Kallmann syndrome in a 47,XXX patient.
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Adult↗
Biomedical subjects
E Fliers
Publications and source records attributed to E Fliers.
Evaluation of endocrine tests. B: screening for hypercortisolism.
BACKGROUND: While reference values for 24-hour free urinary cortisol excretion and the overnight 1 mg dexa-methasone-suppression test in the healthy population are available, cut-off values in patients clinically suspected of Cushing's syndrome have to be established. METHODS: This was a prospective follow-up study in one academic centre of 144 patients with clinical suspicion of Cushing's syndrome (group A) and 50 patients with adrenal incidentaloma (group B) who were referred for putative hypercortisolism between 1 January 1993 and 1 January 2003. The 24-hour urinary free cortisol and post-dexamethasone plasma cortisol were measured. Accurate diagnosis of (absence of) Cushing's syndrome was confirmed by histopathological data and long-term follow-up. Based on the data obtained in group A, sensitivity, specificity and receiver operating characteristic (ROC) curves were calculated. RESULTS: Complete follow-up was obtained in 86%, and partial follow-up was obtained in 8% of patients. Median follow-up was 36 (1 to 122) months. In group A, 17 patients were found to have Cushing's syndrome. In this group median 24-hour urinary free cortisol was 77 (<5 to 51458) mmol/24 hours and median post-dexamethasone plasma cortisol was <50 (<50 to 4900) nmol/l. Area under the ROC curve was 0.958 for 24-hour urinary free cortisol and 0.985 for post-dexamethasone plasma cortisol. Optimal cut-off values were 180 nmol/24 hours (sensitivity 94%, specificity 94%) and 95 nmol/l (sensitivity 100%, specificity 94%) respectively. CONCLUSION: We established cut-off values for 24-hour free urinary cortisol excretion (180 nmol/24 hours) and for post-dexamethasone plasma cortisol (95 nmol/l) in the evaluation of patients referred for hypercortisolism.
Adrenal Cortex Function Tests↗
Establishment of reference values for endocrine tests. Part IV: Adrenal insufficiency.
BACKGROUND: The short Synacthen test, the overnight metyrapone test and the insulin tolerance test are frequently used in the evaluation of patients suspected of adrenal insufficiency. in the present study, we established reference values for these diagnostic tests, as well as for baseline morning plasma cortisol and adrenocorticotrophic hormone (ACTH). METHODS: We studied 50 subjects recruited from the general population, equally distributed according to sex and age between 20 and 69 years. A short ACTH stimulation test (250 microg Synacthen iv), an overnight metyrapone test (2.0, 2.5, or 3.0 g given orally depending on body weight at 23.30 hours) and an insulin tolerance test (0.15 U/kg actrapid iv) were performed. Reference intervals are given as the means +/- 2SD of observed hormone concentrations after logarithmic transformation. RESULTS: The following reference values were established: 09.00 hr plasma cortisol 150 to 802 nmol/l, 09.00 hr plasma ACTH 8 to 93 ng/l, peak plasma cortisol after Synacthen 591 to 1,113 nmol/l, peak plasma cortisol after insulin-induced hypoglycaemia 557 to 1,015 nmol/l, and plasma 11-deoxycortisol after metyrapone 197 to 759 nmol/l. CONCLUSION: We established reference values for diagnostic tests that are useful in the evaluation of patients suspected of primary or secondary/tertiary adrenal insufficiency.
Adrenal Cortex Function Tests↗
Glucocorticoids decrease thyrotropin-releasing hormone messenger ribonucleic acid expression in the paraventricular nucleus of the human hypothalamus.
The way glucocorticoids affect TRH mRNA expression in the paraventricular nucleus of the hypothalamus is still unclear. In view of its relevance for Cushing's syndrome and depression, we measured TRH mRNA expression in human hypothalami obtained at autopsy by means of quantitative TRH mRNA in situ hybridization. In corticosteroid-treated subjects (n = 10), TRH mRNA hybridization signal was decreased as compared with matched control subjects (n = 10) (Mann-Whitney U test, P = 0.02). By inference, hypercortisolism as present in patients with Cushing's syndrome or major depression may contribute to lower serum TSH or symptoms of depression by lowering hypothalamic TRH expression.
Adult↗
Long-term effects of cranial irradiation for childhood malignancy on sleep in adulthood.
BACKGROUND: Cranial radiation therapy (CRT) is required for successful treatment of a variety of brain tumours in childhood. OBJECTIVE: To investigate whether childhood CRT leads to altered sleep-wakefulness organization in adulthood, and to identify the determinants of such alterations. SUBJECTS AND METHODS: Subjective (questionnaires) and objective (actigraphy) measures of circadian rhythmicity and sleep were assessed in 25 individuals, 8-29 years after CRT for medulloblastoma (n=17) or other intracranial tumours (n=8), and in a group of 34 age-matched healthy individuals. Serum GH peak during insulin-induced hypoglycaemia and serum concentrations of prolactin and leptin (expressed per fat mass) were determined in the CRT group. RESULTS: The CRT group showed a markedly increased sleep duration (8.66 h, compared with 7.66 h in controls). In addition, the sleep-wake rhythm showed greater amplitude and less fragmentation, and less tolerance for alterations in the timing of sleep. Regression analysis showed both radiation dosage and neuroendocrine status to be determinants of sleep changes, suggesting that some of the alterations may be normalized with hormone supplementation. CONCLUSION: The present study shows that high-dose cranial radiation therapy in childhood is associated with objective and subjective changes in the sleep-wake rhythm in adulthood.
Adolescent↗
Simultaneous changes in central and peripheral components of the hypothalamus-pituitary-thyroid axis in lipopolysaccharide-induced acute illness in mice.
During illness, major changes in thyroid hormone metabolism and regulation occur; these are collectively known as non-thyroidal illness and are characterized by decreased serum triiodothyronine (T(3)) and thyroxine (T(4)) without an increase in serum TSH. Whether alterations in the central part of the hypothalamus-pituitary-thyroid (HPT) axis precede changes in peripheral thyroid hormone metabolism instead of vice versa, or occur simultaneously, is presently unknown. We therefore studied the time-course of changes in thyroid hormone metabolism in the HPT axis of mice during acute illness induced by bacterial endotoxin (lipopolysaccharide; LPS).LPS rapidly induced interleukin-1beta mRNA expression in the hypothalamus, pituitary, thyroid and liver. This was followed by almost simultaneous changes in the pituitary (decreased expression of thyroid receptor (TR)-beta2, TSHbeta and 5'-deiodinase (D1) mRNAs), the thyroid (decreased TSH receptor mRNA) and the liver (decreased TRbeta1 and D1 mRNA). In the hypothalamus, type 2 deiodinase mRNA expression was strongly increased whereas preproTRH mRNA expression did not change after LPS. Serum T(3) and T(4) fell only after 24 h. Our results suggested almost simultaneous involvement of the whole HPT axis in the downregulation of thyroid hormone metabolism during acute illness.
Acute Disease↗
Diurnal variation in rat liver thyroid hormone receptor (TR)-alpha messenger ribonucleic acid (mRNA) is dependent on the biological clock in the suprachiasmatic nucleus, whereas diurnal variation of TR beta 1 mRNA is modified by food intake.
Previous studies have shown a diurnal variation of certain isoforms of thyroid hormone receptors (TR) in rat liver. The genesis of these diurnal changes is still unknown. To clarify whether the biological clock, located in the hypothalamic suprachiasmatic nucleus (SCN), is involved, we made selective SCN lesions. Rats with an SCN lesion lost their circadian rhythm of plasma corticosterone and TSH when compared with intact animals. TR alpha 1 and TR alpha 2 mRNA expression of control rats was higher in the light period than in the dark period; changes that were abolished in the rats with SCN lesions. In contrast, liver TR beta 1 mRNA of intact rats showed a diurnal variation that failed to reach statistical significance. To evaluate whether these effects could be explained indirectly by the disappearance of rhythmic feeding behavior in rats with SCN lesions, we performed a second experiment in which otherwise intact animals were subjected to a regular feeding (RF) schedule, with one meal every 4 h. When compared with rats with free access to food, RF only affected TR beta 1 mRNA expression and had no effect on the diurnal changes in TR alpha 1 and TR alpha 2. We conclude that liver TR beta 1 expression is most clearly affected by food intake. Diurnal changes in liver TR alpha 1 and TR alpha 2 are controlled by the biological clock in the SCN but not via changes in the daily rhythm of food intake. The findings may have physiological relevance for diurnal variation of T(3)-dependent gene expression, which is supported by a diurnal variation in the expression of the 5'-deiodinase gene.
Animals↗
HIV-associated adipose redistribution syndrome as a selective autonomic neuropathy.
Abnormal body-fat distribution in HIV-1-associated adipose redistribution syndrome (HARS) remains unexplained at present. White adipose tissue is controlled by humoral factors and by neural regulation. Sympathetic innervation stimulates lipolysis, whereas parasympathetic innervation has an anabolic influence on white adipose tissue. Results of neuroanatomical studies showed a clear somatotopy with respect to autonomic control of white adipose tissue by both the sympathetic and parasympathetic branch, with separate sets of autonomic neurons innervating either the subcutaneous or the visceral fat compartment. Thus, the CNS is likely to be a key player in regulation of body-fat distribution. We propose that HARS is mediated by effects of antiretroviral treatment on the CNS and could indicate a change in autonomic balance resulting in redistribution of adipose tissue.
Adipose Tissue↗
[Screening pregnant women for hypothyroidism: as yet only in high risk groups].
Several recent publications have drawn attention to the possible relationship between a lowered serum thyroxine concentration in pregnant women and subsequent retarded neuropsychological development of their children. Experimental evidence suggests that circulating maternal thyroxine is an important source of thyroid hormone for the developing foetal brain during the first trimester. These considerations have led some authors to advocate a population-based screening program for hypothyroidism in pregnancy. However, at present it is unclear when such screening should take place, which screening test should be used, and what the benefit of therapeutic intervention is in terms of neuropsychological outcome. At present, screening seems not warranted, but we would advocate case finding of (subclinical) auto-immune hypothyroidism in certain risk groups (e.g., positive family history for auto-immune thyroid disease, or presence of type 1 diabetes mellitus) since treatment in these cases is warranted. The establishment of the optimal timing and nature of screening for hypothyroidism in pregnant women and of its cost-effectiveness is an attractive goal for a research project in a defined region.
Adult↗
Decreased thyrotropin-releasing hormone gene expression in the hypothalamic paraventricular nucleus of patients with major depression.
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Major Depressive Disorder↗
White adipose tissue: getting nervous.
Neuroendocrine research has altered the traditional perspective of white adipose tissue (WAT) as a passive store of triglycerides. In addition to fatty acids, WAT produces many hormones and can therefore be designated as a traditional endocrine gland actively participating in the integrative physiology of fuel and energy metabolism, eating behaviour and the regulation of hormone secretion and sensitivity. WAT is controlled by humoral factors, para- and intracrine factors and by neural regulation. Sympathetic nerve fibres innervate WAT and stimulate lipolysis, leading to the release of glycerol and free fatty acids. In addition, recent research in rats has clearly shown a functional parasympathetic innervation of WAT. There appears to be a distinct somatotopy within the parasympathetic nuclei: separate sets of autonomic neurones in the brain stem innervate either the visceral or the subcutaneous fat compartment. We therefore propose that the central nervous system (CNS) plays a major role in the hitherto unexplained regulation of body fat distribution. Parasympathectomy induces insulin resistance with respect to glucose and fatty acid uptake in the innervated fat depot and has selective effects on local hormone synthesis. Thus, the CNS is involved not only in the regulation of hormone production by WAT, but also in its hormone sensitivity. The developments in this research area are likely to increase our insights in the pathogenesis of metabolic disorders such as hypertriglyceridemia, diabetes mellitus type 2 and lipodystrophy syndromes.
Adaptation, Physiological↗
Establishment of reference values for endocrine tests. III: Primary aldosteronism.
BACKGROUND: In our laboratory well-defined reference values for the screening test and confirmation test used in the diagnosis of primary aldosteronism were lacking. In this study we established the reference-values of the plasma aldosterone concentration (PA), plasma renin activity (PRA) and PA/PRA ratio after a two-hour upright period, and of the urinary aldosterone excretion after oral sodium loading. METHODS: Fifty healthy volunteers, equally distributed according to sex and aged between 20 and 70 years, went through the screening and confirmation test of primary aldosteronism. PA, PRA and the PA/PRA ratios were measured after a two-hour upright period (screening test). Urinary aldosterone excretion was determined in two 24-hour urine samples after an oral suppletion of 6 g NaCl a day for five days (confirmation test). RESULTS: The following reference values were established: PA (after two-hour upright position) <0.03-1.05 nmol/l (mean: 0.47), PA/PRA ratio 0.05-0.47 (mean: 0.15) and urinary aldosterone excretion after sodium loading <3.0-47.0 nmol/24h (mean: 10.5). PRA showed a significant decrease with advancing age: median values in the 3rd to 7th decade are 3.9, 3.5, 2.5, 1.6 and 2.1 ng A1/ml/h respectively (p=0.04). PA was lower in subjects > or = 50 years old. Age did not affect the PA/PRA ratio or the urinary aldosterone excretion. There were no significant differences between the sexes in any of the above-mentioned parameters. CONCLUSION: In this study we established reference values for the screening and confirmation test used in the diagnosis of primary aldosteronism.
Adult↗
Evaluation of endocrine tests. A: the TRH test in patients with hyperprolactinaemia.
BACKGROUND: In a previous study, we determined reference values for basal and thyrotropin-releasing hormone (TRH)-stimulated plasma concentrations of prolactin (PRL). The aim of the present study was to determine the clinical usefulness of the PRL response to TRH in the work-up of patients with hyperprolactinaemia. METHODS: We studied 92 consecutive patients referred for evaluation of hyperprolactinaemia. Patients with confirmed hyperprolactinaemia were divided into three groups: group A (pharmacological hyperprolactinaemia; n=2), group B (pathological hyperprolactinaemia; n=6) and group C (all other patients). Patients in group C underwent MRI of the pituitary and were subdivided into C1 (normal pituitary on MRI; n=6), C2 (slightly abnormal MRI; n=21), and C3 (evident microadenoma or macroadenoma on MRI; n=25 and 12, respectively). The MRI was technically insufficient in four patients. Basal PRL as determined by fluoroimmunometric assay and the PRL response to 400 microg TRH were determined in all patients. RESULTS: Hyperprolactinaemia was confirmed in 83% of the referred patients. Non-response, defined as a <2.5-fold PRL increase after TRH, occurred in one patient (50%) in group A, in 66% of patients in group B and in 99% of patients in group C. Within group C, basal PRL was not different between group C1 and C2, but higher (p=0.06) in group C3. The absolute PRL increase after TRH did not differ between the three subgroups. The relative PRL increase was smaller (p=0.03) in group C3 but overlapped considerably with groups C1 and C2. All patients except one in group C were so-called non-responders. Basal PRL and absolute PRL increases after TRH correlated with the adenoma diameter on MRI (r=0.66, p=0.0002 and r=0.49, p=0.008, respectively). CONCLUSION: In patients referred for elevated serum PRL, hyperprolactinaemia should be confirmed under standardised conditions. The absolute or relative PRL increase after 400 microg TRH does not help to differentiate between patients with prolactinoma or idiopathic hyperprolactinaemia. Therefore, the TRH stimulation test is not useful in the work-up of hyperprolactinaemia.
Adult↗
[Adipose tissue: an innervated endocrine gland].
Until recently, adipose tissue was considered to function as a passive store of triglycerides and therefore of calories. Fascinating research over the past ten years has altered this traditional perspective. Adipose tissue has been shown to produce hormones. Leptin was discovered in 1994; one of its main functions is to adapt the organism to starvation. Sympathetic nerve fibres were shown to innervate adipose tissue and to facilitate lipolysis leading to the release of glycerol and free fatty acids. In addition, parasympathetic innervation of adipose tissue was recently demonstrated, with anabolic effects. Different sets of autonomic neurons in the brain stem appear to innervate either the abdominal or the subcutaneous fat compartment. This may be the anatomical substrate for the hitherto unexplained regulation of body fat distribution (subcutaneous versus intra-abdominal). Moreover, fat distribution under physiological conditions (sex steroids, glucocorticoids) and pathological conditions (e.g., AIDS lipodystrophy, Cushing syndrome) might be mediated via the central nervous system. The developments in this research area have the potential to increase our insights into the pathogenesis of metabolic disorders such as hypertriglyceridaemia and type-2 diabetes mellitus.
Adipose Tissue↗
[Clinical thinking and decision making in practice. Unexplained rectal blood loss in a patient with multiple endocrine neoplasia type 1 syndrome].
A 55-year-old woman, known with multiple endocrine neoplasia (MEN) type 1, had rectal bleeding and later haematemesis but colonoscopy and gastroduodenoscopy revealed no abnormalities. Due to the normal results for serum gastrin concentration, gastroduodenoscopy and CT scanning of the pancreas, Zollinger-Ellison syndrome was considered to be less likely. Yet the diagnosis could be established on the basis of persistent symptoms and a positive somatostatin receptor scintigraphy. The patient was treated with high doses of a proton pump inhibitor and temporary tube feeding due to weight loss. Follow-up will take place at the endocrinology outpatients' department. Zollinger-Ellison syndrome is a relatively common feature of patients with MEN-1. The diagnosis and localisation of the gastrinoma can be difficult: serum gastrin concentrations can be normal and the sensitivity of CT scanning is low. The primary aim of treating gastrinoma is to control gastric acid hypersecretion by means of high doses of a proton pump inhibitor. The question as to whether surgery is indicated remains controversial.
Decision Making↗
Decreased neuropeptide Y (NPY) expression in the infundibular nucleus of patients with nonthyroidal illness.
In patients with a variety of illnesses, serum concentrations of T3 decrease without giving rise to elevated serum levels of TSH, a phenomenon known as the sick euthyroid syndrome or nonthyroidal illness (NTI). Our previous studies in postmortem brain material showed decreased thyrotropin-releasing hormone (TRH) messenger RNA (mRNA) in the paraventricular nucleus (PVN) of patients with NTI, suggesting a role for TRH cells in the persistence of low TSH levels in NTI. In the present study, we hypothesized that changes in neuropeptide Y (NPY) input from the infundibular nucleus (IFN) to TRH cells in the PVN might be a determinant of decreased TRH expression in NTI. We investigated the hypothalamus of nine patients whose endocrine status had been assessed in a serum sample taken less than 24h before death and we examined NPY expression in the IFN by means of immunocytochemistry and mRNA in situ hybridization using an image analysis system. There was a negative correlation (r = -0.88; p = 0.01) between serum leptin concentrations and total NPY mRNA in the IFN. The total amount of NPY immunoreactivity in the IFN correlated with total NPY mRNA (r = 0.69; p = 0.04). In contrast to the situation in food-deprived rodents, total NPY immunoreactivity in the IFN showed a positive correlation with total TRH mRNA in the PVN (r = 0.77; p = 0.02). The results suggest a role for decreased NPY input from the IFN in the resetting of thyroid hormone feedback on hypothalamic TRH cells in NTI.
Adult↗
The hypothalamic-pituitary-thyroid axis in critical illness.
In severe illness, profound changes occur in the hypothalamic-pituitary-thyroid axis. The observed decrease in serum concentration of both thyroid hormones and thyrotropin (TSH) are not compatible with a negative feedback loop and suggest a major change in setpoint regulation of the hypothalamic-pituitary-thyroid axis. This is supported by post mortem studies showing a decreased expression of thyrotropin-releasing hormone in the hypothalamic paraventricular nucleus of patients with a decreased serum T3 level. In critical illness, serum T3 may even become undetectable without giving rise to an elevated concentration of serum TSH. It is currently not clearly established whether this reflects an adaptation of the organism to illness or instead a potentially harmful condition leading to hypothyroidism at tissue level. There is thus a need for randomized clinical trials in critically ill patients to investigate whether they may benefit from a normalization of thyroid hormone concentration. Recent clinical studies in these patients involving the administration of hypothalamic peptides open up new ways of achieving this.
Critical Illness↗
The suprachiasmatic nucleus generates the diurnal changes in plasma leptin levels.
At present it is not clear which factors are responsible for the diurnal pattern of plasma leptin levels, although the timing of food intake and circulating hormones such as glucocorticoids and insulin have both been proposed as independent determinants. In this study we show that ablation of the biological clock by thermal lesions of the hypothalamic suprachiasmatic nucleus (SCN) completely eliminates the diurnal pattern of plasma leptin levels. By contrast, removal of the diurnal corticosterone signal by adrenalectomy and corticosterone replacement did not affect diurnal plasma leptin levels. More importantly, removal of the nocturnal feeding signal by submitting the animals to a regular feeding schedule of six meals per day did not abolish the diurnal plasma leptin levels. However, both SCN lesions and the regular feeding schedule did cause an increase in the 24-h mean plasma leptin levels. As neither rhythmic feeding, insulin, or corticosterone signals can completely explain the diurnal plasma leptin rhythm, we conclude that biological clock control of the sympathetic input to the adipocyte is essential for regulation of the daily rhythm in leptin release.
Adipocytes↗