Does long-term androgen deficiency lead to metabolic syndrome in middle-aged rats?

Evidence from clinical observational studies and animal experiments suggests that hypogonadism is associated with the metabolic syndrome. In most of the experiments, androgen deficiency is induced by gonadectomy in the adulthood and relatively short-term effects of hypogonadism on metabolic parameters are usually observed. The purpose of this study was to evaluate the metabolic effects of long-term androgen deficiency starting before puberty in middle-aged male rats. The components of the metabolic syndrome were examined in male, female and gonadectomized male rats at the age of 18months. Sex differences were observed in plasma testosterone, cholesterol, high-density lipoproteins and also in body weight and in glycemia dynamics during oral glucose tolerance test. Gonadectomy and long-term hypogonadism did not affect most of the analyzed metabolic parameters such as blood pressure, glycemia, plasma insulin and uric acid. The only exception was the significantly higher liver enzymes in plasma and triacylglycerol in liver found in gonadectomized males. Except low-density lipoprotein, neither treatment of middle-aged males and females with letrozole, nor supplementation of estradiol as the metabolite of testosterone in gonadectomized male rats changed any of the observed metabolic parameters. Our results suggest that long-term hypogonadism started before puberty does not induce metabolic syndrome in middle-aged male rats, but may affect the liver. Sex differences in metabolic parameters in middle-aged rats are not mediated by testosterone. Whether hypogonadism predispose to metabolic syndrome in combination with other risk factors needs further clarification.

Sex differences and sex hormones in anxiety-like behavior of aging rats.

Sex differences in the prevalence of affective disorders might be attributable to different sex hormone milieu. The effects of short-term sex hormone deficiency on behavior, especially on anxiety have been studied in numerous animal experiments, mainly on young adult rats and mice. However, sex differences in aged animals and the effects of long-term hypogonadism are understudied. The aim of our study was to analyze sex differences in anxiety-like behavior in aged rats and to prove whether they can be attributed to endogenous sex hormone production in males. A battery of tests was performed to assess anxiety-like behavior in aged female, male and gonadectomized male rats castrated before puberty. In addition, the aged gonadectomized male rats were treated with a single injection of estradiol or testosterone or supplemented with estradiol for two-weeks. Female rats displayed a less anxious behavior than male rats in most of the conducted behavioral tests except the light-dark box. Long-term androgen deficiency decreased the sex difference in anxiety either partially (open field, PhenoTyper cage) or completely (elevated plus maze). Neither single injection of sex hormones, nor two-week supplementation of estradiol in gonadectomized aged male rats significantly affected their anxiety-like behavior in the elevated plus maze. In conclusion, our results confirm sex differences in anxiety in aged rats likely mediated by endogenous testosterone production in males. Whether long-term supplementation with exogenous sex hormones could affect anxiety-like behavior in elderly individuals remains to be elucidated.

Sex-dependent effects of letrozole on anxiety in middle-aged rats.

Aromatase catalyzes the conversion of testosterone to estradiol and is involved in the physiological effects of sex hormones on brain function. Animal experiments have shown that the aromatase inhibitor, letrozole, can induce anxiety in young ovariectomized females that are used as a model of aging. Whether or not these effects would be similar in intact middle-aged animals is unknown. The aim of our study was to analyze the effects of letrozole on anxiety in middle-aged rats of both sexes. Fifteen month old male and female rats were treated daily with either letrozole or vehicle for 2 weeks. The elevated plus maze was used to test anxiety-like behaviour. Sex differences were found not only in plasma concentrations of testosterone but also in the effects of letrozole treatment on plasma testosterone (P<.05). The interaction between sex and treatment was also proven in locomotor activity (P<.05) and time spent in the open arms of the elevated plus maze (P<.05). Letrozole-treated male rats spent 95% less time in the open arms of the elevated plus maze than the control rats did (P<.05) suggesting an anxiogenic effect of aromatase inhibition. This difference was not found between letrozole-treated and vehicle-treated females. In contrast to previous experiments on young animals, letrozole seems to induce anxiety in male but not in female middle-aged rats. This sex-specific effect might be related to sex differences of oestrogen and androgen signalling in aging brains. These results should be taken into account in clinical applications of letrozole, especially in men.