Activin A Regulation of Gonadotropin-Releasing Hormone Synthesis and Release in vitro

Abstract

Activin is essential for the regulation of normal mammalian reproductive function at both the pituitary and gonadal levels. However, its central actions in the control of the hypothalamic-pituitary-gonadal axis remain largely unexplored. The present study aims to determine whether activin could regulate the reproductive axis at the level of the hypothalamus, through control of the GnRH neuroendocrine system. Using the GnRH-secreting GT1-7 neuronal cell line as a model system, we demonstrate expression of mRNAs encoding activin receptor types I, IB, and II. We examined the effects of activin A on GnRH protein secretion and mRNA levels in GT1-7 cells. Treatment with rh-activin A regulated both GnRH protein secretion and GnRH mRNA expression in the GT1-7 cells in a time-dependent fashion. Using transient transfection assays, we explored a potential transcriptional basis for these changes. Activin A increased reporter gene activity driven by minimal GnRH enhancer and promoter elements, suggesting that activin may regulate GnRH gene expression at the level of transcription. Lastly, activin A treatment of male rat hypothalami, in vitro, increased GnRH protein secretion. Collectively, molecular and physiological evidence support the presence of an activin system which might act at a hypothalamic site to regulate mammalian reproduction via activation of GnRH synthesis and release.

Living and Dying for Sex

“…This is represented by a decrease in gonadal inhibin production [Reichlin, 1998] causing an increase in activin signaling [Gray et al, 2002]. This increase in activins then causes an increase in secretion of GnRH and gonadotropins [MacConell et al, 1999;Schwall et al, 1988;Weiss et al, 1993]. In addition, the age-related decrease in sex steroid production causes a loss of hypothalamic feedback inhibition and also stimulates GnRH and gonadotropin production [Carr, 1998].…”

Expression and Function of Gonadotropin-releasing Hormone (GnRH) Receptor in Human Olfactory GnRH-secreting Neurons

“…FNC-B4 neurons not only produced GnRH and responded to sex steroids, but they were sensitive to odorants in terms of GnRH production (22). In addition, endothelin-1 (23) and activin A (24), well known regulators of the GnRH-secreting neuron (25,26), also modulated their secretory pattern. Thus, FNC-B4 cells with both olfactory and neuroendocrine characteristics, such as those that may occur in the human olfactory epithelium during organogenesis, provide an useful in vitro tool to study those factors potentially involved in olfactory or neuroendocrine phenotype commitment in humans.…”

The endocrine dyscrasia that accompanies menopause and andropause induces aberrant cell cycle signaling that triggers re-entry of post-mitotic neurons into the cell cycle, neurodysfunction, neurodegeneration and cognitive disease

“…In addition, the decrease in gonadal inhibin production at this time (Reichlin 1998) results in decreased activin receptor inhibition, and together with the increase in bioavailable activin (Gray, et al 2002) leads to a further increase in the secretion of GnRH1 and gonadotropins (MacConell, et al 1999; Schwall, et al 1988; Weiss, et al 1993). Thus, the lack of negative feedback from the ovary/testis (progesterone (P 4 ), 17β-estradiol (E 2 ), testosterone and inhibin) is responsible for the unopposed and marked elevations in the secretion of GnRH1 and gonadotropins that is associated with ovarian and testicular senescence (Atwood et al 2005; Chakravarti, et al 1976; Neaves, et al 1984; Reame, et al 1996; Schmidt, et al 1996).…”