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The Journal of Clinical Endocrinology & Metabolism Vol. 88, No. 7 3333-3338
Copyright © 2003 by The Endocrine Society

Androgen Receptor Gene CAG Repeat Polymorphism in the Development of Ovarian Hyperandrogenism

Lourdes Ibáñez, Ken K. Ong, Nigel Mongan, Jarmo Jääskeläinen, Maria Victoria Marcos, Ieuan A. Hughes, Francis de Zegher and David B. Dunger

Endocrine Unit (L.I.), Hospital Sant Joan de Déu, University of Barcelona, E-08950 Barcelona, Spain; Department of Paediatrics (K.K.O., N.M., J.J., I.A.H., D.B.D.), University of Cambridge CB2 2QQ, United Kingdom; Endocrine Unit (M.V.M.), Consorci Hospitalari de Terrassa, Barcelona, Spain; and Department of Paediatrics (F.D.Z.), University of Leuven, B-3000 Leuven, Belgium

Address all correspondence and requests for reprints to: Professor David B. Dunger, Department of Pediatrics, University of Cambridge, Addenbrooke’s Hospital, Level 8, Box 116, Cambridge CB2 2QQ, United Kingdom. E-mail: dbd25{at}cam.ac.uk.

Ovarian hyperandrogenism, a key feature of polycystic ovary syndrome, is preceded by precocious pubarche (PP) (pubic hair < 8 yr) in some populations. We hypothesized that this earlier presentation may relate to increased androgen sensitivity, indicated by androgen receptor gene CAG repeat length. This polymorphism was genotyped in 181 Barcelona girls (age, 10.9 yr; range, 4–19 yr) who had presented with PP, and in 124 Barcelona control girls. PP girls had shorter mean CAG number than Barcelona controls (PP vs. controls: mean, range: 21.3, 7–31 repeats vs. 22.0, 15–32, P = 0.003) and greater proportion of short alleles 20 repeats or less (37.0% vs. 24.6%, P = 0.002). Among post-menarcheal PP girls (n = 69), shorter CAG number (biallelic mean <=20) was associated with higher 17-hydroxy-progesterone levels post leuprolide (P = 0.009), indicative of ovarian hyperandrogenism, higher testosterone levels (P = 0.02), acne (P = 0.03) and hirsutism scores (P = 0.01), and more menstrual cycle irregularities (P = 0.04). In multiple regression, ovarian hyperandrogenism risk was related to both low birth weight (SD <-1.5: odds ratio = 17.0; 95% confidence interval: 4.2–69.2) and shorter mean CAG number (20 or less repeats: odds ratio = 7.3; 1.3–42.0).

In summary, shorter androgen receptor gene CAG number, indicative of increased androgen sensitivity, increases risks for PP and subsequent ovarian hyperandrogenism. Shorter CAG repeat alleles in Barcelona compared with United Kingdom women could lead to higher prevalences of these conditions.

L.I. was supported by a Visiting Fellowship from the European Society for Pediatric Endocrinology (ESPE). J.J. was supported by ESPE Research Fellowship, sponsored by Novo Nordisk. F.d.Z. is a Clinical Research Investigator of the Fund for Scientific Research (Flanders, Belgium). D.B.D. is supported by the Juvenile Diabetes Research Foundation and the Wellcome Trust.

Abbreviations: AR, Androgen receptor gene; DHEAS, dehydroepiandrosterone-sulfate; 17-OHP, 17-hydroxy-progesterone; PCOS, polycystic ovary syndrome; PP, precocious pubarche.




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