Gonadotropin-inhibitory hormone (GnIH) is a
RFamide-related peptide The RFamide peptide family, or the RFamide-related peptides (RFRPs), are a family of neuropeptides. They are characterized by the possession of an Arg-Phe-NH2 motif at their C-terminal extremities.
Members of the family include:
* Neuropeptide FF ...
coded by the ''
NPVF
Neuropeptide VF precursor, also known as pro-FMRFamide-related neuropeptide VF or RFamide-related peptide precursor, is a propeptide that in mammals is encoded by the ''NPVF'' (or ''RPFP'') gene. The ''NPVF'' gene, and thus the propeptide, are e ...
'' gene in mammals.
Discovery
GnIH was discovered in 2000. It is an
RFamide peptide that significantly reduced luteinizing hormone release in Coturnix Japonica (
Japanese quail
The Japanese quail (''Coturnix japonica''), also known as the coturnix quail, is a species of Old World quail found in East Asia. First considered a subspecies of the common quail, it is now considered as a separate species. The Japanese quail ...
). This peptide emerged as the first tropic hormone known to inhibit gonadotropin secretion in the
hypothalamic-pituitary-gonadal axis of vertebrates.
Subsequent research identified GnIH peptide homologs in variety of mammals, including humans.
Structure
GnIH is a neurohormone classified as an RFamide (RFa) or RFamide-related peptide (RFRP), coded by the
NPVF
Neuropeptide VF precursor, also known as pro-FMRFamide-related neuropeptide VF or RFamide-related peptide precursor, is a propeptide that in mammals is encoded by the ''NPVF'' (or ''RPFP'') gene. The ''NPVF'' gene, and thus the propeptide, are e ...
gene in mammals. The complete amino acid sequence varies by species, but all RFa and RFRP peptides contain an arginine-phenylalanine-amine sequence at the
C-terminal
The C-terminus (also known as the carboxyl-terminus, carboxy-terminus, C-terminal tail, C-terminal end, or COOH-terminus) is the end of an amino acid chain (protein or polypeptide), terminated by a free carboxyl group (-COOH). When the protein is ...
. This is seen in both Coturnix Japonica GnIH RFa (Ser-Ile-Lys-Pro-Ser-Ala-Tyr-Leu-Pro-Leu-Arg-Phe-NH2), and the human homolog, RFRP-3 (Val-Pro-Asp-Leu-Pro-Glu-Arg-Phe-NH2).
Production
GnIH neurons reside primarily in the
dorsomedial nucleus of the
hypothalamus
The hypothalamus () is a part of the brain that contains a number of small nuclei with a variety of functions. One of the most important functions is to link the nervous system to the endocrine system via the pituitary gland. The hypothalamu ...
(humans and rodents) and the
paraventricular nucleus
The paraventricular nucleus (PVN, PVA, or PVH) is a nucleus in the hypothalamus. Anatomically, it is adjacent to the third ventricle and many of its neurons project to the posterior pituitary. These projecting neurons secrete oxytocin and a smaller ...
of the hypothalamus (avian species). Some GnIH neuron terminals in both mammalian and avian species project to the
median eminence
The median eminence, part of the inferior boundary of the hypothalamus in the brain, is attached to the infundibulum. The median eminence is a small swelling on the tuber cinereum, posterior to and atop the pituitary stalk; it lies in the area rou ...
.
GnIH and GnRH (gonadotropin releasing hormone) neurons exist in close proximity in the hypothalamus, which may enable the direct inhibition of GnRH neurons by GnIH.
GnIH enters the bloodstream via the hypothalamo-
hypophyseal portal system
The hypophyseal portal system is a system of blood vessels in the microcirculation at the base of the brain, connecting the hypothalamus with the anterior pituitary. Its main function is to quickly transport and exchange hormones between the hypo ...
, the vascular network supplying both the hypothalamus and the
pituitary
In vertebrate anatomy, the pituitary gland, or hypophysis, is an endocrine gland, about the size of a chickpea and weighing, on average, in humans. It is a protrusion off the bottom of the hypothalamus at the base of the brain. The hypoph ...
.
GnIH and GnIH receptor (GnIH-R) mRNA is expressed in the hypothalamus, pituitary, and
ovaries
The ovary is an organ in the female reproductive system that produces an ovum. When released, this travels down the fallopian tube into the uterus, where it may become fertilized by a sperm. There is an ovary () found on each side of the body. T ...
.
GnIH expression is highest during
proestrus and lowest during
estrus
The estrous cycle (, originally ) is the set of recurring physiological changes that are induced by reproductive hormones in most mammalian therian females. Estrous cycles start after sexual maturity in females and are interrupted by anestrous ...
, suggesting the
estrus cycle
The estrous cycle (, originally ) is the set of recurring physiological changes that are induced by reproductive hormones in most mammalian therian females. Estrous cycles start after sexual maturity in females and are interrupted by anestrous p ...
influences release of the hormone. Furthermore, GnIH neuronal cell counts in multiple vertebrates fluctuate with an organism’s parental status.
GnIH cell count may also vary with
breeding season in some species. For instance, European starlings (
Sturnus vulgaris
The common starling or European starling (''Sturnus vulgaris''), also known simply as the starling in Great Britain and Ireland, is a medium-sized passerine bird in the starling family, Sturnidae. It is about long and has glossy black plumage ...
) with greater reproductive success exhibited higher quantities of GnIH-producing cells than did those that were less successful, but this effect did not appear until mid-breeding season.
Receptor action
GnIH binds to the Gαi protein coupled receptor
GPR147 to suppress
adenylyl cyclase
Adenylate cyclase (EC 4.6.1.1, also commonly known as adenyl cyclase and adenylyl cyclase, abbreviated AC) is an enzyme with systematic name ATP diphosphate-lyase (cyclizing; 3′,5′-cyclic-AMP-forming). It catalyzes the following reaction:
:A ...
formation of
cAMP
Camp may refer to:
Outdoor accommodation and recreation
* Campsite or campground, a recreational outdoor sleeping and eating site
* a temporary settlement for nomads
* Camp, a term used in New England, Northern Ontario and New Brunswick to descri ...
and inhibit
protein kinase
A protein kinase is a kinase which selectively modifies other proteins by covalently adding phosphates to them (phosphorylation) as opposed to kinases which modify lipids, carbohydrates, or other molecules. Phosphorylation usually results in a fu ...
cascades affecting
gene expression. GnIH inhibits the same signaling pathway that
GnRH
Gonadotropin-releasing hormone (GnRH) is a releasing hormone responsible for the release of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) from the anterior pituitary. GnRH is a tropic peptide hormone synthesized and releas ...
activates to promote
follicle stimulating hormone
Follicle-stimulating hormone (FSH) is a gonadotropin, a glycoprotein polypeptide hormone. FSH is synthesized and secreted by the gonadotropic cells of the anterior pituitary gland and regulates the development, growth, pubertal maturation, an ...
(FSH) and
luteinizing hormone
Luteinizing hormone (LH, also known as luteinising hormone, lutropin and sometimes lutrophin) is a hormone produced by gonadotropic cells in the anterior pituitary gland. The production of LH is regulated by gonadotropin-releasing hormone (GnRH) ...
(LH) expression. The compound
RF9 is a known GPR147
receptor antagonist.
Effects and physiological function
GnIH-R expression in the pituitary and other brain regions implies GnIH acts directly on the pituitary to downregulate
gonadotropin
Gonadotropins are glycoprotein hormones secreted by gonadotropic cells of the anterior pituitary of vertebrates. This family includes the mammalian hormones follicle-stimulating hormone (FSH) and luteinizing hormone (LH), the placental/ chorioni ...
production, impacting reproductive behaviors.
This neurohormone also acts on the hypothalamus to inhibit the expression of GnRH, which may further inhibit gonadotropin secretion, and
kisspeptin
Kisspeptins (including kisspeptin-54 (KP-54), formerly known as metastin) are proteins encoded by the ''KISS1'' gene in humans. Kisspeptins are ligands of the G-protein coupled receptor, GPR54. ''Kiss1'' was originally identified as a human me ...
, which may inhibit kisspeptin-mediated stimulation of GnRH neurons prior to the preovulatory hormonal surge. GnIH also spurs the production of cytochrome P450
aromatase
Aromatase (), also called estrogen synthetase or estrogen synthase, is an enzyme responsible for a key step in the biosynthesis of estrogens. It is CYP19A1, a member of the cytochrome P450 superfamily, which are monooxygenases that catalyze many ...
, promoting the synthesis of neuroestrogen in the brains of quails and reducing aggressivity in reproductive behaviors.
In male vertebrates, GnIH reduces
testis
A testicle or testis (plural testes) is the male reproductive gland or gonad in all bilaterians, including humans. It is homologous to the female ovary. The functions of the testes are to produce both sperm and androgens, primarily testostero ...
size, lowers
testosterone
Testosterone is the primary sex hormone and anabolic steroid in males. In humans, testosterone plays a key role in the development of male reproductive tissues such as testes and prostate, as well as promoting secondary sexual characteristi ...
secretion, and increases the incidence of
apoptosis in
germ cells
Germ or germs may refer to:
Science
* Germ (microorganism), an informal word for a pathogen
* Germ cell, cell that gives rise to the gametes of an organism that reproduces sexually
* Germ layer, a primary layer of cells that forms during embryo ...
and
Sertoli cells
Sertoli cells are a type of sustentacular "nurse" cell found in human testes which contribute to the process of spermatogenesis (the production of sperm) as a structural component of the seminiferous tubules. They are activated by follicle-stimula ...
of the
seminiferous tubules
Seminiferous tubules are located within the testes, and are the specific location of meiosis, and the subsequent creation of male gametes, namely spermatozoa. Structure
The epithelium of the tubule consists of a type of sustentacular cells known ...
.
These gonadal changes, in addition to GnIH and GnIH-R mRNA expression in the seminiferous tubules, Sertoli cells, and
spermatogonia
A spermatogonium (plural: ''spermatogonia'') is an undifferentiated male germ cell. Spermatogonia undergo spermatogenesis to form mature spermatozoa in the seminiferous tubules of the testis.
There are three subtypes of spermatogonia in humans:
...
, implicate function in
spermatogenesis. In female vertebrates, high doses of GnIH increases ovarian mass and produce
follicle irregularities, such as
vacuole
A vacuole () is a membrane-bound organelle which is present in plant and fungal cells and some protist, animal, and bacterial cells. Vacuoles are essentially enclosed compartments which are filled with water containing inorganic and organic m ...
formation in nuclei and distorted morphology. Ovarian changes in response to GnIH administration, as well as GnIH/GnIH-R mRNA expression in
granulosa cells and
luteal cells in different stages of the estrus cycle, implicate function in development of follicles and
atresia
Atresia is a condition in which an orifice or passage in the body is (usually abnormally) closed or absent.
Examples of atresia include:
*Aural atresia, a congenital deformity where the ear canal is underdeveloped.
* Biliary atresia, a condition i ...
.
Additional biological roles
Stress-induced
adrenal
The adrenal glands (also known as suprarenal glands) are endocrine glands that produce a variety of hormones including adrenaline and the steroids aldosterone and cortisol. They are found above the kidneys. Each gland has an outer cortex whic ...
hormone increase may upregulate GnIH release, as some GnIH neurons have adrenal
glucocorticoid
Glucocorticoids (or, less commonly, glucocorticosteroids) are a class of corticosteroids, which are a class of steroid hormones. Glucocorticoids are corticosteroids that bind to the glucocorticoid receptor that is present in almost every verteb ...
receptors. GnIH may therefore mediate interactions between the HPG and HPA (
hypothalamic-pituitary-adrenal) axes and play a role in stress-related
infertility. GnIH neurons of the paraventricular nucleus in the hypothalamus also express
melatonin receptors. Because melatonin secretion is modulated by environmental light patterns, melatonin influence on GnIH production may enable
photoperiodic
A circadian rhythm (), or circadian cycle, is a natural, internal process that regulates the sleep–wake cycle and repeats roughly every 24 hours. It can refer to any process that originates within an organism (i.e., endogenous
Endogenous subs ...
regulation of reproduction in seasonally breeding birds, rodents, and sheep.
GnIH increases food consumption, implying a role in
appetite. This finding is consistent with the location of most GnIH neurons, as the dorsomedial nucleus of the hypothalamus is involved in appetite regulation. GnIH may allow the energy reserves of an organism to modulate reproduction.
Higher levels of
thyroid hormone suppress GnIH expression, and lower levels of thyroid hormone are associated with higher GnIH levels. The inactivation of GnIH expression prevents
delayed puberty
Delayed puberty is when a person lacks or has incomplete development of specific sexual characteristics past the usual age of onset of puberty. The person may have no physical or hormonal signs that puberty has begun. In the United States, girls ...
caused by
hypothyroidism, demonstrating that GnIH mediates interactions between the HPG and HPT (hypothalamic-pituitary-thyroid) axes. Furthermore, thyroid hormone may function in a pathway for photoperiodic regulation of reproduction involving GnIH and energy status. Melatonin modulates
thyroid-stimulating hormone
Thyroid-stimulating hormone (also known as thyrotropin, thyrotropic hormone, or abbreviated TSH) is a pituitary hormone that stimulates the thyroid gland to produce thyroxine (T4), and then triiodothyronine (T3) which stimulates the metabolism ...
(TSH) production in the anterior pituitary, and TSH promotes thyroid hormone production. Thyroid hormone production influences
metabolism
Metabolism (, from el, μεταβολή ''metabolē'', "change") is the set of life-sustaining chemical reactions in organisms. The three main functions of metabolism are: the conversion of the energy in food to energy available to run c ...
and GnIH production, both of which impact reproduction.
References
{{reflist
Hormones