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Biomedical subjects

S R Bornstein

Publications and source records attributed to S R Bornstein.

At least 109 records · Page 6Linked to original sources
PubMed1998

The interaction between leptin and the hypothalamic-pituitary-thyroid axis.

The description of the adipose tissue hormone leptin has led to important discoveries. Leptin plays a role not only in the regulation of metabolic efficiency, energy expenditure, food intake and adiposity, but also contributes greatly to the adaptation of the organism to starvation. Much of the literature has focused on the physiologic roles of leptin-driven processes as diverse as feeding behavior, body weight, defense to starvation and reproduction. The following discussion summarizes knowledge that has accumulated regarding the interaction between leptin and the hypothalamic-pituitary-thyroid axis.

Adipose Tissue↗
PubMed1998

Leptin and interleukin-6 in sepsis.

Both leptin and interleukin-6 (IL-6) are hypersecreted in acute critical illness, such as sepsis. Leptin is produced by adipocytes, it inhibits appetite and stimulates the sympathetic nervous system, thereby reducing adipose mass. IL-6 is produced by immune cells and adipocytes, it reduces the production of other inflammatory cytokines and stimulates release of acute phase proteins by the liver, participating in the control of inflammation. Leptin inhibits, whereas IL-6 stimulates, the hypothalamic-pituitary-adrenal axis. While high IL-6 levels are associated with poor outcome in critically ill patients, the role of leptin in critical illness and its importance for survival are not known. To examine the relation between IL-6, leptin and cortisol in critical illness, we performed frequent 4 h plasma sampling in eight patients on day 1 of intensive care unit admission for acute sepsis. Sampling was repeated on days 3 and 5 in the five survivors. The levels of all three hormones were markedly elevated; there was a lack of the normal diurnal rhythmicity of leptin and IL-6 and a blunted diurnal rhythmicity of cortisol secretion. A strong negative correlation between mean 24 h plasma IL-6 and leptin was revealed. Although such a relationship could possibly be explained by the negative and positive effects of cortisol hypersecretion on each hormone respectively, a negative correlation between leptin and cortisol was detected, whereas there was no significant correlation between IL-6 and cortisol. Mean IL-6 values were higher (1389.5+/-644.9 vs. 658.8+/-250.5) and leptin levels were lower (2.73+/-1.1 vs. 26.5+/-11.6) in the non-survivors than in the survivors. These findings suggest that IL-6 is not the principal stimulus of leptin hypersecretion in critically ill patients with sepsis. The negative relation between IL-6 and leptin is of potential importance, as high IL-6 levels have been associated with poor outcome in critically ill patients, and relatively low leptin levels may impair sympathetic system and immune functions.

Circadian Rhythm↗
PubMed1998

Circulating leptin levels during acute experimental endotoxemia and antiinflammatory therapy in humans.

Leptin, a newly discovered adipose tissue-derived weight-reducing hormone, is increased in acute inflammation and may be involved in the anorexia and wasting syndrome associated with infection. To determine whether this hormone responds to an acute inflammatory stimulus, plasma leptin concentrations were measured in 12 healthy subjects after intravenous administration of endotoxin. These subjects were randomized to receive concurrently ibuprofen or placebo normal saline (6 in each group). Endotoxin administration resulted in fever, leukocytosis, and an increase in plasma levels of the stress hormones adrenocorticotropic hormone (3.2 +/- 0.3 to 132.6 +/- 75.5 pmol/L, P = .001) and cortisol (431.6 +/- 44 to 796.9 +/- 99 mmol/L, P = .001). Plasma leptin levels, however, did not change significantly from baseline values after administration of endotoxin (0 h: 6.9 +/- 3.1 ng/mL; 6 h: 6.0 +/- 2.2; 24 h: 6.5 +/- 2.8). While ibuprofen suppressed fever and symptoms associated with endotoxemia, it had no effect on the plasma levels of leptin. In conclusion, acute experimental human endotoxinemia is not associated with acute changes in circulating leptin levels.

Adrenocorticotropic Hormone↗
PubMed1998

The presence of chorionic gonadotrophin beta subunit in normal cyclic human endometrium.

The aim of the present study was to determine whether human endometrial cells are able to secrete beta-chorionic gonadotrophin (betaCG). Immunohistochemical studies and in-situ hybridization were performed in order to provide evidence for the occurrence of betaCG in the normal endometrium in 15 patients in the proliferative phase, two patients in the periovulatory phase and 13 patients in the secretory phase. Neither immunohistochemical nor hybridization reactions could be recognized during the proliferative phase. In contrast, both protein and betaCG mRNA were observed in the glandular cells of the endometrium during the secretory phase. The results were supported by Western blotting of secretory phase endometrium extracts and the assessment of the functional secretory capacity of primary endometrium cultures. In comparison with cultured and separated cell fractions, tissue extracts showed a higher betaCG, indicating a regulatory interaction. In conclusion, betaCG can be demonstrated in normal human cyclic endometrium, suggesting a paracrine role in endometrial physiology.

Cells, Cultured↗
PubMed1998

Basal steroidogenic activity of adrenocortical cells is increased 10-fold by coculture with chromaffin cells.

Historically, catecholamine-producing chromaffin cells and steroid-producing adrenocortical cells have been regarded as two independent endocrine systems that are united under a common capsule to form the adrenal gland. There is increasing evidence for bidirectional interactions, with regulatory influences of adrenocortical secretory products on adrenomedullary functions and vice versa. However, the direct involvement of chromaffin cells on the regulation and maintenance of cortical function has not yet been demonstrated. Therefore, we analyzed glucocorticoid secretion and P450 messenger RNA (mRNA) expression in bovine adrenocortical cells in cocultures with chromaffin cells compared with those in pure cortical cell cultures. Cortisol release from cortical cells in coculture with chromaffin cells was 10 times as high (mean +/- SEM, 1035 +/- 119%) as that from the same number of isolated cortical cells (100 +/- 11%). By a [3H]thymidine incorporation assay, it was demonstrated that this effect was not due to a higher proliferation rate. Northern analysis revealed an increasing expression of P450(17alpha) mRNA in the coculture from days 1-5, whereas in isolated cortical cells, P450(17alpha) mRNA decreased, leading to a 6-fold difference on day 5. Inhibitors of protein (cycloheximide) or RNA (actinomycin D) synthesis completely annulled the observed increase in cortisol release, indicating that de novo protein synthesis is required for this activation of adrenocortical steroidogenesis. Addition of the cyclooxygenase inhibitor indomethacin reduced the stimulatory effect, suggesting that this stimulation is in part mediated by PGs. Locally produced ACTH, catecholamines, and interleukin-1 accounted for 43% of the effect. Secretory products of chromaffin cells that act in concert are believed to be responsible for the stimulation of steroidogenesis in the coculture. The coculture system is an in vitro model that corresponds to the in vivo situation in the intact adrenal gland, where both endocrine cell systems are in close contact. Our data demonstrate the requirement of intraadrenal cellular communication for the full strength of the adrenocortical hormonal response.

Adrenal Cortex↗
PubMed1998

Chronic effects of a nonpeptide corticotropin-releasing hormone type I receptor antagonist on pituitary-adrenal function, body weight, and metabolic regulation.

CRH, the principal regulator of the hypothalamic-pituitary-adrenal axis and modulator of autonomic nervous system activity, also participates in the regulation of appetite and energy expenditure. Antalarmin, a pyrrolopyrimidine compound, antagonizes CRH type 1 receptor-mediated effects of CRH, including pituitary ACTH release, stress behaviors, and acute inflammation. We administered antalarmin chronically to evaluate its effects on hypothalamic-pituitary-adrenal axis function and metabolic status. Adult male rats were treated twice daily with 20 mg/kg of i.p. antalarmin or placebo over 11 days. The animals were weighed; plasma ACTH, corticosterone, leptin, and blood glucose levels were determined; and morphometric analyses were performed to determine adrenal size and structure, including sizing, histochemistry, immunohistochemistry, and electron microscopy. Leptin messenger RNA expression in peripheral fat was analyzed by Northern blot. Antalarmin decreased plasma ACTH (mean +/- SD, 2.62 +/- 0.063 pg/ml) and corticosterone concentrations (10.21 +/- 1.80 microg/dl) compared with those in vehicle-treated rats [respectively, 5.3 +/- 2.0 (P < 0.05) and 57.02 +/- 8.86 (P < 0.01)]. Antalarmin had no significant effect on body weight, plasma leptin, or blood glucose concentrations or fat cell leptin messenger RNA levels. The width of the adrenal cortex of animals treated with antalarmin was reduced by 31% compared with that in controls without atrophy of the gland. On the ultrastructural level, adrenocortical cells were in a hypofunctional state characterized by reduced vascularization, increased content of lipid droplets, and tubulovesicular mitochondria with fewer inner membranes. The apoptotic rate was increased in the outer zona fasciculata of animals treated with the antagonist (26.6 +/- 3.58%) compared with that in placebo-treated controls (6.8 +/- 0.91%). We conclude that chronic administration of antalarmin does not affect body weight, carbohydrate metabolism, or leptin expression, whereas it reduces adrenocortical function mildly, without anatomical, clinical, or biochemical evidence of causing adrenal atrophy. These results are promising for future uses of such an antagonist in the clinic.

Adipose Tissue↗
PubMed1998

Plasma leptin levels are increased in survivors of acute sepsis: associated loss of diurnal rhythm, in cortisol and leptin secretion.

Recent animal and human studies have suggested that leptin secretion is closely linked to the functions of the hypothalamic-pituitary-adrenal (HPA) axis and the immune system, both of which are crucial in influencing the course and outcome of critical illness. Therefore, we measured basal plasma leptin levels and examined the circadian secretion of leptin, in parallel with the hormones of the HPA axis and a key cytokine, interleukin-6, in critically ill patients with acute sepsis. Sixteen critically ill patients from the University of Leipzig Intensive Care Unit were recruited for this study. All of these patients fulfilled the standard diagnostic criteria for sepsis. Plasma leptin levels were measured in all patients and controls at 09:00. In addition, in a subgroup of eight critically ill patients and all of the nine controls plasma leptin, cortisol, ACTH and interleukin-6 concentrations were measured every 4 hours for 24 hours. Mean plasma leptin levels were three-fold higher (18.9 +/- 4.5 ng/ml) in critically ill patients than controls (3.8 +/- 1.0 ng/ml, p < 0.05). Similarly, ACTH levels were lower (7.8 +/- 3.4 pmol/l) in patients than in controls (17.1 +/- 1.5 pmol/l, p < .001), while plasma cortisol levels were increased (947.6 +/- 144 nmol/l) in patients compared to controls (361.1 +/- 29, p < 0.001). Morning plasma interleukin-6 levels were markedly elevated in all patients with sepsis (1238.0 +/- 543.1 pg/ml) versus controls (6.4 +/- 1.7, p < 0.001). The controls exhibited a nyctohemeral fluctuation in plasma leptin levels with peak levels at 23:00; in contrast, septic patients, had no nocturnal rise of leptin. In healthy controls, plasma leptin and cortisol had reciprocal circadian rhythms with high nocturnal leptin levels and low nocturnal cortisol concentrations; in critically ill patients, this relation was abolished. Mean leptin levels were three-fold higher in patients who survived the septic episode (25.5 +/- 6.2, n = 10) than in non-survivors (8.0 +/- 3.7, n = 6, p < 0.01). We conclude that in addition to its function as an anti-obesity factor, leptin may play a role in a severe stress state such as acute sepsis.

Biomarkers↗
PubMed1998

Expression of Ob receptor in normal human adrenals: differential regulation of adrenocortical and adrenomedullary function by leptin.

The major effects of leptin, an adipostatic hormone produced in fat tissue, are exerted through the hypothalamic-pituitary-adrenal axis and the systemic sympathetic/adrenomedullary system at the level of the central nervous system. Here, we examined the direct effects of leptin on the adrenal gland, a peripheral end organ of both the hypothalamic-pituitary-adrenal axis and the sympathetic/adrenomedullary system. As cortical and chromaffin tissues are intermingled in the human adrenal, we employed the novel technique of laser capture microdissection to analyze these systems separately. Functional full-length leptin receptor messenger ribonucleic acid and all human isoforms Ob219.1-3 were demonstrated by RT-PCR in both cortical and medullary tissue. Immunohistochemical staining of leptin receptor protein, however, demonstrated a strong signal only in the adrenal cortex, whereas there was weak positive staining in the medulla. Corticotropin (ACTH)-induced adrenal aldosterone, cortisol, and dehydroepiandrosterone secretion was inhibited by leptin in a concentration-dependent manner, whereas this hormone had no significant effect on catecholamine release by primary cultures of human adrenal chromaffin cells. Leptin itself was not expressed in human adrenal tissue, excluding a local paracrine or autocrine function of this peptide. In conclusion, this is the first report identifying functional leptin receptor in human adrenal tissue and showing a differential action of leptin on human adrenocortical and chromaffin hormone production. This peripheral action of leptin on the adrenal gland provides an additional important link between the human stress response and body weight regulation.

Adrenal Cortex↗
PubMed1998

The effect of corticotropin-releasing hormone (CRH) on the adrenal medulla in hypophysectomized rats.

CRH occurs in the adrenal medulla of rats. We were interested to know whether CRH affects meduallary chromaffin cells in the absence of ACTH. We investigated the morphological changes of the adrenal medulla in Sprague Dawley rats with light and electron microscopy in normal rats, hypophysectomized rats, and hypophysectomized rats following injections of CRH (10 micrograms = 3 nmol for three days). Chromaffin cells were characterized by immunohistochemistry (anti-tyrosine hydroxylase). At light microscopy level chromaffin cells of hypophysectomized rats were reduced in number. On electron microscopy the number of granules and cell organelles were decreased. Following injections of CRH the medulla regained a more compact texture with cell organelles homogenously distributed, but with chromaffin granules still being reduced in number. Immunohistochemistry allowed the identification of chromaffin cells located within the adrenal cortex. In hypophysectomized rats these cells showed fewer signs of alterations compared to cells located within the medulla itself and had recovered better after treatment with CRH. In conclusion, CRH seems to exert a trophic effect on chromaffin cells in the absence of pituitary ACTH. This observation may provide further evidence for a close interaction of the two neuroendocrine stress systems.

Adrenal Medulla↗
PubMed1997

Morphological and functional studies of the paracrine interaction between cortex and medulla in the adrenal gland.

Within the last years it has become evident that besides the hypothalamo-pituitary-adrenal axis, extrapituitary mechanisms exist that regulate the activity of the adrenal cortex. In this context, intra-adrenal regulatory mechanisms play an important role. Several secretory products from adrenomedullary cells are able to influence adrenocortical steroidogenesis. Since the main blood flow within the adrenal is directed centripetally from the cortex to the medulla, chromatin cells should act on cortical cells in a paracrine manner. The morphological prerequisite for this regulatory pathway is seen in the close apposition of the two tissues. Within the mammalian adrenal, the two endocrine tissues are interwoven to an astonishing degree with cortical cells located within the medulla and vice versa. It is concluded from morphological and functional studies that paracrine interactions between cortex and medulla play an important role in the regulation of adrenocortical steroidogenesis.

Adrenal Cortex↗
PubMed1997

Using the World Wide Web--a new approach to risk identification of diabetes mellitus.

Diabetes mellitus is a major health problem with a rising tendency world-wide. A new strategy for risk evaluation and data collection of undiagnosed non-insulin-dependent diabetes mellitus (NIDDM) using the World Wide Web (WWW) is presented. An easy-to-handle questionnaire on typical risk factors was converted into an interactive WWW document. The Internet provides the suitable platform for the net-based distribution of the questionnaire form as well as the computer-assisted entering and interpretation of the data (http:(/)/www.uni-leipzig.de/-diabetes). The analysis program, installed on our WWW server, interprets the information and sends the assessment on-line back to the inquiring user PC. The data are also collected anonymously in a database for epidemiological studies. In the test period, 744 world-wide accesses were registered: 433 men, mean age 39.8 +/- 14.4 years (range 10-83) and 311 women, mean age 36.7 +/- 12.7 years (range 11-77). An increased risk for undiagnosed diabetes was identified to 43.6%. The risk profile of male and female users showed no significant gender-related differences. Using the WWW technology can support early detection and adequate treatment of undiagnosed diabetes. This innovative strategy to screen for a high risk profile is an useful, cost-effective and up-to-date tool for broad community health education and epidemiological studies world-wide.

Adolescent↗
PubMed1997

17 alpha-Hydroxylase and chromogranin A in 6th week human fetal adrenals.

The development of the human fetal adrenals starts in the 6th week gestational age and adrenal C19 steroid production becomes of major importance for the maintenance of the pregnancy. Therefore, in the present study, human fetal adrenals at 6 weeks of gestational age were immunostained for 17 alpha-hydroxylase, the key enzyme for the production of C19-steroids. In parallel, chromaffin cells were characterized by immunohistochemical staining for chromogranin A, the major soluble protein in adrenal chromaffin granules. Large 17 alpha-hydroxylase-immunoreactive cells were found in the center of the adrenal anlagen during the 6th week of gestation. At the same developmental stage, chromaffin cells with a neuronal-like appearance occurred in the paraortic area and started to invade the adrenal primordium. Our results show that, even at week 6 gestational age, when chromaffin cells start to enter the adrenal anlagen, human adrenals already contain differentiated, 17 alpha-hydroxylase immunoreactive cortical cells which were located to the center of the primordium.

Adrenal Glands↗
PubMed1997

Corticotropin-releasing hormone-binding protein and its possible role in neuroendocrinological research.

Corticotropin-releasing hormone-binding protein (CRH-BP), predominately produced by the liver, is a glycoprotein with a molecular weight of 37 kDa. The mature protein consists of 7 exons and 6 introns, with 5 tandem disulfide bridges which are essential for the binding of corticotropin-releasing hormone (CRH). This binding protein is distributed and expressed differently from corticotropin-releasing hormone receptors (CRH-Rs), as is the ligand requirement. Most CRH in plasma is bound to its binding protein, is therefore inactive and unable to bind to its receptor. Other competitives can reverse the binding, liberating CRH. Together with the CRH neuropeptides and CRH receptors, CRH-binding protein plays a role in the hypothalamic-pituitary-adrenal axis, in immune/inflammatory reactions as an auto/paracrine proinflammatory regulator, in pregnancy, as well as in some pathological conditions.

Adrenocorticotropic Hormone↗