Brazilian Journal of Pharmaceutical Sciences vol. 46, n. 1, jan./mar., 2010 Article Effects of administering testosterone undecanoate in rats subjected to physical exercise: effects on the estrous cycle, motor behavior and morphology of the liver and kidney Moisés Tolentino Bento-Silva1,3,*, Maria do Carmo de Carvalho e Martins2, Francisco Leonardo Torres-Leal1,3, Talvany Luiz Barros3, Ingrid Lara do Nascimento Ferreira de Carvalho2, Hugo Aparecido Carvalho Filho2, Fernanda Regina de Castro Almeida3 1Department of Physical Education, Federal University of Piauí, 2Department of Physiology and Biophysics, Federal University of Piauí, 3Medicinal Plants Research Center, Federal University of Piauí The aim of the work was evaluate the effects of testosterone undecanoate (TU) treatment combined with moderate physical training on: the estrous cycle, body weight (BW), motor behavior (MB), and the morphohistology of the reproductive system, the liver and kidney in rats. Female Wistar rats (180 g - 250 g) were divided as follows: sedentary + TU (S + TU), trained + TU (T + TU), sedentary + vehicle (S + V), trained + vehicle (T + V). The rats swam 50 min/Day, strapped with a 5% BW load, for 4 weeks. During this training, (BW) was monitored daily as well as the estrous cycle (EC) by vaginal smear. The TU (15 mg/kg s.c) was administered 3 times/week for 4 weeks. At the end of the study, data on MB, BW and morphohistopathological changes in viscera were compiled. The (T + TU) group had on average, a higher (BW) in the fourth week compared to the first week, and (BW) higher than (S + V) and (S + TU) groups. We noted an interruption in the EC and a decrease in weight of ovaries in animals treated with TU. In addition, there was an increase in the relative weight of the heart in groups (T + V) and (T+ TU), and kidneys in group (T + TU). Histopathological analysis showed periportal congestion and isolated foci of hepatic necrosis in rats with TU. Thus, TU combined with training abolished the EC, promoted ovarian atrophy, liver necrosis, cardiac hypertrophy and a decrease in motor activity. Uniterms: Androgenic anabolic steroids/experimental study. Endurance training. Testosterone undecanoate. O objetivo do trabalho foi avaliar o efeito do tratamento com undecanoato de testosterona (UT) combinado ao treinamento físico moderado sobre ciclo estral, peso corporal, estruturas do sistema reprodutor, comportamento motor e morfologia hepática e renal em ratas. Ratas Wistar (180 a 250 g) foram divididas em: sedentárias + UT (S+UT), treinadas + UT (T+UT), sedentárias + veículo (S+V), treinadas + veículo (T+V). As ratas nadaram 50 min/dia com sobrecarga de ~5% do peso corporal por 4 semanas. Durante o período de treinamento foi realizado acompanhamento diário do peso corporal (PC) e do ciclo estral (CE) pelo esfregaço vaginal. O UT (15 mg/kg s.c.) foi administrado 3x/semana durante 4 semanas. Ao final foram avaliados comportamento motor, pesos e alterações histopatológicas de alguns órgãos. O grupo T+UT apresentou PC maior na quarta semana do que na primeira, com pesos corporais maiores que os grupos S+V e S+UT. Houve interrupção no CE e redução do peso dos ovários nos animais tratados com UT. Houve aumento do peso relativo do coração, nos grupos T+V e T+UT, e do peso relativo dos rins, no grupo T+UT. A análise histopatológica revelou congestão periportal e focos isolados de necrose hepática nas ratas com UT. O UT combinado com treinamento produziu supressão do ciclo estral, atrofia ovariana, necrose hepática, hipertrofia cardíaca e redução da atividade motora. Unitermos: Esteróides androgênicos anabólicos/estudo experimental. Exercício físico. Undecanoato de testosterona. *Correspondence: M. T. Bento-Silva. Departamento de Educação Física, Universidade Federal do Piauí, Campus Petronio Portela, s/n - 64049-550 - Teresina - PI, Brasil. E-mail: [email protected] 80 M. T. Bento-Silva, M. C. C. Martins, F. L. Torres-Leal, T. L. Barros, I. L. N. F. Carvalho, H. A. Carvalho Filho, F. R. C. Almeida INTRODUCTION exercise among the female population. Cadore et al. (2008) studied the concentrations of total testosterone, Several studies have emphasized the need for free testosterone and cortisol in individuals who trained physical exercise programs in promoting global health, or otherwise. He noted that home values were similarly due to the positive effect which an active lifestyle has in increased after the training protocol. Another fact reported maintaining health, preventing and reducing the number in the literature refers to the possibility of AAS use, asso- of chronic non-communicable diseases, besides promoting ciated with resistance exercise, reducing the effectiveness the quality of life (Matsudo, 2006). On the other hand, the of sleep (Venancio et al., 2008). Furthermore, Lambert et professional athletes always seek to break existing records, al. (1995), studying the effect of AAS treatment on the which often leads to the use of banned substances such running performance of rats, found that animals treated as anabolic androgenic steroids (AAS). In an attempt to with AAS and subjected to physical training of moderate magnify the results obtained from physical training, ath- intensity showed an increase in resistance of 41% com- letes and non-athletes use AAS as ergogenic resources to pared to the group that received saline, while no changes improve performance and physical appearance (increased were detected in the sedentary groups. muscle mass and tonus) (Perssinen et al., 2002; Maravel et Considering the frequent use of AAS and their po- al., 2005; Bahrke et al., 2004; Franke et al., 1997). These tential health risks, coupled with few studies assessing the steroids (AAS) are synthetic or natural compounds, similar effects of these drugs in females, the objective of this study to testosterone, which act directly upon specific types of was to evaluate the effect of Testosterone Undecanoate receptors (Maravel et al., 2005; Clarkson et al., 1997), mo- treatment (TU) in rats subjected to swimming in term of: dulating inseparably both anabolic and androgenic effects body weight, structures of the reproductive system, the es- (Perssinen et al., 2002; Rabkin et al., 2000; Nasrollah et trous cycle, motor activity, and histopathological changes al., 2001). Currently, over 60 different types of AAS are of heart, liver and kidneys. available for use, varying largely in chemical structure. The use of anabolic androgenic steroids (AAS) has METHODS been the focus of research worldwide, since the adminis- tration of AAS is often associated with various adverse Animals dose-related effects, the most common of which are: masculinization in women and children, hypertension, Experiments were performed on adult female rats atherosclerosis, thrombosis, jaundice, cancer and liver (N = 32) of the Wistar strain, weighing (180-250 g), obtai- cancer, tendon injury, as well as psychiatric and behavioral ned from the laboratory of Research on Medicinal Plants, disorders in both sexes (Maravel et al., 2005). Bahrke et Federal University of Piauí. The animals were kept in al. (2004), report infertility and gynecomastia in men, as Bollman cages, each housing four animals with controlled well as liver problems, impotence and hypertrophy of the room temperature and a light-dark 12/12 h cycle and free clitoris in women. access to water and food. All procedures complied with the Several clinically used substances can often be em- ethical standards set by the Brazilian College of Animal ployed to improve athletic performance, as is the case of Experimentation. Testosterone Undecanoate (TU), clinically prescribed for hormone replacement therapy in men. Several prevalent Treatment studies on non-prescribable AAS have shown that such use is not restricted to men (Thiblin et al., 2005; Mobin et al., The animals were randomly assigned to four groups, 2007). However, physiological and behavioral effects of each comprising eight animals: sedentary treated with TU, AAS are not well understood in women (Clark et al., 1998). trained treated with TU, vehicle-treated sedentary and Although they can be used therapeutically at low trained but treated with vehicle. Each respective group doses to treat aplastic anemia (Velazquez et al., 2004), received the Vehicle or AAS, by a subcutaneous injection osteoporosis (Berning et al., 2001; Kilbourne et al., 2007), of vegetable oil (0.1 mL/100 g/body weight) or testoste- and as antitumor agents in breast cancer (von Bueren et rone undecanoate (Androxon® 15 mg/kg), 3x/week for 4 al., 2007) in women, the beneficial health effects of such weeks (Lindqvist et al., 2005). doses contrast with the risks associated with excessive self-administered doses by women athletes. Physical training Despite the large number of studies involving AAS use, few associate such use with aerobic or endurance The training protocol was adapted from Medeiros et Effects of administering testosterone undecanoate in rats subjected to physical exercise 81 al. (2004), where the rats in the trained groups were sub- immersed in a solution of 10% formalin for histological mitted to a 50 min/day swim in a rectangular cylinder with processing, and fixed in paraffin. The blocks were cut into water at 28±1 °C (5 days/week), for a period of 4 weeks. 7mm-thick slices and stained with hematoxylin-eosin for After the adaptation period to the water, the rats received histological analysis. Histological evaluation took into increasing burdens in the form of load weights attached to account