Clues for early detection of autoimmune Addison's disease - myths and realities.

BACKGROUND: Early detection of autoimmune Addison's disease (AAD) is important as delay in diagnosis may result in a life-threatening adrenal crisis and death. The classical clinical picture of untreated AAD is well-described, but methodical investigations are scarce. OBJECTIVE: Perform a retrospective audit of patient records with the aim of identifying biochemical markers for early diagnosis of AAD. MATERIAL AND METHODS: A multicentre retrospective study including 272 patients diagnosed with AAD at hospitals in Norway and Sweden during 1978-2016. Scrutiny of medical records provided patient data and laboratory values. RESULTS: Low sodium occurred in 207 of 247 (84%), but only one-third had elevated potassium. Other common nonendocrine tests were largely normal. TSH was elevated in 79 of 153 patients, and hypoglycaemia was found in 10%. Thirty-three per cent were diagnosed subsequent to adrenal crisis, in whom electrolyte disturbances were significantly more pronounced (P < 0.001). Serum cortisol was consistently decreased (median 62 nmol L-1 [1-668]) and significantly lower in individuals with adrenal crisis (38 nmol L-1 [2-442]) than in those without (81 nmol L-1 [1-668], P < 0.001). CONCLUSION: The most consistent biochemical finding of untreated AAD was low sodium independent of the degree of glucocorticoid deficiency. Half of the patients had elevated TSH levels. Only a minority presented with marked hyperkalaemia or other nonhormonal abnormalities. Thus, unexplained low sodium and/or elevated TSH should prompt consideration of an undiagnosed AAD, and on clinical suspicion bring about assay of cortisol and ACTH. Presence of 21-hydroxylase autoantibodies confirms autoimmune aetiology. Anticipating additional abnormalities in routine blood tests may delay diagnosis.

Preoperative octreotide therapy and surgery in acromegaly: associations between glucose homeostasis and treatment response.

In acromegaly, high GH/IGF-1 levels associate with abnormal glucose metabolism. Somatostatin analogs (SSAs) reduce GH and IGF-1 but inhibit insulin secretion. We studied glucose homeostasis in de novo patients with acromegaly and changes in glucose metabolism after treatment with SSA and surgery. In this post hoc analysis from a randomized controlled trial, 55 de novo patients with acromegaly, not using antidiabetic medication, were included. Before surgery, 26 patients received SSAs for 6 months. HbA1c, fasting glucose, and oral glucose tolerance test were performed at baseline, after SSA pretreatment and at 3 months postoperative. Area under curve of glucose (AUC-G) was calculated. Glucose homeostasis was compared to baseline levels of GH and IGF-1, change after SSA pretreatment, and remission both after SSA pretreatment and 3 months postoperative. In de novo patients, IGF-1/GH levels did not associate with baseline glucose parameters. After SSA pretreatment, changes in GH/IGF-1 correlated positively to change in HbA1c levels (both p < 0.03). HbA1c, fasting glucose, and AUC-G increased significantly during SSA pretreatment in patients not achieving hormonal control (all p < 0.05) but did not change significantly in patients with normalized hormone levels. At 3 months postoperative, HbA1c, fasting glucose, and AUC-G were significantly reduced in both cured and not cured patients (all p < 0.05). To conclude, in de novo patients with acromegaly, disease activity did not correlate with glucose homeostasis. Surgical treatment of acromegaly improved glucose metabolism in both cured and not cured patients, while SSA pretreatment led to deterioration in glucose homeostasis in patients not achieving biochemical control.

Preoperative octreotide treatment of acromegaly: long-term results of a randomised controlled trial.

OBJECTIVE: Randomised studies have demonstrated a beneficial effect of pre-surgical treatment with somatostatin analogues (SSA) in acromegaly when evaluated early postoperatively. The objective of this study was to evaluate the long-term surgical cure rates. METHODS: Newly diagnosed patients were randomised to direct surgery (n=30) or 6-month pretreatment with octreotide LAR (n=32). The patients were evaluated 1 and 5 years postoperatively. Cure was defined as normal IGF1 levels and by normal IGF1 level combined with nadir GH <2 mU/l in an oral glucose tolerance test, all without additional post-operative treatment. A meta-analysis using the other published randomised study with long-term analyses on preoperative SSA treatment was performed. RESULTS: The proportion of patients receiving post-operative acromegaly treatment was equal in the two groups. When using the combined criteria for cure, 10/26 (38%) macroadenomas were cured in the pretreatment group compared with 6/25 (24%) in the direct surgery group 1 year postoperatively (P=0.27), and 9/22 (41%) vs 6/22 (27%) macroadenomas, respectively, 5 years postoperatively (P=0.34). In the meta-analysis, 16/45 (36%) macroadenomas were cured using combined criteria in the pretreatment group vs 8/45 (18%) in the direct surgery group after 6-12 months (P=0.06), and 15/41 (37%) vs 8/42 (19%), respectively, in the long-term (P=0.08). CONCLUSION: This study does not prove a beneficial effect of SSA pre-surgical treatment, but in the meta-analysis a trend towards significance can be claimed. A potential favourable, clinically relevant response cannot be excluded.

Hyperglycemia, assessed according to HbA1c , and future risk of venous thromboembolism: the Tromsø study.

BACKGROUND: HbA1c , a marker of average plasma glucose level during the previous 8-12 weeks, is associated with the future risk of cardiovascular disease and all-cause mortality. OBJECTIVES: To examine the association between hyperglycemia, assessed according to HbA1c , and the future risk of venous thromboembolism (VTE) in a population-based cohort. METHODS: HbA1c was measured in 16 156 unique subjects (25-87 years) who participated in one or more surveys of the Tromsø study (Tromsø 4, 1994-1995; Tromsø 5, 2001-2002; and Tromsø 6, 2007-2008). All subjects were followed, and incident VTE events were recorded up to 31 December 2010. RESULTS: There were 333 validated first VTE events, of which 137 were unprovoked, during a median follow-up of 7.1 years. HbA1c was not associated with the future risk of VTE in analyses treating HbA1c as a continuous variable, or in categorized analyses. The risk of VTE increased by 5% per one standard deviation (0.7%) increase in HbA1c (multivariable-adjusted hazard ratio [HR] 1.05; 95% confidence interval [CI] 0.97-1.14), and subjects with HbA1c  ≥ 6.5% had a 27% higher risk than those with HbA1c  < 5.7% (multivariable-adjusted HR 1.27; 95% CI 0.72-2.26). There was no significant linear trend for an increased risk of VTE across categories of HbA1c (P = 0.27). CONCLUSIONS: Serum levels of HbA1c were not associated with the future risk of VTE in multivariable analysis. Our findings suggest that hyperglycemia does not play an important role in the pathogenesis of VTE.

Single-nucleotide polymorphism, rs1799941 in the Sex Hormone-Binding Globulin (SHBG) gene, related to both serum testosterone and SHBG levels and the risk of myocardial infarction, type 2 diabetes, cancer and mortality in men: the Tromsø Study.

Low testosterone levels are associated with metabolic and cardiovascular disease risk factor, and have been shown to predict type 2 diabetes mellitus (T2DM), myocardial infarction (MI) and all-cause mortality. It is not known if these associations are causal or not. Recently, it has been shown that the serum testosterone levels are associated with single-nucleotide polymorphisms (SNPs), and we therefore studied the associations between one of these SNPs, rs1799941 on the Sex Hormone-Binding Globulin (SHBG) gene, and MI, T2DM, cancer and death. DNA was prepared from men who participated in the fourth survey of the Tromsø Study in 1994-1995 and who were registered with the endpoints MI, T2DM, cancer or death and a randomly selected control group. For mortality, the observation time was set from 1994, and for the other endpoints from birth. The endpoint data were completed up to 2010-2013. Genetic analyses were successfully performed in 5309 men, of whom 1454 were registered with MI, 638 with T2DM, 1534 with cancer and in 2226 who had died. Men with the minor homozygote genotype had significantly higher levels of total testosterone (14.7%) and SHBG (24.7%) compared with men with the major homozygote genotype, whereas free testosterone levels did not differ significantly between the genotypes. The SNP rs1799941 was not significantly associated with MI, T2DM, cancer or mortality. Thus, our result does not support a causal relationship between total testosterone and SHBG and MI, T2DM, cancer or mortality, suggesting that low testosterone more likely is a marker of poor health.

Supplementation with vitamin D does not increase serum testosterone levels in healthy males.

Cross-sectional studies indicate a positive relation between serum 25-hydroxyvitamin D [25(OH)D] and testosterone. It is not known if this relation is causal, which in theory could be in both directions. A cross-sectional population based study was designed with pooled data from 3 vitamin D randomized clinical trials (RCTs) performed in Tromsø with weight reduction, insulin sensitivity, and depression scores as endpoints, and one testosterone RCT in subjects with low serum testosterone (<11.0 nmol/l) and with body composition as endpoint. Serum 25(OH)D and androgens were measured in 893 males in the cross-sectional part, at baseline and after 6-12 months of supplementation with vitamin D 20 000 IU-40 000 IU per week vs. placebo in the vitamin D RCTs (n=282), and at baseline and after one year treatment with testosterone undecanoate 1 000 mg or placebo injections (at baseline and after 6, 16, 28, and 40 weeks) in the testosterone RCT (n=37). In the cross-sectional study, serum 25(OH)D was found to be a significant and positive predictor of serum testosterone. In the vitamin D RCTs, no significant effect on serum total or free testosterone levels was seen, and in the testosterone RCT no significant effect on serum 25(OH)D was seen. This was unchanged in sub-analyses in subjects with low serum 25(OH)D (or testosterone) levels. In conclusion, in subjects without significant vitamin D deficiency, there is no increase in serum testosterone after high dose vitamin D supplementation. Similarly, in subjects with moderately low serum testosterone levels, substitution with testosterone does not increase serum 25(OH)D.

Serum levels of vitamin D are not associated with future risk of venous thromboembolism. The Tromsø Study.

Previous studies have provided indirect evidence for a possible association between vitamin D status and risk of venous thromboembolism (VTE). However, no study has so far investigated the association between serum levels of 25-hydroxyvitamin D (25(OH)D), the biomarker of vitamin D status, and risk of VTE. The aim of our study was to investigate whether high levels of 25(OH)D were associated with decreased risk of VTE in a prospective population-based study. Serum levels of 25(OH)D were measured in 6,021 men and women, aged 25-84 years, who participated in the Tromsø Study in 1994-1995. Incident VTE-events were registered from date of inclusion through the end of follow-up, September 1, 2007. Cox-regression models were used to calculate hazard ratios (HR) with 95% confidence interval (CI) for VTE. There were 201 incident VTE-events during a median of 10.7 years of follow-up. The risk of VTE did not decrease per one standard deviation (SD) (19.8 nmol/l) increase in serum 25(OH)D (multivariable HR 1.02; 95% CI 0.91-1.22). Moreover, subjects with serum 25(OH)D ≥ 70 nmol/l (upper quartile) did not have decreased risk of VTE compared to those ≤ 44 nmol/l (lower quartile) in age- and sex-adjusted analysis (HR 0.91, 95% CI: 0.60-1.37, p for trend across quartiles 0.9) or multivariable analysis adjusted for age, sex, body mass index, smoking, and physical activity (HR 0.76, 95% CI: 0.45-1.28, p for trend across quartiles 0.9). Subgroup analyses showed no associations between serum levels of 25(OH)D and unprovoked or provoked VTE. In conclusion, in our study, normal serum levels of 25(OH)D were not associated with future risk of VTE, suggesting that vitamin D status does not play an important role in the pathogenesis of VTE. However, our findings did not apply to subjects with vitamin D deficiency (< 30 nmol/l) due to lack of statistical power among these subjects.

CAG repeat number is not inversely associated with androgen receptor activity in vitro.

A negative linear association between androgen receptor (AR) function and the CAG repeat numbers is generally assumed. However, in vivo data concerning the association between CAG number and androgenic effects have been conflicting. Since former in vitro studies mostly have been based on extreme CAG lengths and reporter-systems containing viral promoters, the objective of this study was to investigate ARs with CAG lengths within normal range (16, 22 and 28) in a reporter-assay with the human prostate specific antigen promoter as target. We also wished to elucidate whether the interpretation of the results was depending on the methods used for adjustment of transfection efficiency and protein content. With beta-galactosidase as transfection control, 22CAG had the highest activity (set to 100%) compared with 16CAG [mean 78% (range 41-132), P = 0.005] and 28CAG [68% (26-162), P = 0.006], whereas renilla-luciferase resulted in 16CAG behaving similar to 22CAG [104% (56-165), P = 0.7] and 28CAG having lower activity [59% (33-101), P = 0.004]. In these experiments, also the empty vector displayed considerable background activity. When adjusting for AR protein, the 22CAG genotype had the highest activity; 16CAG and 28CAG displaying 20% (10-47, P < 0.0001) and 12% (5-21, P < 0.0001) thereof. Similar results were obtained with adjustment for total protein. Thus, by normalizing for AR-content, contrary to various control vectors, the highest AR activity was confined to the 22CAG and not 16 CAG, which may at least partly explain the discrepancy in data aiming to link physiological conditions to CAG repeat length.

Endogenous testosterone and the prospective association with carotid atherosclerosis in men: the Tromsø study.

The role of testosterone in the development of cardiovascular disease is controversial. Recent observational studies, however, suggest a protective role of normal endogenous testosterone levels in the development of atherosclerosis. In a cohort from the Tromsø study, 1,101 men had both hormone-levels measured and the right carotid artery examined by ultrasound in 1994 and 2001. We studied the prospective association between sex hormone-levels and progression of carotid intima-media thickness (IMT) and plaque area from 1994 to 2001. We also performed a cross-sectional study of 2,290 men from the population in 2001. The data were analysed by univariate correlations, analyses of covariance and multiple linear regression analyses. In the cross-sectional study, we found an inverse association between testosterone levels and total carotid plaque area (P < 0.05), after adjusting for age, systolic blood pressure, smoking and use of lipid-lowering drugs. We found no prospective associations between sex hormone-levels and change in plaque area or IMT from 1994 to 2001. The lack of prospective associations in our study may be due to increased use of anti-hypertensive and lipid-lowering drugs from 1994 baseline to follow-up.

Effects of vitamin D supplementation on symptoms of depression in overweight and obese subjects: randomized double blind trial.

OBJECTIVES: The objective of the present study was to examine the cross-sectional relation between serum 25-hydroxyvitamin D [25-(OH) D] levels and depression in overweight and obese subjects and to assess the effect of vitamin D supplementation on depressive symptoms. DESIGN: Cross-sectional study and randomized double blind controlled trial of 20,000 or 40,000 IU vitamin D per week versus placebo for 1 year. SETTING: A total of 441 subjects (body mass index 28-47 kg m(-2), 159 men and 282 women, aged 21-70 years) recruited by advertisements or from the out-patient clinic at the University Hospital of North Norway. MAIN OUTCOME MEASURES: Beck Depression Inventory (BDI) score with subscales 1-13 and 14-21. RESULTS: Subjects with serum 25(OH)D levels < 40 nmol L(-1) scored significantly higher (more depressive traits) than those with serum 25(OH)D levels > or = 40 nmol L(-1) on the BDI total [6.0 (0-23) versus 4.5 (0-28) (median and range)] and the BDI subscale 1-13 [2.0 (0-15) versus 1.0 (0-29.5)] (P < 0.05). In the two groups given vitamin D, but not in the placebo group, there was a significant improvement in BDI scores after 1 year. There was a significant decrease in serum parathyroid hormone in the two vitamin D groups without a concomitant increase in serum calcium. CONCLUSIONS: It appears to be a relation between serum levels of 25(OH)D and symptoms of depression. Supplementation with high doses of vitamin D seems to ameliorate these symptoms indicating a possible causal relationship.

Testosterone treatment in elderly men with subnormal testosterone levels improves body composition and BMD in the hip.

Our intention was to examine if subnormal testosterone levels in older men were associated with a reduction in quality of life and physical and mental health, and secondly to examine if testosterone treatment could improve these conditions. We performed a nested case-control study and a 1-year testosterone intervention study. Men with subnormal testosterone had significantly higher weight, fat mass and abdominal adipose tissue. They also had significantly higher glucose and insulin levels, and they had higher triglyceride levels. Testosterone treatment had a large impact on body composition with reduced fat mass and abdominal adipose tissue and increased fat-free mass, but it did not affect weight and glucose and lipid metabolism. Bone mineral density in the hip was significantly higher after the testosterone treatment. Older men with subnormal testosterone levels had an unfavorable metabolic profile. Testosterone treatment improved body composition, but it did not reverse the unfavorable metabolic profile.

Associations between the metabolic syndrome and bone health in older men and women: the Rancho Bernardo Study.

UNLABELLED: We examined the associations of metabolic syndrome (MS) with BMD, osteoporosis, and osteoporotic fractures in 417 men and 671 women from the Rancho Bernardo Study. After adjusting for BMI, MS was associated with lower, not higher BMD. Incidence of osteoporotic non-vertebral fractures was higher in participants with MS. MS may be another risk factor for osteoporotic fractures. INTRODUCTION: The metabolic syndrome (MS) is a cluster of risk factors, including abdominal obesity, high glucose, triglycerides, hypertension and low HDL levels, associated with cardiovascular disease morbidity. The association between components of the MS and bone mineral density (BMD) has been researched, but results are contradictory. METHODS: We used multivariate regression models to examine the cross-sectional associations of MS defined by NCEP-ATP III criteria with BMD and osteoporosis, and the longitudinal association of MS with fractures in 420 men and 676 women from the Rancho Bernardo Study. RESULTS: Prevalence of MS at baseline was 23.5% in men and 18.2% in women. In age-adjusted analyses, men and women with MS had higher BMD at total hip when compared to those without MS (p < 0.001 and p = 0.01, respectively). Men but not women with MS also had higher BMD at femoral neck (p = 0.05). After adjusting for BMI, these associations were reversed, such that MS was associated with lower and not higher BMD. CONCLUSION: Incidence of osteoporotic non-vertebral fractures was higher in participants with MS. MS may be another risk factor for osteoporotic fractures. The association of MS with higher BMD was explained by the higher BMI in those with MS.

Epidemiology: testosterone and the metabolic syndrome.

Low levels of testosterone, hypogonadism, have several common features with the metabolic syndrome. In the Tromsø Study, a population-based health survey, testosterone levels were inversely associated with anthropometrical measurements, and the lowest levels of total and free testosterone were found in men with the most pronounced central obesity. Total testosterone was inversely associated with systolic blood pressure, and men with hypertension had lower levels of both total and free testosterone. Furthermore, men with diabetes had lower testosterone levels compared to men without a history of diabetes, and an inverse association between testosterone levels and glycosylated hemoglobin was found. Thus, there are strong associations between low levels of testosterone and the different components of the metabolic syndrome. In addition, an independent association between low testosterone levels and the metabolic syndrome itself has recently been presented in both cross-sectional and prospective population-based studies. Thus, testosterone may have a protective role in the development of metabolic syndrome and subsequent diabetes mellitus and cardiovascular disease in aging men. However, clinical trials are needed to confirm this assumption.

Components of the metabolic syndrome in long-term survivors of testicular cancer.

BACKGROUND: A possible explanation of the excess cardiovascular risk in testicular cancer (TC) survivors is development of metabolic syndrome. The association between metabolic syndrome and TC treatment is examined in long-term survivors. PATIENTS AND METHODS: In a national follow-up study (1998-2002), 1463 TC survivors (diagnosed 1980-1994) participated. Patients >60 years were excluded in the present study, leaving 1135 patients eligible. The patients were divided in four treatment groups: surgery (n = 225); radiotherapy (n = 446) and two chemotherapy groups: cumulative cisplatin dose (Cis) 850 mg (n = 88). A control group consisted of 1150 men from the Tromsø Population Study. Metabolic syndrome was defined according to a modified National Cholesterol Education Program definition. RESULTS: Both chemotherapy groups had increased odds for metabolic syndrome compared with the surgery group, highest for the Cis >850 group [odds ratio (OR) 2.8, 95% confidence interval (CI) 1.6-4.7]. Also, the Cis >850 group had increased odds (OR 2.1, 95% CI 1.3-3.4) for metabolic syndrome compared with the control group. The association between metabolic syndrome and the Cis >850 group was strengthened after adjusting for testosterone, smoking, physical activity, education and family status. CONCLUSION: TC survivors treated with cisplatin-based chemotherapy have an increased risk of developing metabolic syndrome compared with patients treated with other modalities or with controls.

Low testosterone levels are associated with carotid atherosclerosis in men.

OBJECTIVE: To study the relationship between endogenous sex hormone levels and intima-media thickness (IMT) of the carotid artery measured by ultrasonography. DESIGN: Population-based cross-sectional study. METHODS: Sex hormone levels measured by immunoassay, anthropometric measurements and IMT was studied in 1482 men aged 25-84 years participating in the 1994-1995 Tromsø study. The data were analysed with partial correlation, multiple linear regression and logistic regression analysis. RESULTS: Linear regression models showed that total testosterone and sex hormone-binding globulin levels, but not calculated free testosterone, serum oestradiol or dehydroepiandrosterone sulphate levels were inversely associated with the age-adjusted IMT (P = 0.008 and P < 0.001 respectively). These associations were independent of smoking, physical activity, blood pressure and lipid levels, but were not independent of body mass index (BMI). Excluding men with cardiovascular disease (CVD) did not materially change these results. In a logistic regression model adjusted for the confounding effect of CVD risk factors, men with testosterone levels in the lowest quintile (<9.0 nmol L(-1)) had an independent OR = 1.51 (P = 0.015) of being in the highest IMT quintile. CONCLUSIONS: We found an inverse association between total testosterone levels and IMT of the carotid artery in men that was present also after excluding men with CVD, but was not independent of BMI. The clinical relevance of this, however, is uncertain and needs to be investigated in a clinical setting.

The relationship between blood pressure and serum parathyroid hormone with special reference to urinary calcium excretion: the Tromsø study.

The aim of the present cross-sectional epidemiological study from Tromsø, Northern Norway, was to evaluate the relation between blood pressure and serum PTH, and to examine whether this relation can be explained by a blood pressure-induced increase in urinary calcium. Ten thousand-four hundred and nineteen subjects were invited to participate and 8,128 attended. Those with serum calcium outside the reference range (2.20-2.60 mmol/l), with increased serum creatinine (upper limit 120 micromol/l for men and 100 micromol/l for women) and those using antihypertensive medication were excluded. Three thousand- six hundred and twenty subjects had complete data on outcome measures. Height, weight, blood pressure, serum calcium, PTH, and creatinine were measured and smoking status recorded. A morning urine sample was collected and urinary calcium, sodium and creatinine measured. The urinary calcium/urinary creatinine ratio (Uca/Ucr) and urinary sodium/urinary creatinine ratio (Una/Ucr) were calculated. There was a significant association between both systolic and diastolic blood pressure and serum PTH. The Uca/Ucr increased with increasing blood pressure. However, the Uca/Ucr did not affect the association between blood pressure and serum PTH in a multiple linear regression model. The relationship between blood pressure and serum PTH was also seen in subjects with similar Uca/Ucr, and a negative association between serum PTH and the Uca/Ucr was found. In conclusion, blood pressure and serum PTH are associated. This association cannot be explained by the urinary calcium excretion alone.

Surviving extreme hypercalcaemia--a case report and review of the literature.

We report a case of extreme hypercalcaemia associated with a parathyroid adenoma in a young man. The patient presented with classical symptoms of a hypercalcaemic syndrome, and serum calcium and parathyroid hormone levels were 6.92 mmol L(-1) and 70.2 pmol L(-1) respectively. After stabilizing the patient and reducing the calcium level, a parathyroidectomy was performed. The postoperative course was uneventful with rapidly resolving clinical symptoms. Hypercalcaemic crisis is a rare but life-threatening complication of primary hyperparathyroidism. It should be suspected in acutely ill patients complaining of muscular weakness, gastrointestinal and cerebral symptoms. To reduce mortality, it is essential to correctly diagnose the condition without delay and provide appropriate emergency management correcting hypercalcaemia and dehydration. Successful parathyroidectomy quickly relieves symptoms and prevents recurrence.

Release of TNF-alpha from in vitro-stimulated monocytes is negatively associated with serum levels of apolipoprotein B in patients with type 2 diabetes.

Impaired course of inflammation is a likely mechanism behind a number of diabetic complications. The present study was undertaken to investigate lipopolysaccharide-induced production of tumour necrosis factor (TNF)-alpha in monocytes from patients with type 2 diabetes and to assess its relationship with diabetes-associated metabolic abnormalities. Monocytic TNF-alpha mRNA production was lower in the diabetic participants compared to their corresponding controls. Diabetic subjects who had been receiving simvastatin treatment had TNF-alpha mRNA production similar to that of the healthy participants. The release of TNF-alpha from diabetic cells correlated negatively with serum levels of apolipoprotein B (apoB) (R = -0.755, P = 0.001), total plasma cholesterol (R = - 0.702, P = 0.002) and the presence of retinopathy (R = -0.572, P = 0.021). No such associations were found in the control subjects. In a multiple linear regression model, only the level of apoB and diabetes duration demonstrated significant effects on the release of TNF-alpha, with apoB alone accounting for 57% of the variation. We conclude that production of TNF-alpha mRNA in response to the bacterial stimulant is compromised in poorly controlled type 2 diabetes. Lipid abnormalities are associated with the observed defect. Impaired cytokine production represents a significant defect in the functioning of the immune system and may contribute to aberrations in the course of inflammation in the diabetic state.

Testosterone treatment improves body composition and sexual function in men with COPD, in a 6-month randomized controlled trial.

The aim of this study was to assess the effect of a low-dose testosterone on body composition and pulmonary function, as well as on quality of life, sexuality, and psychological symptoms in patients with chronic obstructive pulmonary disease (COPD). Twenty-nine men with moderate to severe COPD were allocated to receive either 250 mg of testosterone or placebo intra-muscularly, every fourth week, during the 26 weeks study period. Fat-free mass increased in the treatment group (P<0.05), and a significant difference between the treatment and the control group was seen after 26 weeks (P<0.05). Fat mass decreased in the treatment group (P<0.05), and there was a significant difference between the treatment and the control group after 12 weeks (P<0.01). A significantly better erectile function was reported in the treatment group at the final visit (P<0.05), and the overall sexual quality of life was significantly better in the treatment group after 12 weeks (P<0.05). No improvement in pulmonary function was found. In conclusion, administration of a low-dose testosterone to men with COPD for 26 weeks was associated with improvement of body composition, better erectile function and sexual quality of life. Furthermore, there were no clinical or biochemical side effects.

The associations of endogenous testosterone and sex hormone-binding globulin with glycosylated hemoglobin levels, in community dwelling men. The Tromsø Study.

OBJECTIVES: Low levels of endogenous testosterone have been associated with increased risk of cardiovascular disease and atherosclerosis in men. Long-term hyperglycemia, as measured by glycosylated hemoglobin (HbA1c), is related to cardiovascular mortality, and HbA1c across its normal range is also positively related to coronary heart and cardiovascular disease mortality in men. We therefore undertook an analysis of the cross-sectional associations of total testosterone and SHBG levels with HbA1c levels, in a general population of 1419 men aged 25-84. METHODS: Total testosterone, sex hormone-binding globulin (SHBG) and HbA1c were measured by immuno-assay. Partial correlation and multiple regression analyses were used to estimate the associations between total testosterone and SHBG with HbA1c. Analyses of variance and covariance were used to compare men with or without diabetes. RESULTS: In age-adjusted partial correlation HbA1c was inversely associated with total testosterone (p<0.01) and SHBG (p<0.001). HbA1c was positively associated with body mass index (BMI) and waist circumference (WC) (p<0.001). In multiple regression analyses total testosterone, SHBG, age, number of cigarettes smoked, BMI and WC were independently associated with HbA1c levels. Men with a history of diabetes had lower levels of total testosterone in age-adjusted analyses (p<0.05) and lower levels of SHBG in both age- and WC-adjusted analyses (p<0.001 and p<0.01, respectively). CONCLUSION: Lower levels of total testosterone and SHBG were associated with increased HbA1c levels and diabetes independent of concomitant variations in obesity and body fat distribution.