Downregulation of DACH2 Expression in an Adrenocortical Cell Model of PCOS with Adrenal Hyperandrogenism, and in Human Granulosa Cells from Patients with Hyperandrogenic-PCOS: a Link Between Ovaries and Adrenal Glands in PCOS

Ahmed KEM, Frøysa HG, Karlsen OA, Sagen JV, Mellgren G, Verhaegen S, et al. LC-MS/MS based profiling and dynamic modelling of the steroidogenesis pathway in adrenocarcinoma H295R cells. Toxicol In Vitro. 2018;52:332–41. https://doi.org/10.1016/j.tiv.2018.07.002.

Article  CAS  PubMed  Google Scholar 

Berkel C. Inducers and inhibitors of pyroptotic death of granulosa cells in models of premature ovarian insufficiency and polycystic ovary syndrome. Reprod Sci. 2024;31(10):2972–92. https://doi.org/10.1007/s43032-024-01643-3.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Bevilacqua A, Giuliani C, Emidio GD, Myers SH, Unfer V, Tatone C. Murine models and human cell line models to study altered dynamics of ovarian follicles in polycystic ovary syndrome. Adv Biol (Weinh). 2025;9(7):e2400713. https://doi.org/10.1002/adbi.202400713.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Bione S, Rizzolio F, Sala C, Ricotti R, Goegan M, Manzini MC, et al. Mutation analysis of two candidate genes for premature ovarian failure, DACH2 and POF1B. Hum Reprod. 2004;19(12):2759–66. https://doi.org/10.1093/humrep/deh502.

Article  CAS  PubMed  Google Scholar 

Chugh RM, Park HS, Esfandyari S, Elsharoud A, Ulin M, Al-Hendy A. Mesenchymal stem cell-conditioned media regulate steroidogenesis and inhibit androgen secretion in a PCOS cell model via BMP-2. Int J Mol Sci. 2021;22(17):9184. https://doi.org/10.3390/ijms22179184.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Crespo RP, Bachega TASS, Mendonça BB, Gomes LG. An update of genetic basis of PCOS pathogenesis. Arch Endocrinol Metab. 2018;62(3):352–61. https://doi.org/10.20945/2359-3997000000049.

Article  PubMed  PubMed Central  Google Scholar 

Davis RJ, Harding M, Moayedi Y, Mardon G. Mouse Dach1 and Dach2 are redundantly required for Müllerian duct development. Genesis. 2008;46(4):205–13. https://doi.org/10.1002/dvg.20385.

Article  CAS  PubMed  Google Scholar 

Esfandyari S. MiRNA-92a suppresses androgen-producing steroidogenic genes expression in h295r, a human pcos in-vitro theca-like cell model. Fertil Steril. 2020;114(Issue 3):e349–50.

Article  Google Scholar 

Freeman RG. The role of the adrenal glands in the hyperandrogenism associated with the polycystic ovarian syndrome. In: Pal L, Seifer DB, editors. Polycystic ovary syndrome: current and emerging concepts. Cham: Springer International Publishing; 2022. p. 121–32.

Chapter  Google Scholar 

Gourgari E, Lodish M, Keil M, Sinaii N, Turkbey E, Lyssikatos C, et al. Bilateral adrenal hyperplasia as a possible mechanism for hyperandrogenism in women with polycystic ovary syndrome. J Clin Endocrinol Metab. 2016;101(9):3353–60. https://doi.org/10.1210/jc.2015-4019.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Haggard DE, Karmaus AL, Martin MT, Judson RS, Setzer RW, Paul Friedman K. High-throughput H295R steroidogenesis assay: utility as an alternative and a statistical approach to characterize effects on steroidogenesis. Toxicol Sci. 2018;162(2):509–34. https://doi.org/10.1093/toxsci/kfx274.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Illés A, Pikó H, Árvai K, Donka V, Szepesi O, Kósa J, et al. Screening of premature ovarian insufficiency associated genes in Hungarian patients with next generation sequencing. BMC Med Genomics. 2024;17(1):98. https://doi.org/10.1186/s12920-024-01873-z.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Jedidi I, Ouchari M, Yin Q. Sex chromosomes-linked single-gene disorders involved in human infertility. Eur J Med Genet. 2019;62(9):103560. https://doi.org/10.1016/j.ejmg.2018.10.012.

Article  PubMed  Google Scholar 

Kumar A, Woods KS, Bartolucci AA, Azziz R. Prevalence of adrenal androgen excess in patients with the polycystic ovary syndrome (PCOS). Clin Endocrinol. 2005;62(6):644–9.

Article  CAS  Google Scholar 

Naillat F, Yan W, Karjalainen R, Liakhovitskaia A, Samoylenko A, Xu Q, et al. Identification of the genes regulated by Wnt-4, a critical signal for commitment of the ovary. Exp Cell Res. 2015;332(2):163–78. https://doi.org/10.1016/j.yexcr.2015.01.010.

Article  CAS  PubMed  Google Scholar 

Nodin B, Fridberg M, Uhlén M, Jirström K. Discovery of dachshund 2 protein as a novel biomarker of poor prognosis in epithelial ovarian cancer. J Ovarian Res. 2012;5(1):6. https://doi.org/10.1186/1757-2215-5-6.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Pan M, Qian Y, Jiang L, Cao C, Li L. Glucose-dependent insulinotropic peptide (GIP) suppresses androgen biosynthesis in PCOS mouse models and cellular systems. Gynecol Endocrinol. 2025;41(1):2582506. https://doi.org/10.1080/09513590.2025.2582506.

Article  CAS  PubMed  Google Scholar 

Pan ML, Chen LR, Tsao HM, Chen KH. Polycystic ovarian syndrome and the risk of subsequent primary ovarian insufficiency: a nationwide population-based study. Menopause. 2017;24(7):803–9. https://doi.org/10.1097/GME.0000000000000832.

Article  PubMed  Google Scholar 

Popov VM, Wu K, Zhou J, Powell MJ, Mardon G, Wang C, et al. The Dachshund gene in development and hormone-responsive tumorigenesis. Trends Endocrinol Metab. 2010;21(1):41–9. https://doi.org/10.1016/j.tem.2009.08.002.

Article  CAS  PubMed  Google Scholar 

Samandari E, Kempná P, Nuoffer JM, Hofer G, Mullis PE, Flück CE. Human adrenal corticocarcinoma NCI-H295R cells produce more androgens than NCI-H295A cells and differ in 3β-hydroxysteroid dehydrogenase type 2 and 17,20 lyase activities. J Endocrinol. 2007;195(3):459–72. https://doi.org/10.1677/JOE-07-0166.

Article  CAS  PubMed  Google Scholar 

Sanchez-Garrido MA, Tena-Sempere M. Metabolic dysfunction in polycystic ovary syndrome: pathogenic role of androgen excess and potential therapeutic strategies. Mol Metab. 2020;35:100937. https://doi.org/10.1016/j.molmet.2020.01.001.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Sankaranarayanan L, Brewer KJ, Morrow S, Johnson GD, Barrera A, Venukuttan R, et al. Gene regulatory activity associated with polycystic ovary syndrome revealed DENND1A-dependent testosterone production. Nat Commun. 2025;16(1):7697. https://doi.org/10.1038/s41467-025-62884-7.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Suzumori N, Pangas SA, Rajkovic A. Candidate genes for premature ovarian failure. Curr Med Chem. 2007;14(3):353–7. https://doi.org/10.2174/092986707779941087.

Article  CAS  PubMed  Google Scholar 

Torchen LC, Wu M, Thompson B, Beaudouin A. Polycystic ovary syndrome: origins and implications: The significance of functional adrenal hyperandrogenism in polycystic ovary syndrome across the lifespan. Reproduction. 2025;169(6):e250091. https://doi.org/10.1530/REP-25-0091.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Tsai YR, Liao YN, Kang HY. Current advances in cellular approaches for pathophysiology and treatment of polycystic ovary syndrome. Cells. 2023;12(17):2189. https://doi.org/10.3390/cells12172189.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Unfer V, Lepore E, Forte G, Hernández Marín I, Wdowiak A, Pkhaladze L. Hyperandrogenism in polycystic ovary syndrome and adrenal hyperplasia: finding differences to make a specific diagnosis. Arch Gynecol Obstet. 2025;311(1):25–32. https://doi.org/10.1007/s00404-024-07897-1.

Article  PubMed  Google Scholar 

Unlu E, Unlu BS, Yildiz Y, Beker-Acay M, Kacar E, Turamanlar O, et al. Adrenal gland volume assessed by magnetic resonance imaging in women with polycystic ovary syndrome. Diagn Interv Imaging. 2016;97(1):57–63. https://doi.org/10.1016/j.diii.2015.02.004.

Article  CAS 

Comments (0)

No login
gif