| Discovery | In 1971, GnRH was first isolated from the porcineand ovine by Schally1 and Guillemin, respectively.In nonmammalian vertebrates, GnRH was isolatedfrom the chicken in 1982 and the salmon in 1983. Todate, 15 different isoforms of GnRHs have been identified in vertebrates. In nonvertebrate chordates, multiple GnRH-like peptides have been identified intunicates, first from Chelyosoma productum in 1996. |
| Structure | Vertebrate GnRH isoforms consist of 10 aa residueswith a pyroglutamic acid at the N-terminus and an amidated Gly at the C-terminus . Based on the primary structure, phylogenetic analysis, and synteny,multiple GnRH forms are classified into three paralogousgroups: GnRH1, GnRH2, and GnRH3.3, 4 The peptidesare bent with a β-turn around Gly6, and the N-terminaland C-terminal amino acid residues are important forbinding to the GnRH receptor (GnRH-R).5Primary structureThe primary structure of GnRH is highly conserved inthe N-terminus (positions 1–4) and in the C-terminus(positions 9–10). Position 8 is the most variable.
|
| Properties | Mr 1050–1250. GnRH is inactivated in 0.9M HCl at100°C for 60min, and is also inactivated by endopeptidases such as chymotrypsin and papain. mGnRHand cGnRH-I are soluble in water; cGnRH-II andsGnRH are insoluble in water but soluble in 10mMacetic acid. |
| Receptors | GnRH-R is a membrane-bound GPCR belonging to theClass A (rhodopsin-like) subfamily. Two major types ofGnRH-Rs—type I and type II—have been identified invertebrates.The type I GnRH-Rs, presentin mammals, coelacanth, and some cartilaginous fish,lack a C-terminal intracellular domain that is responsiblefor rapid desensitization, and show a strong preferencefor GnRH1. The type II GnRH-Rs, present in both mammalian and nonmammalian species, show a preferencefor GnRH2. The type II GnRH-Rs are further divided intotwo subtypes, IIa and IIb. In some mammals, includinghumans, the type II GnRH-R is a nonfunctional receptorencoded by a pseudogene. The human type I GnRH-Rconsists of 328 aa residues. |
| Clinical implications | Idiopathic hypogonadotropic hypogonadism (IHH) isa family of genetic disorders that is associated withdefects in the production and/or action of hypothalamicpeptide, which controls GnRH. As mentioned above,IHH with anosmia is referred to as KS. In addition, themost common cause of delayed puberty is a functionaldefect in the production of GnRH from thehypothalamus. |
| Synthesis and release | The regulation of GnRH secretion by internal and environmental factors such as growth, energy condition,light, photoperiod, temperature, and social status is critical for reproductive success. Regulatory mechanisms ofGnRH1 neurons involve many stimulatory and inhibitory factors including gonadal steroids, neuropeptides,and neurotransmitters (GABA, glutamate, norepinephrine). Kisspeptin stimulates GnRH1 secretion and haskey roles in the transmission of the negative and positivefeedback effects of gonadal steroids, the metabolic regulation, and the photoperiodic control of reproduction. Gonadotrophin-inhibitory hormone (GnIH) may inhibitgonadotropin secretion by decreasing the activity ofGnRH1 neurons. |
| Description | Gonadotropin-releasing hormone is a decapeptide that is produced in neurosecretorycells within the hypothalamus. GnRH stimulates the synthesis and release of luteinizing hormone (LH) and folliclestimulating hormone (FSH) from the anterior pituitaryand also controls reproductive behavior, thus serving as acentral regulator of reproduction in vertebrates. It is usednot only as a fertility drug but also as an antifertility drug. |
| Indications | GnRH (gonadorelin, luteinizing hormone–releasinghormone) is a decapeptide that stimulates productionof LH and FSH. It is released in bursts from the hypothalamusat regular intervals, about every 2 hours, althoughin women the interval may lengthen in the lutealend of the menstrual cycle.The pituitary gland respondsto these regular pulses by producing LH and FSH. Thepattern of LH and FSH in cycling women, including thelarge burst of LH release before ovulation, can be stimulatedby regular administration of GnRH pulses. Thelarge burst of LH from the pituitary gland appears to beinduced by feedback through estradiol and other productsof the gonads that change the response of the pituitarygland to the GnRH pulses rather than by largechanges in the amounts of GnRH secreted. The stimulatoryresponse to GnRH depends on pulsatile administrationand the timing of the pulses. Continual administrationof GnRH does not have the same effects aspulsatile administration; although production of LHand FSH is stimulated initially, it is suppressed within afew days. Part of this desensitization to GnRH is causedby a decrease in the number of pituitary receptors forGnRH; additional postreceptor mechanisms are alsoimportant in this complete suppression. |
| Indications | Oxytocin (Pitocin, Syntocinon) is a cyclic 8–amino acidpeptide that is synthesized in the paraventricular nucleusof the hypothalamus and transported within hypothalamicneurons (in association with neurophysin)to the posterior pituitary for storage. Its mechanism ofaction involves the direct stimulation of oxytocin receptorsfound on the myometrial cells. Oxytocin circulatesunbound in the plasma, where it has a half-life of approximately15 minutes. It is primarily inactivated in thekidneys and liver.
Oxytocin (Pitocin, Syntocinon) causes milk release (letdown)by stimulating contraction of the myoepithelialcells of the milk ducts in lactating mammary glands; thisforces milk from the alveoli of the breast. Oxytocin releaseis stimulated by suckling and by auditory and visualstimuli, such as a baby’s cry.Oxytocin is available asa nasal spray, which is used as an aid to lactation whenmilk ejection is impaired. |
| Definition | ChEBI: Gonadorelin is a ten-membered synthetic oligopeptide comprising pyroglutamyl, histidyl, tryptophyl, seryl, tyrosyl, glycyl, leucyl, arginyl, prolyl and glycinamide residues joined in sequence. It has a role as a gonadotropin releasing hormone agonist. It is an oligopeptide and a peptide hormone. |
| Biological Functions | Gonadotropin-releasing hormone (GnRH) is a decapeptide that causes the release of the gonadotropins, luteinizing hormone (LH) and follicle-stimulating hormone (FSH), from the anterior pituitary gland, but not in equal amounts (FSH release is partially inhibited by the gonadal protein inhibin). Therefore, GnRH is intimately involved in the control of both male and female reproduction. Medicinal chemists have capitalized on the relatively simple decapeptide structure of GnRH by preparing many analogues as potential fertility and antifertility agents, several of which are commercially available, especially those that are referred to as superagonists. It is known that GnRH can be degraded by enzymatic cleavage between Tyr5-Gly6 and Pro9-Gly10. Structure–activity relationship studies of GnRH analogues have shown that when Gly6 is replaced with certain D-amino acids, as well as with changes in the peptide C terminus, they generally are less susceptible to proteolytic enzymes, resulting in a longer lasting action. For that reason, they are referred to as superagonists. Furthermore, when these D-amino acids at position 6 are hydrophobic, the half-life is enhanced. |
| Mechanism of action | In physiological doses, GnRH agonists are able to induce ovulation and spermatogenesis by increasing LH and FSH levels and the resulting sex steroid levels, as does the normal hormone. In larger pharmacological (therapeutic) doses, however, GnRH agonists, especially the superagonists, block implantation of the fertilized egg, cause luteolysis of the corpus luteum, and can act as postcoital contraceptive agents (although not approved for this latter use). This paradoxical antifertility effect seen with the superagonists has been attributed to the fact that GnRH must be administered in a low-dose, pulsatile manner for it to be therapeutically effective as a fertility agent. Natural GnRH release from the hypothalamus occurs in a pulsatile manner. When GnRH or, especially, a superagonist is administered in pharmacological doses each day, LH and FSH levels will initially rise but then begin to fall after a few days because of target tissue desensitization/downregulation of pituitary GnRH receptors. The continued use of these agents in a nonpulsatile manner will result in a drastic drop of the gonadal steroid levels to near castrate levels in both males and females, thereby giving rise to their use in such conditions as precocious puberty, endometriosis, and advanced metastatic breast and prostate carcinoma.Typically, however, the GnRH superagonists take approximately 2 weeks to finally desensitize the GnRH receptors, and during this time, there is a transient rise in LH and FSH levels, which often results in an initial “flare-up” of the original symptoms. |
| Clinical Use | Because mGnRH has a short half-life of severalminutes, a number of GnRH analogs with high potencyand long half-life have been synthesized. The effects ofGnRH and its analogs are dependent on the dose andmethod of administration. Low doses of GnRH deliveredin a pulsatile fashion restore fertility in hypogonadalpatients. High doses of GnRH or continuous administration first results in an increase in LH and FSH secretion,followed by a decrease in LH and FSH levels due todesensitization, then by a decline in gonadal steroidlevels. The administration of antagonists interruptsGnRH-dependent LH and FSH secretion through competition with endogenous GnRH, but the doses required aremuch higher that the desensitizing agonists. mGnRH isavailable as gonadorelin for veterinary use. VariousGnRH agonists are used in the treatment of hormoneresponsive cancers such as prostate and breast cancers,estrogen-dependent conditions such as endometriosis,and precocious puberty. They are also widely used inART (assisted reproductive technology including IVFET, in vitro fertilization, and embryo transfer) to blockthe endogenous LH surge in the controlled ovarianstimulation |
| Clinical Use | Oxytocin is generally considered to be the drug ofchoice for inducing labor at term. In combination withamniotomy, oxytocin is highly successful in inducingand augmenting labor. When given oxytocin, approximately80% of patients with documented labor disordersprogress into labor and deliver vaginally. It has alsobeen used following incomplete abortion after 20 weeksof gestation (although use of prostaglandins may bepreferred in this instance), and it may be used after fulltermdelivery to prevent or control uterine hemorrhage.Oxytocin in high doses is used to induce abortion. Anoxytocin challenge test (an assessment of the fetal heartrate in response to oxytocin-induced contractions) canbe performed in certain high-risk (e.g., those with hypertension,diabetes, preeclampsia) obstetrical patientsas a measure of fetal well-being. |
| Side effects | Inappropriate use of oxytocin can lead to uterinerupture, anaphylactoid and other allergic reactions, andpossibly maternal death. Prolonged stimulation of uterinecontractions can result in the following fetal adversereactions: persistent uteroplacental insufficiency, sinusbradycardia, premature ventricular contractions, otherarrhythmias, and fetal death. Prolonged use of oxytocincan lead to water intoxication secondary to the antidiuretichormone–like effects of oxytocin. Maternal andfetal cardiovascular parameters should be monitoredduring oxytocin administration. |
| Safety Profile | An experimental teratogen. Human reproductive effects in women by subcutaneous route: menstrual cycle changes and other unspecified effects. Experimental reproductive effects. Used in the treatment of oligospermia and male inferthty. See also LUTEINIZING HORMONE and other luteinizing hormone-releasing hormone entries. |
