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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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Gabriela Aust, Irina Lehmann, Sandy Laue and Werner A Scherbaum

Aust G, Lehmann I, Laue S, Scherbaum WA. Activated and interferon-γ producing thyroid-derived T cells are detected in Graves' disease, thyroid autonomy as well as in non-toxic multinodular goiter. Eur J Endocrinol 1996;135:60–8. ISSN 0804–4643

The relative numbers of activated and interferon gamma (IFN-γ)-producing peripheral blood lymphocytes (PBL) and thyroid-derived lymphocytes (TL) were determined using double surface and intracellular labeling techniques in flow cytometry. Cells were analyzed from 10 patients with Graves' disease (GD), eight patients with thyroid autonomy (TA) and five patients with non-toxic multinodular goiter (NTG). A maximum of 1% IFN-γ+ cells were detected both in unstimulated PBL and TL. Stimulation caused a two- to threefold higher number of IFN-γ+ cells in TL (GD, 48 ± 12%; TA, 48 ± 11%; NTG, 50± 15%) as compared to PBL (GD, 15 ± 7%: TA, 16 ± 8%; NTG, 18 ± 10%) of the same patients. Nearly all IFN-γ+ TL in GD were CD3+ T cells, whereas 10–20% of IFN-γ+ TL in TA and NTG were NK cells. In PBL 80% and in TL almost 100% of IFN-γ+ cells were antigenprimed CD45RO+ cells. Only 25–35% of IFN-γ+ thyroid-derived T cells expressed the CD4 antigen. About 42 ± 10% thyroid-derived T cells in GD, 33 ± 11% in TA and 34 ± 13% in NTG expressed the HLA-DR molecule but not the interleukin 2 (CD25) or the transferrin receptor (CD71). Forty per cent of these HLA-DR+ T cells showed an intracellular staining for IFN-γ and half of them co-expressed the activation antigen CD69. Immunofluorescence double labeling on thyroid cryostat sections demonstrated that HLA-DR+ T cells were also present in situ. The presence of activation antigens on thyroid-derived T cells not only in patients with GD but also in TA and NTG suggests failsafe mechanisms such as anergy, suppression or cytokine regulation in so-called non-immunogenic goiter.

Gabriela Aust, Department of Internal Medicine III, Endocrinology, University of Leipzig, Ph.-Rosenthal-Str. 27, Leipzig, D-04103, Germany

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Sven Schinner, Holger S Willenberg, Matthias Schott and Werner A Scherbaum

Wnt-signaling has recently been identified as a regulator of a number of endocrine functions in health and disease in addition to its original attribution to developmental biology. Wnts are extracellular ligands on frizzled receptors and on lipoprotein receptor-related protein co-receptors. Ligand binding leads eventually to the activation of intracellular signaling cascades; based on the involvement of the transcriptional co-activator β-catenin it can be distinguished between canonical (i.e. β-catenin) and non-canonical Wnt-signaling. Recent studies revealed that canonical Wnt-signaling regulates the function of endocrine organs and contributes to a number of endocrine disorders. In this review, we would like to focus on a) recent mechanistic data on Wnts in pancreatic β-cell function; b) human genetic studies on Wnt signaling in type 2 diabetes mellitus; c) crosstalk between adipocytes and endocrine cells through Wnt-signaling molecules (with a focus on the role of Wnt-signaling in adrenocortical cells).

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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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Winfried G Rossmanith, Annette Handke-Vesely, Ulrike Wirth and Werner A Scherbaum

Rossmanith WG, Handke-Vesely A, Wirth U, Scherbaum WA. Does the gonadotropin pulsatility of postmenopausal women represent the unrestrained hypothalamic–pituitary activity? Eur J Endocrinol 1994;130:485–93. ISSN 0804-4643

Ovarian sex steroids profoundly modulate the gonadotropin pulsatile secretion in women. A gonadotropin pulsatility determined in the absence of any considerable ovarian sex steroid feedback, as in postmenopausal women (PMW), may thus represent the unrestrained activity of the hypothalamic-pituitary axis. We hypothesized that increases in the gonadotropin pulse frequencies and amplitudes during sex steroid replacements may be limited by those determined in the hypogonadal state of PMW. To address this assumption, we investigated the unstimulated the gonadotropin-releasing hormone (GnRH)-stimulated release of luteinizing hormone (LH) and folliclestimulating hormone (FSH) in PMW before and during sequential ovarian sex steroid treatments. Seven PMW (mean age 59.4 years) were studied initially during unreplaced conditions (control studies), then on the last day of a 21-day course of oral estradiol valeriate (F2) administrations (2 mg daily) and, finally, on the last day of a 21-day course of oral estradiol–progesterone (E2/P4) replacements (2 mg of E2 and 200 mg of micronized P4 daily). On all study occasions, blood was drawn at 10-min intervals for 10 h and GnRH (25 μg iv) was administered 8 h after initiation of blood collections. Compared to control conditions, the basal serum estrogen (estrone and E2) and progesterone (P4) concentrations markedly increased (p< 0.001) following oral E2 or E2/P4 treatments. As determined by Cluster pulse algorithm, LH and FSH were found to be released episodically during each study condition. Mean LH and FSH release rates declined (P< 0.05 or less) during E2 and E2/P4 regimens. Compared to control studies, the LH and FSH pulse frequencies and interpulse intervals remained virtually unchanged during E2 replacements. Yet, a slowing (p <0.05) of the LH but not of the FSH interpulse interval was evident during E2/P4 replacements. While the LH pulse amplitudes tended to increase during E2 and E2/P4 treatments, a decrease (p <0.05) was noted for the FSH pulse amplitudes during either replacement regimen. Although the absolute GnRH-stimulated LH and FSH increments were highest (p <0.05 or less) in the hypogonadal state, the percentage GnRH-mediated gonadotropin increments did not differ between the study conditions. Results of the current study demonstrate that ovarian sex steroid replaceent to PMW can influence markedly both the unstimulated and GnRH-stimulated gonadotropin secretion. Yet, the changes in the LH and FSH pulse frequencies and amplitudes during sex steroid replacements are confined to those determined in the hypogonadal state of PMW. Thus, we infer that the gonadotropin pulsatility of PMW may reflect the unrestrained activity of the hypothalamic–pituitary axis.

Winfried G Rossmanith, Department of Obstetrics-Gynecology, University of Ulm, Prittwitzstrasse 43, D-89075 Ulm, Germany