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G P Chrousos

Publications and source records attributed to G P Chrousos.

At least 19 recordsLinked to original sources
PubMed2001

High constitutive glucocorticoid receptor beta in human neutrophils enables them to reduce their spontaneous rate of cell death in response to corticosteroids.

Neutrophils are markedly less sensitive to glucocorticoids than T cells, making it difficult to control inflammation in neutrophil-mediated diseases. Development of new antiinflammatory strategies for such diseases would be aided by an understanding of mechanisms underlying differential steroid responsiveness. Two protein isoforms of the human glucocorticoid receptor (GR) exist, GRalpha and GRbeta, which arise from alternative splicing of the GR pre-mRNA primary transcripts. GRbeta does not bind glucocorticoids and is an inhibitor of GRalpha activity. Relative amounts of these two GRs can therefore determine the level of glucocorticoid sensitivity. In this study, human neutrophils and peripheral blood mononuclear cells (PBMCs) were studied to determine the relative amounts of each GR isoform. The mean fluorescence intensity (MFI) using immunofluorescence analysis for GRalpha was 475 +/- 62 and 985 +/- 107 for PBMCs and neutrophils, respectively. For GRbeta, the MFI was 350 +/- 60 and 1,389 +/- 143 for PBMCs and neutrophils, respectively (P < 0.05). After interleukin (IL)-8 stimulation of neutrophils, there was a statistically significant increase in intensity of GRbeta staining to 2,497 +/- 140 (P < 0.05). No change in GRalpha expression was observed. This inversion of the GRalpha/GRbeta ratio in human neutrophils compared with PBMCs was confirmed by quantitative Western analysis. Increased GRbeta mRNA expression in neutrophils at baseline, and after IL-8 exposure, was observed using RNA dot blot analysis. Increased levels of GRalpha/GRbeta heterodimers were found in neutrophils as compared with PBMCs using coimmunoprecipitation/Western analysis. Transfection of mouse neutrophils, which do not contain GRbeta, resulted in a significant reduction in the rate of cell death when treated with dexamethasone.We conclude that high constitutive expression of GRbeta by human neutrophils may provide a mechanism by which these cells escape glucocorticoid-induced cell death. Moreover, upregulation of this GR by proinflammatory cytokines such as IL-8 further enhances their survival in the presence of glucocorticoids during inflammation.

Adrenal Cortex Hormones↗
PubMed2001

Increased ACTH and cortisol secretion after interleukin-alpha injection in the common marmoset (Callithrix jacchus jacchus).

We have studied the effect of intravenous injection of interleukin-1 (dose range: from 0.25 to 4.5 microg/kg of body weight) on plasma ACTH and cortisol levels in the marmoset, a primate paradygm of peripheral glucocorticoid resistance. Blood sampling were collected and body temperature recorded 0, 15, 30, 60, 120, 180, 240 and 300 min after injection. Interleukin-1 stimulated secretion of ACTH in a dose-dependent fashion. Maximal secretion occurred 120 min after injection, and lasted up to 240 min. Plasma ACTH levels returned to baseline 300 min after interleukin-1 injection. Plasma cortisol levels were related to ACTH levels. Body temperature elevation, which occurred 10-15 min after injection was dose-dependent, and lasted 3 h. Results suggest that the pyrogenic effect of interleukin is associated, in the marmoset, with integrated activation of the hypothalamic-pituitary-adrenal axis. In light of the proneness of marmosets to hyperimmune disorders, our data are consistent with the hypothesized central biological role of IL-1, as well as the pathophysiological relevance of the neuro-endocrine-immune cross-talk during the acute phase response.

Adrenocorticotropic Hormone↗
PubMed2001

The development of a potential single photon emission computed tomography (SPECT) imaging agent for the corticotropin-releasing hormone receptor type.

A high-affinity radioligand for CRHR1 has been prepared that can serve as a template for the development of SPECT imaging agents. The 5-chloro-N-cyclopropylmethyl-N-(2,6-dichloro-4-iodophenyl)-2-methyl-N-propylpyrimidine-4,6-diamine (6b, Ki = 14 nM), and the corresponding 4-bromophenyl analogue (6a, Ki = 21 nM), were synthesized in four steps from compound 3.

Animals↗
PubMed2001

Leptin mediates a proliferative response in human gastric mucosa cells with functional receptor.

BACKGROUND: Recently, the rat stomach was reported as a source of leptin, a hormone mainly secreted by adipocytes. Also Helicobacter pylori-induced gastritis in humans was associated with locally elevated leptin levels. In addition, it was suggested that gastric leptin adjusts the function of the intestinal tract in parallel to the function of hypothalamic satiety centers. AIMS: Here we examined the synthesis and potential physiologic role of leptin in the human stomach. METHODS: RT-PCR was employed to detect leptin mRNA in the human stomach and the human gastric carcinoma cell line AGS while immunogold staining and electron microscopy were used to detect leptin protein. The in vitro effects of leptin on cell proliferation were examined in the AGS cell line. RESULTS: No leptin mRNA could be detected by RT-PCR, yet immunogold labeling and electron microscopy allowed visualization of leptin protein in the human gastric mucosa. At concentrations of 100 nM, leptin led to a significantly increased BrdU-uptake in AGS cells (+27%, p < 0.017). The MAP-kinase-1-specific inhibitor U0126 blocked the leptin-induced cell proliferation in a dose-dependent fashion. CONCLUSIONS: Leptin protein may not be produced but rather stored in human gastric cells. Leptin-induced increases in the proliferation of gastric mucosa cells suggests that leptin might contribute to mucosal integrity and gastroprotection.

Carrier Proteins↗
PubMed2001

Circulating plasma leptin and IGF-1 levels in girls with premature adrenarche: potential implications of a preliminary study.

Premature adrenarche is a condition characterized by precocious development of pubic and/or axillary hair, due to early onset of adrenal androgen secretion. Girls with premature adrenarche may later develop menstrual irregularities, hyperandrogenism, and the classic polycystic ovary syndrome. As leptin is thought to modulate the onset of pubertal development, we measured plasma leptin levels in 7 girls with premature adrenarche, and 8 age-matched comparison girls. Because leptin, the hypothalamic-pituitary-adrenal (HPA), the hypothalamic-pituitary-gonadal axes are functionally interrelated, we also determined salivary and plasma cortisol, dehydroepiandrosterone (DHEA), DHEA-sulfate, androstenedione, estradiol, and estrone. Finally, since IGF-I may play a role in adrenocortical function, we determined plasma levels of IGF-1, and IGF-BP1. Plasma was collected by an intravenous catheter at times 0, 20, and 40 min, starting at 1.30 p.m. Girls with premature adrenarche had a higher body mass index (BMI) and an over two-fold elevation of their plasma leptin than comparison girls. This group also had elevated levels of salivary and plasma cortisol, and increased levels of DHEA, DHEA-S, androstenedione, estradiol and estrone. Plasma IGF-1 and the ratio of IGF-1/IGF-BP1 were elevated. We propose that girls with premature adrenarche may represent an overlapping group characterized by both features of increased adiposity and HPA axis activity, which together, and depending on the genetic/constitutional background of the individual, may account for the development of adrenal hyperandrogenism, and, later, the polycystic ovary syndrome.

Adrenal Glands↗
PubMed2001

Decreased steroid responsiveness at night in nocturnal asthma. Is the macrophage responsible?

As peripheral blood mononuclear cells from patients with nocturnal asthma (NA) exhibit reduced steroid responsiveness at 4:00 A.M. as compared with 4:00 P.M., we hypothesized that NA is associated with increased nocturnal airway cell expression of GRbeta, an endogenous inhibitor of steroid action. Ten subjects with NA and seven subjects with nonnocturnal asthma (NNA) underwent bronchoscopy with bronchoalveolar lavage (BAL) at 4:00 P.M. and 4:00 A.M. BAL lymphocytes and macrophages were incubated with dexamethasone (DEX) at 10(-5) to 10(-8) M. DEX suppressed proliferation of BAL lymphocytes similarly at 4:00 P.M. and 4:00 A.M. in both groups. However, BAL macrophages from NA exhibited less suppression of IL-8 and TNF-alpha production by DEX at 4:00 A.M. as compared with 4:00 P.M. (p = 0.0001), whereas in the NNA group DEX suppressed IL-8 and TNF-alpha production equally at both time points. GRbeta expression was increased at night only in NA, primarily due to significantly increased expression by BAL macrophages (p = 0.008). IL-13 mRNA expression was increased at night, but only in the NA group and addition of neutralizing antibodies to IL-13 reduced GRbeta expression by BAL macrophages. We conclude that the airway macrophage may be the airway inflammatory cell driving the reduction in steroid responsiveness at night in NA, and this function is modulated by IL-13.

Adult↗
PubMed2001

Hydrocortisone suspension and hydrocortisone tablets are not bioequivalent in the treatment of children with congenital adrenal hyperplasia.

In July 1998, Cortef oral suspension (Pharmacia & Upjohn) was reformulated changing the suspending agent tragacanth to xanthan gum. We subsequently observed suboptimal control of hormone levels in a group of children with classic congenital adrenal hyperplasia, despite increasing doses of Cortef suspension and stringent instructions to parents regarding shaking of the bottles of medication. Nineteen children receiving Cortef and fludrocortisone therapy were changed to hydrocortisone tablets and fludrocortisone, with a 10 percent reduction in hydrocortisone dose. A significant decrease in 17-hydroxyprogesterone (235 +/- 120 vs. 27 +/- 7 nmol/L; p</=0.001) and androstenedione (18.9 +/- 18.0 vs. 3.5 +/- 3.5 nmol/L; p=0.002) was observed 4-6 weeks later. Twenty-one percent (4/19) had 17-hydroxyprogesterone and androstenedione levels at or below the detection limit of the assay. Despite a significant reduction in glucocorticoid dose (19.6 +/- 4.7 vs. 17.6 +/- 3.9 mg/M(2)/day; p<0.001), eight children experienced significant weight gain and appetite increase, three experienced trouble sleeping, four experienced moodiness, and three developed hypertension requiring a decrease in fludrocortisone therapy. Hydrocortisone dose was further decreased to 15.2 +/- 2.6 mg/M(2)/day with resolution of symptoms. We conclude that Cortef suspension and hydrocortisone tablets are not bioequivalent and the reformulated form of hydrocortisone oral suspension was inadequate in the control of children with congenital adrenal hyperplasia. Cortef suspension has been recalled as a result of these data.

17-alpha-Hydroxyprogesterone↗
PubMed2001

Polycystic ovary syndrome is associated with obstructive sleep apnea and daytime sleepiness: role of insulin resistance.

Polycystic ovary syndrome (PCOS) is the most common endocrine disorder of premenopausal women, characterized by chronic hyperandrogenism, oligoanovulation, and insulin resistance. Obstructive sleep apnea (OSA) and excessive daytime sleepiness (EDS) are strongly associated with insulin resistance and hypercytokinemia, independently of obesity. We hypothesized that women with PCOS are at risk for OSA and EDS. Fifty-three women with PCOS (age range, 16-45 yr) and 452 control premenopausal women (age range, 20-42), from a general randomized sample for the assessment of prevalence of OSA, were evaluated in the sleep laboratory for 1 night. In addition, women with PCOS were tested for plasma free and weakly bound testosterone, total testosterone, and fasting blood glucose and insulin concentrations. In this study, PCOS patients were 30 times more likely to suffer from sleep disordered breathing (SDB) than the controls [odds ratio = 30.6, 95% confidence interval (7.2-139.4)]. Nine of the PCOS patients (17.0%) were recommended treatment for SDB, in contrast with only 3 (0.6%) of the control group (P < 0.001). In addition, PCOS patients reported more frequent daytime sleepiness than the controls (80.4% vs. 27.0%, respectively; P < 0.001). PCOS patients who were recommended treatment for SDB, compared with those who were not, had significantly higher fasting plasma insulin levels (306.48 +/- 52.39 vs. 176.71 +/- 18.13 pmol/L, P < 0.01) and a lower glucose-to-insulin ratio (0.02 +/- 0.00 vs. 0.04 +/- 0.00, P < 0.05). Plasma free and total testosterone and fasting blood glucose concentrations were not different between the two groups of PCOS women. Our data indicate that SDB and EDS are markedly and significantly more frequent in PCOS women than in premenopausal controls. Also, insulin resistance is a stronger risk factor than is body mass index or testosterone for SDB in PCOS women. These data support our proposal that, independently of gender, sleep apnea might be a manifestation of an endocrine/metabolic abnormality in which insulin resistance plays a principal role.

Adolescent↗
PubMed2001

Middle-aged men show higher sensitivity of sleep to the arousing effects of corticotropin-releasing hormone than young men: clinical implications.

The prevalence of insomnia associated with emotional stress increases markedly in middle-age. Both the top and end hormones of the hypothalamic-pituitary-adrenal axis, i.e. CRH and glucocorticoids, stimulate arousal/wakefulness and inhibit slow wave (deep) sleep in experimental animals and man. The objective of this study was to test the hypothesis that middle-age is characterized by increased sensitivity to the sleep-disturbing effects of the hypothalamic-pituitary-adrenal axis. We studied 12 healthy middle-aged (45.1 +/- 4.9) and 12 healthy young (22.7 +/- 2.8) men by monitoring their sleep by polysomnography for 4 consecutive nights, including in tandem 1 adaptation and 2 baseline nights and a night during which we administered equipotent doses of ovine CRH (1 microg/kg, iv bolus) 10 min after sleep onset. Analyses included comparisons within and between groups using multiple ANOVA and regression analysis. Although both middle-aged and young men responded to CRH with similar elevations of ACTH and cortisol, the former had significantly more wakefulness and suppression of slow wave sleep compared with baseline sleep; in contrast, the latter showed no change. Also, comparison of the change in sleep patterns from baseline to the CRH night in the young men to the respective change observed in middle-aged men showed that middle-age was associated with significantly higher wakefulness and significantly greater decrease in slow wave sleep than in young age. We conclude that middle-aged men show increased vulnerability of sleep to stress hormones, possibly resulting in impairments in the quality of sleep during periods of stress. We suggest that changes in sleep physiology associated with middle-age play a significant role in the marked increase of prevalence of insomnia in middle-age.

Adrenocorticotropic Hormone↗
PubMed2001

Human breast adipocytes express interleukin-6 (IL-6) and its receptor system: increased IL-6 production by beta-adrenergic activation and effects of IL-6 on adipocyte function.

Adipocytes produce the inflammatory cytokine interleukin-6 (IL-6); however, it is not known whether these cells express the IL-6 receptor system, how the secretion of this cytokine is regulated, and whether it has a function within adipose tissue. Using cultured human breast adipocytes, we investigated the expression of IL-6 and its receptor system, the effects of IL-6 on main adipocyte functions, and the regulation of IL-6 secretion by catecholamines and glucocorticoids. In the culture system, immunohistochemistry demonstrated expression of IL-6 and its receptor system, consisting of the ligand-binding IL-6 receptor and the signal-transducing protein gp130, in mature adipocytes, but not in undifferentiated adipocyte precursor cells. In freshly isolated adipocytes, RT-PCR detected messenger ribonucleic acids encoding the above proteins. Chronic incubation of adipocytes with 1 nmol/L IL-6 during adipose differentiation reduced glycero-3-phosphate dehydrogenase (GPDH) activity, a marker of adipocyte differentiation, and triglyceride synthesis to 67 +/- 9% of the basal level (mean +/- SEM; P < 0.05) only on day 21. Incubation of differentiated adipocytes with 10 nmol/L IL-6 for 24 h also resulted in a reduction of GPDH activity to 81 +/- 5% (P < 0.05). On the other hand, 24-h exposure to 10 nmol/L IL-6 increased basal glycerol release by 42 +/- 12% (P < 0.01) and isoproterenol-induced glycerol release by 21 +/- 6% (P < 0.05). The same concentration of IL-6, however, did not alter basal or insulin-stimulated glucose transport. IL-6 secretion was acutely and chronically stimulated by 1 micromol/L isoproterenol (peak of 6.2-fold after 3 h; P < 0.001) and only moderately suppressed by 100 nmol/L cortisol (-36 +/- 10%; P < 0.001). In conclusion, human breast adipocytes release substantial amounts of IL-6 and express IL-6 receptor and gp130. The secretion of IL-6 by adipocytes is strongly stimulated by beta-adrenergic activation and is modestly suppressed by glucocorticoids. IL-6 reduces GPDH activity and stimulates lipolysis, suggesting an autocrine/paracrine role of this cytokine in human adipose breast tissue.

Adipocytes↗
PubMed2000

Glucocorticoids suppress human immunodeficiency virus type-1 long terminal repeat activity in a cell type-specific, glucocorticoid receptor-mediated fashion: direct protective effects at variance with clinical phenomenology.

Glucocorticoid administration and/or excess secretion have been associated with increased Human Immunodeficiency Virus Type-1 (HIV-1) replication and AIDS progression. The HIV-1 long terminal repeat (LTR) promoter contains glucocorticoid-responsive element (GRE)-like sequences that could mediate a positive effect of glucocorticoids on HIV-1. In addition, we recently demonstrated that the HIV-1 accessory protein Vpr is a potent coactivator of the glucocorticoid receptor, which, like the host coactivator p300, potentiates the effect of glucocorticoids on GRE-containing, glucocorticoid-responsive genes. Such an effect may increase the sensitivity of several host target tissues to glucocorticoids by several fold, and may, thus, contribute to a positive effect of glucocorticoids on the HIV-1-LTR in infected host cells. In this study, we determined the direct effect of glucocorticoids on HIV-1-LTR by examining the ability of dexamethasone to modulate the activity of this promoter coupled to the luciferase reporter gene in human cell lines. Dexamethasone markedly inhibited Tat-stimulated, p300- or Vpr-enhanced luciferase activities in a cell-type specific, dose-dependent, and glucocorticoid receptor-mediated fashion. This effect of dexamethasone was not potentiated by Vpr, was antagonized by the glucocorticoid receptor antagonist RU 486 and required the DNA-binding domain of the receptor. These data suggest that the inhibitory effect of glucocorticoids on the HIV-1-LTR may be exerted via non-GRE-dependent inhibition of the strongly positive host transcription factor NF-kappaB, which interacts with the DNA- and ligand-binding domains of the receptor. Alternatively, it is also possible that dexamethasone-activated glucocorticoid receptor competes with other transcription factors for their binding sites on the promoter region or squelches transcription factors shared by HIV-1-LTR and glucocorticoid-responsive promoters. We conclude that glucocorticoids suppress, rather than stimulate, the HIV-1 promoter, thus acting, protectively for the host. Their apparent negative clinical association with AIDS is most likely due to immunosuppression of the host.

Animals↗
PubMed2000

Deletion of tyrosine hydroxylase gene reveals functional interdependence of adrenocortical and chromaffin cell system in vivo.

Catecholamines are produced in the medulla of the adrenal gland and may participate in the intraglandular regulation of its cortex. We analyzed the adrenal structure and function of albino tyrosine hydroxylase-null (TH-null) mice that are deficient in adrenal catecholamine production. Adrenal catecholamines were markedly reduced, and catecholamine histofluorescence was abrogated in 15-day-old TH-null mice. Chromaffin cell structure was strikingly altered at the ultrastructural level with a depletion of chromaffin vesicles and an increase in rough endoplasmic reticulum compared with wild-type mice. Remaining chromaffin vesicles lined up proximally to the cell membrane in preparation for exocytosis providing a "string-of-pearls" appearance. There was a 5-fold increase in the expression of proenkephalin mRNA (502.8 +/- 142% vs. 100 +/- 17.5%, P = 0.016) and a 2-fold increase in the expression of neuropeptide Y (213.4 +/- 41.2% vs. 100 +/- 59.9%, P = 0.014) in the TH-null animals as determined by quantitative TaqMan (Perkin-Elmer) PCR. Accordingly, immunofluorescence for met-enkephalin and neuropeptide tyrosine in these animals was strongly enhanced. The expression of phenylethanolamine N-methyl transferase and chromogranin B mRNA was similar in TH-null and wild-type mice. In TH-null mice, adrenocortical cells were characterized by an increase in liposomes and by tubular mitochondria with reduced internal membranes, suggesting a hypofunctional state of these steroid-producing cells. In accordance with these findings, plasma corticosterone levels were decreased. Plasma ACTH levels were not significantly different in TH-null mice. In conclusion, both the adrenomedullary and adrenocortical systems demonstrate structural and functional changes in catecholamine-deficient TH-null mice, underscoring the great importance of the functional interdependence of these systems in vivo.

Adrenal Glands↗
PubMed2000

Duplication of the mutant RET allele in trisomy 10 or loss of the wild-type allele in multiple endocrine neoplasia type 2-associated pheochromocytomas.

Inherited mutations of the RET proto-oncogene are tumorigenic in patients with multiple endocrine neoplasia type 2 (MEN 2). However, it is not understood why only few of the affected cells in the target organs develop into tumors. Genetic analysis of nine pheochromocytomas from five unrelated patients with MEN 2 showed either duplication of the mutant RET allele in trisomy 10 or loss of the wild-type RET allele. Our results suggest a "second hit" causing a dominant effect of the mutant RET allele, through either duplication of the mutant allele or loss of the wild-type allele, as a possible mechanism for pheochromocytoma tumorigenesis in patients with MEN 2.

Adrenal Gland Neoplasms↗
PubMed2000

Adrenomedullary dysplasia and hypofunction in patients with classic 21-hydroxylase deficiency.

BACKGROUND: Glucocorticoids are essential for the normal development and functioning of the adrenal medulla. Whether adrenomedullary structure and function are normal in patients with congenital adrenal hyperplasia is not known. METHODS: We measured plasma and urinary catecholamines and plasma metanephrines in 38 children with congenital adrenal hyperplasia due to 21-hydroxylase deficiency (25 children with the salt-wasting form and 13 with the simple virilizing form), 39 age-matched normal subjects, and 20 patients who had undergone bilateral adrenalectomy. Adrenal specimens obtained from three other patients with 21-hydroxylase deficiency who had undergone bilateral adrenalectomy and specimens obtained at autopsy from eight other patients were examined histologically. RESULTS: Plasma epinephrine and metanephrine concentrations and urinary epinephrine excretion were 40 to 80 percent lower in the patients with congenital adrenal hyperplasia than in the normal subjects (P<0.05), and the values were lowest in the patients with the most severe deficits in cortisol production. Urinary epinephrine excretion and plasma epinephrine concentrations were at or below the limit of detection of the assay in 8 (21 percent) of the patients with congenital adrenal hyperplasia and in 19 (95 percent) of the patients who had undergone adrenalectomy. In the group of patients with congenital adrenal hyperplasia, plasma epinephrine and metanephrine concentrations and urinary epinephrine excretion were approximately 50 percent lower in those who had been hospitalized for adrenal crises than in those who had not. In three patients with congenital adrenal hyperplasia who had undergone bilateral adrenalectomy, the formation of the adrenal medulla was incomplete, and electron-microscopical studies revealed a depletion of secretory vesicles in chromaffin cells. CONCLUSIONS: Congenital adrenal hyperplasia compromises both the development and the functioning of the adrenomedullary system.

Adolescent↗
PubMed2000

Self-reported sensitivity to chemical exposures in five clinical populations and healthy controls.

Two hundred and twenty-five subjects, including normal volunteers and patients with previously documented seasonal affective disorder (SAD), chronic fatigue syndrome (CFS), Cushing's syndrome, Addison's disease and obsessive-compulsive disorder (OCD), completed a self-rated inventory of reported sensitivity to various chemical exposures. Patients with CFS, Addison's disease and SAD self-reported more sensitivity to chemical exposures than normal controls. In addition, women reported more sensitivity than men. This report suggests that chemical sensitivity may be a relevant area to explore in certain medical and psychiatric populations. A possible relationship between reported chemical sensitivity and hypothalamic-pituitary-adrenal (HPA)-axis functioning is discussed.

Addison Disease↗
PubMed2000

Oral administration of a corticotropin-releasing hormone receptor antagonist significantly attenuates behavioral, neuroendocrine, and autonomic responses to stress in primates.

We evaluated the effects of the lipophilic nonpeptide corticotropin-releasing hormone (CRH) type 1 receptor antagonist antalarmin on the behavioral, neuroendocrine, and autonomic components of the stress response in adult male rhesus macaques. After oral administration, significant antalarmin concentrations were detected in the systemic circulation and the cerebrospinal fluid by a mass spectrometry-gas chromatography assay developed specifically for this purpose. Pharmacokinetic and dose-response studies suggested that an oral dose of 20 mg/kg was optimal for behavioral and endocrine effects. We then administered this dose in a double-blind, placebo-controlled fashion to monkeys exposed to an intense social stressor: namely, placement of two unfamiliar males in adjacent cages separated only by a transparent Plexiglas screen. Antalarmin significantly inhibited a repertoire of behaviors associated with anxiety and fear such as body tremors, grimacing, teeth gnashing, urination, and defecation. In contrast, antalarmin increased exploratory and sexual behaviors that are normally suppressed during stress. Moreover, antalarmin significantly diminished the increases in cerebrospinal fluid CRH as well as the pituitary-adrenal, sympathetic, and adrenal medullary responses to stress. We conclude that CRH plays a broad role in the physiological responses to psychological stress in primates and that a CRH type 1 receptor antagonist may be of therapeutic value in human psychiatric, reproductive, and cardiovascular disorders associated with CRH system hyperactivity.

Administration, Oral↗