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Katharina Binz, Christoph Schmid, Roger Bouillon, E Rudolf Froesch, Kay Jürgensen, and Ernst B Hunziker

Binz K, Schmid C, Bouillon R, Froesch ER, Jürgensen K, Hunziker EB. Interactions of insulin-like growth factor I with dexamethasone on trabecular bone density and mineral metabolism in rats. Eur J Endocrinol 1994;130:387–93. ISSN 0804–4643

Glucocorticoid treatment causes osteoporosis and growth retardation in humans. Insulin-like growth factor I (IGF-I) stimulates differentiation and replication of cultured osteoblast-like cells and induces longitudinal bone growth in IGF-I-deficient rats. We investigated the influence of subcutaneously infused IGF-I on bone and mineral metabolism of male rats treated with a high dose of dexamethasone. Dexamethasone was added to the drinking water in a concentration of 1 mg/l. After 30 days of dexamethasone treatment, recombinant human IGF-I (300 μg/day) or solvent was infused sc by osmotic minipumps for 21 days while dexamethasone was continued. Age-matched untreated male rats served as healthy controls. Dexamethasone-treated rats lost weight. Their IGF-I levels were decreased to 36% of healthy controls. Infusion of IGF-I resulted in an increase in IGF-I serum levels (582% compared to healthy controls) and allowed some weight gain. Osteocalcin and calcitriol levels were markedly decreased in dexamethasone-treated rats and were not influenced significantly by IGF-I infusion. In contrast, IGF-I treatment restored the free calcitriol concentration (molar ratio of calcitriol to vitamin D-binding protein) towards normal. Furthermore, infusion of IGF-I partially corrected the dexamethasone-induced hyperinsulinemia. Histomorphometric analysis revealed no difference in vertebral trabecular bone density (i.e. growth-independent bone remodeling) between the three groups. In contrast, mean trabecular bone density in tibial metaphyses was increased markedly by dexamethasone, presumably due to osteoclast inhibition. Insulin-like growth factor I infusion did not significantly influence these structural metaphyseal bone parameters. We conclude that IGF I-infusion in male rats treated with high doses of dexamethasone reduces insulin resistance and restores calcitriol production but not osteoblast function or responsiveness to calcitriol.

K Binz, Division de Diabétologie, Hôpital Cantonal Universitaire, 1211 Geneva, Switzerland

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Kim Brixen, Henning K Nielsen, Roger Bouillon, Allan Flyvbjerg, and Leif Mosekilde

We measured changes in serum insulin-like growth factor-1 (IGF-1), calcitriol, parathyroid hormone (PTH), thyroid hormones, insulin, and plasma glucagon in response to seven days of treatment with a pharmacological dosage of recombinant human growth hormone (r-hGH) (0.1 IU/kg sc twice daily) or placebo in 20 normal male volunteers to evaluate whether the effect of r-hGH on biochemical bone markers could be attributed to changes in these hormones. Serum IGF-1 (p<0.001) and vitamin D-binding protein (p<0.001) increased steadily during treatment returning to baseline at day 14. Total calcitriol (p<0.01) and free calcitriol index (p<0.001) increased transiently at day 4. Furthermore, serum insulin (p<0.001) and both total (p<0.001) and free triiodothyronine (p<0.02) increased during treatment, while serum PTH and plasma glucagon remained unchanged. In conclusion, pharmacological doses of r-hGH increased not only IGF-1 but also free-calcitriol index, insulin, and free T3. The increase in these hormones may be co-responsible for some of the observed effects of r-hGH on bone turnover and calcium homeostasis.

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Jens Bollerslev, Claudio Marcocci, Manuel Sosa, Jörgen Nordenström, Roger Bouillon, and Leif Mosekilde

Management of patients with mild primary hyperparathyroidism (PHPT) has been widely discussed because most patients today do not have specific symptoms. While surgery is always an option, the recommendations for treatment have shifted, which mostly reflects changes in clinical practice. In this study, we aimed to evaluate evidence for the current recommendations concerning operation vs observation, repletion with vitamin D (VitD) and alternative medical management.

Surgery is followed by normalisation of calcium and parathyroid hormone (PTH) and a decrease in bone turnover followed by an increase in bone mass. It is not known what the consequences would be for the frequency of fractures. Randomised studies have indicated beneficial effects of operation on quality of life (QoL), but the effects have been minor and inconsistent. Operation seems not to be superior to observation for cardiovascular risk factors. Although PHPT patients in average have slightly decreased plasma 25OH VitD, severe symptomatic VitD deficiency seems not to be a characteristic of PHPT patients in Europe. However, if present, we recommend VitD substitution before final decision on surgical treatment. It is unknown whether routine VitD supplementation should be offered preoperatively to all patients with mild PHPT or as part of long-term medical treatment.

Targeted medical management could be an option for patients with contraindications to surgery. Antiresorptive therapy might be appropriate for patients with a low bone mass to prevent further bone loss. Calcimimetics could be tried to control serum calcium levels although there is no evidence of an effect on the hypercalcaemic symptoms or the QoL. Combined therapy with calcimimetics and alendronate could be considered for patients with hypercalcaemia and overt bone disease.

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Bert De Groef, Brigitte R Decallonne, Serge Van der Geyten, Veerle M Darras, and Roger Bouillon

Objective: Perchlorate is a known competitive inhibitor of the sodium/iodide symporter (NIS). Possible thyroid-related effects of environmental perchlorate have created great health concerns, especially in the US, resulting in a debated reference dose (RfD) of 0.0007 mg/kg per day in drinking water recommended by the National Academy of Sciences (NAS). However, the impact of other environmental NIS inhibitors and the role of iodine seem to have received little attention in the whole debate.

Methods: We performed a PubMed search for articles published up to February 2006, using the key terms perchlorate, nitrate, thiocyanate, iodine, NIS, RfD, thyroid (alone or in combinations), with particular attention for human studies. In parallel, we critically analysed the January 2005 NAS’ report, entitled ‘Health implications of perchlorate ingestion’.

Results: The relative potencies of prevalent environmental NIS inhibitors (nitrate, thiocyanate and perchlorate) to inhibit iodine uptake have been estimated repeatedly with robust results. Our calculations show that nitrate and thiocyanate, acquired through drinking water or food, account for a much larger proportion of iodine uptake inhibition than perchlorate. Furthermore, the iodine uptake inhibitory effects of nitrate and thiocyanate – as defined by their legally accepted maximal contaminant levels in drinking water – exceed the potential effect of the proposed RfD for perchlorate by far.

Conclusions: Iodine uptake inhibition and any potential downstream effect by perchlorate are highly dependent on the presence of other environmental NIS inhibitors and iodine intake itself. These potential confounders should therefore be considered in future studies and calculations for risk assessment.

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Frank RE Nobels, Wouter W de Herder, Dik J Kwekkeboom, Willy Coopmans, Andries Mulder, Roger Bouillon, and Steven WJ Lamberts

Nobels FRE, de Herder WW, Kwekkeboom DJ, Coopmans W, Mulder A, Bouillon R, Lamberts SWJ. Serum chromogranin A in the differential diagnosis of Cushing's syndrome. Eur J Endocrinol 1994:131:589–93. ISSN 0804–4643

We evaluated whether measuring serum levels of chromogranin A, a marker of neuroendocrine tumours, could be useful in the differential diagnosis between pituitary, adrenal and ectopic causes of Cushing's syndrome. Thirty patients with Cushing's syndrome were studied. The localization of the tumours responsible was pituitary in 15, adrenal in 5 and ectopic in 10 patients. Serum concentrations of chromogranin A were measured in all patients. Petrosal sinus sampling for chromogranin A was performed in the cases with pituitary-dependent Cushing's syndrome. Immunohistochemical staining for chromogranin A was carried out on part of the tumour specimens. Slightly elevated serum levels of chromogranin A (range 223–262 μg/1) were detected in inferior petrosal sinus and peripheral venous samples from three patients with pituitary-dependent Cushing's syndrome. Serum chromogranin A showed no significant pituitary to peripheral gradient in these patients. Chromogranin A levels were not elevated in cases of adrenal Cushing's syndrome. Markedly elevated concentrations (range 270–13900 μg/1) were shown in seven of 10 patients with neuroendocrine tumours with ectopic adrenocorticotrophin (ACTH) and/or corticotrophin-releasing hormone (CRH) production. Widespread metastasis was present in all these cases. Subjects with "occult" carcinoid tumours, with limited spread, had normal chromogranin A levels Immunohistochemical staining for chromogranin A was positive in three out of five pituitary adenomas and in all neuroendocrine tumours with ectopic ACTH and/or CRH production, while it was negative in all adrenocortical tumour specimens. It is concluded that elevated serum levels of chromogranin A can serve as markers of neuroendocrine tumours with ectopic ACTH and/or CRH production. The circulating levels are dependent mainly on the size of the tumours. Serum chromogranin A is not useful in the diagnosis of so-called occult Cushing's syndrome, caused by ectopic ACTH and/or CRH secretion by small neuroendocrine tumours.

F Nobels, Department of Endocrinology, Onze Lieve Vrouw Hospital, 164 Moorselbaan, 9300 Aalst, Belgium

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Paul Lips, Kevin D Cashman, Christel Lamberg-Allardt, Heike Annette Bischoff-Ferrari, Barbara Obermayer-Pietsch, Maria Luisa Bianchi, Jan Stepan, Ghada El-Hajj Fuleihan, and Roger Bouillon

Vitamin D deficiency (serum 25-hydroxyvitamin D (25(OH)D) <50 nmol/L or 20 ng/mL) is common in Europe and the Middle East. It occurs in <20% of the population in Northern Europe, in 30–60% in Western, Southern and Eastern Europe and up to 80% in Middle East countries. Severe deficiency (serum 25(OH)D <30 nmol/L or 12 ng/mL) is found in >10% of Europeans. The European Calcified Tissue Society (ECTS) advises that the measurement of serum 25(OH)D be standardized, for example, by the Vitamin D Standardization Program. Risk groups include young children, adolescents, pregnant women, older people (especially the institutionalized) and non-Western immigrants. Consequences of vitamin D deficiency include mineralization defects and lower bone mineral density causing fractures. Extra-skeletal consequences may be muscle weakness, falls and acute respiratory infection, and are the subject of large ongoing clinical trials. The ECTS advises to improve vitamin D status by food fortification and the use of vitamin D supplements in risk groups. Fortification of foods by adding vitamin D to dairy products, bread and cereals can improve the vitamin D status of the whole population, but quality assurance monitoring is needed to prevent intoxication. Specific risk groups such as infants and children up to 3 years, pregnant women, older persons and non-Western immigrants should routinely receive vitamin D supplements. Future research should include genetic studies to better define individual vulnerability for vitamin D deficiency, and Mendelian randomization studies to address the effect of vitamin D deficiency on long-term non-skeletal outcomes such as cancer.

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Christine A Simpson, Jane H Zhang, Dirk Vanderschueren, Lei Fu, Teresita C Pennestri, Roger Bouillon, David E C Cole, and Thomas O Carpenter


GC/DBP effects on response to vitamin D supplementation have not been well-studied. Thus we assessed free and total 25-OHD after vitamin D treatment across the six common GC haplotypes.


This double-blind, randomized study compared two vitamin D3 doses in healthy, urban-dwelling 6-month to 10-year-old children at-risk for vitamin D deficiency. Randomization was stratified by GC haplotype.


Children were randomized to receive 2800 or 7000 International Units of vitamin D3 weekly. 25-OHD and 1,25(OH)2D were sampled at baseline and after 1–6 months of supplementation.

Results and conclusions

One hundred ninety-two of 225 enrolled subjects completed the study. After one month, total 25-OHD increased with both doses and were higher with 7000 IU/week (85.5 ± 22.8 nmol/L) compared to 2800 IU/week (76.8 ± 18.0 nmol/L), despite equivalent baseline levels. No further significant increase occurred at 6 months (89.8 ± 35.5 and 74.3 ± 18.3 nmol/L, respectively). Free 25-OHD similarly changed. 25-OHD differed among GC groups at baseline. Although no significant effects of individual GC haplotypes on incremental changes were evident, a trend toward an effect of combined 'at risk' GC alleles on response was evident (P = 0.06). Total 1,25(OH)2D showed modest increases, moreso with the larger dose. In urban-dwelling children at-risk for vitamin D deficiency, 1 month of vitamin D3 2800 IU/week increased 25-OHD across all GC haplotype groups, and somewhat enhanced with 7000 IU/week with no further significant increases after 6 months of supplementation. Free 25-OHD measures offer no monitoring advantage over total 25-OHD.

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David M Lee, Martin K Rutter, Terence W O'Neill, Steven Boonen, Dirk Vanderschueren, Roger Bouillon, Gyorgy Bartfai, Felipe F Casanueva, Joseph D Finn, Gianni Forti, Aleksander Giwercman, Thang S Han, Ilpo T Huhtaniemi, Krzysztof Kula, Michael E J Lean, Neil Pendleton, Margus Punab, Alan J Silman, Frederick C W Wu, and the European Male Ageing Study Group


Low serum 25-hydroxyvitamin D (25(OH)D) and elevated parathyroid hormone (PTH) levels have been linked to insulin resistance, the metabolic syndrome (MetS) and its components. Data in healthy, community-dwelling Europeans are lacking, and previous studies have not excluded subjects receiving drug treatments that may distort the relationship between 25(OH)D/PTH and MetS. The aim of our analysis was to examine the association of 25(OH)D and PTH with Adult Treatment Panel III-defined MetS in middle-aged and older European men.


This was a population-based, cross-sectional study of 3369 men aged 40–79 years enrolled in the European Male Ageing Study.


After exclusion of subjects with missing data, 3069 men with a mean (±s.d.) age of 60±11 years were included in the analysis. Age-adjusted 25(OH)D levels were inversely associated with waist circumference, systolic blood pressure (BP), triglycerides, and glucose (all P<0.01). Age-adjusted PTH levels were only associated with waist and diastolic BP (both P<0.05). After adjusting for age, centre, season and lifestyle factors the odds for MetS decreased across increasing 25(OH)D quintiles (odds ratios 0.48 (95% confidence intervals 0.36–0.64) highest versus lowest quintile; P trend<0.001). This relationship was unchanged after adjustment for PTH, but was attenuated after additional adjustment for homoeostasis model assessment of insulin resistance (0.60 (0.47–0.78); P trend<0.001). There was no association between PTH and MetS.


Our results demonstrate an inverse relationship between 25(OH)D levels and MetS, which is independent of several confounders and PTH. The relationship is partly explained by insulin resistance. The clinical significance of these observations warrants further study.

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David M Lee, Abdelouahid Tajar, Stephen R Pye, Steven Boonen, Dirk Vanderschueren, Roger Bouillon, Terence W O'Neill, Gyorgy Bartfai, Felipe F Casanueva, Joseph D Finn, Gianni Forti, Aleksander Giwercman, Thang S Han, Ilpo T Huhtaniemi, Krzysztof Kula, Michael E J Lean, Neil Pendleton, Margus Punab, Frederick C W Wu, and the EMAS study group


Interrelationships between hormones of the hypothalamic–pituitary–testicular (HPT) axis, hypogonadism, vitamin D and seasonality remain poorly defined. We investigated whether HPT axis hormones and hypogonadism are associated with serum levels of 25-hydroxyvitamin D (25(OH)D) in men.

Design and methods

Cross-sectional survey of 3369 community-dwelling men aged 40–79 years in eight European centres. Testosterone (T), oestradiol (E2) and dihydrotestosterone were measured by gas chromatography–mass spectrometry; LH, FSH, sex hormone binding globulin (SHBG), 25(OH)D and parathyroid hormone by immunoassay. Free T was calculated from total T, SHBG and albumin. Gonadal status was categorised as eugonadal (normal T/LH), secondary (low T, low/normal LH), primary (low T, elevated LH) and compensated (normal T, elevated LH) hypogonadism. Associations of HPT axis hormones with 25(OH)D were examined using linear regression and hypogonadism with vitamin D using multinomial logistic regression.


In univariate analyses, free T levels were lower (P=0.02) and E2 and LH levels were higher (P<0.05) in men with vitamin D deficiency (25(OH)D <50 nmol/l). 25(OH)D was positively associated with total and free T and negatively with E2 and LH in age- and centre-adjusted linear regressions. After adjusting for health and lifestyle factors, no significant associations were observed between 25(OH)D and individual hormones of the HPT axis. However, vitamin D deficiency was significantly associated with compensated (relative risk ratio (RRR)=1.52, P=0.03) and secondary hypogonadism (RRR=1.16, P=0.05). Seasonal variation was only observed for 25(OH)D (P<0.001).


Secondary and compensated hypogonadism were associated with vitamin D deficiency and the clinical significance of this relationship warrants further investigation.