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Torkel Vikan, Henrik Schirmer, Inger Njølstad and Johan Svartberg

Objective

To study the impact of endogenous testosterone levels in community-dwelling men on later risk for myocardial infarction (MI) and all-cause, cardiovascular disease (CVD), and ischemic heart disease (IHD) mortality.

Design

Population-based prospective cohort study.

Methods

For the analyses, we used a cohort of 1568 randomly selected men, with sex-hormone data participating in the fourth Tromsø Study (1994–1995). Defined end points were first-ever MI (fatal or nonfatal), all-cause, CVD, and IHD mortality. A committee performed thorough ascertainment of end points, following a detailed protocol. Complete ascertainment of end points was until 30 September 2007 for all-cause mortality, until 31 December 2005 for CVD/IHD mortality, and until 31 December 2004 for first-ever MI. The prospective association between total and free testosterone and end points were examined using Cox proportional hazard regression, allowing for multivariate adjustment for age and cardiovascular risk factors.

Results

During follow-up, there were 395 deaths from all causes, 130 deaths from CVD and 80 deaths from IHD, while 144 men experienced a first-ever MI. There was a significant increase in all-cause mortality risk for men with free testosterone in the lowest quartile (<158 pmol/l) compared with the higher quartiles after age adjustment hazard ratios (HR 1.24, 95% confidence interval, CI 1.01–1.53) and after multivariate adjustments (HR 1.24, 95% CI 1.01–1.54). Total testosterone was not associated with mortality risk. Likewise, there were no significant changes in risk for first-ever MI across different total or free testosterone levels.

Conclusion

Men with free testosterone levels in the lowest quartile had a 24% increased risk of all-cause mortality.

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Ingrid Nermoen, Eystein S Husebye, Johan Svartberg and Kristian Løvås

Background

Patients with classical congenital adrenal hyperplasia (CAH) require life-long corticosteroid therapy, with uncertain health outcome. Investigations of subjective health status in unselected populations of adult patients are needed.

Objective

To identify all adult Norwegian patients with CAH and obtain population-based data on subjective and psychological health status, working ability and fertility.

Patients, methods and design

Classical CAH patients were identified through search in electronic diagnosis registries at all the university hospitals in Norway. The diagnosis was verified by scrutiny of medical records. The patients were invited to a questionnaire survey including medical history, and the Short Form-36 (SF-36) and Quality of Life Scale questionnaires. The questionnaire responses and fertility data were compared with normative data.

Results

We identified 104 adult patients (101 alive) with classical CAH (63% female), yielding overall incidence at 1/20 000 live births (1/16 000 in females). Seventy-two (72%) responded; median age 38 years (range 18–72). All the SF-36 scales were significantly impaired, most pronounced for general health and vitality perception. Working disability was reported by 19% of the patients, compared with 10% in the general population. The female patients were often single, and the CAH women had only 21% of the expected number of children compared with the general population.

Conclusion

In this population-based survey of patients with classical CAH, we found that subjective health status and working ability were impaired, and that fertility was reduced in females. There is a need for improvement of the medical treatment and the general care of this patient group.

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Torkel Vikan, Henrik Schirmer, Inger Njølstad and Johan Svartberg

Objective

To study the impact of endogenous sex hormone levels in community-dwelling men on later risk for type 2 diabetes.

Design

Population-based prospective cohort study.

Methods

For the analyses, 1454 men who participated in the fourth Tromsø study (1994–1995) were used. Cases of diabetes were retrieved and validated until 31.12.05 following a detailed protocol. The prospective association between sex hormones and diabetes was examined using Cox proportional hazard regression analysis, allowing for multivariate adjustments.

Results

There was a significantly lowered multi-adjusted risk for later diabetes with higher normal total testosterone levels, both linearly per s.d. increase (hazard ratio (HR) 0.71, confidence interval (CI) 0.54–0.92) and in the higher quartiles of total testosterone than in the lowest quartiles (HR 0.53, CI 0.33–0.84). A reduced multi-adjusted risk for incident diabetes was also found for men with higher sex hormone-binding globulin (SHBG) levels, both linearly per s.d. increase (HR 0.55, CI 0.39–0.79) and when comparing the third (HR 0.38, CI 0.18–0.81) and the fourth quartile (HR 0.37, CI 0.17–0.82) to the lowest quartile. The associations with total testosterone and SHBG were no longer significant after inclusion of waist circumference to the multivariate models. Estradiol (E2) was positively associated with incident diabetes after multivariate adjustments including waist circumference when comparing the second (HR 0.49, CI 0.26–0.93) and the third (HR 0.51, CI 0.27–0.96) quartile to the highest quartile.

Conclusion

Men with higher E2 levels had an increased risk of later diabetes independent of obesity, while men with lower total testosterone and SHBG had an increased risk of diabetes that appeared to be dependent on obesity.

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Ingrid Nermoen, Ingeborg Brønstad, Kristian J Fougner, Johan Svartberg, Marianne Øksnes, Eystein S Husebye and Kristian Løvås

Objective

The aim of this study was to determine the genetic, anthropometric and metabolic features in an unselected population of adult Norwegian patients with 21-hydroxylase deficiency (21OHD).

Patients, methods and design

Sixty-four 21OHD patients participated (23 men and 41 women; median age 38.5 years; range 19–72 years) in a cross-sectional study including DNA sequencing of CYP21A2, anthropometric measurements including dual X-ray absorptiometry scanning and biochemical analyses. The results were compared with reference cohorts from the general population.

Results

We identified four novel and plausibly disease-causing CYP21A2 mutations. Gene deletions/conversions (42.1% of alleles), the splice mutation I2 splice (23.0%) and point mutation I172 N (22.2%) were common. The genotype corresponded to clinical phenotype in 92% of the patients. The prevalence of osteopenia was 48% in males and 34% in females. Both men and women had normal BMI but markedly increased fat mass compared with the normal population. Diastolic blood pressure was higher than normal. Thirty-nine per cent of the women had testosterone levels above the normal range; 13% of the men had testosterone levels below normal. Reduced final height was more pronounced in men (median −11.2 cm, −1.77 SDS) than in women (−6.3 cm, −1.07 SDS).

Conclusions

In this population-based survey of 21OHD, we identified four novel mutations and high concordance between genotype and phenotype. The patients had increased fat mass, increased diastolic blood pressure, reduced final height and high frequency of osteopenia among males. These results show unfavourable metabolic features in 21OHD patients indicating a need for improvement of treatment and follow-up.

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Allan Didriksen, Guri Grimnes, Moira Strand Hutchinson, Marie Kjærgaard, Johan Svartberg, Ragnar M Joakimsen and Rolf Jorde

Objective

The serum 25-hydroxyvitamin D (25(OH)D) level is not only dependent on vitamin D intake and production in the skin but also dependent on genetic factors. Thus, in large genome-wide association studies, it has been shown that single nucleotide polymorphisms (SNPs) in the vitamin D binding protein (DBP), as well as in enzymes related to activation or degradation of vitamin D and its metabolites, are as important for the serum 25(OH)D level as the effect of season. How these SNPs affect the serum 25(OH)D response to vitamin D supplementation is uncertain.

Design and methods

Data were pooled from three randomized controlled trials where 40 000 IU vitamin D/week was given for 6 months. Serum 25(OH)D was measured before and at the end of the intervention, and the subjects were genotyped for SNPs related to the serum 25(OH)D level.

Results

Baseline 25(OH)D levels were significantly related to SNPs in the DBP and CYP2R1 genes. Those with SNPs associated with the lowest baseline 25(OH)D levels also had the smallest increase (delta) after supplementation. Those with the lowest baseline serum 25(OH)D (without regard to genotypes) had the highest increase (delta) after supplementation. Subjects with high BMI had lowest baseline 25(OH)D levels and also the smallest increase (delta) after supplementation.

Conclusions

The serum 25(OH)D response to supplementation depends on genes, baseline level, and BMI. However, whether this is clinically important or not depends on the therapeutic window of vitamin D, an issue that is still not settled.

Free access

Johan Svartberg, Sigrid K Brækkan, Gail A Laughlin and John-Bjarne Hansen

Objectives

Low testosterone levels in men have been associated with cardiovascular risk factors and atherosclerosis and lately also an increased risk of both cardiovascular disease (CVD) and all-cause mortality. As arterial CVDs and venous thromboembolism (VTE) have been shown to share common risk factors, the purpose of the present study was to determine the impact of endogenous sex hormone levels on the incidence of VTE in a cohort of men.

Design

A prospective, population-based study.

Methods

Sex hormone measurements were available in 1350 men, aged 50–84, participating in the Tromsø study in 1994–1995. First, lifetime VTE-events during the follow-up were registered up to September 1 2007.

Results

There were 63 incident VTE-events (4.5 per 1000 person-years) during a mean of 10.4 years of follow-up. Age was significantly associated with increased risk of VTE; men 70 years or older had a 2.5-fold higher risk of VTE (HR 2.47, 95% CI 1.19–5.12), compared with those between 50 and 60 years of age. In age-adjusted analyses, endogenous sex hormones levels were not associated with risk of VTE; for each s.d. increase, hazards ratios (95% CI) were 1.06 (0.83–1.35) for total testosterone, 1.02 (0.79–1.33) for free testosterone, and 1.27 (0.94–1.71) for ln-estradiol. In dichotomized analyses comparing men in the lowest total and free testosterone quartile with men in the higher quartiles, hypoandrogenemia was not associated with risk of VTE.

Conclusions

In this population-based study of middle-aged and older men, endogenous sex hormone levels were not associated with 10-year risk of VTE.

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Gunhild Lerstad, Kristin F Enga, Rolf Jorde, Ellen E Brodin, Johan Svartberg, Sigrid K Brækkan and John-Bjarne Hansen

Objective

The relationship between thyroid function and the risk of venous thromboembolism (VTE) has not been addressed in population-based cohorts. We investigated the association between TSH levels and the risk of VTE in a general adult population.

Design

Population-based cohort study.

Methods

TSH was measured in 11 962 subjects aged 25–89 years who participated in Tromsø 4–6 starting in 1994–1995. Incident VTE events were recorded through 31st December 2010. Cox's regression models with TSH as a time-varying covariate were used to calculate hazard ratios (HRs) of VTE by TSH categories (low TSH: <0.05 mU/l; moderately reduced TSH: 0.05–0.19 mU/l; normal TSH: 0.20–4.00 mU/l; moderately elevated TSH: 4.01–5.00 mU/l; and high TSH: >5.00 mU/l) and within the normal range of TSH, modeling TSH as a continuous variable.

Results

There were 289 VTEs during 8.2 years of median follow-up. Subjects with low (prevalence: 0.22%) and high (3.01%) TSH had slightly higher risk estimates for VTE than did subjects with normal TSH (multivariable HRs: 2.16, 95% CI 0.69–6.76 and 1.55, 95% CI 0.87–2.77 respectively), but the CIs were wide. Moreover, there was no association between TSH within the normal range and VTE (HR per 1 mU/l increase: 0.95, 95% CI 0.82–1.11).

Conclusion

Serum levels of TSH within the normal range were not associated with a risk of VTE, whereas low and high TSH levels were rare and associated with a moderately higher risk of VTE. The present findings suggest that only a minor proportion of the VTE risk in the population can be attributed to thyroid dysfunction.

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Gunhild Lerstad, Ellen E Brodin, Johan Svartberg, Rolf Jorde, Jan Brox, Sigrid K Brækkan and John-Bjarne Hansen

Objective

The relationship between serum levels of calcium, parathyroid hormone (PTH) and risk of venous thromboembolism (VTE) has not been addressed in population-based cohorts. We investigated the associations between serum levels of calcium and PTH, with future risk of VTE in a general adult population.

Design

Population-based cohort.

Methods

A total of 27 712 subjects (25–87 years) who participated in Tromsø 4 (1994–1995) and Tromsø 5 (2001–2002) surveys were included in the study, and total calcium and PTH were measured in 27 685 and 8547 subjects respectively. Incident VTE was recorded through December 31, 2012. Cox-regression models with calcium and PTH as time-varying exposures were used to calculate hazard ratios (HR) of VTE by quartiles of calcium and PTH. Quartiles of calcium and PTH were also combined to assess the effect of discordants of both PTH and calcium (e.g. highest and lowest quartiles of both calcium and PTH) on VTE risk using the middle two quartiles as reference.

Results

There were 712 VTEs during 15.0 years of median follow-up. Serum levels of calcium and PTH were not associated with risk of VTE. However, subjects with discordant high serum levels of both calcium and PTH (calcium ≥2.45 mmol/L and PTH ≥4.0 pmol/L) had increased risk of VTE compared to those in subjects with normal calcium and PTH (multivariable HR: 1.78, 95% CI: 1.12–2.84).

Conclusions

Serum levels of calcium and PTH separately were not associated with future risk of VTE, but subjects with high levels of both calcium and PTH had increased risk of VTE compared to those in subjects with normal levels.

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Martina M Erichsen, Kristian Løvås, Kristian J Fougner, Johan Svartberg, Erik R Hauge, Jens Bollerslev, Jens P Berg, Bjarne Mella and Eystein S Husebye

Context

Primary adrenal insufficiency (Addison's disease) is a rare autoimmune disease. Until recently, life expectancy in Addison's disease patients was considered normal.

Objective

To determine the mortality rate in Addison's disease patients.

Design and methods

i) Patients registered with Addison's disease in Norway during 1943–2005 were identified through search in hospital diagnosis registries. Scrutiny of the medical records provided diagnostic accuracy and age at diagnosis. ii) The patients who had died were identified from the National Directory of Residents. iii) Background mortality data were obtained from Statistics Norway, and standard mortality rate (SMR) calculated. iv) Death diagnoses were obtained from the Norwegian Death Cause Registry.

Results

Totally 811 patients with Addison's disease were identified, of whom 147 were deceased. Overall SMR was 1.15 (95% confidence intervals (CI) 0.96–1.35), similar in females (1.18 (0.92–1.44)) and males (1.10 (0.80–1.39)). Patients diagnosed before the age of 40 had significantly elevated SMR at 1.50 (95% CI 1.09–2.01), most pronounced in males (2.03 (1.19–2.86)). Acute adrenal failure was a major cause of death; infection and sudden death were more common than in the general population. The mean ages at death for females (75.7 years) and males (64.8 years) were 3.2 and 11.2 years less than the estimated life expectancy.

Conclusion

Addison's disease is still a potentially lethal condition, with excess mortality in acute adrenal failure, infection, and sudden death in patients diagnosed at young age. Otherwise, the prognosis is excellent for patients with Addison's disease.

Free access

Kristian Løvås, Clara G Gjesdal, Monika Christensen, Anette B Wolff, Bjørg Almås, Johan Svartberg, Kristian J Fougner, Unni Syversen, Jens Bollerslev, Jan A Falch, Penelope J Hunt, V Krishna K Chatterjee and Eystein S Husebye

Context

Patients with primary adrenal insufficiency (Addison's disease) receive more glucococorticoids than the normal endogenous production, raising concern about adverse effects on bone.

Objective

To determine i) the effects of glucocorticoid replacement therapy on bone, and ii) the impact of glucocorticoid pharmacogenetics.

Design, setting and participants

A cross-sectional study of two large Addison's cohorts from Norway (n=187) and from UK and New Zealand (n=105).

Main outcome measures

Bone mineral density (BMD) was measured; the Z-scores represent comparison with a reference population. Blood samples from 187 Norwegian patients were analysed for bone markers and common polymorphisms in genes that have been associated with glucocorticoid sensitivity.

Results

Femoral neck BMD Z-scores were significantly reduced in the patients (Norway: mean −0.28 (95% confidence intervals (CI) −0.42, −0.16); UK and New Zealand: −0.21 (95% CI −0.36, −0.06)). Lumbar spine Z-scores were reduced (Norway: −0.17 (−0.36, +0.01); UK and New Zealand: −0.57 (−0.78, −0.37)), and significantly lower in males compared with females (P=0.02). The common P-glycoprotein (ABCB1) polymorphism C3435T was significantly associated with total BMD (CC and CT>TT P=0.015), with a similar trend at the hip and spine.

Conclusions

BMD at the femoral neck and lumbar spine is reduced in Addison's disease, indicating undesirable effects of the replacement therapy. The findings lend support to the recommendations that 15–25 mg hydrocortisone daily is more appropriate than the higher conventional doses. A common polymorphism in the efflux transporter P-glycoprotein is associated with reduced bone mass and might confer susceptibility to glucocorticoid induced osteoporosis.