Na

Advanced regression

Adapted from Danilovich et al. 2002.

Abbreviations: WT, wild type; mos, months; NA, not applicable.

Adapted from Danilovich et al. 2002.

Abbreviations: WT, wild type; mos, months; NA, not applicable.

have used these animals to examine the status of the ER signaling system and have found that the decrease in estrogen had no impact on ER gene transcription or translation, nor on functional activation of ERs in the uterus, vagina, or adipose tissue of mice (Danilovich et al., 2004). Hypothalamic tissue has yet to be studied. Their initial findings suggest that treatment of these estrogen-deficient animals with estrogen is successful in producing target-specific results, supporting the use of hormone replacement therapy.

Inactivation of luteinizing hormone (LH) receptors results in a mouse that shows acyclicity (and hence infertility), smaller ovaries, and a smaller reproductive tract overall. Ovulation does not occur, and follicular maturation cannot be recovered even with estrogen/ progesterone treatment. Hormonally, these animals have increased gonadotropin levels with detectable, but low levels of ovarian steroid hormones. This appears to be accompanied by decreased ERa and increased ER3 ovarian mRNA, suggestive of effects of LH on ER gene expression (Rao and Lei, 2002). Interestingly, the heterozygotes are virtually indistinguishable from their wildtype littermates, with the exception of a modest increase in FSH and decrease in estrogen levels. As in the FORKO heterozygotes, these animals appear to undergo reproductive senescence earlier than wild types, becoming obese and showing bone loss by one year (Rao and Lei, 2002). As of yet, mechanisms of aging have not been examined in detail in the female heterozygotes, but they offer an alternative model for studying the role of LH in reproduction and on the onset of reproductive aging. Additionally, changes in hypothalamic morphology would be interesting to observe in these knockouts.

The estrogen receptor knockouts (ERKOs) have played a large role in expanding our understanding of the role of estrogen in reproduction. These include the alpha-ERKO (aERKO), beta-ERKO (¬°ERKO), and the double a^ERKO. There is also an aromatase knockout (ArKO) mouse that lacks the enzyme converting testosterone to estradiol. Table 43.6 summarizes the reproductive phenotypes associated with these mutants. The ArKO is an interesting model, in that the animals have complete expression of both ERs, but are lacking aromatase activity, and thus endogenous ovarian estrogens are not synthesized. Because this has not been examined in the context of aging, it will not be discussed in detail here, but a recent study by Britt et al. (2005) observed uterine and ovarian weight and morphology as well as gonado-tropin levels resulting from treatment of wild type and ArKO mice fed soy-free, soy, or the isoflavine genistein (a phytoestrogen) diets from two weeks prenatally to 16 weeks of age. Overall, they found estrogenic effects of

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