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 ovarysyndrome, is preceded by precocious pubarche (PP) (pubic hair< 8 yr) in some populations. We hypothesized that this earlierpresentation may relate to increased androgen sensitivity, indicatedby androgen receptor gene CAG repeat length. This polymorphismwas genotyped in 181 Barcelona girls (age, 10.9 yr; range, 4–19yr) who had presented with PP, and in 124 Barcelona controlgirls. 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 shortalleles 20 repeats or less (37.0% vs. 24.6%, P = 0.002). Amongpost-menarcheal PP girls (n = 69), shorter CAG number (biallelicmean 20) was associated with higher 17-hydroxy-progesteronelevels post leuprolide (P = 0.009), indicative of ovarian hyperandrogenism,higher testosterone levels (P = 0.02), acne (P = 0.03) and hirsutismscores (P = 0.01), and more menstrual cycle irregularities (P= 0.04). In multiple regression, ovarian hyperandrogenism riskwas related to both low birth weight (SD <-1.5: odds ratio= 17.0; 95% confidence interval: 4.2–69.2) and shortermean CAG number (20 or less repeats: odds ratio = 7.3; 1.3–42.0).
In summary, shorter androgen receptor gene CAG number, indicativeof increased androgen sensitivity, increases risks for PP andsubsequent ovarian hyperandrogenism. Shorter CAG repeat allelesin Barcelona compared with United Kingdom women could lead tohigher prevalences of these conditions.
L.I. was supported by a Visiting Fellowship from the EuropeanSociety for Pediatric Endocrinology (ESPE). J.J. was supportedby ESPE Research Fellowship, sponsored by Novo Nordisk. F.d.Z.is a Clinical Research Investigator of the Fund for ScientificResearch (Flanders, Belgium). D.B.D. is supported by the JuvenileDiabetes Research Foundation and the Wellcome Trust.
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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). 
