The role of the brain in female reproductive aging

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Abstract

In middle-aged women, follicular depletion is a critical factor mediating the menopausal transition; however, all levels of the hypothalamic–pituitary–gonadal (HPG) axis contribute to the age-related decline in reproductive function. To help elucidate the complex interactions between the ovary and brain during middle-age that lead to the onset of the menopause, we utilize animal models which share striking similarities in reproductive physiology. Our results show that during middle-age, prior to any overt irregularities in estrous cyclicity, the ability of 17β-estradiol (E2) to modulate the cascade of neurochemical events required for preovulatory gonadotropin-releasing hormone (GnRH) release and a luteinizing hormone (LH) surge is diminished. Middle-aged female rats experience a delay in and an attenuation of LH release in response to E2. Additionally, although we do not observe a decrease in GnRH neuron number until a very advanced age, E2-mediated GnRH neuronal activation declines during the earliest stages of age-related reproductive decline. Numerous hypothalamic neuropeptides and neurochemical stimulatory inputs (i.e., glutamate, norepinephrine (NE), and vasoactive intestinal peptide (VIP)) that drive the E2-mediated GnRH/LH surge appear to dampen with age or lack the precise temporal coordination required for a specific pattern of GnRH secretion, while inhibitory signals such as gamma-aminobutyric acid (GABA) and opioid peptides remain unchanged or elevated during the afternoon of proestrus. These changes, occurring at the level of the hypothalamus, lead to irregular estrous cycles and, ultimately, the cessation of reproductive function. Taken together, our studies indicate that the hypothalamus is an important contributor to age-related female reproductive decline.

Introduction

Although the mean life span of humans continues to increase, the mean age at which women begin the peri-menopausal transition has remained constant at 45.5–47.5 years, a process that lasts about 4 years (Burger et al., 2002, Hidayet et al., 1999, McKinlay et al., 1992, Treloar, 1981, WHO, 1996). Therefore, most women can expect to spend over one third of their lives in the postmenopausal state where the associated chronic decrease in E2 will have far-reaching health implications on bone (Ebeling et al., 1996, Seifert-Klauss et al., 2002), neurodegeneration and stroke (Suzuki et al., 2006, Suzuki et al., 2007, Wise et al., 2005), cognition (Halbreich et al., 1995, Lacreuse, 2006, Paganini-Hill and Henderson, 1994, Rapp et al., 2003, Roberts et al., 1997, Shaywitz et al., 1999, Voytko and Tinkler, 2004), cardiovascular disease (Do et al., 2000, Hall et al., 2002, Luoto et al., 2000, Matthews et al., 2001), and immune function (Keller et al., 2001, Pfeilschifter et al., 2002, Porter et al., 2001). For these reasons, factors underlying the timing of the onset of the menopause and the repercussions of attenuated circulating E2 on women's health are of considerable interest. We utilize animal models to gain insight about the complex interactions between the ovary and the brain leading up to the onset of the menopause and the hypoestrogenic state. During the past five years, we have come to appreciate that during middle-age, the changes that occur in reproductive cyclicity and hormone patterns among women, nonhuman primates, and rodents are strikingly similar (Bellino and Wise, 2003, Downs and Urbanski, 2006, Wise et al., 1999, Wise et al., 2002, Wu et al., 2005). In this review we include a discussion of the differences and similarities of rodent and nonhuman primate model systems for human menopause onset. This review focuses primarily on our work; however, we cite numerous studies from our colleagues that have greatly benefited our understanding of neuroendocrine factors contributing to female reproductive senescence.

Section snippets

Aging of the female hypothalamic–pituitary–ovarian axis

Age-related female reproductive decline involves deficits at all levels of the HPG axis (Peng and Huang, 1972, Rubin, 2000, Wise et al., 1999, Wise et al., 2002). In women, depletion of the postmitotic pool of ovarian follicles and the associated decline in circulating E2 concentrations are traditionally recognized as being the ultimate markers of menopause (vom Saal et al., 1994). In addition to the ovary, the pituitary is likely to contribute to reproductive decline since the LH response to a

Neuronal factors involved in the onset of reproductive senescence

The driving force behind GnRH/LH output relies upon the complex balance between, and timing of, stimulatory and inhibitory inputs to GnRH neurons. By middle-age the orchestration of this balance has deteriorated, which is manifested in reduced GnRH release, leading to a reduction in magnitude and delay in the LH surge (Wise, 1982a, Wise, 1982b, Wise et al., 2002). Much attention has been paid to the role of declining stimulating factors that may contribute to the observed age-effects on the

Aging of circadian signals contribute to reproductive decline

Timing is a critical factor in initiating the preovulatory GnRH/LH surge (Chappell, 2005, de la Iglesia and Schwartz, 2006). A series of seminal studies by John Everett and Charles Sawyer first established that two requirements were necessary to induce a preovulatory LH surge in the female rat: (1) a neurogenic signal during a “critical period”; and (2) a rise in circulating E2 (Everett et al., 1949, Everett and Sawyer, 1950, Everett and Sawyer, 1953, Sawyer et al., 1949). These studies

Rodents

The majority of information on which we base our conclusions regarding the brain's role in the onset of reproductive senescence originates from studies performed in rodents. Some controversy exists as to whether the rodent provides a suitable model for studying reproductive aging in women. Questions surrounding the appropriateness of the rodent model to provide insights into the onset of menopause in women stem from two primary observations. First, the negative feedback effects of E2 on

Summary

The complex and redundant mechanisms governing female reproduction emphasize that no single piece of the HPG axis can completely explain the changes that occur to mediate age-related reproductive decline. Evidence from studies in rats, monkeys and women indicates that female reproductive aging involves all levels of the HPG axis. The balance of stimulatory and inhibitory GnRH neuromodulators becomes temporally disorganized and deteriorates with advancing age. We propose that this imbalance

Acknowledgements

This work was supported by National Institutes of Health grants AG-02224 and AG-17164 to P.M. Wise.

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