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PubMed1998

Coexpression of p53 and tissue transglutaminase genes in human normal and pathologic adrenal tissues.

The presence of p53 and tissue transglutaminase (tTG) gene expressions was investigated in human normal and pathologic adrenal tissues with two aims (1) to determine the tissue content of p53 protein, its messenger ribonucleic acid (mRNA) and, especially, tTG mRNA which has not been previously reported and (2) to study possible differences in the coexpression of p53 and tTG in various adrenal disorders. Using Northern blot analysis, p53 and tTG mRNAs were detected in each adrenal tissue examined including 5 normal human adrenals, 6 aldosterone-producing adenomas, 3 Cushing's adenomas, 1 primary nodular adrenocortical hyperplasia causing Cushing's syndrome in an infant, 12 non-hyperfunctioning adrenocortical adenomas, and 4 adrenocortical carcinomas. The results showed a significant positive correlation between these two mRNAs in all adrenal tissues except adrenocortical carcinomas. Compared to normal adrenals, high p53 mRNA levels were observed in aldosterone-producing and Cushing's adenomas and, most markedly, in a tissue from a primary nodular adrenocortical hyperplasia. Also, Cushing's adenomas had significantly higher tTG mRNA contents. Immunohistochemistry for wild-type and mutant p53 protein showed numerous p53 positive cells with a strong nuclear staining in a tissue from a primary nodular adrenocortical hyperplasia, whereas the p53 positive cells were absent, except those with a faint nuclear staining, in all other adrenal tissues. However, all adrenal tissues showed detectable p53 contents by the more sensitive method of luminometric immunoassay (LIA). Using this method, aldosterone-producing adenomas exhibited significantly higher p53 contents than normal adrenal tissues. These observations may support potentially important roles for p53 and tTG in adrenal pathophysiology, especially in mechanisms which influence the evolution and/or progression of aldosterone-producing and Cushing's adenomas and, most probably, hyperplasias.

Adrenal Gland Neoplasms↗
PubMedDate not supplied

Functional innervation of the adrenal cortex by the splanchnic nerve.

Secretion of steroid hormones by the adrenal cortex is required to maintain whole body homeostasis; that is the ability to maintain blood pressure and volume, carbohydrate, protein and fat metabolism and immune and nervous system function within normal limits is dependent on adrenocortical hormones. The premise of this report is that autonomic-endocrine interactions occurring in the adrenal cortex are required for normal control of steroid secretion. Under non-stress conditions when reduced steroid secretion is required, splanchnic neural activity appears to be inhibitory, whereas during stress conditions when elevated steroid secretion is necessary, neural activity is excitatory. The capacity for innervation to produce both inhibitory and excitatory effects suggests that neural input must be encoded differentially; encoding could be dependent on the neurotransmitter released or on the intra-adrenal target affected. Neural input could act directly at the adrenal cell to affect steroidogenesis or act indirectly by changing adrenal blood flow. An index of the role of innervation has been obtained by assessing adrenal corticosteroid secretion after splanchnicectomy, severing the thoracic splanchnic nerve which is the major source of innervation of the adrenal gland. This approach has resulted in alterations in corticosteroid secretion under non-stress and stress conditions, but in many cases has demonstrated no profound effect on in vivo steroidogenesis. It is likely that splanchnicectomy results in variable secretory responses in part due to the multiplicity of adrenal neurotransmitter systems that are regulated by the splanchnic nerve. Splanchnicectomy alters multiple neurotransmitters at different adrenal sites. Splanchnic innervation acts as an extra-ACTH mechanism in the control of adrenal corticosteroid secretion, yet further elucidation of the physiological conditions under which splanchnic neural activity affects function is clearly warranted.

Adrenal Cortex↗
PubMed2000

Laparoscopic adrenalectomy for large-volume (> or = 5 cm) adrenal masses.

BACKGROUND AND PURPOSE: Laparoscopic adrenalectomy has emerged as the standard of care at many centers for small surgical adrenal masses. However, the role of laparoscopic adrenalectomy in the treatment of large adrenal masses has not been specifically addressed. Our aim was to evaluate the outcome of laparoscopic v open adrenalectomy for large-volume (> or =5 cm) adrenal masses and to compare laparoscopic adrenalectomy for large- and small-volume (<5 cm) masses. PATIENTS AND METHODS: Data from 14 patients with large adrenal masses undergoing laparoscopic adrenalectomy between February 1998 and March 1999 (Group I) were retrospectively compared with 14 contemporary large-volume open adrenalectomies between December 1992 and May 1998 (Group II) and 45 small-volume laparoscopic adrenalectomies between July 1997 and November 1998 (Group III). RESULTS: In Group I and Group II, the mean surgical time (205 min v 216 min) and blood loss (400 mL v 584 mL) were similar. Although the mean adrenal size was also comparable (8 cm v 7.8 cm), the specimen weight of the en bloc adrenal gland and periadrenal fat was greater in Group I (168 g v 106 g). The hospital stay was shorter in Group I (2.4 days v 7.7 days). Minor complications occurred in 21.4% of Group I and 50% of Group II patients. On comparing Group I and Group III (laparoscopic <5 cm), Group I had larger specimen weight (168 g v 51.4 g), longer surgical time (205 min v 158 min), greater blood loss (400 mL v 113 mL), longer hospital stay (2.4 days v 1.5 days), a higher complication rate (21.4% v 8.9%), and a higher incidence of open surgical conversion (14.3% v 2.2%). Over a mean follow-up of 9.9 months, no local or port-site recurrences have been noted in Group I. CONCLUSIONS: Laparoscopic adrenalectomy for large-volume adrenal masses is technically feasible and seems to replicate open surgical oncologic principles of achieving a wide-margin, en bloc excision of the adrenal gland and periadrenal fat. Successful laparoscopic resection is not impacted by the large size of the adrenal mass per se but rather by the presence of local invasion and poorly defined tissue planes that may be encountered in adrenal malignancy. As such, laparoscopic adrenalectomy for large masses should be attempted only by experienced laparoscopic surgeons and then with a low threshold for open conversion.

Adrenal Gland Neoplasms↗
PubMed2004

Differential actions of metyrapone on the fetal pituitary-adrenal axis in the sheep fetus in late gestation.

It is not clear if an increase in intra-adrenal cortisol is required to mediate the actions of adrenocorticotropic hormone (ACTH) on adrenal growth and steroidogenesis during the prepartum stimulation of the fetal pituitary-adrenal axis. We infused metyrapone, a competitive inhibitor of cortisol biosynthesis, into fetal sheep between 125 and 140 days of gestation (term = 147 +/- 3 days) and measured fetal plasma cortisol, 11-desoxycortisol, and ACTH; pituitary pro-opiomelanocortin mRNA and adrenal expression of ACTH receptor (melanocortin type 2 receptor), steroidogenic acute regulatory protein (StAR), 11beta-hydroxysteroid dehydrogenase type 2 (11betaHSD2), cytochrome P450 cholesterol side-chain cleavage (CYP11A1), cytochrome P450 17-hydroxylase (CYP17), 3beta-hydroxysteroid dehydrogenase, and cytochrome P450 21-hydroxylase mRNA; and StAR protein in the fetal adrenal gland. Plasma ACTH and 11-desoxycortisol concentrations were higher (P < 0.05), whereas plasma cortisol concentrations were not significantly different in metyrapone- compared with vehicle-infused fetuses. The ratio of plasma cortisol to ACTH concentrations was higher (P < 0.0001) between 136 and 140 days than between 120 and 135 days of gestation in both metyrapone- and vehicle-infused fetuses. The combined adrenal weight and adrenocortical thickness were greater (P < 0.001), and cell density was lower (P < 0.01), in the zona fasciculata of adrenals from the metyrapone-infused group. Adrenal StAR mRNA expression was lower (P < 0.05), whereas the levels of mature StAR protein (30 kDa) were higher (P < 0.05), in the metyrapone-infused fetuses. In addition, adrenal mRNA expression of 11betaHSD2, CYP11A1, and CYP17 were higher (P < 0.05) in the metyrapone-infused fetuses. Thus, metyrapone administration may represent a unique model that allows the investigation of dissociation of the relative actions of ACTH and cortisol on fetal adrenal steroidogenesis and growth during late gestation.

11-beta-Hydroxysteroid Dehydrogenase Type 2↗
PubMed2004

Primary adrenal insufficiency in childhood and adolescence: advances in diagnosis and management.

OBJECTIVES: Primary adrenal insufficiency occurring in childhood and adolescence is due to abnormalities of gland development, gland responsiveness, and steroid biosynthesis or target organ response. Causes include autoimmune Addison's disease, tuberculosis, HIV, adrenoleukodystrophy, adrenal hypoplasia congenita and syndromes including triple A and IMAGe. We aimed to define the causes of adrenal insufficiency for a cohort of children in Melbourne. METHODS: We reviewed the frequency and variety of presentation of primary adrenal insufficiency to the Royal Children's Hospital over the past 10 years through an audit of patient records, collating demographic information, presentation and investigations. RESULTS: Sixteen cases (13 male, 3 female) of primary adrenal insufficiency were diagnosed at this hospital between January 1993 and July 2003. Median age at presentation was 7.7 years (range: birth to 14.8 years). Symptoms at presentation included weakness, increased pigmentation, abdominal pain, nausea, developmental delay or a reduction in school performance. Four patients presented with adrenal crisis. Median adrenocorticotrophic hormone (ACTH) at diagnosis was 246 pmol/L (range 30-969 pmol/L). Autoantibodies were positive in five patients. Five patients had elevation of very long chain fatty acids. Five patients were diagnosed with autoimmune adrenal insufficiency, five with adrenal hypoplasia congenita, five with adrenoleukodystrophy and one with IMAGe syndrome. CONCLUSIONS: A high index of suspicion results in earlier detection and possible prevention of adrenal crisis with a reduction in associated morbidities. Definitive diagnosis is now possible for almost all cases of primary adrenal insufficiency using technologies for screening autoimmunity, adrenoleukodystrophy (ALD) and genetic screening.

Adolescent↗
PubMed1987

Corticotropin-releasing factor in the adrenal medulla.

Immunoreactive and bioactive corticotropin-releasing factor has been identified in the adrenal gland of dogs, rats and humans. Radioimmunoassay and immunohistochemical experiments have clearly demonstrated that localization of the peptide is confined to the adrenal medulla. CRF-containing cells have a characteristic appearance and are often found in close association with blood vessels. Electron microscopic studies suggest that CRF is secreted at blood vessels within the adrenal medullary vasculature. CRF has also been identified in pheochromocytomas. The amount of the peptide made by such tumors is highly variable as the CRF content of pheochromocytomas may be 20 to 100 times higher or lower than that of normal adrenal tissue. The pathophysiological importance of CRF in pheochromocytomas is unknown. Excessive secretion of the peptide into the peripheral circulation may cause prolonged activation of the pituitary adrenal axis. The peptide may also act within the tumor, although its role remains obscure. Studies on chronically cannulated, awake dogs have shown that CRF is secreted into adrenal venous blood. A gradient exists between adrenal venous and peripheral arterial blood, as CRF is undetectable peripherally under resting conditions. Hemorrhage, a hemodynamic stimulus known to activate a sympathetic adrenal response, increases the CRF secretory rate. The time course of CRF secretion in response to this stimulus parallels that of epinephrine secretion. The physiological significance of adrenal medullary CRF remains to be determined. Although CRF has been shown to affect catecholamine secretion, the peptide appears to be only a weak secretagogue for catecholamines. We suggest that CRF may affect local blood flow within the adrenal medulla and may modify catecholamine secretory rates via this mechanism. The localization of CRF cells in close apposition to blood vessels supports this hypothesis.

Adrenal Gland Neoplasms↗
PubMed1982

Localization of functional adrenal tumors by computed tomography and venous sampling.

Fifty-eight patients with functional lesions of the adrenal gland underwent radiographic evaluation. Twenty-eight patients had primary aldosteronism (Conn syndrome), 20 had Cushing syndrome, and 10 had pheochromocytoma. Computed tomography (CT) correctly identified adrenal tumors in 11 (61%) of 18 patients with aldosteronomas, 6 of 6 patients with benign cortisol-producing adrenal tumors, and 5 (83%) of 6 patients with pheochromocytomas. No false-positive diagnoses were encountered among patients with adrenal adenomas. Bilateral adrenal hyperplasia appeared on CT scans as normal or prominent adrenal glands with a normal configuration; however, CT was not able to exclude the presence of small adenomas. Adrenal venous sampling was correct in each case, and reliably distinguished adrenal tumors from hyperplasia. Recurrent pheochromocytomas were the most difficult to localize on CT due to the surgical changes in the region of the adrenals and the frequent extra-adrenal locations.

Adenoma↗
PubMed2006

Chronic stress induces adrenal hyperplasia and hypertrophy in a subregion-specific manner.

The adrenal gland is an essential stress-responsive organ that is part of both the hypothalamic-pituitary-adrenal axis and the sympatho-adrenomedullary system. Chronic stress exposure commonly increases adrenal weight, but it is not known to what extent this growth is due to cellular hyperplasia or hypertrophy and whether it is subregion specific. Moreover, it is not clear whether increased production of adrenal glucocorticoid after chronic stress is due to increased sensitivity to adrenocorticotropic hormone (ACTH) vs. increased maximal output. The present studies use a 14-day chronic variable stress (CVS) paradigm in adult male rats to assess the effects of chronic stress on adrenal growth and corticosterone steroidogenesis. Exogenous ACTH administration (0-895 ng/100 g body wt) to dexamethasone-blocked rats demonstrated that CVS increased maximal plasma and adrenal corticosterone responses to ACTH without affecting sensitivity. This enhanced function was associated with increased adrenal weight, DNA and RNA content, and RNA/DNA ratio after CVS, suggesting that both cellular hyperplasia and hypertrophy occurred. Unbiased stereological counting of cells labeled for Ki67 (cell division marker) or 4,6-diamidino-2-phenylindole (nuclear marker), combined with zone specific markers, showed that CVS induced hyperplasia in the outer zona fasciculata, hypertrophy in the inner zona fasciculata and medulla, and reduced cell size in the zona glomerulosa. Collectively, these results demonstrate that increased adrenal weight after CVS is due to hyperplasia and hypertrophy that occur in specific adrenal subregions and is associated with increased maximal corticosterone responses to ACTH. These chronic stress-induced changes in adrenal growth and function may have implications for patients with stress-related disorders.

Adrenal Cortex↗
PubMed1994

Does plasma immunoreactive ouabain originate from the adrenal gland?

It was reported recently that the endogenous digitalis-like factor ouabain may mainly originate from the adrenal gland. To ascertain the pathophysiological significance of endogenous ouabain and to examine if it originates in the adrenal gland, we determined plasma immunoreactive ouabain levels in patients with various cardiovascular and endocrine diseases. Plasma immunoreactive ouabain levels were also determined in the adrenal venous blood by adrenal venous sampling. Plasma immunoreactive ouabain levels were significantly increased in patients with essential hypertension, primary aldosteronism, Cushing's syndrome, pheochromocytoma, acromegaly, and chronic renal failure. Plasma immunoreactive ouabain levels were decreased in patients with primary aldosteronism after unilateral adrenalectomy, acromegaly after pituitary adenomectomy, and chronic renal failure after hemodialysis. Plasma immunoreactive ouabain levels in patients after bilateral adrenalectomy were similar to those in healthy subjects. There was no significant step-up of immunoreactive ouabain levels in the adrenal vein from the peripheral vein in three patients, whereas one patient with hypertension and right adrenal tumor but without any known adrenal hormone excess showed higher plasma immunoreactive ouabain levels in the right adrenal vein than those in the peripheral vein. These results suggest an important pathophysiological significance of endogenous ouabain in various cardiovascular and endocrine diseases. It is unlikely that the adrenal gland is a major source of plasma ouabain, although a possible excess production of ouabain by the adrenal tumor remains to be elucidated.

Adrenal Gland Neoplasms↗
PubMed1973

Regulation of adrenal ornithine decarboxylase by adrenocorticotropic hormone and cyclic AMP.

Adrenal ornithine decarboxylase activity was stimulated in a dose-related manner after administration of ACTH or dibutyryl ((6)N-2'-O-dibutyryl) cyclic AMP to hypophysectomized rats. Little effect was observed for 2 h, but striking increases in enzyme activity were observed 4 h after administration of these substances. Effects of ACTH and dibutyryl cyclic AMP were not secondary to stimulation of steroidogenesis, since hydrocortisone had no effect on adrenal ornithine decarboxylase although it did stimulate activity of the enzyme in the liver and kidney.ACTH, given subcutaneously to hypophysectomized rats, induced striking increases in adrenal cyclic AMP levels within 15-30 min with a fall towards the base line in 1 h. Increases in ornithine decarboxylase activity lag several hours after this endogenous cyclic AMP peak, in contrast to the stimulatin of steroidogenesis by the nucleotide that requires only 2-3 min. After graded doses of ACTH, increases in adrenal cyclic AMP levels at 30 min were paralleled by proportional increases in adrenal ornithine decarboxylase activity 4 h after hormone treatment. Whereas maximal levels of adrenal steroidogenesis have been observed at tissue cyclic AMP levels of 6 nmol/g. ACTH is capable of inducing increases in nucleotide levels up to 200 nmol/g or more. These high tissue levels of cyclic AMP, although unneccessary for maximal steroidogenesis, appear to stimulate adrenal ornithine decarboxylase activity. Several results in addition to the time lag in the stimulation of ornithine decarboxylase activity suggest a mechanism involving accumulation of the enzyme or some factor needed for its activity rather than direct activation of the enzyme by cyclic AMP. Thus, the addition of cyclic AMP directly to the ornithine decarboxylase assay mixture in vitro was without stimulatory effect. In addition, actinomycin D or cycloheximide in doses sufficient to block adrenal RNA and protein synthesis, respectively inhibited the stimulation of ornithine decarboxylase activity by ACTH in vivo. An adrenocortical cancer was found to maintain ornithine decarboxylase activity at very high levels, but did so at much lower cyclic AMP levels than those of ACTH-stimulated adrenals. It is concluded that ACTH stimulates adrenal ornithine decarboxylase activity and that this effect may be mediated by cyclic AMP. However, cyclic AMP be mediated by appear to be a determinant of the high level of enzyme activity found in adrenocortical cancer.

Adrenal Gland Neoplasms↗
PubMed1982

Rapid decreases in adrenal and plasma corticosterone concentrations after drinking are not mediated by changes in plasma adrenocorticotropin concentration.

Rats given water to drink only during a brief daily period respond to water presentation with a rapid decline in plasma corticosterone concentration. To determine whether this response is consequent to a decrease in plasma ACTH concentration or whether it reflects a sudden reduction in adrenal responsiveness to ACTH, we allowed rats access to water for 2 h/day at lights on and measured plasma ACTH and adrenal and plasma corticosterone concentrations at 3- or 5-min intervals after the onset of drinking. Adrenal and plasma corticosterone concentrations decreased significantly within 2-3 min after water presentation in the absence of concomitant changes in plasma ACTH concentration. The effect was apparent by 5 days after initiating the restricted drinking schedule and became stronger with time up to 21 days. Further characterization of the response showed that the in vitro corticosterone secretion of adrenals removed at intervals after water presentation followed the same pattern as the in vivo concentration. When empty water bottles were presented, plasma ACTH and corticosterone concentrations increased. Neither adrenal medullary function nor plasma renin concentration was found to be associated with the decline in adrenal responsiveness to ACTH after drinking. Hemisection of the spinal cord of unilaterally adrenalectomized rats attenuated the corticosterone response regardless of whether the hemisection was contralateral or ipsilateral to the remaining adrenal. These data suggest that the decreases in plasma and adrenal corticosterone concentration occurring after drinking in water-restricted rats are not dependent on changes in plasma ACTH concentrations, but may be related to changes in adrenal blood flow, steroid metabolism and distribution, or neural input to the adrenal cortex.

Adrenal Cortex↗
PubMed1996

Functional maturation of the primate fetal adrenal in vivo. II. Ontogeny of corticosteroid synthesis is dependent upon specific zonal expression of 3 beta-hydroxysteroid dehydrogenase/isomerase.

Cortisol, produced by the primate fetal adrenal, regulates the maturation of organ systems necessary for extrauterine life. During most of primate pregnancy, however, the fetal adrenal lacks the enzyme 3 beta-hydroxysteroid dehydrogenase/isomerase (3 beta HSD), which is essential for cortisol synthesis. Therefore, we used immunohistochemistry and in situ hybridization techniques to investigate the developmental expression of 3 beta HSD in the fetal rhesus monkey adrenal from 109 days' gestation until term (165 +/- 5 days) and assessed the role of ACTH in the induction of its expression and localization. We also examined whether ACTH regulates the expression of two other steroidogenic enzymes, cytochrome P450 cholesterol side-chain cleavage (P450scc) and P450 17 alpha-hydroxylase, 17/20-lyase (P450c17), in the fetal rhesus monkey adrenal. To stimulate ACTH secretion from the fetal pituitary in vivo, we administered metyrapone to late gestation fetal rhesus monkeys for 3-7 days. Adrenals were collected from untreated fetuses at 109-125 days (n = 5), 130-148 days (n = 7), 155-172 days (n = 4), and after metyrapone treatment at 135-137 days (n = 4). The cortical width and total amount of 3 beta HSD staining were measured using an image analysis system. 3 beta HSD was localized primarily in the definitive zone cells of the adrenal from fetuses between 109-148 days, whereas at term (155-172 days), 3 beta HSD was localized in both definitive and transitional zone cells. The cortical width and total amount of 3 beta HSD staining in the adrenal increased significantly (P < 0.05) between 148 days (137 +/- 14 microns and 3,689 +/- 522 grains) and 155 days (315 +/- 61 microns and 7,321 +/- 2,008 grains). Interestingly, in metyrapone-treated fetuses at 135-137 days, 3 beta HSD messenger RNA (mRNA) and protein were localized extensively in both the definitive and transitional zones, a pattern seen only in term fetal adrenals in untreated animals. In addition, metyrapone treatment significantly (P < 0.05) increased cortical width (386 +/- 95 microns) and total 3 beta HSD immunostaining (29,063 +/- 13,692 grains) compared with age-matched controls. In contrast to 3 beta HSD, P450scc mRNA was detected in the definitive, transitional, and fetal zones, and its expression was not altered after metyrapone treatment. P450c17 mRNA was detected in the transitional and fetal zones, and the relative abundance was greater in the transitional zone. The relative abundance of P450c17 mRNA was increased in the fetal zone after metyrapone treatment. In summary, at term or after metyrapone treatment, expression of 3 beta HSD is induced in the transitional zone of the fetal rhesus monkey adrenal gland, an indication of functional maturation of the primate adrenal cortex. These data suggest that the ontogenetic increase in fetal pituitary ACTH secretion plays an important role in the induction of 3 beta HSD expression in the transitional zone.

Adrenal Cortex Hormones↗
PubMed1997

Differential gene expression of cytochrome P450 11beta-hydroxylase in rat adrenal cortex after in vivo activation.

In situ hybridization histochemistry was used to monitor the expression of 3beta-hydroxysteroid dehydrogenase, delta4-isomerase (3betaHSD) and cytochrome P450 11beta-hydroxylase (P45011beta) messenger RNA (mRNA) in adult rat adrenals after stimulation in vivo. In Exp 1, adrenals were collected from rats injected with saline or ACTH for 1, 2, 3, or 4 days. Adrenal sections from saline-treated rats showed uniform expression of 3betaHSD mRNA that extended from the adrenal capsule to the medullary border. In contrast, P45011beta mRNA showed high levels in the outer fasciculata and low levels in the inner fasciculata/reticularis. In response to ACTH, the integrated density of 3betaHSD hybridization did not increase until 4 days. The integrated density of P45011beta hybridization increased in ACTH-treated rats between 1-4 days due to increased hybridization in the inner fasciculata/reticularis. In Exp 2, rats were treated with ACTH or saline, and adrenals were harvested at 4, 8, or 24 h. The hybridization density of 3betaHSD did not change after ACTH or saline injection. Increased expression of P45011beta mRNA was observed at 4 and 8 h, but not 24 h post-ACTH. In Exp 3, to determine the response to acute stress, adrenals were collected from rats 24 h after surgical laparotomy. The integrated density of 3betaHSD labeling did not change, whereas both hybridization area and mean density of P45011beta increased. Increased expression of P45011beta mRNA was observed in the inner fasciculata similar to that observed after ACTH injection. In addition, adrenal cells were more responsive to ACTH in vitro after surgical stress. These results suggest that the rat adrenal cortex can respond to acute stress by up-regulation of the expression of steroidogenic enzyme genes and that this occurs in part by increasing the number of cells actively expressing P45011beta mRNA. The adrenal response after stress most likely results at least in part from stimulation by ACTH. These findings suggest that changes in adrenal steroidogenesis in response to ACTH may result from recruitment of steroidogenic cells to synthesize and secrete corticosteroids.

3-Hydroxysteroid Dehydrogenases↗
PubMed1984

Different sensitivity to adrenocorticotropin of dispersed adrenocortical cells from patients with Cushing's disease with macronodular and diffuse adrenal hyperplasia.

A patient with Cushing's syndrome and low plasma ACTH levels had a unilateral adrenal mass (diameter, 3 cm), which proved to consist of adenomatous hyperplasia. Dispersed adrenocortical cells prepared from this mass responded to ACTH with a maximal increment in cortisol release of more than 400%. Five months after operation Cushing's syndrome recurred. Computed tomography scanning showed an enlarged macronodular adrenal gland on the other side. The cells prepared from this adrenal gland were stimulated by ACTH by more than 600%. In adrenal glands from eight other patients with Cushing's disease cells from macroscopic nodules in hyperplastic adrenocortical tissue had increased responsiveness to ACTH in vitro, in comparison to cells from macroscopically diffuse hyperplastic adrenal tissue. The stimulability of the pituitary-adrenal axis (by metyrapone) and its suppressibility (by high dose dexamethasone) did not differ between the two groups of patients. These observations suggest that in the presence of adenomatous or macronodular adrenal hyperplasia lower circulating ACTH levels may sustain hypercortisolism than in diffuse adrenal hyperplasia. The presence of a unilateral adrenal mass and low normal plasma ACTH levels in patients with Cushing's syndrome, therefore, does not unequivocally indicate the presence of an autonomous adrenal adenoma. Tests with metyrapone and dexamethasone should still be carried out in order to make a secure differential diagnosis.

Adrenal Cortex↗
PubMed1975

[Studies on the renin-angiotensin system in adrenal regeneration hypertension (author's transl)].

1) To clarify the role of adrenal enucleation on plasma renin activity (PRA), plasma renin substrate (PRS), PRA response to furosemide administration and vacular reaction to renin in adrenal regeneration hypertension (ARH), serial changes of PRA and PRS during adrenal regeneration, PRA response to furosemide administration, and pressor response to exogenous renin in ARH were investigated by comparison with those of intact rats, unilaterally adrenalectomized rats, and unilaterally nephroadrenalectomized rats with contralateral adrenalectomy or with contralateral adrenal exploration (control) on both tap water and high sodium intake. 2) The control rats drinking saline, when compared with intact rats drinking tap water, showed significant decreases in PRA and, concomitantly, significant increases in PRS throughout the experimental period. In the unilaterally nephroadrenalectomized rats drinking saline, two days after adrenal enucleation or adrenalectomy, a significant increase in PRA, with a concomitant decrease in PRS, was observed. Those changes were less pronounced in the adrenal enucleated group than in the adrenalectomized group. Ten days later PRA markedly decreased to the control level in both groups. PRS rose to the control level on the 10th day after adrenal enucleation without increasing further, while that in the adrenalectomized group remained as low as before. 3) No significant differences in any of the experimental groups were found in diuresis, natriuresis, or in changes in body weight and hematocrit during the one and a half hours after furosemide administration performed at the 9th experimental week. The basal PRA was significantly decreased in the other groups with unilateral nephroadrenalectomy and/or a high sodium intake as compared with the unilaterally adrenalectomized rats drinking tap water. The decrease in basal PRA was much more pronounced in the unilaterally nephroadrenalectomized rats drinking saline, with or without adrenal enucleation. After furosemide administration, PRA significantly increased in the unilaterally adrenalectomized rats drinking saline as well as in the unilaterally nephroadrenalectomized rats drinking tap water, with or without adrenal enucleation, while PRA values in three groups were only a half of the unilaterally adrenalectomized rats drinking tap water. An insignificant increase was found in the unilaterally nephroadrenalectomized rats drinking saline, independent of adrenall enucleation. 4) Pressor responses to hog renin in rats with ARH at the 10th postoperative day, and the 4th and 9th postoperative week did not show any significant differences as compared with those of intact rats drinking tap water and unilaterally nephroadrenalectomized rats drinking saline. 5) The effects of adrenal enucleation on PRA, PRS, PRA response to furosemide administration and pressor response to renin in ARH were discussed based on the observed results.

Adrenal Glands↗
PubMed1989

[21-hydroxylase deficiency associated with adrenal tumor: case report of two brothers].

Described herein are two brothers with 21-hydroxylase deficiency (21-OHD) associated with adrenal tumors, and these possible mechanisms are discussed. A 34-year-old male was admitted on Jan. 9, 1984 because of an enlarged and tender left breast. Physical examination revealed short stature (152 cm, 76.5 kg), gynecomastia and shortening of metacarpal bone. His testes were small (2.6 X 1.6 X 1.9 cm). Urinary excretion of 17-OHCS was within normal range (5.9 mg/day), but those of 17-KS, 17-KGS and pregnanetriol were markedly increased (44.4, 110 and 22.6 mg/day, respectively). Plasma concentrations of progesterone and ACTH and urinary excretions of estrone, estradiol and estriol were also increased. Urinary excretions of 17-KS were decreased to 11.7 mg/day and 17-KGS to 22.3 mg/day after the ingestion of 2 mg/day dexamethasone for two days. The computed tomography and a scintigraphy with 131I-Adosterol revealed a tumor in the left adrenal gland, and the adrenal arteriography revealed a neovascularity and a tumor stain in the tumor. These data indicated that the patient was suffering from both 21-OHD and the left adrenal tumor. At this point, adenoma or adenocarcinoma of the adrenal gland was suspected. The left adrenal tumor (85 g) was resected on April 10, 1984, and the pathological diagnosis was adrenal adenoma. The patient's endocrinological abnormalities, however, did not improve after the operation. Urinary excretions of 17-KS and KGS were increased to 57.9 and 108.5 mg/day, respectively, in the patient's elder brother, and 63.3 and 127.9 mg/day, respectively, in his younger brother, indicating that they also had 21-OHD. Interestingly, an adrenal tumor was diagnosed by abdominal computed tomography in the elder brother who had the same HLA typing as the present case. The three brothers had 21-OHD, and two of them had both 21-OHD and adrenal tumor. To our knowledge, this is the first report documenting the co-existence of adrenal tumors in brothers with 21-OHD. This suggests that adenoma can be one of the complications of 21-OHD, probably due to the chronic stimulation by ACTH, and that a possible linkage to HLA may exist in such cases.

Adenoma↗
PubMed2004

Adrenocortical hyperplasia associated with ACTH-dependent Cushing's syndrome: comparison of the size of adrenal glands with clinical and endocrinological data.

Diffuse or nodular hyperplasia of adrenal glands is associated frequently with ACTH-dependent Cushing's syndrome. We carried out a retrospective analysis of 28 patients with ACTH-dependent Cushing's syndrome admitted to our institution between 1984 and 1999 in order to clarify the incidence of adrenal hyperplasia in ACTH-dependent Cushing's syndrome and also to determine the correlation between adrenal gland images and clinical, biochemical and endocrinological data. Of the 28 patients, 16 (57%) showed diffuse adrenal hyperplasia while only 3 had focal adrenal nodules in the hypertrophied adrenals. There was a positive, significant correlation between the width of the adrenal glands measured on CT and circulating plasma ACTH, cortisol levels and urinary free cortisol (UFC) levels. Duration of the disease also correlated positively with adrenal width. No correlation was found between age and adrenal size and there was no difference in the prevalence of diffuse hyperplasia between normotensive and hypertensive patients. These results suggest that chronic ACTH hypersecretion may lead to diffuse adrenal hyperplasia in patients with ACTH-dependent Cushing's syndrome.

ACTH Syndrome, Ectopic↗
PubMed1996

11 beta-Hydroxysteroid dehydrogenase in the rat adrenal.

11 beta-Hydroxysteroid dehydrogenase (11 beta-HSD) catalyses the interconversion of biologically active cortisol to inactive cortisone in man, and corticosterone to 11-dehydrocorticosterone in rodents. As such, this enzyme has been shown to confer aldosterone-selectivity on the mineralocorticoid receptor and to modulate cortisol/corticosterone access to the glucocorticoid receptor (GR). Two kinetically distinct isoforms of this enzyme have been characterized in both rodents and man; a low-affinity NADP(H)-dependent enzyme (11 beta-HSD1) which predominantly acts as an oxoreductase and, more recently, a high-affinity NAD-dependent uni-directional dehydrogenase (11 beta-HSD2). In this study we have analysed the expression of both 11 beta-HSD1 and 11 beta-HSD2 isoforms in rat adrenal cortex and medulla and have investigated their possible roles with respect to glucocorticoid-regulated enzymes mediating catecholamine biosynthesis in adrenal medullary chromaffin cells. Using a rat 11 beta-HSD1 probe and a recently cloned in-house mouse 11 beta-HSD2 cDNA probe, Northern blot analyses revealed expression of mRNA species encoding both 11 beta-HSD1 (1.4 kb) and 11 beta-HSD2 (1.9 kb) in the whole adrenal. Consistent with this, 11 beta-dehydrogenase activity (pmol 11-dehydrocorticosterone formed/mg protein per h, mean +/- S.E.M.) in adrenal homogenates, when incubated with 50 nM corticosterone in the presence of 200 microM NAD, was 97.0 +/- 9.0 and with 500 nM corticosterone in the presence of 200 microM NADP, was 98.0 +/- 1.4. 11-Oxoreductase activity (pmol corticosterone formed/mg protein per h) with 500 nM 11-dehydrocorticosterone in the presence of 200 microM NADPH, was 187.7 +/- 31.2. In situ hybridization studies of rat adrenal cortex and medulla using 35 S-labelled antisense 11 beta-HSD1 cRNA probe revealed specific localization of 11 beta-HSD1 mRNA expression predominantly to cells at the corticomedullary junction, most likely within the inner cortex. In contrast, 11 beta-HSD2 mRNA was more abundant in cortex versus medulla, and was more uniformly distributed over the adrenal gland. Negligible staining was detected using control sense probes. Ingestion of the 11 beta-HSD inhibitor, glycyrrhizic acid (> 100 mg/kg body weight per day for 4 days) resulted in significant inhibition of adrenal NADP-dependent (98.0 +/- 1.4 vs 42.5 +/- 0.4) and NAD-dependent (97.0 +/- 9.0 vs 73.2 +/- 6.7) 11 beta-dehydrogenase activity and 11-oxoreductase activity (187.7 +/- 31.2 vs 67.7 +/- 15.3). However, while levels of 11 beta-HSD1 mRNA were similarly reduced (0.85 +/- 0.07 vs 0.50 +/- 0.05 arbitrary units), those for 11 beta-HSD2 remained unchanged (0.44 +/- 0.03 vs 0.38 +/- 0.01). Levels of mRNA encoding the glucocorticoid-dependent enzyme phenylethanolamine N-methyltransferase which catalyses the conversion of noradrenaline to adrenaline, were also significantly reduced in those rats given glycyrrhizic acid (1.12 +/- 0.04 vs 0.78 +/- 0.04), while those for the glucocorticoid-independent enzyme tyrosine hydroxylase (1.9 kb), which catalyses the conversion of tyrosine to DOPA, were unchanged (0.64 +/- 0.04 vs 0.61 +/- 0.04). In conclusion, the rat adrenal gland expresses both 11 beta-HSD1 and 11 beta-HSD2 isoforms. 11 beta-HSD1 gene expression is localized to the adrenal cortico-medullary junction, where it is ideally placed to regulate the supply of cortex-derived corticosterone to the medullary chromaffin cells. This, together with our in vivo studies, suggests that 11 beta-HSD1 may play an important role with respect to adrenocorticosteroid regulation of adrenaline biosynthesis. The role of 11 beta-HSD2 in the adrenal remains to be elucidated.

11-beta-Hydroxysteroid Dehydrogenases↗