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17-Hydroxyprogesterone Responses to Gonadotropin-Releasing Hormone Disclose Distinct Phenotypes of Functional Ovarian Hyperandrogenism and Polycystic Ovary Syndrome

Division of Endocrinology (R.P., L.P., A.G.), Department of Internal Medicine, Centre for Applied Biomedical Research, Sant’Orsola-Malpighi Hospital, University Alma Mater Studiorum of Bologna, and Day-Surgery Center (P.P., G.E.C.), Gynepro Medical, 40138 Bologna, Italy

Address all correspondence and requests for reprints to: Renato Pasquali, M.D., Division of Endocrinology, Department of Internal Medicine, Sant’Orsola-Malpighi Hospital, University Alma Mater Studiorum, Via Massarenti 9, 40138 Bologna, Italy. E-mail: renato.pasquali{at}unibo.it.

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

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

Design, Setting, and Participants: We conducted an observational study at an academic hospital that included 148 PCOS women and 22 healthy age-matched normal-weight control women.

Main Outcome Measures: A hormone profile was taken 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), free androgen index (P < 0.01), 17-hydroxyprogesterone (P < 0.05), estrogens (P < 0.05), area under the curve for insulin (insulin_AUC) (P < 0.05), and C-peptide_AUC (P < 0.01) and lower insulin sensitivity (as composite insulin sensitivity index) (P < 0.05) than the NR-PCOS group. The response of 17-hydroxyprogesterone to _1–24ACTH (as percent 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 dehydroepiandrosterone was similar. Finally, the HR-PCOS group had lower percent 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 ß-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 cytochrome P450 17-hydroxylase/17,20-lyase (CYP17) enzyme pathway.

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