Effects of Chronic ACTH Excess on Human Adrenal Cortex

Abstract

Chronic ACTH excess leads to chronic cortisol excess, without escape phenomenon, resulting in Cushing’s syndrome. Excess adrenal androgens also occur: in females, they will overcompensate the gonadotrophic loss, inducing high testosterone; in males, they will not compensate it, inducing low testosterone. Chronic ACTH excess leads to chronic adrenal mineralocorticoid excess and low aldosterone levels: after an acute rise, aldosterone plasma levels resume low values after a few days when ACTH is prolonged. Two other mineralocorticoids in man, cortisol and 11 deoxycorticosterone (DOC), at the zona fasciculata, will not escape the long-term effect of chronic ACTH excess and their secretion rates will remain elevated in parallel. Over all, the concomitant rise in cortisol and 11 DOC will more than compensate the loss of aldosterone, and eventually create a state of chronic mineralocorticoid excess, best evidenced by the accompanying suppression of the renin plasma levels, a further contribution to the suppression of aldosterone secretion. Prolonged in vivo stimulation with ACTH leads to an increase in total adrenal protein and RNA synthesis. Cell proliferation is indicated by an increase in total DNA the resulting adrenocortical hyperplasia participates in the amplified response of the chronically stimulated gland, and the weight of each gland can be greatly increased. The growth-stimulatory effect of ACTH in vivo most likely proceeds through the activation of a local and complex network of autocrine growth factors and their own receptors; a number of compounds, including non-ACTH proopiomelanocortin peptides such as γ3-MSH, have been shown to exert some adrenocortical growth effect.

Dual effects of 9-cis retinoic acid on ACTH-dependent hyperplastic adrenal tissues

“…In patients with Cushing’s disease, adrenals are continuously exposed to elevated ACTH levels and it stands to reason that the effect of 9- cis retinoic acid on ACTH receptor expression may come to play a major role. Of note, long-standing exposure to excess ACTH usually leads to the development of hyperplastic adrenals in these patients 25 , attesting to the preeminent role of ACTH on adrenal secretion and trophism. Given the above, we decided to expand upon our previous findings and investigate the effect of 9- cis retinoic acid on adrenals from patients with Cushing’s disease.…”

Comparison of Steroidogenic Exposure Following the Administration of Repository Corticotropin Injection With a Synthetic ACTH1‐24 Depot and Methylprednisolone in Healthy Subjects

“…Although there was no accumulation, cortisol levels were higher on day 15 (steady state) than on day 1, suggesting increased MC2R sensitivity with repeated dosing. 22 Because cortisol levels remained elevated 24 hours after the administration of synthetic ACTH 1‐24 depot, accumulation in cortisol exposure following daily dosing was observed.…”

Central Precocious Puberty as a Complication of Therapy with Adrenocorticotropin (ACTH) and an Aromatase Inhibitor for Refractory Nephrotic Syndrome

“…The common side effects of ACTH treatment are similar to those seen with glucocorticoids, such as weight gain, Cushingoid facies, fluid retention, hyperglycemia, hypertension, hypokalemia, and increased irritability [3, 5, 6]. Chronically elevated ACTH levels can also lead to excess adrenal androgens, which can in turn lead to increased estrogen [7] and gonadotropin suppression [8]. On the other hand, studies in adult women show ACTH administration can stimulate LH and FSH release, possibly through cortisol [9].…”