Inhibitory effect of diazepam on the activity of the hypothalamic-pituitary-adrenal axis in female rats

Objective Mitotane, a drug used to treat adrenocortical cancer (ACC), inhibits multiple enzymatic steps of adrenocortical steroid biosynthesis, potentially causing adrenal insufficiency. Recent studies in vitro have also documented a direct inhibitory effect of mitotane at the pituitary level. The present study was aimed to assess the hypothalamic–pituitary–adrenal axis in patients with ACC receiving mitotane. Design and methods We prospectively enrolled 16 patients on adjuvant treatment with mitotane after radical surgical resection of ACC, who underwent standard hormone evaluation and h-CRH stimulation. A group of 10 patients with primary adrenal insufficiency (PAI) served as controls for the CRH test. Results We demonstrated a close correlation between cortisol-binding globulin (CBG) and plasma mitotane levels, and a non-significant trend between mitotane dose and either serum or salivary cortisol in ACC patients. We did not find any correlation between the dose of cortisone acetate and either ACTH or cortisol levels. ACTH levels were significantly higher in patients with PAI than that in patients with ACC, both in baseline conditions (88.99 (11.04–275.00) vs 24.53 (6.16–121.88) pmol/L, P = 0.031) and following CRH (158.40 (34.32–275.00) vs 67.43 (8.8–179.52) pmol/L P = 0.016). Conclusions The observation of lower ACTH levels in patients with ACC than that in patients with PAI, both in basal conditions and after CRH stimulation, suggests that mitotane may play an inhibitory effect on ACTH secretion at the pituitary levels. In conclusion, the present study shows that mitotane affects the HPA axis at multiple levels and no single biomarker may be used for the assessment of adrenal insufficiency.

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DIVERGENT RESPONSES OF ARTERIOSCLEROTIC AND NON-ARTERIOSCLEROTIC RATS TO A CATABOLIC DOSE OF CORTISONE

Acta Endocrinologica ◽

10.1530/acta.0.0610509 ◽

1969 ◽

Vol 61 (3) ◽

pp. 509-524 ◽

Cited By ~ 6

Author(s):

Bernard C. Wexler ◽

Jack Saroff

Keyword(s):

Arterial Disease ◽

Hypothalamic Pituitary Adrenal Axis ◽

Female Rats ◽

Ground Substance ◽

Disuse Atrophy ◽

Hypothalamic Pituitary Adrenal ◽

Adrenal Axis ◽

Male And Female Rats ◽

Renal Changes ◽

Pituitary Adrenal Axis

ABSTRACT Male and female rats bred repeatedly develop arteriosclerosis spontaneously. Current information indicates that stimulation of the hypothalamic-pituitary-adrenal axis in association with the active, repeated breeding may be responsible for the increased adrenocortical steroid production which would account for the abnormal lipid, carbohydrate and protein metabolism and arteriosclerosis observed in these animals. Arteriosclerotic breeder rats and non-arteriosclerotic virgin rats were given chronic injections of cortisone. The arteriosclerotic animals showed the most significant catabolic effects due to overdose with steroid, i. e., loss in body weight, disuse atrophy of the adrenal gland, reduced serum corticosterone levels, thymus gland involution, myocardial and renal changes. The excess glucocorticoid caused an acceleration of the usual pattern of development of the arterial disease and increased severity of the pre-existing arteriosclerosis. The excess endogenous steroid did not induce arterial damage in previously non-arteriosclerotic animals. It is believed that the increased activity of the hypothalamic-pituitary-adrenal axis in repeatedly bred rats conditions the arterial wall towards derangement of connective tissue ground substance and elements and the development of arteriosclerosis, i. e., a hormonal basis for the pathogenesis of this model of cardiovascular disease.

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