Mice

Normal wild-type mice Studies examining age-related changes to the mouse HPG axis have demonstrated similar findings to those of the rat, and thus only the highlights and differences will be presented in this section. The mouse lifespan is similar to that of the rat. In mice, the mean maximal life-span is 30 months, during which persistent estrus appears at approximately 12 months, followed by exhaustion of oocytes at 24 months (Finch et al., 1984). Unlike rats, estrogen levels in mice transitioning from persistent estrus to anestrus are low, as is seen in humans and OWMs (Finch et al., 1984). As in rats, mice show a transition from a four- to five-day cycle to longer cycles and delayed onset and attenuation of the GnRH/LH surge in later stages of life (Finch et al., 1984; Nelson et al., 1995).

Changes in ER expression and binding have been studied in depth in mouse models. Overall, age-related decreases in hypothalamic ER expression and receptor binding, and a decrease in the duration of binding have all been reported (Nelson et al., 1995). Bergman et al.

(1991) suggested that there is an age-associated delay in cytosolic ER replenishment in the hypothalamus, which causes the observed decrease in nuclear ER in middle-aged animals. This, accompanied by a decreased amount of time estrogen is spent bound to the receptor, possibly interferes with the positive feedback mechanism associated with ovulation, thus causing eventual delays in estrous cyclicity.

Because the mouse is more similar to humans in ovarian steroid levels and follicular function later in life, this model has been used predominantly for studies into ovarian changes. The few reports examining numbers of GnRH neurons in the hypothalamus showed little or no loss with aging (reviewed in Gore, 2001). Age-related losses in pituitary GnRH receptors were not detected in mice, but increases in GnRH and gonadotropins were, suggesting age-related changes in reproductive status may result from a mechanism independent of GnRH receptor activation (reviewed in Gore, 2001). The latter hormonal increases are similar to those in human and nonhuman primates, and suggestive of a loss of estrogen-negative feedback. Finally, attenuation of the estrogen-induced GnRH/LH surge begins to occur prior to the onset of irregular cyclicity in rodents (Nelson et al., 1995).

Ovarian grafting experiments have been used to examine ovarian versus extra-ovarian influences on reproductive changes occurring in aging animals. Mice have most commonly been used for such studies. Young ovaries implanted into middle-aged animals prior to cessation of cycling extended the period of cyclicity beyond that of intact controls. This is suggestive of ovarian influences. However, this did not restore cycle frequency to the expected four-day cycle of young animals, suggestive of hypothalamic-pituitary influences. Additionally, the preovulatory estrogen and progesterone levels were restored, but the overall amplitude of these surges was not (Nelson et al., 1995). Further transplantation studies showed these results to be age sensitive, as 17-month old, short-term OVX females showed a shorter period of recovered cyclicity (3 mos. of cyclicity was restored in 25% of the young controls) and 25-month-old females showed a very small recovery (30% of 17-month-old) (Felicio et al., 1983). Together, these studies demonstrate the complexity of the reproductive system, as it suggests different but complementary roles of the ovary and the hypothalamus in the regulation of cycle duration and frequency.

As aging occurs, ovarian morphology changes, and the mouse model has been used to examine these changes in detail. Studies in mice have revealed that there is a similar number of oocytes in middle-aged as in aged animals, clutches of ova continue to be released, follicles do mature (albeit in lower number), and administration of hormones can stimulate normal ovulation (Finch et al., 1984). Recent studies also have led to a challenge of one of the main doctrines of female reproduction. It has remained a firm belief that a female is supplied with a certain number of follicles at birth, and as this supply dwindles, the female enters perimenopause. However, Johnson et al. (2004) recently provided evidence for replenishment of ovarian follicles in adult female mice. This group discovered active germ cells in the ovary that seem to replenish the follicular pool. They theorize that there is a fine balance in young adults in which the number of follicles undergoing atresia is matched or surpassed by the number of germ cells undergoing meiosis and forming replacement follicles. As animals age, the number of atretic follicles increases and eventually surpasses the number being replaced, causing an overall decline in the population of ovarian follicles (Johnson et al., 2004). This theory is very new but makes sense. Underlying the old doctrine, in which females were believed to be endowed with a set number of follicles for life, was the question of reproductive survival. It is a basic tenet of biology that the main purpose of all living beings is to reproduce. Hence, where the body is very efficient in most areas, the supposition of a set number of ovarian follicles seems very inefficient. These findings, though extremely recent, pose a new method for looking at follicular decline and may lead to a new arena of research into reproductive aging. Molecular examination of follicular pools may lead to new technologies by which menopause can be treated.

Transgenics

With the publication of the mouse genome, the mouse model has become first and foremost a means by which genetic manipulation can be used to study the role that each gene plays in the system as a whole. There are a number of transgenic and other mice that are used in studying the reproductive system and its component parts, and these animals can also prove useful in the study of mechanisms of reproductive senescence. This section will cover those mutations or knockouts directly affecting the HPG axis. We will not include those that target neuromodulatory systems of this axis, such as the NMDA receptor, GABA receptor, and dopamine-beta-hydoxylase (a biosynthetic enzyme important in catechol-amine synthesis) knockouts, but these, too, may play an important role in examining mechanisms influencing the onset of reproductive aging.

The follitropin receptor knockout mouse (FORKO) is deficient of the FSH receptor (FSH-R). Recall that one of the main indices of the onset of menopause in women and estropause in rodents is an increase in FSH prior to the onset of irregular menstrual cycles. FSH is thought to mediate the apoptosis of follicles, but requires the proper interaction with its receptor to do so (Simoni et al., 1997). Thus, it is possible that changes to the number of FSH-Rs trigger the onset of age-associated ovarian disruption. The FORKO knockout provides one model in which to study this hypothesis.

The FORKO homozygous null (—/—) mouse shows estrogen deficiency, sterility, and acyclicity. Histology of the ovary demonstrates that the follicles cannot proceed past the preantral stage and thus cannot completely mature (Danilovich et al., 2004). The heterozygous null mutant shows a reduction in fertility in adulthood, but can still produce offspring. By seven to nine months, these animals no longer breed, thus demonstrating an earlier onset of senescence (see Table 43.5; Danilovich et al., 2004). In aging heterozygotes (+/—) testosterone levels and gonadotropins are higher than those of the wild types. Estrogen, progesterone, and inhibin are lower. Measured ovulation rate, number of ova released, and presence of corpora lutea are all lower (with no corpora lutea by 12 months in heterozygotes). Finally, there is a greater change in binding to FSH-R in heterozygotes than wild types (Danilovich et al., 2002) (for a summary, see Table 43.5). These characteristics are similar to that of aging women, and are accompanied by acyclicity, skeletal abnormalities, and obesity, all common to menopausal women (Danilovich et al., 2004).

Danilovich et al. (2004) have used these mice to begin investigating changes to the central nervous system accompanied by reproductive senescence, as well as the use of hormone replacement therapy to treat symptoms associated with this condition. They assert that the use of a genetically altered, intact model that does not need surgical manipulation will add to the evaluation of drugs useful for treating menopausal symptoms. Thus far, they

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