based case-control study. Our hypothesis was that one year of testosterone treatment to physiological levels in elderly men would increase the levels of free TFPI Ag in plasma and have a favorable effect on TF-induced coagulation. Twenty-six men with low testosterone levels (< or =11.0 nM) were randomly assigned to treatment with intramuscular testosterone depot injections (testosterone undecanoate 1,000 mg) or placebo in a double-blinded study. Each participant received a total of five injections, at baseline, 6, 16, 28 and 40 weeks, and TF-induced thrombin generation ex vivo and plasma free TFPI Ag were measured after one year. At the end of the study total and free testosterone levels were significantly higher in the testosterone treated group (14.9 +/- 4.5 nM vs. 8.1 +/- 2.4 nM; p < 0.001, and 363.3 +/- 106.6 pM vs. 187.3 +/- 63.2 pM; p < 0.001, respectively). Testosterone treatment for one year did neither cause significant changes in TF-induced thrombin generation ex vivo nor changes in plasma levels of free TFPI Ag. In conclusion, normalising testosterone levels by testosterone treatment for 12 months in elderly men did not affect TF-induced coagulation or plasma TFPI levels. The potential antithrombotic role of testosterone therapy remains to be elucidated.

Impact of testosterone treatment on postprandial triglyceride metabolism in elderly men with subnormal testosterone levels.

OBJECTIVE: To investigate the impact of testosterone supplementation on postprandial triglycerides in elderly men with subnormal endogenous testosterone. MATERIAL AND METHODS: Twenty-six men with subnormal testosterone levels (< or = 11.0 nmol/L) were randomly assigned to treatment with intramuscular testosterone or placebo for one year in a double-blinded study. The participants underwent an oral fat load before and after the treatment period, and serum and chylomicron triglyceride levels were measured fasting and 2, 4, 6 and 8 h afterwards, together with total fat mass and fat-free mass. RESULTS: Total testosterone rose to low-normal levels in the testosterone-treated group. No differences in waist circumference, body mass index, serum levels of total cholesterol, low-density lipoprotein cholesterol, high density lipoprotein cholesterol, fasting triglyceride concentrations or lipase activity between the groups were observed during testosterone treatment. Testosterone treatment did not affect postprandial serum and chylomicron triglyceride levels assessed by area under the curve, incremental area under the curve or triglyceride response. Total fat mass was significantly reduced (p <0.001) while fat-free mass was significantly increased (p < 0.001) in the testosterone-treated group. CONCLUSION: Normalizing testosterone levels in elderly men does not seem to affect the postprandial lipid metabolism to any great extent, but has favourable effects on body composition.

Bulimia nervosa--a primary defect in the hypothalamic-pituitary-adrenal axis?

Bulimia nervosa has been associated with impaired satiety, decreased resting metabolic rate and abnormal neuroendocrine regulation. The aim of this study was to investigate the diurnal cortisol secretion and the pituitary-adrenal response to corticotropin-releasing hormone (CRH) in subjects suffering from bulimia nervosa. Eight female subjects with remitted bulimia nervosa, ages 24-56, and 8 sex- and weight-matched controls volunteered to participate. After an overnight fast they were admitted to the Clinical Research Center for 24 hour recording of plasma cortisol secretion. Blood were drawn every 2nd hour from 8 AM. After another overnight fast, the subjects performed a 120-min CRH test (100 microg i.v.), drawn for measurements of adrenocorticotropin releasing hormone (ACTH) and cortisol. Compared to the control group (CG), the diurnal cortisol secretions in the bulimic group (BG) decreased at time points 6 AM to 2 PM. In the CRH test, the ACTH response was significantly stronger in the BG than in the CG. Similar observations were found for cortisol, although not at significant levels. Remitted bulimic patients exhibit a neuroendocrine pattern of decreased HPA axis activity with a hyperreactivity to CRH. This may indicate a complex and so far poorly understood neuroendocrine dysregulation of HPA axis associated with the disease.