Diminished Adrenal Androgen Secretion In Familial Glucocorticoid Deficiency Implicates A Significant Role For Acth In The Induction Of Adrenarche

OBJECTIVE The mechanism of adrenarche is controversial, and there have been competing claims that its origin is in the hypothalamo-pituitary axis or in the adrenal gland itself. ACTH is a proposed inducer of adrenarche so patients with ACTH resistance due to the familial glucocorticoid deficiency syndrome provide a model to clarify the degree to which ACTH is involved in the regulation of adrenal androgen secretion during adrenarche.DESIGN Random analysis of plasma adrenal androgens and urinary adrenal androgen output in treated patients with familial glucocorticoid deficiency.PATIENTS Eleven patients (6 males and 5 females, aged 6.5-21.6 years, 4 prepubertal, minimum bone age 9 years) with familial glucocorticoid deficiency were studied. In 6, mutations in the coding region of the ACTH receptor are the cause of their ACTH resistance. In the remaining 5 the receptor was normal. MEASUREMENTS Physical examination, basal serum cortisol, basal plasma ACTH, serum cortisol after stimulation with 250 mu g ACTH(1-24), plasma dehydraepiandrosterone-sulphate (DHEAS) and plasma androstenedione (A4), total urinary androgen excretion and single-stranded sequencing of the coding region of the ACTH receptor.RESULTS DHEAS was undetectable in 8, and detectable but below the age-matched reference Values in 3 patients. A4 was measured in 10 patients, and in 3 patients (2 in late puberty) was found to be subnormal whereas in the remaining 7 patients A4 was normal for age and pubertal stage consistent with the gonadal contribution to peripheral A4 levels. Significantly diminished output of urinary adrenal androgen metabolites in 3 patients confirmed the results found in serum. The lack of adrenarche was independent of the presence of a mutation within the ACTH receptor and of the severity of glucocorticoid deficiency. Despite adequate glucocorticoid replacement therapy ACTH levels remained elevated in 10 of the 11 patients.CONCLUSIONS Although reduced adrenocortical inner zone cell number may contribute to the lack of adrenarche, in some patients there appears to be a discrepancy between partial glucocorticoid deficiency and significantly diminished adrenal androgen secretion. These data imply a significant contribution of ACTH to the regulation of adrenarche in normal children either by having a priming effect on the adrenal gland or by acting in concert with other adrenal androgen stimulating factors.