[Show abstract][Hide abstract] ABSTRACT: Context: Little is known about how thyroid diseases affect work ability. Objective: The objective of this study was to evaluate the risk of work disability for patients with thyroid disease compared with the general population. Design, Setting, and Participants: In a longitudinal register study, outpatients (n = 862) with nontoxic goiter, hyperthyroidism, Graves' orbitopathy (GO), autoimmune hypothyroidism, or other thyroid diseases and their matched controls (n = 7043) were observed in the years 1994-2011 in Danish national registers of social benefits, health, and work characteristics. Cox regression analyses estimated adjusted hazard ratios (HRs) for the first year after diagnosis and subsequent years. Main Outcome Measures: Transitions between work, long-term sickness absence, unemployment, and disability pension were measured. Results: Patients differed significantly from the general population with regard to sickness absence, disability pension, return from sickness absence, and unemployment. In the first year after diagnosis, higher risks of sickness absence was seen for GO (HR 6.94) and other hyperthyroid patients (HR 2.08), who also had lower probability of returning from sickness absence (HR 0.62) and higher risk of disability pension (HR 4.15). Patients with autoimmune hypothyroidism showed a lower probability of returning from sickness absence (HR 0.62). In subsequent years, GO patients had significantly higher risk of sickness absence (HR 2.08), lower probability of return from sickness absence (HR 0.51), and unemployment (HR 0.52) and a higher risk of disability pension (HR 4.40). Hyperthyroid patients also had difficulties returning from sickness absence (HR 0.71). Conclusions: Thyroid patients' risk of work disability is most pronounced in the first year after diagnosis and attenuates in subsequent years. GO patients have the highest risk of work disability.
The Journal of clinical endocrinology and metabolism. 06/2014;
[Show abstract][Hide abstract] ABSTRACT: Glucocorticoid therapy is widely used, but withdrawal from glucocorticoids comes with a potential life-threatening risk of adrenal insufficiency. Recent case reports document that adrenal crisis after glucocorticoid withdrawal remains a serious problem in clinical practice. Partly due to difficulties in inter-study comparison the true prevalence of glucocorticoid-induced adrenal insufficiency is unknown, but it might be somewhere between 46 and 100% 24h after glucocorticoid withdrawal, 26-49% after approximately one week, and some patients show prolonged suppression lasting months to years. Adrenal insufficiency might therefore be underdiagnosed in clinical practice. Clinical data do not permit accurate estimates of a lower limit of glucocorticoid dose and duration of treatment, where adrenal insufficiency will not occur. Due to individual variation, neither the glucocorticoid dose nor the duration of treatment can be used reliably to predict adrenal function after glucocorticoid withdrawal. Also the recovery rate of the adrenal glands shows individual variation, which may be why there is currently insufficient evidence to prove the efficacy and safety of different withdrawal regimens. Whether a patient with an insufficient response to an adrenal stimulating test develops clinically significant adrenal insufficiency depends on the presence of stress and resulting glucocorticoid demand and it is thus totally unpredictable and can change relative fast. Adrenal insufficiency should therefore always be taken seriously. Individual variation in hypothalamic-pituitary-adrenal axis function might be due to differences in glucocorticoid sensitivity and might be genetic. Further awareness of the potential side effect of withdrawal of glucocorticoid and further research are urgently needed.
European Journal of Internal Medicine 06/2013; · 2.30 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: OBJECTIVE: We studied whether severity of growth hormone deficiency (GHD) defined as a) GH-peak on stimulation tests (insulin tolerance test (ITT), arginine, glucagon), b) number of additional pituitary deficits, or c) baseline insulin-like growth factor-I (IGF-I) standard deviation score (SDS) could impact the response to GH treatment. We further explored whether d) IGF-I SDS after 24 months of GH replacement, or e) ΔIGF-I SDS from baseline to 24 months was related to the phenotypic response to GH treatment. DESIGN, PATIENTS AND MEASUREMENTS: The patient cohort (n=1752; 50% women) was obtained from KIMS (Pfizer International Metabolic Database). The patients were divided into 3 groups of approximately equal size (tertiles) according to stimulated GH-peak values and baseline IGF-I SDS, and studied at baseline, 12 and 24 months of GH therapy. RESULTS: Lower baseline IGF-I SDS predicted better response in weight, BMI, total cholesterol and triglycerides, while IGF-I SDS after 24 months was associated with reduction in waist/hip ratio, total cholesterol and improved QoL. Age correlated negatively with the response in body weight, BMI, waist, IGF-I SDS and total and LDL cholesterol. RESPONSE IN WEIGHT AND BMI WAS GREATER IN MEN, THAN IN WOMEN, WHEREAS WOMEN SHOWED GREATER IMPROVEMENT IN QOL THAN MEN. PATIENTS WITH MORE SEVERE GHD AS ASSESSED BY LOWER GH-PEAKS AND MORE PITUITARY HORMONE DEFICIENCIES HAD A GREATER INCREASE IN IGF-I SDS. THE INCREASE IN IGF-I SDS WAS ASSOCIATED WITH A REDUCTION IN WAIST/HIP RATIO, AND AN INCREASE IN WEIGHT, BMI, AND TRIGLYCERIDES. THERE WAS NO CORRELATION WITH OTHER LIPIDS, BLOOD PRESSURE OR GLUCOSE.CONCLUSION: Our findings indicate that baseline and 24 months IGF-I and its degree of increase during GH replacement, were more important than stimulated peak GH to predict the phenotypic response.
European Journal of Endocrinology 02/2013; · 3.69 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Maternal euthyroidism during pregnancy is crucial for normal development and, in particular, neurodevelopment of the foetus. Up to 3.5 percent of pregnant women suffer from hypothyroidism. Industrial use of various chemicals-endocrine disrupting chemicals (EDCs)-has been shown to cause almost constant exposure of humans with possible harmful influence on health and hormone regulation. EDCs may affect thyroid hormone homeostasis by different mechanisms, and though the effect of each chemical seems scarce, the added effects may cause inappropriate consequences on, for example, foetal neurodevelopment. This paper focuses on thyroid hormone influence on foetal development in relation to the chemicals suspected of thyroid disrupting properties with possible interactions with maternal thyroid homeostasis. Knowledge of the effects is expected to impact the general debate on the use of these chemicals. However, more studies are needed to elucidate the issue, since human studies are scarce.
Journal of thyroid research. 01/2011; 2011:342189.
[Show abstract][Hide abstract] ABSTRACT: To evaluate the effect of fractionated stereotactic radiotherapy (FSRT) in acromegaly in a retrospective analysis.
Thirty-four patients (17 females, median 43 years (range 30-74)) with acromegaly were treated with FSRT (conformal dynamic arcing, dose 54 Gy, 27-30 fractions) between January 1998 and April 2007. Of the 34 patients, 32 had undergone transsphenoidal adenotomy, and 28 were on medical therapy before FSRT. Patients on medical therapy continued this during and after the irradiation. The treatment was gradually decreased/withdrawn after careful assessment.
Magnetic resonance scanning of the pituitary gland 34 months (median, range 11-95) after irradiation showed stable or reduced volume of the remaining tumour tissue in 31 of 34 patients (91%). Seventeen patients (50%) were biochemically controlled (normalised nadir GH during oral glucose tolerance test and IGF1 <+2 S.D.) 30 months after FSRT (median, range 6-60), and ten of them had true biochemical remission (off medical therapy) 30 months after FSRT (median, range 12-69). Of 28 patients with one or more functioning pituitary axes before irradiation, 8 (29%) developed further deficit of one or two pituitary axes 48 months (median, range 6-102) after FSRT. Of 34 patients, 20 still required medical treatment for acromegaly at the end of this study, mainly those with a short follow-up period after irradiation.
The FSRT seems promising in terms of treatment of acromegaly. Longer follow-up is, however, needed to assess the overall efficacy and safety of FSRT for acromegaly.
European Journal of Endocrinology 04/2010; 162(4):685-94. · 3.69 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Thyroid hormones modulate the immune system and metabolism, influence insulin secretion, and cause decreased glucose tolerance. Thyroid hormones have been described to change the incidence of spontaneous autoimmune thyroiditis in Bio-Breeding/Worcester (BB) rats but it is unknown how these hormones affect the development of type 1 diabetes mellitus (T1DM). The aim was to investigate the influence of changes in thyroid function during postnatal development on the prevalence of T1DM in BB rats and the influence of T3 on the beta cell mass in non-diabetic Wistar rats. BB rats were treated with sodium iodine (NaI) or thyroid stimulating hormone (TSH) neonatally or with tri-iodo-thyronine (T3) during adolescence. At the age of 19 weeks the incidence of T1DM and the degree of insulitis were evaluated. The influence of T3 treatment on the beta cell mass was evaluated in Wistar rats by unbiased stereological methods. The incidence of T1DM in control BB rats was 68% at the age of 19 weeks. NaI and T3 reduced the incidence, whereas TSH had no effect. In Wistar rats T3 treatment increased the beta cell mass per bodyweight. The modulation of thyroid function during postnatal development may thus affect the precipitation of T1DM in genetically susceptible individuals.
[Show abstract][Hide abstract] ABSTRACT: Cold thyroid nodules are common, in particular in iodine-deficient areas, but only a minority of them are malignant requiring surgery. Thyroid peroxidase (TPO) immunostaining of fine-needle aspiration cytology (FNAC) material has proven helpful in diagnosing cells from malignant lesions, but the procedure has its limitations in a routine setting.
To improve diagnosis and reduce surgery rate, the FNAC procedure was replaced by needle core biopsy (NCB), which was routinely stained for TPO by the monoclonal antibody mAb 47.
During a 5-year period 427 consecutive patients with a cold thyroid nodule were evaluated by ultrasound-guided NCB, which had been routinely stained for TPO in an automated immunostainer. Sensitivity and specificity and predictive values of the TPO immunostaining were estimated, based on the final diagnosis obtained from surgical resection.
The majority of nodules with benign NCB diagnosis were not surgically removed, and thus a subgroup of 140 operated nodules formed the basis for the calculations. Sensitivity and specificity for benign and malignant lesions were 100% if the oxyphilic variant of adenomas and minimally invasive follicular carcinomas were excluded. By inclusion of these, the values fell to 89% and 97%, respectively. The predictive value of a positive test was 96% and the predictive value of a negative test was 97%.
TPO immunostaining was found to be a valuable adjunct to morphology in the diagnosis of cold thyroid nodules of the nonoxyphilic type.
[Show abstract][Hide abstract] ABSTRACT: Graves' disease is an autoimmune disease of the thyroid gland. Patients often have affective and cognitive complaints, whether these disappear after treatment remains disputed.
Our objective was to evaluate cerebral biochemistry in acute and treated Graves' disease.
We conducted a prospective study, investigating volunteers once and patients before and 1 yr after treatment.
The study was performed at a radiology department, a memory disorder clinic, and two endocrinology clinics.
Of 53 consecutively referred, newly diagnosed, and untreated patients with Graves' thyrotoxicosis, 27 patients (34 +/- 8 yr) and 33 matched volunteers were included.
Patients were treated with thionamide.
We assessed brain metabolite concentrations.
Proton magnetic resonance spectroscopy of the brain and a battery of biochemical, affective, and cognitive tests were used.
Previously reported findings of reduced choline and myo-inositol in acute Graves' disease were confirmed and reversibility was demonstrated. Parieto-occipital white matter glutamine was and remained significantly reduced (P < 0.01). Acute phase parieto-occipital white matter total choline correlated significantly (r = -0.57; P < 0.01) with impaired thyroid function. Pretreatment total T(3) predicted posttreatment occipital gray matter glutamine (r = -0.52; P < 0.01). Occipital gray matter total choline (r = -0.53; P < 0.01) and parietooccipital white matter glutamate (r = -0.54; P < 0.01) correlated with initial values of selected attention and concentration cognitive scores and predicted them at follow-up.
The persistent reduction of glutamine in white matter, the decreasing glutamate in occipital gray matter, and the correlation with severity of the initial disease as well as with attention and concentration cognitive scores indicated that there was a persistent and possibly progressive disturbance of the glutamate glutamine cycling in Graves' disease.
[Show abstract][Hide abstract] ABSTRACT: The normal cortisol response to an ACTH test remains inconsistently defined, possibly caused by various subject- and test- condition-related factors.
Our objective was to evaluate the impact of newer automated immunoassays; gender, age, body composition, and endogenous sex-hormone levels; corticosteroid-binding globulin levels; and test conditions (fasting/nonfasting, rest/intermittent exercise).
A 250-microg ACTH test (0800-1000 h) was performed in 100 unmedicated subjects, 13 women taking oral contraception (OC), and six men with nephrotic syndrome. Tests were performed fasting supine (n=119), nonfasting supine (n=38), and fasting with intermittent exercise (n=45). Serum cortisol was analyzed by three immunoassays.
Even with a negligible between-assay mean bias, individual samples from unmedicated subjects differed by as much as 110 nmol/liter. The normative 2.5th percentile for total cortisol ranged from 475-523 nmol/liter when analyzed by the three assays. In multivariate analyses, 30-min total cortisol was predicted by baseline cortisol (men plus women) and central adiposity (men) but not by gender, age, and endogenous sex hormones, corticosteroid-binding globulin, fasting/nonfasting, and exercise. Compared with unmedicated subjects, OC women had 2-fold elevated 30-min cortisol (P<0.001) but lowered calculated free cortisol (P<0.001), whereas nephrotic syndrome patients had lowered 30-min cortisol (P<0.01) in two of three assays, but similar calculated free cortisol (P>0.1).
The normal response to an ACTH test is assay specific, even with newer methods, and this also applies to calculated free cortisol. Both total cortisol and calculated free cortisol were severely affected by OC, and the test is therefore only reliable if OC has been discontinued. The ACTH test is, however, robust for most of the other evaluated subject- and test-condition-related factors.
[Show abstract][Hide abstract] ABSTRACT: Deficiency of lysosomal alpha-galactosidase A (alpha-Gal A) in Fabry disease results in cellular accumulation of globotriaosylceramide (Gl3), often leading to end-stage renal failure. Gl3 accumulates in endothelial, glomerular, and tubular cells. Replacement therapy with recombinant alpha-Gal A to some extent reduces cellular accumulation of Gl3 in the kidney. This study shows high lysosomal expression of alpha-Gal A in all tubular segments and interstitial cells of normal human kidney. However, glomeruli and endothelial cells did not express the enzyme to any significant extent. Recombinant enzyme was taken up by rat yolk sac cells in a receptor-associated protein-inhibitive manner, and surface plasmon resonance experiments revealed binding to megalin, indicating a possible mechanism for uptake of alpha-Gal A in the tubular cells. After infusion into experimental animals or patients, alpha-Gal A was recovered in the urine, indicating glomerular filtration. Recombinant alpha-Gal A was also found in kidneys of normal and alpha-Gal A knockout mice by Western blotting and localized to endosomes and lysosomes in proximal tubules, interstitial cells, and glomerular podocytes by immunocytochemistry and autoradiography but not in vascular endothelial cells. In conclusion, intravenously administered enzyme is taken up by interstitial cells, is to some extent filtered in glomeruli, and is taken up by podocytes and reabsorbed by receptor-mediated endocytosis in proximal tubule cells, directly indicating a potential beneficial effect of enzyme replacement therapy for these cells.
Journal of the American Society of Nephrology 01/2007; 18(3):698-706. · 9.47 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Volume is an important variable in assessing the growth and involution of the thyroid gland. The functional unit in the thyroid is the follicle, which consists of thyrocytes surrounding colloid. The size of a follicle depends on the number of cells and the amount of colloid. These are interchangeable and vary according to biological activity. Direct measurements of these variables provide information on structures involved in thyroid hormone synthesis, storage and secretion, and also on changes at the morphological and functional levels. Stereological methods are developed to obtain information on three-dimensional structures from two-dimensional sections and to achieve information on an entire organ by examining a minor part of it. Full-grown male Sprague-Dawley rats were used to develop a set of methods relying on unbiased stereological principles to determine the number of follicles, the total volume of colloid and the inner follicular surface area in the thyroid gland. The total volume of colloid was positively correlated (P < 0.021) with the number of follicles and the inner follicular surface area (P < 0.002) but not to the mean volume of colloid in each follicle. Thus under physiological conditions an increase in the total volume of colloid is associated with an increased number of follicles with a constant size distribution rather than a larger volume of colloid in each follicle. This implies that under physiological conditions there is equilibrium in the size distribution of the volume of colloid in each follicle.
Journal of Anatomy 09/2005; 207(2):117-24. · 2.23 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: In the acute, thyrotoxic phase, patients with Graves' disease often have both thyrotoxic and neuropsychiatric symptoms. The purpose of this prospective study was to examine health-related quality of life (HRQOL) in newly diagnosed and untreated Graves' patients and the effect of antithyroid medical treatment on HRQOL. In addition, we examined the potential influence of thyroid hormones and psychiatric symptoms on the impairment of HRQOL in the thyrotoxic phase.
A total of 30 consecutively referred patients with newly diagnosed and untreated Graves' disease and 34 age-, sex- and education-matched healthy volunteers were included in the study. HRQOL was assessed with the Medical Outcome Study 36-item Short-Form Health Status Survey (SF-36) before treatment, after reaching euthyroidism and 1 year after initiation of treatment.
In the thyrotoxic phase of Graves' disease, HRQOL was significantly impaired, in physical, mental and social dimensions. After reaching euthyroidism, the patients reported much fewer limitations on the subscales of SF-36. One year after initiation of treatment, all SF-36 scores had normalized. However, in some patients, HRQOL continues to be impaired even 1 year after initiation of treatment, as reviewed by the individual analysis. The reduced HRQOL in the acute phase of Graves' disease was correlated to depressive and anxiety symptoms, but thyroid-associated orbitopathy also influenced HLQOL.
Impaired HRQOL is common in the acute phase of Graves' disease. A significant proportion of the patients demonstrated persistent HRQOL impairment 1 year after initiation of treatment. Improvement of HRQOL in these patients remains a challenge for the clinician.
European Journal of Endocrinology 11/2004; 151(5):549-55. · 3.69 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Changes in the functional state of beta cells by neonatal stimulation or adolescent suppression have reduced the incidence of type 1 diabetes mellitus in animal models. The aim of this study was to evaluate the effect of manipulation of the activity of the thyroid gland by neonatal stimulation or by adolescent suppression on the prevalence of spontaneous autoimmune thyroiditis (AIT) in rats.
Bio-Breeding/Worcester (BB) rats were treated neonatally with sodium iodine (NaI) or thyroid stimulating hormone (TSH), or during adolescence by triiodothyronine (T(3)), and the lymphocytic infiltration in the thyroid gland was evaluated.
Neonatal treatment with NaI decreased the prevalence of AIT to 32+/-9% compared with 66+/-5% in the controls (P<0.002), mainly caused by a reduction among the female rats (13+/-9% vs 52+/-8%, P<0.006). TSH had no effect. Post neonatal suppression of the thyroid gland by T(3) had a biphasic response. Early in adolescence the overall prevalence was 14+/-7% compared with 66+/-5% in the controls (P<10(-5)); for female rats AIT was prevented (0+/-0%) compared with 52+/-8% in the controls (P<0.0003) and in male rats the values were 29+/-13% compared with 80+/-6% in the controls (P<0.001). Treatment with T(3) later in adolescence increased the overall prevalence to 81+/-7% compared with 66+/-5% in the controls (not significant). For female rats the prevalence increased to 78+/-9% compared with 52+/-8% in the controls (P=0.04). The degree of thyroiditis among the affected animals was similar in all groups.
Neonatal stimulation of the thyroid gland by iodine or early adolescent suppression by T(3) reduced the prevalence of AIT whereas T(3) given later increased the prevalence of thyroiditis in rats. Thyroid activity at various ages seems to be of importance for the development of autoimmune thyroiditis.
European Journal of Endocrinology 09/2004; 151(3):375-82. · 3.69 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: To evaluate serum thyroglobulin (Tg) level as a marker of the development of thyroid disease when following individuals who received neck irradiation therapy in childhood.
In a non-randomized cross-sectional study Tg was assessed in 172 survivors of childhood cancer 10.8 y (1.9-24) median (range) after diagnosis and 7.9 y (0.9-24.3) median (range) after the end of treatment. The patients were divided into two groups: group 1 included 47 patients who had received irradiation to the neck and group 2 included 125 patients who did not receive irradiation to the neck.
Patients who had received irradiation to the neck had significantly higher Tg levels compared with those who did not receive neck irradiation: median 14.0 (1.0-189.0) microg/L vs median 8.8, (0.7-112.2) microg/L (p < 0.001). Six out of seven patients with elevated Tg levels (>70 microg/L) had received neck irradiation. Among these six patients, two patients developed secondary differentiated thyroid cancer and two patients developed benign thyroid neoplasms. None of the patients who had normal levels of Tg developed thyroid cancer.
A high Tg level should be a cause for further investigation in the follow-up of individuals who have received irradiation therapy in childhood.
[Show abstract][Hide abstract] ABSTRACT: The impact of cranial irradiation (CIR) and chemotherapy on the hypothalamo-pituitary (HP)-adrenal (HPA) axis was assessed in a population-based follow-up study of patients treated for childhood brain tumor not directly involving the HP axis. HPA function was evaluated and compared with that in healthy controls (n = 17), measuring basal cortisol and the peak cortisol response to an insulin tolerance test (ITT) and an ACTH test(.) The cortisol cut-off level was 500 nmol/liter. The biological effective dose (BED) of radiotherapy was determined for the HP region and spine and was expressed in Gray units, as BED gives a means of expressing the biological effects of different dosage schedules in a uniform way. Seventy-three children (46 males and 27 females), less than 15 yr of age when diagnosed during 1970-1997 in the Eastern part of Denmark, were included. The median age at time of radiotherapy was 8.4 yr (range, 0.8-14.9). The median length of follow-up was 15 yr (range, 2-29). Fourteen patients (19%) had basal cortisol levels below 500 nmol/liter and did not respond with a peak cortisol above the cut-off level to either an ACTH test (30 or 60 min) or an ITT, and thus, they had insufficiency of the HPA axis. Even though a peak cortisol above 500 nmol/liter was reached in the rest of the cohort (n = 59) after either an ACTH test (30 or 60 min) or an ITT, they had significantly lower peak cortisol levels compared with controls (P = 0.0099). Thirteen patients failed the ACTH test (30 min), but passed the ACTH test (60 min), implying a risk of misinterpreting the cortisol capacity of the patient if only the ACTH test (30 min) is obtained. The basal cortisol levels and the cortisol levels in the ACTH test (30 min) and the ACTH test (60 min) were significantly lower in the patient group compared with controls. There was a significant correlation between the peak cortisol after the ITT compared with the peak cortisol after the ACTH test (30 or 60 min; r(s) = 0.56; P = 0.0006), but 48% failed the ITT, and there was discordance in 10 of 33 (30%) patients who passed the ACTH but failed the ITT, indicating the recommendation of continuous use of the ITT as the gold standard for evaluation of the HPA axis. Stepwise backward multiple linear regression analysis showed that the best-fit model to predict the peak cortisol level after an ITT included BED (P = 0.04) and length of follow-up (P = 0.06). In contrast, age at RT, chemotherapy, BED to the spine, and gender were not included in the model. In conclusion, these data suggest that CIR for a childhood brain tumor may affect the HPA axis, resulting in secondary adrenal insufficiency, whereas adjuvant chemotherapy does not seem to add to the deleterious effect of CIR. We recommend life-long surveillance of the HPA axis and performing regular ITTs.
[Show abstract][Hide abstract] ABSTRACT: Neuropsychiatric symptoms in the acute thyrotoxic phase of Graves' disease suggest involvement of brain processes. Short-echo-time proton MRS was used to measure the cerebral metabolite profile in newly diagnosed and untreated Graves' disease. Sixteen patients with Graves' disease and 18 age- and sex-matched healthy volunteers were studied. The patients had significantly reduced total choline and myo-inositol in the acute phase of Graves' thyrotoxicosis compared with the healthy volunteers.
[Show abstract][Hide abstract] ABSTRACT: The effect of craniospinal irradiation (CSI) vs. cranial irradiation (CIR) only with or without chemotherapy (CT) on the hypothalamus/pituitary (HP) thyroid axis was assessed in a population-based study of patients treated for a childhood brain tumor not directly involving the HP axis. Thyroid function was evaluated and compared with that in healthy controls (n = 27), measuring TSH, free T4, total T4, total T3, and TRH. The biological effective dose (BED) of radiotherapy, determined for the HP region and spine and expressed in grays (Gy) as BED, gives a means of expressing the biological effects of different dosage schedules in a uniform way. Seventy-one children (45 males and 26 females), less than 15 yr of age when diagnosed between 1970-1997 in the eastern part of Denmark, were included. Twenty-nine had received CSI, and 42 had received CIR only. The median age at time of radiotherapy was 8.4 yr (range, 0.8-14.9). The median length of follow-up was 12.0 yr (range, 2.0-28.0). There was no significant difference between CSI and the CIR only patients with respect to median BED to the HP region. Primary hypothyroidism was found in 24%, of whom 71% had been treated with CSI and 29% with CIR only; 73% had compensated hypothyroidism, and 27% had overt primary hypothyroidism. Central hypothyroidism was found in 6%. Free T4 and total T3 were significantly lower in the CSI and CIR only groups compared with controls. As the CIR only group had significantly higher median basal TSH levels compared with controls and as the CSI compared with the CIR only group and controls had significantly higher median basal TSH levels, we speculate that this was probably due to scattered irradiation from both cranial and spinal fields to the thyroid gland. There was a significant relation between basal TSH and time of follow-up (r(s) = -0.39; P = 0.001). Stepwise backward multiple linear regression analysis showed that the best-fit model to predict basal TSH was free T4 (P < 0.0001), the length of follow-up (P = 0.02), and total T3 (P = 0.06). In contrast, age at radiotherapy, BED to the HP region and spine, and whether the patient had been treated with CT were not included in the model. The TRH test showed significantly exaggerated and prolonged TSH responses for the CSI and CIR only groups compared with controls, indicating HP dysfunction. In conclusion, these data suggest that both CSI and CIR for childhood brain tumor may affect the HP-thyroid axis, resulting in hypothyroidism. CT had no significant influence on HP-thyroid function. We recommend prolonged surveillance of pituitary-thyroid function in long-term survivors of childhood brain tumor and institution of thyroid hormone replacement if the levels of TSH and free T4 are above and below the normal range, respectively, to ensure normal growth and metabolism.