Neuroendocrine control of reproductive aging: roles of GnRH neurons

Abstract

The process of reproductive senescence in many female mammals, including humans, is characterized by a gradual transition from regular reproductive cycles to irregular cycles to eventual acyclicity, and ultimately a loss of fertility. In the present review, the role of the hypothalamic gonadotropin-releasing hormone (GnRH) neurons is considered in this context. GnRH neurons provide the primary driving force upon the other levels of the reproductive axis. With respect to aging, GnRH cells undergo changes in biosynthesis, processing and release of the GnRH decapeptide. GnRH neurons also exhibit morphologic and ultrastructural alterations that appear to underlie these biosynthetic properties. Thus, functional and morphologic changes in the GnRH neurosecretory system may play causal roles in the transition to acyclicity. In addition, GnRH neurons are regulated by numerous inputs from neurotransmitters, neuromodulators and glia. The relationship among GnRH cells and their inputs at the cell body (thereby affecting GnRH biosynthesis) and the neuroterminal (thereby affecting GnRH neurosecretion) is crucial to the function of the GnRH system, with age-related changes in these relationships contributing to the reproductive senescent process. Therefore, the aging hypothalamus is characterized by changes intrinsic to the GnRH cell, as well as its regulatory inputs, which summate to contribute to a loss of reproductive competence in aging females. Reproduction (2006) 131 403-414

Estrogen, Menopause, and the Aging Brain: How Basic Neuroscience Can Inform Hormone Therapy in Women

“…GnRH cell numbers do not change appreciably with aging so this is probably not the causal event for these alterations documented above (for review, see Yin and Gore, 2006). Rather, inputs to GnRH neurons from other neurotransmitters and glia in the CNS appear to be very important in causing age-associated changes in GnRH output (Gore, 2004).…”

“…The early menopause transition is associated with lower ovarian inhibin secretion, which in turn reduces the restraint on both the hypothalamus and pituitary and results in elevated pituitary gonadotropin [folliclestimulating hormone (FSH)] secretion. In addition to reduced ovarian inhibin secretion, age-related increases in gonadotropinreleasing hormone (GnRH) production could contribute to the elevated pituitary gonadotropin levels (Maffucci and Gore, 2006;Yin and Gore, 2006). Importantly, ovarian estradiol secretion is normal or at times elevated during this early stage of the menopause transition (Santoro, 2005).…”

“…The female rat is an important animal model of reproductive aging because it is big enough to perform reproductive physiol-ogy measures (e.g., hormone sampling), small enough to house cheaply, its genome is known, and available antibodies and probes enable investigators to study molecular and cellular mechanisms of reproductive aging (Maffucci and Gore, 2006;Yin and Gore, 2006). Like primates, rats have reproductive cycles, but, rather than the 28 d menstrual cycle, young adult female rats experience 4 d estrous cycles.…”

“…often turn to the ovariectomized (OVX) rat model. Using age-appropriate rats at young, middle-aged, and old ages, we ovariectomize the animals, wait 1 month, and then give ET (i.e., estradiol), with or without progestins, in physiologically relevant dosages Yin and Gore, 2006). Another important difference between primates and rodents is that postmenopausal increases in GnRH or surrogates for GnRH (e.g., gonadotropins or gonadotropin-free a subunit) occur during the perimenopause (Hall and Gill, 2001;Maffucci and Gore, 2006), whereas in rodents, GnRH neurosecretion and the preovulatory GnRH/LH surge declines at estropause (Rubin and Bridges, 1989).…”

Resumption of ovarian function after 4 years of estro-progestin treatment in a young woman with Crohn’s disease and premature ovarian insufficiency: a case report

“…It has been demonstrated that, as aging progresses, gonadotropin levels decrease, as do gonadotropin pulse frequency and amplitude. As a matter of fact, early postmenopausal women (45-55 years) have significantly higher gonadotropin levels compared to late postmenopausal women (70-80 years) [22]. Moreover, there is also evidence that GnRH neurons undergo age-related impairment in terms of biosynthesis, processing, and release of the GnRH decapeptide before reproductive failure, suggesting a contributory role of GnRH cells to reproductive failure itself [23].…”