Suppression of the hypothalamic-pituitary-adrenal axis after subcutaneous cortisone acetate administration in rats.

Groups of female rats were injected daily for 14 days with 10 mg of cortisone acetate subcutaneously, to study the mechanisms of glucocorticoid suppression on the hypothalamic-pituitary-adrenal axis. Pituitary adrenocorticotropic hormone (ACTH) content, plasma ACTH, adrenal venous corticosterone, adrenal weights, and the catabolic effects on body weight were studied simultaneously (under stressful and non-stressful conditions) before, during, and up to six weeks after cortisone. This study confirmed the results of other investigators that cortisone acetate caused catabolic weight loss and adrenal atrophy, but it was noted to persist up to six weeks after the injections. Glucocorticoid acetate was more effective in causing ACTH-axis suppression than succinate or phosphate preparations, and the effects were dose and time related. Significant depletion of pituitary ACTH content, suppression of plasma ACTH, and corticosterone secretion occurred five to seven days after beginning cortisone acetate (p=<0.001); it was continuous throughout the injection schedule (p=<0.001); it remained for two to four weeks after the cortisone was discontinued (p=<0.001). The animals showed minimum plasma ACTH responsiveness to severe acute stress during this two to four-week suppression phase, but rapid recovery occurred thereafter. Plasma ACTH was undetectable up to six weeks post-cortisone when the animals were not under stress. This may be related to residual cortisone acetate found at the injection sites, or to an altered or different ACTH-axis control mechanism. The sequence of events during recovery from cortisone suppression appeared to be (1) repletion of corticotrophin-releasing hormone (by inference), (2) repletion of pituitary ACTH content, (3) secretion of plasma ACTH, (4) reversal of adrenal atrophy, and (5) subsequent secretion of corticosterone.     

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.     

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.     

Effect of hydrocortisone succinate on growth of Chlamydia pneumoniae in vitro.

We examined the effect of hydrocortisone succinate on the growth of three isolates of Chlamydia pneumoniae in vitro. There was a significant increase in the number of inclusions seen in two of the C. pneumoniae strains in the presence of hydrocortisone. There was no significant increase in the number of inclusions with various concentrations of hydrocortisone over time. The addition of hydrocortisone did not affect the in vitro activities of azithromycin, erythromycin, and doxycycline against C. pneumoniae.     

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。     

重组白细胞介素-2对小鼠下丘脑-垂体-肾上腺轴的影响

目的：研究重组白细胞介素２（ｒＩＬ－ ２） 对下丘脑－ 垂体－ 肾上腺轴的作用。方法：采用ｒＩＬ－ ２ 静脉注入（Ｂ组注入前用抗－ ＣＲＨ 血清预处理） ,测定注入ｒＩＬ－ ２ 后不同时间ＣＲＨ,ＡＣＴＨ 及ＣＯＲＴ 血浆含量变化。结果：ｒＩＬ－ ２ 可使不同水平的ＣＲＨ,ＡＣＴＨ,ＣＯＲＴ 血浆含量升高（Ａ 组）（ Ｐ＜ ０－０１） ,当预先注入抗－ ＣＲＨ 血清后ＡＣＴＨ、ＣＯＲＴ 的升高不被阻断（Ｂ 组） 。结论：ｒＩＬ－ ２ 对ＨＰＡＡ 的激活作用不是通过ＣＲＨ 介导的     

Dysregulation of hypothalamic-pituitary-adrenal axis function in depressed alcoholic patients

Hypothalamic-pituitary-adrenal (HPA) axis function was examined in 28 hospitalized, withdrawing alcoholic patients. Fourteen patients met DSM-III criteria for Major Depressive Disorder. Elevated 8 a.m. basal cortisols were noted in 7 depressed alcoholic patients (50%) and no non-depressed alcoholics (P less than 0.01). Escape from dexamethasone suppression was noted in 9 depressed alcoholics (64%) and no non-depressed alcoholics (P less than 0.005). The measurement of HPA axis function may be a useful marker for endogenous depression in an alcoholic population.     

Effects of glucocorticoids on the hypothalamic-pituitary-adrenal axis in children and adults

Inhaled and intranasal corticosteroids are widely used as effective, first-line treatments for asthma and allergic rhinitis. Despite a good safety profile of these formulations, there is increasing concern about their propensity to produce systemic adverse effects. Suppression of the hypothalamic-pituitary-adrenal axis is one of the most important potential complications. This article reviews the effects of inhaled and intranasal corticosteroids on the hypothalamic-pituitary-adrenal axis function in adults and children.     

Impaired mitogen-induced lymphocyte responses and the hypothalamic-pituitary-adrenal axis in depressive disorders

The lymphocyte stimulation responses to the mitogens phytohemagglutinin (PHA), concanavalin A (Con A) and pokeweed (PWM) were investigated in 30 hospitalized depressed women undergoing a dexamethasone suppression test (DST). Patients were classified according to DSM-III as having major depression with melancholia, without melancholia, and minor depression. The Hamilton Depression Rating Scale (HDRS) and the State-Trait Anxiety Inventory (STAI) were measured. Patients with major depression showed significantly decreased lymphocyte stimulation induced by PHA, Con A, and PWM as compared to those with minor depression. These differences could not be attributed to age, body weight, weight loss, total number of leukocytes, menopausal status, sleep disturbances, concomitant use of low-dosage benzodiazepines or length of drug-free period before testing. The group mean differences in lymphocyte stimulation counts were not affected by the severity of illness or the severity of state and trait anxiety. There were no significant differences in the lymphocyte responses to PHA, Con A, and PWM between DST non-suppressors and DST suppressors. No significant correlations were established between baseline and post dexamethasone cortisol values and the lymphocyte stimulation counts.