New data about experimental Sipple syndrome in the rat

Sipple syndrome, associating a C cells or parafollicular thyroid tumor and a pheochromocytoma of the medullary part of adrenal gland, can be experimentally induced with the use of an antithyroid drug, the thiamazole, in the rat. The treatment is applied here either between 3 and 11 months, or between 6 and 14 months of age. Tumors appear a long time after the treatment is stopped. Hypotheses are proposed to explain this phenomenon.     

Cushing's syndrome due to unilateral adrenal nodular hyperplasia with incomplete inhibition of the contralateral gland

A 57-year-old woman was demonstrated to be affected by adrenocorticotropic hormone (ACTH)-independent Cushing's syndrome. Computed-axial tomography of the abdomen demonstrated an expansion of the left adrenal. In apparent contrast with these findings, adrenal scintigraphy demonstrated radiocholesterol uptake also by the right gland. At surgery, the left adrenal was found to be hard and enlarged and was excised, while the right gland was found of normal appearance and left in place. Histologic examination of the excised gland demonstrated nodular hyperplasia. Early after surgery, plasma cortisol returned to normal values with a normal circadian rhythm and complete inhibition by low dose dexamethasone; the response of plasma cortisol to ACTH was normal. The patient represents a rare case of unilateral adrenal nodular hyperplasia. Radiocholesterol uptake by the contralateral gland and early recovery from adrenal atrophy after surgery are exceptional findings and suggest incomplete inhibition of endogenous ACTH.     

Pituitary resistance to thyroid hormone--a case report

Pituitary resistance to thyroid hormone is a very rare cause of hyperthyroidism. It is characterized by normal, or elevated TSH concentration with high concentration of T3 and T4. Here, we present a case of a 24-year-old woman who suffered from mild thyrotoxicosis and diffuse goiter for several years. She had elevated fT3 and fT4 with slightly elevated TSH concentration. Pituitary adenoma was excluded as magnetic resonance imaging showed normal pituitary gland, alpha subunit was within normal range and TSH concentration increased after TRH administration. Sonography revealed normoechogenic, slightly enlarged thyroid gland. Previously, she was given thiamazole, but without any significant amelioration. Thus, the diagnosis of the syndrome of pituitary resistance to thyroid hormone was established. The patient was given bromocriptine at a dose of 10 mg per day. After 2 months of treatment she achieved a state of constant euthyrosis and following next few months thyroid volume diminished.     

A case of Cushing's syndrome associated with possible adrenomedullary hyperplasia

A 57-year-old male, who had been suffered from hypertension and diabetes mellitus for 10 years, was admitted to the hospital because of thirst, lassitude and muscle wasting. On admission, his urinary excretion of 17-OHCS and plasma cortisol levels were elevated without diurnal variations. Plasma ACTH levels were found to be very low with repeated determinations. Dexamethasone suppression test, 2 mg 4 times a day orally for 2 days, showed no changes in plasma cortisol levels and only a mild reduction in urinary 17-OHCS excretion. Estimation of urinary catecholamines showed an increase only in norepinephrine. Abdominal computerized tomography and radionuclide scanning of adrenal glands with 131I-adosterol demonstrated a well-defined adrenal mass in the left side without apparent changes in the right side. 131I-metaiodobenzylguanidine scintigraphy was negative. At surgery, his left adrenal medulla was found to be hypertrophic in addition to the cortical tumor. The left adrenal gland was also removed. After surgery, excretion of urinary catecholamines fell to nearly the normal range and he was discharged without insulin and antihypertensive drugs. Microscopically, the cortical tumor is an adenoma consisting of lipid laden cells and eosinophilic compact cells. Medullary cells were distinctly hyperplastic in appearance and many of the cells were extensively vacuolated, suggesting an active functional status. The present report describes a patient with Cushing's syndrome who showed increased urinary catecholamine excretion due to the possible coexistence of adrenal medullary hyperplasia. As far as we know, this is the first case of Cushing's syndrome with this abnormality.     

Combined adrenal myelolipoma and medullary hyperplasia

OBJECTIVE: A patient is reported with hypertension due to combined medullary adrenal hyperplasia and myelolipoma. METHODS: A 52-year-old woman with long-standing hypertension was evaluated for an incidentally discovered large tumor of the left adrenal. Left adrenalectomy was performed for a presumptive clinical diagnosis of pheochromocytoma. RESULTS: Histopathologic examination revealed a mixed tumor consisting of a large myelolipoma with infiltrating foci of adrenal medulla. CONCLUSIONS: A patient is described with hypertension, myelolipoma and adrenal medullary hyperplasia; following adrenalectomy, however, blood pressure and biochemical abnormalities normalized.     

Heparin-releasable lipase activity of rat adrenals, ovaries and testes.

The presence of NaCl-resistant, neutral triacylglycerol hydrolase (lipase) activity in rat adrenal gland, ovary and testis was studied. Both adrenals and ovaries but not testes were found to contain such a lipase. The activity of the enzyme in the adrenal gland was lowered during cortisol treatment and hypothyroidism. An elevated adrenal lipase activity was found during hyperthyroidism. Pseudo-pregnant and lactating rats had higher ovarian lipase activities than cyclic rats. Ovarian lipase activity in lactating rats was positively correlated with the serum concentrations of progesterone and of 20 alpha-hydroxyprogesterone and negatively correlated with the high-density-lipoprotein non-esterified cholesterol concentration. The lipase activity of adrenals and of ovaries was largely releasable from these organs by heparin and could be inhibited by an antibody against heparin-releasable liver lipase. This indicated that the lipase is extracellularly located and is similar to 'liver' lipase. A possible role of this lipase in adrenals and ovaries is discussed.     

Endocrine and neurogenic regulation of the orphan nuclear receptors Nur77 and Nurr-1 in the adrenal glands.

nurr77 and nurr-1 are growth factor-inducible members of the steroid/thyroid hormone receptor gene superfamily. In order to gain insight into the potential roles of nur77 in the living organism, we used pharmacologic treatments to examine the expression of nur77 in the mouse adrenal gland. We found that nur77 and nurr-1 are induced in the adrenal gland upon treatment with pentylene tetrazole (Ptz; Metrazole). This induction is separable into distinct endocrine and neurogenic mechanisms. In situ hybridization analysis demonstrates that nur77 expression upon Ptz treatment in the adrenal cortex is localized primarily to the inner cortical region, the zona fasciculata-reticularis, with minimal induction in the zona glomerulosa. This induction is inhibitable by pretreatment with dexamethasone, indicating involvement of the hypothalamic-pituitary-adrenal axis in the activation of adrenal cortical expression. When mice were injected with adrenocorticotrophic hormone (ACTH), nur77 expression in the adrenal gland spanned all cortical layers including the zona glomerulosa, but medullary expression was not induced. Ptz also induces expression of both nur77 and nurr-1 in the adrenal medulla. Medullary induction is likely to have a neurogenic origin, as nur77 expression was not inhibitable by dexamethasone pretreatment and induction was seen after treatment with the cholinergic neurotransmitter nicotine. nur77 is also inducible by ACTH, forskolin, and the second messenger analog dibutyryl cyclic AMP in the ACTH-responsive adrenal cortical cell line Y-1. Significantly, Nur77 isolated from ACTH-stimulated Y-1 cells bound to its response element whereas Nur77 present in unstimulated cells did not. Moreover, Nur77 in ACTH-treated Y-1 cells was hypophosphorylated at serine 354 compared with that in untreated cells. These results, taken together with the previous observation that dephosphorylation of serine 354 affects DNA binding affinity in vitro, show for the first time that phosphorylation of Nur77 at serine 354 is under hormonal regulation, modulating its DNA binding affinity. Thus, ACTH regulates Nur77 in two ways: activation of its gene and posttranslational modification. A promoter analysis of nur77 induction in Y-1 cells indicates that the regulatory elements mediating ACTH induction differ from those required for induction in the adrenal medullary tumor cell line PC12 and in 3T3 fibroblasts.     

Vasoactive intestinal peptide stimulation modulates the expression of Bcl-2 family members in the adrenal gland of the lizard Podarcis sicula

The adrenal gland of the lizard Podarcis sicula is formed by a dorsal ribbon of chromaffin cells, generally defined as medullary tissue, arranged along a central part of steroidogenic cells considered as cortical tissue. These two tissues produce catecholamines and steroids as part of the hypothalamo-hypophyseal-adrenal gland axis. Recent studies have demonstrated that Podarcis sicula adrenal gland is not only under hypothalamo-hypophyseal axis control but that several peptides may influence the physiological activity of the gland; among these, vasoactive intestinal peptide is able to enhance strongly both catecholamine and steroid hormone production. The aim of the present study was to verify whether vasoactive intestinal peptide administration could become deleterious. For this reason, we monitored the pattern of expression of two members of the Bcl-2 family, Bcl-2 and Bax, in control and vasoactive intestinal peptide treated specimens. Furthermore, we also tested if peptide treatment induces apoptosis by TUNEL assay.     

Primary antiphospholipid syndrome: an unusual cause of adrenal insufficiency

We describe a boy, 10 years and 5 months old, who developed acute adrenal gland insufficiency which was confirmed by hormonal investigation. Abdominal magnetic resonance imaging showed unilateral enlargement of the right adrenal gland, whereas the other gland seemed normal - no cause was apparent. Three months later the patient presented with thrombosis in the right femoral vein and in the veins of the right leg. Autoantibodies against cardiolipin were strongly positive, while antinuclear antibodies and antibodies against double-stranded deoxyribonucleic acid were absent. There was no evidence of antiphospholipid syndrome associated with drugs, connective tissue disorders, or malignancies, strongly suggesting the diagnosis of primary antiphospholipid syndrome. The development of adrenal insufficiency has been reported in primary antiphospholipid syndrome due to adrenal hemorrhage following vascular occlusion of adrenal vessels or secondary to anticoagulant therapy. It was interesting to note that in our patient adrenal gland insufficiency preceded other clinical evidence of the syndrome by 3 months. The primary antiphospholipid syndrome should be considered a possible cause of Addison's disease when the etiology is not obvious.     

THE RELATIONSHIP OF THE REFERRING PHYSICIAN TO THE PSYCHIATRIST

Tumors of the adrenal glands produce hormones which cause a variety of symptoms and signs including high blood pressure, excessive growth of hair on the body and precocious sexual development. By recently developed tests, it has been possible to differentiate high blood pressure due to these tumors from hypertension due to other causes. Removal of these tumors will often alleviate changes caused by them. Localization of the tumor and appraisal of the condition of the contralateral gland should be carried out preoperatively if possible. In this, several kinds of roentgen studies are helpful. Infusions of drugs during operation can be used to control the blood pressure which otherwise would vary widely. During a ten-year period (1942 to 1951) there were observed at the Los Angeles County General Hospital 100 proved cases of non-secreting and secreting primary neoplasms of the adrenal glands. In addition, there were three cases of Cushing's syndrome due to bilateral adrenal cortical hyperplasia, and ten probable cases (four, pheochromocytomas; five, Cushing's syndrome; one, adrenogenital syndrome) in which operation was not done.     

The structure and expression of the preproenkephalin gene.

Enkephalins are pentapeptides with opioid activity which are found in a wide variety of tissues. Studies of enkephalin-containing peptides from the adrenal gland have established that the mature pentapeptides are derived by proteolytic processing of a precursor protein. We have shown that human adrenal medullary tumours contain mRNA which can be translated in vitro to yield a single major enkephalin precursor. The sequence of cloned cDNA shows that the preproenkephalin mRNA encodes four copies of met-enkephalin, two copies of met-enkephalin extended sequences and one copy of leu-enkephalin; each copy is flanked by paired basic amino acids which are presumably recognised by the processing protease. We have used the cloned human cDNA as a hybridisation probe to detect the corresponding mRNAs in rat adrenal gland and, in smaller amounts, in rat brain. We have been unable to detect in brain any other cross-hybridising mRNAs which might encode other putative precursor proteins.     

Effect of Oxotremorine on Ornithine Decarboxylase Activity of the Adrenal Gland in Rat

Abstract: In this work we have studied the mechanism for the increase of adrenal ODC (ornithine decarboxylase, EC 4.1.1.17) activity provoked by oxotremorine, a muscarinic agonist. 1. Oxotremorine increased medullary ODC activity maximally at 2 h. Cortical enzyme responded much more slowly. 2. Blockade of peripheral muscarinic receptors with methylatropine partially reduced the response to oxotremorine in the medulla, but not cortex. 3. Hy-pophysectomy abolished the cortical, but not the medullary, responses to oxotremorine. Methylatropine reduced the effect of oxotremorine on medullary ODC in hypophysectomized rats. 4. In unilaterally splanchnicotomized rats oxotremorine caused an increase of ODC activity of the denervated adrenal gland relative to control value; activities in both medulla and cortex were significantly lower than those observed in the innervated gland. Evidence was obtained for a compensatory increase of ODC activity of the adrenal cortex (but not medulla) on the intact side of unilaterally operated rats. 5. Surgical intervention, in the form of a sham operation for transection of the spinal cord, leads to an increase of ODC activity in both parts of the adrenal gland. Transection of the cord attenuates these increases. 6. The additional increase of medullary ODC activity owing to the administration of oxotremorine to sham-operated rats is partially reduced in the adrenal medulla by muscarinic blockade, and completely in the cortex. This effect of methylatropine in regard to cortical ODC activity was not apparent in the other experiments with intact or unilaterally splanchnicotomized (unoperated side) rats. The results with unilaterally splanchnicotomized rats and those with transected spinal cord suggest that oxotremorine-induced modifications of adrenal ODC activity are centrally mediated, above the level of origin of the splanchnic nerves in the spinal cord (T_8–10). Experiments with hypophysectomized rats show that the response of the adrenal cortex to oxotremorine is entirely mediated by the hypophysis.     

Characterization of opioid peptides from maternal and fetal sheep adrenal glands

Enkephalin immunoreactive material from adrenal glands was characterized both in maternal and fetal sheep at various gestational ages. Whole gland extracts from both maternal and fetal sheep contained three major peaks of Enk immunoreactivity corresponding to apparent molecular weights of 10,000, 2800, and less than 1200 daltons. The majority of maternal adrenal Enk immunoreactivity was found in medullary tissue, although cortex also contained low but detectable amounts. This was also the case in newborn lambs and 139 day fetuses, where adrenal cortex was sufficiently developed to allow extraction and quantitation of opioid material. In fetuses at mid-gestation (70-80 days), adrenal medullary Enk immunoreactivity was approximately 75% of maternal values. Met-Enk and Leu-Enk content in 139 day fetal medulla were 70 and 76% of maternal values respectively, while newborn Met- and Leu-Enk medullary content were similar to maternal values. The molar ratio of Met-Enk to Leu-Enk was approximately 4:1 in both maternal and fetal adrenal medulla, and 2:1 in adrenal cortex, suggesting different synthetic processing of opioid peptides in the two tissues. The early appearance of significant levels of adrenal medullary Enk immunoreactivity and subsequent development paralleling that of catecholamines suggest a predominant role for adrenal enkephalins in regulation of fetal cardiovascular function early in gestation.     

Capsaicin-sensitive adrenal sensory fibers participate in compensatory adrenal growth in rats

Compensatory adrenal growth, in which one gland undergoes hyperplasia after removal of the other, is mediated by a neural reflex. In the present studies, a method employing capsaicin to selectively remove adrenal sensory fibers was developed and applied to determine whether adrenal capsaicin-sensitive fibers participate in compensatory adrenal growth. The splanchnic nerves of anesthetized male rats were treated with capsaicin or vehicle. Capsaicin treatment selectively removed adrenal calcitonin gene-related peptide-positive fibers. One week after drug treatment, rats underwent left adrenalectomy or sham surgery and recovered for 5 days. Capsaicin treatment bilaterally or to the left splanchnic nerve alone (i.e., the afferent nerve in the reflex) impaired compensatory adrenal growth at 5 days compared with vehicle controls, whereas capsaicin treatment to the right splanchnic nerve alone did not affect growth. Moreover, left adrenalectomy induced c-Fos immunolabeling in ipsilateral dorsal spinal cord that was prevented by capsaicin treatment. These data suggest that adrenal capsaicin-sensitive afferent nerves participate in compensatory adrenal growth and that this effect is primarily on the afferent limb of the reflex.     

Renin-angiotensin system and plasma aldosterone in Cushing's syndrome

The renin-angiotensin system was studied in eight patients with Cushing's syndrome (four with adrenal adenoma and four with adrenal hyperplasia) and in five normal controls. Basal plasma renin activity (PRA) and aldosterone concentration (PAC) were similar in supine position among Cushing's syndrome due to adrenal adenoma (PRA; 1.0 +/- 0.3 ng/ml/h, PAC; 7.4 +/- 1.0 ng/dl, mean +/- SE), those due to adrenal hyperplasia (1.0 +/- 0.2, 6.9 +/- 0.8) and the controls (0.8 +/- 0.1, 6.4 +/- 0.4). The PRA after furosemide (1 mg/kg i.v.) and 120 min. upright posture stimulation was similar among Cushing's syndrome due to adrenal adenoma (2.2 +/- 0.7 ng/ml/h), those due to adrenal hyperplasia (2.6 +/- 1.7) and the controls (2.5 +/- 1.2). However, the PAC response after the stimulation in Cushing's syndrome due to adrenal hyperplasia (7.1 +/- 1.2 ng/dl) was significantly lower than that in the controls (17.5 +/- 2.1) (p less than 0.01), although there was no significant difference between the PAC response in Cushing's syndrome due to adrenal adenoma (12.6 +/- 1.0) and the controls. These results indicate that PAC response to furosemide and upright pasture stimulation might be suppressed in Cushing's syndrome due to adrenal hyperplasia.     

Hyperparathyroidism associated with Cushing's syndrome due to an adrenal cortical adenoma

Two patients with the rare association of Cushing's syndrome and primary hyperparathyroidism are reported. Initially, both patients suffered from Cushing's syndrome due to adrenal cortical adenomas with typical features and laboratory findings. Five years after treatment of the Cushing's syndrome by removal of the tumor, asymptomatic mild hypercalcemia was incidentally noticed in both patients, which suggested the occurrence of primary hyperparathyroidism. An enlarged parathyroid gland was removed surgically in both cases and was histologically shown to be a parathyroid adenoma. The levels of serum calcium returned to normal after parathyroidectomy. Papillary adenocarcinoma of the thyroid in one patient and adenomatous goiter in the other were also incidentally detected at operation. These findings suggest that Cushing's syndrome resulting from an adrenal cortical adenoma may be another presentation of multiple endocrine neoplasia type I.     

Receptors for insulin and insulin-like growth factor-I in the human adrenal gland

Human adrenal glands contain high-affinity receptors for insulin and insulin-like growth factor I (IGF-I). Comparative studies with rat, hamster and human adrenal membranes confirmed that IGF-I receptors are most abundant in rat and hamster adrenals, whereas insulin and IGF-I receptors are present in equivalent numbers in human adrenal glands. Covalent crosslinking studies revealed that the human adrenal gland IGF-I receptor binding subunit migrated on dodecyl sulfate polyacrylamide gels with Mr = 135,000, which is identical to the migration of IGF-I receptor binding subunits isolated from other tissues. Autoradiography of frozen human adrenal slices incubated with [125I]insulin showed prominent, displaceable binding of this radioligand to the zona reticularis, zona glomerulosa, vasculature and medulla; in contrast, [125I]IGF-I binding to human adrenal tissue was most prominent in the zona reticularis and negligible in the medullary region.     

A possible association between aldosterone response to vasopressin and circadian change of aldosterone in the patients with aldosterone-producing adenoma

Vasopressin was reported to stimulate secretion of both cortisol and aldosterone through eutopic V1a receptors in adrenal gland. Recently, adrenal hyper-responsiveness of plasma cortisol to vasopressin with eutopic overexpession of V1a receptors has been reported in Cushing's syndrome, such as a majority of cases of ACTH-independent macronodular adrenal hyperplasia and some cases of Cushing's adenomas. There were a few reports regarding the aldosterone response to vasopressin in aldosterone-producing adenoma. The aim of our study was to investigate the aldosterone response to vasopressin and its pathophysiological roles in the patients with aldosterone-producing adenoma. Vasopressin-loading test was performed in 10 patients with aldosterone-producing adenoma, and in 16 patients with non-functioning adrenal tumors. The roles of the aldosterone response to vasopressin were analyzed in terms of hormonal secretion and the expression of V1a receptor mRNA on the operated adrenal gland in aldosterone-producing adenoma. We found that (1) a varying aldosterone response to vasopressin was observed, (2) absolute response of plasma aldosterone in aldosterone-producing adenoma was significantly higher than that in non-functioning tumor, (3) aldosterone response rate to vasopressin was significantly and negatively correlated with the decline rate (%) in plasma aldosterone from morning to evening in aldosterone-producing adenoma, (4) V1a receptor mRNA was expressed at various values in aldosterone-producing adenoma, and (5) surgical removal of aldosterone-producing adenoma eliminated the aldosterone response to vasopressin observed in patients with aldosterone-producing adenoma. These findings indicated that vasopressin might be involved in the coordination of aldosterone secretion through eutopic expression of V1a receptor in aldosterone-producing adenoma.     

Morphofunctional characteristics of the adrenal glands in the progeny from females with experimental hypothyroidism]

Under study were the morphofunctional features of adrenal glands of 1, 10, 20, 30 and 40-day-old rats born by females with experimental hypothyrosis obtained by bilateral subtotal parathyroidectomy and blocade of the gland functioning by mercazolil (3 mkg/kg). The experimental treatment preceded pregnancy. The antithyroid drug was injected during pregnancy and lactation. The posterity of experimental animals was established to have a decreased need in oxygen as compared with controls. Their adrenal glands were of less weight (especially in off-springs of parathryodidectomized rats in the neonatal period). There are a number of morphometrical and histochemical signs suggesting the suppression of the functioning of the cortical and medullary substance, including the period of adaptation of the organism to the extrauterine life.     

Distinct populations of macrophages in the adult rat adrenal gland: a subpopulation with neurotrophin-4-like immunoreactivity

Macrophages are widely distributed in lymphohaemopoietic and many other mammalian tissues, where they are mainly involved in host defence mechanisms, phagocytosis, wound repair, and secretion of growth factors. Increasing evidence suggests that secretory products of macrophages can influence adrenal gland functions. In the present study, we have used specific antibodies to ED1 (cytoplasmic antigen), ED2 (membrane antigen), ED8 (membrane antigen), and OX-6 (MHC class II/membrane antigen) as markers for macrophages to examine their distribution within the adult rat adrenal gland. ED2 and OX-6 recognize distinct subpopulations of adrenal gland macrophages, whereas macrophages immunoreactive (-ir) for ED1 and ED8 could not be detected. OX-6-ir macrophages were most numerous in the cortical reticularis and glomerulosa zones, while only few cells were found in the zona fasciculata and in the adrenal medulla. Macrophages immunoreactive for ED2 were restricted to the adrenal medulla. The majority of these macrophages were associated with vascular sinuses or chromaffin cells. By double-immunolabelling we found that most of ED2-ir medullary macrophages contain neurotrophin-4 (NT-4)-like ir. Attempts to clarify whether macrophages take up NT-4 from NT-4-ir chromaffin cells indicated that medullary macrophages are immunonegative for chromogranin A and neuropeptide Y, two major secretory products of chromaffin cells. In situ hybridizations and immunofluorescence showed expression of the neurotrophin receptor TrkA, but not TrkB in the adrenal medulla. In vitro studies indicated that NT-4, similar to nerve growth factor, can induce c-fos-ir in chromaffin cells. We conclude that chromaffin cells are putative targets for adrenal medullary NT-4, whose functions remain to be clarified.