Gonadotropin-releasing hormone

Gonadotropin-releasing hormone (GnRH), also known as luteinizing hormone-releasing hormone (LHRH) and luliberin, as well as gonadorelin (INN), is a trophic is_associated_with::peptide is_associated_with::hormone responsible for the release of is_associated_with::follicle-stimulating hormone (FSH) and is_associated_with::luteinizing hormone (LH) from the is_associated_with::anterior pituitary. GnRH is synthesized and released from GnRH neurons within the is_associated_with::hypothalamus. The peptide belongs to is_associated_with::gonadotropin-releasing hormone family. It constitutes the initial step in the is_associated_with::hypothalamic–pituitary–gonadal axis.

Structure
The identity of GnRH was clarified by the 1977 is_associated_with::Nobel Laureates is_associated_with::Roger Guillemin and is_associated_with::Andrew V. Schally:

pyroGlu-His-Trp-Ser-Tyr-Gly-Leu-Arg-Pro-Gly-NH2

As is standard for is_associated_with::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 is_associated_with::proteinogenic amino acids, except for pyroGlu, which refers to is_associated_with::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 is_associated_with::carboxamide.

Synthesis
The is_associated_with::gene, GNRH1, for the GnRH precursor is located on is_associated_with::chromosome 8. In mammals, the linear decapeptide end-product is synthesized from a 92-is_associated_with::amino acid preis_associated_with::prohormone 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 is_associated_with::estrogen levels in the body.

Function
GnRH is secreted in the hypophysial portal bloodstream at the is_associated_with::median eminence. The portal blood carries the GnRH to the is_associated_with::pituitary gland, which contains the is_associated_with::gonadotrope cells, where GnRH activates its own receptor, is_associated_with::gonadotropin-releasing hormone receptor (GnRHR), a seven-transmembrane G-protein-coupled receptor that stimulates the beta isoform of is_associated_with::Phosphoinositide phospholipase C, which goes on to mobilize is_associated_with::calcium and is_associated_with::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 is_associated_with::proteolysis within a few minutes.

GnRH activity is very low during is_associated_with::childhood, and is activated at is_associated_with::puberty or is_associated_with::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., is_associated_with::hypothalamic suppression) or organic lesions (trauma, tumor). Elevated is_associated_with::prolactin levels decrease GnRH activity. In contrast, hyperinsulinemia increases pulse activity leading to disorderly LH and FSH activity, as seen in is_associated_with::polycystic ovary syndrome (PCOS). GnRH formation is congenitally absent in is_associated_with::Kallmann syndrome.

Control of FSH and LH
At the pituitary, GnRH stimulates the synthesis and secretion of the is_associated_with::gonadotropins, is_associated_with::follicle-stimulating hormone (FSH), and is_associated_with::luteinizing hormone (LH). These processes are controlled by the size and frequency of GnRH pulses, as well as by feedback from is_associated_with::androgens and is_associated_with::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, is_associated_with::ovulation, and is_associated_with::corpus luteum maintenance in the female, and is_associated_with::spermatogenesis in the male.

Neurohormone
GnRH is considered a is_associated_with::neurohormone, a is_associated_with::hormone produced in a specific neural cell and released at its neural terminal. A key area for production of GNRH is the is_associated_with::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 is_associated_with::dendrites. These bundle together so they receive shared synaptic input, a process that allows them to synchronize their GnRH release.

The GnRH neurons are regulated by many different afferent neurons, using several different transmitters (including is_associated_with::norepinephrine, is_associated_with::GABA, is_associated_with::glutamate). For instance, is_associated_with::dopamine appears to stimulate LH release (through GnRH) in estrogen-progesterone-primed females; dopamine may inhibit LH release in ovariectomized females. is_associated_with::Kisspeptin appears to be an important regulator of GnRH release. GnRH release can also be regulated by is_associated_with::estrogen. It has been reported that there are kisspeptin-producing neurons that also express estrogen receptor alpha.

Other organs
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 is_associated_with::placenta and in the is_associated_with::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. is_associated_with::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.

Medical uses
Natural GnRH was previously prescribed as gonadorelin hydrochloride (Factrel) and gonadorelin diacetate tetrahydrate (Cystorelin) for use in treating human diseases. Modifications of the is_associated_with::decapeptide structure of GnRH to increase half life have led to GnRH1 analog medications that either stimulate (GnRH1 agonists) or suppress (is_associated_with::GnRH antagonists) the gonadotropins. These synthetic analogs have replaced the natural hormone in clinical use.

Its analogue is_associated_with::Leuprolide is used for continuous infusion, to treat is_associated_with::Breast carcinoma, is_associated_with::endometriosis, is_associated_with::prostate carcinoma, and following research in the 1980s by researchers, including Dr. is_associated_with::Florence Comite of Yale University, it was used to treat is_associated_with::precocious puberty.

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 is_associated_with::white-crowned sparrows. In is_associated_with::mammals, GnRH injections facilitate sexual behavior of female display behaviors as shown with the is_associated_with::musk shrew’s (Suncus murinus) reduced latency in displaying rump presents and tail wagging towards males.

An elevation of GnRH raises males’ is_associated_with::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 is_associated_with::reproductive physiology and is_associated_with::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.

Veterinary use
The natural hormone is also used in veterinary medicine as a treatment for cattle with cystic is_associated_with::ovarian disease. The synthetic analogue is_associated_with::Deslorelin is used in veterinary reproductive control through a sustained-release implant.