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1.
Front Endocrinol (Lausanne) ; 15: 1353151, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38348415

RESUMO

Reproduction in mammals is controlled by hypothalamic gonadotropin-releasing hormone (GnRH) neurons. Recent studies from our laboratory established that the basal ganglia of the human brain contain additional large populations of GnRH synthesizing neurons which are absent in adult mice. Such extrahypothalamic GnRH neurons mostly occur in the putamen where they correspond to subsets of the striatal cholinergic interneurons (ChINs) and express GnRHR autoreceptors. In an effort to establish a mouse model for functional studies of striatal GnRH/GnRHR signaling, we carried out electrophysiological experiments on acute brain slices from male transgenic mice. Using PN4-7 neonatal mice, half of striatal ChINs responded with transient hyperpolarization and decreased firing rate to 1.2 µM GnRH, whereas medium spiny projection neurons remained unaffected. GnRH acted on its specific receptor because no response was observed in the presence of the GnRHR antagonist Antide. Addition of the membrane-impermeable G protein-coupled receptor inhibitor GDP-ß-S to the internal electrode solution eliminated the effect of GnRH. Further, GnRH was able to inhibit ChINs in presence of tetrodotoxin which blocked action potential mediated events. Collectively, these data indicated that the receptor underlying the effects of GnRH in neonatal mice is localized within ChINs. GnRH responsiveness of ChINs was transient and entirely disappeared in adult mice. These results raise the possibility to use neonatal transgenic mice as a functional model to investigate the role of GnRH/GnRHR signaling discovered earlier in adult human ChINs.


Assuntos
Hormônio Liberador de Gonadotropina , Receptores LHRH , Animais , Masculino , Camundongos , Neurônios Colinérgicos , Hormônio Liberador de Gonadotropina/farmacologia , Mamíferos , Camundongos Transgênicos , Transdução de Sinais
2.
Sci Rep ; 14(1): 31, 2024 01 02.
Artigo em Inglês | MEDLINE | ID: mdl-38167999

RESUMO

Triple-negative breast cancer (TNBC) treatment is challenging and frequently characterized by an aggressive phenotype and low prognosis in comparison to other subtypes. This paper presents fabricated implantable drug-loaded microporous poly-di-methyl-siloxane (PDMS) devices for the delivery of targeted therapeutic agents [Luteinizing Hormone-Releasing Hormone conjugated paclitaxel (PTX-LHRH) and Luteinizing Hormone-Releasing Hormone conjugated prodigiosin (PG-LHRH)] for the treatment and possible prevention of triple-negative cancer recurrence. In vitro assessment using the Alamar blue assay demonstrated a significant reduction (p < 0.05) in percentage of cell growth in a time-dependent manner in the groups treated with PG, PG-LHRH, PTX, and PTX-LHRH. Subcutaneous triple-negative xenograft breast tumors were then induced in athymic female nude mice that were four weeks old. Two weeks later, the tumors were surgically but partially removed, and the device implanted. Mice were observed for tumor regrowth and organ toxicity. The animal study revealed that there was no tumor regrowth, six weeks post-treatment, when the LHRH targeted drugs (LHRH-PTX and LHRH-PGS) were used for the treatment. The possible cytotoxic effects of the released drugs on the liver, kidney, and lung are assessed using quantitative biochemical assay from blood samples of the treatment groups. Ex vivo histopathological results from organ tissues showed that the targeted cancer drugs released from the implantable drug-loaded device did not induce any adverse effect on the liver, kidneys, or lungs, based on the results of qualitative toxicity studies. The implications of the results are discussed for the targeted and localized treatment of triple negative breast cancer.


Assuntos
Antineoplásicos , Neoplasias de Mama Triplo Negativas , Humanos , Feminino , Animais , Camundongos , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Siloxanas , Receptores LHRH/genética , Camundongos Nus , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Hormônio Liberador de Gonadotropina/farmacologia , Linhagem Celular Tumoral
3.
Brain Behav Immun ; 115: 295-307, 2024 01.
Artigo em Inglês | MEDLINE | ID: mdl-37884161

RESUMO

GV1001 protects neural cells from amyloid-ß (Aß) toxicity and other stressors in in vitro studies and demonstrates clinically beneficial effects in patients with moderate to severe Alzheimer's disease (AD). Here, we investigated the protective effects and mechanism of action of GV1001 in triple transgenic AD (3xTg-AD) mice. We found that GV1001 improved memory and cognition in middle- and old-aged 3xTg-AD mice. Additionally, it reduced Aß oligomer and phospho-tau (Ser202 and Thr205) levels in the brain, and mitigated neuroinflammation by promoting a neuroprotective microglial and astrocyte phenotype while diminishing the neurotoxic ones. In vitro, GV1001 bound to gonadotropin releasing hormone receptors (GnRHRs) with high affinity. Levels of cyclic adenosine monophosphate, a direct downstream effector of activated GnRHRs, increased after GV1001 treatment. Furthermore, inhibition of GnRHRs blocked GV1001-induced effects. Thus, GV1001 might improve cognitive and memory functions of 3xTg-AD mice by suppressing neuroinflammation and reducing Aß oligomers levels and phospho-tau by activating GnRHRs and their downstream signaling pathways.


Assuntos
Doença de Alzheimer , Humanos , Camundongos , Animais , Pessoa de Meia-Idade , Idoso , Doença de Alzheimer/metabolismo , Camundongos Transgênicos , Receptores LHRH , Doenças Neuroinflamatórias , Proteínas tau/genética , Proteínas tau/metabolismo , Peptídeos beta-Amiloides/metabolismo , Hormônio Liberador de Gonadotropina , Modelos Animais de Doenças
4.
Int J Mol Sci ; 24(21)2023 Nov 04.
Artigo em Inglês | MEDLINE | ID: mdl-37958948

RESUMO

Human sexual and reproductive development is regulated by the hypothalamic-pituitary-gonadal (HPG) axis, which is primarily controlled by the gonadotropin-releasing hormone (GnRH) acting on its receptor (GnRHR). Dysregulation of the axis leads to conditions such as congenital hypogonadotropic hypogonadism (CHH) and delayed puberty. The pathophysiology of GnRHR makes it a potential target for treatments in several reproductive diseases and in congenital adrenal hyperplasia. GnRHR belongs to the G protein-coupled receptor family and its GnRH ligand, when bound, activates several complex and tissue-specific signaling pathways. In the pituitary gonadotrope cells, it triggers the G protein subunit dissociation and initiates a cascade of events that lead to the production and secretion of the luteinizing hormone (LH) and follicle-stimulating hormone (FSH) accompanied with the phospholipase C, inositol phosphate production, and protein kinase C activation. Pharmacologically, GnRHR can be modulated by synthetic analogues. Such analogues include the agonists, antagonists, and the pharmacoperones. The agonists stimulate the gonadotropin release and lead to receptor desensitization with prolonged use while the antagonists directly block the GnRHR and rapidly reduce the sex hormone production. Pharmacoperones include the most recent GnRHR therapeutic approaches that directly correct the misfolded GnRHRs, which are caused by genetic mutations and hold serious promise for CHH treatment. Understanding of the GnRHR's genomic and protein structure is crucial for the most appropriate assessing of the mutation impact. Such mutations in the GNRHR are linked to normosmic hypogonadotropic hypogonadism and lead to various clinical symptoms, including delayed puberty, infertility, and impaired sexual development. These mutations vary regarding their mode of inheritance and can be found in the homozygous, compound heterozygous, or in the digenic state. GnRHR expression extends beyond the pituitary gland, and is found in reproductive tissues such as ovaries, uterus, and prostate and non-reproductive tissues such as heart, muscles, liver and melanoma cells. This comprehensive review explores GnRHR's multifaceted role in human reproduction and its clinical implications for reproductive disorders.


Assuntos
Hipogonadismo , Síndrome de Klinefelter , Puberdade Tardia , Feminino , Masculino , Humanos , Receptores LHRH/genética , Receptores LHRH/metabolismo , Hipogonadismo/tratamento farmacológico , Hipogonadismo/genética , Hipogonadismo/metabolismo , Hormônio Liberador de Gonadotropina/metabolismo , Hormônio Luteinizante/metabolismo , Hormônio Foliculoestimulante
5.
Int J Mol Sci ; 24(20)2023 Oct 16.
Artigo em Inglês | MEDLINE | ID: mdl-37894912

RESUMO

Gonadotropin-releasing hormone (GnRH) is pivotal in regulating human reproduction and fertility through its specific receptors. Among these, gonadotropin-releasing hormone receptor type I (GnRHR I), which is a member of the G-protein-coupled receptor family, is expressed on the surface of both healthy and malignant cells. Its presence in cancer cells has positioned this receptor as a primary target for the development of novel anti-cancer agents. Moreover, the extensive regulatory functions of GnRH have underscored decapeptide as a prominent vehicle for targeted drug delivery, which is accomplished through the design of appropriate conjugates. On this basis, a rationally designed series of anthraquinone/mitoxantrone-GnRH conjugates (con1-con8) has been synthesized herein. Their in vitro binding affinities range from 0.06 to 3.42 nM, with six of them (con2-con7) demonstrating higher affinities for GnRH than the established drug leuprolide (0.64 nM). Among the mitoxantrone based GnRH conjugates, con3 and con7 show the highest affinities at 0.07 and 0.06 nM, respectively, while the disulfide bond present in the conjugates is found to be readily reduced by the thioredoxin (Trx) system. These findings are promising for further pharmacological evaluation of the synthesized conjugates with the prospect of performing future clinical studies.


Assuntos
Antineoplásicos , Neoplasias , Humanos , Antineoplásicos/síntese química , Antineoplásicos/imunologia , Antineoplásicos/metabolismo , Antineoplásicos/farmacologia , Hormônio Liberador de Gonadotropina/metabolismo , Fatores Imunológicos , Terapia de Imunossupressão , Imunossupressores , Mitoxantrona , Neoplasias/tratamento farmacológico , Receptores LHRH/metabolismo
6.
Int J Mol Sci ; 24(20)2023 Oct 17.
Artigo em Inglês | MEDLINE | ID: mdl-37894950

RESUMO

Crucial roles in embryo implantation and placentation in humans include the invasion of the maternal decidua by extravillous trophoblasts and the motile behavior of decidual endometrial stromal cells. The effects of the epidermal growth factor (EGF) and GnRH-II in the endometrium take part in early pregnancy. In the present study, we demonstrated the coaction of EGF- and GnRH-II-promoted motility of human decidual endometrial stromal cells, indicating the possible roles of EGF and GnRH-II in embryo implantation and early pregnancy. After obtaining informed consent, we obtained human decidual endometrial stromal cells from decidual tissues from normal pregnancies at 6 to 12 weeks of gestation in healthy women undergoing suction dilation and curettage. Cell motility was evaluated with invasion and migration assays. The mechanisms of EGF and GnRH-II were performed using real-time PCR and immunoblot analysis. The results showed that human decidual tissue and stromal cells expressed the EGF and GnRH-I receptors. GnRH-II-mediated cell motility was enhanced by EGF and was suppressed by the knockdown of the endogenous GnRH-I receptor and EGF receptor with siRNA, revealing that GnRH-II promoted the cell motility of human decidual endometrial stromal cells through the GnRH-I receptor and the activation of Twist and N-cadherin signaling. This new concept regarding the coaction of EGF- and GnRH-promoted cell motility suggests that EGF and GnRH-II potentially affect embryo implantation and the decidual programming of human pregnancy.


Assuntos
Caderinas , Fator de Crescimento Epidérmico , Feminino , Humanos , Gravidez , Caderinas/metabolismo , Movimento Celular , Decídua/metabolismo , Endométrio/metabolismo , Fator de Crescimento Epidérmico/farmacologia , Fator de Crescimento Epidérmico/metabolismo , Hormônio Liberador de Gonadotropina/metabolismo , Receptores LHRH/metabolismo , Células Estromais/metabolismo , Trofoblastos/metabolismo
7.
Cell Commun Signal ; 21(1): 284, 2023 10 12.
Artigo em Inglês | MEDLINE | ID: mdl-37828510

RESUMO

BACKGROUND: Gonadotropin-releasing hormone (GnRH) receptors are essential for reproduction and are expressed in numerous urogenital, reproductive, and non-reproductive cancers. In addition to canonical G protein-coupled receptor signaling, GnRH receptors functionally interact with several receptor tyrosine kinases. AXL is a receptor tyrosine kinase expressed in numerous tissues as well as multiple tumors. Here we tested the hypothesis that AXL, along with its endogenous ligand Gas6, impacts GnRH receptor signaling. METHODS: We used clonal murine pituitary αT3-1 and LßT2 gonadotrope cell lines to examine the effect of AXL activation on GnRH receptor-dependent signaling outcomes. ELISA and immunofluorescence were used to observe AXL and GnRH receptor expression in αT3-1 and LßT2 cells, as well as in murine and human pituitary sections. We also used ELISA to measure changes in ERK phosphorylation, pro-MMP9 production, and release of LHß. Digital droplet PCR was used to measure the abundance of Egr-1 transcripts. A transwell migration assay was used to measure αT3-1 and LßT2 migration responses to GnRH and AXL. RESULTS: We observed AXL, along with the GnRH receptor, expression in αT3-1 and LßT2 gonadotrope cell lines, as well as in murine and human pituitary sections. Consistent with a potentiating role of AXL, Gas6 enhanced GnRH-dependent ERK phosphorylation in αT3-1 and LßT2 cells. Further, and consistent with enhanced post-transcriptional GnRH receptor responses, we found that Gas6 increased the abundance of Egr-1 transcripts. Suggesting functional significance, in LßT2 cells, Gas6/AXL signaling stimulated LHß production and enhanced GnRH receptor-dependent generation of pro-MMP9 protein and promoted cell migration. CONCLUSIONS: Altogether, these data describe a novel role for AXL as a modulator of GnRH receptor signaling. Video Abstract.


Assuntos
Receptor Tirosina Quinase Axl , Receptores LHRH , Camundongos , Humanos , Animais , Receptores LHRH/metabolismo , Metaloproteinase 9 da Matriz/metabolismo , Transdução de Sinais , Hormônio Liberador de Gonadotropina/metabolismo , Hormônio Liberador de Gonadotropina/farmacologia , Receptores Proteína Tirosina Quinases/metabolismo
8.
PLoS One ; 18(10): e0287151, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37816015

RESUMO

OBJECTIVE: Pt-Mal-LHRH is a newly synthesized chemotherapeutic agent that was designed to selectively target the luteinizing hormone-releasing hormone (LHRH) receptor expressed by triple negative breast cancer (TNBC). The aim of this study was to evaluate the therapeutic dosing, tumor reduction efficacy, and selective distribution of Pt-Mal-LHRH in-vivo. METHODS AND RESULTS: LHRH tissue expression levels in-vivo were investigated using western blotting and LHRH was found to be increased in reproductive tissues (mammary, ovary, uterus). Further, Pt-Mal-LHRH was found to have increased TNBC tumor tissue platinum accumulation compared to carboplatin by inductively coupled plasma mass spectrometry analysis. The platinum family, compound carboplatin, was selected for comparison due to its similar chemical structure and molar equivalent doses were evaluated. Moreover, in-vivo distribution data indicated selective targeting of Pt-Mal-LHRH by enhanced reproductive tissue accumulation compared to carboplatin. Further, TNBC tumor growth was found to be significantly attenuated by Pt-Mal-LHRH compared to carboplatin in both the 4T1 and MDA-MB-231 tumor models. There was a significant reduction in tumor volume in the 4T1 tumor across Pt-Mal-LHRH doses (2.5-20 mg/kg/wk) and in the MDA-MB-231 tumor at the dose of 10 mg/kg/wk in models conducted by an independent contract testing laboratory. CONCLUSION: Our data indicates Pt-Mal-LHRH is a targeting chemotherapeutic agent towards the LHRH receptor and reduces TNBC tumor growth in-vivo. This study supports drug conjugation design models using the LHRH hormone for chemotherapeutic delivery as Pt-Mal-LHRH was found to be a more selective and efficacious than carboplatin. Further examination of Pt-Mal-LHRH is warranted for its clinical use in TNBCs, along with, other reproductive cancers overexpressing the LHRH receptor.


Assuntos
Antineoplásicos , Neoplasias de Mama Triplo Negativas , Feminino , Humanos , Receptores LHRH , Neoplasias de Mama Triplo Negativas/patologia , Carboplatina/uso terapêutico , Platina/uso terapêutico , Hormônio Liberador de Gonadotropina , Linhagem Celular Tumoral , Antineoplásicos/uso terapêutico
9.
J Gynecol Obstet Hum Reprod ; 52(9): 102664, 2023 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-37669732

RESUMO

The French National College of Obstetricians and Gynecologists (CNGOF) published guidelines for managing endometriosis-associated pain in 2018. Given the development of new pharmacological therapies and a review that was published in 2021, most national and international guidelines now suggest a new therapeutic approach. In addition, a novel validated screening method based on patient questionnaires and analysis of 109-miRNA saliva signatures, which combines biomarkers and artificial intelligence, opens up new avenues for overcoming diagnostic challenges in patients with pelvic pain and for avoiding laparoscopic surgery when sonography and MRI are not conclusive. Dienogest (DNG) 2 mg has been a reimbursable healthcare expense in France since 2020, and, according to recent studies, it is at least as effective as combined hormonal contraception (CHC) and can be used as an alternative to CHC for first-line treatment of endometriosis-associated pain. Since 2018, the literature concerning the use of DNG has grown considerably, and the French guidelines should be modified accordingly. The levonorgestrel intrauterine system (LNG IUS) and other available progestins per os, including DNG, or the subcutaneous implant, can be offered as first-line therapy, gonadotropin-releasing hormone (GnRH) agonists with add-back therapy (ABT) as second-line therapy. Oral GnRH antagonists are promising new medical treatments for women with endometriosis-associated pain. They competitively bind to GnRH receptors in the anterior pituitary, preventing native GnRH from binding to GnRH receptors and from stimulating the secretion of luteinizing hormone and follicle-stimulating hormone. Consequently, estradiol and progesterone production is reduced. Oral GnRH antagonists will soon be on the market in France. Given their mode of action, their efficacy is comparable to that of GnRH agonists, with the advantage of oral administration and rapid action with no flare-up effect. Combination therapy with ABT is likely to allow long-term treatment with minimal impact on bone mass. GnRH antagonists with ABT may thus be offered as second-line treatment as an alternative to GnRH agonists with ABT. This article presents an update on the management of endometriosis-associated pain in women who do not have an immediate desire for pregnancy.


Assuntos
Endometriose , Feminino , Humanos , Endometriose/complicações , Endometriose/diagnóstico , Endometriose/tratamento farmacológico , Receptores LHRH , Inteligência Artificial , Dor Pélvica/tratamento farmacológico , Dor Pélvica/etiologia , Hormônio Liberador de Gonadotropina/uso terapêutico , Antagonistas de Hormônios/uso terapêutico
10.
Drug Des Devel Ther ; 17: 2325-2333, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37559910

RESUMO

Androgen deprivation therapy, primarily via a gonadotropin-releasing hormone receptor agonist or antagonist together with or without an androgen receptor antagonist, remains the mainstay of medical treatment for advanced prostate cancer. Meanwhile, relugolix has been developed as the first orally active, non-peptide, selective antagonist for the gonadotropin-releasing hormone receptor. Previous randomized studies involving patients with prostate cancer have demonstrated comparable efficacy in androgen suppression between relugolix vs other gonadotropin-releasing hormone antagonists or agonists. This review summarizes available data on the design and development of relugolix and its therapeutic application, and discusses if relugolix represents a promising oral alternative to injectable androgen deprivation therapy. Based on current published evidence, further investigation is likely required to determine the actual clinical benefits of relugolix therapy against prostate cancer.


Assuntos
Neoplasias da Próstata , Masculino , Humanos , Neoplasias da Próstata/tratamento farmacológico , Receptores LHRH , Hormônio Liberador de Gonadotropina/agonistas , Antagonistas de Androgênios/farmacologia , Antagonistas de Androgênios/uso terapêutico , Androgênios/uso terapêutico
11.
Front Endocrinol (Lausanne) ; 14: 1183278, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37124730

RESUMO

From the time of its discovery and isolation in the mammalian hypothalamus, the decapeptide, gonadotropin-releasing hormone (GnRH), has also been found to be expressed in non-hypothalamic tissues and can elicit a diverse array of functions both in the brain and periphery. In cancer, past studies have targeted the gonadotropin-releasing hormone receptors (GnRHR) as a way to treat reproductive cancers due to its anti-tumorigenic effects. On the contrary, its metabolite, GnRH-(1-5), behaves divergently from its parental peptide through putative orphan G-protein coupled receptor (oGPCR), GPR101. In this review, we will focus on the potential roles of GnRH-(1-5) in the periphery with an emphasis on its effects on endometrial cancer progression.


Assuntos
Neoplasias do Endométrio , Hormônio Liberador de Gonadotropina , Feminino , Humanos , Hormônio Liberador de Gonadotropina/metabolismo , Fragmentos de Peptídeos/metabolismo , Receptores LHRH/metabolismo
12.
Clin Exp Pharmacol Physiol ; 50(7): 610-617, 2023 07.
Artigo em Inglês | MEDLINE | ID: mdl-37186405

RESUMO

Endometriosis is an oestrogen-dependent disease in which endometrial-like tissue grows outside the uterus in women of reproductive age. Accordingly, control of oestradiol (E2) levels is an effective treatment for endometriosis. Because gonadotropin-releasing hormone (GnRH) is the main controller of E2 secretion, control of GnRH signalling by GnRH antagonism is an effective strategy for the treatment of sex hormone-dependent diseases such as endometriosis. The purpose of the present study was to evaluate the effects of the potent, orally available and selective GnRH antagonist linzagolix on experimental endometriosis in rats and compare them with those of dienogest, which is used clinically to treat endometriosis. Experimental endometriosis was induced in female rats at the proestrus stage of the oestrous cycle via autotransplantation of endometrial tissue into the renal subcapsular space. Linzagolix significantly decreased cyst volumes compared with the control group at doses of 50 mg/kg or more. Indeed, a suppressive effect of dienogest on cyst volume was observed only at the highest dose evaluated (1 mg/kg). The effective concentration of linzagolix, calculated as the free form of the last-observed drug concentration, was ~1 µmol/L in endometriosis model rats. The present study also reveals that linzagolix exerts a sustained inhibitory effect on E2 secretion, indicating that the suppressive effect on endometriosis cyst volumes could be attributed to its pharmacological suppression of GnRH signalling and serum E2 concentrations. Altogether, our findings indicate that linzagolix may be a useful therapeutic intervention for hormone-dependent diseases including endometriosis.


Assuntos
Cistos , Endometriose , Humanos , Feminino , Ratos , Animais , Receptores LHRH , Endometriose/tratamento farmacológico , Hormônio Liberador de Gonadotropina/uso terapêutico , Antagonistas de Hormônios/farmacologia , Antagonistas de Hormônios/uso terapêutico , Cistos/tratamento farmacológico
13.
BMC Med ; 21(1): 129, 2023 04 03.
Artigo em Inglês | MEDLINE | ID: mdl-37013610

RESUMO

BACKGROUND: Gonadotropin-releasing hormone (GnRH) antagonists are a promising therapeutic approach for treating hormone-dependent prostate cancer. Currently, the mainstream GnRH antagonists are polypeptide agents administered through subcutaneous injection. In this study, we evaluated the safety, pharmacokinetics (PK), and pharmacodynamics (PD) of SHR7280, an oral small molecule GnRH antagonist, in healthy men. METHODS: This phase 1 trial was a randomized, double-blind, placebo-controlled, and dose-ascending study. Eligible healthy men were randomized in a 4:1 ratio to receive either oral SHR7280 tablets or placebo twice daily (BID) for 14 consecutive days. The SHR7280 dose was initiated at 100 mg BID and then sequentially increased to 200, 350, 500, 600, 800, and 1000 mg BID. Safety, PK, and PD parameters were assessed. RESULTS: A total of 70 subjects were enrolled and received the assigned drug, including 56 with SHR7280 and 14 with placebo. SHR7280 was well-tolerated. The incidence of adverse events (AEs, 76.8% vs 85.7%) and treatment-related AEs (75.0% vs 85.7%), as well as the severity of AEs (moderate AEs, 1.8% vs 7.1%) were similar between the SHR7280 group and placebo group. SHR7280 was rapidly absorbed in a dose-dependent manner, with a median Tmax of each dose group ranging from 0.8 to 1.0 h on day 14 and a mean t1/2 ranging from 2.8 to 3.4 h. The PD results demonstrated that SHR7280 exhibited a rapid and dose-proportional suppression of hormones, including LH, FSH, and testosterone, with maximum suppression achieved at doses of 800 and 1000 mg BID. CONCLUSIONS: SHR7280 showed an acceptable safety profile, as well as favorable PK and PD profiles within a dose range of 100 to 1000 mg BID. This study proposes a rationale for further investigation of SHR7280 as a potential androgen deprivation therapy. TRIAL REGISTRATION: Clinical trials.gov NCT04554043; registered September 18, 2020.


Assuntos
Hormônio Liberador de Gonadotropina , Neoplasias da Próstata , Receptores LHRH , Humanos , Masculino , Antagonistas de Androgênios , Relação Dose-Resposta a Droga , Método Duplo-Cego , Hormônio Liberador de Gonadotropina/antagonistas & inibidores , Neoplasias da Próstata/tratamento farmacológico
14.
Mol Med Rep ; 27(4)2023 04.
Artigo em Inglês | MEDLINE | ID: mdl-36799164

RESUMO

Hypothalamic inflammation is a pathophysiological basis of polycystic ovarian syndrome (PCOS), while overactivated and/or excess M1 polarized microglia are considered to be the main reason for the occurrence of hypothalamic inflammation. Therefore, in vitro and in vivo experiments were performed to assess the relationships between microglia­mediated inflammatory reactions and endocrine functions in the PCOS hypothalamus. The expression of gonadotropin­releasing hormone (GnRH) receptor (GnRHR) was demonstrated in hypothalamic microglia, and it was found that low concentration, GnRH agonist, leuprolide acetate accelerated the expression of M2 polarization marker CD206, while high concentration leuprolide acetate increased the expression of M1 polarization marker CD86 in vitro. Furthermore, aerobic exercise not only reduced the levels of serum testosterone, luteinizing hormone and GnRH and the amount of overactivated microglia, but also increased the number of M2 microglia in the hypothalamus of letrozole­induced PCOS rats. In combination, these results not only demonstrated the expression of GnRHR in hypothalamic microglia, but also demonstrated that GnRH can induce microglial polarization, while aerobic exercise may improve the microglia­mediated inflammatory reaction by reducing the expression of GnRHR in the hypothalamic microglia of PCOS rats.


Assuntos
Síndrome do Ovário Policístico , Feminino , Humanos , Ratos , Animais , Síndrome do Ovário Policístico/metabolismo , Receptores LHRH/genética , Leuprolida/farmacologia , Microglia/metabolismo , Hormônio Liberador de Gonadotropina/metabolismo
15.
Drug Des Devel Ther ; 17: 369-380, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36789095

RESUMO

Estrogens play a critical role in the pathogenesis of endometriosis and it is logical to assume that lowering estradiol levels with oral gonadotropin-releasing hormone (GnRH) antagonists may prove effective, especially in women who fail to respond to progestogens. Indeed, due to progesterone resistance, oral contraceptives and progestogens work well in two-thirds of women suffering from endometriosis, but are ineffective in 33% of women. Oral GnRH antagonists have therefore been evaluated for management of premenopausal women with endometriosis-associated pelvic pain. The first publication on these drugs reported the efficacy of elagolix. The present paper is a narrative review of linzagolix, which is an orally administered GnRH receptor antagonist with low pharmacokinetic/pharmacodynamic variability. It binds to and blocks the GnRH receptor in the pituitary gland, resulting in a dose-dependent drop in luteinizing hormone (LH) and follicle-stimulating hormone (FSH) production. This reduction in LH and FSH levels in turn leads to a dose-dependent decline in estrogen. Phase 2 and 3 trials are reviewed and discussed here. There is a place for GnRH antagonists in the management of symptomatic endometriosis, and linzagolix with or without add-back therapy (ABT) is one option that can be used at low doses, avoiding the need for ABT, which is contraindicated in some patients.


Assuntos
Endometriose , Hormônio Liberador de Gonadotropina , Humanos , Feminino , Endometriose/tratamento farmacológico , Receptores LHRH , Progestinas , Estradiol/farmacologia , Hormônio Foliculoestimulante , Hormônio Luteinizante , Antagonistas de Hormônios/uso terapêutico , Estrogênios
16.
Front Endocrinol (Lausanne) ; 14: 1341162, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-38260130

RESUMO

Gonadotropin-releasing hormone (GnRH1) and its receptor (GnRHR1) drive reproduction by regulating gonadotropins. Another form, GnRH2, and its receptor (GnRHR2), also exist in mammals. In humans, GnRH2 and GnRHR2 genes are present, but coding errors in the GnRHR2 gene are predicted to hinder full-length protein production. Nonetheless, mounting evidence supports the presence of a functional GnRHR2 in humans. GnRH2 and its receptor have been identified throughout the body, including peripheral reproductive tissues like the ovary, uterus, breast, and prostate. In addition, GnRH2 and its receptor have been detected in a wide number of reproductive cancer cells in humans. Notably, GnRH2 analogues have potent anti-proliferative, pro-apoptotic, and/or anti-metastatic effects on various reproductive cancers, including endometrial, breast, placental, ovarian, and prostate. Thus, GnRH2 is an emerging target to treat human reproductive cancers.


Assuntos
Hormônio Liberador de Gonadotropina , Receptores LHRH , Neoplasias Urogenitais , Feminino , Humanos , Masculino , Células Germinativas , Hormônio Liberador de Gonadotropina/genética , Receptores LHRH/genética , Neoplasias Urogenitais/genética
17.
Ital J Pediatr ; 48(1): 184, 2022 Nov 12.
Artigo em Inglês | MEDLINE | ID: mdl-36371229

RESUMO

BACKGROUND: Congenital hypogonadotropic hypogonadism (CHH) is a clinically and genetically heterogeneous disease characterized by absent or incomplete puberty and infertility. Clinical characteristics are secondary to insufficient gonadotropin secretion, caused by deficient gonadotropin-releasing hormone (GnRH) production, secretion, or action. Loss-of-function variants of the gonadotropin-releasing hormone receptor (GNRHR) are associated with CHH without anosmia. CHH was previously considered a permanent condition, but in the past two decades, cases of spontaneous recovery of CHH have been reported. The reversal of hypogonadism in CHH is currently unpredictable, and can happen unnoticed. CASE PRESENTATION: The male proband was diagnosed with CHH due to compound heterozygosity for two previously reported pathogenic missense variants in the GNRHR gene, NM_000406.2:c.416G > A (NP_000397.1:p.Arg139His) and c.785G > A (p.Arg262Gln) at 16 years of age. In addition to arrested partial puberty, he had a low testosterone level, gonadotropins in the range of early puberty, and a normal inhibin B level. A therapy with increasing doses of intramuscular testosterone undecanoate was received for 2.5 years, while there was no change in testicular volume. At the age of 19 years, testosterone supplementation was interrupted. During the next two years, he had spontaneous pubertal development to achieve a testicular volume of 20 mL, with normal adult levels of gonadotropins and testosterone. CONCLUSIONS: Genetic diagnostics can help discriminate congenital hypogonadotropic hypogonadism, deserving therapeutic intervention, from the self-limited constitutional delay of growth and puberty (CDGP). Patients with GNRHR associated hypogonadism can experience spontaneous recovery of the hypothalamic-pituitary-gonadal axis. Spontaneous testis enlargement in patients with central hypogonadism not taking gonadotropins or pulsatile GnRH therapy can indicate recovery of hypogonadism.


Assuntos
Hipogonadismo , Receptores LHRH , Adulto , Humanos , Masculino , Adulto Jovem , Receptores LHRH/genética , Receptores LHRH/uso terapêutico , Hipogonadismo/diagnóstico , Hipogonadismo/tratamento farmacológico , Hipogonadismo/genética , Hormônio Liberador de Gonadotropina/uso terapêutico , Hormônio Liberador de Gonadotropina/genética , Gonadotropinas/uso terapêutico , Testosterona/uso terapêutico
18.
J Mech Behav Biomed Mater ; 136: 105461, 2022 12.
Artigo em Inglês | MEDLINE | ID: mdl-36195050

RESUMO

The adhesive interactions between molecular recognition units (such as specific peptides and antibodies) and antigens or other receptors on the surfaces of tumors are of great value in the design of targeted nanoparticles and drugs for the detection and treatment of specific cancers. In this paper, we present the results of a combined experimental and theoretical study of the adhesion between Luteinizing Hormone Releasing Hormone (LHRH)/Epherin type A2 (EphA2)-AFM coated tips and LHRH/EphA2 receptors that are overexpressed on the surfaces of human Triple Negative Breast Cancer (TNBC) tissues of different histological grades. Following a histochemical and immuno-histological study of human tissue extracts, the receptor overexpression, and their distributions are characterized using Immunohistochemistry (IHC), Immunofluorescence (IF), and a combination of fluorescence microscopy and confocal microscopy. The adhesion forces between LHRH or EphA2 and human TNBC breast tissues are measured using force microscopy techniques that account for the potential effects of capillary forces due to the presence of water vapor. The corresponding adhesion energies are also determined using adhesion theory. The pull off forces and adhesion energies associated with higher grades of TNBC are shown to be greater than those associated with normal/non-tumorigenic human breast tissues, which were studied as controls. The observed increase in adhesion forces and adhesion energies are also correlated with the increasing incidence of LHRH/EphA2 receptors at higher grades of TNBC. The implications of the results are discussed for the development of targeted nanostructures for the detection and treatment of TNBC.


Assuntos
Hormônio Liberador de Gonadotropina , Receptores LHRH , Neoplasias de Mama Triplo Negativas , Humanos , Linhagem Celular Tumoral , Hormônio Liberador de Gonadotropina/química , Nanopartículas , Receptores LHRH/química , Neoplasias de Mama Triplo Negativas/patologia
19.
Am Fam Physician ; 106(4): 397-404, 2022 10.
Artigo em Inglês | MEDLINE | ID: mdl-36260896

RESUMO

Endometriosis is an inflammatory condition caused by the presence of endometrial tissue in extra-uterine locations and can involve bowel, bladder, and all peritoneal structures. It is one of the most common gynecologic disorders, affecting up to 10% of people of reproductive age. Presentation of endometriosis can vary widely, from infertility in asymptomatic people to debilitating pelvic pain, dysmenorrhea, and period-related gastrointestinal or urinary symptoms. Diagnosis of endometriosis in the primary care setting is clinical and often challenging, frequently resulting in delayed diagnosis and treatment. Although transvaginal ultrasonography is used to evaluate endometriosis of deep pelvic sites to rule out other causes of pelvic pain, magnetic resonance imaging is preferred if deep infiltrating endometriosis is suspected. Laparoscopy with biopsy remains the definitive method for diagnosis, although several gynecologic organizations recommend empiric therapy without immediate surgical diagnosis. Combined hormonal contraceptives with or without nonsteroidal anti-inflammatory drugs are first-line options in managing symptoms and have a tolerable adverse effect profile. Second-line treatments include gonadotropin-releasing hormone (GnRH) receptor agonists with add-back therapy, GnRH receptor antagonists, and danazol. Aromatase inhibitors are reserved for severe disease. All of these treatments are effective but may cause additional adverse effects. Referral to gynecology for surgical management is indicated if empiric therapy is ineffective, immediate diagnosis and treatment are necessary, or patients desire pregnancy. Alternative treatments have limited benefit in alleviating pain symptoms but may warrant further investigation.


Assuntos
Endometriose , Feminino , Humanos , Gravidez , Anti-Inflamatórios não Esteroides/uso terapêutico , Inibidores da Aromatase/uso terapêutico , Anticoncepcionais , Danazol/uso terapêutico , Endometriose/terapia , Endometriose/tratamento farmacológico , Hormônio Liberador de Gonadotropina/uso terapêutico , Hormônio Liberador de Gonadotropina/agonistas , Dor Pélvica/terapia , Dor Pélvica/tratamento farmacológico , Receptores LHRH/uso terapêutico
20.
J Chem Inf Model ; 62(20): 5009-5022, 2022 Oct 24.
Artigo em Inglês | MEDLINE | ID: mdl-36184840

RESUMO

The gonadotrophin-releasing hormone (GnRH) is a central regulator of the human reproductive system and exerts physiological effects by binding to GnRH1R. The GnRH-GnRH1R system is a promising therapeutic target for the maintenance of reproductive function. There are several GnRH1R agonists on the market, but like GnRH, they are all peptide compounds and are limited by their way of administration (subcutaneous or intramuscular injection). To date, no published GnRH1R small molecule agonists have been reported. In this paper, the HTRF-based screening method has been used to screen our in-house chemical library, and we found and confirmed CD304 as a hit compound. Subsequently, structure optimization led to the discovery of compound 6d, exhibited with a certain GnRH1R activation activity (EC50: 1.59 ± 0.38 µM). Further molecular dynamics simulation experiments showed that 6d can well bind to the orthosteric site of GnRH1R through forming a hydrogen-bonding interaction with Y2836.51. Binding of 6d further induces conformational changes in TM6 and TM7, promoting the formation of a continuous water channel in GnRH1R, thereby promoting GnRH1R activation. This well-characterized hit compound will facilitate the further development of novel small molecule agonists of GnRH1R.


Assuntos
Hormônio Liberador de Gonadotropina , Receptores LHRH , Humanos , Hormônio Liberador de Gonadotropina/farmacologia , Receptores LHRH/agonistas , Receptores LHRH/química , Bibliotecas de Moléculas Pequenas/farmacologia , Ligação de Hidrogênio
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