Neuroendocrine Modulation and Repercussions of Female Reproductive Aging

Abstract

The menopause marks the end of a woman's reproductive life. During the postmenopausal period, plasma estrogen concentrations decrease dramatically and remain low for the rest of her life, unless she chooses to take hormone replacement therapy. During the past 20 years, we have learned that changes in the central nervous system are associated with and may influence the timing of the menopause in women. Recently, it has become clear that estrogens act on more than just the hypothalamus, pituitary, ovary, and other reproductive organs. In fact, they play roles in a wide variety of nonreproductive functions. With the increasing life span of humans from approximately 50 to 80 years and the relatively fixed age of the menopause, a larger number of women will spend over one third of their lives in the postmenopausal state. It is not surprising that interest has increased in factors that govern the timing of the menopause and the repercussions of the lack of estrogen on multiple aspects of women's health. We have used animal models to better understand the complex interactions between the ovary and the brain that lead to the menopause and the repercussions of the hypoestrogenic state. Our results show that when rats reach middle age, the patterns and synchrony of multiple neurochemical events that are critical to the preovulatory gonadotropin-releasing hormone (GnRH) surge undergo subtle changes. The precision of rhythmic pattern of neurotransmitter dynamics depends on the presence of estradiol. Responsiveness to this hormone decreases in middle-aged rats. The lack of precision in the coordination in the output of neural signals leads to a delay and attenuation of the luteinizing hormone surge, which lead to irregular estrous cyclicity and, ultimately, to the cessation of reproductive cycles. We also have examined the impact of the lack of estrogen on the vulnerability of the brain to injury. Our work establishes that the absence of estradiol increases the extent of cell death after stroke-like injury and that treatment with low physiological levels of estradiol are profoundly neuroprotective. We have begun to explore the cellular and molecular mechanisms that underlie this novel nonreproductive action of estrogens. In summary, our studies show that age-related changes in the ability of estradiol to coordinate the neuroendocrine events that lead to regular preovulatory GnRH surges contribute to the onset of irregular estrous cycles and eventually to acyclicity. Furthermore, we have shown that the lack of estradiol increases the vulnerability of the brain to injury and neurodegeneration.

Low reproductive success in Per1 and Per2 mutant mouse females due to accelerated ageing?

“…Young adult Per mutant females show the same oestrous cycle pattern lasting 4-5 days as wild-type females (unpublished data). This regularity in oestrus cyclicity provides a hint for the regularity in the rhythmicity of the luteinizing hormone (LH) surge and ovarian hormones facilitating fertility and embryonal development (Day et al 1989, Diaz et al 2000, Wise et al 2002, Miller et al 2004, Nelson 2005. Contrary to this, adult Clock mutant females reveal prolonged irregular cycles associated with elevated rates of foetal reabsorption and pregnancy failures (Miller et al 2004, Kennaway 2005, Dolatshad et al 2006.…”

“…persistent vaginal cornification or leukocytosis, characterise the age-related decline of cyclicity in rats and mice (Nelson et al 1982, Matt et al 1987, Markowska 1999. The initial phases of declining in cyclicity from the 13th month of age onwards are prolonged and irregular cycles and cause a delay in the preovulatory rise of oestradiol (Nelson et al 1981, Wise et al 2002. These prolonged oestrogen secretions in mice and rats have been explained as being a result of incomplete or delayed luteinisation (Nelson et al 1982, Matt et al 1987.…”

HDC gene polymorphisms are associated with age at natural menopause in Caucasian women

“…What is more interesting, histamine could induce ovulation in the isolated perfused ovary [39]. In addition, histamine is an important neuro-modulator in the central nervous system which also exerts a role in the regulation of AANM [40]. Some studies focusing on the biological function of histamine at hypothalamus suggested that histamine influenced the secretion of GnRH (gonadotropinreleasing hormone), GTH (gonadotropic hormone), and even estrogen [22,41,42], which are the key molecules for the regulation of female reproduction system.…”

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]. Likewise, there are excellent reviews covering the entire spectrum of the pathophysiology of early and late menopause [217][218][219][220][221].…”