Differences in neonatal exposure to estradiol or testosterone on ovarian function and hormonal levels Rodrigo R. Marcondes a,⇑ , Kátia C. Carvalho a , Daniele C. Duarte a , Natália Garcia a , Vinícius C. Amaral a , Manuel J. Simões b , Edson G. Lo Turco c , José M. Soares Jr. a , Edmund C. Baracat a , Gustavo A.R. Maciel a,⇑ a Disciplina de Ginecologia, Laboratório de Ginecologia Estrutural e Molecular (LIM 58), Faculdade de Medicina da Universidade de São Paulo, 01246903 São Paulo, Brazil b Departamento de Morfologia e Genética, Disciplina de Histologia e Biologia Estrutural, Universidade Federal de São Paulo, 04023900 São Paulo, Brazil c Departamento de Cirurgia, Disciplina de Urologia, Setor de Reprodução Humana, Universidade Federal de São Paulo, 04024002 São Paulo, Brazil article info Article history: Received 3 September 2014 Revised 3 January 2015 Accepted 14 January 2015 Available online 24 January 2015 Keywords: Polycystic ovary syndrome Animal models LH receptor Steroid 17-Alpha-hydroxylase abstract Exposure to an excess of androgen or estrogen can induce changes in reproductive function in adult ani- mals that resemble polycystic ovary syndrome in humans. However, considerable differences exist among several types of animal models. Little is known about the molecular features of steroidogenesis and folliculogenesis in the ovaries of rats exposed to different sex steroids as neonates. Here, we evalu- ated the impact of androgen and estrogen exposure on the ovaries of adult female rats during their neo- natal period in the gene expression of Lhr and Cyp17a1, two key players of steroidogenesis. We also assessed hormone levels, folliculogenesis and the theca-interstitial cell population. The study was per- formed on the second postnatal day in thirty female Wistar rats that were sorted into the following three intervention groups: testosterone, estradiol and vehicle (control group). The animals were euthanized 90 days after birth. The main outcomes were hormone serum levels, ovary histomorphometry and gene expression of Lhr and Cyp17a1 as analyzed via quantitative real-time PCR. We found that exposure to excess testosterone in early life increased the LH and testosterone serum levels, the LH/FSH ratio, ovarian theca-interstitial area and gene expression of Lhr and Cyp17a1 in adult rats. Estrogen induced an increase in the ovarian theca-interstitial area, the secondary follicle population and gene expression of Lhr and Cyp17a1. All animals exposed to the sex steroids presented with closed vaginas. Our data suggest that tes- tosterone resulted in more pronounced reproductive changes than did estrogen exposure. Our results might provide some insight into the role of different hormones on reproductive development and on the heterogeneity of clinical manifestations of conditions such as polycystic ovary syndrome. Ó 2015 Elsevier Inc. All rights reserved. 1. Introduction Exposure to excessive androgen or estrogen can induce changes in the reproductive functions of several animal models that resem- ble polycystic ovary syndrome (PCOS) in humans (Franks, 2012). A growing body of evidence has suggested that several metabolic conditions may be related to the fetal period or early life events (Barker, 1990, 1993; Franks, 2012). Genetic predisposition and environmental insults, such as maternal obesity, diet and exposure to several substances, including sex steroids (Franks, 2012), could trigger some specific metabolic phenotypes that might manifest during adulthood. In this sense, PCOS has gained attention because it displays reproductive function abnormalities (e.g., anovulation and disordered ovarian follicle development) and metabolic traits (insulin resistance, metabolic syndrome and obesity) beginning in puberty that seems to fit this hypothesis (Legro et al., 1998; Vink et al., 2006; Franks et al., 2008b; Chen et al., 2011). However, because this hypothesis is difficult to prove in humans, animal models might be invaluable in the exploration of this issue. PCOS is an endocrine disorder characterized by hyperandroge- nism and chronic anovulation and is related to impairment in the hypothalamic–pituitary–ovarian axis and ovarian abnormalities (Baptiste et al., 2010). LH levels are elevated in 40–50% of patients with PCOS (Homburg, 2008), probably due to hypothalamic dys- function (Pastor et al., 1998). Higher levels of LH lead to an increased androgen production by the theca cells (Chang, 2007; Magoffin, 2006). Additionally, overexpression of cytochrome P450c17 (CYP17), a key steroidogenic enzyme, has been shown to convert pregnenolone and progesterone into dehydroepiandroster- one (DHEA) and androstenedione, respectively (Magoffin, 2006; http://dx.doi.org/10.1016/j.ygcen.2015.01.006 0016-6480/Ó 2015 Elsevier Inc. All rights reserved. ⇑ Corresponding authors at: Avenida Dr. Arnaldo, 455, sala 2113, São Paulo, SP 01246903, Brazil. E-mail addresses: marcondes_rr@hotmail.com (R.R. Marcondes), garmaciel@g- mail.com (G.A.R. Maciel). General and Comparative Endocrinology 212 (2015) 28–33 Contents lists available at ScienceDirect General and Comparative Endocrinology journal homepage: www.elsevier.com/locate/ygcen