Identification and characterization of a gonadotropin-inhibitory system in the brains of mammals

Abstract

Successful reproduction requires maintenance of the reproductive axis within fine operating limits through negative feedback actions of sex steroids. Despite the importance of this homeostatic process, our understanding of the neural loci, pathways, and neurochemicals responsible remain incomplete. Here, we reveal a neuropeptidergic pathway that directly links gonadal steroid actions to regulation of the reproductive system. An RFamide (Arg-Phe-NH 2) peptide that inhibits gonadotropin release from quail pituitary was recently identified and named gonadotropin-inhibitory hormone (GnIH). Birds are known to have specialized adaptations associated with gonadotropin-releasing hormone (GnRH) regulation to optimize reproduction (e.g., encephalic photoreceptors), and the existence of a hypothalamic peptide inhibiting gonadotropins may or may not be another such specialization. To determine whether GnIH serves as a signaling pathway for sex steroid regulation of the reproductive axis, we used immunohistochemistry and in situ hybridization to characterize the distribution and functional role of this peptide in hamsters, rats, and mice. GnIH-immunoreactive (GnIH-ir) cell bodies are clustered in the mediobasal hypothalamus with pronounced projections and terminals throughout the CNS. In vivo GnIH administration rapidly inhibits luteinizing hormone secretion. Additionally, GnIH-ir neurons form close appositions with GnRH cells, suggesting a direct means of GnRH modulation. Finally, GnIH-ir cells express estrogen receptor-␣ and exhibit robust immediate early gene expression after gonadal hormone stimulation. Taken together, the distribution of GnIH efferents to neural sites regulating reproductive behavior and neuroendocrine secretions, expression of steroid receptors in GnIH-ir nuclei, and GnIH inhibition of luteinizing hormone secretion indicate the discovery of a system regulating the mammalian reproductive axis.luteinizing ͉ mating ͉ reproduction T he final common pathway in the neural regulation of reproduction is the gonadotropin-releasing hormone (GnRH) neuronal system. Neurons that synthesize and secrete GnRH occupy a midventral continuum from the diagonal band of Broca to the mediobasal hypothalamus (1). GnRH neurons regulating gonadotropin secretion project to the median eminence to control synthesis and secretion of the pituitary gonadotropins, luteinizing hormone (LH), and follicle-stimulating hormone (FSH) (2-4).In both males and females, gonadal steroids act through negative feedback to maintain the reproductive axis within the favorable operating limits necessary for fertility and successful mating. Negative feedback control of the GnRH system could be accomplished by sex hormones acting on either cognate receptors expressed in GnRH neurons or on gonadal-steroid-responsive systems upstream of GnRH. Although early evidence before this millennium suggested only the latter (5-11), more recent evidence suggests that both of these mechanisms act in concert to regulate precisely the reproductive axis in females (12-1...

Seasonal effects of GnIH on basal and GnRH-induced goldfish somatotrope functions

“…Although it is unclear whether the pineal gland and melatonin are involved in the control of gGnIH in goldfish, it is an important modulator in avians and mammals , Chowdhury et al 2013. Estradiol (E 2 ) increases early gene expression in, and alters the activities of, GnIH-immunoreactive cells in hamsters (Kriegsfeld et al 2006, Gibson et al 2008, whereas it decreases Gnih mRNA expression in mice (Molnár et al 2011). In goldfish, gGnIH implantation stimulated serum testosterone levels in males, although it had no effect on E 2 levels in females (Qi et al 2013).…”

Controle sobre GnRH durante o anestro pós-parto em bovinos

“…Nesse sentido, recentemente foi descoberto um hormônio, cujos neurônios secretores apresentam receptores de estrógeno, sendo denominado hormônio inibidor de gonadotrofinas (GnIH). O GnIH desempenha um papel na regulação negativa da secreção de LH em aves (TSUTSUI et al, 2000) e mamíferos (KRIEGSFELD et al, 2006). Esse hormônio é complementar ao papel da kisspeptina, a qual estimula a liberação de GnRH (KAISER & KUOHUNG, 2005).…”

“…O sistema nervoso central (SNC) interpreta informações periféricas, que o induzem a priorizar a demanda energética para processos indispensáveis. Assim, a síntese e liberação do GnRH é reduzida (I'ANSON et al, 1997;KRIEGSFELD et al, 2006), afetando principalmente a ovulação. Os sítios potenciais de reflexo da nutrição na função ovariana incluem (i) o hipotálamo, via regulação da frequência de GnRH; (ii) a hipófise, regulando a síntese e liberação das gonadotrofinas e hormônio do crescimento; e (iii) o ovário, regulando o crescimento folicular, esteroidogênese e a atividade de fatores de crescimento e suas proteínas de ligação (DISKIN et al, 2003).…”

“…Nesses animais, neurônios imunoreativos (ir) para o GnIH são exclusivamente encontrados no núcleo hipotalâmico paraventricular, enquanto fibras GnIH são encontradas em outras regiões do cérebro, incluindo a eminência média (UKENA et al, 2003). Neurônios GnIHir possuem estreita relação com células GnRH-ir, sugerindo uma possível interação entre neurônios GnIH e GnRH (KRIEGSFELD et al, 2006).…”

“…A administração de GnIH tanto por via periférica como intracerebroventricular em hamsters ovariectomizadas resultou na redução das concentrações de LH plasmático, proporcionando evidências do papel do GnIH como um fator inibidor de gonadotrofinas (KRIEGSFELD et al, 2006). cDNAs que codificam novos RFRPs similares ao GnIH têm sido descritos (HINUMA et al, 2000).…”