Abstract. A 26-year-old female with ACTH deficiency, hyperprolactinemia and benign intracranial hypertension is reported. Her symptoms of adrenocortical insufficiency and persistent amenorrhea appeared after her last child birth one year previously. During an infectious disease she became critically ill with hypotension and was treated with iv penicillin. A bacterial infection was, however, not diagnosed. After 4 days she developed symptoms and signs of intracranial hypertension. She improved gradually within 10 days without specific therapy against the intracranial pressure. Endocrine investigation disclosed a secondary adrenocortical failure. The lesion appeared to be located in the pituitary gland since plasma ACTH and cortisol did not respond to CRH. A moderately elevated serum PRL was found, whereas the pituitary reserves of TSH, GH, LH and FSH were normal, as was a computed tomographic scan of the pituitary gland. The patient was given cortisone substitution therapy and recovered immediately. Within the following year she regained normal menstruations and became pregnant. A possible autoimmune etiology of her isolated ACTH deficiency precipitated in the puerperium is discussed.
Sylvi Aanderud and Rolf Jorde
Monica Sneve, Nina Emaus, Ragnar Martin Joakimsen and Rolf Jorde
To explore the relation between serum parathyroid hormone (PTH) and bone mineral density (BMD), adjusted for lifestyle factors including smoking.
The Tromsø Study is a population-based study performed for the fifth time in 2001. Serum PTH was measured and the subjects filled in a questionnaire covering lifestyle factors. BMD at the hip, distal and ultradistal forearm was measured.
Complete datasets were available in 1442 men and 1368 women. Age, body mass index and serum PTH were strong predictors of BMD level at the hip in both genders. No significant relation was seen between serum PTH and BMD at the distal or ultradistal forearm. When smokers and non-smokers were analysed separately, the relation between PTH and BMD at the hip was significant in current non-smokers only. In males, current non-smokers had significantly higher BMD at all three measurement sites compared with current smokers. Male former smokers had values in between current and never smokers. There was a significant and negative relation between number of years smoked and BMD at the hip. In male former smokers, there was an increase in BMD with increasing years since smoking cessation.
Serum PTH is negatively associated with BMD at the hip, and the relation seems to be masked, or diminished, by smoking. Smoking reduces BMD at the hip, distal and ultradistal forearm in males, and the effect appears to be mainly time and not dose dependent.
Hanne Vea, Rolf Jorde, Georg Sager, Stein Vaaler and Johan Sundsfjord
To evaluate the effect of β1-blockade (metoprolol) on the plasma glucose thresholds initiating counterregulatory hormone responses and symptoms of hypoglycemia, we used a modified glucose clamp technique to produce a standardized gradual glucose decline from 5.0 to 2.0 mmol/l in nine patients with insulin-dependent diabetes mellitus (IDDM) (HbAlc range 6.7–10.3%, duration of diabetes 5–18 years, autonomous neuropathy present in three of the patients). The responses were studied once with metroprolol and once with placebo, in random order. With the β1-selective blockade, epinephrine release was triggered at a significantly higher (p<0.02) plasma glucose level (3.5 mmol/l) than it was with placebo (3.0 mmol/l). Metoprolol did not change thresholds for growth hormone (3.7/3.5 mmol/l), cortisol (2.9/2.9 mmol/l), glucagon (2.8/2.8 mmol/l) or for pancreatic polypeptide (2.8/2.7 mmol/l). The peak responses of epinephrine and growth hormone were significantly higher (p<0.01) with the β1-blockade. Metoprolol did not change the thresholds for neuroglycopenic and autonomic symptoms. Six out of the seven patients who answered yes to having hypoglycemia did so at a higher blood glucose with metoprolol than without. In our study, the β1-selective blockade altered the responses of counterregulatory hormones, but it did not change the thresholds for hypoglycemic symptoms.
Allan Didriksen, Anders Burild, Jette Jakobsen, Ole Martin Fuskevåg and Rolf Jorde
The objective was to assess the amount of vitamin D3 stored in adipose tissue after long-term supplementation with high dose vitamin D3.
A cross-sectional study on 29 subjects with impaired glucose tolerance who had participated in a randomized controlled trial with vitamin D3 20 000 IU (500 μg) per week vs placebo for 3–5 years.
Abdominal subcutaneous fat tissue was obtained by needle biopsy for the measurements of vitamin D3 and 25-hydroxyvitamin D3 (25(OH)D3). Body fat was measured with dual-energy X-ray absorptiometry, and serum 25(OH)D3 level was quantified.
In the subjects given vitamin D3, the median concentrations of serum 25(OH)D3, fat vitamin D3, and fat 25(OH)D3 were 99 nmol/l, 209 ng/g, and 3.8 ng/g, respectively; and correspondingly in the placebo group 62 nmol/l, 32 ng/g, and 2.5 ng/g. If assuming an equal amount of vitamin D3 stored in all adipose tissue in the body, the median body store was 6.6 mg vitamin D3 and 0.12 mg 25(OH)D3 in those given vitamin D3.
Subcutaneous adipose tissue may store large amounts of vitamin D3. The clinical importance of this storage needs to be determined.
Moira Strand Hutchinson, Guri Grimnes, Ragnar Martin Joakimsen, Yngve Figenschau and Rolf Jorde
Ecologic and observational studies have suggested an association between serum 25-hydroxyvitamin D (25(OH)D) levels and cardiovascular disease (CVD) risk factors, CVD mortality, and cancer mortality. Based on this, low serum 25(OH)D levels should be associated with higher all-cause mortality in a general population. This hypothesis was tested in the present study.
The Tromsø study is a longitudinal population-based multipurpose study initiated in 1974 with focus on lifestyle-related diseases. Our data are based on the fourth Tromsø study carried out in 1994–1995.
Information about death and cause of death was registered by obtaining information from the National Directory of Residents and the Death Cause Registry. Serum 25(OH)D was measured in 7161 participants in the fourth Tromsø study. Results are presented for smokers (n=2410) and non-smokers (n=4751) separately as our immunoassay seems to overestimate 25(OH)D levels for smokers.
During a mean 11.7 years of follow-up, 1359 (19.0%) participants died. In multivariate regression models, there was a significantly increased risk of all-cause mortality (hazard ratio (HR) 1.32, confidence interval (CI) 1.07–1.62) among non-smoking participants in the lowest 25(OH)D quartile when compared with participants in the highest quartile. Equivalent results for smokers were not significant (HR 1.06, CI 0.83–1.35).
Low serum 25(OH)D levels were associated with increased all-cause mortality for non-smokers, but the results did not reach statistical significance for smokers. However, low 25(OH)D levels are known to be associated with impaired general health, and randomized controlled studies are needed to address the question of causality.
Allan Didriksen, Guri Grimnes, Moira Strand Hutchinson, Marie Kjærgaard, Johan Svartberg, Ragnar M Joakimsen and Rolf Jorde
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.
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.
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.
Gunhild Lerstad, Ellen E Brodin, Johan Svartberg, Rolf Jorde, Jan Brox, Sigrid K Brækkan and John-Bjarne Hansen
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.
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.
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).
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.
Stina T Sollid, Moira Y S Hutchinson, Vivian Berg, Ole M Fuskevåg, Yngve Figenschau, Per M Thorsby and Rolf Jorde
To determine the relationship between serum total 25-hydroxyvitamin D (25(OH)D), directly measured free 25(OH)D and calculated free 25(OH)D with regard to vitamin D-binding protein (DBP) phenotypes, sex, BMI, age and season, and their interrelationship to vitamin D supplementation.
Design, patients and interventions
A randomized controlled trial with 20 000 IU of vitamin D3 per week or placebo for 12 months was designed. A total of 472 subjects, 236 in each of the intervention groups, were included in the analyses.
Main outcome measures
Baseline serum concentrations and increases in serum total 25(OH)D, directly measured free 25(OH)D, calculated free 25(OH)D and DBP.
Serum total 25(OH)D and DBP concentrations were significantly lower in subjects with the phenotype Gc2/Gc2 compared to phenotypes with the Gc1S allele, and lower in males compared to females. When using directly measured free 25(OH)D, the differences related to DBP phenotypes and sexes were clearly diminished. All calculated free 25(OH)D concentrations were overestimated compared to the directly measured free 25(OH)D. Serum parathyroid hormone showed an inverse correlation with all vitamin D parameters analyzed. The increases after 12 months of vitamin D supplementation were not significantly different for any of the vitamin D parameters regardless of DBP phenotype, sex or age. Supplementation with vitamin D did not affect serum DBP.
Direct measurements of free 25(OH)D reduce the differences seen in total 25(OH)D between DBP phenotype groups and sexes, probably caused by differences in DBP concentrations. With conditions affecting serum DBP concentrations, direct measurements of free 25(OH)D should be considered.
Gunhild Lerstad, Kristin F Enga, Rolf Jorde, Ellen E Brodin, Johan Svartberg, Sigrid K Brækkan and John-Bjarne Hansen
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.
Population-based cohort study.
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.
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).
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.
Guri Grimnes, Bjørg Almaas, Anne Elise Eggen, Nina Emaus, Yngve Figenschau, Laila Arnesdatter Hopstock, Moira Strand Hutchinson, Paal Methlie, Albena Mihailova, Monica Sneve, Peter Torjesen, Tom Wilsgaard and Rolf Jorde
The authors and the journal apologise for errors in the Introduction section of this paper published in the European Journal of Endocrinology 2010 vol 163 pp 339–348. Lines 11–14 of the Introduction section should read as follows:
This reflects the amount of vitamin D ingested from food (ergocalciferol (vitamin D2) or cholecalciferol (vitamin D3)) and the amount of vitamin D produced in the skin during ultraviolet B (UVB) exposure (vitamin D3)
and not as published.