Review Impact of androgen/estrogen ratio: Lessons learned from the aromatase over-expression mice q Xiangdong Li a, * , Nafis Rahman b a State Key Laboratory of the Agro-Biotechnology, Faculty of Biological Sciences, China Agricultural University, Beijing 100094, China b Department of Physiology, Institute of Biomedicine, Faculty of Medicine, University of Turku, FIN-20520, Turku, Finland article info Article history: Received 10 December 2007 Revised 30 July 2008 Accepted 31 July 2008 Available online 14 August 2008 Keywords: Androgen/estrogen ratio Androgen/estrogen balance in males Estrogen excess Aromatase over-expression Transgenic mice abstract The estrogen signaling plays a pivotal role not only in female reproduction but also in recent years its emerging importance in the males has been shown too. As estrogens and androgens seem to be the two sides of one coin, the better understanding of this physiological and pathophysiological role of andro- gen/estrogen balance is becoming more crucial. Aromatase is the key enzyme to synthesize estrogens from androgens. Along with the progress of new technologies and tools like transgenic facilities, we are able to analyze in more detail about the involvement of aromatase in the molecular mechanisms underlying the androgen/estrogen essential balance. This review would be dealing with the use of trans- genic models over-expressing aromatase in order to analyze the effects of an estrogen/androgen ratio increase in mice, especially on male reproductive biology. Ó 2008 Elsevier Inc. All rights reserved. 1. Introduction 1.1. Generation of the aromatase over-expression mouse models It has been postulated that estrogens and androgens are both trivial to determine biological response in a tissue- and gender- specific manner [for a review, (Sharpe, 1997)]. It is very likely that the adequate balance in the androgen/estrogen ratio seems to be the most important clinically relevant factor in this process. In or- der to understand better the physiological and pathophysiological roles of androgen/estrogen balance, until now two significant aro- matase over-expressing transgenic mouse models have been pro- duced (Table 1). In Table 1 we have analyzed the significant phenotypic differences between the two existing aromatase over- expressing transgenic (TG) murine models. In this review article, we will further concentrate more on the characterization findings and on learned lessons from the mouse model with an imbalance in sex hormone metabolism by the expression of human aromatase gene under the human ubiquitin c promoter (AROM+) and also will discuss future directions in this specific field of research. Before analyzing different models for studying the role of estro- gen in males including the different two available aromatase over- expressing TG models used for not only over-expression studies, we would also like to mention about the estrogen sulfotransferase knockout mouse model. The estrogen sulfotransferase knockout TG murine model has the potential also to reflect the estrogen over-expression effects in a murine model. An estrogen metabolic enzyme, estrogen sulfotransferase (EST) deficient mice have been developed through targeted disruption of the EST gene (Qian et al., 2001). Although knockout males were fertile and phenotypi- cally normal initially at 2 months of age, they developed age-depen- dent (12 months of age or older) Leydig cell hypertrophy/ hyperplasia and seminiferous tubule damage with reduced sperm motility by 80% and producing smaller litters compared with age- matched wild-type males (Qian et al., 2001), probably due to the lo- cal estrogen action (Qian et al., 2001). The most prominent abnor- mality was the presence of numerous hypertrophic or hyperplastic Leydig cells in these mice, where the presence of numerous giant yellow cells containing multiple dark stained nu- clei were described too. Finally, at the age of 12 months and older males, seminiferous tubule damage was also observed in the major- ity of EST knockout TG murine testis sections (Qian et al., 2001). These findings might establish a role for EST in the male reproduc- tive system and may further indicate that the intracrine and para- crine estrogen activity can be modulated by a ligand transformation enzyme under a physiological setting. 1.2. Aromatase over-expressing mice under the MMTV promoter (int- 5/aromatase) Clinically, aromatase was reported in very low quantities in normal human mammary gland and over-expressed in more than 0016-6480/$ - see front matter Ó 2008 Elsevier Inc. All rights reserved. doi:10.1016/j.ygcen.2008.07.025 q This study has been supported by the grants from National Science Foundation of China (NFSC) Grant Nos. 30671506 and 30711130057 (X.L.) and Academy of Finland (N.R.). * Corresponding author. Fax: +86 10 6273 4389. E-mail address: xiangdongli@cau.edu.cn (X. Li). General and Comparative Endocrinology 159 (2008) 1–9 Contents lists available at ScienceDirect General and Comparative Endocrinology journal homepage: www.elsevier.com/locate/ygcen