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

• 3) Using a phosphotyrosine phosphatase assay based on molybdate-malachite green, treatment of quiescent EFO-21 and EFO-27 ovarian cancer cells and quiescent Ishikawa and Hec-1A endometrial cancer cells with 100 nM of the LHRH agonist triptorelin resulted in a 4-fold increase in PTP activity (P < 0.001) [16].
• Therapy in premenopausal women with advanced, oestrogen positive or/and progesterone positive breast cancer: surgical oophorectomy versus the LHRH analogue, Zoladex [17].
• Combination therapy using LHRH and somatostatin analogues plus dexamethasone in androgen ablation refractory prostate cancer patients with bone involvement: a bench to bedside approach [18].
• A widely used application of intracrinology is the treatment of prostate cancer where the testicles are blocked by an LHRH agonist while the androgens made locally in the prostate from DHEA are blocked by a pure antiandrogen [19].
• We report the case of a 69-year-old patient treated for stage C adenocarcinoma of the prostate with the combination of the luteinizing hormone-releasing hormone agonist [D-Trp6, des-Gly-NH2(10)] LHRH ethylamide and the antiandrogen nilutamide (Anandron) who developed simultaneous liver and lung toxicity [20].

Biological context of GNRH1

• Two blocks of strong linkage disequilibrium were identified that spanned GNRHR and one was identified spanning GNRH1; within each block, more than 80% of chromosomes carried one of a few common haplotypes [21].
• No missense variants were found in either gene, except for a previously identified single nucleotide polymorphism (SNP) in GNRH1 that was not associated with late pubertal development [21].
• We conclude that genetic variation in GNRH1 and GNRHR is not likely to be a substantial modulator of pubertal timing in the general population [21].
• The zebrafish genome appears to lack an ortholog to human GNRH1, and the human genome appears to lack an ortholog of gnrh3 [22].
• The expression of GnRH (GnRH-I, LHRH) and its receptor as a part of an autocrine regulatory system of cell proliferation has been demonstrated in a number of human malignant tumors, including cancers of the ovary [23].

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