Suppression of the hypothalamic-pituitary-adrenal axis after oral hydrocortisone succinate ingestion in rats.

Groups of Holtzman female rats were fed 10 mg/day of hydrocortisone succinate orally to study the responsiveness of the hypothalamic-pituitary-adrenal axis to acute stress. Pituitary ACTH content, plasma ACTH, adrenal venous corticosterone, and adrenal weights were studied simultaneously in experimental and control rats before, during, and up to two weeks after oral hydrocortisone administration. There was a significant decrease in pituitary ACTH content (p=<0.001), suppression of plasma ACTH and corticosterone in response to acute stress (p=<0.001), and adrenal atrophy during and following oral hydrocortisone administration. After discontinuing the hydrocortisone it required three to five days for the rats to respond adequately to acute stress. However, it was seven to ten days post-hydrocortisone before plasma ACTH and corticosterone responses to acute stress had returned to basal values, but decreased pituitary ACTH content and partial adrenal atrophy continued throughout the ten-day post-hydrocortisone study interval. Recovering from the suppressive effects of oral hydrocortisone was more rapid than following parenteral hydrocortisone. However, oral hydrocortisone causes identical but less sustained suppression of the hypothalamic-pituitary-adrenal axis as observed in animals treated with parenteral glucocorticoid preparations.     

Changes in subcutaneous connective tissue of rats after injection of cortisone

Summary The author studied the effect of cortisone on the relative quantities of different cell forms on the histochemical characterstics of cells and of ground substance in the subcutaneous tissue of normal rats. Cortisone stimulated the process of fibroblast differentiation, causing a striking increase in the mean percentage of the most differentiated fibroblasts (fibrocytes). Cortisone provoked no degeneration of fibroblasts or any changes of histochemical peculiarities in the ground substance or in the connective tissue cells. No increase in the amount of the ground substance was noted during differentiation of fibroblasts into fibrocytes.(Presented by Active Member of AMN SSSR A. D. Timofeevskii) Translated from Byulleten' Éksperimental'noi Biologii i Meditsiny, Vol. 50, No. 7, pp. 99–102, July 1960     

Suppression of hypothalamic-pituitary-adrenal axis activity with inhaled flunisolide and fluticasone propionate in adult asthma patients.

BACKGROUND: Suppression of the hypothalamic-pituitary-adrenal (HPA) axis, a potential systemic effect of inhaled corticosteroid therapy, can be quantified by monitoring serum, urinary, and salivary cortisol levels. OBJECTIVES: 1) Compare the effects on HPA axis of the inhaled corticosteroids flunisolide and fluticasone propionate versus placebo and oral prednisone. 2) Estimate dose-potency ratio for HPA-axis suppression. METHODS: Multicenter, randomized, placebo-controlled, open-label, 21-day trial. Active regimens were flunisolide 500 and 1,000 microg, twice daily; fluticasone propionate 110, 220, 330, and 440 microg, twice daily; and prednisone, 7.5 mg daily. Enrolled patients were nonsmokers, 18 to 50 years of age, with persistent mild-to-moderate asthma and had not used oral, nasal, or inhaled corticosteroids for 6 months before study. Main outcome measures were area under serum cortisol concentration curve for 22 hours (AUC(0-22h)); 24-hour urinary cortisol level; and 8 AM salivary cortisol level. RESULTS: One hundred fifty-three patients were randomly assigned to active treatment or placebo; 125 patients completed the study and were at least 80% compliant with their regimens. Both fluticasone propionate and flunisolide caused dose-dependent suppression of HPA axis, which was statistically greater for fluticasone propionate (P = 0.0003). Dose-potency ratio showed 4.4 times more serum-cortisol suppression/microgram increase in dose with fluticasone propionate than with flunisolide. Diurnal pattern of serum cortisol suppression was persistent with fluticasone propionate and "remitting" with flunisolide. Salivary and urinary cortisol data were qualitatively similar to serum cortisol results. CONCLUSIONS: Fluticasone caused significantly more suppression of HPA axis than flunisolide. Flunisolide may provide a safe option for patients with asthma requiring long-term inhaled corticosteroid therapy.     

Eosinophils and the integrity of the hypothalamic-pituitary-adrenal axis.

The level of blood eosinophils was studied in patients with adrenalectomy and/or hypophysectomy and in patients with asthma and eosinophilia. In the latter group was a patient who had asthma associated with hypopituitarism, which is cited in detail. It is concluded that blood eosinophils are independent from the integrity of the hypothalamic-pituitary-adrenal axis.     

Functional evaluation of the hypothalamic-pituitary-adrenal axis

The regulation of hypothalamic pituitary-adrenal (HPA) axis is controlled by three major factors: stress, circadian rhythm and negative feedback. Hypothalamic CRF binds to CRF receptor on ACTH cells and stimulates synthesis and secretion of ACTH. However, vasopressin binds to V1b receptor and enhances CRF induced ACTH secretion. ACTH stimulate secretion of cortisol and DHEA-S. Cortisol inhibits secretion of CRF and ACTH with negative feedback mechanism. To evaluate the ability of the hypothalamus to secrete CRF, insulin-induced hypoglycemia and metyrapone tests are used. For evaluation of the secretion of pituitary ACTH and adrenal cortisol, a CRF test is useful. Autonomic secretion of ACTH and/or cortisol is evaluated with a dexamethasone suppression test.     

Chronic subcutaneous leptin infusion diminishes the responsiveness of the hypothalamic-pituitary-adrenal (HPA) axis in female rhesus monkeys

The fat derived protein leptin has its anorexic action through a number of neuropeptides including an upregulation of corticotropin releasing hormone (CRH) expression in the hypothalamus. However, the influence of leptin on these neuropeptides may be different during stress. The present study used ovariectomized female rhesus monkeys (n=8) to further define the effect of leptin on HPA responsivity. To accomplish this, we assessed the effects of constant leptin infusion on cortisol and ACTH secretion in both a predictable and unpredictable situation as well as in response to dexamethasone suppression-CRH stimulation test. We hypothesized that leptin would attenuate the increase in cortisol and ACTH to a novel, unpredictable situation and would enhance glucocorticoid negative feedback and diminish the response to CRH. Animals were assessed under control placebo conditions and during a 28 day infusion with recombinant human leptin (6 microg/kg/day, SC). Within each treatment condition, HPA responsivity was assessed during no estradiol replacement and acute estradiol replacement that produced serum concentrations of approximately 40 pg/ml. However, the results indicated that neither estradiol alone or in combination with leptin had any consistent effect on the outcome measures. Compared to the control condition, leptin had no effect on the cortisol diurnal rhythm; however, evening but not morning plasma ACTH concentrations were significantly lower during leptin infusion. In contrast, the response in plasma cortisol and ACTH to an unpredictable situation was significantly attenuated by chronic leptin infusion. Furthermore, leptin enhanced glucocorticoid negative feedback and blunted CRH-induced increase in both cortisol and ACTH. Taken together, these data suggest that in the female monkey, leptin has little effect on basal cortisol. However, when the HPA axis is activated, leptin attenuates the neuroendocrine response by enhancing glucocorticoid negative feedback. These data underscore the potential importance of leptin in maintaining homeostasis through its diverse interaction with the HPA axis.     

A single lipopolysaccharide administration is sufficient to induce a long-term desensitization of the hypothalamic-pituitary-adrenal axis

We have previously shown that a single exposure of adult rats to a severe emotional stressor such as immobilization is able to exert a long-term desensitization of the response of the hypothalamic-pituitary-adrenal (HPA) axis to the same stimulus when applied days to weeks later. Surprisingly, the intensity of the effect increased with time elapsed between the two exposures, suggesting that we are dealing with a new type of stress-associated phenomenon. Taking into account the clinical importance of tolerance to endotoxin, in the present study we assessed whether a single exposure to an immunological stressor such as lipopolysaccharide can induce effects similar to those of immobilization. Rats injected with lipopolysaccharide (1 mg/kg) showed a reduction of the response of the corticotropin-releasing factor mRNA in the paraventricular nucleus of the hypothalamus after a new lipopolysaccharide injection 4, but not 2 weeks later. In an additional experiment using a different blood sampling procedure, adrenocorticotropin hormone, corticosterone and tumor necrosis factor-alpha responses were reduced approximately to the same extent by previous experience with lipopolysaccharide either 1 or 4 weeks before.Our data suggest that a previous single exposure to lipopolysaccharide induces a long-lasting tolerance of the HPA axis that likely involves some kind of learning-like brain plasticity.     

The central amygdala modulates hypothalamic-pituitary-adrenal axis responses to systemic interleukin-1beta administration

This paper focuses on the role of glycoproteins in activity-dependent synaptic plasticity. The effect of the different inhibitors of protein glycosylation, Tunicamycin, Brefeldin A and Swainsonine, on long-term potentiation was studied in the CA1 region of rat hippocampal slices. Bath application of the inhibitors 60 min before and during tetanization did not interfere with the induction of long-term potentiation of the field excitatory postsynaptic potential. However, the potentiation in inhibitor-treated slices decreased to baseline levels during 90-180 min. Significant differences in the potentiation in non-treated slices were detectable 80 min (Tunicamycin), 60 min (Brefeldin A) and 75 min (Swainsonine) after tetanization, thus indicating the prevention of long-term potentiation maintenance. The application of Swainsonine 120 and 240 min after tetanization did not influence the potentiated field excitatory postsynaptic potential. These data demonstrate the need for undisturbed glycoprotein processing in a time window around long-term potentiation induction to maintain later phases of long-term potentiation and essential functional implications of protein glycosylation in mechanisms underlying synaptic plasticity.     

The hypothalamic-pituitary-adrenal (HPA) axis in habitual smokers.

Nicotine is a strong activator of the hypothalamus pituitary adrenal (HPA) axis. Smoking of only two cigarettes consistently activates the HPA axis of habitual smokers. However, while being a habitual smoker only induces small changes of basal HPA axis activity, smoking induces an attenuated responsiveness of the HPA axis to psychological stress, but not to injection of corticotropin releasing hormone (CRH) or physiological load. The latter points to alterations at hypothalamic or other central structures. The further consequences of decreased HPA axis responsiveness are discussed. Chronic inflammation of the airways is a common consequence of habitual smoking, and smokers often present with low-grade systemic inflammation, which may be mediated by HPA axis alterations. However, habitual smokers' monocytes are reported to show an increased sensitivity towards the inflammation suppressing effects of cortisol, while on the one hand, inflammation of the airways appears to be relatively resistant towards glucocorticoid treatment. In conclusion, this pattern of attenuated cortisol responses and decreased glucocorticoid sensitivity may be causally related to disinhibition of inflammatory processes and thereby further stimulate adverse health outcomes, such as airway inflammation or atherosclerosis.     

Circadian rhythms on hypothalamic-pituitary-adrenal axis hormones and cytokines of collagen induced arthritis in rats

This study is designed to identify whether circadian rhythms of the hormones of the hypothalamic-pituitary-adrenal (HPA) axis are associated with corresponding circadian fluctuations in cytokines in a rat model of collagen-induced arthritis (CIA). CIA is induced in Wistar rats by an intradermal injection of bovine type II collagen emulsified with complete adjuvant at the left foot. On day 33, in both the CIA and the control rats, circulating adrenocorticotropin hormone (ACTH) and corticosterone, tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6) and IL-1beta were evaluated at 6 h intervals from 00:00 to 24:00, and analyzed by statistics and cosinor-rhythmometry. The results showed that plasma corticosterone in CIA rats had a trough at 18:00 and reached a peak at 06:00 significantly. While peak values were presented in TNF-alpha at 24:00 and in IL-6 from 06:00 and 18:00 to 24:00. CIA rats exhibit abnormal circadian rhythms, with degrading amplitudes of corticosterone and IL-6, elevating amplitude of TNF-alpha, and marked phase shifts in corticosterone and IL-6. Our investigation suggests that the disorders of HPA axis in CIA rats may be related to the influence of inflammation mediators on hypothalamic centers. The circadian rhythms of hormones and cytokines in CIA rats may be reset due to the defective function of the HPA axis.     

Noradrenergic inputs to the paraventricular hypothalamus contribute to hypothalamic-pituitary-adrenal axis and central Fos activation in rats after acute systemic endotoxin exposure

Noradrenergic (NA) neurons within the nucleus of the solitary tract (NST) and caudal ventrolateral medulla (VLM) innervate the hypothalamic paraventricular nucleus (PVN) to initiate and modulate hypothalamic-pituitary-adrenal (HPA) axis responses to interoceptive stress. Systemic endotoxin (i.e. bacterial lipopolysaccharide, LPS) activates NA neurons within the NST and VLM that project to the PVN and other brain regions that receive interoceptive signals. The present study examined whether NA neurons with axonal inputs to the PVN are necessary for LPS to activate Fos expression within the PVN and other interoceptive-related brain regions, and to increase plasma corticosterone. Male Sprague-Dawley rats received bilateral stereotaxic microinjections of DSAP (saporin toxin conjugated to an antibody against dopamine-beta-hydroxylase, DbH) into the PVN to destroy NA inputs. Control rats were microinjected with vehicle into the PVN or received no PVN injections. Two weeks later, DSAP and control rats were injected i.p. with LPS (200 microg/kg BW) or saline vehicle, and perfused with fixative 2.5-3 h later. Brain tissue sections were processed to reveal nuclear Fos protein and cytoplasmic DbH immunolabeling. DSAP lesions depleted NA terminals in the PVN and bed nucleus of the stria terminalis, reduced the number of NA cell bodies in the NST and VLM, attenuated PVN Fos activation after LPS, and attenuated LPS-induced increases in plasma corticosterone. These findings support the view that NA projections from hindbrain to hypothalamus are necessary for a full HPA axis response to systemic immune challenge.     

Nasal provocation of patients with allergic rhinitis and the hypothalamic-pituitary-adrenal axis.

BACKGROUND: Allergic rhinitis is a common problem involving activation of nasal mast cells and irritability. The hypothalamic-pituitary-adrenal (HPA) axis is stimulated in cases of emotional or environmental stress, and mast cells have been implicated in stress-induced immune responses. OBJECTIVE: To investigate whether intranasal challenge of patients allergic to a single antigen would stimulate the HPA axis. METHODS: Plasma corticotropin and cortisol levels were measured 20, 40, 60, 80, 100, and 120 minutes after intranasal antigen administration in healthy volunteers (n=3) and in patients with rhinitis who are allergic to Parietaria (n=10). RESULTS: Mean +/- SD corticotropin levels were 24.43 +/- 14.38 pg/mL in patients compared with 8.83 + 5.02 pg/mL in controls, and this increase was statistically significant (P = .049). Patient cortisol levels also increased to a mean +/- SD of 8.87 +/- 4.90 pg/mL (at 40 minutes) compared with 4.36 +/- 1.72 pg/mL in controls (P = .11 due to 1 outlier). Compared with individual patient prechallenge levels, corticotropin levels increased in 7 patients and cortisol levels increased in 5 at 40 minutes. CONCLUSION: These results suggest that allergic rhinitis may activate the HPA axis. A larger study with additional controls is required for definitive conclusions.     

Galanin in the regulation of the hypothalamic-pituitary-adrenal axis (Review)

Galanin is a regulatory 30- or 29-amino acid peptide, widely distributed in the nervous system and gut, that acts via three subtypes of G protein-coupled receptors, named GAL-R1, GAL-R2 and GAL-R3. Findings have been accumulated that galanin regulates neuroendocrine hypothalamic axes, including the hypothalamic-pituitary-adrenal (HPA) one. Galanin and its receptors are expressed in the hypothalamic paraventricular and supraoptic nuclei, anterior pituitary and adrenal medulla. Adrenal cortex does not express galanin, but is provided with GAL-R1 and GAL-R2. The bulk of evidence indicates that galanin stimulates the activity of the central branch of the HPA axis (i.e. the release of corticotropin-releasing hormone and ACTH), thereby enhancing glucocorticoid secretion from the adrenal cortex. Investigations carried out in the rat show that galanin is also able to directly stimulate corticosterone (glucocorticoid) secretion from adrenocortical cells, through GAL-R1 and GAL-R2 coupled to the adenylate cyclase-protein kinase A signaling cascade, and nor-epinephrine release from adrenal medulla. There is indication that galanin may also enhance corticosterone release via an indirect paracrine mechanism involving the local release of catecholamines, which in turn activate beta-adrenoceptors located on adrenocortical cells. The physiological relevance in the rat of the glucocorticoid secretagogue action of galanin is suggested by the demonstration that the blockade of galanin system significantly lowers basal corticosterone secretion. There is also evidence that galanin plays a role in the modulation of HPA-axis response to stress, as well as in the pathogenesis of pituitary adenomas and perhaps of pheochromocytomas.     

Impaired recovery of hypothalamic-pituitary-adrenal axis function and hypoglycemic seizures after high-dose inhaled corticosteroid therapy in a toddler.

BACKGROUND: Corticosteroids are the treatment of choice for children with persistent reactive airway disease. In these patients, taper and discontinuation of systemic therapy is often facilitated by transition to high-dose inhaled corticosteroid treatment. OBJECTIVE: To report a case of impaired hypothalamic-pituitary-adrenal (HPA) axis recovery and adrenal crisis associated with prolonged high-dose inhaled therapy after long-term systemic corticosteroid treatment. METHODS: A 32-month-old child with severe airway obstruction and wheezing was treated with long-term daily systemic (intravenous and oral) corticosteroids followed by high-dose inhaled fluticasone (440 to 1,320 microg/day). This child presented in adrenal crisis, as evidenced by severe hypoglycemia and seizures, I day after receiving the influenza vaccine. After hydrocortisone replacement and a long taper of fluticasone, the child's adrenal function returned to normal. RESULTS: At the time of seizure, the serum glucose was 1 mg/dL. An electroencephalogram, computed tomographic scan, and magnetic resonance imaging of the brain were normal. Adrenal insufficiency was documented (morning serum cortisol, 0.6 microg/dL; after adrenocorticotrophic hormone stimulation, 8.4 microg/dL). Repeat evaluation 3 weeks after discontinuation of all corticosteroid therapy demonstrated normal HPA axis function. CONCLUSIONS: After treatment with long-term systemic steroids, high-dose inhaled corticosteroid therapy can impair recovery of the HPA axis and place patients at risk for adrenal crisis.     

The involvement of noradrenergic mechanisms in the suppressive effects of diazepam on the hypothalamic-pituitary-adrenal axis activity in female rats

Aim

To elucidate the involvement of noradrenergic system in the mechanism by which diazepam suppresses basal hypothalamic-pituitary-adrenal (HPA) axis activity.

Methods

Plasma corticosterone and adrenocorticotropic hormone (ACTH) levels were determined in female rats treated with diazepam alone, as well as with diazepam in combination with clonidine (α₂-adrenoreceptor agonist), yohimbine (α₂-adrenoreceptor antagonist), alpha-methyl-p-tyrosine (α-MPT, an inhibitor of catecholamine synthesis), or reserpine (a catecholamine depleting drug) and yohimbine.

Results

Diazepam administered in a dose of 2.0 mg/kg suppressed basal HPA axis activity, ie, decreased plasma corticosterone and ACTH levels. Pretreatment with clonidine or yohimbine failed to affect basal plasma corticosterone and ACTH concentrations, but abolished diazepam-induced inhibition of the HPA axis activity. Pretreatment with α-MPT, or with a combination of reserpine and yohimbine, increased plasma corticosterone and ACTH levels and prevented diazepam-induced inhibition of the HPA axis activity.

Conclusion

The results suggest that α₂-adrenoreceptors activity, as well as intact presynaptic noradrenergic function, are required for the suppressive effect of diazepam on the HPA axis activity.Benzodiazepines are used for their anxiolytic, sedative-hypnotic, muscle relaxant, and anticonvulsant properties in the treatment of a variety of neuropsychiatric disorders (1,2), including anxiety and depression, which are often related to disturbances in the activity of hypothalamic-pituitary-adrenal (HPA) axis (3,4). Although these drugs exert most of their pharmacological effects via γ-aminobutyric acid_A (GABA_A) receptors (5,6), benzodiazepine administration has been associated with alterations in neuroendocrine function both in experimental animals and humans (7-9). However, even after years of extensive studies, the complex mechanisms by which these widely used drugs produce their effects on the HPA axis are still not known.Although most of the previous studies have demonstrated that classical benzodiazepines such as diazepam decrease the HPA axis activity in stressful contexts (10-14), under basal conditions they have been shown to stimulate (9,11,15-18), inhibit (15,19-22), and not affect (17,23-25) the HPA axis activity. Such diverse results might be related to several factors such as the dose and gender (15,16,20,21,26-28), or may also be a consequence of the net effect of non-selective benzodiazepines on the various GABA_A receptor isoforms (9).Our previous studies demonstrated that while diazepam (1 mg/kg) produced no change in plasma corticosterone levels in male rats (15,20), it decreased basal levels of corticosterone in female rats (15,26). However, although diazepam inhibited the HPA axis activity of female rats following administration of lower doses (1 or 2 mg/kg) (15,20,21,26), it stimulated the HPA axis activity following administration of high doses (10 mg/kg) (15,16,26). Moreover, whereas the suppressive effect of the lower doses of diazepam (2.0 mg/kg) on the HPA axis activity in female rats involves the GABA_A receptor complex (21), increases in corticosterone levels by a higher dose of diazepam (10 mg/kg) do not involve the stimulation of GABA_A receptors (16). In addition, stimulatory effect of 10 mg/kg diazepam on the HPA axis activity in rats seems not to be mediated by the benzodiazepine/GABA/channel chloride complex or by peripheral benzodiazepine receptors, but rather by a cyclic adenosine monophosphate (AMP)-dependent mechanism (18).Since our previous results suggested that the effect of a high dose of diazepam on the activity of the HPA axis in female rats might be due to a blockade of α₂-adrenergic receptors (16), the aim of this study was to elucidate whether noradrenergic system also has a modulatory role in the inhibitory effect of 2.0 mg/kg diazepam on basal plasma adrenocorticotropic hormone (ACTH) and corticosterone levels in female rats.     

鼠重组白细胞介素—1对小鼠下丘脑—垂体—肾上腺轴的影响

探讨重组白细胞介素（rIL-1)对下丘脑－垂体肾上轴的作用。采用rIL-1静脉注入（C组注入前用抗－HRH血清预处理）,测定注入rIL-1后不同时间CRH、ACTH及CORT血浆含量变化。结果表明,rIL-1可使CRH,ACTH,CORT血浆含量有不同水平的升高（B组）,预先注射抗－CRH血清可阻断该效应（C组）,说明rIl-1对HPAA的激活作用是通过CRH介导的。