Luteinizing hormone/chorionic gonadotrophin receptor overexpressed in granulosa cells from polycystic ovary syndrome ovaries is functionally active

Kanamarlapudi, Venkateswarlu; Gordon, Uma; Bernal, Andrés López

doi:10.1016/j.rbmo.2016.03.003

Cited by 37 publications

(17 citation statements)

References 41 publications

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“…One previous study in GCs from hSAFs found a significantly higher expression of LHCGR in PCOS, and, interestingly, this was a feature of most follicles analyzed in that study (15). We also demonstrated a higher LHCGR expression in GCs from PCO hSAFs and PCOS GLCs, as has been shown previously (43, 44).…”

Section: Discussionsupporting

confidence: 90%

Gene Expression in Granulosa Cells From Small Antral Follicles From Women With or Without Polycystic Ovaries

Owens

Kristensen

Lerner

et al. 2019

The Journal of Clinical Endocrinology &Amp; Metabolism

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Context Polycystic ovary syndrome (PCOS) is the most common cause of anovulation. A key feature of PCOS is arrest of follicles at the small- to medium-sized antral stage. Objective and Design To provide further insight into the mechanism of follicle arrest in PCOS, we profiled (i) gonadotropin receptors; (ii) characteristics of aberrant steroidogenesis; and (iii) expression of anti-Müllerian hormone (AMH) and its receptor in granulosa cells (GCs) from unstimulated, human small antral follicles (hSAFs) and from granulosa lutein cells (GLCs). Setting GCs from hSAFs were collected at the time of cryopreservation of ovarian tissue for fertility preservation and GLCs collected during oocyte aspiration before in vitro fertilization/intracytoplasmic sperm injection. Participants We collected hSAF GCs from 31 women (98 follicles): 10 with polycystic ovaries (PCO) and 21 without. GLCs were collected from 6 women with PCOS and 6 controls undergoing IVF. Main Outcome Measures Expression of the following genes: LHCGR, FSHR, AR, INSR, HSD3B2, CYP11A1, CYP19, STAR, AMH, AMHR2, FST, INHBA, INHBB in GCs and GLCs were compared between women with PCO and controls. Results GCs in hSAFs from women with PCO showed higher expression of LHCGR in a subset (20%) of follicles. Expression of FSHR (P < 0.05), AR (P < 0.05), and CYP11A1 (P < 0.05) was lower, and expression of CYP19A1 (P < 0.05), STAR (P < 0.05), HSD3B2 (P = NS), and INHBA (P < 0.05) was higher in PCO GCs. Gene expression in GL cells differed between women with and without PCOS but also differed from that in GCs. Conclusions Follicle arrest in PCO is characterized in GCs by differential regulation of key genes involved in follicle growth and function.

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Section: Discussionsupporting

confidence: 90%

Gene Expression in Granulosa Cells From Small Antral Follicles From Women With or Without Polycystic Ovaries

Owens

Kristensen

Lerner

et al. 2019

The Journal of Clinical Endocrinology &Amp; Metabolism

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“…Recent genome-wide association cohort studies (GWAS) into PCOS discovered new susceptibility loci associated with 17 genes [reviewed by [15]]: DENN domaincontaining 1A (DENND1A), luteinising hormone/chorionic gonadotrophin receptor (LHCGR), follicle stimulating hormone beta subunit (FSHB), follicle stimulating hormone receptor (FSHR), yes associated protein 1 (YAP1), insulin receptor (INSR), ras-related protein RAB5B, TOX high mobility group box family member 3 (TOX3), high mobility group AThook 2 (HMGA2), chromosome 9 open reading frame 3 (C9orf3), GATA binding protein 4 (GATA4), Erb-B2 receptor tyrosine kinase 4 (ERBB4), DNA repair protein (RAD50), thyroid adenoma associated (THADA), sulphite oxidase (SUOX), Ca2+/calmodulin-dependent protein kinase (KRR1) and the small ubiquitin-like modifier 1 pseudogene 1 (SUMO1P1) [16][17][18][19]. Many human studies have been conducted in an effort to investigate these PCOS candidate genes, particularly DENND1A and its variants [20], TOX3 [21], FSHR [22], LHCGR [23] and INSR [24]. Another PCOS susceptibility loci was identified earlier by case-cohort studies using microsatellite analyses and it is located in an intron of fibrillin 3 (FBN3) [25].…”

Section: Introductionmentioning

confidence: 99%

Could perturbed fetal development of the ovary contribute to the development of polycystic ovary syndrome in later life?

et al. 2020

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Polycystic ovary syndrome (PCOS) affects around 10% of young women, with adverse consequences on fertility and cardiometabolic outcomes. PCOS appears to result from a genetic predisposition interacting with developmental events during fetal or perinatal life. We hypothesised that PCOS candidate genes might be expressed in the fetal ovary when the stroma develops; mechanistically linking the genetics, fetal origins and adult ovarian phenotype of PCOS. In bovine fetal ovaries (n = 37) of 18 PCOS candidate genes only SUMO1P1 was not expressed. Three patterns of expression were observed: early gestation (FBN3, GATA4, HMGA2, TOX3, DENND1A, LHCGR and FSHB), late gestation (INSR, FSHR, and LHCGR) and throughout gestation (THADA, ERBB4, RAD50, C8H9orf3, YAP1, RAB5B, SUOX and KRR1). A splice variant of FSHB exon 3 was also detected early in the bovine ovaries, but exon 2 was not detected. Three other genes, likely to be related to the PCOS aetiology (AMH, AR and TGFB1I1), were also expressed late in gestation. Significantly within each of the three gene groups, the mRNA levels of many genes were highly correlated with each other, despite, in some instances, being expressed in different cell types. TGFβ is a well-known stimulator of stromal cell replication and collagen synthesis and TGFβ treatment of cultured fetal ovarian stromal cells inhibited the expression of INSR, AR, C8H9orf3 and RAD50 and stimulated the expression of TGFB1I1. In human ovaries (n = 15, < 150 days gestation) many of the same genes as in bovine (FBN3, GATA4, HMGA2, FSHR, DENND1A and LHCGR but not TOX3 or FSHB) were expressed and correlated with each other. With so many relationships between PCOS candidate genes during development of the fetal ovary, including TGFβ and androgen signalling, we suggest that future studies should determine if perturbations of these genes in the fetal ovary can lead to PCOS in later life.

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“…While the etiopathogenesis of PCOS remains elusive, it likely involves aberrant hormonal responses mediated by ovarian granulosa cells (GCs) during the progression of follicular development. Previous studies have reported that PCOS is associated with elevated luteinizing hormone (LH) and overexpression and overactivation of the luteinizing hormone/chorionic gonadotropin receptor (LHCGR) in GCs from PCOS patients and that this prevents follicle maturation and ovulation 12 – 16 . Impaired GC function is associated with disruption of folliculogenesis and with elevated intraovarian androgens and circulating anti-Müllerian hormone levels 17 – 23 .…”

Section: Introductionmentioning

confidence: 99%

Identification of reference genes for qRT-PCR in granulosa cells of healthy women and polycystic ovarian syndrome patients

Zhao

Lü

et al. 2017

Sci Rep

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Comparative gene expression analysis by qRT-PCR is commonly used to detect differentially expressed genes in studies of PCOS pathology. Impaired GC function is strongly associated with PCOS pathogenesis, and a growing body of studies has been dedicated to identifying differentially expressed genes in GCs in PCOS patients and healthy women by qRT-PCR. It is necessary to validate the expression stability of the selected reference genes across the tested samples for target gene expression normalization. We examined the variability and stability of expression of the 15 commonly used reference genes in GCs from 44 PCOS patients and 45 healthy women using the GeNorm, BestKeeper, and NormFinder statistical algorithms. We combined the rankings of the three programs to produce a final ranking based on the geometric means of their stability scores. We found that HPRT1, RPLP0, and HMBS out of 15 examined commonly used reference genes are stably expressed in GCs in both controls and PCOS patients and can be used for normalization in gene expression profiling by qRT-PCR. Future gene-expression studies should consider using these reference genes in GCs in PCOS patients for more accurate quantitation of target gene expression and data interpretation.

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Luteinizing hormone/chorionic gonadotrophin receptor overexpressed in granulosa cells from polycystic ovary syndrome ovaries is functionally active

Cited by 37 publications

References 41 publications

Gene Expression in Granulosa Cells From Small Antral Follicles From Women With or Without Polycystic Ovaries

Gene Expression in Granulosa Cells From Small Antral Follicles From Women With or Without Polycystic Ovaries

Could perturbed fetal development of the ovary contribute to the development of polycystic ovary syndrome in later life?

Identification of reference genes for qRT-PCR in granulosa cells of healthy women and polycystic ovarian syndrome patients

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