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B Bulow, B Ahren and EM Erfurth

BACKGROUND: The adipocyte products, leptin and tumour necrosis factor (TNF)alpha, are associated with atherosclerotic diseases and may be factors contributing to the enhanced cardiovascular risk in hypopituitary patients with growth hormone (GH) deficiency. OBJECTIVE: To investigate whether leptin and TNFalpha are increased in a group of hypopituitary women previously found to have increased cardiovascular morbidity, and to compare them with matched individuals of the same sex and age and with similar body composition. DESIGN AND PATIENTS: Thirty-three GH-deficient women with a median age of 64 years (range 39-77 years) were investigated cross-sectionally. The patients were compared with 33 controls matched for sex, age, smoking habits, educational level and residence. METHODS: Body composition was measured by bioimpedance analysis. Fasting concentrations of leptin, TNFalpha and insulin were analysed in patients and controls. RESULTS: There was no significant difference in body mass index or fat mass between patients and controls (both P > or =0.4). Serum leptin did not differ significantly between patients and controls. However, when serum leptin concentrations were expressed per kilogram fat mass, the patients had significantly greater concentrations (P=0.01). Serum TNFalpha and TNFalpha per kilogram fat mass were also significantly greater in the patients (both P=0.001). In contrast, serum insulin did not differ significantly between patients and controls. In the patients, serum leptin concentrations correlated positively with kilogram fat mass (r=0.54, P=0.002). Leptin concentration per kilogram fat mass was positively correlated with insulin (r=0.40, P=0.03). CONCLUSIONS: In contrast to serum concentrations of TNFalpha, serum leptin did not differ from that in controls, implying that leptin is not a major contributor to the previously found increase in cardiovascular morbidity in the hypopituitary women investigated. However, the patients had increased leptin concentrations per unit fat mass, indicating an altered adipocyte secretory function in this group.

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EM Erfurth, B Bulow, CH Nordstrom, Z Mikoczy, L Hagmar and U Stromberg

BACKGROUND: Reduced life expectancy has been shown in patients with hypopituitarism, mainly caused by cardiovascular diseases. A major cause of hypopituitarism is pituitary adenomas, and radiotherapy may be employed as a treatment modality to reduce the post-operative regrowth rate of these tumours. Recently, we showed that in patients with craniopharyngiomas, tumour regrowth foreshadowed a fourfold risk increase for death. For patients with pituitary adenomas, the impact of regrowth on life expectancy is, however, not known. OBJECTIVE: To assess the impact of a reoperation due to a regrowth of a pituitary macroadenoma on mortality, taking into account other candidate prognostic factors. DESIGN AND PATIENTS: In 281 patients with operated and irradiated macroadenomas, excluding acromegaly and Cushing's disease, 35 patients had a regrowth (median follow-up 16.6 years). Possible risk factors for tumour regrowth were investigated by Cox regression models. RESULTS: For tumour regrowth, age, calendar time at primary surgery, gender and extension of tumour growth had no statistically significant impact. For younger patients, the proportion of regrowths was higher, but after age-stratified Cox regression analysis only regrowth was shown to have a significant impact on mortality, with a more than doubled mortality risk for patients with tumour regrowth as compared with the non-regrowing tumour patients (hazard ratio=2.24, P<0.001). This finding was corroborated by cohort analyses using the general population as an external comparison group. CONCLUSION: Among patients with irradiated pituitary macroadenomas, excluding acromegaly and Cushing's disease, a doubled mortality rate was observed for those reoperated for tumour regrowth as compared with patients with non-regrowing tumours.

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Pernille Vejbjerg, Nils Knudsen, Hans Perrild, Peter Laurberg, Inge Bülow Pedersen, Lone B Rasmussen, Lars Ovesen and Torben Jørgensen

Objective: Patients with overt hypothyroidism show decreased echogenicity of the thyroid at ultrasonography (US). The aim of this study was to investigate the association between echogenicity of the thyroid/irregular echo pattern, and thyroid function in the general population, i.e. subjects without overt thyroid disease.

Design: A cross-sectional investigation of 4649 randomly selected adult subjects.

Methods: Blood samples were analysed for serum TSH, thyroid hormones and thyroid autoantibodies. US of the thyroid was performed.

Results: Participants with decreased echogenicity (n=379) had a higher mean TSH (1.65 mU/l) compared with subjects with normal echogenicity (1.21 mU/l, P<0.0001). The association was stronger in subjects with markedly decreased echogenicity (4.20 mU/l, P<0.0001). A similar association was seen when the subjects were divided into subgroups according to the level of TSH; more subjects with high levels of TSH had decreased echogenicity (P<0.0001). Likewise, more subjects with high levels of TSH had an irregular echo pattern (P<0.0001). Subjects with decreased echogenicity had a higher risk of having thyroid autoantibodies than subjects without decreased echogenicity (P<0.0001). This association was stronger when echogenicity was markedly decreased.

Conclusions: We demonstrated an association between hypoechogenicity at thyroid US and higher levels of serum TSH even in subjects without overt thyroid disease, suggesting decreased echogenicity as an early sign of thyroid dysfunction. Irregular echo pattern, whether accompanied by hypoechogenicity or not, was another possible marker of thyroid failure. This indicates a possible use of thyroid US in detecting early and subclinical thyroid dysfunction.

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Peter Laurberg, Torben Jørgensen, Hans Perrild, Lars Ovesen, Nils Knudsen, Inge Bülow Pedersen, Lone B Rasmussen, Allan Carlé and Pernille Vejbjerg

Objective: Denmark was an area of iodine deficiency, and mandatory iodine fortification of table salt and salt in bread (13 p.p.m. iodine) was initiated in 2000/2001. The Danish investigation on iodine intake and thyroid disease (DanThyr) is the monitoring of the iodine fortification program.

Design and methods: DanThyr consists of three main parts: a study of population cohorts initialized before (n = 4649) and after (n = 3570) iodization of salt, a prospective identification of incident cases of overt hyper- and hypothyroidism in a population of around 550 000 people since 1997, and compilation of data from the national registers on the use of thyroid medication, thyroid surgery, and radioiodine therapy. Studies were carried-out in parallel in subcohorts living in areas with differences in iodine content of ground water.

Results: The study showed profound effects of even small differences in iodine intake level on the prevalence of goiter, nodules, and thyroid dysfunction. Mild and moderate iodine deficiency was associated with a decrease in serum TSH with age. Other environmental factors were also important for goiter development (increase in risk, smoking and pregnancy; decrease in risk, oral contraception and alcohol consumption), and the individual risk depended on the genetic background. Environmental factors had only a minor influence on the prevalence of thyroid autoantibodies in the population. There were more cases of overt hypothyroidism in mild than in moderate iodine deficiency caused by a 53% higher incidence of spontaneous (presumably autoimmune) hypothyroidism. On the other hand, there were 49% more cases of overt hyperthyroidism in the area with moderate iodine deficiency. The cautious iodine fortification program, aiming at an average increase in iodine intake of 50 μg/day has been associated with a 50% increase in incidence of hyperthyroidism in the area with the most severe iodine deficiency. The incidence is expected to decrease in the future, but there may be more cases of Graves’ hyperthyroidism in young people.

Conclusion: A number of environmental factors influence the epidemiology of thyroid disorders, and even relatively small abnormalities and differences in the level of iodine intake of a population have profound effects on the occurrence of thyroid abnormalities. Monitoring and adjustment of iodine intake in the population is an important part of preventive medicine.

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Pernille Vejbjerg, Nils Knudsen, Hans Perrild, Peter Laurberg, Allan Carlé, Inge Bülow Pedersen, Lone B Rasmussen, Lars Ovesen and Torben Jørgensen


The iodine status of a population is traditionally evaluated by either urinary iodine (UI) excretion or by some measure of thyroid volume and the prevalence of goitre. In this prospective study of a mandatory iodization programme, we aimed to evaluate serum thyroglobulin (Tg) as a marker of iodine status in the population.


Two identical cross-sectional studies were performed before (1997–1998, n=4649) and after (2004–2005, n=3570) the initiation of the Danish iodization programme in two areas with mild and moderate iodine deficiency. Serum Tg was measured from blood samples. Thyroid volume was measured by ultrasonography.


Before iodization, the median serum Tg was considerably higher in moderate than in mild iodine deficiency. Iodization led to a lower serum Tg in all examined age groups. The marked pre-iodization difference in Tg level between the regions was eliminated. The prevalence of Tg above the suggested reference limit (40 μg/l) decreased from 11.3 to 3.7% (P<0.0001). Using bootstrapping, we demonstrated a higher efficacy of Tg than of thyroid volume to show a difference between pre- and post-iodization values.


We found serum Tg to be a suitable marker of iodine nutrition status in the population. The results may suggest that the Danish iodization programme has led to a sufficient iodine intake, even if the median UI excretion is still marginally low according to WHO criteria.