Adrenal hyperandrogenism in adolescent girls with a history of low birthweight and precocious pubarche

OBJECTIVE Girls with precocious pubarche (PP) are at increased risk for ovarian dysfunction, hyperinsulinism and dyslipidaemia in adolescence, in particular when PP is preceded by reduced fetal growth. However, it is not known whether PP girls still have adrenal hyperandrogenism after puberty and if so, which fraction of PP girls develops so-called functional adrenal hyperandrogenism (FAH), an entity characterized by ACTH-dependent 17-ketosteroid excess. PATIENTS AND DESIGN Data were longitudinally collected from 47 girls with PP: at birth (weight for gestational age), at diagnosis of PP (age 6.7 +/- 1.1 years) and in adolescence (age 15.0 +/- 1.9 years). MEASUREMENTS Serum dehydroepiandrosterone sulphate (DHEAS) and androstenedione were measured at PP diagnosis, as well as the 17-hydroxyprogesterone (17-OHP) response to ACTH; postpubertal evaluation included assessment of adrenal and ovarian function, and of insulin responses to a glucose load. PP girls were considered to have FAH in adolescence if both DHEA and androstenedione responses to ACTH were excessive (> 1500 ng/dl and > 350 ng/dl, respectively). RESULTS At diagnosis of PP, girls had high DHEAS and androstenedione levels, as well as high 17-OHP responses to ACTH. In adolescence, PP girls had a normal BMI, presented with mild hirsutism and had high baseline and post-ACTH concentrations of most adrenal androgens, low SHBG levels and tended to have hyperinsulinemia and to present biological signs of ovarian hyperandrogenism. More than a third of the PP cohort developed FAH in adolescence. Neither baseline DHEAS, androstenedione, nor post-ACTH 17-OHP values at diagnosis of PP predicted the development of FAH in adolescence. In PP girls, only a low weight at birth was found to be significantly associated with subsequent FAH. CONCLUSIONS These longitudinal findings in girls with PP point to the possibility of an endocrine sequence of prenatal onset: low weight at birth, PP in childhood and adrenal hyperandrogenism in adolescence. The pathophysiological mechanisms underpinning this newly recognized sequence remain to be identified.