Growth retardation as well as the development of Cushingoid features in adrenally insufficient patients treated with the currently accepted replacement dose of cortisol (33-41 mumol/day.m2; 12-15 mg/m2.day) prompted us to reevaluate the cortisol production rate (FPR) in normal subjects and patients with Cushing's syndrome, using a recently developed thermospray liquid chromatography-mass spectrometry method. The stable isotope [9,12,12-2H3]cortisol was infused continuously for 31 h at about 5% of the anticipated FPR. Blood samples were obtained at 20-min intervals for 24 h, spun, and pooled in 4-h groups. Tracer dilution in plasma was determined by liquid chromatography/mass spectrometry. The method was validated with controlled infusions in 6 patients with adrenal insufficiency. Results from 12 normal volunteers revealed a FPR of 27.3 +/- 7.5 mumol/day (9.9 +/- 2.7 mg/day) or 15.7 mumol/day.m2; 5.7 mg/m2. day). A previously unreported circadian variation in FPR was observed. Patients with Cushing's syndrome demonstrated unequivocal elevation of FPR and cortisol concentration correlated during each sample period in normal volunteers, indicating that cortisol secretion, rather than metabolism, is mainly responsible for changes in plasma cortisol. Our data suggest that the FPR in normal subjects may be lower than previously believed.

Computed tomographic (CT) scans of the adrenal glands were obtained in nine patients with Cushing disease as a result of an adrenocorticotropic hormone (ACTH)-secreting pituitary adenoma and macronodular hyperplasia of the adrenal glands. The findings were compared retrospectively with those in six patients with Cushing syndrome as a result of an autonomous adrenal adenoma and 16 with Cushing syndrome as a result of ectopic ACTH production. Seven of nine patients with macronodular adrenal hyperplasia had hyperplastic adrenal glands in addition to single or multiple focal adrenal nodules. The six patients with hypercortisolism caused by an autonomous adrenal adenoma showed atrophic (four patients) or normal (two patients) ipsilateral and contralateral adrenal glands. Fourteen of 16 patients with the ectopic ACTH syndrome had hyperplasia of the adrenal glands without nodularity, and only two had focal nodules.

This study was undertaken to examine the role of adrenal androgen excess in the pathogenesis of polycystic ovary syndrome (PCOS) and, if such was present, to assess its reversibility using dexamethasone given in physiological dosage at night. Mean plasma testosterone (T), T/sex-hormone binding globulin (T/SHBG) ratio, androstenedione, and 17-OH-progesterone levels were elevated in the 19 patients studied. Plasma estrone values were elevated, whereas estradiol levels were normal. Plasma FSH was decreased and LH responsiveness to LHRH was exaggerated. Metyrapone, an 11-hydroxylase inhibitor, was administered at 2400 h to induce hypocortisolemia and compensatory ACTH secretion so that adrenal androgen and glucocorticoid responsiveness to endogenous stimulation could be examined. Plasma T, androstenedione, and 11-deoxycortisol responses to metyrapone were excessive in PCOS patients, thus indicating a specific adrenal abnormality. After 3 months treatment with dexamethasone, 0.5 mg at night, mean plasma T/SHBG and androstenedione declined to normal, and mean plasma dehydroepiandrosterone and dehydroepiandrosterone sulfate declined to below normal. The mean estrone value was slightly lower during dexamethasone. Plasma LH responsiveness to LHRH was no longer significantly different from normal, but FSH was suppressed. During treatment androgen responsiveness to metyrapone stimulation was normal, whereas 11-deoxycortisol responsiveness was suppressed. Fifteen patients completed 3 months of treatment with dexamethasone. Of these, 10 resumed regular menstruation. The latter group had suppression of plasma T, T/SHBG, androstenedione, dehydroepiandrosterone, and dehydroepiandrosterone sulfate. Only plasma androstenedione fell significantly in the remainder. These observations support the hypothesis that, in at least some patients, PCOS develops in response to abnormal gonadotropin secretion induced by hyperestronemia occurring as a consequence of excessive adrenal androgen secretion.

The plasma concentrations of sex hormone-binding globulin (SHBG) and sex steroids determine the nonprotein bound or free steroid fraction, which probably exerts the biological activity of sex steroids. Androgens lower and estrogens raise SHBG levels. The established pubertal fall in SHBG levels occurring in men has been attributed to rising androgen levels. In this study we examined the relationship between plasma SHBG and androgens in four men with untreated isolated gonadotropin deficiency and in two siblings with complete androgen insensitivity. In patients with untreated isolated gonadotropin deficiency there was a highly significant inverse correlation between SHBG levels and age (r = -0.9, P less than 0.001), although testosterone levels did not rise and there was no relationship between SHBG levels and testosterone, androstenedione, or dehydroepiandrosterone-sulfate. Two 46 XY siblings, who were phenotypic females, with complete androgen insensitivity had a marked decline in SHBG levels from 28.0 ng/ml at 9 yr to 17.1 ng/ml at 13 yr and from 15.2 ng/ml at 12 yr to 8.1 ng/ml at 16 yr, respectively. These observations indicate that the fall in SHBG levels during the second decade of life occurs irrespective of androgen activity and is under the control of other unidentified influences.