Gonadotropin-Releasing Hormone Neuroterminals and Their Microenvironment in the Median Eminence: Effects of Aging and Estradiol Treatment

Abstract

The GnRH decapeptide controls reproductive function through its release from neuroendocrine terminals in the median eminence, a site where there is a convergence of numerous nerve terminals and glial cells. Previous work showed dynamic changes in the GnRH-glial-capillary network in the median eminence under different physiological conditions. Because aging in rats is associated with a diminution of GnRH release and responsiveness to estradiol feedback, we examined effects of age and estradiol treatment on these anatomical interactions. Rats were ovariectomized at young (4 months), middle-aged (11 months), or old (22-23 months) ages, allowed 4 wk to recover, and then treated with vehicle or estradiol for 72 h followed by perfusion. Immunofluorescence of GnRH was measured, and immunogold electron microscopic analyses were performed to study the ultrastructural properties of GnRH neuroterminals and their microenvironment. Although the GnRH immunofluorescent signal showed no significant changes with age and estradiol treatment, we found that the median eminence underwent both qualitative and quantitative structural changes with age, including a disorganization of cytoarchitecture with aging and a decrease in the apposition of GnRH neuroterminals to glia with age and estradiol treatment. Thus, although GnRH neurons can continue to synthesize and transport peptide, changes in the GnRH neuroterminal-glial-capillary machinery occur during reproductive senescence in a manner consistent with a disconnection of these elements and a potential dysregulation of GnRH neurosecretion.

Endocannabinoids and prostaglandins both contribute to GnRH neuron-GABAergic afferent local feedback circuits

“…Furthermore, estradiol acts on endothelial cells to induce retraction of tanycyte processes from GnRH neuron terminals (de Seranno et al 2010); similar mechanisms may exist to regulate astrocyte apposition near the somata of these neurons. In this regard, several studies have shown that changes in steroid milieu, and in particular estradiol, alter glial apposition to GnRH neurons in a manner correlated with number of synapses (Baroncini et al 2007;King and Letourneau 1994;Kozlowski and Coates 1985;Meister et al 1988;Prevot et al 1998Prevot et al , 1999Witkin et al 1991Witkin et al , 1995Witkin et al , 1997Xiong et al 1997;Yin et al 2009aYin et al , 2009b. This apposition can change in a diurnal manner consistent with the estradiol-induced changes in GnRH neuron activity (Cashion et al 2003).…”

Effects of GnRH immunization on the reproductive axis and thymulin

“…These changes were associated with altered astrocyte-neuron contacts and synaptic remodeling in immunized rats. The stimulation of hormones, especially gonadal steroids, on the activities of astrocytes in the Arc and ME (Blutstein et al 2009, Yin et al 2009, Yeo & Herbison 2014, at least demonstrated that testosterone reduced plastic rearrangements of glial-GnRH neurons adhesiveness. By contrast, testosterone increased the number of astrocytes in the hippocampus reduced GFAP expression and stimulated the reactive astrocyte hypertrophy in the infarct area of the rat brain (Pan et al 2005, Emamian et al 2010.…”

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

“…In addition, ovariectomy in rats has been associated with alterations in gonadotroph morphology in terms of hypertrophy that may be reversed by estradiol treatment, particularly in young rats [23]. It could be hypothesized that a long-time estro-progestin treatment was required to induce gonadotroph shrinkage in our patient, as well as to restore her pituitary and hypothalamus sensitivity to sex steroids.…”

“…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]. Therefore, differently to what happen in older women, our patient GnRH neurons could have produced a powerful and supraphysiological response to the estrogen deprivation as well as to the presumable fall in inhibin B level, similarly to what has been found to happen in ovariectomized mice, where GnRH pulsatility is increased toward saturation after ovariectomy [8].…”