In vivo and in vitro effects of AVP and V1a receptor antagonist on Cushing's syndrome due to ACTH-independent bilateral macronodular adrenocortical hyperplasia.

We examined the possibility that AVP and V1a receptors were involved in regulating cortisol production in a 49 year old man with ACTH-independent bilateral macronodular adrenocortical hyperplasia (AIMAH), and investigated the effects of a V1a receptor antagonist. An i.v. injection of a small dose (0.1 or 0.3 U) of AVP, insulin-induced hypoglycaemia, upright posture tests, and oral administration of a V1a receptor antagonist (OPC-21268; 300 mg), and its repeated administration at a dose of 600 mg/day for 8 days were performed. An in vitro study of dispersed cells obtained from resected AIMAH tissue was also conducted. Plasma ACTH, AVP and cortisol levels and 24-h urinary free cortisol excretion were measured in the in vivo studies and cortisol concentrations in incubation media in the in vitro study. Injection of small doses of AVP stimulated cortisol secretion without any elevation of plasma ACTH. Insulin-induced hypoglycaemia caused a rise in plasma AVP followed by an increase in plasma cortisol. Although plasma cortisol levels were not affected by single or repeated administrations of OPC-21268, 24-h urinary free cortisol excretion was significantly decreased by the repeated treatment. In the in vitro study, more cortisol was stimulated by AVP from adrenal cells of the AIMAH tissue than from those of a normal adrenal gland, and this secretion was completely suppressed by OPC-21268. These results suggested that hypersensitivity to AVP may have contributed to overproduction of cortisol in this case of ACTH-independent bilateral macronodular adrenocortical hyperplasia, and may have contributed to its pathogenesis.

Growth hormone secretion in human acromegalic pituitary adenomas: cyclic adenosine monophosphate and protein kinase C responses.

We examined the effect of phorbol ester on growth hormone (GH)-releasing hormone (GRH)-induced GH secretion and cyclic adenosine monophosphate (cAMP) production in three pituitary adenomas and thyrotropin-releasing hormone (TRH)- and corticotropin-releasing hormone (CRH)-induced redistribution of protein kinase C (PKC) from cytosol to membrane in a pituitary adenoma resected from patients with acromegaly. GRH stimulated GH secretion in accordance with cAMP production in three cases, whereas 12-O-tetradecanoyl phorbol-13 acetate (TPA) stimulated GH secretion with cAMP production in one case. Simultaneous addition of GRH and TPA enhanced cAMP production in three pituitary adenomas. Moreover, addition of TPA with GRH resulted in additive secretion of GH in vitro. In one case, we were able to measure PKC activity and prove translocation of PKC stimulated by TRH and CRH in accordance with GH secretion in vitro and in vivo. These results suggest that TPA, an activator of PKC, has a stimulatory effect on GRH-induced cAMP production and that, finally, TRH- and CRH-induced PKC activation may cause greater secretion of GH by enhancement of cAMP production in human GH-hypersecreting adenoma cells.

Inhibition of aldosterone turn-off phenomenon following chronic adrenocorticotropin treatment with in vivo administration of antiglucocorticoid and antioxidants in rats.

Chronic adrenocorticotropin (ACTH) treatment in rats leads to a fall in aldosterone secretion (aldosterone turn-off or "aldosterone escape" phenomenon) with a concomitant rise in corticosterone. To elucidate whether ACTH-induced aldosterone suppression is mediated by steroid type II receptor or related to a free-radical effect by over-synthesized corticosterone, we examined the effects of a glucocorticoid antagonist, RU486, and antioxidants dimethyl sulfoxide (DMSO) and vitamin E, on the aldosterone turn-off phenomenon in rats. Each rat received daily for 5 days a different dose of ACTH-Z (5, 10, 20 or 40 micrograms/100 g body weight) 1 mg RU486/100 g body weight, 100 microliters (1.3 mmol) DMSO/100 g body weight or 2 mg vitamin E/100 g body weight with subcutaneous injection. Plasma steroid levels and in vitro release of steroids from the adrenal capsule were measured. The ACTH-Z treatment caused a dose-dependent increase in corticosterone and a decrease in aldosterone in both plasma and adrenal capsule experiments, as well as an increase in adrenal weights. For the following study 5 micrograms/100 g body weight of ACTH-Z was used. Administration of RU486 alone caused no change in plasma aldosterone level compared to controls, even though the steroid type II receptor was blocked, as evidenced by significant increases in plasma ACTH and corticosterone levels. Concomitant administration of RU486 and ACTH-Z increased both plasma corticosterone and aldosterone levels (p < 0.01) but decreased adrenal capsule corticosterone production (p < 0.05) compared to the rats treated with ACTH-Z alone.(ABSTRACT TRUNCATED AT 250 WORDS)

Responses of plasma adrenocortical steroids to low dose ACTH in normal subjects.

OBJECTIVE: The standard ACTH test in clinical use employs a pharmacological dose of ACTH which assesses the maximum secretory capacity of the adrenal cortex. We have investigated the responses of plasma adrenocortical steroids including cortisol, aldosterone and dehydroepiandrosterone (DHEA) to physiological doses of ACTH (ACTH 1-24, tetracosactide, Cortrosyn) and determined the minimal dose which induces a response equivalent to that induced by a pharmacological dose of ACTH. DESIGN: Rapid ACTH tests at various physiological (0-1, 0.5, 1 and 5 micrograms) and standard pharmacological (250 micrograms) intravenous doses. SUBJECTS: Seven healthy normal volunteers. MEASUREMENTS: Plasma cortisol, aldosterone and DHEA were measured. Peak value and the increment from basal value were used as indices of responses. RESULTS: Each steroid responded to physiological doses of ACTH in a dose dependent manner. The minimum dose inducing an equivalent response to 250 micrograms ACTH was 0.5 micrograms for peak and incremental values in cortisol and DHEA, while that for aldosterone was 0.1 microgram. The time to peak for each steroid was delayed as the dose increased. Plasma aldosterone and DHEA peaked significantly earlier than plasma cortisol in 1-5 micrograms and 0.5-5-micrograms ACTH tests, respectively. CONCLUSIONS: These results suggest that the sensitivity of secretion to physiological doses of ACTH in descending order is aldosterone > DHEA = cortisol. When peak and incremental values are used, sufficient doses of ACTH are 0.1 microgram for plasma aldosterone and 0.5 microgram for plasma cortisol and DHEA in the rapid ACTH test.

[ACTH-independent bilateral adrenocortical macronodular hyperplasia (AIMAH): report of a case].

We treated a case of ACTH-independent bilateral adrenocortical macronodular hyperplasia (AIMAH), a rare disease. The patient was a 49 year-old man having chief complaints of facial edema, muscle wasting and typical Cushing's syndrome symptoms. He was diagnosed with AIMAH by specific hormonal tests for Cushing's syndrome and CT scan. Bilateral total adrenalectomy was performed in a two-stage operation for bilateral macronodular adrenocortical hyperplasia. The resected adrenal tumor weighed 57 g on the right side and 78 g on the left, and both had a yellowish nodular surface. The histological appearance was typical AIMAH. A total of 23 AIMAH reported cases was reviewed.