| luteinizing hormone/choriogonadotropin receptor | OKDB#: 1 |
| Symbols: | LHCGR | Species: | human | ||
| Synonyms: | HHG, LHR, LCGR, LGR2, ULG5, LHRHR, LSH-R, LH/CGR, LH/CG-R | Locus: | 2p16.3 in Homo sapiens | HPMR |
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| General Comment |
The LH receptor is a seven transmembrane, Gs protein-coupled plasma membrane protein with a large ectodomain containing leucine-rich repeats important for LH/hCG binding. Unlike its rodent counterparts, the human LH receptor is highly specific in ligand recognition and does not bind LH from non-primate species (Jia et al., 1991). ////Discovery of BAY-298 and BAY-899: Tetrahydro-1,6-naphthyridine-Based, Potent and Selective Antagonists of the Luteinizing Hormone Receptor Which Reduce Sex Hormone Levels In Vivo. Wortmann L et al. (2019) The human luteinizing hormone receptor (hLH-R) is a member of the glycoprotein hormone family of GPCRs, activated by luteinizing hormone (hLH) and essentially involved in the regulation of sex hormone production. Thus, hLH-R represents a valid target for the treatment of sex hormone-dependent cancers and diseases (polycystic ovary syndrome, uterine fibroids, endometriosis) as well as contraception. Screening of the Bayer compound library led to the discovery of tetrahydrothienopyridine derivatives as novel, small molecule (SMOL) hLH-R inhibitors and to the development of BAY-298, the first nanomolar hLH-R antagonist reducing sex hormone levels in vivo. Further optimization of physicochemical, pharmacokinetic and safety parameters led to the identification of BAY-899 with an improved in vitro profile and proven efficacy in vivo. BAY-298 and BAY-899 serve as valuable tool compounds to study hLH-R signaling in vitro and to interfere with the production of sex hormones in vivo.//////////////////
First Evidence of Ovulation Induced by Oral LH Agonists in Healthy Female Volunteers of Reproductive Age. Gerrits M et al. Context:Two new low-molecular-weight LH agonists (Org 43553 and Org 43902) were shown to induce ovulation in preclinical experiments.Objective:Our objective was to assess the safety, pharmacokinetics, and pharmacodynamics of Org 43553 and Org 43902 when administered to healthy females.Design and Setting:Org 43553 and 43902 studies were randomized, placebo-controlled, single-rising-dose first-in-human trials, which included 159 healthy female volunteers. Part 1 of the studies assessed the safety and pharmacokinetics. Part 2 evaluated the pharmacodynamics effect of a single oral dose of Org 43553 (25-900 mg) or Org 43902 (30-300 mg) to induce ovulation after the development of a large preovulatory follicle, whereas the endogenous LH surge was suppressed due to GnRH antagonist treatment while follicular development was supported with recombinant FSH.Results:Org 43553 and 43902 were safe and well tolerated. Both compounds showed a fast absorption after oral intake, with peak concentrations reached within 0.5 to 1 hour. The elimination half-life of Org 43553 was 30 to 47 hours and that of Org 43902 was 17 to 22 hours. Ovulation induction confirmed by midluteal progesterone rise =15 nmol/L was proven in both studies, also when excluding subjects with an endogenous LH rise. The minimal effective dose for ovulation induction was 300 mg in both studies and resulted in an ovulation rate of 83% and 82%, respectively.Conclusions:These first proof-of-concept studies both demonstrated that a single oral intake of an low-molecular-weight LH agonist induces ovulation of the preovulatory follicle in pituitary-suppressed female volunteers of reproductive age.
NCBI Summary: This gene encodes the receptor for both luteinizing hormone and choriogonadotropin. This receptor belongs to the G-protein coupled receptor 1 family, and its activity is mediated by G proteins which activate adenylate cyclase. Mutations in this gene result in disorders of male secondary sexual character development, including familial male precocious puberty, also known as testotoxicosis, hypogonadotropic hypogonadism, Leydig cell adenoma with precocious puberty, and male pseudohermaphtoditism with Leydig cell hypoplasia. [provided by RefSeq, Jul 2008] |
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| General function | Receptor | ||||
| Comment | Transcriptional effect of the luteinizing hormone surge in bovine granulosa cells during the peri-ovulation period. Gilbert I et al. The LH surge induces panoply of events that are essential for ovulation and corpus luteum formation. The transcriptional responses to the LH surge of pre-ovulatory granulosa cells are complex and still poorly understood. In the present study, a genome wide bovine oligo array was used to determine how the gene expression profiles of granulosa cells are modulated by the LH surge. Granulosa cells from three different statuses were used (1) 2 h before the induction of the LH surge, (2) 6 h and (3) 22 h after the LH surge to assess the short and long term effects of this hormone on follicle differentiation. The results obtained were a list of differentially expressed transcripts for each granulosa cell group. To provide a comprehensive understanding of the processes at play, biological annotations were used to reveal the different functions of transcripts, confirming that the LH surge acts in a temporal manner. The pre-LH group is involved in typical tasks such as cell division, development and proliferation, while the short response of the LH surge included features such as response to stimulus, vascularisation and lipid synthesis, which are indicative of cells preparing for ovulation. The late response of granulosa cells revealed terms associated with protein localization and intra-cellular transport corresponding to the future secretion task that will be required for the transformation of granulosa cells into corpus luteum. Overall, results described in this study provide new insights into the different transcriptional steps that granulosa cells go through during ovulation and before luteinization. The gonadotropin (LH and FSH) and TSH receptors within the seven-TM G protein-coupled receptor family are unique in that they have unusually large extracellular domains as the ligand binding site and share high homology in their transmembrane regions. Differential expression and functional characterization of luteinizing hormone receptor (LHR) splice variants in human luteal cells: implications for luteolysis. Dickinson RE et al. The human LH receptor (LHR) plays a key role in luteal function and the establishment of pregnancy through its interaction with the gonadotropins LH and human chorionic gonadotropin (hCG). We previously identified four splice variants of the LHR in human luteinized granulosa cells (LGC) and corpora lutea (CL). Real-time quantitative PCR revealed that expression of the full-length LHR (LHRa) and the most truncated form (LHRd) changed significantly in CL harvested at different stages of the ovarian cycle (P<0.01, ANOVA). LHRa expression was reduced in the late luteal CL (P<0.05). Conversely, an increase in LHRd expression was observed in the late luteal CL (P<0.01). Chronic manipulation of hCG in LGC primary cultures supported the in vivo findings. LHRd encodes a protein lacking the transmembrane and Carboxyl terminal domains. COS-7 cells expressing LHRd were unable to produce cAMP in response to LH stimulation. COS-7 cells co-expressing LHRd and LHRa also failed to generate cAMP in response to LH suggesting that this truncated form has a negative effect on the signaling of LHRa. Immunofluorescence staining of LGC and COS-7 cells implied that there is a reduction in cell surface expression of LHRa when LHRd is present. Overall these results imply expression of LHR splice variants is regulated in the human CL. Furthermore, during functional luteolysis a truncated variant could modulate the cell surface expression and activity of full-length LHR. | ||||
| Cellular localization | Plasma membrane | ||||
| Comment | GWAS123 /// Polymorphism in the Alternative Donor Site of the Cryptic Exon of LHCGR: Functional Consequences and Associations with Testosterone Level. Liu W et al. (2017) Selective splicing is a feature of luteinizing hormone receptor (LHCGR). A cryptic exon (LHCGR-exon 6A) was found to be derived from alternative splicing in intron 6 of the LHCGR gene, which including two transcripts LHCGR-exon 6A-long and LHCGR-exon 6A-short. We addressed the functional consequences of SNP rs68073206, located at the +5 position of an alternative 5' splice donor site, and observed its association with male infertility in the subjects with azoospermia, oligoasthenozoospermia and normozoospermia. The translation product of splicing variant LHCGR-exon 6A was expressed in the cytoplasm and exhibited no affinity with (125)I]-hCG. No dominant negative effect was observed in cells co-expressed with LHCGR-exon 6A and wild-type LHCGR. The long transcript (LHCGR-exon 6A-long) was significantly elevated in the granulosa cells with G/G genotypes, which could be reproduced in vitro by mini-gene construct transfection. Genotyping analysis showed no association between rs68073206 and male infertility. However, this polymorphism was significantly associated with testosterone levels in normozoospermic subjects (n = 210). In conclusion, SNP rs68073206 in the splicing site of the cryptic exon 6A of the LHCGR gene affect the splicing pattern in the gene, which may play a role in the modulation of the LHCGR sensitivity in the gonads.////////////////// A low molecular weight agonist signals by binding to the transmembrane domain of TSHR and LHCGR. [J?hke H et al. Many cognate low molecular weight (LMW) agonists bind to seven transmembrane-spanning receptors (7TMRs) within their transmembrane helices (TMHs). The thienopyrimidine org41841 was identified previously as an agonist for the luteinizing hormone/chorionic gonadotropin receptor (LHCGR) and suggested to bind within its TMHs because it did not compete for LH binding to the LHCGR ectodomain. Because of its high homology with LHCGR, we predicted that thyroid-stimulating hormone receptor (TSHR) might be activated by org41841 also. We show that org41841 is a partial agonist for TSHR but with lower potency than for LHCGR. Analysis of 3-dimensional molecular models of TSHR and LHCGR predicted a binding pocket for org41841 in common clefts between TMHs 3, 4, 5, 6 and 7 and extracellular loop 2 in both receptors. Evidence for this binding pocket was obtained in signaling studies with chimeric receptors that exhibited improved responses to org41841. Furthermore, a key receptor-ligand interaction between the highly conserved negatively charged E3.37 and the amino group of org41841 predicted by docking of the ligand into the 3-dimensional TSHR model was experimentally confirmed. These findings provide the first evidence that, in contrast to the ectodomain binding of cognate ligands, a LMW agonist can bind to and activate glycoprotein hormone receptors via interaction with their transmembrane domain. | ||||
| Ovarian function | Follicle development, Antral follicle growth, Follicle atresia, Ovulation, Steroid metabolism, Luteinization, Luteolysis, Oocyte maturation | ||||
| Comment | Persistent cAMP signaling by internalized LH receptors in ovarian follicles. Lyga S et al. (2016) A crucial event in female reproduction occurs at mid-cycle, when a luteinizing hormone (LH) peak induces the final maturation of ovarian follicles. LH signals via a G protein-coupled receptor (GPCR) selectively expressed in the outermost follicular cell layers. However, how LH signals are relayed inside these cells and finally to the oocyte is incompletely understood. Here, we monitored LH signaling in intact ovarian follicles of transgenic mice expressing a fluorescent cAMP sensor. We found that LH stimulation induces two phases of cAMP signaling in all cell layers surrounding the oocyte. Interfering with LH receptor internalization abolished the second, persistent cAMP phase and partially inhibited oocyte meiosis resumption. These data suggest that persistent cAMP signals from internalized LH receptors contribute to transmitting LH effects inside follicle cells and ultimately to the oocyte. Thus, this study indicates that the recently proposed paradigm of cAMP signaling by internalized GPCRs is implicated in receptor function and is physiologically relevant.////////////////// Aging-related premature luteinization of granulosa cells is avoided by early oocyte retrieval. Wu YG et al. (2015) Why IVF pregnancy rates decline sharply after age 43 is unknown. In this study, we compared granulosa cell (GC) function in young oocyte donors (n=31, ages 21-29), middle-aged (n=64, ages 30-37) and older infertile patients (n=41, ages 43-47). Gene expressions related to gonadotropin activity, steroidogenesis, apoptosis and luteinization were examined by real-time PCR and western blot in GCs collected from follicular fluid. FSH receptor (FSHR), aromatase (CYP19A1) and 17β-hydroxysteroid dehydrogenase (HSD17B) expression were found down regulated with advancing age, while LH receptor (LHCGR), P450scc (CYP11A1) and progesterone receptor (PGR) were up regulated. Upon in vitro culture, GCs were found to exhibit lower proliferation and increased apoptosis with aging. While FSH supplementation stimulated GCs growth and prevented luteinization in vitro. These observations demonstrate age-related functional declines in GCs, consistent with premature luteinization. To avoid premature luteinization in women above age 43, we advanced oocyte retrieval by administering human chorionic gonadotropin at maximal leading follicle size of 16 mm (routine 19-21 mm). Compared to normal cycles in women of similar age, earlier retrieved patients demonstrated only a marginal increase in oocyte prematurity, yet exhibited improved embryo numbers as well as quality and respectable clinical pregnancy rates. Premature follicular luteinization appears to contribute to rapidly declining IVF pregnancy chances after age 43, and can be avoided by earlier oocyte retrieval.////////////////// Intercellular signaling via cyclic GMP diffusion through gap junctions restarts meiosis in mouse ovarian follicles. Shuhaibar LC et al. (2015) Meiosis in mammalian oocytes is paused until luteinizing hormone (LH) activates receptors in the mural granulosa cells of the ovarian follicle. Prior work has established the central role of cyclic GMP (cGMP) from the granulosa cells in maintaining meiotic arrest, but it is not clear how binding of LH to receptors that are located up to 10 cell layers away from the oocyte lowers oocyte cGMP and restarts meiosis. Here, by visualizing intercellular trafficking of cGMP in real-time in live follicles from mice expressing a FRET sensor, we show that diffusion of cGMP through gap junctions is responsible not only for maintaining meiotic arrest, but also for rapid transmission of the signal that reinitiates meiosis from the follicle surface to the oocyte. Before LH exposure, the cGMP concentration throughout the follicle is at a uniformly high level of ∼2-4 μM. Then, within 1 min of LH application, cGMP begins to decrease in the peripheral granulosa cells. As a consequence, cGMP from the oocyte diffuses into the sink provided by the large granulosa cell volume, such that by 20 min the cGMP concentration in the follicle is uniformly low, ∼100 nM. The decrease in cGMP in the oocyte relieves the inhibition of the meiotic cell cycle. This direct demonstration that a physiological signal initiated by a stimulus in one region of an intact tissue can travel across many layers of cells via cyclic nucleotide diffusion through gap junctions could provide a general mechanism for diverse cellular processes.////////////////// LH receptor mediates the ovulation-induction effect of the preovulatory LH surge. It is also important for the survival action of LH and essential for follicular and luteal steroidogenesis. Prevention of the Onset of Ovarian Hyperstimulation Syndrome (OHSS) in the Rat After Ovulation Induction with a Low Molecular Weight Agonist of the LH Receptor Compared with hCG and rec-LH. van de Lagemaat R et al. Ovarian hyperstimulation syndrome (OHSS) incidentally occurs in controlled ovarian stimulation protocols and is associated with human chorionic gonadotropin (hCG) administration. OHSS is caused by increased vascular permeability (VP) and thought to be mediated by hypersecretion of vascular endothelial growth factor (VEGF) by granulosa cells. Low molecular weight (LMW)-LH agonists have a similar mode of action but a shorter half-life compared with hCG, which could potentially lead to a clinical benefit in reducing the risk for OHSS in controlled ovarian stimulation protocols. The objective of this study is to investigate the role of an orally active LMW-LH agonist in OHSS induction compared with recombinant LH (rec-LH) and hCG. Immature rats were hyperstimulated with pregnant mare serum gonadotropin, and ovulation was induced by hCG, rec-LH or a LMW-LH agonist. The degree of VP was determined by Evans Blue in the abdominal cavity. Ovaries were weighed, and VEGF concentration in the ovary was determined. Pregnant mare serum gonadotropin stimulation followed by single-dose hCG or rec-LH resulted in clear enlargement of the ovaries and increased VP and VEGF levels. However, ovulation induction with a single dose of the LMW-LH agonist did not result in increased VP and VEGF levels, and even multiple dosing to mimic a longer exposure did not induce OHSS symptoms. In conclusion, we demonstrated that the oral LMW-LH agonist did not induce VP in rat, indicative for OHSS, possibly due to reduced VEGF production. If this is translatable to human, this could potentially represent a clinical benefit in reducing the risk for OHSS when using these compounds in controlled ovarian stimulation protocols. Induction of ovulation by a potent, orally active, low molecular weight agonist (Org 43553) of the luteinizing hormone receptor. van de Lagemaat R et al. BACKGROUND In assisted reproductive technology, human chorionic gonadotrophin (hCG) is administered subcutaneously for the induction of oocyte maturation and ovulation. Our efforts to develop orally bioavailable luteinizing hormone (LH) receptor agonists have led to the discovery of Org 43553, a low molecular weight (LMW) LH receptor (LH-R) agonist. METHODS Org 43553 was tested in vitro and in vivo in pre-clinical pharmacological models to demonstrate efficacy and oral availability. RESULTS Org 43553 is a potent stimulator of the human LH-R in vitro (EC(50) 3.7 nM). In primary mouse Leydig cells, Org 43553 stimulated testosterone production. Pharmacokinetic analyses showed high oral bioavailability in rats (79%) and dogs (44%) with a shorter half-life compared with hCG (3.4 versus 5.6 h in the rat). Ovulation induction by Org 43553 was demonstrated in immature mice as well as in cyclic rats after single-dose oral administration (50 mg/kg). The ovulated oocytes were of good quality as demonstrated by successful fertilization and implantation of normal embryos. In male rats, testosterone production was substantially induced after oral administration. CONCLUSIONS Org 43553 is the first LMW LH-R mimetic with demonstrated in vivo efficacy upon oral administration and could therefore replace subcutaneously administered hCG. The elimination half-life of Org 43553 is substantially shorter than hCG, which could potentially represent a clinical benefit in reducing the risk of ovarian hyperstimulation syndrome (OHSS). | ||||
| Expression regulated by | FSH, LH, Steroids, Growth Factors/ cytokines, Eicosanoids, TCF, mir136, retinoic acid | ||||
| Comment | The cell type-specific expression of Lhcgr in mouse ovarian cells: evidence for a DNA-demethylation dependent mechanism. Kawai T et al. (2018) The LH receptor (LHCGR) is expressed at low levels in mural granulosa cells and cumulus cells of antral follicles but is induced dramatically in granulosa cells but not in cumulus cells by FSH. Therefore, we hypothesized that FSH not only activates transcription factors controlling Lhcgr expression but also alters other events to permit and enhance Lhcgr expression in granulosa cells but not in cumulus cells. In granulosa cells, the level of DNA methylation in the Lhcgr promoter region was significantly decreased by equine chorionic gonadotropin (eCG) in vivo. However, in cumulus cells, hypermethylation of the Lhcgr promoter remained after eCG-stimulation. eCG induced estrogen production from testosterone (T) and retinoic acid (RA) synthesis in granulosa cells. When either T or RA in the presence or absence of FSH was added to granulosa cell cultures, the combined treatment with FSH and RA induced demethylation of Lhcgr-promoter region and Lhcgr expression. FSH-dependent RA synthesis was negatively regulated by co-culture of granulosa cells with denuded oocytes, suggesting that oocyte-secreted factors down-regulate RA production in cumulus cells where Lhcgr expression was not induced. Strikingly, treatment of cultured cumulus-oocyte complexes (COCs) with a SMAD inhibitor, SB431542 significantly induced RA production, demethylation of Lhcgr-promoter region and Lhcgr expression in cumulus cells. These results indicate that the demethylation of the Lhcgr-promoter region is mediated, at least in part, by RA synthesis and is a key mechanism regulating the cell-type specific differentiation during follicular development process.////////////////// Role of microRNA-136-3p on the Expression of Luteinizing Hormone-Human Chorionic Gonadotropin Receptor mRNA in Rat Ovaries. Kitahara Y 2013 et al. MicroRNAs (miRNAs) are small non-coding RNAs that interact with mRNAs and trigger either translation repression or RNA cleavage of target genes. In this study, we investigated whether miRNA was involved in down-regulation of the luteinizing hormone receptor (LHR) in rat ovaries. An miRNA microarray was used to analyze the overall miRNA expression profile of rat ovaries in association with the down-regulation of LHR mRNA. We found that 23 miRNAs were highly expressed during this period. Combining these results with data from a bioinformatics database, clustering analysis led us to focus on miR-136-3p for further analysis. In both in vivo and in vitro studies, miR-136-3p levels were increased at 6 h after hCG administration, concurrent with the down-regulation of LHR mRNA. Moreover, transfection of cultured granulosa cells with miR-136-3p resulted in a significant decreased in LHR mRNA levels in comparison with those of cells transfected with negative control. In contrast, transfection with an miR-136-3p inhibitor increased LHR mRNA levels. Finally, cotransfection of granulosa cells with the miR-136-3p inhibitor and a reporter vector containing the 3'-untranslated region (UTR) of LHR mRNA and Renilla luciferase coding sequence revealed that miR-136-3p bound c to the 3'-UTR of LHR mRNA. These data demonstrated that miR-136-3p participated in the down-regulation of LHR mRNA by binding directly to LHR mRNA. ///////////////////////// Lhcgr Expression Granulosa Cells: Roles for PKA-Phosphorylated ?catenin, TCF3, and FOXO1. Law NC et al. Ovarian follicles lacking FSH or FSH receptors fail to progress to a preovulatory stage, resulting in infertility. One hallmark of the preovulatory follicle is the presence of luteinizing hormone choriogonadotropin receptors (LHCGR) on granulosa cells (GCs). However, the mechanisms by which FSH induces Lhcgr gene expression are poorly understood. Our results show that protein kinase A (PKA) and phosphoinositide 3-kinase (PI3K)/AKT pathways are required for FSH to activate both the murine Lhcgr-luciferase reporter and expression of Lhcgr mRNA in rat GCs. Based on results showing that an adenovirus (Ad) expressing a steroidogenic factor 1 (SF1) mutant that cannot bind ?catenin abolished FSH-induced Lhcgr mRNA, we evaluated the role of ?catenin in the regulation of Lhcgr gene expression. FSH promoted the PKA-dependent, PI3K-independent phosphorylation of ?catenin on Ser552 and Ser665. FSH activated the ?catenin/T cell factor (TCF) artificial promoter-reporter TOPFlash via a PKA-dependent, PI3K-independent pathway; dominant-negative (DN) TCF abolished FSH-activated Lhcgr-luciferase reporter and induction of Lhcgr mRNA; microarray analysis of GCs treated with Ad-DN-TCF and FSH identified the Lhcgr as the most down-regulated gene. Chromatin immunoprecipitation results placed ?catenin phosphorylated on Ser552 and Ser675 and SF1 on the Lhcgr promoter in FSH-treated GCs; TCF3 was constitutively associated with the Lhcgr promoter. Transduction with an Ad-phospho-?catenin mutant (Ser552/665/Asp) enhanced Lhcgr mRNA expression in FSH-treated cells greater than 3-fold. Finally, we identified a recognized PI3K/AKT target forkhead box O1 as a negative regulator of Lhcgr mRNA expression. These results provide a new understanding of the complex regulation of Lhcgr gene expression in GCs. Erickson GF, et al reported the FSH induction of functional LH receptors in granulosa cells cultured in a chemically defined medium. Nature. 1979 May 24;279(5711):336-8. gene expression decreased. Luteinization of porcine preovulatory follicles leads to systematic changes in follicular gene expression. Agca C et al. The LH surge initiates the luteinization of preovulatory follicles and causes hormonal and structural changes that ultimately lead to ovulation and the formation of corpora lutea. The objective of the study was to examine gene expression in ovarian follicles (n = 11) collected from pigs (Sus scrofa domestica) approaching estrus (estrogenic preovulatory follicle; n = 6 follicles from two sows) and in ovarian follicles collected from pigs on the second day of estrus (preovulatory follicles that were luteinized but had not ovulated; n = 5 follicles from two sows). The follicular status within each follicle was confirmed by follicular fluid analyses of estradiol and progesterone ratios. Microarrays were made from expressed sequence tags that were isolated from cDNA libraries of porcine ovary. Gene expression was measured by hybridization of fluorescently labeled cDNA (preovulatory estrogenic or -luteinized) to the microarray. Microarray analyses detected 107 and 43 genes whose expression was decreased or increased (respectively) during the transition from preovulatory estrogenic to -luteinized (P<0.01). Cells within preovulatory estrogenic follicles had a gene-expression profile of proliferative and metabolically active cells that were responding to oxidative stress. Cells within preovulatory luteinized follicles had a gene-expression profile of nonproliferative and migratory cells with angiogenic properties. Approximately, 40% of the discovered genes had unknown function. | ||||
| Ovarian localization | Oocyte, Cumulus, Granulosa, Theca, Luteal cells, Surface epithelium | ||||
| Comment | Patsoula E, et al 2003 reported that unfertilized oocytes and zygotes and embryos at the 2-cell, 4-cell, morula, and blastocyst stage were selected for study. A polymerase chain reaction methodology was used to analyze human oocytes and embryos. Messenger RNA was reverse transcribed and amplified with FSH and LH receptor specific primers.Transcripts for the FSH receptor were detected in oocytes and zygotes and embryos at the 2-cell, morula, and blastocyst stage, while no message was detected in embryos at the 4-cell stage. Transcripts for the LH receptor were observed in oocytes and zygotes and morula- and blastocyst-stage embryos, whereas no message was detected in embryos at the 2-cell and 4-cell stage. Gonadotropin Induced Superovulation Drives Ovarian Surface Epithelia Proliferation in CD1 mice. Burdette JE et al. The ovarian surface epithelium (OSE) is a monolayer of cells that surround the ovary and accommodate repeated tear and repair in response to ovulation. OSE cells are thought to be the progenitors of 90% of ovarian cancers. Currently, the total amount of proliferation of the OSE has not been reported in response to one ovulatory event. In this study, proliferation of the OSE was quantified in response to superovulation induced by intraperitoneal injection of pregnant mare serum gonadotropin (PMSG) and human chorionic gonadotropin (hCG) in immature 27-day-old CD1 mice using bromodeoxyuridine (BrdU). BrdU incorporation into the OSE cells was measured from the time of hCG injection for a total cumulative label of 12 h. BrdU incorporation was also measured from the time of PMSG injection for a total label of 60 h to correlate proliferation with specific gonadotropin stimulation. The OSE proliferation was significantly higher in superovulated animals compared with control mice at all time points. Proliferation was also analyzed in discrete anatomical sections and indicated that OSE covering antral follicles and corpora lutea proliferated more rapidly than OSE distal to follicular growth. Finally, apoptosis was assessed in response to ovulation and virtually no cell death within the OSE was detected. These data demonstrate that the OSE, especially near antral follicles and corpora lutea, proliferates significantly in response to the gonadotropins PMSG and hCG. Therefore, ovarian surface cell division in response to ovulation could contribute to ovarian cancer by proliferation-induced DNA mutations and transformed cell progression. Changes in mouse granulosa cell gene expression during early luteinization. McRae RS et al. Changes in gene expression during granulosa cell luteinization have been measured using serial analysis of gene expression (SAGE). Immature normal mice were treated with pregnant mare serum gonadotropin (PMSG) or PMSG followed, 48 h later, by human chorionic gonadotropin (hCG). Granulosa cells were collected from preovulatory follicles after PMSG injection or PMSG/hCG injection and SAGE libraries generated from the isolated mRNA. The combined libraries contained 105,224 tags representing 40,248 unique transcripts. Overall, 715 transcripts showed a significant difference in abundance between the two libraries of which 216 were significantly down-regulated by hCG and 499 were significantly up-regulated. Among transcripts differentially regulated, there were clear and expected changes in genes involved in steroidogenesis as well as clusters of genes involved in modeling of the extracellular matrix, regulation of the cytoskeleton and intra and intercellular signaling. The SAGE libraries described here provide a base for functional investigation of the regulation of granulosa cell luteinization. | ||||
| Follicle stages | Secondary, Antral, Preovulatory, Corpus luteum | ||||
| Comment | Localization of Luteinizing Hormone Receptor Protein in the Human Ovary. Yung Y 2014 et al. The luteinizing hormone receptor (LHR) plays a pivotal role during follicular development. Consequently, its expression pattern is of major importance for research and has clinical implications. Despite the accumulated information regarding LHR expression patterns, our understanding of its expression lin the human ovary specifically at the protein level is incomplete. Therefore, our aim was to determine the LHR protein localization and expression pattern in the human ovary. We examined the presence of LHR by immunohistochemical staining of human ovaries and western blots of mural granulosa and cumulus cells aspirated during IVF treatments. We were not able to detect LHR protein staining in primordial or primary follicles. We observed equivocal positive staining in granulosa cellss and theca cells of secondary follicles. The first appearance of a clear signal of LHR protein was observed in granulosa cells and theca cells of small antral follicles, and there was evidence of increasing LHR production as the follicles mature to the preovulatory stage. After ovulation, LHR protein was ubiquitously produced in the corpus luteum. To confirm the expression pattern in granulosa cells and cumulus cells, we performed western blots and found that LHR expression was stronger in granulosa cells than in cumulus cells, with the later demonstrating low, but still significant, amounts of LHR protein. In summary, we conclude that LHR protein starts to appear on granulosa cells and theca cells of early antral follicles, and low but significant expression of LHR exists also in the cumulus cells. These results may have implications for the future design of clinical protocols and culture mediums for in-vitro fertilization and especially in-vitro maturation of oocytes. ///////////////////////// The LH receptor is present in theca cells from secondary and larger follicles. Receptor protein is not found in granulosa cells from preantral and early antral follicles but is induced in the granulosa cells of antral and preovulatory follicles following FSH treatment. | ||||
| Phenotypes |
PCO (polycystic ovarian syndrome) POF (premature ovarian failure) |
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| Mutations |
27 mutations
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| Genomic Region | show genomic region | ||||
| Phenotypes and GWAS | show phenotypes and GWAS | ||||
| Links |
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| created: | March 9, 1999, midnight | by: |
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| last update: | March 18, 2020, 12:50 p.m. | by: | hsueh email: |
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