Postpubertal outcome in girls diagnosed of premature pubarche during childhood: Increased frequency of functional ovarian hyperandrogenism

Abstract

The postpubertal outcome of a group of girls diagnosed of premature pubarche during childhood was assessed 1) to determine the incidence of functional ovarian hyperandrogenism (FOH) through the ovarian-steroidogenic response to the GnRH agonist leuprolide acetate, 2) to validate leuprolide acetate stimulation in FOH diagnosis, and 3) to ascertain whether FOH-predictive biochemical markers exist at the diagnosis of premature pubarche. Of 35 patients (age, 15.4 ± 1.5 yr), 16 showed hirsutism, oligomenorrhea, and elevated baseline testosterone and/or androstenedione (Δ4-A) levels. Subcutaneous administration of leuprolide acetate (500 μg) produced similar increases in gonadotropin levels in oligomenorrheic patients, regularly menstruating patients (n = 19), and controls (n = 12; age, 15.3 ± 1.3 yr) when tested at 6 h. Of all of the steroids measured, 17-hydroxyprogesterone (17-OHP) and Δ4-A levels 24 h postleuprolide acetate stimulation were significantly higher in oligomenorrheic patients than in the other two groups (P < 0.0001). No overlapping in 17-OHP responses occurred between oligomenorrheic patients and the other groups. Baseline dehydroepiandrosterone sulfate and Δ4-A levels at the diagnosis of premature pubarche correlated with 17-OHP values postleuprolide acetate challenge (r = 0.47; P < 0.005 and r = 0.67; P < 0.0001, respectively). These results show a distinct leuprolide acetate challenge response in 45% of the postpubertal premature pubarche girls studied, suggestive of an increased incidence of FOH, and support the need for continued routine postmenarcheal evaluation of this group of patients. Responses of 17-OHP to leuprolide acetate challenge facilitate the identification of FOH patients, establish this test as a reliable diagnostic tool in FOH diagnosis, and confirm the ovaries as the source of hyperandrogenemia in most patients with androgen excess. Although increased 17-OHP responses after leuprolide acetate stimulation seem to occur more frequently in girls with elevated dehydroepiandrosterone sulfate and/ or Δ4-A levels at the diagnosis of premature pubarche, specific biochemical markers predictive of FOH in this group of patients are still lacking.