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Physiology, Gonadotropin Inhibitor


Physiology, Gonadotropin Inhibitor

Article Author:
Nicole Martinez
Article Author:
Kristina Novotny
Article Editor:
Khalid Alsayouri
Updated:
10/4/2020 3:52:58 PM
For CME on this topic:
Physiology, Gonadotropin Inhibitor CME
PubMed Link:
Physiology, Gonadotropin Inhibitor

Introduction

In the year 2000, an unidentified hypothalamic neuropeptide found in the quail bird was shown to inhibit gonadotropin hormone release, which researchers later termed gonadotropin-inhibitory hormone (GnIH). This was the first discovery of a hypothalamic neuropeptide that inhibits gonadotropin release in any vertebrate. It is a hormone considered to be one of the first avian RFamide peptides (a family of neuropeptides that contain a C terminal Arg-The-NH2 motif and are members of G protein-coupled receptor superfamily) that inhibits both reproductive behaviors and pituitary gonadotrope (cells in the anterior pituitary that synthesize LH and FSH) function in birds and mammals. GnIH neurons are localized in the dorsomedial nucleus and paraventricular nucleus of the hypothalamus in mammals. The GPR-147 receptor is a GnIH receptor that is expressed in both the gonadotropes and the gonadotropin-releasing hormone (GnRH) neurons. By binding to the GPR-147 receptor, GnIH exerts its inhibitory effects on both the gonadotropes and the GnRH neurons.[1][2][3]

Cellular

The gonadotropin-inhibitory hormone belongs to the family of RFamide related peptide (RFRP). All RFRPs carry an LPXRF-amide (X represents L or Q) motif at their C termini. GnIH receptor is a G protein-coupled receptor 147 (GPR147) which works through the Gαi protein to inhibit cAMP production by reducing intracellular cAMP levels and protein kinase A activity which translates into the inhibition of synthesis and release of the gonadotropin hormones FSH and LH.[4]

Development

In the year 2000, a group of researchers isolated a new hypothalamic neuropeptide which works by inhibiting gonadotropin release, originally identified in the hypothalamus of the Japanese quail bird (Coturnix japonica).[4] Researchers named this neuropeptide gonadotropin-inhibitory hormone (GnIH). Since then, further research has identified it in many vertebrates, mammals, and primates, including in the human hypothalamus.[5]

Organ Systems Involved

The concentration of GnIH is primarily in the dorsomedial and paraventricular nucleus of the hypothalamus. These GnIH neurons project to the median eminence of the hypothalamus to control the anterior pituitary function.[1] Apart from its effects on the hypothalamic-pituitary-gonadal axis to maintain normal reproductive ability, GnIH may also act directly on the gonads and other endocrine organs like the adrenal and thyroid glands to regulate reproduction.[5][6]

Function

The following are the functions of GnIH[3][7][8][9]:

  • Inhibits gonadotropin (FSH and LH) secretion from the anterior pituitary gland
  • Inhibits reproduction
  • Inhibition of gonadal development
  • Regulator of steroidogenesis and gametogenesis
  • Decreases LH pulse amplitude
  • Involved in pubertal delay due to imbalance in the hypothalamic-pituitary-adrenal axis (HPA), hypothalamic-pituitary-gonadal axis (HPG) and hypothalamic-pituitary-thyroid (HPT) axes
  • Mediates stress-induced reproductive dysfunction

Mechanism

GnIH binds and stimulates the GPR147 receptor to suppress adenylyl cyclase formation which ultimately suppresses gonadotrope function. The inhibitory effects of GnIH on reproduction is mainly accomplished at the hypothalamic-pituitary level. Gonadotropin-releasing hormone (GnRH) neurons and gonadotropes are major targets of GnIH action based on the interaction and distribution of the GnIH receptor.[10] Apart from being a negative regulator of reproductive behavior and inhibiting gonadotropins, GnIH also acts on kisspeptins (a group of peptide fragments encoded by the KISS1 gene in humans).[11] Kisspeptins are present in the lateral preoptic area and arcuate nucleus of the hypothalamus and play a role in initiating the preovulatory GnRH/luteinizing hormone (LH) surge, which is crucial for ovulation.[12] Kisspeptins and GnIH are two neuropeptides of the hypothalamus. They have an essential role in the regulation of the reproductive axis. Kisspeptins are stimulators of the reproductive axis, while GnIH is the inhibitory opponent.

Related Testing

Numerous studies have shown the presence of GnIH in several species including non-human primates, vertebrates, mammals, and humans.[13][6] Since its discovery, GnIH has advanced our knowledge of hypothalamic control and regulation of gonadotropes, reproductive physiology, and behavior, by acting on the brain and pituitary gland. Recent evidence indicates that GnIH may be useful in the treatment of endometriosis, uterine fibroids, precocious puberty, breast cancer, benign prostatic hyperplasia, and prostate cancer, and may function as a contraceptive.[5]

Pathophysiology

GnIH (aka RFamide-related peptide, RFRP) is a recently discovered hypothalamic neuropeptide that regulates reproduction by working directly on the anterior pituitary via the GnIH receptor to cause a decrease in the synthesis and release of LH and FSH thus regulating steroidogenesis and gametogenesis.[14]

Clinical Significance

LH and FSH Levels

GnIH induces a significant decrease in the expression of LH and FSH mRNA, as seen in in-vitro studies of quail birds and chickens. Both in vivo and in vitro studies in birds suggest that GnIH inhibits the synthesis and release of gonadotropins. Since LH normally stimulates synthesis and release of testosterone in Leydig cells, GnIH decreases plasma testosterone concentration during development, thus suppressing testicular growth. Furthermore, GnIH administration induces apoptosis in spermatocytes, spermatogonia, and Sertoli cells. The decrease in the survival of these cells leads to a significant decrease in the diameter of the seminiferous tubules.[14]

Thyroid Hormone-Mediated GnIH Regulation

Thyroid hormones are essential for body growth, brain development, metabolism, and proper function of the reproductive system. Therefore, children with thyroid disorders can experience a delay in pubertal development.

Researchers have conducted molecular studies in an attempt to understand the effect of thyroid hormone on puberty. GnIH neurons in the hypothalamus express thyroid-receptor alpha (TR-alpha) and thyroid-receptor beta (TR-beta). Furthermore, putative thyroid hormone-response elements (TREs) are present in the promoter region of the GnIH gene in mice. Studies have found that thyroid dysfunction alters GnIH expression in the hypothalamus by inducing chromatin modification in the GnIH promoter region in female mice through H3-acetylation and H3K9-trimethylation, which induces and represses expression of GnIH respectively. It is considered that an elevated level of thyroid hormone decreases GnIH expression, whereas a lower level of thyroid hormone increases GnIH expression. It also has been shown that elevated levels of thyrotropin-releasing hormone, a hormone released from the hypothalamus that stimulates the anterior pituitary to synthesize thyroid-stimulating hormone, in hypothyroidism induce hyperprolactinemia and alter GnRH pulsatile secretion, which leads to delayed puberty. In conclusion, the effects of abnormal thyroid hormone levels on puberty may be mediated by GnIH.

Glucocorticoid-Mediated GnIH Activation

Stress is known to inhibit reproductive function mediated via the hypothalamic GnIH system. Studies on birds and mammals have shown that the inhibitory effect of stress on reproductive function becomes mediated by high concentrations of circulating glucocorticoids acting via the GC receptor (GR) and GC response element (GRE) in the GnIH promoter region. The higher the level of stress, the more GC bound GR is recruited to GRE, thus upregulating GnIH expression. This data implies that GnIH may act as a gating system for the effects of stress on the reproductive axis at different times of the year.[10]


References

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[2] Tachibana T,Sato M,Takahashi H,Ukena K,Tsutsui K,Furuse M, Gonadotropin-inhibiting hormone stimulates feeding behavior in chicks. Brain research. 2005 Jul 19;     [PubMed PMID: 15979587]
[3] Tsutsui K,Bentley GE,Bedecarrats G,Osugi T,Ubuka T,Kriegsfeld LJ, Gonadotropin-inhibitory hormone (GnIH) and its control of central and peripheral reproductive function. Frontiers in neuroendocrinology. 2010 Jul;     [PubMed PMID: 20211640]
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[9] Kirby ED,Geraghty AC,Ubuka T,Bentley GE,Kaufer D, Stress increases putative gonadotropin inhibitory hormone and decreases luteinizing hormone in male rats. Proceedings of the National Academy of Sciences of the United States of America. 2009 Jul 7;     [PubMed PMID: 19541621]
[10] Son YL,Ubuka T,Tsutsui K, Molecular Mechanisms of Gonadotropin-Inhibitory Hormone (GnIH) Actions in Target Cells and Regulation of GnIH Expression. Frontiers in endocrinology. 2019;     [PubMed PMID: 30858828]
[11] Tng EL, Kisspeptin signalling and its roles in humans. Singapore medical journal. 2015 Dec;     [PubMed PMID: 26702158]
[12] Smith JT,Shahab M,Pereira A,Pau KY,Clarke IJ, Hypothalamic expression of KISS1 and gonadotropin inhibitory hormone genes during the menstrual cycle of a non-human primate. Biology of reproduction. 2010 Oct;     [PubMed PMID: 20574054]
[13] Iwasa T,Matsuzaki T,Yano K,Irahara M, Gonadotropin-Inhibitory Hormone Plays Roles in Stress-Induced Reproductive Dysfunction. Frontiers in endocrinology. 2017     [PubMed PMID: 28424661]
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