Gonadotropin-releasing hormone: Difference between revisions
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==Overview== | ==Overview== | ||
'''Gonadotropin-releasing hormone''' ('''GnRH'''), also known as '''luteinizing hormone-releasing hormone''' ('''LHRH''') and '''luliberin''', is a [[trophic hormone|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_Neuron|GnRH neurons]] within the [[hypothalamus]]. The peptide belongs to [[gonadotropin-releasing hormone family]]. It constitutes the initial step in the [[hypothalamic–pituitary–gonadal axis]]. | '''Gonadotropin-releasing hormone''' ('''GnRH'''), also known as '''luteinizing hormone-releasing hormone''' ('''LHRH''') and '''luliberin''', is a [[trophic hormone|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_Neuron|GnRH neurons]] within the [[hypothalamus]]. The peptide belongs to [[gonadotropin-releasing hormone family]]. It constitutes the initial step in the [[hypothalamic–pituitary–gonadal axis]]. | ||
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== Function == | == Function == | ||
GnRH is secreted in the [[Hypophyseal portal system|hypophysial]] portal bloodstream at the [[median eminence]]. | GnRH is secreted in the [[Hypophyseal portal system|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 (biochemistry)|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. | ||
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, [[insulin|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]]. | 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, [[insulin|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]]. | ||
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=== Control of FSH and LH === | === 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). | 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. | 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. | 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. | ||
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=== Neurohormone === | === Neurohormone === | ||
GnRH is considered a [[neurohormone]], a [[hormone]] produced in a specific [[Neuron|neural cell]] and released at its [[Neuron#Anatomy and histology|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_Neuron|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 [[dendrite]]s. These bundle together so they receive shared [[Synapse|synaptic]] input, a process that allows them to synchronize their GnRH release. | GnRH is considered a [[neurohormone]], a [[hormone]] produced in a specific [[Neuron|neural cell]] and released at its [[Neuron#Anatomy and histology|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_Neuron|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 [[dendrite]]s. These bundle together so they receive shared [[Synapse|synaptic]] input, a process that allows them to synchronize their GnRH release. | ||
The [[GnRH_Neuron|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|estrogen receptor alpha]]. | |||
The [[GnRH_Neuron|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. | |||
=== Other organs === | === Other organs === | ||
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== Effects of behavior == | == Effects of behavior == | ||
GnRH production/release is one of the few confirmed examples of behavior influencing hormones, rather than the other way around. | 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_Neuron|GnRH neurons]]. Specifically, males that are more territorial have larger [[GnRH_Neuron|GnRH neurons]] than males that are less territorial males. Differences are also seen in females, with breeding females having smaller [[GnRH_Neuron|GnRH neurons]] than controls females. These examples suggest that GnRH is a socially regulated hormone. | ||
== Medical uses == | == Medical uses == | ||
{{main|gonadotropin-releasing hormone agonist}} | {{main|gonadotropin-releasing hormone agonist}} | ||
Natural GnRH was previously prescribed as gonadorelin hydrochloride (Factrel) | Natural GnRH was previously prescribed as gonadorelin hydrochloride (Factrel)for use in treating human diseases. Modifications of the [[decapeptide]] structure of GnRH to increase half life have led to [[GnRH analog|GnRH1 analog]] medications that either stimulate ([[GnRH agonist|GnRH1 agonist]]s) or suppress ([[GnRH antagonist]]s) the gonadotropins. These synthetic analogs have replaced the natural hormone in clinical use. | ||
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]]. | 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]]. | ||
== Animal sexual behavior == | == 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 sparrow]]s. | 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 sparrow]]s. 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. | |||
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_Neuron|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. | 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_Neuron|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 == | == Veterinary use == | ||
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The natural hormone is also used in veterinary medicine as a treatment for cattle with cystic [[ovarian disease]]. The synthetic analogue [[Deslorelin]] is used in veterinary reproductive control through a sustained-release implant. | The natural hormone is also used in veterinary medicine as a treatment for cattle with cystic [[ovarian disease]]. The synthetic analogue [[Deslorelin]] is used in veterinary reproductive control through a sustained-release implant. | ||
== References == | ==References== | ||
{{reflist| | {{reflist|2}} | ||
{{Hormones}} | {{Hormones}} | ||
{{Neuropeptides}} | {{Neuropeptides}} | ||
[[Category:Peptide hormones]] | [[Category:Peptide hormones]] | ||
[[Category:Sex hormones]] | [[Category:Sex hormones]] | ||
[[Category:Drug]] | [[Category:Drug]] | ||
Revision as of 13:59, 7 April 2015
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Overview
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.
Structure
The identity of GnRH was clarified by the 1977 Nobel Laureates Roger Guillemin and Andrew V. Schally:
pyroGlu-His-Trp-Ser-Tyr-Gly-Leu-Arg-Pro-Gly-NH2
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.
Synthesis
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.
Function
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.
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.
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.
Neurohormone
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. 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.
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 placenta and in the gonads. GnRH and GnRH receptors are also found in cancers of the breast, ovary, prostate, and endometrium.[1]
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.
Medical uses
Natural GnRH was previously prescribed as gonadorelin hydrochloride (Factrel)for use in treating human diseases. Modifications of the decapeptide structure of GnRH to increase half life have led to GnRH1 analog medications that either stimulate (GnRH1 agonists) or suppress (GnRH antagonists) the gonadotropins. These synthetic analogs have replaced the natural hormone in clinical use.
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.
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.
Veterinary use
The natural hormone is also used in veterinary medicine as a treatment for cattle with cystic ovarian disease. The synthetic analogue Deslorelin is used in veterinary reproductive control through a sustained-release implant.
References
- ↑ Schally AV (1999). "Luteinizing hormone-releasing hormone analogs: their impact on the control of tumorigenesis". Peptides. 20 (10): 1247–62. doi:10.1016/S0196-9781(99)00130-8. PMID 10573298.