MECHANISMS IN ENDOCRINOLOGY: Autocrine/paracrine regulatory mechanisms in adrenocortical neoplasms responsible for primary adrenal hypercorticism

Abstract

A wide variety of autocrine/paracrine bioactive signals are able to modulate corticosteroid secretion in the human adrenal gland. These regulatory factors, released in the vicinity of adrenocortical cells by diverse cell types comprising chromaffin cells, nerve terminals, cells of the immune system, endothelial cells, and adipocytes, include neuropeptides, biogenic amines, and cytokines. A growing body of evidence now suggests that paracrine mechanisms may also play an important role in the physiopathology of adrenocortical hyperplasias and tumors responsible for primary adrenal steroid excess. These intra-adrenal regulatory systems, although globally involving the same actors as those observed in the normal gland, display alterations at different levels, which reinforce the capacity of paracrine factors to stimulate the activity of adrenocortical cells. The main modifications in the adrenal local control systems reported by now include hyperplasia of cells producing the paracrine factors and abnormal expression of the latter and their receptors. Because steroid-secreting adrenal neoplasms are independent of the classical endocrine regulatory factors angiotensin II and ACTH, which are respectively suppressed by hyperaldosteronism and hypercortisolism, these lesions have long been considered as autonomous tissues. However, the presence of stimulatory substances within the neoplastic tissues suggests that steroid hypersecretion is driven by autocrine/paracrine loops that should be regarded as promising targets for pharmacological treatments of primary adrenal disorders. This new potential therapeutic approach may constitute an alternative to surgical removal of the lesions that is classically recommended in order to cure steroid excess.European Journal of Endocrinology 169 R115-R138

Common Genetic Variants of the Human Steroid 21-Hydroxylase Gene (CYP21A2) Are Related to Differences in Circulating Hormone Levels

“…The third steroid, 17-OHP, having an elevated response to ACTH in the carriers of c5 haplotypes, is the substrate of the steroid 21-hydroxylase enzyme and the enzyme is functionally unidirectional [1], hence the direct effect of CYP21A2 haplotypes hardly explain the elevated 17-OHP response. We hypothesize that the paracrine regulation of adrenal steroidogenesis [35], either directly or indirectly activated by higher cortisol response may the mediate elevated 17-OHP response, and, in fact, an intraadrenal positive regulatory loop exerted by cortisol is observed in some cases [36].…”

Genetics of primary macronodular adrenal hyperplasia

“…Additional work indicated that PMAH tissues also produce serotonin, vasopressin, glucagon, and other factors that further contribute to the paracrine regulatory loops of cortisol secretion and cell proliferation (Lefebvre et al 2013). These findings bolster the proposal that paracrine adrenal production of ACTH is central to the cortisol-facilitated regulation of PMAH.…”

Ethylenediaminetetraacetic Acid Inhibits <b><i>Vibrio Vulnificus</i></b>-Induced Dendritic Cell Apoptosis by Lowering [Ca²⁺]_i

“…Therefore, an increase in [Ca 2+ ] i is an initiator of apoptosis in V. vulnificus B2 infection. Ca 2+ regulates many signaling pathways such as protein kinase C (PKC), extracellular signal-regulated kinase (ERK) and c-Jun N-terminal kinase (JNK), which can mediate apoptosis [37,38]. We found that m-Tor and STAT3 signaling pathway were involved in DC apoptosis induced by V. vulnificus B2, where m-Tor expression was inhibited, while p-STAT-727 expression was activated, eventually downregulating Bcl-2 expression.…”