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Monika Ehrhart-Bornstein, Stefan R Bornstein and Werner A Scherbaum

Common textbooks of endocrinology envisage the adrenal cortex and the adrenal medulla as two functionally separate systems that are regulated independently from one another. Even worse, the mononuclear cells that are present within the normal human adrenal gland have been largely neglected or regarded as innocent bystanders. In this review we would like to draw attention to the close morphological and functional interplay between these systems and to propagate the notion that there is a meaningful cross-talk between the sympathico chromaffin system, the hypothalamus-pituitary-adrenocortical axis and the immune system at the level of the peripheral gland.

Morphological evidence for an interaction between the adrenal medulla and the adrenal cortex

The location of chromaffin cells within the adrenal cortex has been described in different species (1, 2), including humans (3). We were able to provide evidence, via specific immunostaining of chromaffin cells with antibodies to synaptophysin or chromogranin A, that in

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Winfried G Rossmanith, Claudia Stäbler, Reiner Benz, Stefan R Bornstein and Werner A Scherbaum

The exact role of ovarian sex steroids in the neuroendocrine regulation of thyrotropin (TSH) release in women can only be accurately assessed in the absence of any considerable ovarian sex steroid feedback upon the hypothalamic-pituitary unit. Consequently, the unstimulated episodic and thyrotropin-releasing hormone (TRH) stimulated TSH secretion was evaluated in postmenopausal women before and during sequential ovarian sex steroid replacements. Seven euthyroid women (mean age: 59.4 years) were studied initially without any sex steroid replacement (control studies), then on the last day of a 21-day course of oral estradiol-valeriate (E2) administration (2 mg daily) and finally, on the last day of a 21-day course of oral estradiol-progesterone (E2/P4) replacement (2 mg E2 and 200mg micronized P4 daily). During all study occasions, blood was sampled at 10 min intervals for 10 h, while TRH (200 μg iv) was administered 8 h after initiation of blood collections. Compared to the control conditions, serum E2 and P4 concentrations markedly increased (p< 0.001) following oral E2 or E2/P4 treatments. Total triiodothyronine (T3) and thyroxine (T4) concentrations and free T3 and T4 equivalents remained unchanged during E2 and E2/P4 regimens. In the unstimulated secretory profiles, TSH was found to be episodically released, with little interindividual variability for each study condition. Since the TSH pulse attributes (pulse amplitudes, frequencies, interpulse intervals, mean TSH concentrations, by Cluster pulse algorithm) did not significantly change during E2 and E2/P4 replacements, the episodic character of TSH secretion virtually remained unchanged by sex steroid replacements. In addition, the TRH-stimulated TSH releases during E2 and E2/P4 replacement therapies closely resembled those during control conditions. These observations demonstrate that both the unstimulated episodic and TRH-stimulated TSH secretion are unaffected by ovarian sex steroid replacement in hypogonadal women. Collectively, our findings suggest that ovarian sex steroids may not be critically involved in the neuroendocrine regulation of TSH secretion in women.

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Christina Pamporaki, Michael Bursztyn, Manja Reimann, Tjalf Ziemssen, Stefan R Bornstein, Fred C G J Sweep, Henri Timmers, Jacques W M Lenders and Graeme Eisenhofer

Background

Higher plasma concentrations of catecholamines in winter than in summer are established; whether this impacts plasma concentrations of metanephrines used for the diagnosis of pheochromocytoma is unknown.

Objective

In this study, we examined seasonal variations in plasma concentrations of metanephrines, the impact of this on diagnostic test performance and the influences of forearm warming (‘arterialization’ of venous blood) on blood flow and measured concentrations.

Methods

Measurements of plasma concentrations of metanephrines were recorded from 4052 patients tested for pheochromocytoma at two clinical centers. Among these patients, 107 had tumors. An additional 26 volunteers were enrolled for measurements of plasma metanephrines and forearm blood flow before and after forearm warming.

Results

There was no seasonal variation in the plasma concentrations of metanephrines among patients with pheochromocytoma, whereas among those without tumors, plasma concentrations of normetanephrine were higher (P<0.0001) in winter than in summer. Lowest concentrations of normetanephrine were measured in July, with those recorded from December to April being more than 21% higher (P<0.0001). These differences resulted in a twofold higher (P=0.0012) prevalence of false-positive elevations of normetanephrine concentrations in winter than in summer, associated with a drop in overall diagnostic specificity from 96% in summer to 92% in winter (P=0.0010). Forearm warming increased blood flow and lowered (P=0.0020) plasma normetanephrine concentrations.

Conclusions

Plasma concentrations of normetanephrine are subject to seasonal variation with a resulting higher prevalence of false-positive results in winter than in summer. Lowered plasma concentrations of normetanephrine with forearm warming suggest an effect of temperature. These results have implications for considerations of temperature to minimize false-positive results.

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Mariko Sue, Victoria Martucci, Florina Frey, Jacques W M Lenders, Henri J Timmers, Mariola Pęczkowska, Aleksander Prejbisz, Brede Swantje, Stefan R Bornstein, Wiebke Arlt, Martin Fassnacht, Felix Beuschlein, Mercedes Robledo, Karel Pacak and Graeme Eisenhofer

Objective

Testing for succinate dehydrogenase subunit B (SDHB) mutations is recommended in all patients with metastatic phaeochromocytomas and paragangliomas (PPGLs), but may not be required when metastatic disease is accompanied by adrenaline production. This retrospective cohort study aimed to establish the prevalence of SDHB mutations among patients with metastatic PPGLs, characterised by production of adrenaline compared with those without production of adrenaline, and to establish genotype–phenotype features of metastatic PPGLs according to underlying gene mutations.

Design and methods

Presence of SDHB mutations or deletions was tested in 205 patients (114 males) aged 42±16 years (range 9–86 years) at diagnosis of metastatic PPGLs with and without adrenaline production.

Results

Twenty-three of the 205 patients (11%) with metastatic PPGLs had disease characterised by production of adrenaline, as defined by increased plasma concentrations of metanephrine larger than 5% of the combined increase in both normetanephrine and metanephrine. None of these 23 patients had SDHB mutations. Of the other 182 patients with no tumoural adrenaline production, 51% had SDHB mutations. Metastases in bone were 36–41% more prevalent among patients with SDHB mutations or extra-adrenal primary tumours than those without mutations or with adrenal primary tumours. Liver metastases were 81% more prevalent among patients with adrenal than extra-adrenal primary tumours.

Conclusion

SDHB mutation testing has no utility among patients with adrenaline-producing metastatic PPGLs, but is indicated in other patients with metastatic disease. Our study also reveals novel associations of metastatic spread with primary tumour location and presence of SDHB mutations.