New Anti-Müllerian Hormone Target Genes Involved in Granulosa Cell Survival in Women With Polycystic Ovary Syndrome

2020 ◽  
Author(s):  
Chrystèle Racine ◽  
Carine Genêt ◽  
Camille Bourgneuf ◽  
Charlotte Dupont ◽  
Florence Plisson-Petit ◽  
...  
Keyword(s):  
Polycystic Ovary Syndrome ◽  
Cell Survival ◽  
Target Genes ◽  
Polycystic Ovary ◽  
Molecular Evidence ◽  
Ovary Syndrome ◽  
Proliferation And Apoptosis ◽  
Follicle Atresia

Abstract Purpose A protective effect of anti-Müllerian hormone (AMH) on follicle atresia was recently demonstrated using long-term treatments, but this effect has never been supported by mechanistic studies. This work aimed to gain an insight into the mechanism of action of AMH on follicle atresia and on how this could account for the increased follicle pool observed in women with polycystic ovary syndrome (PCOS). Methods In vivo and in vitro experiments were performed to study the effects of AMH on follicle atresia and on the proliferation and apoptosis of granulosa cells (GCs). RNA-sequencing was carried out to identify new AMH target genes in GCs. The expression of some of these genes in GCs from control and PCOS women was compared using microfluidic real time quantitative RT-PCR. Results A short-term AMH treatment prevented follicle atresia in prepubertal mice. Consistent with this result, AMH inhibited apoptosis and promoted proliferation of different models of GCs. Moreover, integrative biology analyses of 965 AMH target genes identified in 1 of these GC models, confirmed that AMH had initiated a gene expression program favoring cell survival and proliferation. Finally, on 43 genes selected among the most up- and down-regulated AMH targets, 8 were up-regulated in GCs isolated from PCOS women, of which 5 are involved in cell survival. Main conclusions Our results provide for the first time cellular and molecular evidence that AMH protects follicles from atresia by controlling GC survival and suggest that AMH could participate in the increased follicle pool of PCOS patients.

scholarly journals PAPSS2 Deficiency Causes Androgen Excess via Impaired DHEA Sulfation—In Vitro and in Vivo Studies in a Family Harboring Two Novel PAPSS2 Mutations

2015 ◽  
Vol 100 (4) ◽  
pp. E672-E680 ◽  
Author(s):  
Wilma Oostdijk ◽  
Jan Idkowiak ◽  
Jonathan W. Mueller ◽  
Philip J. House ◽  
Angela E. Taylor ◽  
...  
Keyword(s):  
Polycystic Ovary Syndrome ◽  
Polycystic Ovary ◽  
Challenge Test ◽  
Compound Heterozygous ◽  
Androgen Excess ◽  
Ovary Syndrome ◽  
Functional Impact ◽  
Low Serum

Context: PAPSS2 (PAPS synthase 2) provides the universal sulfate donor PAPS (3′-phospho-adenosine-5′-phosphosulfate) to all human sulfotransferases, including SULT2A1, responsible for sulfation of the crucial androgen precursor dehydroepiandrosterone (DHEA). Impaired DHEA sulfation is thought to increase the conversion of DHEA toward active androgens, a proposition supported by the previous report of a girl with inactivating PAPSS2 mutations who presented with low serum DHEA sulfate and androgen excess, clinically manifesting with premature pubarche and early-onset polycystic ovary syndrome. Patients and Methods: We investigated a family harboring two novel PAPSS2 mutations, including two compound heterozygous brothers presenting with disproportionate short stature, low serum DHEA sulfate, but normal serum androgens. Patients and parents underwent a DHEA challenge test comprising frequent blood sampling and urine collection before and after 100 mg DHEA orally, with subsequent analysis of DHEA sulfation and androgen metabolism by mass spectrometry. The functional impact of the mutations was investigated in silico and in vitro. Results: We identified a novel PAPSS2 frameshift mutation, c.1371del, p.W462Cfs*3, resulting in complete disruption, and a novel missense mutation, c.809G>A, p.G270D, causing partial disruption of DHEA sulfation. Both patients and their mother, who was heterozygous for p.W462Cfs*3, showed increased 5α-reductase activity at baseline and significantly increased production of active androgens after DHEA intake. The mother had a history of oligomenorrhea and chronic anovulation that required clomiphene for ovulation induction. Conclusions: We provide direct in vivo evidence for the significant functional impact of mutant PAPSS2 on DHEA sulfation and androgen activation. Heterozygosity for PAPSS2 mutations can be associated with a phenotype resembling polycystic ovary syndrome.

scholarly journals Enhanced Thecal Androgen Production Is Prenatally Programmed in an Ovine Model of Polycystic Ovary Syndrome

Endocrinology ◽  
2012 ◽  
Vol 153 (1) ◽  
pp. 450-461 ◽  
Author(s):  
Kirsten Hogg ◽  
Julia M. Young ◽  
Elizabeth M. Oliver ◽  
Carlos J. Souza ◽  
Alan S. McNeilly ◽  
...  
Keyword(s):  
Polycystic Ovary Syndrome ◽  
Polycystic Ovary ◽  
Female Offspring ◽  
Fetal Life ◽  
Ovary Syndrome ◽  
Androgen Synthesis ◽  
Basal Expression ◽  
Thecal Cells

One of the hallmarks of polycystic ovary syndrome (PCOS) is increased ovarian androgen secretion that contributes to the ovarian, hormonal, and metabolic features of this condition. Thecal cells from women with PCOS have an enhanced capacity for androgen synthesis. To investigate whether this propensity is a potential cause, rather than a consequence, of PCOS, we used an ovine prenatal androgenization model of PCOS and assessed ewes at 11 months of age. Pregnant Scottish Greyface ewes were administered 100 mg testosterone propionate (TP) or vehicle control twice weekly from d 62 to 102 of gestation, and female offspring (TP = 9, control = 5) were studied. Prenatal TP exposure did not alter ovarian morphology or cyclicity, or plasma androgen, estrogen, and gonadotropin concentrations, at this stage. However, follicle function was reprogrammed in vivo with increased proportions of estrogenic follicles (P < 0.05) in the TP-exposed cohort. Furthermore, in vitro the thecal cells of follicles (>4 mm) secreted more LH-stimulated androstenedione after prenatal androgenization (P < 0.05), associated with increased basal expression of thecal StAR (P < 0.01), CYP11A (P < 0.05), HSD3B1 (P < 0.01), CYP17 (P < 0.05), and LHR (P < 0.05). This provides the first evidence of increased thecal androgenic capacity in the absence of a PCOS phenotype, suggesting a thecal defect induced during fetal life.

scholarly journals Investigation of the Mechanism of Zishen Yutai Pills on Polycystic Ovary Syndrome: A Network Pharmacology and Molecular Docking Approach

2021 ◽  
Vol 2021 ◽  
pp. 1-14
Author(s):  
Yingyin Chen ◽  
Xinyi Chai ◽  
Ying Zhao ◽  
Xinqian Yang ◽  
Caiting Zhong ◽  
...  
Keyword(s):  
Molecular Docking ◽  
Chinese Medicine ◽  
Traditional Chinese Medicine ◽  
Polycystic Ovary Syndrome ◽  
Target Genes ◽  
Polycystic Ovary ◽  
Network Pharmacology ◽  
Analysis Tool ◽  
Ovary Syndrome

Background. Zishen Yutai Pills (ZSYTP) is a prescription based on traditional Chinese medicine used to treat kidney-deficient pattern in traditional Chinese medicine. It is also widely used clinically for the treatment of polycystic ovary syndrome (PCOS) with positive results. This study aims to explore the potential pharmacological mechanism of ZSYTP for the treatment of PCOS by a network pharmacology approach. Methods. Compounds were collected from the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform and Bioinformatics Analysis Tool for Molecular mechanism of Traditional Chinese Medicine and TCM Database@ Taiwan, and the corresponding targets were retrieved from PubChem, Swiss Target Prediction, STITCH, and DrugBank. Meanwhile, PCOS targets were retrieved from the GeneCards database, the Online Mendelian Inheritance in Man database, National Center for Biotechnology Information Database, and DrugBank. Subsequently, multiple network construction and gene enrichment analyses were conducted with Cytoscape 3.8.2 software. Based on the previous results in the study, molecular docking simulations were done. Results. 205 active compounds and 478 ZSYTP target genes were obtained after screening by ADME consideration. 1881 disease-related targets were obtained after removing duplicates. 148 intersection target genes between drug and disease targets were isolated. Gene ontology enrichment analysis and Kyoto Encyclopedia of Genes and Genomes analysis highlighted multiple gene functions and different signaling pathways to treat PCOS. Further molecular docking demonstrated the practicality of in vivo action of ZSYTP to a certain extent. Conclusions. It is possible that the pharmacological effect of ZSYTP on PCOS is linked to the hypoxia-inducible factor 1 (HIF-1) signaling pathway, improving insulin resistance, the variation on gene expression such as RNA splicing, and regulation of mRNA metabolic process. This study paves the way for further research investigating its mechanisms.

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