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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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Antonio Balsamo, Alessandro Cicognani, Monia Gennari, Wolfgang G Sippell, Soara Menabò, Federico Baronio, and Felix G Riepe

Objective: The renal form of pseudohypoaldosteronism type 1 (PHA1) is a rare disease caused by mutations in the human mineralocorticoid receptor gene (NR3C2).

Design: Aim of the study was to analyze the NR3C2 gene in three Italian patients with clinical signs of renal PHA1 and to evaluate the distribution of the -2G > C, c.538A > G, and c.722C > T single nucleotide polymorphism (SNP) pattern in the PHA1 patients and in 90 controls of the same ethnic origin.

Methods: Analysis of the NR3C2 gene sequence and of the polymorphic SNP markers. Functional characterization of the detected novel NR3C2 mutations utilizing aldosterone-binding assays and reporter gene transactivation assays.

Results: One novel nonsense (Y134X) and one novel frameshift (2125delA) mutation were detected. They exhibited no aldosterone binding and no transactivation abilities. No mutation was detected in the third patient. Haploinsufficiency of NR3C2 was ruled out by microsatellite analysis in this patient. The c.722T SNP was detected in 97% of alleles in the Italian population which is significantly different from the general German or US population.

Conclusions: Molecular analysis of the NR3C2 gene in PHA1 patients is warranted to detect novel mutations in order to clarify the underlying genetic cause, which may extend the insight into relevant functional regions of the hMR protein. The effect the different distribution of the c.722T SNP is not clear to date. Further studies are necessary to provide evidence as to a possible advantage of a less sensitive hMR in southern countries.

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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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Felix G Riepe, Wiebke Ahrens, Nils Krone, Regina Fölster-Holst, Jochen Brasch, Wolfgang G Sippell, Olaf Hiort, and Carl-Joachim Partsch

Objective: To clarify the molecular defect for the clinical finding of congenital hypothyroidism combined with the manifestation of calcinosis cutis in infancy.

Case report: The male patient presented with moderately elevated blood thyrotropin levels at neonatal screening combined with slightly decreased plasma thyroxine and tri-iodothyronine concentrations, necessitating thyroid hormone substitution 2 weeks after birth. At the age of 7 months calcinosis cutis was seen and the patient underwent further investigation. Typical features of Albright’s hereditary osteodystrophy (AHO), including round face, obesity and delayed psychomotor development, were found.

Methods and results: Laboratory investigation revealed a resistance to parathyroid hormone (PTH) with highly elevated PTH levels and a reduction in adenylyl cyclase-stimulating protein (Gsα) activity leading to the diagnosis of pseudohypoparathyroidism type Ia (PHP Ia). A novel heterozygous mutation (c364T > G in exon 5, leading to the amino acid substitution Ile-106 → Ser) was detected in the GNAS gene of the patient. This mutation was not found in the patient’s parents, both of whom showed normal Gsα protein activity in erythrocytes and no features of AHO. A de novo mutation is therefore likely.

Conclusions: Subcutaneous calcifications in infancy should prompt the clinician to a thorough search for an underlying disease. The possibility of AHO and PHP Ia should be considered in children with hypothyroidism and calcinosis cutis. Systematic reviews regarding the frequency of calcinosis in AHO are warranted.