The rhesus monkey (Macaca mulatta) has been a biomedical model for reproductive studies in women since the early 1900s (Heape, 1900). Female rhesus monkeys are pubertal by 2.5 to 3.5 years of age and exhibit menstrual cycles approximately 28 days in length, similar to humans. Furthermore, rhesus monkeys experience a reproductive decline much like that of human menopause around 24 years (Gilardi et al., 1997; Bellino and Wise, 2003). Urinary hormone profiles demonstrated that, like women, menopause in rhesus monkeys is associated with amenorrhea, low urinary estrogen conjugates, and irregular patterns of urinary concentrations of progesterone metabolites (Gilardi et al., 1997). Urinary FSH levels also increase in postmenopausal rhesus monkeys (Shideler et al., 2001).
Key components of the reproductive decline Human fecundity declines rapidly after age 40, with a decrease in the follicular ''ovarian reserve'' and increased abnormalities in oocyte quality. However, little is known about the mechanism that initiates menopause. Age alone is not a reliable predictor of menopause, but endocrine disturbances often precede noticeable irregularities in menstrual cyclicity. Few longitudinal studies have addressed these endocrine aspects of ovarian senescence; morphologic studies, when performed, are derived from ovarian specimens obtained retrospectively from aging women of unknown endocrine status. Thus, the rhesus monkey is an ideal model for investigating the mechanisms underlying menopause beacuse females display similar neuroendocrine mechanisms in the menstrual cycle.
There has been extensive research on the hypothalamic changes that accompany ovarian decline in multiple species. In humans, pituitary gonadotropins show age-related changes with a transient increase in plasma luteinizing hormone (LH) and a dramatic increase in follicle stimulating hormone (FSH). Isolating age-related changes in hypothalamic response from ovarian aging is difficult; however, a number of studies have been conducted using the rodent model. Previous studies have examined the response of the HPG axis at various stages in the life cycle of the female as well as the functional changes of the hypothalamus and pituitary gland with aging. Wise (1991) reported decreased amplitude and frequency in LH secretion in older rats and a decline in the number of activated GnRH neurons, despite normal cycles (Scarbrough and Wise, 1990; Lloyd et al., 1994). These papers by Wise and colleagues and many others point to alterations in the systems that modulate GnRH as key elements of the reproductive decline. Overall, these studies indicate that hypothalamic response decreases, potentially in tandem with declining ovarian function (Wise, 1991; Mills et al., 2002; Micevych et al., 2003). In addition, ovarian secretion of inhibin is beginning to be studied and may emerge as an important element of the aging process (Groome et al., 1994; 1996; Welt et al., 1999). Data collected in female nonhuman primates and in humans suggest that there are similar mechanisms operating during the perimenopausal transition (Klein et al., 1996; Bellino and Wise, 2003).
The perimenopausal transition: A time of changing hormones
As the perimenopausal transition progresses, there is declining function of the hypothalamic-pituitary-gonadal axis (HPG axis), ultimately resulting in cessation of ovarian function and menopause. The average age of menopause in women is approximately 51 years, resulting in a postreproductive period that extends for nearly 1/3 of their lives (Treolar et al., 1981). If menopause merely affected fertility, the study of ovarian aging would likely not be of such high priority. As mentioned earlier, a number of other physiological systems are also affected by the sudden withdrawal of hormonal support associated with menopause, including bone density, cardiovascular health, cognition and possibly some cancers (Gosden, 1985; Prior, 1998; Sherwin, 2003).
Characterization of perimenopausal transition Rhesus monkeys that have been observed at the Oregon National Primate Research Center (ONPRC) indicate that the frequency of regular menstrual cyclicity declines with age (Wu et al., 2004; Zelinski-Wooten, unpublished data). Approximately 70% of rhesus females between the ages of 20 and 22 years did not exhibit the onset of irregular cycles, but by 23-25 years of age, 50% of females did have irregular cycles. The data from ONPRC agrees with that published by Gilardi and colleagues (1997) at the California Regional Primate Research Center, where the mean age of old animals displaying regular cycles was 22 years, those displaying irregular cycles (i.e., perimeno-pausal) was 24 years, and postmenopausal monkeys of 29 years as compared to normal cycles observed in young adult females (Zelinski-Wooten et al., 1999).
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