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Frontiers in Endocrinology 2022The pubertal development onset is controlled by a network of genes that regulate the gonadotropin releasing hormone (GnRH) pulsatile release and the subsequent increase... (Review)
Review
The pubertal development onset is controlled by a network of genes that regulate the gonadotropin releasing hormone (GnRH) pulsatile release and the subsequent increase of the circulating levels of pituitary gonadotropins that activate the gonadal function. Although the transition from pre-pubertal condition to puberty occurs physiologically in a delimited age-range, the inception of pubertal development can be anticipated or delayed due to genetic and epigenetic changes or environmental conditions. Most of the genetic and epigenetic alterations concern genes which encode for kisspeptin, GnRH, LH, FSH and their receptor, which represent crucial factors of the hypothalamic-pituitary-gonadal (HPG) axis. Recent data indicate a central role of the epigenome in the regulation of genes in the hypothalamus and pituitary that could mediate the flexibility of pubertal timing. Identification of epigenetically regulated genes, such as Makorin ring finger 3 () and Delta-like 1 homologue (), respectively responsible for the repression and the activation of pubertal development, provides additional evidence of how epigenetic variations affect pubertal timing. This review aims to investigate genetic, epigenetic, and environmental factors responsible for the regulation of precocious and delayed puberty.
Topics: Humans; Puberty, Precocious; Puberty, Delayed; Gonadotropin-Releasing Hormone; Puberty; Epigenesis, Genetic; Ubiquitin-Protein Ligases
PubMed: 36619551
DOI: 10.3389/fendo.2022.1019468 -
Acta Bio-medica : Atenei Parmensis Sep 2019Central precocious puberty (CPP) is defined as an early pubertal development that occurs before the age of 9 years in boys and 8 years in girls. It results from... (Review)
Review
Long-term effects and significant Adverse Drug Reactions (ADRs) associated with the use of Gonadotropin-Releasing Hormone analogs (GnRHa) for central precocious puberty: a brief review of literature.
Central precocious puberty (CPP) is defined as an early pubertal development that occurs before the age of 9 years in boys and 8 years in girls. It results from premature activation of the hypothalamic-pituitary-gonadal axis. Gonadotropin-releasing hormone agonists (GnRHa) have been the gold standard therapy for CPP for more than 30 years. These compounds have a high affinity for the pituitary LHRH receptor and are resistant to enzymatic degradation. Through continuous stimulation, GnRHa inhibit the pulsatile secretion of gonadotropin, resulting in hormonal suppression, cessation of pubertal development, and normalization of growth and skeletal maturation rates. The goal of therapy is to halt pubertal progression and delay epiphyseal maturation that leads to improvement of final adult height. There are no widely accepted guidelines for how long to continue treatment with a GnRHa for CPP, and individual practice varies widely. Furthermore, conflicting results have been published on the long-term effects of GnRHa therapy in patients with CPP. Therefore, we reviewed the current literature focusing our attention on the long-term effects and the significant adverse drug reactions (ADRs) observed during treatment with GnRHa in patients with CPP. Our review may provide the necessary data to enable clinicians to administer GnRHa in the safest and most appropriate way. Further studies are necessary to identify the mechanisms of development of potential adverse drug reactions related to GnRHa therapy in CPP.
Topics: Body Height; Body Weight; Bone Density; Drug-Related Side Effects and Adverse Reactions; Female; Gonadotropin-Releasing Hormone; Humans; Polycystic Ovary Syndrome; Puberty, Precocious
PubMed: 31580327
DOI: 10.23750/abm.v90i3.8736 -
Fertility and Sterility Oct 2001
Topics: Drug Therapy, Combination; Female; Gonadotropin-Releasing Hormone; Humans; Leuprolide; Norpregnenes; Premenstrual Syndrome
PubMed: 11680434
DOI: 10.1016/s0015-0282(01)02072-6 -
Fertility and Sterility Jan 2000
Topics: Female; Gonadotropin-Releasing Hormone; Hormone Antagonists; Humans; Ovulation Induction
PubMed: 10632404
DOI: 10.1016/s0015-0282(99)00448-3 -
Endocrine Reviews Oct 2019This review presents a comprehensive discussion of the clinical condition of delayed puberty, a common presentation to the pediatric endocrinologist, which may present... (Review)
Review
This review presents a comprehensive discussion of the clinical condition of delayed puberty, a common presentation to the pediatric endocrinologist, which may present both diagnostic and prognostic challenges. Our understanding of the genetic control of pubertal timing has advanced thanks to active investigation in this field over the last two decades, but it remains in large part a fascinating and mysterious conundrum. The phenotype of delayed puberty is associated with adult health risks and common etiologies, and there is evidence for polygenic control of pubertal timing in the general population, sex-specificity, and epigenetic modulation. Moreover, much has been learned from comprehension of monogenic and digenic etiologies of pubertal delay and associated disorders and, in recent years, knowledge of oligogenic inheritance in conditions of GnRH deficiency. Recently there have been several novel discoveries in the field of self-limited delayed puberty, encompassing exciting developments linking this condition to both GnRH neuronal biology and metabolism and body mass. These data together highlight the fascinating heterogeneity of disorders underlying this phenotype and point to areas of future research where impactful developments can be made.
Topics: Animals; Epigenesis, Genetic; Female; Gonadotropin-Releasing Hormone; Humans; Male; Phenotype; Puberty, Delayed; Sex Characteristics
PubMed: 31220230
DOI: 10.1210/er.2018-00248 -
Asian Journal of Andrology 2021Androgen deprivation therapy (ADT) with gonadotropin-releasing hormone (GnRH) agonists and antagonists is the mainstay of advanced prostate cancer treatment. Both drug... (Review)
Review
Androgen deprivation therapy (ADT) with gonadotropin-releasing hormone (GnRH) agonists and antagonists is the mainstay of advanced prostate cancer treatment. Both drug classes decrease levels of luteinizing hormone and follicle-stimulating hormones (FSH), thereby lowering testosterone to castrate levels. This is associated with adverse events (AEs), including cardiovascular (CV) disorders, bone fractures, metabolic dysfunction, and impaired cognitive function. This literature review discusses these AEs, with a focus on CV and bone-related events. A hypothesis-generating meta-analysis of six clinical trials showed a potentially increased risk for CV disorders with GnRH agonists versus the GnRH antagonist degarelix. While no study has directly compared GnRH agonists versus antagonists with a primary CV outcome, one hypothesis for this observation is that GnRH agonists lead to initial surges in FSH that may negatively impact CV health, whereas antagonists do not. GnRH agonists are associated with metabolic and cognitive AEs and while data are lacking for GnRH antagonists, no differences in risk are predicted. Other common AEs with ADT include injection site reactions, which are much more common with degarelix than with GnRH agonists, which may reflect differing administration and injection techniques. Future studies are needed to further evaluate and compare the safety profiles of GnRH agonists and antagonists, especially in patients with pre-existing CV disease and other co-morbidities. Physicians should carefully evaluate benefits and risks when prescribing ADT and ensure that side effects are well managed.
Topics: Androgen Antagonists; Gonadotropin-Releasing Hormone; Humans; Male; Prostatic Neoplasms
PubMed: 32655041
DOI: 10.4103/aja.aja_22_20 -
General and Comparative Endocrinology Aug 2018Gonadotropin-releasing hormone (GnRH) was first discovered in mammals on account of its effect in triggering pituitary release of gonadotropins and the importance of... (Review)
Review
Gonadotropin-releasing hormone (GnRH) was first discovered in mammals on account of its effect in triggering pituitary release of gonadotropins and the importance of this discovery was recognized forty years ago in the award of the 1977 Nobel Prize for Physiology or Medicine. Investigation of the evolution of GnRH revealed that GnRH-type signaling systems occur throughout the chordates, including agnathans (e.g. lampreys) and urochordates (e.g. sea squirts). Furthermore, the discovery that adipokinetic hormone (AKH) is the ligand for a GnRH-type receptor in the arthropod Drosophila melanogaster provided evidence of the antiquity of GnRH-type signaling. However, the occurrence of other AKH-like peptides in arthropods, which include corazonin and AKH/corazonin-related peptide (ACP), has complicated efforts to reconstruct the evolutionary history of this family of related neuropeptides. Genome/transcriptome sequencing has revealed that both GnRH-type receptors and corazonin-type receptors occur in lophotrochozoan protostomes (annelids, mollusks) and in deuterostomian invertebrates (cephalochordates, hemichordates, echinoderms). Furthermore, peptides that act as ligands for GnRH-type and corazonin-type receptors have been identified in mollusks. However, what has been lacking is experimental evidence that distinct GnRH-type and corazonin-type peptide-receptor signaling pathways occur in deuterostomes. Importantly, we recently reported the identification of two neuropeptides that act as ligands for either a GnRH-type receptor or a corazonin-type receptor in an echinoderm species - the common European starfish Asterias rubens. Discovery of distinct GnRH-type and corazonin-type signaling pathways in this deuterostomian invertebrate has demonstrated for the first time that the evolutionarily origin of these paralogous systems can be traced to the common ancestor of protostomes and deuterostomes. Furthermore, lineage-specific losses of corazonin signaling (in vertebrates, urochordates and nematodes) and duplication of the GnRH signaling system in arthropods (giving rise to the AKH and ACP signaling systems) and quadruplication of the GnRH signaling system in vertebrates (followed by lineage-specific losses or duplications) accounts for the phylogenetic distribution of GnRH/corazonin-type peptide-receptor pathways in extant animals. Informed by these new insights, here we review the history of research on the evolution of GnRH/corazonin-type neuropeptide signaling. Furthermore, we propose a standardized nomenclature for GnRH/corazonin-type neuropeptides wherein peptides are either named "GnRH" or "corazonin", with the exception of the paralogous GnRH-type peptides that have arisen by gene duplication in the arthropod lineage and which are referred to as "AKH" (or red pigment concentrating hormone, "RCPH", in crustaceans) and "ACP".
Topics: Amino Acid Sequence; Animals; Evolution, Molecular; Gonadotropin-Releasing Hormone; Insect Proteins; Neuropeptides; Phylogeny; Signal Transduction; Terminology as Topic
PubMed: 28622978
DOI: 10.1016/j.ygcen.2017.06.007 -
Targeted Oncology Mar 2023Relugolix (Orgovyx), an orally active nonpeptide gonadotropin-releasing hormone (GnRH) receptor antagonist that provides rapid testosterone suppression, is indicated in... (Review)
Review
Relugolix (Orgovyx), an orally active nonpeptide gonadotropin-releasing hormone (GnRH) receptor antagonist that provides rapid testosterone suppression, is indicated in the USA for the treatment of advanced prostate cancer and in the EU for advanced hormone-sensitive prostate cancer. In the pivotal phase III HERO trial in men with advanced prostate cancer, once-daily oral relugolix (with a loading dose on day 1) led to a sustained castration rate over 48 weeks of treatment of > 90%, a rate that was non-inferior to that provided by intramuscular leuprolide depot every 3 months (with an exploratory analysis further indicating the superiority of relugolix over leuprolide). Relugolix was generally well tolerated, having an adverse event profile that is consistent with testosterone suppression. Furthermore, there is evidence that relugolix may be associated with a lower risk of major adverse cardiac events compared with leuprolide. With the ability to provide the rapid testosterone suppression (with no initial surge in testosterone upon treatment initiation) combined with the benefits of oral administration and potentially improved cardiac safety, relugolix presents a valuable treatment option for men with advanced prostate cancer where androgen deprivation therapy is indicated.
Topics: Male; Humans; Prostatic Neoplasms; Leuprolide; Gonadotropin-Releasing Hormone; Androgen Antagonists; Testosterone
PubMed: 36652173
DOI: 10.1007/s11523-022-00944-4 -
Cells Feb 2021Endometrial cancer (EC) is one of the most common gynecological malignancies. Gonadotropin releasing hormone (GnRH) is a decapeptide first described to be secreted by... (Review)
Review
Endometrial cancer (EC) is one of the most common gynecological malignancies. Gonadotropin releasing hormone (GnRH) is a decapeptide first described to be secreted by the hypothalamus to regulate pituitary gonadotropin secretion. In this systematic review, we analyze and summarize the data indicating that most EC express GnRH and its receptor (GnRH-R) as part of an autocrine system regulating proliferation, the cell cycle, and apoptosis. We analyze the available data on the expression and function of GnRH-II, its putative receptor, and its signal transduction. GnRH-I and GnRH-II agonists, and antagonists as well as cytotoxic GnRH-I analogs, have been shown to inhibit proliferation and to induce apoptosis in human EC cell lines in pre-clinical models. Treatment with conventional doses of GnRH-agonists that suppress pituitary gonadotropin secretion and ovarian estrogen production has become part of fertility preserving therapy of early EC or its pre-cancer (atypical endometrial hyperplasia). Conventional doses of GnRH-agonists had marginal activity in advanced or recurrent EC. Higher doses or more potent analogs including GnRH-II antagonists have not yet been used clinically. The cytotoxic GnRH-analog Zoptarelin Doxorubicin has shown encouraging activity in a phase II trial in patients with advanced or recurrent EC, which expressed GnRH-R. In a phase III trial in patients with EC of unknown GnRH-R expression, the cytotoxic GnRH doxorubicin conjugate was not superior to free doxorubicin. Further well-designed clinical trials exploiting the GnRH-system in EC might be useful.
Topics: Adult; Aged; Endometrial Neoplasms; Female; Gonadotropin-Releasing Hormone; Humans; Middle Aged; Signal Transduction
PubMed: 33535622
DOI: 10.3390/cells10020292 -
Expert Review of Endocrinology &... Mar 2019Precocious puberty (PP) is one of the most common reasons for referral to pediatric endocrinologists. Gonadotropin-releasing hormone analogs (GnRHas) are the gold... (Review)
Review
INTRODUCTION
Precocious puberty (PP) is one of the most common reasons for referral to pediatric endocrinologists. Gonadotropin-releasing hormone analogs (GnRHas) are the gold standard for the treatment of central precocious puberty (CPP) and have an impressive record of safety and efficacy. However, ongoing refinements in diagnosis and management continue to lead to important advancements in clinical care.
AREAS COVERED
The aim of this review is to cover current considerations and controversies regarding the diagnosis of CPP, as well as new findings in regards to etiology and treatment modalities.
EXPERT COMMENTARY
There is emerging evidence of monogenic etiologies of CPP and significant progress in the expansion of newer formulations of GnRHas. Despite these exciting developments, areas of uncertainty in the diagnosis and treatment of CPP remain. While long-term outcomes of patients treated for CPP are encouraging, only short-term follow-up is available with respect to the newer extended release GnRHa preparations, and how they compare with historically used formulations is unknown. A particular shortage of information exists pertaining to CPP in boys and regarding the psychological implications of PP in girls, and more research is needed. Continued investigation will yield new insights into the underlying genetics and optimal treatment strategies for CPP.
Topics: Gonadotropin-Releasing Hormone; Humans; Puberty, Precocious; Risk Factors; Treatment Outcome
PubMed: 30763521
DOI: 10.1080/17446651.2019.1575726