Suppression Of Cortisol Secretion Research Articles

ACTH-provoked cortisol peaks during sleep and their effect on the endogenous secretory activity.

The effects of low physiological doses of ACTH on nocturnal plasma cortisol patterns were investigated in six male subjects. Concomitant sleep EEG recordings were analysed in relation to the cortisol level. 250 ng ACTH1-24 (Synacthène), injected through an indwelling catheter at a period of low adreno-cortical activity (2400 h), induced a cortisol peak followed by a four to five-hour period without any cortisol secretion. The same dose of ACTH injected at 0430 h, when cortisol secretory activity was high, did not entirely abolish endogenous secretion, which was diminished for a shorter time (2.5 hr). The ACTH-provoked cortisol peaks of comparable size to endogenous secretory peaks, can suppress cortisol secretion for several hours. This suppressive capacity depends on timing in relation to high or low secretory activity periods. However, spontaneous cortisol peaks have no appreciable effect on further secretory episodes. This difference in suppressive capacities suggests that the 24 hr cortisol rhythm is regulated independently of such feedback mechanisms.

Enhancement of adrenal cortisol secretion after intravenous high dose dexamethasone.

To assess the possible existence of a short loop feedback mechanism of direct glucocorticoid suppression on the adrenal glands, we performed a series of tests employing insulin hypoglycemia or ACTH infusions to obtain adrenal stimulation by ACTH levels that remained within the physiological range. Although the rapidity of glucocorticoid suppression of the pituitary thwarted efforts to use endogenous ACTH as a stimulus, we were able to mimic the stressed state by very low dose ACTH infusions (0.05 microgram/kg BW). No inhibition of cortisol secretion in response to ACTH infusions was detected in tests done after administration of dexamethasone compared to placebo [mean integrated response, 29.37 +/- 1.91 (+/- SE) vs. 29.12 +/- 1.12 microgram . h/dl, respectively]. Furthermore, when high doses of dexamethasone were administered iv, a small paradoxical increase in cortisol secretion was found (33.82 +/- 1.44 microgram . h/dl) without a difference in ACTH levels. These data do not support the concept of significant direct glucocorticoid inhibition of adrenal secretion. Non-ACTH factors that may enhance cortisol secretion in the presence of ACTH may exist.

Cortisol escape from morphine suppression

Twenty-one unmedicated, sequentially admitted psychiatric patients of either sex and four male healthy volunteers were given an intravenous injection of 2.5 mg morphine. Blood samples were drawn immediately before and at 30-minute intervals for 3 hours after the injection and assayed for cortisol. Morphine suppressed cortisol secretion. Early resumption of cortisol secretion (escape) was more frequent in patients with a diagnosis of major depressive disorder and with abnormal dexamethasone suppression test results. The sensitivity of this infusion paradigm for the diagnosis of major depressive disorder was 40%, and the specificity was 82%. The implications of these findings for the pathophysiology of depression are discussed.

The dexamethasone suppression and metyrapone tests in depression

The dexamethasone suppression test (DST) and the metyrapone test (MT), a useful and reliable procedure for assessing the integrity of the hypothalamic-pituitary-adrenal (HPA) axis, were performed in 28 patients suffering from major depressive illness with melancholia. The relationship between the DST and MT appeared to be complex. Patients who failed to suppress cortisol secretion after dexamethasone administration had higher postmetyrapone cortexolone levels and cortexolone/cortisol ratios than suppressors. However, there was a wide range of metyrapone responses in patients exhibiting abnormal DST results. This suggests that failure of adequate suppression after 1 mg of dexamethasone in depressed patients does not necessarily reflect homogeneity in the HPA axis disturbances of such patients.

EFFECT OF PROPOFOL, THIOPENTONE AND ETOMIDATE ON ADRENAL STEROIDOGENESIS IN VITRO

The i.v. anaesthetic agents propofol, thiopentone and etomidate inhibited ACTH-stimulated production of cortisol by guineapig dispersed adrenal cells in a dose-related manner. For two of the drugs, propofol and thiopentone, inhibition occurred over a similar concentration range: 2 X 10(-5) - 5 X 10(-4) mol litre-1. With etomidate, inhibition occurred over a much lower concentration range (5 X 10(-8) - 5 X 10(-6) mol litre-1). The concentrations of anaesthetic which induced 50% inhibition of cortisol secretion were propofol 1.7 X 10(-4), thiopentone 1.6 X 10(-4), and etomidate 1.0 X 10(-7) mol litre-1.

Opioid Regulation of Hypothalamic-Pituitary-Adrenal Function in Depression

A morphine infusion paradigm was used to investigate opioid mechanisms in the regulation of the hypothalamic-pituitary-adrenal (HPA) axis in depression. The subjects were unmedicated psychiatric inpatients and healthy volunteers. Morphine suppressed cortisol secretion. Early resumption of cortisol secretion was associated with a diagnosis of major depression and abnormal dexamethasone suppression test results. Our data suggest that the hyperactivity of the HPA axis observed in depression is abnormally resistant to opioid inhibition as well as glucocorticoid feedback.

Number of cortisol time-points and dexamethasone suppression test sensitivity for major depression

Failure to suppress cortisol secretion after administration of dexamethasone has been reported to be a diagnostic marker for major depression and to have prognostic implications when repeated after antidepressant treatment. The pulsatile pattern of cortisol secretion suggested to us that increasing the number of post-dexamethasone cortisol determinations might significantly increase the sensitivity of the dexamethasone suppression test (DST) for major depression. With a conventional two-point DST (1600 h and midnight), 5% of 20 normal volunteers, 8% of 13 inpatients with non-major depressions, and 31% of 65 inpatients with primary major depression failed to suppress. With six post-dexamethasone points (0800 h, 1200 h, 1600 h, 2000 h, 2200 h, midnight), the respective percentages were 10, 15 and 44%. The additional points increased the sensitivity from 31 to 44%, mostly by identifying more major depressives with a “late escape” pattern. If a clinician is using the DST to establish a marker for major depression that can be repeated to monitor response to treatment and the likelihood of relapse, then perhaps the increased sensitivity of the six-point DST would be helpful, despite a modest decrease in specificity from 94 to 88%.

The dexamethasone suppression test in hospitalized prepubertal depressed children.

The dexamethasone suppression test was performed on 20 hospitalized prepubertal children who met DSM-III criteria for major depressive disorder. Fourteen children (70%) did not suppress cortisol secretion at either 8:00 a.m. or 4:00 p.m. The 4:00 p.m. value alone predicted 93% of the nonsuppressors.

Basal plasma HGH and cortisol levels and the effect of clonidine administration in female migrainous patients.

Clonidine, a central alpha-adrenergic agent and prophylactic antimigraine drug is known to stimulate human growth hormone (HGH) release and to suppress cortisol secretion. A possible association between basal hormonal levels and response to either acute clonidine test or chronic treatment in female migrainous patients was investigated. 15 females, aged 18-43 years, suffering from migraine, underwent an acute clonidine test by administration of a single oral dose of 0.15 mg. High basal HGH levels (greater than or equal to 9 ng/ml) were observed in 6 patients, while the other 9 patients demonstrated normal low basal HGH levels. Acute clonidine administration induced a marked rise of HGH in 8 of the 9 patients with low basal HGH. In 4 of the 8 responders HGH levels exceeded 20 ng/ml and 3 subjects reached the acromegalic range (greater than 90 ng/ml). The mean response in this group was higher than in a reference group consisting of children and adolescents. It is suggested that the basal hypersecretion and the hyperresponsiveness of HGH to clonidine provocation test in some migrainous patients results from a hypersensitivity of the central alpha-adrenergic receptors. 12 of the 15 females were treated for 10 weeks with clonidine at gradually increased doses of 0.05 mg/day up to a maximal dose of 0.15 mg/day. A marked suppressive effect on cortisol secretion was observed in the migrainous patients after acute and chronic administration of clonidine. No correlation was observed between HGH and cortisol response to acute or chronic clonidine administration and the prophylactic effect of clonidine on migraine.

Escape from dexamethasone suppression: Possible role of an impaired inhibitory opioid mechanism

1. 1. Several lines of evidence indicate that the activity of the hypothalamus-pituitary-adrenal (HPA) axis in depression is disinhibited. 2. 2. Escape from dexamethasone suppression, although not limited to is more frequent in patients with endogenous depression compared to normals or patients with other psychiatric diagnoses. 3. 3. Norepinephrine, serotonin and acetylcholine have been implicated in the pathophysiology of this neuroendocrine abnormality. 4. 4. Morphine, 5 mg intravenously, suppressed Cortisol secretion in healthy volunteers (n = 4) and the majority of 32 psychiatric inpatients. 5. 5. However, patients with endogenous depression and abnormal dexamethasone suppression test results show early resumption (escape) of cortisol secretion following the initial suppression induced by morphine. 6. 6. It is concluded that the pathophysiology of this neuroendocrine abnormality is not limited to classical neurotransmitter-HPA axis interaction but that it also involves opioid inhibitory mechanisms.

Suppression of Cortisol Secretion by Human Growth Hormone*

The adrenocortical responses to the daily administration of 10 mg human GH (hGH) for 4-6 days were compared in 12 patients with Cushing's disease, 2 patients with cortisol-secreting adrenal cortical adenoma, and 4 healthy subjects. The administration of hGH resulted in a significant mean percent decrease in urinary 17-hydroxycorticosteroids [17OHCS; 30 +/- 7.8 (SE)], cortisol secretion rate (32 +/- 5.5), plasma 17OHCS (31 +/- 5.1), and urinary 17-ketosteroids (46 +/- 6.0) in the patients with Cushing's disease. In contrast, it did not significantly decrease urinary or plasma 17OHCS or the cortisol secretion rate in the other groups of subjects similarly studied. Treatment with hGH did not impair the adrenocortical response to exogenous ACTH, but it decreased the response to metyrapone in all subjects tested. In one of the healthy subjects who had exhibited diminished response to metyrapone on hGH, measurement of plasma ACTH levels demonstrated a lower rise after the administration of the drug. Treatment with hGH did not alter the peripheral metabolism of cortisol, as measured by cortisol turnover rates. We conclude that hGH inhibits ACTH release and that this effect is maximally demonstrated in patients with increased hypothalamic-pituitary-adrenal function.

Treatment of Cushing's disease with adrenal blocking drugs and megavoltage therapy to the pituitary

Eighteen patients with Cushing's disease were seen over a 40-month period and considered for treatment by pituitary irradiation and adrenal blocking drugs. Fourteen patients entered the study and each received megavoltage therapy to give a mean dose of 4600 rad to the pituitary over 31 days. Each patient was treated for one (two patients) or two (12 patients) years with one or both of the adrenocortical enzyme inhibitors, metyrapone or aminoglutethmide to suppress cortisol secretion. Doses were adjusted to maintain urinary free cortisol secretion below 300 nmol/24 h. One patient failed to complete the trial. Normal urinary free cortisol excretion and plasma cortisol concentration were maintained after treatment in eight of the remaining 13 patients after therapy. Only one patient required cortisol replacement and normal menstrual function was restored in five of the six women. The remaining five patients relapsed and four were subsequently treated by total adrenalectomy. It was noted that the patients who responded to treatment were substantially younger than the therapeutic failures. It is suggested that this treatment is most useful in the management of younger patients.

Failure of Angiotensin II to Inhibit Corticotropin-Stimulated Cortisol Secretion*

In view of the reported inhibitory effect of angiotensin II on cortisol secretion in human subjects, the effect of local angiotensin infusions on steroid secretion maintained by ACTH was examined by using sheep with cervical autotransplanted adrenal glands. During sustained submaximal stimulation by exogenous ACTH (40--80 microunit/min), the addition of local infusions of angiotensin II (1.6--160.0 ng/min) caused increased aldosterone and smaller increments in cortisol secretion in most experients. There was no evidence of inhibition of cortisol secretion by angiotensin. When similar experiments were undertaken during maximum stimulation by ACTH (16.6 mU/min), increments in aldosterone, but not in cortisol secretion, were observed. These studies exclude an acute inhibitory effect of angiotensin on cortisol biosynthesis, at least in ovine adrenal glands, during stimulation by ACTH.

The effect of cyproterone acetate on adrenal cortical function in children with precocious puberty

8 children with precocious puberty were treated with cyproterone acetate (CPA). During treatment there were no definite clinical signs of depressed adrenocortical function. The plasma cortisol concentrations were grossly depressed and the diurnal cortisol rhythm was abolished. Two months after discontinuation of CPA treatment the adrenocortical function had greatly improved. The lysin-vasopressin stimulation test revealed in one child a normal, in another child an exaggerated ACTH response during CPA therapy. Fasting plasma ACTH concentrations were elevated compared with normal controls, but they were very low compared with patients with Addison's disease. The results suggest that CPA has a twofold effect leading to adrenocortical insufficiency: i.e., inhibition of cortisol secretion by the adrenals themselves and inhibition of ACTH secretion at the hypothalamopitiuitary level.

Suppression by dexamethasone of interrenal activity in adult sockeye salmon ( Oncorhynchus nerka)

Dexamethasone injected intraperitoneally as a single dose of 1 mg/kg of body weight suppressed cortisol secretion in response to stress in sexually maturing sockeye salmon. The full effect of a single dose was still evident after 5 and 6 days in most fish and in many fish after 12 days. Sexually maturing sockeye salmon which had received either four doses of dexamethasone during a period of 47 days or six doses during 75 days, were compared with controls which had received similar regimens of peanut oil. The progressive increase in interrenal hypertrophy during the treatment period seen in the peanut oil controls was abolished in the fish receiving dexamethasone.

Effects of Aminoglutethimide Upon Adrenal Function and Cortisol Metabolism in Cushing's Syndrome

ABSTRACT The effects of aminoglutethimide upon adrenal cortical function have been investigated in 3 patients with Cushing's syndrome. One of them harbored a pulmonary oat cell carcinoma which was secreting an ACTH-like substance. Two other patients had nontumorous adrenal cortical hyperfunction. In the first individual, aminoglutethimide induced temporary inhibition of cortisol secretion. In the second patient, the drug reduced cortisol secretion and urinary 17-OHCS but plasma 17-OHCS did not change. In the third patient, the drug induced a fall in urinary 17-OHCS without change in either cortisol secretion or plasma 17-OHCS. A control subject without Cushing's syndrome, similarly treated, exhibited the same response as the third patient. Transient natruresis occurred in 3 of the 4 subjects studied. In 2 of the 3 individuals with Cushing's syndrome, a transient suppression of aldosterone excretion was observed. The data suggest that aminoglutethimide does not effectively suppress adrenal cortical functio...

Effects of amino-glutethimide on adrenal function in man.

ABSTRACT The effects of amino-glutethimide on adrenocortical function have been studied in 24 subjects, including 10 patients with Cushing's syndrome, 3 with primary aldosteronism and 1 with secondary hyperaldosteronism. Aminoglutethimide inhibited adrenal secretion of both cortisol and aldosterone. Inhibition of cortisol secretion was most clearly demonstrable in a patient with Cushing's syndrome caused by autonomous steroid secretion from an adrenal adenoma. In normal subjects, administration of large doses of amino-glutethimide was accompanied by consistent increases in plasma ACTH, and it is likely that these “compensatory” increases in ACTH were responsible for maintaining near-normal cortisol secretion rates and plasma 17-hydroxycorticosteroid (17-OHCS) concentrations in these subjects. Decreases in cortisol secretion occurred in 7 of 9 patients with Cushing's disease given amino-glutethimide, and this was of modest therapeutic value in 4 of these patients treated for several months. The most consis...