Dataset Information

Switching from a gonadotropin-releasing hormone (GnRH) agonist to a GnRH antagonist in prostate cancer patients: A systematic review and meta-analysis.

ABSTRACT:

Introduction

We sought to address whether there are clinical responses when patients who are failing gonadotropin-releasing hormone (GnRH) agonist therapy are switched to degarelix. Androgen-deprivation therapy remains the backbone of treatment for disseminated prostate cancer and may be achieved with orchiectomy, GnRH agonists, or degarelix, a GnRH antagonist.

Methods

We conducted a systematic review and meta-analysis with a search of the BIOSIS Previews, Embase, International Pharmaceutical Abstracts, MEDLINE, and Google Scholar databases using key terms. Quantitative meta-analysis was performed to provide a pooled estimate of prostate specific antigen (PSA) response at three months.

Results

Thirteen studies were identified, eight of which were included in the qualitative and quantitative analyses. Patient characteristics were broadly similar between the studies. Out of 155 patients across all included studies, 20 had stable PSA after the switch (12.9%), 14 had a 10-30% decrease in PSA (9.0%), three had a 30-50% decrease (1.9%), and 13 had a more than 50% decrease (8.4%). Random effects meta-analysis of these data demonstrated a pooled response rate of 27.75% (95% confidence interval 18.9-36.5%; I²=7.9%). Changes in testosterone levels following the switch could not be quantitatively assessed due to lack of sufficient data.

Conclusions

Our results suggest that a switch to GnRH antagonist following progression on a GnRH agonist may result in a stable or decreased PSA at three months in about 30% of patients. This information should be considered among the potential options to discuss with patients with a rising PSA on GnRH agonist therapy.

SUBMITTER: Atchia KS

PROVIDER: S-EPMC7012296 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature

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Publications

Switching from a gonadotropin-releasing hormone (GnRH) agonist to a GnRH antagonist in prostate cancer patients: A systematic review and meta-analysis.

Atchia Kaleem S KS Wallis Christopher J D CJD Fleshner Neil N Toren Paul P

Canadian Urological Association journal = Journal de l'Association des urologues du Canada 20190723 2

<h4>Introduction</h4>We sought to address whether there are clinical responses when patients who are failing gonadotropin-releasing hormone (GnRH) agonist therapy are switched to degarelix. Androgen-deprivation therapy remains the backbone of treatment for disseminated prostate cancer and may be achieved with orchiectomy, GnRH agonists, or degarelix, a GnRH antagonist.<h4>Methods</h4>We conducted a systematic review and meta-analysis with a search of the BIOSIS Previews, Embase, International Ph ...[more]

PMID: 31348745

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Project description:Gonadotropin-releasing hormone (GnRH) regulates reproduction. The human GnRH receptor lacks a cytoplasmic carboxy-terminal tail but has amino acid sequence motifs characteristic of rhodopsin-like, class A, G protein-coupled receptors (GPCRs). This review will consider how recent descriptions of X-ray crystallographic structures of GPCRs in inactive and active conformations may contribute to understanding GnRH receptor structure, mechanism of activation and ligand binding. The structures confirmed that ligands bind to variable extracellular surfaces, whereas the seven membrane-spanning ?-helices convey the activation signal to the cytoplasmic receptor surface, which binds and activates heterotrimeric G proteins. Forty non-covalent interactions that bridge topologically equivalent residues in different transmembrane (TM) helices are conserved in class A GPCR structures, regardless of activation state. Conformation-independent interhelical contacts account for a conserved receptor protein structure and their importance in the GnRH receptor structure is supported by decreased expression of receptors with mutations of residues in the network. Many of the GnRH receptor mutations associated with congenital hypogonadotropic hypogonadism, including the Glu2.53(90) Lys mutation, involve amino acids that constitute the conserved network. Half of the ~250 intramolecular interactions in GPCRs differ between inactive and active structures. Conformation-specific interhelical contacts depend on amino acids changing partners during activation. Conserved inactive conformation-specific contacts prevent receptor activation by stabilizing proximity of TM helices 3 and 6 and a closed G protein-binding site. Mutations of GnRH receptor residues involved in these interactions, such as Arg3.50(139) of the DRY/S motif or Tyr7.53(323) of the N/DPxxY motif, increase or decrease receptor expression and efficiency of receptor coupling to G protein signaling, consistent with the native residues stabilizing the inactive GnRH receptor structure. Active conformation-specific interhelical contacts stabilize an open G protein-binding site. Progress in defining the GnRH-binding site has recently slowed, with evidence that Tyr6.58(290) contacts Tyr5 of GnRH, whereas other residues affect recognition of Trp3 and Gly10NH2. The surprisingly consistent observations that GnRH receptor mutations that disrupt GnRH binding have less effect on "conformationally constrained" GnRH peptides may now be explained by crystal structures of agonist-bound peptide receptors. Analysis of GPCR structures provides insight into GnRH receptor function.

Project description:BackgroundThe main objective of the present work was to compare the effects of the gonadotropin-releasing hormone agonist (GnRH-a) and GnRH antagonist (GnRH-ant) on the gene expression profiles of oocytes obtained from Iranian infertile couples undergoing in vitro fertilization (IVF).MethodsFifty infertile couples who underwent IVF between June 2012 and November 2013 at the Infertility Center of Tehran Women General Hospital, Tehran University of Medical Sciences, were included in this study. We included women that had undergone IVF treatment because of male factor, tubal factor, or unexplained infertility. The women randomly underwent controlled ovarian stimulation (COS) with either the GnRH-a (n = 26) or the GnRH-ant (n = 24). We obtained 50 germinal vesicle (GV) oocytes donated by women in each group. After the sampling, pool of 50 GV oocytes for each group was separately analyzed by quantitative polymerase chain reaction (qPCR).ResultThe expression levels of Adenosine triphosphatase 6 (ATPase 6), Bone morphogenetic protein 15 (BMP15), and Neuronal apoptosis inhibitory protein (NAIP) genes were significantly upregulated in the GnRH-ant group compared to the GnRH-a group, with the fold change of 3.990 (SD ± 1.325), 6.274 (SD ± 1.542), and 2.156 (SD ± 1.443), respectively, (P < 0.001). Growth differentiation factor 9 (GDF9) mRNA did not have any expression in the GnRH-a group; however, GDF9 mRNA was expressed in the GnRH-ant group. Finally, it was found that the genes involved in the DNA repairing and cell cycle checkpoint did not have any expression in either group.ConclusionThe present study showed, for the first time, the expression levels of genes involved in the cytoplasmic maturity (BMP15, GDF9), adenosine triphosphate production (ATPase 6), and antiapoptotic process (NAIP), in human GV oocytes were significantly higher in the GnRH-anta group than in the GnRH-a group in COS. Higher expression level of these genes when GnRH-ant protocol is applied, this protocol seems to be a more appropriate choice for women with poly cystic ovarian syndrome, because it can probably improve the expression of the aforementioned genes.Trial registrationCurrent Controlled Trials: IRCT 2014031112307 N3.

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Dataset Information

Switching from a gonadotropin-releasing hormone (GnRH) agonist to a GnRH antagonist in prostate cancer patients: A systematic review and meta-analysis.

Introduction

Methods

Results

Conclusions

Publications

Switching from a gonadotropin-releasing hormone (GnRH) agonist to a GnRH antagonist in prostate cancer patients: A systematic review and meta-analysis.

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