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Michael Roden, Peter Nowotny, Heinrich Vierhapper, and Werner Waldhäusl

Abstract.

To evaluate the sensitivity of basal TSH concentrations as determined by an "ultrasensitive" IRMA-assay (RIA-gnost h-TSH-monoclonal, Behring) versus a "negative" TRH test (defined as an increment of TSH ≥0.2 mU/l 20 min after administration of 400 μg TRH iv) in the diagnosis of hyperthyroidism we examined 193 consecutive patients from our thyroid outpatient clinic: 34 patients displayed hyperthyroidism (total T4: 184.4±26.0 μmol/l, effective thyroxine index: 1.25±0.08), whereas 12 had isolated T3-hyperthyroidism (total T3: 3.47±0.48 nmol/l). Employing the producer's definition of subnormal ("suppressed") bTSH concentrations (≤0.1 mU/l), only 19 (41.3%) hyperthyroid patients would have been detected; on the other hand, one euthyroid patient would have been recognized false positively as hyperthyroid. Using the TRH test as criterion led to the correct diagnosis in 42 (sensitivity: 91.3%) hyperthyroid patients, whereas two had low bTSH concentrations (≤0.5 mU/l), but a normal TSH response to TRH (>2.0 mU/l). Raising the threshold concentration to 0.2 and, subsequently, to 0.4 mU TSH/l increased the number of correct results to 38 (sensitivity: 82.6%) and 43 (93.5%), respectively. This was associated with a concomitant decrease in specificity in the diagnosis of hyperthyroidism from 93.7 (0.1 mU/l) to 27.9% (0.4 mU/l). In conclusion, despite ultrasensitive methods for estimation of low TSH concentrations, the TRH test remains an irreplaceable tool for the correct diagnosis of hyperthyroidism.

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Martin Reincke, Michael Peter, Wolfgang G Sippell, and Bruno Allolio

Abstract

Recent reports have shown an exaggerated response of 17-hydroxyprogesterone in up to 70% of patients with incidentally detected adrenal adenomas ('incidentalomas'). This has been explained by pre-existing 21-hydroxylase deficiency which may be a pathogenetic factor in the development of adrenal tumours. However, other defects in steroidogenesis, such as mild 11β-hydroxylase deficiency, could also result in increased 17-hydroxyprogesterone secretion. We therefore studied the glucocorticoid and mineralocorticoid pathways in patients with adrenal 'incidentalomas' by measuring multiple adrenal steroids before and after 1–24 ACTH stimulation. Twenty patients with adrenal 'incidentalomas' (14 females, 6 males) and 27 healthy controls (14 females, 13 males) were studied. All subjects underwent a 1–24 ACTH stimulation test (250 μg i.v.) with determination of progesterone, 11-deoxycorticosterone, corticosterone, 17-hydroxyprogesterone, 11-deoxycortisol and cortisol at O and 60 min. All steroids were measured by RIA after extraction and HPLC. Patients with 'incidentalomas' had higher stimulated concentrations of 17-hydroxyprogesterone (21·6 ± 8·4 vs 4·2 ± 0·3 nmol/l; P ≤ 0·001), 11-deoxycortisol (8·1 ± 1·2 vs 3·6 ± 0·3 nmol/l; P ≤ 0·001), progesterone (8·28 ± 2·82 vs 1·08 ± 0·15 nmol/l; P ≤ 0·001), and 11-deoxycorticosterone (2·1 ± 0·39 vs 0·78 ± 0·12 nmol/l; P = 0·002) compared with controls. In contrast, cortisol and corticosterone concentrations were not different. There was evidence for impairment of 11β-hydroxylase activity by an increased 11-deoxycortisol/cortisol ratio (0·012 ± 0·003 vs 0·005 ± 0·001 in controls; P = 0·002) and 11-deoxycorticosterone/corticosterone ratio (0·04 ± 0·003 vs 0·015 ± 0·003; P = 0·003). The conclusions reached were that patients with adrenal 'incidentalomas' have increased responses of precursors of the mineralocorticoid and glucocorticoid pathway including 17-hydroxyprogesterone after stimulation with ACTH. This seems to be caused by impairment of 11β-hydroxylase activity rather than by impaired 21-hydroxylase activity in these tumours.

European Journal of Endocrinology 136 196–200

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Emanuel R Christ, Michael H Cummings, Michael Stolinski, Nicola Jackson, Peter J Lumb, Anthony S Wierzbicki, Peter H Sönksen, David L Russell-Jones, and A Margot Umpleby

Background: Epidemiological studies suggest that hypopituitary patients have an increased risk for cardiovascular mortality. The dyslipidaemia associated with this condition is often characterised by an increase in total cholesterol (TC) and low-density lipoprotein (LDL) cholesterol (LDL-C) and may contribute to these findings. The underlying mechanisms are not fully elucidated.

Materials and Methods: LDL apolipoprotein B (apoB) production rate and metabolic clearance rate were measured in seven patients with hypopituitarism (including GH deficiency) under stable conventional replacement therapy (three males and four females; age 40–16.1 years; body mass index 29.0–6.1 kg/m2 (means ± s.d.)) and seven age-, gender- and body mass index-matched control subjects with an infusion of 1-13C-leucine. Fasting lipid profile and lipid composition of LDL were also measured.

Results: Fasting TC, triglycerides (TG), high-density lipoprotein-C, LDL-C and free fatty acid concentrations were not different between hypopituitary patients and control subjects. LDL-TG (P < 0.006) and LDL-TG/LDL apoB ratio (P < 0.02) were significantly increased in hypopituitary patients. LDL apoB pool size was not statistically different between patients and control subjects. In the hypopituitary patients, LDL apoB metabolic clearance rate (P < 0.05) and LDL apoB production rate (P < 0.02) were lower than in the control subjects.

Conclusions: The present results suggest that LDL apoB turnover and LDL composition is altered in hypopituitary patients. Whether these findings explain the increased risk for cardiovascular disease in hypopituitary patients remains to be established.

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Peter W. Stacpoole, A. G. Kasselberg, Michael Berelowitz, and William Y. Chey

Abstract.

We report here 2 patients with somatostatinsecreting tumours and hypersomatostatinaemia. One subject, a 36 year old woman with diabetes, flushing, labile blood pressure and diarrhoea, had elevated basal plasma levels of somatostatin-like immunoreactivity (SLIR) and calcitonin. Plasma SLIR increased further following tolbutamide administration. Plasma levels of prostaglandin E2 (PGE2) and pancreatic polypeptide (PP), normal in the basal state, showed exaggerated responses to pentagastrin and secretin, respectively. Immunocytochemistry of the tumour tissue revealed cells containing somatostatin-, calcitonin-, PGE2- and PP-like immunoreactivity. The other patient, a 52 year old male, had an SLIR-secreting tumour of the proximal duodenum and elevated basal and post-tolbutamide SLIR levels but no signs or symptoms suggestive of increased SLIR production. Tumour tissue revealed cells containing somatostatin- and calcitonin-like immunoreactivity.

We conclude that patients with somatostatinomas do not always exhibit a predictable syndrome. Patients with these tumours may exhibit a range of clinical, biochemical and immunocytochemical features typical of endocrine tumours of mixed-cell origin, such that the dominant signs and symptoms associated with these neoplasms cannot readily be ascribed to overproduction of any single hormone.

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Peter E. Goretzki, Michael West, Rainer Koob, Christine Koller, K. Joseph, and Hans-Dietrich Röher

Abstract. Primary cell cultures of normal and adenomatous human thyroid tissues were incubated with TSH or ammonium sulphate precipited IGG fractions (1 mg/ml) of sera from patients with different thyroid diseases (Graves' disease: active n = 7 in remission n = 12; thyroid autonomy n = 39; simple euthyroid goitre n = 15) and were compared to controls (n = 26). [3H]thymidine incorporation in primary thyrocyte cultures demonstrated a typical bell shape curve after incubation with EGF and TSH with a maximal effect at 10–100 μIU/ml. This effect, however, was inconsistent and positive only in 2 of 7 primary cultures. Only TSH positive cultures were used for IgG studies. 16–28% of IGG fractions from sera of thyroid patients caused high (more than X + 5 sd of controls) stimulation of [3H]thymidine incorporation. Dose response curves of IgG fractions of 19 additional patients (Graves' disease in remission n = 15; thyroid autonomy n = 4) showed an increase in [3H]thymidine incorporation at 0.1 mg protein/ml for 10 patients and at low concentrations of 10–5 mg/ml for 5 patients. There was a good correlation (r = 0.72) (P < 0.0001) between positive findings in TSH-binding inhibition (TBII) and AC-stimulation (TSI) IGG fractions but none between stimulation of [3H]thymidine incorporation and any other thyroid specific immunoglobulin nor thyroid function nor any other available data. Immunoglobulins stimulating [3H]thymidine incorporation differ therefore from TBII and TSI. The growth effect of these immunoglobulins, however, has yet to be determined.

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Clemens Fürnsinn, Peter Nowotny, Michael Roden, Madeleine Rohac, Thomas Pieber, Sabina Parzer, and Werner Waldhäusl

To compare the effect of short- vs long-term amylin infusion on insulin sensitivity, glucose tolerance and serum calcemia, euglycemic-hyperinsulinemic clamp (26 pmol·kg−1·min−1) and glucose tolerance tests (2.4 mmol/kg over 30 min) were performed in lean Zucker rats. Three infusion protocols were employed: control group: 24 h of iv saline; short-term amylin exposure: 22 h of iv saline followed by 2 h of iv amylin (20 μg/h); long-term amylin exposure: 24 h of iv amylin (20 μg/h). Insulin resistance was induced by short-term amylin infusion during euglycemic clamping, as shown by a 41% decrease in space-corrected glucose infusion rates (μmol·kg−1·min−1; control group, 106.0±15.0; short-term iv amylin, 62.7±15.0; p<0.00 5). After long-term amylin exposure, insulin sensitivity was identical to control values (109.9±6.7). This fading action of amylin was confirmed by data from the glucose tolerance test, demonstrating glucose intolerance after short- but not after long-term amylin exposure. Serum calcium concentration decreased during short-term (2 h) amylin infusion (from 2.52±0.15 to 2.09±0.12 mmol/l; p<0.01) and hypocalcemia of a similar extent also was present after 22 h and 24 h of amylin exposure (2.10±0.09 and 2.04±0.14 mmol/l, respectively). The data demonstrate that short-term amylin infusion induces insulin resistance and glucose intolerance, both of which vanish during long-term (>22 h) amylin exposure, being apparently independent of induced hypocalcemia.

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Michael Reinhardt, Dieter Emrich, Thomas Krause, Peter Bräutigam, Egbert Nitzsche, Hildegard Blattmann, Carl Schümichen, and Ernst Moser

Reinhardt M, Emrich D, Krause T, Bräutigam P, Nitzsche E, Blattmann H, Schümichen C, Moser E. Improved dose concept for radioiodine therapy of multifocal and disseminated functional thyroid autonomy. Eur J Endocrinol 1995;132:550–6. ISSN 0804–4643

The present study analyzes the improvement of the outcome of radioiodine therapy in non-immunogenic hyperthyroidism by adapting the target dose to the 99mTc-pertechnetate thyroid uptake under suppression (TcTUs) prior to radioiodine therapy. The TcTUs is a substitute for the non-suppressible iodine turnover. The 89 patients presented with a basal thyrotropin level of <0.1 mU/l, normal values for free triiodothyronine and thyroxine and with multifocal or disseminated thyroid autonomy. These terms describe the scintigraphic distribution pattern of autonomous iodine turnover. Thirty-two patients had a TcTUs between 1.6 and 3.2% (group A) and 57 had a TcTUs > 3.2% (group B). Fifty-five patients (three of group A and 52 of group B) were treated previously for overt hyperthyroidism with antithyroid drugs. Target doses of 150 and 200 Gy were used in both groups and 300 Gy in group B only. Six months after radioiodine therapy, a basal TSH level of ≥ mU/l as criterion of therapy success was observed in 94% of group A and in 54% of group B. Further differentiation of group B shows an increasing success rate with the target dose used: 45% after 150 Gy, 50% after 200 Gy and 90% after 300 Gy. In patients with a basal TSH level of <0.5 mU/l after radioiodine therapy, the TcTUs was evaluated again. Persistence of functional thyroid autonomy, defined as TcTUs > 1.6%, was found in 89% (one patient of group A, 24 patients of group B) and still observed a high extent of autonomous function in 25% of them, evidenced by a TcTUs > 3.2% (seven patients of group B, target doses of 150 or 200 Gy). No case of overt hypothyroidism was observed within the first 6 months after radioiodine therapy and no difference was found in therapy outcome between multifocal and disseminated thyroid autonomy. As a consequence, the target dose should be adapted to the TcTUs prior to radioiodine therapy in the range of 150–300 Gy to the total thyroid gland.

Michael Reinhardt, Abteilung Nuklearmedizin, Radiologische Universitätsklinik, Hugstetter Straße 55. 79106 Freiburg im Breisgau, Germany

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Carl-Joachim Partsch, Sievert Abrahams, Niels Herholz, Michael Peter, Johannes D Veldhuis, and Wolfgang G Sippell

Partsch C-J, Abrahams S, Herholz N, Peter M, Veldhuis JD, Sippell WG. Variability of pulsatile luteinizing hormone secretion in young male volunteers. Eur J Endocrinol 1994;131:263–72. ISSN 0804–4643

Characteristics of spontaneous pulsatile luteinizing hormone secretion were compared in ten young healthy men in three 24-h profiles obtained at intervals of 14 days and 3 months. The ages of the volunteers ranged from 19 to 25 years, and heights and weights were within normal limits. Blood samples were taken at 10-min intervals and plasma luteinizing hormone (LH) was determined in the same immunoradiometric assay using monoclonal antibodies. Conventional pulse detection was carried out with PULSAR and CLUSTER programs. In addition, a simultaneous multiple parameter DECONVOLUTION was applied. As a group, no significant differences between the three profile series were found for any of the calculated parameters of LH concentration or LH secretion. However, most parameters showed low correlation coefficients between the three study periods, suggesting that substantial individual variations might contribute to the more reliable group results. Median coefficients of variation (cv) for the individual subject ranged from 9.7% (interpulse interval and endogenous half-life) to 37.7% (mass per burst). However, the maximal individual cv observed was 78.4%. Intra-individual variability was lower than the variability between subjects for quantitative properties of LH concentration and secretion, although not significantly so for all parameters. In conventional pulse detection, the highest individual reliability was found for mean and integrated LH concentrations (median cv 10.2 and 13.7%, respectively), number of pulses per 24 h (CLUSTER, median cv 12.2%), mean pulse amplitude (PULSAR, median cv 10%) and interpulse interval (CLUSTER, median cv 9.7%). In DECONVOLUTION analysis, the endogenous LH half-life (median cv 9.7%), secretory burst amplitude (median cv 14.8%) and interburst interval (median cv 14.5%) revealed the lowest intra-individual variation. In contrast, the half-duration of a secretory episode and the mass of LH secreted per burst proved to be the least reliable measures (median cv 32.7% and 37.7%, respectively). Calculated endogenous LH production rates correlated highly (p < 0.01) across all three sessions. The relative frequencies of the LH peak amplitudes/heights and peak widths (durations) showed almost identical distribution curves for all three sampling periods. In conclusion, a high reproducibility of group results for both integrative parameters and pulse characteristics of LH concentrations and secretion were found in normal men. However, intra-individual reliability was variable and at times considerable, depending on the parameter chosen. These observations suggest caution in the interpretation of single LH profiles from individual subjects or patients unless the variation reported herein is considered.

C-J Partsch, Institut für Reproduktionsmedizin, Westfälische Wilhelms-Universität, Steinfurter Straβe 107, D-48149 Münster, Germany

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Harald J Schneider, Michael Buchfelder, Henri Wallaschofski, Anton Luger, Gudmundur Johannsson, Peter H Kann, and Anders Mattsson

Objective

There is no single clinical marker to reliably assess the clinical response to growth hormone replacement therapy (GHRT) in adults with growth hormone deficiency (GHD). The objective of this study was to propose a clinical response score to GHRT in adult GHD and to establish clinical factors that predict clinical response.

Design

This was a prospective observational cohort study from the international KIMS database (Pfizer International Metabolic Database).

Methods

We included 3612 adult patients with GHD for proposing the response score and 844 patients for assessing predictors of response. We propose a clinical response score based on changes in total cholesterol, waist circumference and QoL-AGHDA quality of life measurements after 2 years of GHRT. A score point was added for each quintile of change in each variable, resulting in a sum score ranging from 3 to 15. For clinical response at 2 years, we analysed predictors at baseline and after 6 months using logistic regression analyses.

Results

In a baseline prediction model, IGF1, QoL-AGHDA, total cholesterol and waist circumference predicted response, with worse baseline parameters being associated with a favourable response (AUC 0.736). In a combined baseline and 6-month prediction model, baseline QoL-AGHDA, total cholesterol and waist circumference, and 6-month change in waist circumference were significant predictors of response (AUC 0.815).

Conclusions

A simple clinical response score might be helpful in evaluating the success of GHRT. The baseline prediction model may aid in the decision to initiate GHRT and the combined prediction model may be helpful in the decision to continue GHRT.

Free access

Felix Schreiner, Magdalini Tozakidou, Rita Maslak, Ute Holtkamp, Michael Peter, Bettina Gohlke, and Joachim Woelfle

Objective

17-Hydroxyprogesterone (17-OHP) screening for classical congenital adrenal hyperplasia (CAH) is part of many newborn screening programs worldwide. Cut-off values are relatively high, and screening sensitivity does not reach 100%. Recently, the glucocorticoid receptor (GR) N363S-variant has been linked to relatively low degree of virilization and comparatively lower 17-OHP serum concentrations in clinically diagnosed female CAH patients. We sought to determine whether functional GR gene variants, either increasing (N363S, BclI) or decreasing GR sensitivity (R23K), underlie the variable 17-OHP screening levels in healthy newborns.

Design

GR genotypes were compared with 17-OHP screening values in 1000 random samples from routine screening. 17-OHP was measured by conventional immunoassay (TRFIA) and a liquid chromatography–tandem mass spectrometry method (LC–MS/MS), which has been shown to increase screening specificity by steroid profiling and avoiding cross-reactions of the 17-OHP-antibody.

Results

There was no significant association of 17-OHP with GR genotypes, even after inclusion of gestational and postnatal age as covariates. However, among LC–MS/MS steroid measurements, we observed some unexpected trends, including lower 11-deoxycortisol concentrations in both 363S- and 23K-carriers. For carriers of the frequent BclI variant, linear regression analysis revealed a significant increase of 4-androstenedione levels with every mutant allele inherited.

Conclusions

Functional GR variants do not underlie the variation of 17-OHP values observed in healthy individuals. However, whether and to which extent genetically determined differences in individual GR sensitivity influence 17-OHP screening levels in conditions of a pathological hypothalamus-pituitary-adrenal gland-axis stimulation and thus may explain false-negative screening results in those affected by CAH remains to be investigated.