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Cholesterol metabolism in the adrenal cortex.

Adrenal cortical mitochondria contain a mixed function oxidase capable of converting cholesterol to pregnenolone; this enzyme requires NADPH, oxygen and cholesterol. This cholesterol side chain cleavage enzyme system contains a Flavoprotein, an iron sulphur protein and a specific cytochrome P450 termed cytochrome P450scc. ACTH stimulates the adrenal cortex by activating adenyl cyclase producing an elevated intracellular concentration of cAMP. This in turn increases the activity of a cytosolic cAMP dependent protein kinase. Adrenal cortical cytosol contains a cholesterol ester hydrolase which is activated by ATP and a protein kinase. This enzyme may be deactivated by a phosphoprotein phosphatase. The adrenal cortex contains lipid droplets that are rich in esterified cholesterol. Cholesterol ester hydrolase can release free cholesterol from the lipid droplets. The free cholesterol released may be used to supplement the mitochondrial cholesterol as a pregnenolone precursor. Steroid hormone production by the adrenal cortex exhibits a diurnal rhythm and correlates with the activity of the cytosolic cholesterol ester hydrolase. The acute steroidogenic response to ACTH may be in part attributed to the availability of free cholesterol to the mitochondrial cholesterol side chain cleavage enzyme complex. The intracellular movement of free cholesterol from lipid droplets to mitochondrial inner membranes may be impeded by protein synthesis inhibitors such as cycloheximide. The precise mechanism of this block in steroidogenesis remains to be elucidated. Various drugs and oestrogenic hormones suppress the plasma and adrenal cholesterol concentrations. If adrenal cells are deficient in cholesterol, these cells exhibit a diminished response to ACTH. The response to this hormone can be corrected by supplying cholesterol via exogenous plasma lipoproteins. The route that free cholesterol follows within the adrenal cortical cell and the physiological factors influencing free cholesterol movement in such cells are important issues to be explored in future.

Adrenal Cortex↗

Nuclear bodies in the normal and hyperfunctional human adrenal cortex.

Adrenal pieces obtained from six female patients, three without increased adrenocortical function and three with Cushing's disease, showed, in all adrenal cortex zones, cells containing simple and complex nuclear bodies. The simple nuclear bodies were spherical or ovoid and had a filamentous structure surrounded by a clear halo. Complex nuclear bodies were more numerous and heterogeneous in patients with adrenal pathology, and they were spherical with a proteinaceous filamentous capsule surrounding a core; the core was granular, filamentous or a mixture of granular and filamentous material, sometimes with a reticular or concentric arrangement. Some bodies showed vacuolar or multilocular aspect, and others had a close relationship with the nucleolus or appeared near the interchromatin granules. The meaning of adrenal nuclear bodies is discussed as well as their relationship with ACTH stimulation.

Adolescent↗

Endocrine emergencies. Disorders of the adrenal cortex.

Adrenal crisis represents the major endocrine emergency with a fatal outcome if not properly recognized and correctly treated. It can present as the first manifestation of acute or chronic primary adrenal failure. Secondary adrenal insufficiency with usually less dramatic manifestations can cause mental disturbances, electrolyte or metabolic disorders severe enough to warrant prompt correction and therapeutic intervention. This is particularly true in cases of abrupt cessation of steroid treatment, pituitary apoplexy and Sheehan's syndrome. Hyperfunction of the adrenal cortex, be it hypercorticism or hypermineralocorticism, can also require rapid treatment of electrolyte disorders and hypertension. The symptoms and differential diagnosis of these entities are described as well as their proper treatment. In order to confirm later the diagnosis, the need to secure biological samples for hormone determination before starting treatment is emphasized.

Acute Disease↗

Transplantation of parathyroid, adrenal cortex and adrenal medulla using procedures which successfully prolonged islet allograft survival.

Life-long hormone replacement therapy is today the only form of therapy for several endocrine insufficiencies. Transplantation of endocrine tissues could represent a more physiological approach to the treatment of different syndromes such as adrenal insufficiency, diabetes or hypoparathyroidism. Successful experimental islet transplantation across major histocompatibility barriers using cultural pretreatment of the insulin producing tissue in conjunction with temporary immunosuppression of the recipients, encouraged us to attempt similar approaches with parathyroids, adrenal cortex and adrenal medulla. Either bilateral parathyroidectomy or bilateral adrenalectomy were performed on the recipient rats before transplantation, followed by the implantation of parathyroid, adrenal cortical or adrenal medullary tissue beneath the renal capsule. The tissue was transplanted either immediately after its dissection or after pretreatment with 1 week culture. Some of the recipients received a short term cyclosporine treatment. The results indicated that parathyroid and adrenal medulla transplants were often infiltrated by mononuclear cells 30 days after transplantation. In contrast, adrenal cortical tissue was well preserved 4 weeks after transplantation, without showing any sign of rejection when a combination of pre-transplant culture of the adrenal tissue and temporary cyclosporine treatment of the recipients was used.

Adrenal Cortex↗

Effect of constant light and darkness on the mitotic activity of adrenal cortex undergoing adrenal regeneration or compensatory growth in male Wistar rats.

The effect of constant light and darkness on the mitotic activity of the adrenal cortex in the course of adrenal regeneration and compensatory growth in male Wistar rats was investigated. Three separate experiments were performed in different seasons. It was found, that on the tenth day of both regeneration and compensatory growth, constant darkness decreased the mitotic activity of the adrenal cortex, and in contrast, constant light had no significant effect when compared with the controls.

Adrenal Cortex↗

Comparison of the adrenalytic activity of mitotane and a methylated homolog on normal adrenal cortex and adrenal cortical carcinoma.

Mitotane is an important adrenalytic drug for the treatment of adrenal cancer whose use is limited by toxicity. Reports from another laboratory indicated that a methylated homolog of Mitotane (Mitometh) tested in guinea pigs possessed comparable adrenalytic activity but was less toxic than Mitotane. This observation prompted us to undertake a comparative study of these two drugs on the basis that Mitometh may be a superior agent for the treatment of adrenal cancer. Preliminary studies in guinea pigs failed to show a significant adrenalytic effect for either Mitotane or Mitometh. Thus, we extended the study to 13 mongrel dogs weighing 12-15 kg that were treated daily with Mitometh or Mitotane (50-100 mg/kg) for 6 or 12 days. Cortisol decreased to undetectable levels and adrenocorticotropic hormone (ACTH) rose to 10 times the baseline levels within 72 h in Mitotane-treated animals. Despite the achievement of similar drug levels, Mitometh treatment in dogs failed to suppress cortisol or increase ACTH. To determine whether these differences were due to differences in bioavailability, we measured the relative concentration of Mitotane and Mitometh in homogenates of adrenal cortex obtained from Mitotane- and Mitometh-treated dogs. The adrenal concentration of Mitometh determined in Mitometh-treated dogs was 5 times higher than the concentration of Mitotane measured in Mitotane-treated animals. Whereas the adrenal glands of Mitotane-treated dogs showed hemorrhage and necrosis, the Mitometh-treated animals showed no adrenal damage. Despite the lack of adrenalytic activity, Mitometh maintained its toxicity as demonstrated by microscopic evidence of hepatic necrosis and an increase in hepatic enzymes. The adrenalytic effects of both agents was also studied in vitro using a human functioning adrenal cortical carcinoma cell line, NCI-H295. Whereas Mitotane strongly suppressed cell growth, Mitometh had a weaker effect. We conclude that Mitometh is not likely to be effective in the therapy of adrenal cancer. Moreover, the results of this study are supportive of the view that metabolic transformation of Mitotane is in some way linked to its adrenalytic action.

Adrenal Cortex↗

[Functional relations of the adrenal cortex, thyroid and pineal body. II. Adrenal cortex reaction following epiphysectomy and administration of melatonin].

Histologic-cytological and morphometrical changes were investigated in the adrenal cortex of male Wistar-rats following pinealectomy and application of melatonin in eu-, hypo-, and hyperthyroid situations. A rat experiment (at an average of 45 d) to find a possible functional connection between the pineal gland and the adrenal cortex was carried out. In the literature, there are only a few of informations about the role of the pineal in regulating ACTH secretion. The results are very contrarily. We found that pinealectomy is connected with a progressive transformation and melatonin with a little regressive transformation in the adrenal cortex. But, it is not evident, that the glomerular zone is activated after both pinealectomy and application of melatonin. In our opinion, the glomerular zone and the secretion of aldosterone increased after as well pinealectomy as melatonin. Application of melatonin diminishes the function of the pineal gland (see group 4-pinealectomy plus melatonin-where was found a progressive transformation). Under these experimental conditions, one can speak of a "pharmacological pinealectomy" after application of melatonin alone. However, the effect of melatonin on the fascicular zone and the glomerular zone is different. The effects of pinealectomy or application of melatonin in combination with methylthiouracil or thyroxin are relatively unimportant.

Adrenal Cortex↗