In Vivo Function of the Oestrogen Receptors

The development of mice lacking the ERa (aERKO) or ERft (ftERKO) gene have proved to be valuable tools in evaluating the in vivo function of these receptors. The aERKO mice were generated in 1993, and the disruption of ERa expression not only caused infertility in both sexes, but also had profound effects on behaviour (Couse and Korach, 1999). Specifically, pre- and neonatal development of female reproductive organs such as uterus, ovary and mammary gland was almost normal, but maturation of these organs during and after puberty was severely impaired. The aERKO females also failed to display sexual receptivity when treated with the hormonal regime of oestrogen and progesterone that normally induces receptivity in wild-type mice. Surprisingly, adult aERKO males have significantly fewer epididymal sperm than heterozygous or wild-type males, caused by the disruption of spermatogenesis and degeneration of the seminiferous tubules, which becomes apparent 10 weeks after birth. Furthermore, these males develop obesity after sexual maturation, in addition to exhibiting decreased normal male-typical aggressive behaviour, including offensive attacks, and show a reduced number of mount attempts as compared with wild-type animals. Interestingly, both sexes of the aERKO mice also show a 20-25% reduction in bone density, implying that ERa is crucial for proper bone maturation and mineralization. However, the only described case of oestrogen insensitivity in a human male, which was normally masculinized, had incomplete epiphyseal closure with a history of continued growth into adulthood, and also osteoporosis probably induced by increased bone turnover.

More recently, the generation of ftERKO mice revealed that ERft does not affect normal development, and mice lacking ERft are indistinguishable grossly and histologi-cally as young adults from their littermates (Couse and Korach, 1999). Females are fertile and exhibit normal sexual behaviour, but have fewer and smaller litters owing to reduced ovarian efficiency, and multiple resorbed fetuses. Older males lacking ERft display signs of prostate and bladder hyperplasia. In contrast to the aERKO animals, the ftERKO females exhibit normal breast development and lactate normally, while all components of sexual behaviour in ftERKO mice were found to be intact. These observations indicate that unlike ERa, ERft is essential for normal ovulation efficiency but not for female or male sexual differentiation, fertility or lactation.

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