Estrogen, synaptic plasticity and hypothalamic reproductive aging

Unlike primates who undergo ovarian failure and loss of sex steroids at the end of reproduction, aging rodents undergo constant vaginal estrus followed by constant diestrus and finally anestrus, which indicates the absence of responsive ovarian follicles. The latter state is analogous to menopause in women. The timing of the appearance of constant estrus is determined by many factors including estrogen exposure in the brain during development and the number of times that the animal gets pregnant. The chief site of this reproductive aging in rat brains is the arcuate nucleus of the hypothalamus. The transition from normal cycles to constant estrus parallels the females' gradually decreased ability to respond to administered estradiol with a cycle of inhibition followed by disinhibition of gonadotrophin-releasing hormone. Evidence has accumulated indicating this to be due to a loss of the rat's ability to respond to markedly elevated estradiol with the usual arcuate nucleus neuro-glial plasticity that supports the estrogen-induced gonadotrophin surge (EIGS). Just as male rats are not capable of an EIGS, aged females loose this ability through repeated EIGS. Experiments indicate that in male rats the hypothalamic synaptology that develops as a result of exposure to testicular androgens in the perinatal period (brain sexual differentiation) is a result of conversion of testosterone from the testes to estrogen in the brain and is therefore due to early estrogen exposure. Aging females appear to reach a synaptology similar to males and constant estrus as a result of repeated exposure to ovarian estrogens during their reproductive careers. The relative role of aging and hormonal factors remains unclear. Morphological evidence is presented that indicates the above effects of estrogen involve changes in hypothalamic arcuate nucleus neurons and glia, including changes in the organization of perikaryal membranes as well as arcuate nucleus synaptology and the load of peroxidase in the astroglia. A possible role for free radicals (reactive oxygen species) in hypothalamic reproductive aging has been proposed. Such a mechanism is supported by evidence that the anti-oxidant vitamin E delays the onset of constant estrus and the accumulation of glial peroxidase in aging female rats. However, since the synaptology and peroxidase load in constant estrus females is independent of the age at which the constant estrus occurs, it appears that the role of (repeated) estradiol exposure is more deterministic of hypothalamic failure than is aging, per se.