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【Endocrinology】PCOS的动物模型能够帮助我们认识其
A number of animal models for PCOS have emerged over several decades, including rodents, sheep, and primates. The advantages of using the rat or mouse include the ability to provide a constant genetic background and controlled environment as well as capitalizing on the short life cycle to explore both reproductive and long-term metabolic effects. However, interpretation of any ovarian abnormalities has to be made in the light of the differences between rodents and primates in ovarian follicular formation and recruitment and in the ovulation cycle. Multiple cystic follicles in anovulatory rodents do not necessarily equate, in morphology or function, to those in women with polycystic ovaries. Nevertheless, the rodent may still be a useful model to study, for example, the specific effects of androgens on early follicle development, on control of gonadotropin secretion (16), and, in particular, to examine the metabolic effects of exposure to excess androgen (17, 18). As in the Rhesus monkey and sheep (see below), the administration of large doses of androgen either to pregnant females (prenatal androgenization) or in postnatal life may result in the very metabolic abnormalities that are characteristic of many women with PCOS.
The prenatally androgenized (PA) sheep and Rhesus monkey have provided considerable insight into the role of androgen in genesis of both reproductive and metabolic abnormalities (19). These findings support the hypothesis that exposure to excess androgen during key windows of development (including in utero) lead to many of the features of the syndrome in adulthood. In common with humans (and in contrast to rodents), both are monoovulatory species that have completed ovarian follicle formation during fetal life. The PA Rhesus monkey during adulthood displays abnormal ovarian morphology, ovarian hyperandrogenism (and adrenal androgen excess), hypersecretion of LH, insulin resistance, and anovulation in relation to increased body weight (20, 21, 22). Studies to date in the PA sheep have yielded similar findings with respect to reproductive and metabolic sequelae (23). Indeed, PA models, whether using rodents, sheep, or primates, probably best relate to endocrine and metabolic sequelae of PCOS but are less informative in terms of the primary defect. We are still left with the question: where does excess androgen come from and when? There is evidence for a primary ovarian defect in human PCOS, but there is no very firm evidence that the typical ovarian abnormalities of PCOS (24), aberrant preantral as well as antral follicle development or stromal hyperplasia, can accurately be reproduced in any animal model. Nevertheless, early preantral follicle development has been shown to be abnormal in the PA sheep (25, 26), suggesting that androgens may have a role in the etiology of this salient feature of the polycystic ovary. Interestingly, abnormalities of ovarian cyclicity in the ewe can be exaggerated by excessive weight gain (27), mimicking the observations in women with PCOS. Excess androgen may be both the consequence and the cause of the ovarian abnormality. We have proposed that PCOS has its origins in early life and that the polycystic ovary is genetically predisposed to hypersecrete androgens, certainly at puberty but also in the early postnatal period or even during fetal development (20, 28). The dogma has been that the fetal ovary is not steroidogenically active, but recent data indicate that theca cells are present in the human fetal ovary and clearly express 17-hydroxylase, the key enzyme in androgen biosynthesis (29). Excess androgen production by the ovary in human fetal or adult life may, in turn, contribute to ovarian follicular abnormalities in adulthood.
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作者:admin@医学,生命科学 2010-11-25 17:11
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