Abstract It is known that hypothyroidism delays puberty in mammals. Interaction between the hypothalamo-pituitary-thyroid (HPT) and hypothalamo-pituitary-gonadal (HPG) axes may be important processes in delayed puberty. Gonadotropin-inhibitory hormone (GnIH) is a newly discovered hypothalamic neuropeptide that inhibits gonadotropin synthesis and release in quail. It now appears that GnIH is conserved across various mammals and primates, including humans, and inhibits reproduction. We have further demonstrated that GnIH is involved in pubertal delay induced by thyroid dysfunction in female mice. Hypothyroidism delays pubertal onset with the increase in hypothalamic GnIH expression and the decrease in circulating gonadotropin and estradiol levels. Thyroid status regulates GnIH expression by epigenetic modification of the GnIH promoter region. Furthermore, knockout of GnIH gene abolishes the effect of hypothyroidism on delayed pubertal onset. Accordingly, it is considered that GnIH is a mediator of pubertal disorder induced by thyroid dysfunction. This is a novel function of GnIH that interacts between the HPT-HPG axes in pubertal onset delay. This mini-review summarizes the structure, expression, and function of GnIH and highlights the action of GnIH in pubertal disorder induced by thyroid dysfunction. Thyroid hormones [THs; thyroxine and triiodothyronine (T3)] are important regulators of somatic growth, metabolism, brain development, and other vital processes in developing and adult mammals (1–3). THs also facilitate proper development and function of the reproductive system (4, 5). Particularly, the participation of THs in pubertal development has been suggested by the increase in the conversion of thyroxine to bioactive T3 during pubertal onset (6). Therefore, children with hypothyroidism generally have delayed pubertal development (7–9). From a neuroendocrine perspective, pubertal process is accomplished by the activation of the gonadotropin-releasing hormone (GnRH) neural network, which means that the mature pattern of GnRH secretion in the hypothalamus activates the entire reproductive system (10). There are several reports that speculate how thyroid disorders induce abnormal puberty based on interaction between the two neuroendocrine systems [i.e., hypothalamo-pituitary-thyroid (HPT) axis and hypothalamo-pituitary-gonadal (HPG) axis] (11–13). However, the mechanism of TH action on pubertal onset is still unclear, although some mediators involved in the HPT-HPG interaction have been suggested in mammals (11–13). In addition, conflicting results regarding the effect of abnormal thyroid status on reproductive development have been obtained in mammals (14, 15). Gonadotropin-inhibitory hormone (GnIH) is a newly discovered hypothalamic neuropeptide that actively inhibits gonadotropin synthesis and release, which was first identified in quail (16). After the discovery of GnIH (16), it has been demonstrated that GnIH is conserved across various vertebrates, such as mammals and primates including humans [(17–19); for review, see (20–23)]. GnIH is also known as RFamide-related peptide (RFRP) in mammals and primates [for review, see (20–23)]. The role of GnIH as a negative regulator of reproduction by inhibiting gonadotropin secretion has been demonstrated not only in birds but also in mammals and primates [(17–19); for review, see (20–23)]. Inhibitory action of GnIH on reproduction is mainly accomplished at the hypothalamo-pituitary level [for review, see (20–23)]. In most mammalian species studied, cell bodies of GnIH neurons are located in the dorsomedial hypothalamic area (24–26), and their fibers contact with GnRH neurons that express GnIH receptors (GPR147 and GPR74) (18, 19, 27, 28). Although GPR147 and GPR74 are paralogous, GnIH has a higher affinity for GPR147, and GPR147 is considered to be the primary receptor for GnIH [for review, see (20–23)]. Direct inhibitory actions of GnIH on GnRH neurons in their neuronal activity and firing rate as well as GnRH release have been demonstrated in mammals (29–31). In contrast to GnIH, the product of Kiss1 gene, kisspeptin, is a potent stimulator of the hypothalamo-pituitary system to control puberty onset and normal reproductive performance in mammals (32). GnIH may also act as an inhibitory factor on kisspeptin neurons because a subset of kisspeptin neurons expresses GnIH receptors and receives GnIH fiber contact in mammals (33). In addition to the action of GnIH on GnRH and kisspeptin neurons in the hypothalamus, GnIH neurons also project to the median eminence (ME) to regulate anterior pituitary function via GnIH receptor that is expressed in gonadotropes (18, 19, 34). GnIH decreases secretion of pituitary gonadotropins, luteinizing hormone (LH), and follicle-stimulating hormone (FSH) in many mammalian species (27, 35–37). Thus, it is considered that GnIH is a key regulator of the HPG axis. Importantly, both GnIH expression and its neuronal activation decrease markedly in the early prepubertal stage in the hypothalamus of female mice (38, 39), when the pulsatile GnRH secretion is increased after a quiescent period during infancy. Accordingly, the decrease in GnIH expression in this period may be important to initiate puberty under normal physiological conditions. Based on these findings as a background, our recent studies focusing on the timing of pubertal onset have demonstrated that GnIH is involved in reproductive dysfunction induced by abnormal thyroid status (Fig. 1). This mini-review summarizes the discovery of GnIH and how GnIH studies advanced our understanding of reproductive neuroendocrinology and then highlights the involvement of GnIH in pubertal disorder induced by thyroid dysfunction. Figure 1. View largeDownload slide Interactions among the hypothalamo-pituitary-adrenal (HPA), HPT, and HPG axes by glucocorticoid (GC), TH, and GnIH. Interaction between the HPA axis and the HPG axis mediated by GC and GnIH has been demonstrated (40, 41). Stress increases the expression of GnIH, and GC increases GnIH expression in birds and mammals. GnIH neurons express GR. Thus, stress reduces gonadotropin secretion through the increase in GnIH expression in mammals and birds. In contrast, although the interaction between the HPT axis and HPG axis has been suggested (11–13), the mechanisms of TH action on pubertal onset are still unclear in mammals. Our recent study (42) indicated that TH-mediated HPG regulation may be initiated by changes in the expression of GnIH, which acts at the most upstream level of the HPG axis by inhibiting the activity of GnRH neurons to reduce circulating levels of gonadotropins (LH and FSH) and gonadal sex steroids. Importantly, high concentrations of TH decrease GnIH expression, whereas a lower level of TH increases GnIH expression. Further, the increased GnIH expression induced by hypothyroidism may delay pubertal onset (42). See text for details. ACTH, adrenocorticotropic hormone; CRH, corticotropin-releasing hormone; TRH, thyrotropin-releasing hormone. Figure 1. View largeDownload slide Interactions among the hypothalamo-pituitary-adrenal (HPA), HPT, and HPG axes by glucocorticoid (GC), TH, and GnIH. Interaction between the HPA axis and the HPG axis mediated by GC and GnIH has been demonstrated (40, 41). Stress increases the expression of GnIH, and GC increases GnIH expression in birds and mammals. GnIH neurons express GR. Thus, stress reduces gonadotropin secretion through the increase in GnIH expression in mammals and birds. In contrast, although the interaction between the HPT axis and HPG axis has been suggested (11–13), the mechanisms of TH action on pubertal onset are still unclear in mammals. Our recent study (42) indicated that TH-mediated HPG regulation may be initiated by changes in the expression of GnIH, which acts at the most upstream level of the HPG axis by inhibiting the activity of GnRH neurons to reduce circulating levels of gonadotropins (LH and FSH) and gonadal sex steroids. Importantly, high concentrations of TH decrease GnIH expression, whereas a lower level of TH increases GnIH expression. Further, the increased GnIH expression induced by hypothyroidism may delay pubertal onset (42). See text for details. ACTH, adrenocorticotropic hormone; CRH, corticotropin-releasing hormone; TRH, thyrotropin-releasing hormone. Discovery of GnIH Based on the hypothesis of Harris (43), who proposed that hypothalamic neurons secrete neurohormones from the ME into the hypophysial portal system to control the secretion of anterior pituitary hormones, teams led by Guillemin or Schally independently discovered several important neurohormones, including thyrotropin-releasing hormone (44, 45), GnRH (46, 47), and growth hormone–inhibiting hormone (somatostatin) (48), in the brain of mammals, and they were awarded a Nobel Prize in 1977 for the discoveries of these neurohormones. GnRH, a hypothalamic neuropeptide stimulating the release of LH and FSH from gonadotropes in the anterior pituitary, was discovered in mammals in the beginning of the 1970s (46, 47). Subsequently, several GnRHs have also been identified in other vertebrates (49–52). Based on extensive GnRH studies, it was believed that GnRH is the only hypothalamic neuropeptide regulating gonadotropin release in mammals and other vertebrates. In 2000, however, Tsutsui et al. (16) discovered a novel hypothalamic neuropeptide that actively inhibits gonadotropin release in quail and termed it GnIH. Subsequent GnIH studies over the past decade and a half have demonstrated that GnIH is highly conserved among vertebrates, from agnathans to humans, acting as a key factor regulating reproduction [for reviews, see (20–23, 53)]. Recent studies by Tsutsui’s group (54, 55) have further demonstrated that GnIH has several important functions beyond the regulation of reproduction. Based on 15 years of GnIH research, it is now generally accepted that GnIH acts on the anterior pituitary and the brain to regulate reproductive physiology and behavior [for reviews, see (20–23, 53)]. GnIH Structure and Function GnIH is a novel hypothalamic RFamide peptide Ser-Ile-Lys-Pro-Ser-Ala-Tyr-Leu-Pro-Leu-Arg-Phe-NH2 (SIKPSAYLPLRFamide), which was discovered in quail (16). This novel neuropeptide actively inhibited gonadotropin release from the anterior pituitary of quail, providing the first hypothalamic neuropeptide inhibiting gonadotropin release in any vertebrate (16). Therefore, this neuropeptide was named GnIH (16). In birds, cell bodies and terminals for GnIH neurons are located in the paraventricular nucleus (PVN) and ME, respectively (16). The C-terminal structure of GnIH is identical to chicken LPLRFamide, the first reported RFamide peptide in vertebrates (56), which is considered to be a degraded C-terminal fragment of GnIH [for reviews, see (20, 21)]. After the discovery of GnIH in quail (16), a cDNA encoding the precursor for GnIH was cloned in quail (57) and other avian species [for reviews, see (20, 21)]. The GnIH precursor encompasses one GnIH and two GnIH gene-related peptides (GnIH-RP-1 and GnIH-RP-2) that possess a common C-terminal LPXRFamide (X = L or Q) motif in all avian species studied [for reviews, see (20, 21)]. Subsequently, GnIH was identified as a mature peptide in the brain of starlings (58) and zebra finches (59) and GnIH-RP-2 was also identified in quail (57). GnIH is a key factor inhibiting avian reproduction because GnIH inhibits gonadotropin release in most avian species studied [for reviews, see (20, 21)]. GnIH treatment decreases plasma LH concentrations and the expressions of common α, LHβ, and FSHβ subunit mRNAs in mature birds (60). GnIH treatment further induces testicular apoptosis, and decreases the size of seminiferous tubules in mature birds (60). In immature birds, GnIH treatment suppresses normal testicular growth (60). Based on extensive avian studies [for reviews, see (20, 21)], GnIH appears to inhibit gonadal development and maintenance by decreasing gonadotropin synthesis and release in birds. To clarify the conservation of GnIH peptide in other vertebrates, Tsutsui and colleagues further identified GnIH in the brain of various mammals and primates including humans [for reviews, see (20–23, 53)]. All the identified mammalian and primate GnIH peptides also possess a common C-terminal LPXRFamide (X = L or Q) motif [for reviews, see (20–23, 53)]. Thus, mammalian and primate GnIH peptides are LPXRFamide peptides, like avian GnIH and GnIH-RPs. Mammalian and primate GnIH peptides are also known as RFRP-1 and -3 from their C-terminal structures [for reviews, see (20, 21)]. Subsequent studies have demonstrated that mammalian GnIHs inhibit gonadotropin synthesis and release and GnRH-elicited gonadotropin secretion in mammals and primates like in birds [for reviews, see (20–23, 53)]. For example, avian GnIH and hamster GnIHs (RFRP-1 and -3) inhibit LH release in Syrian hamsters (25) and Siberian hamsters (61). Similarly, rat GnIH (RFRP-3) inhibits LH release (35) and GnRH-elicited gonadotropin release (28, 36) in rats. In addition, mammalian GnIH (RFRP-3) inhibits GnRH-elicited gonadotropin secretion and reduces LH pulse amplitude in sheep (34, 62) and cows (63). Furthermore, human/ovine GnIH (RFRP-3) inhibits GnRH-elicited gonadotropin secretion in ovine (19, 34). These studies indicate that not only avian GnIH but also mammalian and primate GnIH inhibit gonadotropin synthesis and release and GnRH-elicited gonadotropin secretion [for reviews, see (20–23, 53)]. In addition to the central actions of GnIH in mammals and birds, direct regulation of gonadal activity by gonadal GnIH is becoming clear [for reviews, see (20–23, 53)]. In mammals and birds, both GnIH and GnIH receptor are expressed in steroidogenic cells and germ cells in the testis and ovary [for reviews, see (20–23, 53)]. Recent observations indicate that GnIH may act directly on gonads by autocrine or paracrine manners to suppress gonadal steroid production and germ cell differentiation and maturation [for reviews, see (20–23, 53)]. Hormonal and Neurochemical Regulation of GnIH Expression Tsutsui and colleagues further analyzed the regulatory mechanisms of GnIH expression in the brain to understand the physiological role of GnIH in reproduction. It is known that stress can reduce reproduction in vertebrates (64). Kirby et al. (40) reported that immobilization stress increases the expression of GnIH in the dorsomedial hypothalamic area associated with inhibition of the HPG axis in rats. The increase in GnIH expression under stress is abolished by adrenalectomy and GnIH neurons express glucocorticoid receptor (GR) (40). Accordingly, GnIH is considered to be an important integrator of stress-induced suppression of reproductive function (Fig. 1). Recently, Son et al. (41) also found that in quail GR is expressed in GnIH neurons in the PVN, and the treatment with corticosterone (the major glucocorticoid in birds and rodents) increases GnIH expression (41). Furthermore, GR is expressed in rHypoE-23, a GnIH-expressing neuronal cell line derived from rat hypothalamus. Corticosterone treatment also increases GnIH expression in rHypoE-23 (41). It thus appears that stress reduces gonadotropin secretion through the increase in GnIH expression in mammals and birds (Fig. 1). Reproduction of photoperiodic mammals and birds depends on the annual changes in nocturnal secretion of melatonin (65–68). Ubuka et al. (70) therefore investigated whether melatonin is involved in the regulation of GnIH expression in quail, a highly photoperiodic avian species. The pineal gland and eyes are known to be the major sources of melatonin in quail (71). Ubuka et al. (70) first found that melatonin removal by pinealectomy, combined with orbital enucleation, decreases the expression of GnIH in the quail brain (70). By contrast, melatonin administration to pinealectomy combined with orbital enucleation in birds increases GnIH expression in the quail brain (70). Chowdhury et al. (72) further found that melatonin treatment increases not only GnIH expression but also GnIH release in quail. Importantly, GnIH release increases under short-day (SD) photoperiods, when nocturnal secretion of melatonin increases (72). Interestingly, GnIH neurons in the PVN express Mel1c, a melatonin receptor subtype, in quail (70). It thus appears that melatonin derived from the pineal gland and eyes acts directly on GnIH neurons via its receptor to increase GnIH expression and release in birds (23, 70, 72). In contrast to birds, melatonin reduces GnIH expression in hamsters, a photoperiodic mammalian species (61, 73, 74). GnIH expression is reduced in sexually quiescent hamsters exposed to SD photoperiods, compared with sexually active animals under long-day photoperiods (61, 73). These photoperiodic differences in GnIH expression are abolished by melatonin removal and melatonin administration to long-day hamsters reduce GnIH expression to SD levels (61, 73). There are also reports indicating that GnIH expression is controlled by melatonin in sheep (75, 76) and rats (77). Taken together, GnIH expression is photoperiodically modulated via a melatonin-dependent process in mammals and birds, although there is some species difference in the regulation of GnIH expression by melatonin [for reviews, see (20–23, 53)]. Because reproductive physiology and behavior are variable, both within and between individuals, social interaction may be an important environmental cue to influence GnIH expression in the brain. Delville et al. (78) and Cornil et al. (79) reported that the presence of a female bird rapidly decreases plasma testosterone (T) concentrations in male quail. Tsutsui and colleagues therefore investigated the neurochemical mechanism that alters reproductive physiology by social interaction. Tobari et al. (54) first found that in male quail, the release of norepinephrine (NE) increases rapidly when viewing a female conspecific. GnIH expression also increases in the PVN of male quail, with the associated decrease in circulating LH levels, when males view a female (54). Subsequently, Tobari et al. (54) found that NE application to male quail stimulates GnIH release. Importantly, GnIH neurons express α2A-adrenergic receptor and are innervated by noradrenergic fibers in male quail (54). Thus, female presence increases NE release in the PVN and stimulates GnIH release, resulting in the decrease in circulating LH and T levels in male quail (54). GnIH’s Role in Hypothyroidism-Induced Delayed Puberty It is known that thyroid disorder is associated with abnormal pubertal development. However, the mechanism of TH action on pubertal onset is still unclear, although interactions between the HPT and HPG axes have been suggested (11–13) (Fig. 1). We hypothesized that TH-mediated HPG regulation may be initiated by the change in the expression of GnIH, which acts at the most upstream level of the HPG axis by inhibiting the activity of GnRH neurons to reduce gonadotropin secretion from gonadotropes [for reviews, see (20–23, 53)] (Fig. 1). To clarify the possible role of GnIH as a novel mediator between the HPT and HPG axes, Kiyohara et al. (42) recently examined the effect of abnormal thyroid status on pubertal onset in female mice and assessed the changes in the HPG axis. Female mice with hypothyroidism, which is induced by the long-term treatment with propylthiouracil (PTU), show marked delay in pubertal onset (42). In hypothyroid female mice, hypothalamic GnIH mRNA expression is increased (42). In addition, circulating LH and E2 levels are decreased in hypothyroid status concomitant with the increase in hypothalamic GnIH mRNA expression (42). Thus, it is considered that hypothyroidism may delay pubertal onset of female mice by the increase in GnIH expression in the hypothalamus and the decrease in circulating LH and E2 levels (42) (Fig. 1). To further clarify the involvement of GnIH in pubertal disorder induced by hypothyroidism, Kiyohara et al. (42) induced hypothyroidism into GnIH-knockout (KO) female mice. GnIH-KO mice were generated by deletion of the exon 2 in GnIH precursor gene encoding GnIH (42 and unpublished data). Administration of PTU to GnIH-KO mice also effectively induces hypothyroidism with the reduced levels of circulating T3 (42). Importantly, hypothyroidism-induced delayed puberty as observed in wild-type female mice was not seen in PTU-administered GnIH-KO female mice (42). Thus, GnIH may mediate hypothyroid status on delayed pubertal onset (Fig. 1). To understand the regulatory mechanism of GnIH action on hypothyroidism-induced pubertal delay, molecular studies were further conducted as follows: first, it was shown that GnIH neurons in the hypothalamus express both TH receptors (TRα and TRβ) (42), suggesting that TRs may convey TH signals directly to GnIH neurons. Second, there are several putative TH-response elements within a 3-kb upstream region from the mouse GnIH open reading frame. Unexpectedly, both TRs cannot directly bind to these TH-response elements present in the GnIH promoter region in chromatin immunoprecipitation assays (42), implying that TH (T3) may act via nongenomic action by membrane TRs (80). However, H3 acetylation status, which is correlated with gene activation, is increased in hypothyroid female mice compared with control mice (42). It is therefore considered that thyroid status may regulate chromatin modification of the GnIH promoter region, resulting in the change in GnIH gene expression. Functional Significance of GnIH Action on Pubertal Disorder There are several reports indicating the influence of abnormal thyroid status on pubertal disorders involving the two neuroendocrine systems, the HPT axis and the HPG axis (11–13). Dittricha et al. (11) showed that the elevated levels of thyrotropin-releasing hormone in hypothyroidism induce hyperprolactinemia and alter GnRH pulsatile secretion, which lead to delayed LH response, resulting in delayed puberty. Other papers indicate that the increased thyrotropin levels activate gonadal function by stimulating FSH receptor in gonads, because the structure of FSH and thyrotropin receptors is similar, which is responsible for precocious puberty (12, 13). However, the mechanism underlying how TH acts on the HPG axis has not been fully elucidated, although these papers have suggested the presence of some mediators in HPT-HPG interaction (11–13). We found that thyroid dysfunction alters GnIH expression in the hypothalamus by changing chromatin modification of the GnIH promoter region in female mice (42). This is a novel function of GnIH as a mediator between the HPT and HPG axes (42) (Fig. 1). Importantly, female mice with hypothyroidism showed delayed pubertal onset with the increased GnIH expression. We confirmed that the effect of hypothyroidism on pubertal delay is mediated by GnIH, because puberty was not delayed in hypothyroidism-induced GnIH-KO female mice (42). Thus, GnIH may be the critical factor to mediate the effect of abnormal thyroid status on pubertal onset (Fig. 1). To obtain a firm conclusion, further detailed studies are needed. Conclusion GnIH is a newly discovered hypothalamic neuropeptide that actively inhibits gonadotropin synthesis and release. GnIH studies over the past decade and a half have demonstrated that GnIH serves as a key player regulating reproduction across vertebrates. Recent studies further indicate that GnIH is involved in pubertal disorder induced by thyroid dysfunction. This is a novel function of GnIH, mediating the interaction of the HPT-HPG axes in abnormal puberty. Abbreviations: FSH follicle-stimulating hormone GnIH gonadotropin-inhibitory hormone GnRH gonadotropin-releasing hormone GR glucocorticoid receptor HPG hypothalamo-pituitary-gonadal HPT hypothalamo-pituitary-thyroid KO knockout LH luteinizing hormone ME median eminence NE norepinephrine PTU propylthiouracil PVN paraventricular nucleus RFRP RFamide-related peptide SD short-day T3 triiodothyronine TH thyroid hormone. Acknowledgments This review is dedicated to K.T.’s beloved wife, Rieko Tsutsui. The authors thank Takayoshi Ubuka, Monash University, for valuable discussion and editing of this review. Financial Support: The works described in this review were supported in part by Grants-in-Aid for Scientific Research 22132004 (to K.T.) and 22227002 (to K.T.) and Grants-in-Aid for JSPS Research Fellows 2402082 (to Y.L.S.) and 15F15909 (to Y.L.S.) from the Ministry of Education, Science and Culture, Japan. Disclosure Summary: The authors have nothing to disclose. References 1. 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