The 21-Hydroxylase-Deficient Adrenal Hyperplasias: More Than ACTH Oversecretion

Abstract

Twenty-one hydroxylase (21-OH)-deficient classic adrenal hyperplasia (CAH) and nonclassic adrenal hyperplasia (NCAH) are two of the most common genetic disorders known to man, yet the mechanism(s) resulting in steroid excess remains unclear. Overactivation of the hypothalamic-pituitary-adrenal (HPA) axis and increased ACTH secretion appear to be important mechanisms resulting in steroid excess in untreated patients, at least in the classic forms of the disorder. Nonetheless, most NCAH patients do not demonstrate overactivity of the HPA axis. A few of these patients may demonstrate a mild degree of ACTH hyper-responsiveness to corticotropin-releasing hormone stimulation, and up to 40% have radiologic evidence of adrenocortical hyperplasia and/or isolated adenomas, suggesting that some degree of chronic ACTH excess is present. Another mechanism resulting in adrenocortical excess in adrenal hyperplasia, and primarily in NCAH, follows the alteration in enzyme kinetics resulting from the mutation of 21-OH. The mutated enzyme product is less efficient than the wild type, resulting in an increased precursor to product ratio, independent of ACTH levels. Hence, progesterone (P4) and 17-hydroxyprogesterone (17-HP) levels in these patients may remain above normal even in the presence of excess glucocorticoid administration. Overactivity of the renin-angiotensin system may also be important in stimulating adrenocortical steroidogenesis in patients with salt-wasting and in some with simple virilizing CAH. Alterations in ovarian and gonadotropic function, with the appearance of a polycystic ovary-like picture, also contribute to the androgen excess of these patients. Functional ovarian abnormalities in patients with CAH or NCAH may relate to a number of causes, including prenatal masculinization of the hypothalamic-pituitary-ovarian (HPO) axis by adrenal androgens, continued disruption of the HPO axis by persistently elevated P4 or androgen levels, and/or a direct glucocorticoid effect. Finally, these data suggest that the measurement of P4 or 17-HP may not be the most accurate marker of therapeutic efficacy, and suppression of both the ovaries and adrenals may be necessary for optimum steroidogenic control.

Congenital Adrenal Hyperplasia

“…14,15 Some CYP21A2 missense mutations alter enzyme kinetics. 16 The mutated enzyme protein is synthesized, but is less efficient than the wild type. The net result is an increased precursor to product ratio, independent of ACTH levels.…”

Nonclassic congenital adrenal hyperplasia

“…Many missense mutations associated with NCAH generate a mutated enzyme protein, which is functionally less efficient than the wild type. It has been speculated that some missense mutations cause a 'dominant negative effect' due to altered enzyme kinetics [19]. Some patients with NCAH may experience increased androgen excess due to the 'backdoor' or 'alternative pathway' in which either progesterone or 17-OHP are converted by 5a-reductases and 3a-hydroxysteroid dehydrogenases to more potent androgens such as dihydrotestosterone [20].…”

Congenital Adrenal Hyperplasia

“…The 17-OHP and progesterone concentrations may be elevated even in the presence of excessive glucocorticoid administration. 100 Replacement therapy doses should not be based on 17-OHP concentrations because normalization of 17-OHP and progesterone concentrations generally indicates excessive glucocorticoid hormone replacement therapy. Dehydroepiandrosterone sulfate (DHEAS) concentrations are readily suppressed during treatment and cannot be used to assess the adequacy of replacement glucocorticoid therapy.…”