|Gonadotropin-releasing hormone 1 (luteinizing-releasing hormone)|
from PDB 1YY1
|Symbols||; GNRH; GRH; HH12; LHRH; LNRH|
|RNA expression pattern|
|This article needs additional citations for verification. (January 2013)|
Gonadotropin-releasing hormone (GnRH), also known as luteinizing hormone-releasing hormone (LHRH) and luliberin, is a trophic peptide hormone responsible for the release of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) from the anterior pituitary. GnRH is synthesized and released from GnRH neurons within the hypothalamus. The peptide belongs to gonadotropin-releasing hormone family. It constitutes the initial step in the hypothalamic–pituitary–gonadal axis.
The gene, GNRH1, for the GnRH precursor is located on chromosome 8. In mammals, the linear decapeptide end-product is synthesized from a 92-amino acid preprohormone in the preoptic anterior hypothalamus. It is the target of various regulatory mechanisms of the hypothalamic–pituitary–gonadal axis, such as being inhibited by increased estrogen levels in the body.
As is standard for peptide representation, the sequence is given from amino terminus to carboxyl terminus; also standard is omission of the designation of chirality, with assumption that all amino acids are in their L- form. The abbreviations appearing are to standard proteinogenic amino acids, except for pyroGlu, which refers to pyroglutamic acid, a derivative of glutamic acid. The NH2 at the carboxyl terminus indicates that rather than terminating as a free carboxylate, it terminates as a carboxamide.
GnRH is considered a neurohormone, a hormone produced in a specific neural cell and released at its neural terminal. A key area for production of GNRH is the preoptic area of the hypothalamus, which contains most of the GnRH-secreting neurons. GnRH neurons originate in the nose and migrate into the brain, where they are scattered throughout the medial septum and hypothalamus and connected by very long >1-millimeter-long dendrites. These bundle together so they receive shared synaptic input, a process that allows them to synchronize their GnRH release.
GnRH is secreted in the hypophysial portal bloodstream at the median eminence. The portal blood carries the GnRH to the pituitary gland, which contains the gonadotrope cells, where GnRH activates its own receptor, gonadotropin-releasing hormone receptor (GnRHR), a seven-transmembrane G-protein-coupled receptor that stimulates the beta isoform of Phosphoinositide phospholipase C, which goes on to mobilize calcium and protein kinase C. This results in the activation of proteins involved in the synthesis and secretion of the gonadotropins LH and FSH. GnRH is degraded by proteolysis within a few minutes.
Control of FSH and LH
At the pituitary, GnRH stimulates the synthesis and secretion of the gonadotropins, follicle-stimulating hormone (FSH), and luteinizing hormone (LH). These processes are controlled by the size and frequency of GnRH pulses, as well as by feedback from androgens and estrogens. Low-frequency GnRH pulses lead to FSH release, whereas high-frequency GnRH pulses stimulate LH release.
There are differences in GnRH secretion between females and males. In males, GnRH is secreted in pulses at a constant frequency; however, in females, the frequency of the pulses varies during the menstrual cycle, and there is a large surge of GnRH just before ovulation.
GnRH secretion is pulsatile in all vertebrates [there is no evidence that this is correct -- the only empirical evidence to date is for a handful of mammals], and is necessary for correct reproductive function. Thus, a single hormone, GnRH1, controls a complex process of follicular growth, ovulation, and corpus luteum maintenance in the female, and spermatogenesis in the male.
GnRH activity is very low during childhood, and is activated at puberty or adolescence. During the reproductive years, pulse activity is critical for successful reproductive function as controlled by feedback loops. However, once a pregnancy is established, GnRH activity is not required. Pulsatile activity can be disrupted by hypothalamic-pituitary disease, either dysfunction (i.e., hypothalamic suppression) or organic lesions (trauma, tumor). Elevated prolactin levels decrease GnRH activity. In contrast, hyperinsulinemia increases pulse activity leading to disorderly LH and FSH activity, as seen in polycystic ovary syndrome (PCOS). GnRH formation is congenitally absent in Kallmann syndrome.
The GnRH neurons are regulated by many different afferent neurons, using several different transmitters (including norepinephrine, GABA, glutamate). For instance, dopamine appears to stimulate LH release (through GnRH) in estrogen-progesterone-primed females; dopamine may inhibit LH release in ovariectomized females. Kisspeptin appears to be an important regulator of GnRH release. GnRH release can also be regulated by estrogen. It has been reported that there are kisspeptin-producing neurons that also express estrogen receptor alpha.
GnRH is found in organs outside of the hypothalamus and pituitary, and its role in other life processes is poorly understood. For instance, there is likely to be a role for GnRH1 in the placenta and in the gonads. GnRH and GnRH receptors are also found in cancers of the breast, ovary, prostate, and endometrium.
Effects of behavior
GnRH production/release is one of the few confirmed examples of behavior influencing hormones, rather than the other way around. Cichlid fish that become socially dominant in turn experience an upregulation of GnRH secretion whereas cichlid fish that are socially subordinate have a down regulation of GnRH secretion. Besides secretion, the social environment as well as their behavior affects the size of GnRH neurons. Specifically, males that are more territorial have larger GnRH neurons than males that are less territorial males. Differences are also seen in females, with breeding females having smaller GnRH neurons than controls females. These examples suggest that GnRH is a socially regulated hormone.
Animal sexual behavior
GnRH activity influences a variety of sexual behaviors. Increased levels of GnRH facilitate sexual displays and behavior in females. GnRH injections enhance copulation solicitation (a type of courtship display) in white-crowned sparrows. In mammals, GnRH injections facilitate sexual behavior of female display behaviors as shown with the musk shrew’s (Suncus murinus) reduced latency in displaying rump presents and tail wagging towards males.
An elevation of GnRH raises males’ testosterone capacity beyond a male’s natural testosterone level. Injections of GnRH in male birds immediately after an aggressive territorial encounter results in higher testosterone levels than what is observed naturally during an aggressive territorial encounter.
A compromised GnRH system has aversive effects on reproductive physiology and maternal behavior. In comparison to female mice with a normal GnRH system, female mice with a 30% decrease in GnRH neurons are poor caregivers to their offspring. These mice are more likely to leave their pups scattered rather than grouped together, and will take significantly longer to retrieve their pups.
GnRH is available as gonadorelin hydrochloride (Factrel®) and gonadorelin diacetate tetrahydrate (Cystorelin®) for injectable use. It has a chemical composition and structure identical to the natural hormone, identified from porcine or ovine hypothalami. It is currently used for evaluating hypothalamic-pituitary gonadotropic function. Studies have described it being used via an infusion pump system to induce ovulation in patients with hypothalamic hypogonadism.
It is also used in veterinary medicine as a treatment for cattle with cystic ovarian disease.
Its analogue Leuprolide is used for continuous infusion, to treat Breast carcinoma, endometriosis, prostate carcinoma, and following research in the 1980s by researchers, including Dr. Florence Comite of Yale University, it was used to treat precocious puberty. The analogue Deslorelin is used in veterinary reproductive control through a sustained-release implant.
Agonists and antagonists
While GnRH has been synthesized and become available, its short half-life requires infusion pumps for its clinical use. Modifications of the decapeptide structure of GnRH have led to GnRH1 analog medications that either stimulate (GnRH1 agonists) or suppress (GnRH antagonists) the gonadotropins. It is important to note that, through downregulation, agonists are also able to exert a prolonged suppression effect.
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