Identification of novel neurohormones that play important roles in the regulation of pituitary function is essential for the progress of neurobiology. The decapeptide gonadotropin-releasing hormone ...(GnRH) is the primary factor responsible for the hypothalamic control of gonadotropin secretion. Gonadal sex steroids and inhibin inhibit gonadotropin secretion via feedback from the gonads, but a neuropeptide inhibitor of gonadotropin secretion was, until recently, unknown in vertebrates. In 2000, a novel hypothalamic dodecapeptide that inhibits gonadotropin release was identified in quail and termed gonadotropin-inhibitory hormone (GnIH). This was the first demonstration of a hypothalamic neuropeptide inhibiting gonadotropin release in any vertebrate. GnIH acts on the pituitary and GnRH neurons in the hypothalamus via a novel G protein-coupled receptor for GnIH to inhibit gonadal development and maintenance by decreasing gonadotropin release and synthesis. GnIH neurons express the melatonin receptor and melatonin stimulates the expression of GnIH. Because GnIH exists and functions in several avian species, GnIH is considered to be a new key neurohormone controlling avian reproduction. From a broader perspective, subsequently the presence of GnIH homologous peptides has been demonstrated in other vertebrates. Mammalian GnIH homologous peptides also act to inhibit reproduction by decreasing gonadotropin release in several mammalian species. Thus, the discovery of GnIH has opened the door to a new research field in reproductive neurobiology. This review summarizes the advances made in our understanding of the biosynthesis, mode of action and functional significance of GnIH, a newly discovered key neurohormone, and its homologous peptides.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Highlights • GnIH acts as a key player for regulation of reproduction and behavior. • GnIH modifies neurosteroid milieu for regulation of reproductive behavior. • 7α-Hydroxypregnenolone acts as a key ...player for regulation of locomotor behavior. • Pineal neurosteroids act as key players for regulation of brain functions.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
•GnIH is a newly discovered hypothalamic neurohormone in animals and human.•GnIH acts via GPR147 and inhibits gonadotropin secretion and reproductive function.•GnIH synthesis is regulated by the ...integration of environmental and internal factors.•Abnormal changes in GnIH cause pubertal disorder and reproductive dysfunction.•GnIH studies are ongoing for drug development for reproductive dysfunction.
The discovery of novel neurohormones is important for the advancement of neuroendocrinology. In early 1970s, gonadotropin-releasing hormone (GnRH), a hypothalamic neuropeptide that promotes gonadotropin release, was identified to be an endogenous neurohormone in mammals. In 2000, thirty years later, another hypothalamic neuropeptide, gonadotropin-inhibitory hormone (GnIH), that inhibits gonadotropin release, was found in quail. GnIH acts via GPR147 and inhibits gonadotropin release and synthesis and reproductive function in birds through actions on GnRH neurons in the hypothalamus and pituitary gonadotrophs. Later, GnIH was found in other vertebrates including humans. GnIH studies have advanced the progress of reproductive neuroendocrinology. Furthermore, recent GnIH studies have indicated that abnormal changes in GnIH expression may cause pubertal disorder and reproductive dysfunction. Here, we describe GnIH discovery and its impact on the progress of reproductive neuroendocrinology. This review also highlights advancement and perspective of GnIH studies on drug development for pubertal disorder and reproductive dysfunction. (149/150)
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Based on extensive studies on gonadotropin-releasing hormone (GnRH) it was assumed that GnRH is the only hypothalamic neurohormone regulating gonadotropin release in vertebrates. In 2000, however, ...Tsutsui's group discovered gonadotropin-inhibitory hormone (GnIH), a novel hypothalamic neuropeptide that inhibits gonadotropin release, in quail. Subsequent studies by Tsutsui's group demonstrated that GnIH is conserved among vertebrates, acting as a new key neurohormone regulating reproduction. GnIH inhibits gonadotropin synthesis and release through actions on gonadotropes and GnRH neurons via GnIH receptor, GPR147. Thus, GnRH is not the sole hypothalamic neurohormone controlling vertebrate reproduction. The following studies by Tsutsui's group have further demonstrated that GnIH has several important functions in addition to the control of reproduction. Accordingly, GnIH has drastically changed our understanding about reproductive neuroendocrinology. This review summarizes the discovery of GnIH, progress in GnIH research on reproductive physiology and behavior and perspective of GnIH research on neuroendocrine regulation of reproduction.
•GnIH is a hypothalamic neuropeptide that inhibits gonadotropin secretion.•GnIH acts on gonadotropes and GnRH neurons via GnIH receptor, GPR147.•GnIH is conserved among vertebrates.•GnIH may be used to treat precocious puberty or reproductive disfunction.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
•GnIH is a potent regulator of reproduction inhibiting the HPG axis at every level.•Stress-induced HPA activation negatively impacts on reproduction.•The GnIH system is modulated by various types of ...stressors.•GnIH mediates stress-induced reproductive dysfunction by direct action of GR.
Under stressful condition, reproductive function is impaired due to the activation of various components of the hypothalamic–pituitaryadrenal (HPA) axis, which can suppress the activity of the hypothalamic-pituitary–gonadal (HPG) axis at multiple levels. A hypothalamic neuropeptide, gonadotropin-inhibitory hormone (GnIH) is a key negative regulator of reproduction that governs the HPG axis. Converging lines of evidence have suggested that different stress types and their duration, such as physical or psychological, and acute or chronic, can modulate the GnIH system. To clarify the sensitivity and reactivity of the GnIH system in response to stress, we summarize and critically review the available studies that investigated the effects of various stressors, such as restraint, nutritional/metabolic and social stress, on GnIH expression and/or its neuronal activity leading to altered HPG action. In this review, we focus on GnIH as the potential novel mediator responsible for stress-induced reproductive dysfunction.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
•GnIH has hypophysiotropic and non-hypophysiotropic functions.•GnIH inhibits gonadotropin synthesis and release via the GnIH receptor GPR147.•GnIH synthesis and release are controlled by ...environmental and internal factors.•Abnormality in GnIH causes pubertal disorder and reproductive dysfunction.
The discovery of gonadotropin-inhibitory hormone (GnIH) in 2000 has led to a new research era of reproductive neuroendocrinology because, for a long time, researchers believed that only gonadotropin-releasing hormone (GnRH) regulated reproduction as a neurohormone. Later studies on GnIH demonstrated that it acts as a new key neurohormone inhibiting reproduction in vertebrates. GnIH reduces gonadotropin release andsynthesis via the GnIH receptor GPR147 on gonadotropes and GnRH neurons. Furthermore, GnIH inhibits reproductive behavior, in addition to reproductive neuroendocrine function. The modification of the synthesis of GnIH and its release by the neuroendocrine integration of environmental and internal factors has also been demonstrated. Thus, the discovery of GnIH has facilitated advances in reproductive neuroendocrinology. Here, we describe the advances in reproductive neuroendocrinology driven by the discovery of GnIH, research on the effects of GnIH on reproductive physiology and behavior, and the regulatory mechanisms underlying GnIH synthesis and release.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
It is essential to discover novel neuropeptides that regulate the functions of pituitary, brain and peripheral secretory glands for the progress of neuroendocrinology. Gonadotropin-releasing hormone ...(GnRH), a hypothalamic neuropeptide stimulating gonadotropin release was isolated and its structure was determined by Schally's and Guillemin's groups at the beginning of the 1970s. It was subsequently shown that GnRH is highly conserved among vertebrates. GnRH was assumed the sole hypothalamic neuropeptide that regulates gonadotropin release in vertebrates based on extensive studies of GnRH over the following three decades. However, in 2000, Tsutsui's group isolated and determined the structure of a novel hypothalamic neuropeptide, which inhibits gonadotropin release, in quail, an avian species, and named it gonadotropin-inhibitory hormone (GnIH). Following studies by Tsutsui's group demonstrated that GnIH is highly conserved among vertebrates, from humans to agnathans, and acts as a key neuropeptide inhibiting reproduction. Intensive research on GnIH demonstrated that GnIH inhibits gonadotropin synthesis and release by acting on gonadotropes and GnRH neurons via GPR147 in birds and mammals. Fish GnIH also regulates gonadotropin release according to its reproductive condition, indicating the conserved role of GnIH in the regulation of the hypothalamic-pituitary-gonadal (HPG) axis in vertebrates. Therefore, we can now say that GnRH is not the only hypothalamic neuropeptide controlling vertebrate reproduction. In addition, recent studies by Tsutsui's group demonstrated that GnIH acts in the brain to regulate behaviors, including reproductive behavior. The 18 years of GnIH research with leading laboratories in the world have significantly advanced our knowledge of the neuroendocrine control mechanism of reproductive physiology and behavior as well as interactions of the HPG, hypothalamic-pituitary-adrenal and hypothalamic-pituitary-thyroid axes. This review describes how GnIH was discovered and GnIH research progressed in this new research era of reproductive neuroendocrinology.
In 2000, Tsutsui and colleagues discovered a neuropeptide gonadotropin-inhibitory hormone (GnIH) that inhibits gonadotropin release in birds. Subsequently, extensive studies during the last 15 years ...have demonstrated that GnIH is a key neurohormone that regulates reproduction in vertebrates, acting in the brain and on the pituitary to modulate reproduction and reproductive behavior. On the other hand, deprivation of food and other metabolic challenges inhibit the reproductive axis as well as sexual motivation. Interestingly, recent studies have further indicated that GnIH controls feeding behavior in vertebrates, such as in birds and mammals. This review summarizes the discovery of GnIH and its conservation in vertebrates and the neuroendocrine control of feeding behavior and reproductive behavior by GnIH.
The decapeptide gonadotropin‐releasing hormone (GnRH) is the primary factor responsible for the hypothalamic control of gonadotropin secretion in vertebrates, but a hypothalamic neuropeptide ...inhibiting gonadotropin secretion was, until recently, unknown in vertebrates. In 2000, we discovered a novel hypothalamic dodecapeptide that inhibits gonadotropin release in quail and termed it gonadotropin‐inhibitory hormone (GnIH). GnIH acts on the pituitary and GnRH neurons in the hypothalamus via a novel G protein‐coupled receptor for GnIH to inhibit gonadal development and maintenance by decreasing gonadotropin release and synthesis. The pineal hormone melatonin is a key factor controlling GnIH neural function. Because GnIH exists and functions in several avian species, GnIH is considered to be a new key neuropeptide controlling avian reproduction. After the discovery of GnIH in birds, the presence of GnIH homologs has been demonstrated in other vertebrates from fish to humans. Interestingly, mammalian GnIH homologs also act to inhibit reproduction by decreasing gonadotropin release in several mammalian species. It is concluded that GnIH and GnIH homologs act to inhibit gonadotropin release in higher vertebrates.
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BFBNIB, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, UL, UM, UPUK
The aim of this study was to evaluate the effects of in vivo and in vitro treatments with RFamide-related peptide 3 (RFRP3), a mammalian gonadotropin-inhibitory hormone ortholog, on testicular ...activities, i.e. spermatogenesis and steroidogenesis, in mice. Mice were treated in vivo with different doses of RFRP3 (control: 0.02 μg, 0.2 μg, and 2.0 μg/day) for 8 days. For in vitro study, the testes of mice were evaluated with different doses of RFRP3 (control: 1 and 10 ng/ml) with or without LH (control: 10 and 100 ng/ml) for 24 h at 37 °C. RFRP3 treatment produced significant changes in the body mass, circulating steroid level, and testicular activity in mice. RFRP3 treatment also caused dose-dependent histological changes in spermatogenesis, such as decline in germ cell proliferation and survival markers and increase in apoptotic markers in testis. Both in vivo and in vitro studies showed the inhibitory effect of RFRP3 on testosterone synthesis in the testis. RFRP3 inhibited the expression of the receptor for LH (LHCGR), STAR protein, cytochrome P450 side-chain cleavage (CYP11A1) and 3β-hydroxysteroid dehydrogenase in the testis, and testosterone secretion dose dependently. This study also suggested that the inhibitory effect of RFRP3 in the testis may be mediated through local production of GnRH. Thus, RFRP3 inhibits testicular steroidogenesis and spermatogenesis either indirectly through GnRH or by directly influencing germ cell proliferation, survival, and apoptosis.
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