Leptin is secreted by the white adipose tissue and modulates energy homeostasis. Nutritional, neural, neuroendocrine, paracrine, and autocrine factors, including the sympathetic nervous system and the adrenal medulla, have been implicated in the regulation of
leptin secretion. Classic
congenital adrenal hyperplasia (CAH) is characterized by a defect in
cortisol and
aldosterone secretion, impaired development and function of the adrenal medulla, and adrenal
hyperandrogenism. To examine
leptin secretion in patients with classic CAH in relation to their adrenomedullary function and
insulin and
androgen secretion, we studied 18 children with classic CAH (12 boys and 6 girls; age range 2-12 yr) and 28 normal children (16 boys and 12 girls; age range 5-12 yr) matched for body mass index (BMI). Serum
leptin concentrations were significantly higher in patients with CAH than in control subjects (8.1 +/- 2.0 vs. 2.5 +/- 0.6 ng/ml, P = 0.01), and this difference persisted when
leptin values were corrected for BMI. When compared with their normal counterparts, children with CAH had significantly lower plasma
epinephrine (7.1 +/- 1.3 vs. 50.0 +/- 4.2, P < 0.001) and free
metanephrine concentrations (18.4 +/- 2.4 vs. 46.5 +/- 4.0, P < 0.001) and higher fasting serum
insulin (10.6 +/- 1.4 vs. 3.2 +/- 0.2 microU/ml, P < 0.001) and
testosterone (23.7 +/- 5.3 vs. 4.6 +/- 0.5 ng/dl, P = 0.003) concentrations.
Insulin resistance determined by the homeostasis model assessment method was significantly greater in children with classic CAH than in normal children (2.2 +/- 0.3 vs. 0.7 +/- 0.04, P < 0.001).
Leptin concentrations were significantly and negatively correlated with
epinephrine (r = -0.50, P = 0.001) and free
metanephrine (r = -0.48, P = 0.002) concentrations. Stepwise multiple linear regression analysis indicated that serum
leptin concentrations were best predicted by BMI in both patients and controls. Gender predicted serum
leptin concentrations in controls but not in patients with classic CAH. No association was found between the dose of
hydrocortisone and serum
leptin (r = -0.17, P = 0.5) or
insulin (r = 0.24, P = 0.3) concentrations in children with CAH. Our findings indicate that children with classic CAH have elevated fasting serum
leptin and
insulin concentrations, and
insulin resistance. These most likely reflect differences in long-term adrenomedullary hypofunction and
glucocorticoid therapy. Elevated
leptin and
insulin concentrations in patients with CAH may further enhance adrenal and ovarian
androgen production, decrease the therapeutic efficacy of
glucocorticoids, and contribute to later development of
polycystic ovary syndrome and/or the
metabolic syndrome and their complications.