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PubMed1996

Functional maturation of the primate fetal adrenal in vivo: I. Role of insulin-like growth factors (IGFs), IGF-I receptor, and IGF binding proteins in growth regulation.

The rapid growth of the primate fetal adrenal from midgestation until term is regulated by ACTH secreted by the fetal pituitary. Previous studies suggest that the trophic actions of ACTH are mediated by insulin-like growth factor II (IGF-II) synthesized by fetal adrenal cortical cells. To characterize further the role of IGF-II in the regulation of fetal adrenal growth, we investigated the expression of the messenger RNAs (mRNAs) encoding IGF-I, IGF-II, IGF-I receptor (IGF-IR) and IGF binding protein (IGFBP) 1-6 in the fetal rhesus monkey adrenal in vivo from 109 days of gestation until term (165 +/- 5 days) using in situ hybridization. To assess the role of ACTH in the regulation of expression of the IGF system in vivo, we administered metyrapone (3-7 days) to late gestation fetal rhesus monkeys (n = 4) in utero to increase fetal pituitary ACTH secretion. IGF-II mRNA was abundant in the definitive, transitional and fetal zones of the adrenal cortex from 109 days until term. IGF-IR mRNA was expressed in the definitive, transitional and fetal zones and decreased to nondetectable levels at term. IGFBP-2 and IGFBP-6 mRNAs were expressed in the definitive, transitional, and fetal zones, whereas IGFBP-1, -3, -4, and -5 were not detected in adrenal cells. The effects of increasing ACTH secretion on the growth of the specific zones of the adrenal were determined using morphometric techniques. Metyrapone treatment approximately doubled adrenal weight, which was due to an increase in the area of the definitive, transitional, and fetal zones with decreased cell density of the definitive, transitional, and fetal zones compared with controls and not due to a change in total cell number. Therefore, the increase in adrenal weight after metyrapone treatment was due to hypertrophy of the three cortical zones; there was no effect on adrenal medullary growth. The relative abundance of the mRNAs encoding IGF-II and the IGF-IR was increased after metyrapone treatment, whereas the localization and relative abundance of IGFBP 1-6 mRNAs were not altered by metyrapone treatment. We conclude that the ontogenetic increase in adrenal growth may be regulated, at least in part, by locally synthesized IGF-II, and the cessation of adrenal growth that occurs at term may be mediated by the decrease in the IGF-IR. The adrenal cortical expression of IGFBP-2 and IGFBP-6 suggests that these IGFBPs may modulate the IGF-IGF-IR interaction. Metyrapone treatment, which likely increased fetal pituitary ACTH secretion, causes a coordinated increase in expression of IGF-II and IGF-IR in fetal adrenal cortical cells, which may be an important mechanism of regulation of fetal adrenal cortical growth.

Adrenal Glands↗
PubMed1993

Mitogenic action, regulation, and localization of insulin-like growth factors in the human fetal adrenal gland.

Polypeptide growth factors may play an important role in the regulation of human fetal adrenal cortical growth by mediating the tropic actions of ACTH. The abundance of mRNA encoding insulin-like growth factor-II (IGF-II) is high in the human fetal adrenal gland and is stimulated by ACTH in cultured fetal adrenal cortical cells. Therefore, we studied the mitogenic action, regulation, and localization of IGF-II and a closely related peptide, IGF-I, in primary cultures of human fetal adrenal cortical cells and whole human fetal adrenal glands. Recombinant human IGF-I and IGF-II stimulated proliferation of fetal adrenal cortical cells in a dose-dependent fashion (1-1000 ng/mL; 0.133-133 nM). At 1000 ng/mL (133 nM), both peptides increased cell number 1.8- to 2-fold. Combinations of IGF-I or -II (100 ng/mL; 13.3 nM) with basic fibroblast growth factor (bFGF; 0.1 ng/mL; 6 pM) or epidermal growth factor (EGF; 1.0 ng/mL; 0.17 nM) had a greater effect on proliferation than bFGF, EGF, or either of the IGFs alone, suggesting an additive interaction. IGF-II mRNA was detected in cultured adrenal cortical cells by in situ hybridization analysis, and its abundance was stimulated by ACTH. In contrast, IGF-I mRNA was not detected in cultured fetal zone cells and was not regulated by ACTH. In whole human fetal adrenal glands, IGF-II mRNA was detected in the definitive and fetal zones and in the capsule, whereas IGF-I mRNA was detected only in the capsule and not in the two cortical zones. Using Northern blot analysis, we found that mRNA encoding IGF-II was present in high abundance in fetal adrenal glands (16-22 weeks) and barely detectable in adult adrenals, whereas mRNA encoding IGF-I was present in very low abundance in the fetal adrenal, but was high in adult human adrenals. As IGF-II expression is high in the human fetal adrenal cortex and is regulated by ACTH, we propose that it is the dominant of the two IGFs regulating human fetal adrenal growth. The cooperative mitogenic effect of IGF-II with bFGF and EGF and the regulation of its expression by ACTH support the hypothesis that IGF-II may act as a mediator, in concert with bFGF and possibly EGF, of the tropic action of ACTH in regulating the rapid growth of the human fetal adrenal cortex during midgestation.

Adrenal Glands↗
PubMed2003

Diagnosis of adrenal insufficiency.

BACKGROUND: The cosyntropin stimulation test is the initial endocrine evaluation of suspected primary or secondary adrenal insufficiency. PURPOSE: To critically review the utility of the cosyntropin stimulation test for evaluating adrenal insufficiency. DATA SOURCES: The MEDLINE database was searched from 1966 to 2002 for all English-language papers related to the diagnosis of adrenal insufficiency. STUDY SELECTION: Studies with fewer than 5 persons with primary or secondary adrenal insufficiency or with fewer than 10 persons as normal controls were excluded. For secondary adrenal insufficiency, only studies that stratified participants by integrated tests of adrenal function were included. DATA EXTRACTION: Summary receiver-operating characteristic (ROC) curves were generated from all studies that provided sensitivity and specificity data for 250-microg and 1-microg cosyntropin tests; these curves were then compared by using area under the curve (AUC) methods. All estimated values are given with 95% CIs. DATA SYNTHESIS: At a specificity of 95%, sensitivities were 97%, 57%, and 61% for summary ROC curves in tests for primary adrenal insufficiency (250-microg cosyntropin test), secondary adrenal insufficiency (250-microg cosyntropin test), and secondary adrenal insufficiency (1-microg cosyntropin test), respectively. The area under the curve for primary adrenal insufficiency was significantly greater than the AUC for secondary adrenal insufficiency for the high-dose cosyntropin test (P < 0.001), but AUCs for the 250-microg and 1-microg cosyntropin tests did not differ significantly (P > 0.5) for secondary adrenal insufficiency. At a specificity of 95%, summary ROC analysis for the 250-microg cosyntropin test yielded a positive likelihood ratio of 11.5 (95% CI, 8.7 to 14.2) and a negative likelihood ratio of 0.45 (CI, 0.30 to 0.60) for the diagnosis of secondary adrenal insufficiency. CONCLUSIONS: Cortisol response to cosyntropin varies considerably among healthy persons. The cosyntropin test performs well in patients with primary adrenal insufficiency, but the lower sensitivity in patients with secondary adrenal insufficiency necessitates use of tests involving stimulation of the hypothalamus if the pretest probability is sufficiently high. The operating characteristics of the 250-microg and 1-microg cosyntropin tests are similar.

Adrenal Insufficiency↗
PubMed1998

Adrenal sparing surgery for renal cell carcinoma.

OBJECTIVE: To investigate the feasibility of adrenal sparing surgery for selected renal cell carcinoma (RCC), since the necessity of routine adrenalectomy during radical nephrectomy for RCC has been challenged in recent years. METHODS: 178 patients underwent perifascial nephrectomy in a 16-year period. Of these patients, 96 had ipsilateral adrenal gland preserved during nephrectomy and 82 underwent concomitant adrenalectomy. 75 excised adrenal specimens were examined pathologically. Disease specific survival rates were assessed according to the pathological stage of the tumors. RESULTS: Of the 75 patients, 53 presented a macroscopically normal adrenal gland without pathohistological changes. The other 22 patients were suspected to have adrenal metastasis intraoperatively, while only 5 of them were confirmed to have adrenal involvement by histopathology. Two patients in the adrenal gland preservation group developed ipsilateral adrenal recurrence and synchronous or metachronous contralateral adrenal metastasis during follow-up, although both were documented to have a normal-appearing adrenal gland intraoperatively. Five patients with adrenal metastasis and 2 patients with adrenal recurrence had large renal tumors. The survival difference among subgroups of patients undergoing adrenalectomy or with adrenal gland left in situ was not statistically significant. CONCLUSION: Adrenal sparing surgery could be done for patients with small renal tumors along with macroscopically normal ipsilateral adrenal glands.

Adolescent↗
PubMed2005

Real-time and power Doppler imaging of fetal adrenal hemorrhage.

Adrenal hemorrhages are not uncommon in newborns, but they may occur before birth. The incidence of adrenal hemorrhages based on extensive necropsy has been estimated as about 1.7 per 1000 births. With the increasing use of ultrasonography, prenatal recognition of fetal adrenal hemorrhages has become more common in recent years. We report an echogenic abdominal mass, which was found at 36 weeks of gestation using real-time ultrasound, and was enlarged during the 2-week follow-up period. No trauma history was noted during the pregnancy. Since the mass was close to the kidney, we performed power Doppler imaging to localize the lesion and tried to make a differential diagnosis. The left adrenal mass was posterior to the stomach and was without pulsatile blood flow inside. After birth, sonography confirmed a solid homogenous adrenal mass in the newborn. Seven days after birth, the persistent adrenal echogenic mass without resolution by computerized tomography led to a diagnosis of neuroblastoma. The mass was removed by surgery and adrenal hemorrhage diagnosed. The outcome of the adrenal hemorrhage was excellent. The differential diagnosis in unilateral adrenal mass is difficult from the images of 2-D ultrasound since similar pictures may occur among them. In this case, accurate localization of an adrenal mass is feasible using power Doppler imaging (PDI) before birth by determining its blood supply from the middle suprarenal artery. At the same time, fetal adrenal hemorrhages can be demonstrated as an avascular mass, which is the major difference from adrenal tumors. In conclusion, PDI offered more information to localize the adrenal glands from other lesions by separating the blood supply. In addition, the avascular adrenal mass favors the prenatal diagnosis of adrenal hemorrhage.

Adrenal Gland Diseases↗
PubMed1991

Relationship between apolipoprotein E mRNA expression and tissue cholesterol content in rat adrenal gland.

Among extrahepatic tissues the adrenal gland has one of the highest concentrations of apoE mRNA and the highest rate of apoE synthesis. In the present investigation several previously described in vivo treatments were used to assess the relationship between apoE expression and cellular cholesterol in the rat adrenal gland. Treatment of rats with 4-aminopyrazolo[3,4-d]pyrimidine (4-APP) to lower serum cholesterol concentration and deplete adrenal gland cholesterol content decreased adrenal gland apoE mRNA concentration. These adrenal responses were blocked by dexamethasone (DEX) suggesting that the effect of 4-APP occurred indirectly via stimulation of the adrenal gland by endogenous adrenocorticotrophic (ACTH). Relative to control rats, DEX treatment increased both adrenal gland cholesterol content and apoE mRNA concentration. Concurrent ACTH and DEX administration reduced both adrenal gland cholesterol content and apoE mRNA concentration relative to DEX-treated rats. ACTH administration also rapidly decreased adrenal gland apoE mRNA concentration and cholesterol content in rats pretreated with DEX. In all the above experiments, adrenal gland cholesterol content and apoE mRNA concentration were positively correlated (r = 0.78, P = 0.0001). In contrast, aminoglutethimide treatment, which blocks adrenal gland steroidogenesis and greatly increases adrenal gland cholesterol content, was without effect on apoE mRNA concentration. ACTH administration to rats treated with DEX + aminoglutethimide resulted in decreased adrenal apoE mRNA despite greatly increased adrenal cholesterol content. This uncoupling of adrenal gland cholesterol content and apoE mRNA concentration suggests that apoE mRNA expression and cellular cholesterol are regulated independently by ACTH.

Adrenal Glands↗
PubMed2001

Autonomy of cortisol secretion in clinically silent adrenal incidentaloma.

Recent progress in non-invasive imaging techniques have resulted in an increasing frequency of adrenal incidentaloma discovery. In addition, even clinically silent adrenal tumor has been suggested to possess a subtle production of adrenal hormones. The aim of the study was to ascertain the autonomy of cortisol production in clinically silent adrenocortical incidentaloma. We investigated the hypothalamic-pituitary-adrenal axis in 38 patients with adrenal incidentaloma. Basal plasma cortisol level was reproducibly within normal range in all the patients with adrenal incidentaloma, but was also normal in half of the Cushing's syndrome cases studied. Eighteen of 38 patients showed plasma cortisol above 3 microg/dl after 1 mg dexamethasone (Dex) and above 1 microg/dl after 8 mg Dex, respectively, and were defined as preclinical Cushing's syndrome. These patients were subjected to further evaluation of the autonomy of cortisol production. The incidence of positive findings indicating autonomy of cortisol secretion was as follows: suppressed basal plasma ACTH level in 44%, loss of normal diurnal rhythm in 79%, lack of ACTH response to CRF in 35%, decreased plasma DHEA-S level in 28%, significant laterality of 131I-adosterol uptake in 75%, atrophy of the contralateral side of the adrenal on CT scan in 6%, and histological atrophy of the adjacent adrenal cortex in 56%, respectively. The endocrine feature relevant to the hypothalamic-pituitary-adrenal axis varied from patient to patient, ranging from the non-functioning adrenal adenoma to Cushing's syndrome. In addition, the results of each test did not coincide with others in each patient. These results clearly demonstrated that the incidence of autonomy of cortisol production in the clinically silent adrenal incidentaloma is not infrequent, showing significant diversity. Systemic evaluation of the hypothalamic-pituitary-adrenal axis before adrenal surgery is warranted for an appropriate glucocorticoid replacement after adrenal surgery.

Adrenal Gland Neoplasms↗
PubMed1961

Selective adrenal necrosis and apoplexy induced by 7, 12-dimethylbenz(a)anthracene.

Invariably in every normal rat a single dose of 7, 12-dimethylbenz(a)anthracene, by mouth or injected in a vein, was found to cause apoplexy and massive necrosis in the inner zones of the adrenal cortex; the zona glomerulosa, the adrenal medulla, and a small region of cortex adjacent to the great adrenal vessels were spared from damage. DMBA caused these selective lesions in females and in males of 2 strains of rats. Hemorrhage and necrosis were observed in no organ other than the adrenal gland. Whereas adrenal glands were heavily damaged by DMBA, pituitary and ovary escaped injury by the compound. A single huge but sublethal feeding of o, p'-DDD caused degenerative changes of minor magnitude in the adrenals and only in a small percentage of rats; the property of inducing adrenal damage was not shared by other polynuclear aromatic hydrocarbons which were investigated, including strong carcinogens. Presence of adrenal medulla is not a prerequisite to damage of the adrenal cortex by DMBA. The adrenal damage occurred in rats, given DMBA, from which the pituitary had been removed but the lesions were smaller in extent and less in incidence as post-hypophysectomy atrophy of the adrenal cortex progressed. The entire DMBA molecule was necessary to induce adrenal damage; fragments of this molecule did not induce adrenal lesions. Two components which are of cardinal importance in this specific damaging effect are: (a) electronic factor; (b) steric factor. The level of isocitric dehydrogenase in adrenal is modified considerably by presence or absence of estradiol-17beta.

Adrenal Cortex↗
PubMed2003

The role of calretinin, inhibin, melan-A, BCL-2, and C-kit in differentiating adrenal cortical and medullary tumors: an immunohistochemical study.

Morphologic distinction between adrenal cortical and medullary tumors can be difficult. Previous studies have shown inhibin, melan-A, and BCL-2 to be useful markers for adrenal cortical tumors. We have recently observed a high level of calretinin expression in normal adrenal cortex but not the medulla and therefore evaluated its diagnostic application for adrenal tumors in comparison with inhibin, melan-A, and BCL-2. C-kit is a transmembrane tyrosine kinase receptor. Immunodetection of c-kit expression has been recently used for tumor diagnosis, and c-kit-positive tumors can potentially benefit from kit kinase inhibitor treatment. Although c-kit expression was reported in adrenal medulla and pheochromocytoma, it has not been evaluated in adrenal cortical tumors. In this study, 28 adrenal cortical tumors (12 carcinomas, 16 adenomas), 20 pheochromocytomas, and 20 extraadrenal paragangliomas were evaluated for calretinin, inhibin, melan-A, BCL-2, and c-kit expression by standard immunohistochemical assays on paraffin sections. The percentage of immunoreactivity in adrenal cortical tumors was as follows: calretinin, 96%; melan-A, 89%; inhibin, 92%; BCL-2, 20%; and c-kit, 5%. Normal adrenal medulla did not stain for c-kit but was positive for BCL-2. Eighty-six percent of pheochromocytomas stained for BCL-2 and none for calretinin, with the exception of the ganglioneuromatous areas in composite pheochromocytomas (n = 5). Extraadrenal paragangliomas showed reactivity with calretinin in 25%, melan-A in 5%, inhibin in 16%, BCL-2 in 38%, and c-kit in 8% of the cases. Our results indicate that calretinin is the most sensitive among all the adrenal markers tested. Like melan-A and inhibin, calretinin is also a very specific marker in differentiating cortical from medullary adrenal tumors. In addition, calretinin can be used to confirm a composite pheochromocytoma. BCL-2 does not appear to be useful in differentiating adrenal cortical from medullary tumors. C-kit is not useful in the diagnosis of adrenal tumors, and kit kinase inhibitor might have a limited role in the treatment of adrenal tumors and paraganglioma because of the low frequency of c-kit expression in these tumors.

Adrenal Cortex Neoplasms↗
PubMed2005

Minor morphologic abnormalities of adrenal glands at CT: prognostic importance in patients with lung cancer.

PURPOSE: To determine the prognostic importance of minor morphologic abnormalities of the adrenal glands at computed tomography (CT) in patients with lung cancer. MATERIALS AND METHODS: The study was approved by the committee on human research; written informed consent was not required. The authors retrospectively identified 197 patients with lung cancer who underwent serial chest or abdominal CT and did not have a focal adrenal mass at baseline CT. Two readers independently classified the morphologic features of each adrenal gland as normal, smoothly enlarged, or nodular at initial CT examination. They separately recorded the presence or absence of metastases to the adrenal glands (ie, any new focal adrenal mass) at final CT examination; a third independent reader arbitrated when interpretations were discordant (n = 11). Multivariate Cox proportional hazard models were used to assess for associations between baseline adrenal gland morphologic features and subsequent development of adrenal metastases. RESULTS: At initial CT, reader 1 classified 253 (64%), 70 (18%), and 71 (18%) of the 394 adrenal glands and reader 2 classified 258 (65%), 45 (11%), and 91 (23%) of these glands as normal, smoothly enlarged, or nodular, respectively. The readers had moderate interobserver agreement regarding the classification of adrenal gland morphologic features (kappa = 0.54). Metastases subsequently developed in 13 adrenal glands in 11 patients. Cox proportional hazard models revealed no significant association between baseline adrenal gland morphologic features and subsequent development of adrenal metastases (P = .50 and P = .20 for readers 1 and 2, respectively). CONCLUSION: In patients with lung cancer, smooth enlargement or nodularity of the adrenal glands at baseline CT is not associated with increased risk of subsequently developing adrenal metastases.

Adrenal Gland Neoplasms↗
PubMed1985

[Image diagnosis of adrenal disorders--II. Cushing's syndrome].

Comparative study of image diagnosis of ultrasonography (US) by linear electronic scanner, computed tomography (CT), and adrenal scintigraphy was performed in 14 patients with Cushing's syndrome. Adrenal imaging by scintigraphy was performed at the 5th and 6th day or further 7th day following the injection of 1 mCi of Adosterol. Cushing's disease (11 cases) US failed to detect the adrenals in 4 cases examined. Measurement of the adrenals on CT film demonstrated the enlargement of adrenals (greater than mean + 2SD) in 6 of 7 cases (85.7%). Scintiscanning showed the increased uptake of bilateral adrenals in 4 of 10 cases (40%). Adrenal scintigraphy with dexamethasone pretreatment (DP) still demonstrated the isotope uptake of bilateral adrenals in all of those 4 cases tested, although the other 6 cases were not studied with DP. From these findings, it was suggested that the measurement of adrenal size by CT was useful for the additional image diagnosis of Cushing's disease, and the adrenal scintigraphy with DP was also available for complementary study of Cushing's disease. Cushing's syndrome due to adrenocortical adenoma (3 cases) In one case examined by US, which had the smallest adenoma (0.6 X 1.0 X 2.0 cm) in this syndrome, the adenoma was not detected. All of 3 adrenal adenomas (2.6 X 2.6 X 2.2 cm to 0.6 X 1.0 X 2.0 cm) were detected by CT. Adrenal scintigraphy demonstrated good uptake by adrenal adenoma but no visualization of the contralateral adrenal in every case.

Adenoma↗
PubMed2000

[Magnetic resonance techniques used in the differentiation of adrenal tumors].

Noninvasive differentiation of adrenal masses by imaging studies as computed tomography and magnetic resonance imaging is an accepted diagnostic procedure in patients with extraadrenal neoplasm and discovered on imaging studies adrenal mass or in patients with incidentally discovered adrenal mass. Significant impact on possibilities of differentiation of adrenal masses with magnetic resonance imaging was due to introduction to adrenal imaging such techniques as chemical shift imaging and dynamic imaging with paramagnetic contrast agent. Differentiation of adrenal masses with magnetic resonance imaging involves following parameters: tumor diameter, signal intensity of adrenal mass on T2 weighted images, lipid contents in adrenal tumor evaluated with chemical shift imaging and washout of paramagnetic contrast agent from adrenal mass evaluated with dynamic examination. The best results, reaching 100% sensitivity and 100% specificity in differentiation adrenal adenomas from non-adenomas, can be achieved by combined analysis of all mentioned parameters. In regard to availability and costs computed tomography not magnetic resonance imaging is the examination of choice in visualization of adrenal glands and their pathology and in differentiation of adrenal masses. Adrenal tumors on non-enhanced images with density below 0 Hounsfield units can reliably be diagnosed as adenomas, whereas adrenal tumors with density above 20 Hounsfield units can reliably be diagnosed as non-adenomas. Tumors with density in 0-20 Hounsfield range are ambiguous in character, that in many cases can be determined in magnetic resonance imaging.

Adrenal Gland Neoplasms↗
PubMed1998

In vitro and in vivo primate evaluation of carbon-11-etomidate and carbon-11-metomidate as potential tracers for PET imaging of the adrenal cortex and its tumors.

METHODS: With the purpose of developing a PET imaging agent for tumors of the adrenal cortex, we developed syntheses for 11C-etomidate and its methyl analog, 11C-metomidate. (R)-[O-ethyl-1-11C]Etomidate and (R)-[O-methyl-11C]metomidate were prepared by reaction of the appropriate respective 11C-labeled alkyl iodide and the tetrabutylammonium salt of the carboxylic acid derivative. The specificity of binding to the adrenal cortex was tested through the use of frozen section autoradiography of different tissues of the rat, pig and human. Inhibition of tracer binding was evaluated with etomidate, ketoconazole and metyrapone, well-known inhibitors of enzymes for steroid synthesis. Tracer binding to different human tumor samples was compared to immunohistochemical staining with antibodies for the steroid synthesis enzymes P450 11beta (11beta-hydroxylase), P450 scc (cholesterol side-chain cleavage enzyme), P450 C21 (21 -hydroxylase) and P450 17alpha (17alpha-hydroxylase). Three PET investigations, one with 11C-etomidate and two with 11C-metomidate, were performed in rhesus monkey sections, including the adrenals, liver and kidneys. Time-activity curves were generated from measured tracer uptake in these organs. RESULTS: In frozen section autoradiography of various tissues, high binding was seen in the adrenal cortex from all species, as well as in the tumors of adrenal cortical origin. The level of liver binding was about 50% of that in the adrenals, whereas that of all other organs was <10% of the adrenal binding. The adrenal binding was blocked by etomidate and ketoconazole at low doses but not by metyrapone. The binding in the adrenal tumor samples correlated with immunostaining for P450 11beta . PET studies in the monkey demonstrated high uptake in the adrenals with excellent visualization. The uptake increased with time without indication of washout. Slightly lower uptake was seen in the liver as compared to the adrenals, and in the late images, no organs other than adrenals and liver were seen. CONCLUSION: These investigations indicate that 11C-etomidate and 11C-metomidate have the potential to be useful specific agents for the visualization of the normal adrenal cortex and to provide positive identification of adrenal cortical tumors.

Adrenal Cortex↗
PubMed2003

Capsaicin-sensitive nerve fibers: a potential extra-ACTH mechanism participating in adrenal regeneration in rats.

Pituitary-derived factors, including ACTH, have been widely implicated in initiating adrenal regeneration. However, recent work has demonstrated that adrenal regeneration is also modulated by adrenal nerves that extensively reinnervate the regenerating adrenal. Moreover, transection of the splanchnic nerve removes sensory calcitonin gene-related peptide (CGRP) and preganglionic sympathetic vesicular acetylcholine transporter (VAChT)-positive fibers from the regenerating gland and delays regeneration. However, it is not known whether the splanchnic nerve effects on adrenal regeneration are mediated by the CGRP-positive or VAChT-positive innervation. The present studies use the drug capsaicin, a neurotoxin selective for a subset of primary afferent neurons, to specifically remove CGRP-positive fibers from the adrenal gland and assess subsequent effects on the recovery of adrenal mass and function after surgical enucleation. Male, Sprague-Dawley rats were anesthetized and treated with capsaicin (vs. vehicle) periaxonally to the thoracic splanchnic nerve (33 mM, 15 minutes) or systemically (30-100 mg/kg for 4 days, s.c.). After 7-12 days of recovery, rats received right adrenalectomy and left adrenal enucleation. At 14 and 21 days postenucleation, prestress and poststress plasma and adrenals glands were collected; adrenals were weighed and fixed for immunolabeling of CGRP-positive nerve fibers. Periaxonal capsaicin treatment decreased adrenal CGRP content prior to surgical enucleation; however, reinnervation by CGRP-positive fibers was not prevented and regeneration was not affected. Systemic capsaicin treatment attenuated the reinnervation by CGRP-positive fibers and increased the rate, but not extent, of adrenal regeneration. These results support the hypothesis that adrenal innervation represents an extra-ACTH mechanism to modulate the rate of adrenal regeneration.

Adrenal Glands↗
PubMed2002

Early development of the adrenal glands in the grass snake Natrix natrix L. (Lepidosauria, Serpentes).

The aim of the study was to investigate the development and differentiation of the adrenal glands in the grass snake (Natrix natrix L.) during the early stages of ontogenesis, i.e., from egg-laying to hatching of the first specimens. The material used for the studies consisted of a collection of embryos of the grass snake. The Natrix eggs were incubated in the laboratory at a constant temperature of 30 degrees C and 100% relative humidity. Embryos were isolated in a regular sequence of time from egg-laying to hatching. The age of the embryos was qualified according to normal tables for this species. For histological and histochemical investigations, the smallest embryos were fixed in toto. From the oldest embryos, the medial region with the mesonephros and adrenal primordium were resected. Depending on the requirements of histochemical methods, the material was fixed in various fixatives, namely, 10% formalin solution, Bouin, Wood and Millonig fluid, embedded in paraffin and sectioned into serial transversal, sagittal and longitudinal sections. The sections for review were stained with H&E and azan. For detection of adrenaline and noradrenaline in chromaffin tissue, the Wood and Honoré methods were used. SGC cells were detected with the silver stain method after Bodian. For electron microscopic studies, the adrenal gland was fixed in 2.5% glutaraldehyde and 2.0% paraformaldehyde 1:1 in 0.1 M phosphate buffer at pH 7.4 and post-fixed in 1.5% osmic acid in the same buffer. The fixed sections of the adrenal glands were embedded in Epon 812. Semithin and ultrathin sections were cut on ultramicrotome ultratome IV. Semithin sections were stained with methylene blue and ultrathin sections were routinely contrasted with uranyl acetate and lead citrate, then examined and photographed with the JEM JEOL 1220 electron microscope. According to morphological and metrical observation in the course of the grass snake embryo development, one can distinguish 12 stages of development. The primordia of the adrenal cortex appear at the first trimester of egg incubation as two asymmetrical strands between the mesonephros and aorta dorsalis. They are made of dense mesenchymal cells. At the second trimester of development, primordia are penetrated by chromaffinoblasts and capillaries. The mesenchymal cells differentiate into interrenal cells, while chromaffinoblasts are arranged dorsally of the gland. The glands are enclosed by the capsule which separates them from the mesonephros. At the third trimester of the eggs incubation, only noradrenaline appears in a chromaffin tissue. At the moment of snake hatching, the adrenal glands are completely differentiated, both in their structure and their function. The primordia of the interrenal tissue differentiate from mesenchymal cells similarly to mammals. During the development of the snake interrenal tissue, several types of cells can be recognized, varying in the degree of differentiation and in ultrastructural features: 1. Undifferentiated cells with features of mesenchymal cells 2. Differentiating mesenchymal cells 3. Transitional cells with features of mesenchymal and steroidogenic cells 4. Differentiating interrenal cells with pleomorphic mitochondria and numerous lipid droplets 5. Embryonic interrenal cells containing circular lipid droplets and underdeveloped smooth endoplasmic reticulum 6. Transitional interrenal cells containing mitochondria with tubular and vesicular cristae, large lipid droplets, numerous myelin structures, and well-developed smooth endoplasmic reticulum 7. Degenerating cells of embryonic interrenal tissue 8. Differentiating mesenchymal cells with features of fibroblasts The above classification is very schematic and presumptive. In developing adrenal glands at the first trimester of egg incubation type 1 and 2 cells predominate. Type 3 and 4 cells were observed at the second trimester of the adrenal primordia development. At the third trimester of egg incubation, embryonic adrenal glands were composed of the type 5 cells. At the moment of snake hatching, interrenal tissue contained type 5 and 6 cells. In the next days of the adrenal gland development, at the border between the cortex and in medulla as under the capsule, numerous cells were degenerated. During the entire development period the adrenal capsule was built from type 7 cells. The chromaffin tissue of the adrenal glands is derived from the neural crest. These findings agree with the findings of all embryologists. The first chromaffinoblasts infiltrated the adrenal cortex primordium around stage IV of development. They were mixed with interrenal cells and just at hatching they were localized dorsally of the gland. The chromaffinoblasts differentiated gradually from neuron-like cells to typical chromaffinocytes. All the chromaffinoblasts contained the chromaffin granules. The size and numerical density of the chromaffin granules increased with development. Just before hatching, the cells of the chromaffin tissue contained only noradrenaline. Differentiation chromaffinoblasts into chromaffin cells are probably stimulated and controlled by the influence of hormones, which are produced by the cells of the interrenal tissue. According to morphological, histochemical and ultrastructural observation in the course of adrenal differentiation and development in the grass snake, six morphological phases can be distinguished.

Adrenal Glands↗
PubMed2000

Influence of morphine treatment in pregnant rats on the mineralocorticoid activity of the adrenals in their neonates.

Exposure of pregnant rats to morphine, from day 11 to day 18 of gestation, was previously reported to induce both an adrenal atrophy and hypoactivity of the glucocorticoid function in newborns at term, but did not affect, in vitro, the responsiveness of those glands to adrenocorticotrophin hormone (ACTH) concerning corticosterone release. Moreover, these effects were mediated by maternal hormones from the adrenal glands. In the present work, we investigated the effects of a prenatal morphine exposure on the mineralocorticoid activity of the adrenals in neonates. The first aim of the present study was to determine in these newborns 1) the adrenal and plasma aldosterone concentrations at birth time and during the early postnatal period 2) the plasma levels of Na+ and K+ at birth time, 3) the in vitro responsiveness of the newborn adrenals to angiotensin II (A(II)) and ACTH. The second aim of our study was to investigate the mineralocorticoid activity of the adrenals in newborns from adrenalectomized mothers treated with morphine during gestation. According to present data morphine given to intact mothers induced in newborns a severe adrenal atrophy but increased adrenal aldosterone content and plasma aldosterone level. However, prenatal morphine was unable to affect significantly Na+/K+ ratio in both mothers and newborns. In vitro, the adrenals of neonates from morphine-treated mothers were unresponsive to An and ACTH for promoting aldosterone release; in contrast, aldosterone secretion was significantly stimulated by high potassium levels (55 mEq). Maternal adrenalectomy performed one day before the beginning of morphine treatment prevented morphine-induced adrenal atrophy but was unable to affect significantly the adrenal mineralocorticoid function of the offspring. Such data suggest that a prenatal morphine exposure stimulated both aldosterone synthesis and release in neonates. However, this basal hyperfunction did not appear to be coupled with an enhanced adrenal responsivity to AII or ACTH. Prenatal morphine-induced hyperactivity of the mineralocorticoid function of the newborn adrenals, which drastically contrast with hypoactivity of the glucocorticoid one, was independent of adrenal factors from maternal origin.

Adrenal Glands↗
PubMed2001

Expression of nicotinic acetylcholine receptors in human and rat adrenal medulla.

Neuronal nicotinic receptors (nAChRs) are expressed in the brain but also in the peripheral tissues including the adrenal medulla. However, it is unclear which nAChRs are present in the human adrenal medulla. In the study, receptor binding assay, Western blot and RT-PCR have been performed to investigate the expression of nAChRs in adrenal medulla from human, rat and mouse. The results showed that in human adult adrenal medulla, mRNAs for nAChR alpha3, alpha4, alpha5, alpha7, beta2, beta3, and beta4 subunits but not beta2 in the fetal human adrenal medulla were expressed. Saturation binding of [3H]epibatidine showed two binding sites in human aged adrenal medulla. The specific binding of [3H]epibatidine (0.1 nM) was significantly higher in human fetal compared to human aged adrenal medulla. mRNAs for the alpha3, alpha4, alpha5, alpha7, beta2, and beta4 subunits but not the beta3 were detectable in adult rat and mouse adrenal medulla. No differences in gene-expression of the nAChRs were observed between new born, adult and aged rat adrenal medulla. Saturation binding of [3H]epibatidine showed only one binding site in rat adrenal medulla. Lower protein levels for the nAChR subunits were observed in the rat adrenal medulla compared to rat brain. There was lower protein levels of the nAChRs in aged rat adrenal medulla compared to the young rats. Sub-chronic treatment of nicotine to rats did not influence level of the nAChRs in the adrenal medulla. In conclusion, the expression of nAChRs in adrenal medulla is age- related and species dependent.

Adrenal Medulla↗
PubMed2003

Adrenal TGFbeta1 mRNA levels fall during late gestation and are not regulated by cortisol in the sheep fetus.

During mammalian development there are periods when the fetal adrenal is either relatively refractory or increasingly sensitive to trophic stimulation. This pattern of regulation of adrenal growth and function ensures that the fetal lungs, liver, brain and kidney are exposed in a programmed temporal sequence to the genomic actions of circulating glucocorticoids. The factors which act to maintain periods of adrenal quiescence are not known. In the present study we have measured the level of messenger RNA (mRNA) expression of a putative inhibitor of adrenal steroidogenesis, transforming growth factor beta 1 (TGFbeta1), and a key steroidogenic enzyme, cytochrome P450 17alpha hydroxylase (CYP17), during periods of adrenal quiescence and activation in the sheep fetus. We have also investigated the relative roles of the fetal hypothalamic-pituitary axis and cortisol in the regulation of expression of adrenal TGFbeta1 and CYP17 mRNA during late gestation. Adrenal expression of TGFbeta1 was greatest at around 100 days gestation, at a time when the fetal sheep adrenal is relatively refractory to trophic stimulation and there was an inverse relationship between the expression of TGFbeta1 and CYP17 mRNA in the adrenal gland during the peripartum period. Whilst disconnection of the fetal hypothalamic-pituitary disconnection (HPD) axis resulted in a decrease in adrenal CYP 17 mRNA expression, there was no effect of fetal HPD, with or without cortisol replacement, on adrenal TGFbeta1 mRNA expression in late gestation. Thus TGFbeta1 may play a role in inhibiting adrenal steroidogenesis and ensuring that the adrenal remains relatively refractory to trophic stimulation during mid gestation. The maintenance of low adrenal TGFbeta1 expression during late gestation is not dependent, however, on stimulation by the fetal hypothalamic-pituitary axis.

Adrenal Cortex↗