Ovarian Aging and Menopause: Current Theories, Hypotheses, and Research Models

Abstract

Aging of the reproductive system has been studied in numerous vertebrate species. Although there are wide variations in reproductive strategies and hormone cycle components, many of the fundamental changes that occur during aging are similar. Evolutionary hypotheses attempt to explain why menopause occurs, whereas cellular hypotheses attempt to explain how it occurs. It is commonly believed that a disruption in the hypothalamic-pituitary-gonadal axis is responsible for the onset of menopause. Data exist to demonstrate that the first signs of menopause occur at the level of the brain or the ovary. Thus, finding an appropriate and representative animal model is especially important for the advancement of menopause research. In primates, there is a gradual decline in the function of the hypothalamic-pituitary-gonadal (HPG) axis ultimately resulting in irregularities in menstrual cycles and increasingly sporadic incidence of ovulation. Rodents also exhibit a progressive deterioration in HPG axis function; however, they also experience a period of constant estrus accompanied by intermittent ovulations, reduced progesterone levels, and elevated circulating estradiol levels. It is remarkable to observe that females of other classes also demonstrate deterioration in HPG axis function and ovarian failure. Comparisons of aging in various taxa provide insight into fundamental biological mechanisms of aging that could underlie reproductive decline.

Chromosomal instability in rhesus macaque preimplantation embryos

“…Ovaries from rhesus monkeys with advanced maternal age also exhibit a reproductive decline and follicular depletion similar to that observed in humans (45,46). In addition, the hypothalamicpituitary-gonadal (HPG) function declines gradually, resulting in more irregular menstrual cycles and intermittent incidences of ovulation (47). Using a 5-color FISH assay for human chromosomes 13, 16, 18, X and Y, representing rhesus macaque chromosomes 17, 20, 18, X and Y respectively, baseline levels of chromosomal error rates have now been established in preimplantation embryos from young monkeys.…”

Impact of Aging on Steroid Hormone Biosynthesis and Secretion

“…Although significant information is also currently available about the impact of aging on ovarian steroidogenesis using experimental animal models [203][204][205][206][207][208][209][210][211], to conserve space and given the fact that physiological events connected with the reproductive cyclicity and ovarian sex steroid synthesis in animals, particularly rodents, are significantly different from that of humans, we will restrict our discussion to the aging human ovary only. Also, although aging is known to indirectly influence the ovarian steroid hormone production through modulation of the hypothalamic-pituitaryovarian axis, again, due to space constraints, this aspect of ovarian regulation will not be discussed here, but interested readers may wish to consult several recent excellent reviews that specifically cover this topic [212][213][214][215][216].…”

“…In brief, plasma levels of estradiol begin to rise around the mid-point of the follicular or proliferative phase, increasing almost linearly for the last few days, and reach a maximum level 1 day before ovulation (i.e., LH and FSH peaks) [226,227]. Thereafter, estradiol levels decline rapidly, rise slightly during the middle of the luteal or secretory phase and, subsequently, decline rapidly reaching a basal level shortly before the initiation of menstruation and the next cycle [226,211]. The plasma levels of progesterone remain low in menstrual phase and follicular phase, but rise steadily following ovulation reaching maximum levels around the middle of the luteal phase and decline rapidly afterwards reaching a baseline shortly before the onset of the menses [226,227].…”

Aging in male primates: reproductive decline, effects of calorie restriction and future research potential

“…In humans, women experience reproductive quiescence at approximately 50 years of age (Kidd et al 2001;Buwe et al 2005;Wu et al 2005). In men, aging follows a more gradual time course with functional deterioration at several sites within the HPG axis, including central neuroendocrine regulators, hypothalamic gonadotropin-releasing hormone, pituitary gland gonadotropins, and testicular testosterone (Ottinger 1998;Harman et al 2001;Moffat et al 2002).…”