Nonhuman Primate Models Old World Monkeys

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Nonhuman primates (NHP) are classified as Old World monkeys, New World monkeys, and Great Apes. The Old World monkeys (OWM) are most commonly used in biomedical research, and, of these, the Asian macaques and the baboons of Africa are most frequently used. OWMs have a genetic makeup approximately 92.5 to 95% similar to humans and undergo similar reproductive processes as humans. The NHP reproductive cycle is approximately 28 to 30 days, with a follicular, prolif-erative, and luteal phase that results in a hormonal milieu similar to that in humans (Hendrickx et al., 1995) (see Figure 43.2). Additionally, in aging OWMs, as in humans, a decrease in fertility and changes in HPG hormone levels are accompanied by the onset of irregular menstrual cycles and finally, cessation of menses. However, OWMs spend a much shorter period (15-23%) of their

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Figure 43.2 Hormonal changes accompanying the primate (human and nonhuman primates) and rodent normal reproductive cycles. In both primates and rodents, an increase in estrogen occurs immediately prior to the GnRH/LH surge, followed by a slight surge in FSH. A gradual increase in progesterone occurs just prior to ovulation. Levels of progesterone are elevated during the luteal phase of primates, and during diestrus in rodents.

Figure 43.2 Hormonal changes accompanying the primate (human and nonhuman primates) and rodent normal reproductive cycles. In both primates and rodents, an increase in estrogen occurs immediately prior to the GnRH/LH surge, followed by a slight surge in FSH. A gradual increase in progesterone occurs just prior to ovulation. Levels of progesterone are elevated during the luteal phase of primates, and during diestrus in rodents.

lifespan in an anovulatory state, as compared to humans (50%) (Tardif et al, 1992; Bellino and Wise, 2003), making it difficult to study postmenopausal changes. Additionally, researchers face high costs to obtain and care for these animals (expensive due to the cost involved in maintaining them for 20+ years), the supply is limited, and there is a higher risk of loss of data due to age-related illness or death. Thus, two models have been developed to alleviate these challenges: the intact, aged, and the ovariectomized, young monkey.

The intact, aged model, though costly, provides a natural model of studying hormonal and neural changes associated with aging. Researchers can use this model to look toward modifications in brain structures as well as ovarian hormones when considering reproductive aging. Thus, differences in neuronal morphology, neuronal populations, and receptor density in the aging brain can be observed. Additionally, studies examining age-associated genetic alterations and relations to neural changes, and age-associated diseases, such as osteoporosis, cardiovascular diseases, and vasomotor symptoms (e.g., hot flash) can be undertaken in this model. These factors make the aged OWM a favored model for studies of reproductive senescence.

Studies in intact, aged macaques and baboons focus primarily on the perimenopausal period, when menstrual cycle variability increases, fecundity decreases, and hormonal status first changes. Humans and OWMs show very similar changes in urinary estrogen and progestin profiles once they begin perimenopause. However, there are a few differences in the timing of the hormonal transition to perimenopause: middle-aged women show a period of increase in FSH and decrease in inhibin A along with a cyclically high level of estrogen prior to onset, whereas rhesus monkeys do not (Bellino and Wise, 2003). Hence rhesus monkeys show a more immediate transition to perimenopause, whereas the human transition is more gradual. In both humans and OWMs, the onset of perimenopause is accompanied by declines in estrogen and progesterone levels, and a shorter follicular phase is observed during the menstrual cycle. In accordance with this, LH/FSH levels increase, partly due to the release from negative feedback associated with estrogen release (Bellino and Wise, 2003). Although this transition in macaques may occur as early as 18 to 20 years of age, it has been noted that rhesus monkeys may not show this transition until 25 years of age or later, an age equivalent to 65 to 90 years in humans (Gore et al., 2004). It is for this reason that the intact, aged monkey model has yet to meet its research potential, as these animals undergo reproductive senescence so late in their life cycle that they are difficult both to attain and maintain.

Activity of the HPG axis of intact, aged monkeys has been assessed in two studies. First, Woller et al. (2002) demonstrated changes in LH pulsatile activity in late perimenopausal and postmenopausal rhesus monkeys, showing not only increases in mean LH amplitude, but also increases in pulse amplitude and higher baseline LH levels when compared to young animals. Estrogen levels of the aged monkeys were also lower; no differences were observed in progesterone. Gore et al. (2004) used push-pull perfusion to measure changes in GnRH levels in peri-and postmenopausal monkeys and recorded increases in mean GnRH concentrations and higher pulse amplitudes compared to young monkeys. These latter data are consistent with the observed changes in LH pulses (Woller et al., 2002) and suggest a novel mechanism by which hormonal changes may affect the onset of reproductive aging. Taken together, the age-associated increases in pulsatile GnRH and gonadotropin, even prior to complete ovarian senescence, indicate a role of the hypothalamus and the pituitary, respectively, in reproductive senescence in a NHP model. Moreover, the observations of age-related changes in pulsatility and accompanying neural changes promise to enhance our understanding of the finer mechanism of reproductive decline.

Even though intact, aging animals provide some advantages for studying age-associated neural changes, researchers often turn to the young, ovariectomized (OVX) animal as a substitute. Ovariectomized animals have a negligible level of circulating estrogen and cessation of menses. Thus, these monkeys model changes that occur during reproductive aging. It is important to remember that these are not aged animals, and that the loss of estrogen in a young monkey by OVX does not necessarily mimic natural, age-related changes in estrogen in the aged brain. However, they have proven to be effective for studying at least some of the neural changes associated with estrogen loss and replacement, including changes to hormone receptor densities and neuronal morphology and populations of neuropeptides and neuromodulators associated with the HPG axis. Concurrently, researchers can uncover the benefits of estrogen replacement therapy (ERT) and the acute and chronic treatment effects of ERT on diseases and symptoms associated with menopause.

As discussed earlier, aged animals show an increase in GnRH and LH levels, and estrogen loss may contribute to these observed increases (Woller et al., 2002; Bellino and Wise, 2003; Gore et al., 2004). The OVX, young monkey model has extended these results to show inhibitory effects of estrogen on GnRH release (Chongthammakun and Terasawa, 1993), GnRH mRNA expression (El Majdoubi et al., 1998; Krajewski et al., 2003), and circulating LH concentrations (El Majdoubi et al., 1998). Parallel results have been reported in humans, in which estrogen replacement for postmenopausal women diminishes LH and FSH levels as compared to nontreated women (Gill et al., 2002), and decreases in GnRH mRNA occur following estradiol replacement (Rance and Uswandi, 1996). Additionally, effects of estrogen on hypothalamic neuropeptides associated with GnRH pulsatility have been suggested for norepinephrine and neuropeptide Y. Both of these neuromodulators demonstrate pulsatile release, and increase just prior to the GnRH surge associated with ovulation. Estrogen replacement in OVX females upregulates norepinephrine release and increases the sensitivity of GnRH release to neuro-peptide Y, suggesting that neuromodulators playing a role in reproductive aging undergo changes with the age-associated decline in estrogen levels (Terasawa, 1998).

Estrogen receptor expression in neuroendocrine and other brain regions is important to consider in the aging model. In recent years, estrogen has been found to be responsible not only for feedback actions upon the hypothalamus, but also other neurophysiological functions such as cognition and neuroprotection. Two nuclear estrogen receptors, ERa and ER^, have been localized in mammalian brain tissue, each showing unique expression patterns in subregions of the hypothalamus (Chakraborty and Gore, 2004). The roles of ERa and ER^, as well as the interplay between these two receptors in reproductive aging (i.e., whether they are modulatory, inhibitory, or reciprocal) remain undetermined. It is important to understand the changing dynamics of these receptors in the aging hypothalamus, so as to uncover the potential roles that these play in endocrine function as well as endocrine aging. One study by Gundlah et al. (2000)

reported that administration of estrogen followed by progesterone in OVX macaque monkeys decreases ERa mRNA and protein expression in the ventromedial hypothalamus, an area associated with sexual behavior, but has minimal effects on ER^. Age-associated decreases in ER populations in various nuclei of the hypothalamus very likely contribute to declines in sexual behavior, ovulation, and fecundity as well as observed changes in HPG hormone levels. Additionally, cognitive decline, onset of stroke, osteoporosis, and other age-related diseases may be in close correlation with such decreases. Studies to this effect have not been extensively pursued in NHPs to determine the presence or absence of these changes, but the finding of Gundlah et al. (2000) and those in other animal models (discussed elsewhere) suggest that this warrants further examination. Understanding the distribution and activation of estrogen receptors and their collective role in reproduction and other physiological processes will prove important in future studies of disease and reproductive aging.

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