Effect of chronic administration of an aromatase inhibitor to adult male rats on pituitary and testicular function and fertility

The aim of the present study was to evaluate the effects of the administrat ion of a potent non-steroidal aromatase inhibitor, anastrozole, on male rep roductive function in adult rats. As anastrozole was to be administered via the drinking water, a preliminary study was undertaken in female rats and showed that this route of administration was effective in causing a major d ecrease in uterine weight (P<0.02). In an initial study in male adult rats, anastrozole (100 mg/l or 100 mg/l) was administered via the drinking water for a period of 9 weeks. Treatment with either dose resulted in a signific ant increase (similar to 10%) in testis weight and increase in plasma FSH c oncentrations (P<0.01) throughout the 9 weeks. Mating was altered in both g roups of anastrozole-treated rats, as they failed to produce copulatory plu gs. Histological evaluation of the testes from anastrozole-treated rats rev ealed that spermatogenesis was grossly normal. In a more detailed study, ad ult rats were treated with 200 mg/l anastrozole via the drinking water for periods ranging front 2 weeks to 1 year. Plasma FSH and testosterone concen trations were increased significantly (P<0.001) during the first 19 weeks o f treatment. However, LH concentrations were increased only at 19 weeks (P< 0.001) in anastrozole-treated rats, and this coincided with a further incre ase in circulating and intratesticular testosterone concentrations (P<0.05) . No consistent change in inhibin-B concentrations was observed during the study. Suppression of plasma oestradiol concentrations could not be demonst rated in anastrozole-treated animals, but oestradiol concentrations in test icular interstitial fluid were reduced by 18% (P<0.01). Mating was again in hibited by anastrozole treatment, but could be restored by s.c, injection o f oestrogen, enabling demonstration that rats treated for 10 weeks or 9 mon ths were still fertile. Testis weight was increased by 19% and 6% after tre atment for 19 weeks and 1 year, respectively. Body weight was significantly decreased (P<0.01) by 19 weeks of anastrozole treatment; after 1 year the animals appeared to have less fat as indicated by a 27% decrease in the wei ght of the gonadal fat pad. The majority of anastrozole-treated animals had testes with normal spermatogenesis but, occasionally, seminiferous tubules showed abnormal loss of germ cells or contained only Sertoli cells. Ten pe rcent of anastrozole-treated animals had testes that appeared to contain on ly Sertoli cells, and one rat had 'giant' testes in which the tubule lumens were severely dilated. Morphometric analysis of the normal testes at 19 we eks showed no difference in the number of Sertoli cells or germ cells, or t he percentage volumes of the seminiferous epithelium, tubule lumens and int erstitium between control and anastrozole-treated rats. On the basis of the present findings, oestrogen appears to be involved in the regulation of FS H secretion and testosterone production, and is also essential for normal m ating behaviour in male rats. Furthermore, these data suggest that the brai n and the hypothalamo-pituitary axis are considerably more susceptible than is the testis to the effects of an aromatase inhibitor. Anastrozole treatm ent has resulted in a model of brain oestrogen insufficiency.