Expression of genes controlling steroid metabolism and action in granulosa-lutein cells of women with polycystic ovaries

Lerner, Avi; Owens, Lisa; Coates, Melanie; Simpson, Craig A.; Poole, Graham; Velupillai, Jocelyne; Liyanage, Maneshka; Christopoulos, George; Lavery, Stuart; Hardy, Kate; Franks, Paul W.

doi:10.1016/j.mce.2019.02.015

Cited by 21 publications

(16 citation statements)

References 46 publications

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“…A melt curve was completed to ensure a single product was formed. The relative mRNA expression of each gene was calculated by using the housekeeping genes β -actin and β 2 -microglobulin, which have been validated as stable reference genes in these cells (38).…”

Section: Methodsmentioning

confidence: 99%

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: Methodsmentioning

confidence: 99%

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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“…Previous studies have demonstrated that the HSD17B1 converts and catalyses the oestrone to the more active oestradiol in the final of oestradiol biosynthesis (He et al., 2016; Jarvensivu et al., 2015), the biological process of which is mainly finished in ovarian granulosa cells, and HSD17B1 has been the GC function‐related makers. Much evidence has recommended that the HSD17B1 contributes to maintain the normal steroid hormone concentration in fertility (Hakkarainen et al., 2015), reproductive longevity (Lerner et al., 2019) and reproductive performance (Liu et al., 2009). The core promoter is the key and heart element that regulates the transcription initiations of genes (Danino et al., 2015).…”

Section: Discussionmentioning

confidence: 99%

“…During the oestradiol biosynthesis, the final and essential step is to convert and catalyse the oestrone to the more potent and active oestradiol by the protein coded by the hydroxysteroid 17‐beta dehydrogenase 1 ( HSD17B1 ) gene (He et al., 2016; Jarvensivu et al., 2015) (He et al., 2016). In humans, compared to that of heathy women, the GCs from women with polycystic ovaries have showed reduced mRNA expression of HSD17B1 (Lerner et al., 2019), and the mRNA expression of HSD17B1 is significantly lower in women with breast cancer than controls (Savolainen‐Peltonen et al., 2018). These findings support the notion that the expression of HSD17B1 has highly implicated in the steroid metabolism, and the abnormal expression of HSD17B1 will cause hormonal imbalances (Saloniemi et al., 2009; Scarabino et al., 2015) and result in female reproductive deficiency (Hakkarainen et al., 2015).…”

Section: Introductionmentioning

confidence: 99%

FoxA2 and p53 regulate the transcription of HSD17B1 in ovarian granulosa cells of pigs

Yuan

Zhou

Qiao

et al. 2020

Reprod Domestic Animals

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The oestrogens have been highly implicated in the fertility of female animals. It is widely known that the oestrogens are primarily synthetized by the ovarian granulosa cells (GCs), and the final and essential step of this process is to catalyse the oestrone to the more active oestradiol by the protein coded by hydroxysteroid 17‐beta dehydrogenase 1 (HSD17B1) gene. However, the molecular mechanism regarding the transcription of HSD17B1 remains to be fully elucidated in ovarian GCs. In this study, the 5’‐deletion, luciferase assay and chromatin immunoprecipitation (ChIP) were utilized to explore the molecular regulation of transcription of HSD17B1 with the porcine ovarian GCs as the cellular model. After the deletions with −2105 to −1754 bp, −1753 to −1429 bp, −1430 to −1081 bp and −1082 to −730 bp, the relative luciferase activity of HSD17B1 promoter did not change significantly, but the deletion of −731 to −332 bp significantly increased the relative luciferase activity of HSD17B1 promoter, and an insertion (GTTT) that might raise the transcription of HSD17B1 was identified at −401 bp of HSD17B1. These findings suggested the region from −731 to +38 bp was the core promoter of HSD17B1, and the region between −731 to −332 bp might be a silence element for HSD17B1. Furthermore, the forkhead box A2 (FoxA2) directly bound at −412 to −401 bp to negatively but p53 bound at −383 to −374 bp to positively regulate the transcription and translation of HSD17B1 in ovarian GCs. These findings will improve our understanding on HSD17B1‐mediated oestrogens and provide useful information for further investigations into fertility of females.

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“…Results frequently diverge depending on the ovarian stimulation protocol used and/or on the number of included patients. In mural GC, CYP19A1 expression is described to be either unmodified [ 91 , 92 ] or down-regulated [ 90 , 93 , 94 ] in PCOS when compared to non-PCOS. However, in cumulus GC, CYP19A1 mRNA levels are higher in PCOS when compared to heathy women [ 95 ].…”

Section: Importance Of E2 Signaling In Pcosmentioning

confidence: 99%

“…These data suggest the existence of differential CYP19A1 expression regulations in GC, depending on their proximity to the oocyte. The down-regulation of both CYP11A1 (encoding cytochrome P450 cholesterol side-chain cleavage enzyme, or P450SCC) and HSD17B1 (encoding 17β-hydroxysteroid dehydrogenase enzyme, or 17-βHSD) and up-regulation of SULT1E1 (sulfotransferase Family 1E Member 1) mRNA expression are observed in mural luteinized GC of PCOS as compared to non-PCOS women [ 93 ]. P450SCC catalyzes the conversion of cholesterol to pregnenolone, while 17-βHSD and SULT1E1 play a role in estrogen metabolism and biosynthesis [ 93 ].…”

Section: Importance Of E2 Signaling In Pcosmentioning

confidence: 99%

Estradiol Signaling at the Heart of Folliculogenesis: Its Potential Deregulation in Human Ovarian Pathologies

Chauvin

Cohen‐Tannoudji

Guigon

2022

IJMS

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Estradiol (E2) is a major hormone controlling women fertility, in particular folliculogenesis. This steroid, which is locally produced by granulosa cells (GC) within ovarian follicles, controls the development and selection of dominant preovulatory follicles. E2 effects rely on a complex set of nuclear and extra-nuclear signal transduction pathways principally triggered by its nuclear receptors, ERα and ERβ. These transcription factors are differentially expressed within follicles, with ERβ being the predominant ER in GC. Several ERβ splice isoforms have been identified and display specific structural features, which greatly complicates the nature of ERβ-mediated E2 signaling. This review aims at providing a concise overview of the main actions of E2 during follicular growth, maturation, and selection in human. It also describes the current understanding of the various roles of ERβ splice isoforms, especially their influence on cell fate. We finally discuss how E2 signaling deregulation could participate in two ovarian pathogeneses characterized by either a follicular arrest, as in polycystic ovary syndrome, or an excess of GC survival and proliferation, leading to granulosa cell tumors. This review emphasizes the need for further research to better understand the molecular basis of E2 signaling throughout folliculogenesis and to improve the efficiency of ovarian-related disease therapies.

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Expression of genes controlling steroid metabolism and action in granulosa-lutein cells of women with polycystic ovaries

Cited by 21 publications

References 46 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

FoxA2 and p53 regulate the transcription of HSD17B1 in ovarian granulosa cells of pigs

Estradiol Signaling at the Heart of Folliculogenesis: Its Potential Deregulation in Human Ovarian Pathologies

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