Table 432

Summary of the actions of select neuromodulators on the GnRH system

Agonist action

Antagonist action

Input onto HPG axis

Estrogen regulation

Age-related changes

Potentiates GnRH/LH release; enhances mRNA and protein expression.

Attenuates GnRH/LH release; decreases mRNA and protein expression.

Direct synapse at GnRH cell bodies and presence of receptor on GnRH perikarya and terminals.

Glutamate receptors and ERa and 3 are coexpressed in hypothalamus and POA.

Decline of NMDAR sensitivity and effects in the aging hypothalamus.

Attenuates GnRH/LH release; may inhibit preovulatory LH surge.

Potentiates GnRH/LH release; may cause early preovulatory LH surge.

Direct action on GnRH neurons via synapses and presence of receptors.

GABA cells in hypothalamus are colocalized with ERa.

Declines in GABA synthesis in POA with aging.

Stimulates pulsatile and preovulatory GnRH/LH release.

Alpha-adrenergic receptor antagonists prevent preovulatory LH surge.

Neurons project in the vicinity of GnRH neurons (indirect input). Presence of a1B- and a2A-adrenergic receptors on GnRH neurons.

A2 NE neurons express ERs; all E cell types express ERs.

Decreased NE turnover with aging.

Potentiates GnRH/LH release.

Inhibition of gene expression with antisense oligonucleotides or protein with immunoneutralization inhibits the LH surge.

Synaptic contacts with GnRH cell bodies and processes in POA and median eminence.

ERa coexpression with NPY cells in arcuate nucleus.

Decreased NPY hypothalamic gene expression with age.

Table modified from Smith et al. 2001. Specific aging-related citations: Glutamate (Gore 2002); GABA (Cashion et al., 2004); NE (Wise et al., 1997); NPY (Wise et al., 1997). Abbreviations: NE, norepinephrine; E, epinephrine; NPY, neuropeptide Y; ER, estrogen receptor; GABA, gamma-aminobutyric acid; NMDAR; N-methyl-D-aspartate receptor; POA, preoptic area.

Gore, 2002). Although all classes of glutamate receptors may be involved, the NMDA receptor (NMDAR) is most strongly implicated in this role. NMDARs, made up of heteromeric subunits, undergo age-related changes in subunit expression, both on GnRH neurons as well as in the surrounding hypothalamus-POA. A possible decline in NMDAR sensitivity to GLU has been reported with aging (Gore et al., 2000b). Finally, both ERa and ER3 are colocalized with NMDAR subunits (Chakraborty et al., 2003b), indicating that estrogen and GLU can act upon the same target cells to exert their effects.

2. GABA: The main inhibitory neurotransmitter in the central nervous system, which interacts with GnRH neurons to suppress the preovulatory GnRH/LH surge. Like glutamate, the GABA influence on GnRH function is estrogen-sensitive and GABA receptors are colocalized with ERs in the hypothalamus (Smith and Jennes, 2001). Changes in GABA synthesis in the POA accompany changes in age and estrous cycle stage (Cashion et al., 2004).

3. Catecholamines: Epinephrine and norepinephrine release strongly correlate with or are even causal to GnRH/LH pulse frequency and amplitude, and both are found in axons juxtaposed to GnRH neurons in the septum and diagonal band of Broca. Additionally, the A2 cell group of noradrenergic neurons and all cell groups of the adrenergic neurons express ERs, suggestive of direct action of estrogen on these neurons (Smith and Jennes, 2001). Wise et al. (1997) noted decreased norepi-nephrine (NE) turnover rates in middle-aged females in a number of hypothalamic nuclei. Middle-aged animals also lose diurnal rhythms of NE activity, suggesting a mechanism by which declines in NE activity are related to declines in the pulsatile regulation of GnRH release.

4. NPY: NPY gene expression and secretion are decreased in middle-aged compared to young animals, and pulsatile release of NPY is also associated with GnRH/LH release (Rubin, 2000). Again, these effects are modulated by estrogen (Smith and Jennes, 2001).

5. Together, these alterations are suggestive of changes to the pulsatile regulation of GnRH by its neurotransmitter inputs. We believe that age-related changes to these and other neuromodula-tory systems are key factors contributing to the age-related dysregulation of GnRH function.

Steroid hormones ERa: The effects of gonadal steroid hormones in the brain are mediated by the hormone receptors, which are expressed at high levels in a number of rat hypo-thalamic regions associated with reproduction. With regard to the two nuclear ERs, some regions express only one receptor, and others have overlapping expression. In general, these regions of overlap are most strongly implicated in the control of reproductive behavior and physiology (Chakraborty and Gore, 2004). Studies on the role of changing ovarian steroid feedback in aging rats have quantified hypothalamic ERa using a number of techniques, including estradiol binding assays, in situ hybridization, and protein expression by immunohistochemistry. Rubin et al. (1986) reported age-related, region-specific (preoptic area and medial basal hypothalamus) decreases in estradiol binding in the OVX, middle-aged rat. Wise and Parsons (1984) reported a similar finding in OVX, steroid-treated animals and Brown et al. (1990) extended this, finding similar results in aged animals as compared to young and middle-aged. More recent studies using in situ hybridization of ERa gene expression are summarized in Table 43.3, and in general, they demonstrate little to no changes in mRNA expression in the observed regions in aging rats. However, this technique does not take into account possible post-transcriptional or translational changes to ERa expression. Experiments using immunohistochemistry to examine protein expression in the hypothalamus show no age-related changes to ERa cell number in the medial preoptic nucleus (MPN) of intact (Madeira et al., 2000) or OVX, steroid-treated (Chakraborty et al., 2003a) females at young, middle-aged, and aged stages. Chakraborty et al. (2003a) also extended their studies to include the anteroventral periventricular nucleus and ventromedial nucleus, and showed an increase in ERa cell number from middle-age to aged animals in these regions. Thus, there are nuclei-specific changes in ERa expression in the aging rat hypothalamus, and uncovering the roles of these nuclei in reproductive aging will be vital to understanding the mechanism behind senescence. Effects of estrogen on expression of its ER have been studied in an age-related context. In the previous study by Chakraborty et al. (2003a), estrogen had little effect on overall ER expression in OVX rats of any age in the anteroventral periventricular nucleus, medial preoptic nucleus, arcuate nucleus, and ventromedial nucleus. Wise and Parsons (1984), when examining ERa nuclear DNA expression, found that estrogen treatment did have effects on ERa expression, with a two-day treatment causing decreases in OVX, middle-aged females in the preoptic area and medial basal hypothalamus. This effect was no longer apparent after four days of estrogen treatment. The techniques used in these studies differed in that the former study examined protein expression and the latter studied gene expression. This suggests a mechanism for posttranscriptional or translational changes to ERa mRNA that may compensate for the observed down-regulation of gene expression with estrogen treatment. Additionally, the ER may undergo age-related changes to protein expression, but only in very specific subpopulations. For example, a study

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