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S R Bornstein

Publications and source records attributed to S R Bornstein.

At least 127 records · Page 7Linked to original sources
PubMed1997

Interleukin-6 and the interleukin-6 receptor in the human adrenal gland: expression and effects on steroidogenesis.

Interleukin (IL)-6 is a potent activator of the human hypothalamicpituitary-adrenal axis. After chronic administration of IL-6 in humans, there is a substantial elevation of cortisol, whereas ACTH levels are blunted. Thus, we investigated whether IL-6 and/or the IL-6 receptor (IL-6R) are expressed in the human adrenal gland and whether IL-6 could cause the release of steroid hormones by a direct action on adrenal cells in primary culture. The expression of IL-6 and IL-6R was investigated with RT-PCR and immunohistochemistry, and the effects on human adrenal steroidogenesis were tested with IL-6 in vitro. To avoid effects mediated by macrophages, we depleted adrenal primary cultures from macrophages using specific mouse antihuman CD68 and sheep antimouse IgG conjugated magnetic beads. The results showed that 1): IL-6 and IL-6R are expressed in adrenal cell cultures, including all cell types and those depleted of macrophages; 2) IL-6R is mainly expressed in the zona reticularis and the inner zona fasciculata; positive signals from the zona glomerulosa and the medulla occurred in single cells; and 3) IL-6 regulates adrenal synthesis of mineralocorticoids, glucocorticoids, and androgens in vitro, dependent on time and dose, in the absence of macrophages. After 24 h, aldosterone secretion increased to 172 +/- 28% SEM, cortisol to 177 +/- 27% SEM, and dehydroepiandrosterone to 153 +/- 20% SEM of basal secretion. These findings, in combination with previous investigations, suggest that IL-6 exerts its acute action via the hypothalamus and the pituitary. In the adrenal gland, however, IL-6 seems to be a long-term regulator of stress response, integrating the responses of all cortical zones to stimuli from the immune and endocrine system.

Adrenal Glands↗
PubMed1997

Relevance of major histocompatibility complex class II expression as a hallmark for the cellular differentiation in the human adrenal cortex.

Major histocompatibility complex (MHC) class II antigens are expressed on adrenocortical cells of the zona reticularis and have been shown to be a marker of dignity. This suggests a correlation to the zellular differentiation of the adrenal cortex. Therefore, we immunohistochemically investigated the MHC class II expression in the context of the ontogenesis of the zonal and cellular differentiation in fetal, postnatal, childhood, and adult adrenals. Cell types and cell turnover were studied using specific immune markers (including expression of CD95/ Fas), in situ end labeling of apoptosis, and electron microscopy. We show that prenatal (fetal and definitive) steroid cells, as well as postnatal adrenals, reveal no expression of MHC class II. In childhood, these antigens first appear by the fourth year, in parallel with the differentiation of reticularis cells. The expression index in childhood was 7.43% +/- 2.78 (mean +/- SEM), in adult adrenals 18.63% +/- 3.14 (third decade), and 15.15% +/- 1.26 (fourth through sixth decade). In conclusion, MHC class II expression and the development of the functional maturation of the adult adrenal cortex occur simultaneously. The expression of MHC class II on steroid cells may thus be involved in potential immune-adrenal interactions.

Adrenal Cortex↗
PubMed1997

Evidence for a novel peripheral action of leptin as a metabolic signal to the adrenal gland: leptin inhibits cortisol release directly.

The crucial role of glucocorticoids in obesity and insulin resistance and the actions of the OB protein leptin on the hypothalamic-pituitary-adrenal (HPA) axis suggest that there is an important interaction of leptin with the glucocorticoid system. Therefore, we designed a study to test the effect of leptin directly on adrenocortical steroidogenesis. Primary cultures of bovine adrenocortical cells were incubated with increasing concentrations (10-1,000 ng/ml) of recombinant mouse leptin for 24 h, and the effects of leptin on basal and ACTH-stimulated cortisol secretion were determined. The accumulation of P450 17alpha mRNA following incubation with ACTH (10 nmol/l) and leptin (10-1,000 ng/ml) was analyzed by Northern blot. Adrenocortical cells were characterized by immunohistochemical staining for 17alpha-hydroxyprogesterone. Leptin (10-1,000 ng/ml) inhibited basal and ACTH-stimulated cortisol release. At a concentration that occurs in obese individuals in vivo (100 ng/ml), it reduced basal cortisol secretion to 52.7 +/- 37% (mean +/- SE). The rise in cortisol secretion following maximal ACTH stimulation (10 nmol/l) was blunted to 55.2 +/- 27%. At more physiological concentrations of ACTH (0.1 nmol/l), the inhibition of cortisol release by coincubation with low doses of leptin (10 ng/ml) was even more pronounced, leading to a reduction to 32.8% (1,248 +/- 134 vs. 410 +/- 157 nmol/l). Addition of OB protein (10-1,000 ng/ml) led to a dose-dependent reduction of ACTH-stimulated cytochrome P450 17alpha mRNA accumulation (from 80 to 45%), suggesting that leptin regulates adrenal steroidogenesis at the transcriptional level. These data clearly demonstrate that leptin inhibits cortisol production in adrenocortical cells and therefore appears to be a metabolic signal that directly acts on the adrenal gland.

Adrenal Glands↗
PubMed1997

[Clinical picture, diagnosis and therapy of acromegaly patients in Eastern and Western Germany].

Acromegaly, a chronic disease characterized by an excessive secretion of growth hormone (GH), is not commonly diagnosed timely enough. Therefore, investigations have been conducted through standardized questionnaires concerning the path to diagnosis, clinical data, therapy, and the patient care of 46 acromegalic patients. The acquired information has been compared in the former Eastern and Western German states. The mean duration of disease before diagnosis was estimated to be 6.1 +/- 5.3 years in the area surrounding Erlangen and 9.3 +/- 7.3 years in the Leipzig and Dresden areas. Despite current trends, a significant difference could not be established regarding the age in which the first symptoms are noted, time of diagnosis, and the delay between the two points in time General practitioners have diagnosed about 35 percent of the occurrences of acromegaly, 15 percent of the cases were accidentally found and about as many were discovered in hospitals. 11 percent of the occurrences were diagnosed by neurologists and another 11 percent by internists. The remaining cases were established by eye specialists. ENT departments, orthopedic specialists or gynaecologists. The most frequent symptoms are increased acral growth, coarse facial features and excessive sweating. For 91 percent of the acromegaly patients, surgery was voted as the therapy of choice. Acromegalic patients have learned the most about their disease through personal contact with doctors, especially endocrine specialists. Many patients are not informed enough about the possible complications of their disease. Through gathered data, it has been concluded that in Eastern and Western Germany the disease has not been identified soon enough. Interdisciplinary teamwork among doctors is a basis for early diagnosis, as well as better patient awareness and education.

Acromegaly↗
PubMed1996

Expression of interleukin-1 in human pheochromocytoma.

Cytokines and in particular interleukin 1 (IL-1) play a role in the micro-environment of various tumors. In addition, it is well established that IL-1 is a neurotrophic, angiogenetic and fibrogenetic factor. Using in situ hybridization we analyzed the expression of endogenous IL-1 in human pheochromocytoma (PCC). With the help of specific antibodies to B- and T-cells, macrophages, and neuroendocrine cell antigens, we characterized the distribution and localization of various cell types in human PCC. The combination of immunohistochemistry and in situ hybridization was eminently suited to defining the exact cellular source of IL-1 expression. In situ hybridization and immunostaining revealed that IL-1 mRNA was located primarily in the tumor cell itself. IL-1 may therefore constitute an important paracrine/autocrine factor in neuroendocrine tumors.

Adrenal Gland Neoplasms↗
PubMed1996

Angiotensin II regulates both adrenocortical and adrenomedullary function in isolated perfused pig adrenals.

The effect of angiotensin II (ANG II) on all four zones of the adrenal gland was studied in preparations of isolated perfused porcine adrenals. The experimental design offered the possibility to analyze directly the actions of ANG II while preserving the structure of the gland. ANG II stimulated aldosterone, cortisol, and androstenedione release in a dose-dependent manner. At a final ANG II concentration of 10(-8) M aldosterone increased from 0.7 +/- 0.05 to 3.4 +/- 0.9 ng/ml, cortisol from 50 +/- 5 to 430 +/- 60 micrograms/l, and androstenedione from 1.4 +/- 0.2 to 4.4 +/- 0.8 ng/ml. In addition, ANG II provoked a release of adrenaline from 4.1 +/- 0.6 to 27.5 +/- 0.5 micrograms/ml and of noradrenaline from 5.5 +/- 1.1 to 36.0 +/- 8.7 micrograms/ml. Our results show that secretion of both adrenocortical steroids and adrenomedullary catecholamines can be evoked by ANG II. ANG II seems to influence not only the function of the zona glomerulosa but the function of the entire adrenal gland.

Adrenal Cortex↗
PubMed1996

Megaoesophagus in a patient with autoimmune polyglandular syndrome type II.

Dysphagia and vomiting are frequently present in untreated Addison's disease. These non-specific symptoms may be due either to the metabolic disorder and myopathy or to disorders associated with Addison's disease. We describe a patient with autoimmune adrenal failure as a feature of autoimmune polyglandular syndrome (APS) type II. This patient was referred initially because of megaoesophagus. The association of megaoesophagus with Addison's disease or any of the three types of APS has not previously been described in humans. The association of megaoesophagus and adrenal failure, however, is known to occur in Allgrove's syndrome, a disease with primary manifestation in childhood characterized by adrenal failure, achalasia and alacrimia. Moreover, there are several reports on the association of megaoesophagus with adrenocortical insufficiency and other autoimmune endocrine diseases in dogs. Vomiting and dysphagia usually resolve with hormone substitution in patients with isolated Addison's disease. In our patient these symptoms disappeared in spite of the radiological persistence of megaoesophagus, which might have been overlooked if the diagnosis of Addison's disease had been made earlier. The occurrence of megaoesophagus might be more common than previously suspected and we suggest a systematic search for similar findings in other patients with autoimmune Addison's disease, even when minor dysphagia is present.

Esophageal Achalasia↗
PubMed1996

Ultrastructural dynamics of mitochondrial morphology in varying functional forms of human adrenal cortical adenoma.

Adrenal cortical mitochondria display an extensive capacity to adapt morphologically to the functional state of the adrenal cortical cell. In the present study, we have used transmission electron microscopy to analyze cortical tissues from 3 normal human adrenal glands (zona fasciculata and zona glomerulosa), and from 8 steroid-secreting adrenal cortical adenomas (3 cortisol-producing, 4 aldosterone-producing, and 1 progesterone-producing tumor), correlating both clinical and biochemical features with cellular ultrastructure. The morphology of mitochondria was related to the enzyme activity and steroid-biosynthetic capacity of each tumor. Cells from aldosterone-producing adenomas demonstrated a large number of elongated tubular mitochondria with characteristic bridging of inner membranes, producing a lamellar-type pattern. Cells from cortisol-producing adenomas showed large round mitochondria with vesicular or tubulovesicular inner membranes surrounded by a characteristic dilated smooth endoplasmic reticulum. A highly unusual progesterone-producing adenoma, in which a deficiency of 21 alpha-hydroxylase activity was demonstrated, showed a peculiar type of enlarged lamellar mitochondria with bright inner matrix and a reduced number of inner membranes. Therefore, the ultrastructural characteristics of adrenal cortical mitochondria appear to be potential markers for the differentiation of steroid-producing adenomas. These studies point to the possibility of a broader use of electron microscopy in the study of adrenal tumors.

Adenoma↗
PubMed1996

Cellular communication in the neuro-adrenocortical axis: role of vasoactive intestinal polypeptide (VIP).

It is well established now that adrenocortical function, besides being regulated through systemic factors, is influenced by intra-adrenal mechanisms. In this context paracrine influences between the sympathoadrenal system and the adrenal cortex play an important role. As a prerequisite for these interactions, adrenal medullary cells and cortical cells are highly interwoven as revealed by immunohistochemistry. The potential role of VIP in the regulation of human adrenal steroidogenesis was now investigated in human adrenal cells in primary culture. The primary cultures contained both, cortical and chromaffin cells which were found to be in close cellular contact as revealed by immunocytochemistry. VIP enhanced cortisol secretion from adrenal cells in a dose-dependent manner with a maximal effect at 10(-7) M. VIP stimulated the release of dehydroepiandrosterone (DHEA), testosterone, androstenedione, and aldosterone significantly. The addition of propranolol, a beta-adrenergic antagonist, to the incubation medium attenuated VIP-induced corticosteroid secretion. It is concluded that VIP is a paracrine messenger in the human adrenal that could regulate adrenocortical function at least in part via catecholamines released from the medulla.

Adrenal Cortex↗
PubMed1996

Direct effects of interleukin-6 on human adrenal cells.

Interleukin-6 (IL-6), which is expressed in the human adrenal gland, was found to be a very potent activator of the human HPA axis. So far nothing is known about a local paracrine or autocrine influence of IL-6 within the human adrenal. In this study, the expression of IL-6 and the IL-6 receptor by human adrenal cells in vitro could be demonstrated by immunohistochemistry. Possible effects of IL-6 on steroid release were tested by incubating human adrenal cells in vitro with IL-6 [10(-8) M]. Adrenal steroids were stimulated by IL-6: aldosterone 184 +/- 23, cortisol 198 +/- 19, DHEA 140 +/- 8 and androstenedione 136 +/- 5 (results are means +/- s.e.m. in %). In conclusion, IL-6 can act directly on human adrenal cells and appears to be an important paracrine or autocrine factor.

Adrenal Glands↗
PubMed1996

Differential regulation of apoptosis in the normal human adrenal gland.

Analysis of apoptosis in the human adrenal appears to be of eminent importance in the understanding of adrenal structure, zonation, and function. In this study we investigated the programmed cell death of normal adrenal tissues on the basis of apoptotic index by the nonradioactive in situ end labeling of DNA fragments, proliferating cell nuclear antigen, (PCNA), CD95 (cluster of differentiation), major histocompatibility complex class II immunohistochemistry, and ultrastructural analysis. The highest apoptotic index was detected in the outermost zones of the adrenal cortex, mainly in the zona glomerulosa. A labeling index of 50.46 +/- 5.22% (mean +/- SEM) for zona glomerulosa, 9.36 +/- 1.68% for zona fasciculata, 3.90 +/- 0.78% for zona reticularis, and 7.37 +/- 1.62% for the zona medullaris was found. Immunohistochemistry was used to distinguish between apoptotic and S phase cells. Positive anti-PCNA staining occurred in the inner cortical zones, whereas anti-CD95 signals appeared throughout the whole cortex, albeit at a much weaker level. MHC class II expression, which is known to be associated with programmed cell death, was demonstrated in the inner cortical zone. The data showed that mechanisms of cell death other than necrosis occur in the adrenal. In conclusion, we found a differential regulation of cell death for each zone of the adrenal cortex; the old theories of adrenal zonation (migrational vs. zonal or transformation theory) may, in fact, correlate with each other.

Adrenal Glands↗
PubMed1996

MHC class II expression--a new tool to assess dignity in adrenocortical tumours.

One in seventy randomly selected individuals is supposed to host an adrenal mass. The increasing number of incidentally detected adrenocortical adenomas requires the effective and reliable evaluation of dignity. So far this has been determined through a difficult multi-parametric analysis. Since MHC class II antigens are expressed in the normal adrenal cortex with a restriction to the zona reticularis, we examined 28 adrenocortical incidentalomas, 10 adenomas, 13 cortical carcinomas, 2 metastases, 10 controls as well as the adrenocortical carcinoma cell line NCI-H295 immunohistochemically for the expression of HLA class II antigens. We showed, that the majority of the adenomas still express class II antigens, whereas the expression is abrogated in all carcinomas examined. Our results indicate, that the detection of HLA class II positive tumour cells excludes malignancy. Therefore, MHC class II antigens may serve as a novel tumour marker in the evaluation of dignity in adrenocortical tumours. These findings could change the strategy for the assessment of adrenal masses.

Adrenal Cortex Neoplasms↗
PubMed1996

Human adrenal cells express tumor necrosis factor-alpha messenger ribonucleic acid: evidence for paracrine control of adrenal function.

Tumor necrosis factor (TNF) is gaining increasing importance in clinical medicine. It plays a role in the interaction of the immune system with the hypothalamic-pituitary-adrenal axis. In the present study various morphological methods, including immunohistochemistry, electron microscopy, and in situ hybridization were applied to characterize the localization and distribution of TNF in the human adrenal gland. Double immunostaining revealed an astonishing degree of intermingling of steroid-producing cells and chromaffin cells. Macrophages could be found in all regions of the adrenal gland, but particularly in the transition zone of cortex and medulla. The steroid-producing cells of the inner zone of the cortex express major histocompatibility complex class II molecules. On the ultrastructural level, immune cells, steroid cells, and catecholamine-producing cells were found in direct contact. The combination of immunohistochemistry and in situ hybridization was optimally suited to define the exact cellular source of TNF in the human adrenal. TNF is produced in macrophages, but above all in 17 alpha-hydroxylase-positive cells (steroid-producing cells) in the zona reticularis and medulla. No signal was found in chromaffin cells. TNF may induce major histocompatibility complex class II in human adrenal gland in a paracrine or autocrine manner. It is concluded that TNF may have an important role in normal human adrenal physiology.

Adrenal Cortex↗
PubMed1996

Functional aspects of the effect of prolactin (PRL) on adrenal steroidogenesis and distribution of the PRL receptor in the human adrenal gland.

Hyperprolactinemia is one of the most common disorders in endocrinology. A role for PRL on the human adrenal gland has been postulated in various clinical studies. We have demonstrated for the first time the expression of the PRL receptor in the human adrenal gland and in human adrenal primary cell cultures using PCR and immunohistochemical methods. Using immunostaining, we could detect the PRL receptor in all three zones of the adrenal cortex. Only weak staining was observed in the adrenal medulla. The influence of PRL on the secretion of cortisol, aldosterone, and androgens in human primary cell cultures was investigated. After stimulation with PRL (10(-7) mol/L), we measured increased concentrations of cortisol (155 +/- 9.8%; P < 0.005%), aldosterone (122 +/- 3.7%; P < 0.005), and dehydroepiandrosterone (121 +/- 8.6%; P < 0.05) in the cell supernatant. PRL did not affect the expression of messenger ribonucleic acid of cytochrome P45017 alpha in human adrenal cell cultures. In conclusion, we found the PRL receptor in the human adrenal gland. We postulate that PRL has a direct effect on adrenal steroidogenesis, thereby regulating adrenal function, which may be of particular relevance in clinical disorders with hyperprolactinemia.

Adrenal Cortex Hormones↗
PubMed1996

Evaluation of apoptotic parameters in normal and neoplastic human adrenal.

The migration and proliferation of adrenocortical cells is accompanied by mechanisms of cellular knock-out. We compared the programmed cell death of normal and malignant adrenocortical tissues on the basis of apoptotic rates by the nonradioactive in situ end-labelling of DNA-fragments, immunohistochemistry against PCNA, CD95 and ultrastructural analysis. The highest labelling index (LI) was detectable in the outermost zones of the adrenal cortex of normal adrenals. Average LI in normal adrenal cortex was 20% whereas only 2% was detectable in adrenocortical neoplasms. MHC class II, which was previously shown to be involved in programmed cell death in lymphocyte populations (1), was detectable in normal and benign but not in malignant adrenocortical neoplastic cells. In conclusion, the analysis of apoptosis provides new aspects of normal adrenal zonation and allows the differentiation between normal and neoplastic adrenal cortex although the differentiation between malignant and benign neoplasms requires further markers.

Adrenal Cortex↗
PubMed1995

Long-term effect of octreotide in acromegaly on insulin resistance.

An important feature of acromegaly is a reduced action of insulin on hepatic gluconeogenesis and peripheral glucosal disposal. Octreotide (SMS) exerts complex effects on hormonal and metabolic regulations affecting glucose homeostasis. Eight patients with active acromegaly despite surgical intervention (age 44.8 +/- 3.5 years, BMI 27.3 +/- 1.6 kg/m2, lean body mass (LBM) 70 +/- 3.2%, blood glucose 5.24 +/- 0.26 mmol/l, HbA1c < or = 6.5%) were investigated before and after 6 months of treatment with SMS in an open trial. SMS was injected sc. at a dosage between 100-200 micrograms t.i.d. Mean GH and IGF1 levels during SMS therapy were significantly reduced (GH 9.6 +/- 1.9 ng/ml vs. 4.9 +/- 1.3 ng/ml, p < 0.05; IGF1 729.5 +/- 84 ng/ml vs. 415 +/- 49 ng/ml, p < 0.05). OGTT and euglycaemic-clamp-studies were performed before and after 6 months of SMS treatment. The glucosal disposal rate on average (insulin infusion rate 40 mU/m2/min) was not significantly changed following SMS treatment (McLBM before 3.60 +/- 0.38, after 3.95 +/- 0.41 mg/kg LBM/min). There was a positive correlation (r = 0.620) between the individual change of IGF1 and the change of McLBM. Additionally there was no significant difference of serum basal insulin levels (0.19 +/- 0.01 vs. 0.23 +/- 0.06 nmol/l) as well as basal C-peptide levels (0.79 +/- 0.07 vs. 0.47 +/- 0.04 nmol/l) before and with SMS treatment. We therefore conclude that long-term treatment of acromegalic patients with SMS, which achieves a successful reduction of GH and IGF1 levels, does not always guarantee a significant improvement in glucose metabolism.(ABSTRACT TRUNCATED AT 250 WORDS)

Acromegaly↗