Neuropeptides in the gonads: from evolution to pharmacology - PubMed (original) (raw)

Neuropeptides in the gonads: from evolution to pharmacology

Nicolette L McGuire et al. Front Pharmacol. 2010.

Abstract

Vertebrate gonads are the sites of synthesis and binding of many peptides that were initially classified as neuropeptides. These gonadal neuropeptide systems are neither well understood in isolation, nor in their interactions with other neuropeptide systems. Further, our knowledge of the control of these gonadal neuropeptides by peripheral hormones that bind to the gonads, and which themselves are under regulation by true neuropeptide systems from the hypothalamus, is relatively meager. This review discusses the existence of a variety of neuropeptides and their receptors which have been discovered in vertebrate gonads, and the possible way in which such systems could have evolved. We then focus on two key neuropeptides for regulation of the hypothalamo-pituitary-gonadal axis: gonadotropin-releasing hormone (GnRH) and gonadotropin-inhibitory hormone (GnIH). Comparative studies have provided us with a degree of understanding as to how a gonadal GnRH system might have evolved, and they have been responsible for the discovery of GnIH and its gonadal counterpart. We attempt to highlight what is known about these two key gonadal neuropeptides, how their actions differ from their hypothalamic counterparts, and how we might learn from comparative studies of them and other gonadal neuropeptides in terms of pharmacology, reproductive physiology and evolutionary biology.

Keywords: GnIH; GnRH; RFRP; ovary; primate; testes; vertebrate.

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Figures

Figure 1

Figure 1

Theoretical construct of local gonadotropin-releasing hormone (GnRH) action on follicular development in the mammalian ovary, based on experimental evidence. GnRH and GnRH receptor (GnRH-R) are expressed on granulosa cells at all stages of follicular development and on granulosa-luteal cells of corpora lutea. Prehierarchical follicles (1) are not stimulated by Follicle stimulating hormone (FSH) and gonadal GnRH reduces granulosa cell numbers by reducing proliferation and increasing apoptosis in these follicles (Takekida et al., 2003). As follicles gain the ability to respond to FSH, they overcome this inhibition and grow into small/medium hierarchical follicles (2). GnRH increases apoptosis of granulosa cells in these follicles, but this does not cause a significant reduction in the secretion of already low levels of estradiol (E2) and progesterone (P) (Takekida et al., 2003). FSH, P and E2 enhance the growth of these follicles into large hierarchical follicles(3). GnRH reduces granulosa cell proliferation, aromatase activity (Gore-Langton et al., 1981) and luteinizing hormone receptor (LH-R) expression (Hsueh et al., 1980) while continuing to increase granulosa cell apoptosis (Takekida et al., 2003). All of these factors contribute to a significant decrease in the secretion of E2 and P from these follicles (Hsueh et al., ; Takekida et al., 2003). The reduction in LH-R also makes the follicle less able to respond to the LH surge with ovulation. If large hierarchical follicles are not able to overcome this inhibition, their growth will cease and they would become atretic(4). If a large hierarchical follicle does overcome inhibition by GnRH it can become the corpus luteum (5) post-ovulation. GnRH decreases LH-R and FSH-R expression in, reduces secretion of progesterone from and increases apoptosis of granulosa-luteal cells (Kang et al., , ; Zhao et al., 2000). The highest expression of GnRH and GnRH-R occurs at the end of the luteal phase (Chakrabarti et al., 2008), indicating GnRH may be a contributing factor to luteolysis. The diagram on the right is a representation of the photomicrograph on left, showing the relative location of each follicular stage for clarity.

Figure 2

Figure 2

In situ hybridization for RF-amide related peptide (RFRP) and its receptor (OT7T022) in rhesus macaque (Macaca mulatta) ovary. RFRP antisense probe labels mRNA in granulosa cells and oocytes (A). An adjacent section incubated with RFRP sense probe (control) is shown in (B). OT7T022 antisense probe labels mRNA in granulosa cells and oocytes (C). An adjacent section incubated with OT7T022 sense probe (control) is shown in (D). Black arrows, granulosa cells. Striped arrowheads, oocytes.

Figure 3

Figure 3

In situ hybridization for RF-amide related peptide (RFRP) and its receptor (OT7T022) in rhesus macaque (Macaca mulatta) testis. RFRP antisense probe labels mRNA in Leydig cells, spermatogonia and spermatocytes (A). An adjacent section incubated with RFRP sense probe (control) is shown in (B). OT7T022 antisense probe labels mRNA in Leydig cells, Sertoli cells, spermatogonia and spermatocytes (C). An adjacent section incubated with OT7T022 sense probe (control) is shown in (D). White arrows, Leydig cells. Gray arrows, spermatogonia. Black arrows, spermatocytes. Black arrowheads, Sertoli cells. All figures to scale, scale bar = 50 μm.

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