Context: The exaggerated 17-hydroxyprogesterone response to GnRH agonists, that reflects functional ovarian hyperandrogenism (FOH), is believed to be the prominent abnormality in women with polycystic ovary syndrome (PCOS).

Objective: To quantify the prevalence of PCOS with FOH, and to evaluate whether the presence of FOH may distinguish different clinical and biochemical phenotypes.

Design: Observational study.

Setting: Academic hospital.

Participants: 148 PCOS women and 22 healthy age-matched normal-weight control women.

Main Outcome Measures: Hormone profile at baseline and in response to _1–24ACTH and to a GnRH agonist, buserelin, administered during dexamethasone suppression

Results: Based on the data obtained in the control subjects, the PCOS patients were divided into two groups, one with a normal (NR-PCOS, n=78) and one with a high 17-hydroxyprogesterone response (HR-PCOS, n=70) to buserelin. The two groups of PCOS subjects had similar anthropometric parameters and clinical signs of hyperandrogenism. Age and body weight at menarche were significantly lower and higher, respectively, in the HR-PCOS group than the NR-PCOS group. Moreover, the HR-PCOS group had higher basal testosterone (P< 0.001), FAI (P< 0.01), 17-hydroxyprogesterone (P< 0.05), estrogens (P< 0.05), insulin_AUC (P< 0.05) and C-peptide_AUC (P< 0.01), and lower insulin sensitivity (as ISI_-composite) (P< 0.05) than the NR-PCOS group. The response of 17-hydroxyprogesterone to _1–24ACTH (as %variation) was lower in the HR-PCOS group with respect to the NR-PCOS group (P< 0.05), whereas the response of cortisol, androstenedione and DHEA was similar. Finally, the HR-PCOS group had lower % suppression of androstenedione (P< 0.001) and 17-hydoxyprogesterone (P< 0.05) to dexamethasone. In a multiple regression model applied in all PCOS women, insulin_AUC but not androgens or markers of insulin resistance predicted the 17-hydroxyprogesterone response to buserelin to a highly significant extent (t=3.269; p< 0.01).

Conclusions: This study indicates that the paradigm that FOH is a specific feature of the PCOS status can no longer be sustained. We have shown that women with an exaggerated 17-hydroxyprogesterone response to a GnRH agonist, buserelin, are characterized by more severe hyperandrogenemia, glucose-stimulated -cell insulin secretion and worse insulin resistance than those without evidence of FOH. Our data may be consistent with the hypothesis that excess insulin may represent a candidate factor responsible for FOH in these women, through the overactivation of the CYP17 enzyme pathway.