Serum thyroxine and triiodothyronine radioimmunoassay values in the normal ferret

The European ferret, Mustela putorius furo, has become increasingly popular as an animal model in biomedical research. However, certain important normal clinical data have not been established for the ferret. In this study, serum thyroxine (T4) and 3,3',5-triiodothyronine (T3) values were obtained from ferrets by the use of commercial radioimmunoassays. Sera from 44 animals, 31 males (27 intact and 4 castrated) and 13 females (10 intact and 3 spayed) were assayed. Serum T4 values ranged from 1.01-8.29 micrograms/dl for males (mean = 3.24 +/- 1.65 micrograms/dl), and 0.71-3.43 micrograms/dl for females (mean = 1.87 +/- 0.79 micrograms/dl). Serum T4 values of adult female ferrets, juvenile ferrets (less than 1 year old) of either sex, and castrated males were similar to the normal T4 values of the cat, 1.20-3.80 micrograms/dl. Intact adult male ferrets had higher serum T4 values which were more comparable to those of the normal dog 1.52-3.60 micrograms/dl. Serum T3 values ranged from 0.45-0.78 ng/ml for males (mean = 0.58 +/- 0.09 ng/ml), and 0.29-0.73 ng/ml for females (mean = 0.53 +/- 0.13 ng/ml). These values are comparable to those of dogs and cats which are 0.50-1.50 ng/ml.     

Dissociation of plasma cortisol and ACTH responses to dexamethasone in healthy subjects

We examined the plasma cortisol and ACTH concentrations after graded doses of dexamethasone in a group of young, healthy adults. The decrease in cortisol was uniform in all subjects, and in 8 subjects there was a high degree of correspondence with the plasma ACTH concentration. The remaining 5 subjects had no change in plasma ACTH concentration during dexamethasone administration. All subjects had an expected diurnal change in cortisol on 2 pretreatment days and there was a corresponding diurnal change in ACTH for those subjects who had associated ACTH and cortisol responses after dexamethasone, while those with dissociated ACTH and cortisol after dexamethasone had no diurnal ACTH pattern. These findings were consistent with the 24-hour pattern of ACTH and cortisol before and after 1.0 mg of dexamethasone in 2 of the same subjects. These results are further evidence for ACTH independent regulation of adrenal function and indicate that pituitary-adrenal regulation in man is more complex than the traditional model of ACTH-cortisol feedback would predict.     

Saliva and serum cortisol dynamics following intravenous dexamethasone in normal volunteers

In order to further explore the utility of saliva cortisol as an accurate measure of adrenal steroid production, dexamethasone (DEX) and saline were administered intravenously at 0800h to eight normal male volunteers in a randomized design, and the effects on serum and saliva cortisol concentrations were measured at hourly intervals from 0800h-2300h. Saliva cortisol values were highly correlated to serum cortisol levels within-subjects under both conditions (r = 0.78, p less than 0.025), however correlations were reduced in the DEX day sample pairs. Across-subject correlations at each time point were considerably more variable, reflecting interindividual differences in the saliva to serum cortisol ratios. No consistent time lag of saliva cortisol values in response to serum cortisol fluctuations was observed. These data suggest that saliva cortisol is an excellent index of changes in adrenal production of cortisol over time within individuals; however, it also suggests that salivary cortisol measures have less usefulness in comparing values across groups of individuals.     

The cortisol response to awakening in relation to different challenge tests and a 12-hour cortisol rhythm.

Recent studies have shown that cortisol levels rapidly increase within the first 30 minutes after awakening. This response is rather robust over weeks or months and is altered by chronic stress and burnout. The present study investigated to what extent the cortisol response to awakening relates to responses following hCRH, ACTH(1-24), or psychosocial stress challenges in 22 healthy subjects. Furthermore, a 12-hour circadian cortisol profile was obtained to compare the morning response with cortisol levels obtained throughout the day. Results show that the morning cortisol response was of similar magnitude to that following injection of 1 microg/kg h-CRH or exposure to a brief psychosocial stressor (TSST). All of these were significantly smaller compared to maximal stimulation of the adrenal cortex by ACTH(1-24). Correlation analyses revealed that the morning cortisol response was closely related only to the cortisol response following 0.25 mg ACTH(1-24) (r=0.63, p=0.002). We conclude that the morning cortisol response to awakening can provide important information on the (re)activity of the HPA axis in addition to more 'traditional' methods like hCRH or Synacthen challenge tests. The sensitivity/capacity of the adrenal cortex appears to play a crucial role for the magnitude of cortisol responses observed after awakening.     

Suppression of basal plasma cortisol and adrenal androgen concentrations, but not of ACTH and cortisol responses to hCRH by low-dose dexamethasone in rhesus monkeys

Glucocorticoid treatment at replacement doses does not result in a suppression of ACTH and cortisol responses to corticotropin-releasing hormone (CRH), while basal plasma concentrations of cortisol and adrenal androgens are efficiently suppressed 34 h after starting treatment. This finding could be demonstrated in rhesus monkeys receiving a continuous infusion of dexamethasone (1 microgram/kg per h) for 48 h and confirms our observations in patients on alternate-day prednisone therapy and in patients with congenital adrenal hyperplasia on glucocorticoid replacement therapy. We conclude that the decrease of basal adrenal steroid secretion resulting from glucocorticoid replacement therapy represents an effect on hypothalamic rather than on pituitary function.     

The role of calcium ions in the mechanism of ACTH stimulation of cortisol synthesis

Removal of free calcium ions from the incubation medium of isolated bovine adrenocortical cells with EGTA reduced basal cortisol synthesis and blocked the effects of ACTH; additional calcium restored normal steroid synthesis. Calcium channel blockers, verapamil and nitrendipine and the calmodulin antagonist, trifluoperazine inhibited ACTH-stimulated cortisol synthesis in a dose-dependent manner (IC50s of 6.2, 10 and 5.2 microM, respectively). Steroidogenic effects of dibutyryl cyclic AMP were prevented with 50 microM verapamil or trifluoperazine. Calcium ionophore A23187 at 1 microM increased cortisol synthesis 2-3 fold which was less than the normal response to ACTH. Stimulatory effects of ionophore and cyclic AMP or ACTH were not additive. ACTH-stimulation of cortisol synthesis appears to involve cyclic AMP-dependent uptake of extracellular calcium ions, possibly by a mechanism requiring calmodulin. Increases in intracellular calcium ions cannot wholly mimic ACTH actions.     

Responsiveness of cortisol and dehydroepiandrosterone to ACTH in children

In a total of 101 children, the dehydroepiandrosterone (DHA) and cortisol (F) levels were measured before and after ACTH (Synacten) administration. F responsiveness was unchanged during development, while DHA responsiveness in healthy children was highest during adrenarche. In hypopituitary patients DHA levels were lower than in the controls, but responsiveness to ACTH showed similar changes during development. Children with Turner's syndrome and hypergonadotrophic males had the response in elevated DHA levels while ACTH-induced DHA response related to bone-age matched controls. We conclude that regulation of adrenal androgens is mediated by both ACTH and another hypothalamo-pituitary hormone, perhaps independent of gonadal activation, but requiring gonadal integrity.     

Abnormal dexamethasone suppression tests in a rifampicin-treated patient with suspected Cushing's syndrome

The dexamethasone suppression test is a useful endocrinological test to diagnose Cushing's syndrome. However, its interpretation may be influenced by many factors such as stress, alcohol, failure to ingest the dexamethasone, altered metabolism, drug interaction and obesity. This report illustrates such an instance, whereby the result of the test was erratic due to the anti-tuberculous drug rifampicin. Rifampicin has been found to profoundly attenuate the biological effects of dexamethasone, probably by enhancing its metabolism in the liver. The exact mechanism of the drug interaction remains elusive, though induction of hepatic CYP3A4 enzyme complex is a possible mechanism. In a patient treated with rifampicin, the results of dexamethasone suppression tests thus have no diagnostic value and can be very misleading.     

Effects of dexamethasone and dexamethasone plus naltrexone on pituitary response to GnRH and TRH in normal women.

The hypothesis that glucocorticoids have a direct central inhibitory effect on the reproductive axis is sutained by the identification of glucocorticoid receptors on GnRH-secreting neurons and gonadotropic pituitary cells. It has been proposed that glucocorticoids and opioids interact centrally in the regulation of the GnRH-LH axis. The inhibitory effect of glucocorticoids may manifest not only directly through the hormone-receptor link, but also indirectly through an increase in opioid tone. The aim of this study was to evaluate the role of glucocorticoids and glucocorticoids combined with an opioid antagonist, in the regulation of basal and GnRH- and TRH-stimulated secretion of LH, FSH and Prl in 7 women with normal menstrual cycles. Blood samples were obtained every 10 min for an hour. GnRH (50 microgram) and TRH (200 microgram) were administered and blood sampling was continued every 15 min for 2 h (day 1). At 5 a.m. the next day, naltrexone (50 mg) was given and at 8 a.m. the GnRH-TRH test was repeated (day 2). At 5 a.m. on day 3, the patients took 2 mg oral dexamethasone and the test was repeated. At 5 a.m. on day 4, the patients took naltrexone and dexamethasone and at 8 a.m. the GnRH-TRH test was repeated. Administration of naltrexone did not cause significant changes in basal concentrations of LH and FSH and their response to GnRH. The area under the curve of the LH response to GnRH on day 3 was significantly less than on days 1, 2 and 4. Administration of naltrexone (day 2) did not cause any significant increase in basal and TRH-stimulated levels of Prl with respect to day 1. On day 3, dexamethasone caused a reduced response of Prl to TRH. Pretreatment with naltrexone (day 4) prevented this reduction. These results suggest that suppression of the response of LH to GnRH induced by dexamethasone may be partly mediated by endogenous opioids. Dexamethasone led to a reduction in the response of Prl to TRH, and naltrexone blocked this suppression. Hence the suppression of Prl and LH by dexamethasone must be partly mediated by endogenous opioids, which must therefore inhibit pituitary secretion of Prl.     

Overnight dexamethasone suppression test: normal responses and the diagnosis of Cushing's syndrome

Serum cortisol levels were measured the morning after the administration of 1 mg of dexamethasone. Only 5 of 190 subjects had serum cortisol levels greater than 2 micrograms/dL. Thus, the normal value after dexamethasone suppression is less than 2 micrograms/dL rather than less than 5 micrograms/dL as has generally been accepted. The distinction is important because some individuals with Cushing's syndrome partially suppress their cortisol levels to less than 5 but more than 2 micrograms/dL during the test procedure. Thus, the use of 5 micrograms/dL as the normal value may lead to an unnecessary delay in diagnosis.     

Inhibition of the ACTH adrenal response to stress by treatment with hydrocortisone, prednisolone and dexamethasone in the rat

16- and 4-week-old intact and adrenalectomized rats have been treated with different doses of the three glucocorticoids hydrocortisone, prednisolone and dexamethasone by gavage. The delayed feedback effect on plasma ACTH and corticosterone response to an ether stress have been assessed. Almost complete suppression of corticosterone response 20 min after an ether stress and an ACTH suppression to 20% of control values 5 min after an ether stress were observed with 25 micrograms of dexamethasone, 10 mg of prednisolone and 20 mg of hydrocortisone. Although the percent inhibition of corticosterone and ACTH response to stress was comparable, a striking dissociation of the ACTH and corticosterone release was observed in terms of absolute concentrations. A mean ACTH concentration of 462 ng/l after 25 micrograms of dexamethasone was measured together with a barely measurable corticosterone concentration of 3 micrograms%. Similarly, after 10 mg of prednisolone, the mean ACTH concentration was 404 ng/l, whilst the mean corticosterone concentration was 3 micrograms%. This dissociation demonstrates that the corticosterone concentration on its own does not necessarily reflect the ACTH release. At 4 weeks of age, the ACTH response to stress is more difficult to suppress than in adult animals. This is more obvious after adrenalectomy, where the excessive ACTH secretion was less inhibited by all glucocorticoids used. The time between the last steroid gavage and stress must be considered. In 4-week-old animals the ACTH response 16 h after 12.5 micrograms of dexamethasone was inhibited by 22%, whereas 4 h after the same dexamethasone dose the inhibition was 85%.(ABSTRACT TRUNCATED AT 250 WORDS)     

Hypercortisolism and the resistance to dexamethasone suppression during gestation

Maternal adrenocortical function was studied by measuring plasma cortisol and urinary free cortisol during gestation. Changes in suppressibility of pituitary-adrenocortical function were determined by dexamethasone administration. Urinary free cortisol as well as plasma cortisol increased during the course of gestation. The suppressibility by dexamethasone became less effective as pregnancy advanced. These results suggest that pregnant women have pituitary-adrenocortical hyperfunction and tissue refractoriness to glucocorticoid which increases during the course of gestation.