Basic and clinical aspects of intraadrenal regulation of steroidogenesis

The adrenal gland combines essential components of the autonomic nervous sy stem and the PIPA axis in close contact. From morphological analyses employ ing immunohistochemistry, in situ hybridization, the novel technique of las er capture microdissection, and electron microscopy, it has been has shown that the chromaffin cells of the adrenal medulla and the steroid-producing cells of the adrenal cortex are extensively intermingled and functionally i nterrelated. In in vitro studies, a variety of regulatory factors produced and released by the adrenal medulla were identified as playing an important role in modulating adrenocortical function. An isolated adrenocortical cel l deprived of its tissue integrity, input from the nervous system, or inter cellular communication with chromaffin, vascular, and immune cells of the a drenal gland, loses its normal capacity to produce glucocorticolds and to a dequately respond to the homeostatic challenges of stress. Adrenocortical c ells in co-culture with chromaffin cells produced ten times more glucocorti coids than the same number of pure adrenocortical cells and demonstrated ma rked up-regulation in the mRNA expression of cytochrome p450 enzymes and ST AR in the co-culture, while this expression was downregulated in isolated c ells. Transgenic animal models of over-expression or deletion of enzymes in volved in catecholamine synthesis, as well as of altered function of compon ents of the HPA axis, provide evidence that the mutual interdependence of t he sympatho-adrenal system and the HPA axis at the level of the adrenal gla nd is of physiologic relevance in vivo. Alterations in intercellular commun ications, local production of neuropeptides, growth factors and cytokines, and aberrant expression of ectopic receptors on adrenal cells have been imp licated in adrenal cell growth, development, hyperplasia, tumor formation, autonomous hormone production, and autoimmune disease. Moreover, we describ ed a direct cellular interaction of lymphocytes with adrenal cells as a nov el non-cytokine mediated mechanism of immune endocrine interactions. Highlighting the importance of the extra-pituitary mechanisms of adrenocort ical regulation, be them neural or immune, is a worthwhile starring point f or a more complete analysis of the human stress system in vivo.