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Four monkeys were tested in varied short-term groupings in which individual monkeys were predicted to be alternatively the highest, the lowest, and the intermediate animal in dominance. Their overt behaviors in each hour test, especially submissive behaviors in subordinate animals, correlated well with rank; but measures of blood cortisol and 17-hydroxycorticosteroid secretion did not.
The effect of rifampicin on the metabolism of isoniazid in human volunteer subjects has been investigated. The urinary metabolites of isoniazid after a single dose and after six daily doses of isoniazid plus rifampicin were examined. The isoniazid-rifampicin combination clearly increased the ratio of urinary 6-beta-hydroxycortisol to 17-hydroxycorticosteroids, indicating that induction of the microsomal enzymes had occurred. However, no significant changes in the urinary metabolites of isoniazid were detected, and therefore it is not possible to predict the effect of rifampicin on isoniazid hepatotoxicity.
The effect of pregnancy on hepatic drug-metabolizing enzyme activity was investigated in nine healthy pregnant women using the ratio of 6-hydroxycortisol (6-OHF), to total 17-hydroxycorticosteroid (17-OHCS) in 24-hour urine as an index of the hepatic monooxygenase activity. The values of 6-OHF and the ratio (713 +/- 250 micrograms/d and 0.323 +/- 0.242; mean +/- SD) before delivery were significantly higher than they were during early puerperium (395 +/- 145 micrograms/d and 0.114 +/- 0.055) and approximately three months after delivery (237 +/- 67 micrograms/d and 0.066 +/- 0.034). Although the values three months after delivery were comparable to those found in the nonpregnant group (n = 10; 228 +/- 48 micrograms/d and 0.081 +/- 0.031), 6-OHF values one week after delivery were significantly higher than those observed in the control group. These observations suggest that drug-metabolizing enzyme induction may occur during pregnancy.
Low-dose dexamethasone suppression testing has been recommended for biochemical screening when Cushing's syndrome is suspected. The criterion for normal suppression of cortisol after dexamethasone is controversial. To assess diagnostic utility (sensitivity), we report the results of low-dose dexamethasone suppression testing in 103 patients with spontaneous Cushing's syndrome. There were 80 patients with Cushing's disease (78%), 13 with the ectopic ACTH syndrome (13%), and 10 with cortisol-producing adrenocortical adenomas (10%). Fourteen (18%) of 80 patients with Cushing's disease suppressed serum cortisol to less than 5 micro g/dl (<135 nmol/liter) after the overnight 1-mg test, whereas six patients (8%) actually showed suppression of serum cortisol to less than 2 micro g/dl (<54 nmol/liter). In addition, the 2-d, low-dose dexamethasone suppression test yielded false-negative results in 38% of patients when urine cortisol was used and 28% when urinary 17-hydroxycorticosteroids were used. Serum cortisol after the 1-mg test correlated with baseline urinary free cortisol (r = 0.705, P < 0.001), plasma ACTH level (r = 0.322, P = 0.001), and urinary free cortisol after the 2-d test (r = 0.709, P = 0.001). This study provides evidence that low-dose dexamethasone may suppress either plasma cortisol or urinary steroids to levels previously thought to exclude Cushing's syndrome and that these tests should not be used as the sole criterion to exclude the diagnosis of endogenous hypercortisolism.
The effect of the serotonin antagonist, cyproheptadine (Cypro), on metyrapone-induced stimulation of the pituitary-adrenal axis was evaluated in nine normal subjects. The subjects underwent standard oral metyrapone tests (750 mg every four h, for six doses) while taking no medications and while receiving oral Cypro (4 mg every six h). Cypro administration caused a significant reduction in: 1) baseline 17-hydroxycorticosteroid (17-OH) excretion (-31 +/- 7.2%), 2) the increase above baseline in 24 h 17-OH excretion on the day after metyrapone (-32 +/- 4.9%), 3) serum 11-deoxycortisol concentrations 8 h (-45 +/- 5.5%) and 24 h (-18 +/- 3.6%) after the first dose of metyrapone, and 4) plasma ACTH concentration 8 h (-32 +/- 8.2%) and 24 h (-22 +/- 8.0%) after the first dose of metyrapone. When compared with the control test, Cypro administration did not alter: 1) baseline 17-ketosteroid secretion, 2) the fall in serum cortisol concentration while taking metyrapone, 3) the serum free metyrapone concentration, 4) cortisol metabolism, 5) the adrenal response to ACTH, and 6) assay methods for measurement of serum and urinary corticosteroids. Our data suggest that Cypro can reduce pituitary-adrenal responsiveness by reducing plasma ACTH concentrations. If Cypro acts as a serotonin antagonist, our data lends support to the idea that serotoninergic mechanisms are important in the control of pituitary ACTH secretion in normal human subjects.
A 17-year-old women received 12,000 rads of alpha-particle radiation for the treatment of Cushing's disease. One day after the completion of therapy, the patient developed nausea, vomiting, headache, and postural hypotension. Laboratory evaluation demonstrated a marked fall of the previously elevated urinary 17-hydroxycorticosteroids (17-OHCS) and undetectable plasma cortisols. The urinary 17-OHCS transiently returned to supranormal levels but over a 2 1/2-week period decreased and then remained low. The patient also demonstrated a subnormal urinary aldosterone excretion in relation to plasma renin activity (PRA) during 10 mEq/24 h sodium restriction. The remainder of the endocrine evaluation was normal, suggesting that pituitary function otherwise remained intact. One and one-half years after alpha-particle therapy, the patients's urinary 17-OHCS were normal and responded normally to metyrapone. The relationship between urinary aldosterone excretion and PRA also was normal. It is postulated that there was an infarction of an ACTH secreting pituitary tumor leaving the remainder of the pituitary intact. Achronically elevated circulating level of ACTH with sudden loss of ACTH secretion appeared to have been responsible for the initial low urinary aldosterone as well as the low urinary 17-OHCS. This is the first reported case of a presumed pituitary tumor infarction in association with alpha-particle pituitary radiation.
Significant circadian rhythns in urinary excretion of cyclic AMP, cyclic GMP, creatinine, 17-hydroxycorticosteroids and inorganic phosphorus were demonstrated in three normal subjects (two males and one post-menopausal female) who collected serial 4-h specimens for periods of 33, 22, and 14 days, respectively. Peak excretion of the above substances occurred, respectively, at approximately 1500-1700, 2300-0200, 1700-1800, 1100-1300, and 1800-2200 h. The estimated amplitudes of the rhythms expressed as a percentage of the mean 4-h excretion rate were 12-13%, 9-13%, 9-15%, 30-78% and 22-26%, respectively. With the possible exception of cyclic GMP, all of the observed rhythms appeared to be sinusoidal, with normal periods of 24 h. The rhythms in both cyclic AMP and creatinine excretion, but not in the remaining substances may be explained largely in terms of the known rhythm in glomerular filtration rate. The factors responsible for the rhythm in cyclic GMP excretion are unknown.
Urinary 6beta-hydroxycortisol (6betaOHF) excretion was measured and compared with free cortisol and 17-hydroxycorticosteroid (17OH) excretion in normal children, patients with Cushing's syndrome or disease (CSD), and patients during cortisol therapy. Normal 6betaOHF excretion in children was 0.23 +/- 0.03 mg/m2/24 h (mean +/- SE). No sex difference was found. ACTH infusion (40 U/day for 5 days) and high dose cortisol altered the 6 betaOHF:17OH ratio so that it was indistinguishable from the ratio seen in CSD. The fact that both Cushing's disease and high dose cortisol therapy caused the same change in the 6 betaOHF:17OH ratio suggests that cortisol and not ACTH induced 6beta-hydroxylase in hypercortisolemic subjects. Since the 6betaOHF:17OH ratio in CSD patients was always well above the normal range, measurement of 6betaOHF excretion was a better and more rapid test for chronic hypercortisolemia than urinary 17OH or free cortisol. Thus, measurement of urinary 6betaOHF is suggested as a good diagnostic test for hypercortisolemic states.
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.
We measured urinary 6 beta-hydroxycortisol (6 beta OHF) excretion in normal children and in children receiving anticonvulsant therapy with phenobarbital or diphenylhydantoin, 6 beta OHF excretion increased 4- to 7-fold during anticonvulsant therapy. The marked increase in the ratios of 5 beta OHF to 17-hydroxycorticosteroid and 6 beta OHF to free cortisol suggests that the measured increase in urinary 6 beta OHF may serve as an index of induction of the microsomal mixed function oxidase system. This noninvasive approach allows rapid assessment of the effects of drugs and foreign compounds on microsomal hydroxylation of cortisol. This convenient probe can be applied, with particular ease, to further studies in children in whom characterization of the effects of drugs and xenobiotic compounds on hepatic hydroxylation is of interest.
Receptor-mediated uptake of low density lipoproteins (LDL) provides an important source of cholesterol for corticosteroid synthesis by human adrenocortical cells grown in tissue culture. Recent studies have indicated an impaired adrenocortical response to prolonged ACTH stimulation in patients with abetalipoproteinemia (who lack plasma LDL) and in patients with homozygous familial hypercholesterolemia (FH), who have a virtual absence of high affinity LDL receptors. In the present study we examined parameters of adrenocortical function in four women with well characterized heterozygous FH to assess whether a 50% reduction in the number of LDL receptors measured in vitro influenced the response of the adrenal cortex to prolonged stimulation with ACTH. Biochemical studies of the binding, internalization, and degradation of [125I]LDL were undertaken in cultured skin fibroblasts from each patient, and all patients had reduced LDL receptor activity. The adrenocortical response to a 36-h iv infusion of alpha ACTH-(1-24) (Cortrosyn) was evaluated in the four patients with heterozygous FH and in five normal women. Stimulation with iv ACTH resulted in rapid increases in the serum concentrations of cortisol in both groups and plateau concentrations of 55-60 micrograms/dl. The rates of increase and the plateau concentrations were similar in the control and FH patients. Similarly, rates of excretion of 17-hydroxycorticosteroids and cortisol were similar in the normal subjects and FH patients. These results indicate that a 50% reduction in the number of high affinity LDL receptors due to the presence of one abnormal gene at the LDL receptor locus does not result in any impairment in the delivery of cholesterol to the adrenal cortex during conditions of maximal corticosteroid production.
This report describes studies of a man suspected of having primary cortisol resistance. This conclusion is based on his high plasma cortisol levels and high 24-h urinary 17-hydroxycorticosteroid and cortisol excretion, plus the fact that he had no manifestations of Cushing's syndrome. Among family members tested, his mother also had hypercortisolemia. Both mother and son had high levels of unbound plasma cortisol, but their plasma ACTH concentrations were within the normal range. Both were partially resistant to dexamethasone adrenal suppression, and both had mild hypertension without hypokalemia. To study this apparent end-organ resistance to cortisol, we examined the glucocorticoid receptors in peripheral mononuclear cells. Using whole cell assays, glucocorticoid receptors in both patients were found to have reduced total binding capacity. We conclude that these two patients, members of the same family, have primary cortisol resistance accompanied by a reduced number of glucocorticoid receptors.
The polycystic ovary syndrome (PCO) is frequently associated with elevated plasma levels of adrenal androgens and/or abnormal adrenal androgen responses to hormonal stimulation and suppression. Because of the overlap in the output of hormones between the adrenal glands and the ovaries, we measured adrenal iodocholesterol accumulation as an index of adrenocortical function in 11 women with PCO confirmed by laparoscopy or culdoscopy. All patients had normal dexamethasone suppression of plasma cortisol or urinary 17-hydroxycorticosteroid excretion. 6 beta-[131I]Iodomethylnorcholesterol (NP-59) adrenal scintiscans showed bilateral and excessive adrenal cortical uptake in PCO patients [0.46 +/- 0.08% (+/- SE) of the administered dose compared to 0.21 +/- 0.01% in a group of normal women; P less than 0.05]. The elevation of adrenal cortical NP-59 uptake in PCO was quantitatively similar to that in women with ACTH-dependent Cushing's syndrome (0.64 +/- 0.11%; P greater than 0.1). These data support the presence of abnormal adrenal cortical function in patients with PCO. The adrenal dysfunction of PCO most likely represents abnormal control of adrenal androgen production/secretion.
The effects of burn trauma in men on the production of adrenal and testicular steroids was investigated. Whereas there were significant increases in serum cortisol levels and urinary 17-hydroxycorticosteroid excretion soon after thermal injury, there were significant decreases in serum dehydroepiandrosterone sulfate, dehydroepiandrosterone, androstenedione, and testosterone concentrations during the first 4 weeks following burn trauma. Serum androstenediol and androstenediol sulfate levels also were reduced, though insignificantly, 10-23 days postburn. Serum LH levels were unchanged during the postburn interval. Since urinary 17-ketosteroid excretion was normal or below normal rather than increased, the decline in serum C19-steroid levels probably resulted from decreased glandular secretion rather than increased rates of metabolism and excretion. Low dehydroepiandrosterone sulfate and/or testosterone levels were found in some men several months after recovery from their burns. These data suggest that thermal injury leads to acute inhibition of adrenal and testicular C19-steroid secretion, but stimulation of adrenal glucocorticosteroid production, and that endocrine function in many instances is not normalized after complete healing of the burned surfaces. The mechanisms and physiological consequences of such changes in the steroid milieu of men after burn trauma are unknown.
We previously reported that female baboons overfed during infancy were not fatter at weaning, but developed hypertrophic obesity after puberty. To clarify the mechanisms of this dietary effect on adipocyte hypertrophy, we determined the effects of infant overfeeding on preweaning plasma hormone and triglyceride levels and their relationship with fat cell volume at weaning (19 weeks of age). Newborn female baboons from 3 sires and 24 dams were fed either 280 kilojoules (normally fed; n = 12) or 395 kilojoules (overfed; n = 10) per 100 g Similac formula for 18 weeks. Both formulas contained 9.2%, 43.1%, and 48.5% of calories as protein, carbohydrate, and fat, respectively. During the first 9 weeks, overfed infants had significantly higher fasting and postprandial insulin, total T3, and free T3 concentrations; lower cortisol levels; and lower excretion of urinary 17-hydroxycorticosteroids (17-OHCS) than normally fed infants. These effects were no longer significant at 17-18 weeks. Infant diet did not influence fasting and postprandial plasma triglyceride levels, and fat cell volume was not influenced by energy intake. However, fat cell volume was positively associated with postprandial triglyceride concentrations and inversely associated with postmeal nadir cortisol levels. These results demonstrate that infant overfeeding initiates early alterations in insulin, T3, free T3, and cortisol, but these effects persist only as long as there is a significant increase in energy intake.
Familial Cushing's syndrome is rare, and when it occurs, it is usually associated with primary micronodular dysplasia. We report two cases, a mother and daughter, who each presented with clinical features of Cushing's syndrome at age 38 yr and were found to have ACTH-independent macronodular adrenal hyperplasia. In each case, bilateral adrenalectomy revealed the massively thickened adrenal cortex with nodules up to 1.3 cm in diameter and hyperplasia between nodules. Dynamic testing showed no suppression of free cortisol with high dose dexamethasone and no stimulation of 17-hydroxycorticosteroids with metyrapone. Two samples of serum obtained preoperatively from one patient that showed ACTH immunoreactivity of 4.6 and less than 2.2 pmol/L, respectively, each showed less than 2.2 pmol/L ACTH bioactivity. The lack of suppression with high dose dexamethasone, lack of stimulation with metyrapone, and low levels of ACTH immunoreactivity and bioactivity suggest that the bilateral hyperplasia was not dependent upon ACTH. These patients represent the first cases of ACTH-independent macronodular adrenal hyperplasia occurring in two generations of one family and illustrate the expanding clinical spectrum of Cushing's syndrome.
The dexamethasone-suppressed CRH test (Dex-CRH test) differentiates patients with Cushing's syndrome (CS) from those with pseudo-Cushing states, who have decreased ACTH responses to CRH because of negative feedback exerted by chronic hypercortisolism. Normal subjects, however, have not been studied with the Dex-CRH test, raising concern that this test might not separate patients with CS from patients with normal adrenal function. To determine whether the criterion that separates CS from pseudo-Cushing states also would differentiate patients with Cushing's disease (CD) from individuals with eucortisolism, we studied 20 healthy volunteers during low-dose (2 mg/day) dexamethasone suppression, and then during the Dex-CRH test (CRH stimulation test performed 2 h after completion of low-dose dexamethasone suppression), and contrasted their results with those of 20 patients with surgically proven mild CD [urine free cortisol (UFC) < 1000 nmol/day). Basal UFC was significantly greater in patients with CD (P < 0.001) but within the normal range (55-250 nmol/day) in 4 patients. During low-dose dexamethasone suppression, a UFC less than 100 nmol/day (36 micrograms/day) was found in all but 1 volunteer subject, and a urine 17-hydroxycorticosteroid excretion less than 14.6 mumol/day (5.3 mg/day) was found in all but 2 subjects. During the Dex-CRH test, plasma cortisol less than 38 nmol/L was found in all 20 normal volunteers until 30 min after CRH administration. By contrast, the 15-min CRH-stimulated plasma cortisol exceeded 38 nmol/L in all patients with CD (P < 0.001). Plasma dexamethasone measured just before CRH administration was similar in normal volunteers (13.0 +/- 6.1 mumol/L) and patients with CD (16.4 +/- 6.4 mumol/L). We conclude that cortisol measurements obtained during the Dex-CRH test are suppressed in normal volunteers below those found in mild CD. These results suggest that the Dex-CRH test may be useful in the evaluation of CS in patients without significant hypercortisoluria. However, its value in patients with episodic hormonogenesis has not been tested.
Pharmacological effects on anti-diuresis, anti-ulceration, anti-dementia and learning function of 50% ethanolic extract (AO-ext) from Alpiniae Fructus (fruit of Alpinia oxyphylla) removed seed vessel were investigated in order to prove the evidence of the efficacy of Alpiniae Fructus on the ancient herbal literature. AO-ext showed the effects of anti-diuresis, anti-ulceration, anti-dementia and on increase in the learning function in animals. And also, AO-ext exhibited the increasing effect on the serum 11-hydroxycorticosteroid (11-OHCS) level in the above-described experimental animals and in intact and hypophysectomized rats.