Evidence for Ovarian Senescence in Rhesus Monkeys

The number of potentially viable oocytes available to the reproducing female depends on the size of the primordial follicle population within the ovary. In humans, primarily due to follicular atresia and secondarily because of follicular recruitment, the numbers of primordial follicles decrease dramatically from birth to the onset of menopause. At the end of the reproductive lifespan, the ''ovarian reserve'' of viable follicles and oocytes is essentially depleted, and the ovary is said to be senescent (Faddy and Gosden, 1996). Concomitantly, ovulatory activity ceases and levels of estrogen decrease markedly. As a result, FSH secretion increases strikingly because of diminished negative feedback from estrogen (Walker, 1995). Bioactive FSH retrieved from postmeno-pausal women's urine was in high demand for a number of years as a means to stimulate ovaries of infertile women to produce large numbers of follicles and oocytes. However, such ovarian stimulation for ART becomes ineffective once the ovarian reserve is seriously depleted and oocyte quality is reduced (Hansen et al., 2003). Female rhesus macaques are excellent models for studying the loss of reproductive capacity with increasing age. They are reproductively active over about 20 years starting at about age 5, and undergo similar pathological and hormonal changes to human females nearing the end of their reproductive lifespan (Shideler et al., 2001). Although there have been several reports on ovarian changes in macaques, including oocyte numbers, most studies examined younger females and did not study older animals (ages 15-25) that would be expected to show ovarian senescence. In view of this, our laboratory conducted a study of the ovarian reserve in rhesus macaque females across a wide age range (ages ~1-25), covering the entire reproductive lifespan of this species. Histological examination of ovarian sections showed clear evidence of follicular depletion with increasing age, especially in the older age groups (Nichols et al., 2005).

Ovaries were collected over a 5-year period at the Tulane National Primate Research Center (Covington, LA) and archived for later examination. These ovaries (64 pairs total) were divided into several groups by age (<5, >5-10, >10-15, >15-20 and >20 years old) to examine age-related changes in ovarian morphology. A representative histological section from each ovary was examined for the number of primordial, primary or antral follicles it contained (Figure 39.1).

We found that, while the percentage of antral follicles remained nearly unchanged across age groups, the percentages of primary and primordial follicles changed significantly with age (Figure 39.2).

This change reflects the degenerative processes occurring within the ovary. Similarly, the total numbers of follicles in each of the three classes significantly decreased with increasing age of the female. Because growth of

Figure 39.1 Follicles representing various stages of development in the rhesus ovary. Primordial follicles (A) are characterized by a flattened granulosa cell border. The representative primary follicle (B) demonstrates several layers of granulosa cells surrounding the oocyte and a developed zona pellucida. Antral follicles (C) contain a well-developed antrum. Reproduced from Nichols et al. (2005) Hum. Reprod. 20:79-83 ©European Society of Human Reproduction and Embryology. Reproduced by permission of Oxford University Press/Human Reproduction.

Figure 39.1 Follicles representing various stages of development in the rhesus ovary. Primordial follicles (A) are characterized by a flattened granulosa cell border. The representative primary follicle (B) demonstrates several layers of granulosa cells surrounding the oocyte and a developed zona pellucida. Antral follicles (C) contain a well-developed antrum. Reproduced from Nichols et al. (2005) Hum. Reprod. 20:79-83 ©European Society of Human Reproduction and Embryology. Reproduced by permission of Oxford University Press/Human Reproduction.

Female Lifespan Ovarian Reserve

Figure 39.2 Ovarian sections illustrating changing follicle populations with increasing age. Reproduced from Nichols et al. (2005) Hum. Reprod. 20:79-83 ©European Society of Human Reproduction and Embryology. Reproduced by permission of Oxford University Press/Human Reproduction.

Figure 39.2 Ovarian sections illustrating changing follicle populations with increasing age. Reproduced from Nichols et al. (2005) Hum. Reprod. 20:79-83 ©European Society of Human Reproduction and Embryology. Reproduced by permission of Oxford University Press/Human Reproduction.

primary follicles is gonadotropin-dependent (Macklon and Fauser, 1999), many of the newly formed primary follicles in older females cease development or become atretic, possibly due to lack of FSH receptors on the surrounding follicular cells. Loss of ovarian reserve was most obvious in females undergoing the perimeno-pausal and menopausal transition (age group 20-25 y.o.), with scattered and atretic follicles, occasional primordial follicles and reduced amounts of stromal tissue. Interestingly, the number of births within each female was significantly correlated with the proportion of primordial and primary follicles independent of her age, with the mean percentage of primordial follicles decreasing and the percentage of primary follicles increasing. This was likely because females who give birth to a large number of offspring are pregnant or lactating for much of their reproductive lifespan. The menstrual cycle stops during pregnancy/lactation, because of continued production of progesterone, which blocks FSH production and secretion from the pituitary gland (Pohl et al., 1982). As a result, recruitment and growth of primary follicles are halted, while recruitment and loss of the primordial follicles continues unabated throughout life because they are independent of gonadotropins.

This study (Nichols et al., 2005) illustrates that in several important respects, the rhesus monkey is an appropriate model for studying age-related loss of fertility in human females. However, it is not a perfect model because some details of human menopause are not shared by macaque females. For example, in humans there is a subtle and gradual onset of menopause-related changes before irregular cycling begins (Santoro, 2002), whereas macaques appear to undergo abrupt changes at the onset of irregular cycles (Shideler et al., 2001). Also, in this study we did not observe any age-related differences in sex hormone or gonadotropin levels in the rhesus females. However, this is not surprising because we had only one time point measurement for each female from a single blood sample drawn at the time of necropsy, so no comparative data during the reproductive lifespan of each female were available. Additional studies with the rhesus macaque model could be useful for understanding mechanisms underlying reproductive aging, so that it might be possible to devise ART strategies to address this phenomenon.

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