A Rationale for Mineralocorticoid Supplementation in Classic Congenital Adrenal Hyperplasia

Abstract

most common example of this phenomenon is Cushing syndrome due to high endogenous or exogenous cortisol exposure. Iatrogenic Cushing syndrome, characterized by inhibition of statural growth in children, excess weight gain, metabolic syndrome, and hypertension, may be ob-served in CAH patients receiving excessive glucocorti-coid treatment [6] . This is why it is important to balance the need for suppression of adrenal androgen precursors with the opposing practical dictum of minimizing gluco-corticoid exposure, particularly in growing children.One way to achieve the desired balance is to treat clas- sic CAH patients from infancy with a combination of moderate doses of both glucocorticoid and mineralocor-ticoid supplements. A systematic review and meta-analy-sis of treatment outcomes in CAH patients revealed that those children who received long-term treatment with mineralocorticoids achieved significantly better adult heights compared with those who were prescribed gluco-corticoids alone [7] . On the other hand, investigators have observed elevated 24-hour ambulatory blood pres-sure in children [8] and adults [9] with CAH. However, it has not been demonstrated that young adults with CAH suffer clinically significant cardiac morbidities or mortal-ity [10] . Taken together, the implication of the available data is that clinicians should prudently prescribe miner- The study by Mooij et al. [1] in this issue underscores the interrelatedness of adrenal cortical steroids in achiev-ing balance in the treatment of patients with congenital adrenal hyperplasia (CAH). In this set of in vitro experi-ments, the investigators delineate the nature of 17-hy-droxyprogesterone and progesterone interference with the ability of aldosterone to transactivate the mineralo-corticoid receptor (MR). This occurs at the level of recep-tor transactivation, rather than nuclear translocation. It is reasonable to infer from these data that a similar in vivo phenomenon occurs at the high 17-hydroxyprogesterone levels and low physiologic aldosterone levels measured in inadequately controlled classic CAH patients. It has long been recognized that elevated plasma renin levels reflect-ing low aldosterone production and/or activity are found among CAH patients with elevated steroid 21-hydroxy-lase precursors [2, 3] . Previous in vitro studies have con-firmed the hypothesis that progesterone and its analogs are the culprits inhibiting MR [4] . An obvious corollary of these findings is exacerbation of sodium wasting in CAH patients, potentially impeding normal growth and even triggering adrenal crisis. In contrast to the ability of progesterones to interfere with aldosterone-induced MR activity, cortisol may bind to and activate the MR causing hypertension [5] . The