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GNRH1  -  gonadotropin-releasing hormone 1...

Homo sapiens

Synonyms: GNRH, GRH, HH12, LHRH, LNRH, ...
 
 
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Disease relevance of GNRH1

  • Binding sites for LHRH (now known in genome and microarray databases as GNRH1), were found on 52% of human breast cancers, about 80% of human ovarian and endometrial cancers, and 86% of human prostatic carcinoma specimens [1].
  • The inhibiting rates of (125)I-LHRH and LHRH on the proliferation of human liver cancer HEPG cells were not significantly different [2].
  • OBJECTIVE: More than 80% of human ovarian cancers express LHRH and its receptor [3].
  • This might be responsible for the different actions of LHRH in anterior pituitary and in prostate cancer [4].
  • A sensitive multipoint assay capable of measuring receptors for LHRH and its analogs using 5-10 micrograms membrane protein/incubation tube was used to determine binding characteristics of different agonists and antagonists of LHRH in membranes of male rat pituitary and human breast cancer specimens [5].
 

Psychiatry related information on GNRH1

  • TRH/LHRH stimulation test and Alzheimer's disease [6].
  • These results suggest an effect of LHRH blockade at a critical period which impairs early testicular growth and causes a permanent reduction in growth [7].
  • Inappropriate sexual behavior and denervation supersensitivity of limbic and midbrain LHRH receptors in Tourette's syndrome [8].
  • Despite continued impaired weight growth, pubertal patients do attain essentially normal gonadotrophin secretory responses to LHRH administration and are similar to subjects with constitutional delayed adolescent development in reproductive endocrine physiology [9].
  • Taking into account social and psychological factors, patients with advanced prostate carcinoma will soon be able to be treated with a longer acting LHRH depot formulation every 3 months an alternative of the 1-month depot now widely used clinically [10].
 

High impact information on GNRH1

  • Ketoconazole in the management of precocious puberty not responsive to LHRH-analogue therapy [11].
  • LHRHa significantly decreased basal (P less than 0.025) and LHRH-stimulated (P less than 0.01) gonadotropin levels as well as serum estradiol (P less than 0.05) [12].
  • We studied the biologic activity of a long-acting analogue of luteinizing hormone-releasing hormone, D-Trp6-Pro9-NEt-LHRH (LHRHa), in five normal men and four hypogonadotropic men previously unresponsive to natural LHRH [13].
  • LHRH agonists and human breast cancer cells [14].
  • Undoubtedly, the integration of these events is orchestrated by both ovarian steroids, E2 and P. Evidence accumulated in recent years has failed to affirm the perceived notion that E2 is an adequate peripheral signal for the timely, robust discharge of LHRH on proestrus [15].
 

Chemical compound and disease context of GNRH1

 

Biological context of GNRH1

 

Anatomical context of GNRH1

  • The proliferation of human ovarian cancer cell lines is reduced by both LHRH agonists and antagonists [3].
  • During sustained GNRH1 agonist treatment that markedly reduced (96%-98%) serum LH and testosterone (T) and decreased serum FSH (68%-72%), the testes of GNRH1 agonist-treated Tg-FSHR* mice remained significantly larger than treated nontransgenic controls [24].
  • However, after 8 wk of GNRH1 agonist treatment, the total spermatogonia, spermatocyte, or postmeiotic spermatid numbers were reduced to equivalent levels in Tg-FSHR* and nontransgenic mice [24].
  • In species that ovulate spontaneously, two key events mediate the stimulation of preovulatory gonadotropin surges: 1) neurosecretion of a preovulatory LHRH surge and 2) an acute increase in responsiveness of the pituitary gland to the LHRH neurosecretory trigger [25].
  • Chromaffin cells contain noradrenaline and metenkephalin, and some contain SP or LHRH; they are endocrine cells controlled by preganglionic fibers and can have a modulatory effect on principal neurons endowed with appropriate receptors [26].
 

Associations of GNRH1 with chemical compounds

  • To test the efficacy of targeted chemotherapy based on LHRH analogs, we recently developed a cytotoxic analog of LHRH, designated AN-152, which consists of [D-Lys6]LHRH covalently linked to one of the most widely used chemotherapeutic agents, doxorubicin (DOX) [1].
  • As in the case of DOX, AN-201 was coupled to carrier peptide [D-Lys6]LHRH to form a superactive targeted cytotoxic LHRH analog, AN-207 [1].
  • As shown by quantitative Western blotting, EGF-induced tyrosine autophosphorylation of EGF receptors was reduced 45-63% after LHRH (100 nM) treatment (P < 0.001) [16].
  • An analogous mechanism may operate in pituitary gonadotrophs, in which ligand-independent transactivation of progesterone receptors mediates integration of neurosecretory and estrogen positive feedback signals, leading to increased pituitary responsiveness to LHRH [25].
  • The somatostatin-immunoreactive material is located in neurons different from those containing immunoreactive LHRH, vasotocin or mesotocin [27].
 

Physical interactions of GNRH1

  • The affinity and receptor volume of LHRH-PE40 and LHRH binding to LHRHR on the membrane surface of human liver cancer cells were measured with radioligand receptor assay [2].
 

Enzymatic interactions of GNRH1

  • Moreover, LHRH substantially antagonized the PTX-catalyzed ADP-ribosylation of G protein alpha(i) [16].
 

Regulatory relationships of GNRH1

  • CONCLUSIONS: Cytotoxic LHRH analogue AN-152 could be considered for targeted chemotherapy of DOX-resistant breast cancers expressing LHRH-R [28].
  • These results indicate that ES-inducible P receptor (PR) in the pituitary can be activated in a ligand-independent manner by intracellular messengers giving rise to enhanced basal and LHRH-stimulated gonadotropin secretion [29].
 

Other interactions of GNRH1

  • The proliferation of these cells is dose- and time-dependently reduced by GnRH-II in a greater extent than by GnRH-I (GnRH, LHRH) superagonists [23].
  • The basis and design of a trial that will compare surgical oophorectomy with the LHRH analogue, Zoladex, in the treatment of premenopausal women with advanced, oestrogen receptor-positive or progesterone receptor-positive breast cancer, is described [17].
  • Inhibition of epidermal growth factor (EGF)-induced c-fos expression by LHRH, however, was mediated through pertussis toxin (PTX)-sensitive G protein alpha(i) [16].
 

Analytical, diagnostic and therapeutic context of GNRH1

  • Because LHRH receptors are not expressed on most normal tissues, they represent a specific target for cancer chemotherapy with antineoplastic agents linked to an LHRH vector molecule [1].
  • Treatment of ovarian cancer cell cultures with antiserum to LHRH significantly increased (up to mean+/-s.e.m. 121.0 +/- 2.8% of controls, Newman-Keuls P <0.001) proliferation of EFO-21 and EFO-27 cells [3].
  • Functional testing of the expressed protein in vitro confirmed high affinity binding of multiple forms of GNRH: Localization of GnRH-R messenger RNA using RT-PCR revealed that it is widely distributed in the brain and retina as well as elsewhere in the body [30].
  • Manipulation of astroglial-derived cytokines and nitric oxide (NO) in GT1-1 neuron-astroglia cocultures, underscores a potential cross-talk between different intra/inter-cellular mediators in the dynamic control of LHRH release [31].
  • LHRH analogs have become a promising modality in prostate cancer therapy as an alternative to surgical castration, and the use of these agents is generally considered to be safe [32].

References

  1. Targeting of cytotoxic luteinizing hormone-releasing hormone analogs to breast, ovarian, endometrial, and prostate cancers. Nagy, A., Schally, A.V. Biol. Reprod. (2005) [Pubmed]
  2. Ability of luteinizing hormone releasing hormone-Pseudomonas aeruginosa exotoxin 40 binding to LHRH receptor on human liver cancer cells. Gong, S.L., Zhao, G., Zhao, H.G., Lu, W.T., Liu, G.W., Zhu, P. World J. Gastroenterol. (2004) [Pubmed]
  3. LHRH might act as a negative autocrine regulator of proliferation of human ovarian cancer. Emons, G., Weiss, S., Ortmann, O., Gründker, C., Schulz, K.D. Eur. J. Endocrinol. (2000) [Pubmed]
  4. The luteinizing hormone-releasing hormone receptor in human prostate cancer cells: messenger ribonucleic acid expression, molecular size, and signal transduction pathway. Limonta, P., Moretti, R.M., Marelli, M.M., Dondi, D., Parenti, M., Motta, M. Endocrinology (1999) [Pubmed]
  5. Comparison of different agonists and antagonists of luteinizing hormone-releasing hormone for receptor-binding ability to rat pituitary and human breast cancer membranes. Fekete, M., Bajusz, S., Groot, K., Csernus, V.J., Schally, A.V. Endocrinology (1989) [Pubmed]
  6. TRH/LHRH stimulation test and Alzheimer's disease. Warner, M.D., Vinogradov, S., Peabody, C.A., Widrow, L., Davies, H.D., Minkoff, J.R., Winograd, C.H. Biol. Psychiatry (1990) [Pubmed]
  7. Sertoli cell maturation is impaired by neonatal passive immunization with antiserum to luteinizing hormone-releasing hormone. Vogel, D.L., Gunsalus, G.L., Bercu, B.B., Musto, N.A., Bardin, C.W. Endocrinology (1983) [Pubmed]
  8. Inappropriate sexual behavior and denervation supersensitivity of limbic and midbrain LHRH receptors in Tourette's syndrome. Sandyk, R., Kwo-on-Yuen, P.F., Awerbuch, G., Bamford, C.R. Journal of clinical psychopharmacology. (1988) [Pubmed]
  9. The reproductive endocrine system in cystic fibrosis: 2. Changes in gonadotrophins and sex steroids following LHRH. Reiter, E.O., Stern, R.C., Root, A.W. Clin. Endocrinol. (Oxf) (1982) [Pubmed]
  10. A new extra long acting depot preparation of the LHRH analogue Zoladex. First endocrinological and pharmacokinetic data in patients with advanced prostate cancer. Dijkman, G.A., del Moral, P.F., Plasman, J.W., Kums, J.J., Delaere, K.P., Debruyne, F.M., Hutchinson, F.J., Furr, B.J. J. Steroid Biochem. Mol. Biol. (1990) [Pubmed]
  11. Ketoconazole in the management of precocious puberty not responsive to LHRH-analogue therapy. Holland, F.J., Fishman, L., Bailey, J.D., Fazekas, A.T. N. Engl. J. Med. (1985) [Pubmed]
  12. Short-term treatment of idiopathic precocious puberty with a long-acting analogue of luteinizing hormone-releasing hormone. A preliminary report. Comite, F., Cutler, G.B., Rivier, J., Vale, W.W., Loriaux, D.L., Crowley, W.F. N. Engl. J. Med. (1981) [Pubmed]
  13. The biologic activity of a potent analogue of gonadotropin-releasing hormone in normal and hypogonadotropic men. Crowley, W.F., Beitins, I.Z., Vale, W., Kliman, B., Rivier, J., Rivier, C., McArthur, J.W. N. Engl. J. Med. (1980) [Pubmed]
  14. LHRH agonists and human breast cancer cells. Wilding, G., Chen, M., Gelmann, E.P. Nature (1987) [Pubmed]
  15. Mandatory neuropeptide-steroid signaling for the preovulatory luteinizing hormone-releasing hormone discharge. Kalra, S.P. Endocr. Rev. (1993) [Pubmed]
  16. Antiproliferative signaling of luteinizing hormone-releasing hormone in human endometrial and ovarian cancer cells through G protein alpha(I)-mediated activation of phosphotyrosine phosphatase. Gründker, C., Völker, P., Emons, G. Endocrinology (2001) [Pubmed]
  17. Therapy in premenopausal women with advanced, oestrogen positive or/and progesterone positive breast cancer: surgical oophorectomy versus the LHRH analogue, Zoladex. Robert, N.J., Dalton, W.S., Osborne, C.K., Abeloff, M. Horm. Res. (1989) [Pubmed]
  18. Combination therapy using LHRH and somatostatin analogues plus dexamethasone in androgen ablation refractory prostate cancer patients with bone involvement: a bench to bedside approach. Koutsilieris, M., Bogdanos, J., Milathianakis, C., Dimopoulos, P., Dimopoulos, T., Karamanolakis, D., Halapas, A., Tenta, R., Katopodis, H., Papageorgiou, E., Pitulis, N., Pissimissis, N., Lembessis, P., Sourla, A. Expert opinion on investigational drugs. (2006) [Pubmed]
  19. DHEA and its transformation into androgens and estrogens in peripheral target tissues: intracrinology. Labrie, F., Luu-The, V., Labrie, C., Simard, J. Frontiers in neuroendocrinology. (2001) [Pubmed]
  20. Simultaneous liver and lung toxicity related to the nonsteroidal antiandrogen nilutamide (Anandron): a case report. Gomez, J.L., Dupont, A., Cusan, L., Tremblay, M., Tremblay, M., Labrie, F. Am. J. Med. (1992) [Pubmed]
  21. Determination of sequence variation and haplotype structure for the gonadotropin-releasing hormone (GnRH) and GnRH receptor genes: investigation of role in pubertal timing. Sedlmeyer, I.L., Pearce, C.L., Trueman, J.A., Butler, J.L., Bersaglieri, T., Read, A.P., Clayton, P.E., Kolonel, L.N., Henderson, B.E., Hirschhorn, J.N., Palmert, M.R. J. Clin. Endocrinol. Metab. (2005) [Pubmed]
  22. Chromosomal organization, evolutionary relationship, and expression of zebrafish GnRH family members. Kuo, M.W., Lou, S.W., Postlethwait, J., Chung, B.C. J. Biomed. Sci. (2005) [Pubmed]
  23. Role of gonadotropin-releasing hormone (GnRH) in ovarian cancer. Gründker, C., Emons, G. Reprod. Biol. Endocrinol. (2003) [Pubmed]
  24. Maintenance of Spermatogenesis by the Activated Human (Asp567Gly) FSH Receptor During Testicular Regression Due to Hormonal Withdrawal. Allan, C.M., Garcia, A., Spaliviero, J., Jimenez, M. Biol. Reprod. (2006) [Pubmed]
  25. New concepts of the neuroendocrine regulation of gonadotropin surges in rats. Levine, J.E. Biol. Reprod. (1997) [Pubmed]
  26. Synaptic organization of amphibian sympathetic ganglia. Lascar, G., Eugene, D., Taxi, J. Microsc. Res. Tech. (1996) [Pubmed]
  27. Immunocytochemical demonstration of somatostatin-containing neurons in the hypothalamus of the domestic mallard. Blähser, S., Fellmann, D., Bugnon, C. Cell Tissue Res. (1978) [Pubmed]
  28. Targeted doxorubicin-containing luteinizing hormone-releasing hormone analogue AN-152 inhibits the growth of doxorubicin-resistant MX-1 human breast cancers. Bajo, A.M., Schally, A.V., Halmos, G., Nagy, A. Clin. Cancer Res. (2003) [Pubmed]
  29. Effects of progesterone (P) and antiprogestin RU486 on LH and FSH release by incubated pituitaries from rats treated with the SERM LY11701 8-HCl and/or recombinant human FSH. Bellido, C., Aguilar, R., Garrido-Gracia, J.C., Sánchez-Criado, J.E. J. Endocrinol. Invest. (2002) [Pubmed]
  30. Gonadotropin-releasing hormone receptor in the teleost Haplochromis burtoni: structure, location, and function. Robison, R.R., White, R.B., Illing, N., Troskie, B.E., Morley, M., Millar, R.P., Fernald, R.D. Endocrinology (2001) [Pubmed]
  31. Luteinizing hormone-releasing hormone is a primary signaling molecule in the neuroimmune network. Marchetti, B., Gallo, F., Farinella, Z., Tirolo, C., Testa, N., Romeo, C., Morale, M.C. Ann. N. Y. Acad. Sci. (1998) [Pubmed]
  32. Apoplexy of clinically silent pituitary adenoma during prostate cancer treatment with LHRH analog. Blaut, K., Wi??niewski, P., Syrenicz, A., Sworczak, K. Neuro Endocrinol. Lett. (2006) [Pubmed]
 
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