Genetic variants of estrogen beta and leptin receptors may cause gynecomastia in adolescent Erdal Eren a, ⁎, Tuba Edgunlu b , Huseyin Anil Korkmaz c , Esra Deniz Papatya Cakir d , Korcan Demir e , Esin Sakalli Cetin f , Sevim Karakas Celik g a Harran University, School of Medicine, Department of Pediatric Endocrinology, Sanliurfa, Turkey b School of Health Sciences, Mugla Sitki Kocman University, Mugla, Turkey c Pediatric Endocrinology Clinic, Dr. Behçet Uz Children's Research and Training Hospital, Izmir, Turkey d Pediatric Endocrinology Clinic, Mersin Hospital of Women and Children's Health and Diseases, Mersin, Turkey e Pediatric Endocrinology Clinic, Gaziantep Children Hospital, Gaziantep, Turkey f Department of Medical Biology, School of Medicine, Mugla Sitki Kocman University, Mugla, Turkey g Department of Medical Genetics, School of Medicine, Bulent Ecevit University, Zonguldak, Turkey abstract article info Article history: Received 14 January 2014 Received in revised form 25 February 2014 Accepted 5 March 2014 Available online 10 March 2014 Keywords: Gynecomastia Puberty Estrogen Leptin Polymorphism Objective: Gynecomastia is a benign breast enlargement in males that affects approximately one-third of adoles- cents. The exact mechanism is not fully understood; however, it has been proposed that estrogen receptors and aromatase enzyme activity may play important roles in the pathogenesis of gynecomastia. While many studies have reported that aromatase enzyme (CYP19) gene polymorphism is associated with gynecomastia, only one study has shown a relationship between estrogen receptor (ER) alpha and beta gene polymorphism and gyneco- mastia. Thus, the aim of this study was to evaluate the relationships between CYP19 (rs2414096), ER alpha (rs2234693), ER beta (rs4986938), leptin (rs7799039), and leptin receptor (rs1137101) gene polymorphisms and gynecomastia. Methods: This study included 107 male adolescents with gynecomastia and 97 controls. Total serum testosterone (T) and estradiol (E2) levels were measured, and DNA was extracted from whole blood using the PCR–RFLP technique. The polymorphic distributions of CYP19, ER alpha, ER beta, leptin and leptin receptor genes were compared. Results: The median E2 level was 12.41 (5.00–65.40) pg/ml in the control group and 16.86 (2.58–78.47) pg/ml in the study group (p b 0.001). The median T level was 2.19 (0.04–7.04) ng/ml in the control group and 1.46 (0.13–12.02) ng/ml in the study group (p = 0.714). There was a significant relationship between gynecomastia and leptin receptor rs1137101 (p = 0.002) and ER beta receptor rs4986938 gene polymorphisms (p = 0.002). Conclusions: According to our results, increased E2 level and ER beta gene rs4986938 polymorphism might ex- plain why some adolescents have gynecomastia. Leptin receptor gene rs1137101 polymorphism might affect susceptibility to gynecomastia. © 2014 Elsevier B.V. All rights reserved. 1. Introduction Gynecomastia is defined as benign enlargement of the breast tissue in males. It is generally encountered in infants, adolescents, and elderly men. This condition is observed in approximately 30% of adults, but it may be encountered at higher rates in adolescents (Braunstein, 1993; Kumanov et al., 2007). The highest incidence of pubertal gynecomastia was determined as 65% at 14 years of age (Niewoehner and Nuttal, 1984). While the exact mechanism is not fully understood, it has been proposed that estrogen receptors and aromatase enzyme (CYP19) activ- ity may play important roles in the pathogenesis of gynecomastia (Lee et al., 1990). Gynecomastia develops mainly due to disequilibrium be- tween estrogen and androgen in the breast tissue (Braunstein, 1999). CYP19 activity, which converts androstenedione and testosterone to es- trone and estradiol, respectively, is the most important factor in the equilibrium. Activating mutation can cause familial gynecomastia by in- creasing the aromatase activity in this gene (Shozu et al., 2003). It has been reported that overexpression of CYP19 enlarged breast tissue in transgenic male mice (Li et al., 2002). Gene 541 (2014) 101–106 Abbreviations: CYP19, aromatase enzyme; ER, estrogen receptor; T, testosterone; E2, estradiol; STAT3, signal transducer and activator of transcription 3; SDS, standard devia- tion score; BMI, body mass index; FSH, Follicle stimulating hormone; LH, luteinizing hor- mone; DHEAS, dehydroepiandrosterone sulfate; PCR–RFLP, polymerase chain reaction– restriction fragment length polymorphism; OR, odds ratio; CI, confidence interval. ⁎ Corresponding author at: Uludag University, Faculty of Medicine, Department of Pediatrics, Gorukle Yerleskesi, Bursa, Turkey. E-mail address: dreeren@gmail.com (E. Eren). http://dx.doi.org/10.1016/j.gene.2014.03.013 0378-1119/© 2014 Elsevier B.V. All rights reserved. Contents lists available at ScienceDirect Gene journal homepage: www.elsevier.com/locate/gene