PubMed · 13902869
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P GUINET, M PELLET, P A APPEAU. 1962-02-15. [New data on hypocorticism].. https://pubmed.ncbi.nlm.nih.gov/13902869/
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The effect of intracerebroventricular infusion of compound 48/80 (C48/80), a mast cell secretagogue, on adrenal cortisol secretion was investigated in dogs under pentobarbital sodium anesthesia. A marked increase in adrenal cortisol secretion was elicited by C48/80 along with a concomitant increase in the plasma levels of cortisol and immunoreactive ACTH, but neither arterial blood pressure and heart rate nor the plasma histamine level altered significantly. Pretreatment with either anti-CRF antiserum or pyrilamine maleate (H(1) histamine-receptor antagonist) significantly attenuated the C48/80-evoked increase in cortisol secretion, but pretreatment with metiamide (H(2)-receptor antagonist) significantly potentiated it. Significant attenuation of the C48/80-evoked increase in cortisol also occurred in dogs given ketotifen, a mast cell stabilizing drug, before pharmacologic challenge. In the pars tuberalis and median eminence (ME), mast cells were highly concentrated in close association with the primary plexus of the hypophysial portal system. Degranulated mast cells were extensively found in the ME of C48/80-treated animals. These results suggest that mast cells located in these regions liberated histamine within the brain as a result of degranulation induced by C48/80 and that this led to activation of the hypothalamic-pituitary-adrenocortical axis.
The mature adrenal cortex is dependent upon proopiomelanocortin (POMC)-derived peptides for the maintenance of its size, structure, and endocrine function. Recent studies in mice genetically deficient in POMC have suggested that early exposure to POMC-derived peptides might also be necessary for the development of a functionally competent adrenal. We examined adrenal morphology and function in an independent line of mice lacking all POMC-derived peptides (Pomc-/-). Adrenal glands were found in all mice, although the glands of Pomc-/- mice had markedly reduced weight compared with control animals (0.5 +/- 0.1 vs. 2.1 +/- 0.1 mg, respectively; P < 0.05) and had disrupted cortical architecture. In Pomc-/- mice, plasma corticosterone was undetectable, and plasma aldosterone was significantly reduced compared with wild-type mice (498 +/- 88 vs. 1845 +/- 168 nmol/liter, respectively; P < 0.001). Heterozygous mice (Pomc+/-) had smaller adrenal glands with significantly lower levels of corticosterone both basally and in response to CRH and ACTH than wild-type mice, indicating that two functional copies of the Pomc gene are necessary to support the fully normal function of the hypothalamic-pituitary-adrenal axis. Three-month-old Pomc-/- mice were treated for 10 d with a highly specific ACTH analog. This treatment restored adrenal weight, cortical morphology, and plasma corticosterone to the levels seen in wild-type littermates. In conclusion, murine adrenal glands can develop without exposure to endogenous POMC-derived peptides during fetal and neonatal life. Although such glands are atrophic and hypofunctional, exposure to ACTH alone can restore their size, morphology, and corticosterone secretion.
The potential for a variety of environmental contaminants to disturb endocrine function in wildlife and humans has been of recent concern. While much effort is being focused on the assessment of effects mediated through steroid hormone receptor-based mechanisms, there are potentially several other mechanisms that could lead to endocrine disruption. Recent studies have demonstrated that a variety of xenobiotics can alter the gene expression or activity of enzymes involved in steroidogenesis. By altering the production or catalytic activity of steroidogenic or steroid-catabolizing enzymes, these chemicals have the potential to alter the steroid balance in organisms. To assess the potential of chemicals to alter steroidogenesis, an assay system was developed using a human adrenocortical carcinoma cell line, the H295R cell line, which retains the ability to synthesize most of the important steroidogenic enzymes. Methods were developed, optimized, and validated to measure the expression of 10 genes involved in steroidogenesis by the use of real-time quantitative reverse transcriptase PCR. The effects of several model chemicals known to alter steroid metabolism, both inducers and inhibitors, were assessed. Similar expression patterns were observed for chemicals acting through common mechanisms of action. Time-course studies demonstrated distinct time-dependent expression profiles for chemicals able to modulate steroid metabolism. The assay, which allows simultaneous analysis of the expression of numerous steroidogenic enzymes, would be useful as a sensitive and integrative screen for the many effects of chemicals on steroidogenesis.