ReviewGonadotropin-inhibitory hormone (GnIH): A new key neurohormone controlling reproductive physiology and behavior
Introduction
A neuropeptide identified as gonadotropin-inhibitory hormone (GnIH) was found in the quail hypothalamus in 2000, and it was found to be a novel inhibitory endogenous neurohormonal peptide of reproduction. Since its identification, the subsequent 20 years of research on GnIH has led to a significant advancement of our knowledge about the neuroendocrine regulation of reproduction. Thus, the discovery of novel neurohormones contributes significantly to the advances in reproductive neuroendocrinology.
Probing novel neurohormones started based on a new concept of “neurosecretion” proposed by Scharrer in the 1920s. He considered that hypothalamic neurons ending in the neurohypophysis secrete neurohormones to endocrine organs. Bargmann in 1949 recognized this seminal concept. Since then, novel neurohormones, oxytocin (Livermore and Du Vigneaud, 1949) and vasopressin (Turner et al., 1951), were found to be important hypothalamic neuropeptides secreted from the neurohypophysis in mammals.
In 1948, Harris (Harris, 1948) also proposed that hypothalamic neurons ending at the median eminence (ME) may secrete neurohormones into the hypophysial portal system from the ME to control the secretion of anterior pituitary hormones, including gonadotropins follicle-stimulating hormone (FSH) and luteinizing hormone (LH) and thyroid stimulating hormone (TSH), adrenocorticotropic hormone (ACTH), and growth hormone (GH). Then Schally’s and Guillemin’s groups independently discovered important neurohormones in the brain of mammals, and these include thyrotropin-releasing hormone (TRH) (Burgus et al., 1969, Boler et al., 1969), gonadotropin-releasing hormone (GnRH) (Matsuo et al., 1971, Burgus et al., 1972) and growth hormone-inhibiting hormone (somatostatin) (Brazeau et al., 1973). A Nobel Prize was awarded in 1977 to Schally and Guillemin for the discovery of these novel neurohormones.
In the early 1970s, GnRH, a hypothalamic neuropeptide that stimulates the release of gonadotropins from the anterior pituitary gonadotropes was identified in mammals (Matsuo et al., 1971, Burgus et al., 1972). Since then, it has been shown that GnRH is greatly conserved in terms of its amino acid sequence, although there have also been over 20 different sequences found among vertebrates (King and Millar, 1982, Miyamoto et al., 1982, Miyamoto et al., 1984, Sherwood et al., 1986). Extensive research on GnRH led to the idea that GnRH is the sole hypothalamic neurohormone controlling gonadotropin secretion in vertebrates. However, in 2000, thirty years later of the discovery of GnRH, Tsutsui’s group discovered a novel hypothalamic neuropeptide that inhibits gonadotropin release, which they named gonadotropin-inhibitory hormone (GnIH), in the Japanese quail (Coturnix japonica), an avian species (Tsutsui et al., 2000).
GnIH discovery has initiated a new chapter in the research on reproductive neuroendocrinology because it was widely accepted till then that GnRH is the only neurohormone of hypothalamus controlling the release of pituitary gonadotropins. Later studies of Tsutsui’s group have shown that GnIH sequence is also conserved among species from fish to higher vertebrates including humans (Homo sapiens) and that GnIH acts as a new critical inhibitory neurohormone of reproduction (for reviews, see (Kriegsfeld et al., 2015, Tsutsui, 2009, Tsutsui, 2016, Tsutsui and Ubuka, 2012, Tsutsui and Ukena, 2006, Tsutsui et al., 2006, Tsutsui et al., 2007, Tsutsui et al., 2010, Tsutsui et al., 2010, Tsutsui et al., 2012, Tsutsui et al., 2013, Tsutsui et al., 2015, Tsutsui et al., 2018, Ukena and Tsutsui, 2005)). Furthermore, it has been shown that GnIH has multiple roles besides controlling reproduction (Tobari et al., 2014, Ubuka et al., 2014). It now emerges that GnIH shows effects on the pituitary and the brain to regulate reproductive function as well as also various behaviors such as reproductive behavior via altered neurosteroid biosynthesis in the brain (Ubuka et al., 2014). Consequently, the following 20 years of research on GnIH has significantly contributed to enhance our knowledge on the neuroendocrine regulation of reproductive physiology and behavior (for reviews, see (Tsutsui and Ubuka, 2016, Ubuka et al., 2013, Kriegsfeld et al., 2015, Tsutsui, 2009, Tsutsui, 2016, Tsutsui and Ubuka, 2012, Tsutsui et al., 2006, Tsutsui et al., 2007, Tsutsui et al., 2010, Tsutsui et al., 2010, Tsutsui et al., 2012, Tsutsui et al., 2013, Tsutsui et al., 2015, Tsutsui et al., 2018)). Recent GnIH studies have further indicated that abnormal changes in GnIH expression may cause pubertal disorder and reproductive dysfunction in mammals.
2020 is the 20th anniversary of the discovery of gonadotropin-inhibitory hormone (GnIH). This review describes breakthrough in neuroendocrinology by the discovery of GnIH and impact of GnIH research on the progress of reproductive neuroendocrinology based on intensive studies from leading scientists in this new research era. This review also highlights advancement and perspective of GnIH research on drug development for pubertal disorder and reproductive dysfunction based on recent findings.
Section snippets
Breakthrough in neuroendocrinology by the discovery of GnIH
For a long time, since the identification of GnRH in mammals in 1971, researchers in the field of neuroendocrinology believed that GnRH is the only neurohormone from hypothalamus, which regulates gonadotropin release. However, in 2000, thirty years later of the discovery of GnRH, GnIH was identified as a new key hypothalamic neurohormone that reduces gonadotropin release in birds. The discovery of GnIH called this long-held belief into question. The newly identified gonadotropin-inhibitory
Impact of GnIH research on the progress of reproductive neuroendocrinology
The discovery of GnIH in 2000 has led to a new era of research in reproductive neuroendocrinology because GnRH is not the sole hypothalamic neurohormone controlling gonadotropin release and vertebrate reproductive function. The following 20 years of GnIH studies have demonstrated that GnIH acts as a new key neurohormone inhibiting reproduction throughout the vertebrates. GnIH reduces gonadotropin release and synthesis via its effect mediated through the GnIH receptor GPR147 on gonadotropes and
Advancement of GnIH research on pubertal disorder by the novel GnIH action in abnormal puberty
Thyroid disorder is known to be connected with abnormal pubertal development. Previous studies indicated the effect of abnormal thyroid status on pubertal disturbances that involve two neuroendocrine systems, the hypothalamo-pituitary-thyroid (HPT) axis and the HPG axis. However, the mode of action of thyroid hormone (TH) on the HPG axis is not fully elucidated. Recent studies have shown the involvement of GnIH in thyroid dysfunction induced pubertal disorder. This is a novel action for GnIH in
Perspective of GnIH research on drug development for precocious puberty and reproductive dysfunction
The deletion or the reduction in GnIH expression is considered to result in central precocity. In contrast, the acceleration of GnIH expression may cause central reproductive dysfunction. Several studies are investigating how abnormal expressions of GnIH induce precocious puberty and dysfunctional reproductive ability. Thus, agonists of GnIH have the therapeutic potential for treating central precocious puberty. On the other hand, antagonists of GnIH may be used therapeutically to address
Conclusions and future directions
GnIH is a newly identified hypothalamic neurohormone that effectively inhibits gonadotropin release and synthesis in birds. GnIH studies in the past 20 years have shown that GnIH sequence is greatly preserved among vertebrates including humans and GnIH exerts its activity as a critical neurohormone reducing reproduction. GnIH inhibits gonadotropin release and synthesis by acting via the GnIH receptor GPR147 on gonadotropes and GnRH neurons. The identification of GnIH has gave a great influence
Acknowledgments
This review is dedicated to Tsutsui’s beloved wife, Rieko Tsutsui. The works described in this review were supported at least partially by Grants-in-Aid for Scientific Research from the Ministry of Education, Science and Culture, Japan (18107002, 22132004, 22227002 and 20H03296 to KT). I am grateful to the following collaborators, J. C. Wingfield, G. E. Bentley, L. J. Kriegsfeld, P. J. Sharp, I. J. Clarke, R. P. Millar, S. A. Sower, Y. Tobari, Y. L. Son, M. Kiyohara, H. Yin, Y. Muneoka, K.
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