The Adrenal Gland in the Center

This issue of Hormone and Metabolic Research is dedicated to reviews and scientific articles on topics presented at the 10^th Adrenal Conference and Symposium of the Section on the Adrenal Gland, Hypertension, and Steroids of the German Society for Endocrinology, which was held in Dresden, Germany in January 2012. This meeting was supported by the DFG-funded Clinical Research Unit 252-Microenvironment of the Adrenal in Health and Disease and covered a broad spectrum of topics pertinent to function and dysfunction of the adrenal gland and its unique microenvironment, as well as therapeutic approaches for disorders related to the adrenal gland.

In the first paper of this issue, Willenberg and colleagues provide an opinion on the interesting hypothesis that the unique adrenal microenvironment and in particular the zonation of the adrenal cortex are shaped by a glucocorticoid gradient, which is built up by the centripetal blood flow of the adrenal gland [1]. This opinion strengthens the hypothesis that an intimate crosstalk between adrenocortical cells and endothelial cells exists in the highly vascularized gland [2].

Disorders of the adrenal gland include alterations in steroid hormone production. In congenital adrenal hyperplasia due to 21-hydroxylase deficiency the elevated 17α-hydroxyprogesterone is metabolized to dihydrotestosterone, resulting in virilization. The underlying biochemical alterations based on metabolomic studies are reviewed comprehensively in the manuscript by Kamrath et al. [3].

Addison’s disease is an adrenal disorder associated with adrenal insufficiency. Interestingly, the quality of life in patients with Addison’s disease is largely affected by the latency time between first symptoms and diagnosis as well as by the co-prevalence of further autoimmune diseases, such as coeliac disease, atrophic gastritis, and primary ovarian failure. Moreover, disease-associated reduction in quality of life is significantly lower in female patients and when disease manifests at older ages [4]. In an effort to improve quality of life in patients with adrenal insufficiency, Langenheim et al. assessed replacement therapy with overnight modified-release prednisone. Patients with adrenal insufficiency take glucocorticoid replacement therapy after waking up, which results in a significant delay, as compared to the physiological cortisol secretion and thereby fatigue. This problem may be overcome by overnight modified-release prednisone, which may have the advantage of restoring the circadian glucocorticoid action and thereby reducing fatigue in patients [5].

Adrenal insufficiency is also a feature of the rare autosomal recessive disease, triple A syndrome, caused by mutations in the AAAS gene encoding the nucleoporin ALADIN. The study by Koehler et al. compared several genes associated with oxidative stress and antioxidant defense in fibroblasts from triple A syndrome patients and control patients and identified 7 genes, which were differentially regulated in patients’ cells. These data suggest that an altered response to oxidative stress may be involved in the pathophysiology of the triple A syndrome [6].

Not only syndromes associated with adrenal insufficiency but also disorders with excessive steroid production by the adrenal gland are a focus of the present issue. Grossman and colleagues review comprehensively the treatment options for Cushing’s disease, which results from excessive production of ACTH by a pituitary adenoma. They discuss the advantages, limitations, and remission rates obtained with transsphenoidal surgery, radiotherapy, medical therapy, including steroidogenesis inhibitors, such as metyrapone and ketoconazole, or a glucocorticoid receptor blocker, as well as bilateral adrenalectomy [7]. Another key issue in Cushing’s syndrome is the methodic tools engaged for diagnosis, including the advantages and disadvantages of immunoassays and chromatographic and mass spectrometric techniques, which are reviewed by Deutschbein et al. [8].

Lichtenauer and colleagues attempted to characterize the adrenocortical cell line NCI-H295 as a model for hyperaldosteronism. They identified culture conditions, including the use of potassium, ACTH, angiotensin II, and importantly fibroblast growth factor as important stimuli of aldosterone release in these cells; however, the aldosterone levels reached were significantly lower than the aldosterone levels measured in cultures from primary cells from aldosterone producing adenomas, suggesting that a better alternative than NCI-H295 needs to be identified for hyperaldosteronism studies [9].

Adrenocortical carcinoma is an aggressive tumor with few therapeutic options available. Jurowich et al. reviewed the existing literature with regard to laparoscopic adrenalectomy as an alternative to open adrenalectomy, coming to the conclusion that the latter is still the standard treatment [10]. Given the difficulties in treating adrenocortical carcinoma it is important to identify new therapeutic targets. Survivin might represent such a new target based on the studies by Fassnacht et al. that identified survivin expression to be higher in adrenocortical carcinomas as compared to adenomas. Interestingly, survivin knockdown increased apoptosis in adrenocortical carcinoma cells [11].

This issue also paid much attention to another adrenal tumor, pheochromocytoma. Two comprehensive reviews by Matro et al. [12] and Prejbisz et al. [13] give excellent updates with regards to therapeutic approaches and problems associated with pheochromocytoma-related mortality (due to cardiovascular complications or metastatic disease). In addition, the review by Matro et al. discusses the novel therapeutic approaches that could develop based on the new molecular targets that have been identified by genetic means with a special emphasis on malignant pheocromocytoma and paraganglioma resulting from mutations in the succinate dehydrogenase subunit B [12].

The chromaffin cells of the adrenal medulla originate from the neural crest. Understanding neural stem cells will help understanding chromaffin progenitors [14] [15]. Androutsellis-Theotokis et al. performed a comprehensive analysis of nuclear hormone receptors in the course of neural stem cell differentiation and addressed the role of dexamethasone and aldosterone in this context [16].

The adrenal gland has a broad involvement in and impact on physiologic and pathophysiologic aspects of the whole organism. For instance, the adrenal gland and adrenal steroids, for example, cortisol and aldosterone may impact insulin resistance and type 2 diabetes. In this context, Saha and colleagues demonstrated in vivo modified lipoproteins and especially VLDL can stimulate adrenocortical aldosterone and cortisol release in a manner dependent on ERK1/2. In addition, VLDL from individuals with impaired glucose tolerance was more capable in inducing aldosterone and cortisol synthesis in NCI-H295R cells, as compared to VLDL from individuals with normal glucose tolerance [17]. Along the same line, linking the adrenal gland with metabolic dysfunction, the group of Raasch demonstrated that angiotensin II impairs glucose utilization in obese Zucker rats by increasing HPA axis activity through a mechanism that requires the presence of the adrenal gland, as evidenced by experiments with adrenalectomized rats [18].

In conclusion, the advances related to the adrenal gland and its disorders presented or reviewed in the course of this conference and in the present issue of Hormone and Metabolic Research underline the importance of the adrenal microenvironment for the whole organism. In addition, recent research findings have identified several novel pathways and molecular targets that need to be exploited therapeutically in the next years.

• References

• 1 Dringenberg T, Schwitalla M, Haase M, Scherbaum WA, Willenberg HS. Control of CYP11B2/CYP11B1 expression ratio and consequences for the zonation of the adrenal cortex. Horm Metab Res 2013; 45: 81-85
• 2 Chavakis T, Kanczkowski W, Willenberg HS, Bornstein SR. Endothelial dysfunction: a critical determinant in inflammation-associated adrenal insufficiency?. Eur J Clin Invest 2011; 41: 917-919
• 3 Kamrath C, Hartmann MF, Wudy SA. Androgen synthesis in patients with congenital adrenal hyperplasia due to 21-hydroxylase deficiency. Horm Metab Res 2013; 45: 86-91
• 4 Meyer G, Hackemann A, Penna-Martinez M, Badenhoop K. What affects quality of life in autoimmune Addison’s disease?. Horm Metab Res 2013; 45: 92-95
• 5 Langenheim J, Ventz M, Hinz A, Quinkler M. Modified-release prednisone decreases complaints and fatigue compared to standard prednisolone in patients with adrenal insufficiency. Horm Metab Res 2013; 45: 96-101
• 6 Koehler K, End K, Kind B, Landgraf D, Mitzscherling P, Huebner A. Changes in differential gene expression in fibroblast cells from patients with triple A syndrome under oxidative stress. Horm Metab Res 2013; 45: 102-108
• 7 Juszczak A, Ertorer ME, Grossman A. The therapy of Cushing’s disease in adults and children: an update. Horm Metab Res 2013; 45: 109-117
• 8 Deutschbein T, Petersenn S. Screening for Cushing’s syndrome: new immunoassays require adequate normative data. Horm Metab Res 2013; 45: 118-123
• 9 Lichtenauer UD, Shapiro I, Osswald A, Meurer S, Kulle A, Reincke M, Riepe F, Beuschlein F. Characterization of NCI-H295R cells as an in vitro model of hyperaldosteronism. Horm Metab Res 2013; 45: 124-129
• 10 Jurowich C, Fassnacht M, Kroiss M, Germer CT, Reibetanz J. Is there a role for laparoscopic adrenalectomy in patients with suspected adrenocortical carcinoma? A critical appraisal of the literature. Horm Metab Res 2013; 45: 130-136
• 11 Sbiera S, Kroiss M, Thamm T, Beyer M, Majidi F, Kuehner D, Wobser M, Becker JC, Adam P, Ronchi C, Allolio B, Fassnacht M. Survivin in adrenocortical tumors – pathophysiological implications and therapeutic potential. Horm Metab Res 2013; 45: 137-146
• 12 Matro J, Giubellino A, Pacak K. Current and future therapeutic approaches for metastatic pheochromocytoma and paraganglioma: focus on SDHB tumors. Horm Metab Res 2013; 45: 147-153
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• 18 Müller-Fielitz H, Raasch W. Angiotensin II impairs glucose utilization in obese Zucker rats by increasing HPA activity via an adrenal-dependent mechanism. Horm Metab Res 2013; 45: 173-180