{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,10]],"date-time":"2026-09-10T03:36:02Z","timestamp":1789011362812,"version":"build-2803163510"},"reference-count":55,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2026,5,18]],"date-time":"2026-05-18T00:00:00Z","timestamp":1779062400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["CIMB"],"abstract":"<jats:p>Polycystic ovarian syndrome (PCOS) affects over 116 million women globally and is typically linked with excess androgens such as testosterone. Many patients, however, display classic PCOS symptoms despite normal serum androgen. One proposed mechanism for these cases involves a shortened CAG (i.e., encodes glutamine) repeat length in the androgen receptor (AR) gene, which increases AR activity without elevating testosterone. Fewer glutamine repeats alter the AR\u2019s N-terminal domain and may contribute to strengthened interactions with co-activators and enhanced transcription of androgen-regulated genes. Heightened AR activity in hypothalamus neurons stimulates increased pulsatile release of gonadotropin-releasing hormone (GnRH), which disrupts pituitary secretion dynamics and favors luteinizing hormone (LH) over follicle-stimulating hormone (FSH). This altered LH\/FSH ratio leads to impaired folliculogenesis, anovulation and other hallmark PCOS symptoms. Targeting AR activity directly, for example by using compounds that covalently modify the AR N-terminal domain to suppress activity, may therefore offer a more precise treatment strategy for PCOS.<\/jats:p>","DOI":"10.3390\/cimb48050526","type":"journal-article","created":{"date-parts":[[2026,5,19]],"date-time":"2026-05-19T15:17:23Z","timestamp":1779203843000},"page":"526","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Reduced CAG Repeats in the Androgen Receptor Gene May Independently Cause Polycystic Ovarian Syndrome"],"prefix":"10.3390","volume":"48","author":[{"given":"Rhea","family":"Sharma","sequence":"first","affiliation":[{"name":"Biology Department, Rutgers The State University of New Jersey, Camden, NJ 08103, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4096-2872","authenticated-orcid":false,"given":"Daniel H.","family":"Shain","sequence":"additional","affiliation":[{"name":"Biology Department, Rutgers The State University of New Jersey, Camden, NJ 08103, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,5,18]]},"reference":[{"key":"ref_1","unstructured":"World Health Organization (2026, February 14). Polycystic Ovary Syndrome. WHO Fact Sheets 2026. Available online: https:\/\/www.who.int\/news-room\/fact-sheets\/detail\/polycystic-ovary-syndrome."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"3181","DOI":"10.1093\/nar\/22.15.3181","article-title":"The length and location of CAG trinucleotide repeats in the androgen receptor N-terminal domain affect transactivation function","volume":"22","author":"Chamberlain","year":"1994","journal-title":"Nucleic Acids Res."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"e250226","DOI":"10.1530\/JOE-25-0226","article-title":"Phenotypic variations in polycystic ovary syndrome: Metabolic risks and emerging biomarkers","volume":"267","author":"Ma","year":"2025","journal-title":"J. Endocrinol."},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Daan, N.M.P., Koster, M.P.H., de Wilde, M.A., Eijkemans, M.J.C., and Fauser, B.C.J.M. (2016). Biomarker profiles in women with PCOS and PCOS offspring; a pilot study. PLoS ONE, 11.","DOI":"10.1371\/journal.pone.0165033"},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Rodriguez Paris, V., and Bertoldo, M.J. (2019). The mechanism of androgen actions in PCOS etiology. Med. Sci., 7.","DOI":"10.3390\/medsci7090089"},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Emanuel, R.H., Roberts, J., Docherty, P.D., Lunt, H., Campbell, R.E., and M\u00f6ller, K. (2022). A review of the hormones involved in the endocrine dysfunctions of polycystic ovary syndrome and their interactions. Front. Endocrinol., 13.","DOI":"10.3389\/fendo.2022.1017468"},{"key":"ref_7","first-page":"18","article-title":"The role of androgen receptor activity mediated by the CAG repeat polymorphism in the pathogenesis of PCOS","volume":"6","author":"Baculescu","year":"2013","journal-title":"J. Med. Life"},{"key":"ref_8","first-page":"46","article-title":"Studies of gonadotropin-releasing hormone (GnRH) action using GnRH receptor-expressing pituitary cell lines","volume":"18","author":"Kaiser","year":"1997","journal-title":"Endocr. Rev."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"722","DOI":"10.1016\/j.bbrc.2009.02.138","article-title":"FOXO3a is involved in the apoptosis of naked oocytes and oocytes of primordial follicles from neonatal rat ovaries","volume":"381","author":"Liu","year":"2009","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"214","DOI":"10.1016\/j.cca.2019.11.003","article-title":"Polycystic ovarian syndrome: Correlation between hyperandrogenism, insulin resistance and obesity","volume":"502","author":"Zeng","year":"2020","journal-title":"Clin. Chim. Acta"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"949","DOI":"10.1210\/endo-113-3-949","article-title":"Granulosa Cell Differentiation in Vitro: Induction and Maintenance of Follicle-Stimulating Hormone Receptors by Adenosine 3\u20325\u2032-Monophosphate","volume":"113","author":"Knecht","year":"1983","journal-title":"Endocrinology"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"709","DOI":"10.1093\/humupd\/dmw027","article-title":"Interactions between androgens, FSH, anti-M\u00fcllerian hormone and estradiol during folliculogenesis in the human normal and polycystic ovary","volume":"22","author":"Dewailly","year":"2016","journal-title":"Hum. Reprod. Update"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1544","DOI":"10.1016\/j.fertnstert.2009.12.060","article-title":"Circulating maternal testosterone concentrations at 18 weeks of gestation predict circulating levels of antim\u00fcllerian hormone in adolescence: A prospective cohort study","volume":"94","author":"Hart","year":"2010","journal-title":"Fertil. Steril."},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Yue, C.Y., Li, H.W.R., Wong, B.P.C., Ip, W.K., Yeung, W.S.B., Ho, P.C., and Ng, E.H.Y. (2018). Threshold value of anti-M\u00fcllerian hormone for the diagnosis of polycystic ovary syndrome in Chinese women. PLoS ONE, 13.","DOI":"10.1371\/journal.pone.0203129"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"668","DOI":"10.1016\/S2213-8587(22)00163-2","article-title":"Polycystic ovary syndrome","volume":"10","author":"Joham","year":"2022","journal-title":"Lancet Diabetes Endocrinol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"42649","DOI":"10.1038\/s41598-025-26718-2","article-title":"Insulin resistance in polycystic ovary syndrome phenotypes and the vicious cycle model in its etiology","volume":"15","author":"Szkodziak","year":"2025","journal-title":"Sci. Rep."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"182","DOI":"10.1590\/0004-2730000003051","article-title":"Polycystic ovary syndrome: Reviewing diagnosis and management of metabolic disturbances","volume":"58","author":"Spritzer","year":"2014","journal-title":"Arq. Bras. Endocrinol. Metab."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"e3464","DOI":"10.1002\/dmrr.3464","article-title":"Metabolic syndrome and its components in different phenotypes of polycystic ovary syndrome","volume":"38","author":"Krentowska","year":"2022","journal-title":"Diabetes Metab. Res. Rev."},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Dadachanji, R., Patil, A., Joshi, B., and Mukherjee, S. (2021). Elucidating the impact of obesity on hormonal and metabolic perturbations in polycystic ovary syndrome phenotypes in Indian women. PLoS ONE, 16.","DOI":"10.1371\/journal.pone.0246862"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1419","DOI":"10.2147\/DMSO.S299558","article-title":"The relationship of anti-M\u00fcllerian hormone in polycystic ovary syndrome patients with different subgroups","volume":"14","author":"Ran","year":"2021","journal-title":"Diabetes Metab. Syndr. Obes."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"834","DOI":"10.1038\/s41591-018-0035-5","article-title":"Elevated prenatal anti-M\u00fcllerian hormone reprograms the fetus and induces polycystic ovary syndrome in adulthood","volume":"24","author":"Tata","year":"2018","journal-title":"Nat. Med."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"R161","DOI":"10.1530\/JME-18-0079","article-title":"Ovarian and extra-ovarian mediators in the development of polycystic ovary syndrome","volume":"61","author":"Puttabyatappa","year":"2018","journal-title":"J. Mol. Endocrinol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"12","DOI":"10.1016\/j.mce.2007.10.010","article-title":"Effect of bisphenol A on steroid hormone production in rat ovarian theca-interstitial and granulosa cells","volume":"283","author":"Zhou","year":"2008","journal-title":"Mol. Cell. Endocrinol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1217","DOI":"10.1289\/ehp.0901257","article-title":"Neonatal exposure to bisphenol a and reproductive and endocrine alterations resembling the polycystic ovarian syndrome in adult rats","volume":"118","author":"Bourguignon","year":"2010","journal-title":"Environ. Health Perspect."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1507\/endocrj.51.165","article-title":"Positive relationship between androgen and the endocrine disruptor, bisphenol A, in normal women and women with ovarian dysfunction","volume":"51","author":"Takeuchi","year":"2004","journal-title":"Endocr. J."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"439","DOI":"10.1016\/bs.vh.2023.01.001","article-title":"The androgen receptor","volume":"123","author":"Blair","year":"2023","journal-title":"Vitam. Horm."},{"key":"ref_27","first-page":"1167","article-title":"Androgen receptor (AR)-CAG trinucleotide repeat length and idiopathic male infertility: A case-control trial and a meta-analysis","volume":"17","author":"Mobasseri","year":"2018","journal-title":"EXCLI J."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"3320","DOI":"10.1073\/pnas.94.7.3320","article-title":"The CAG repeat within the androgen receptor gene and its relationship to prostate cancer","volume":"94","author":"Giovannucci","year":"1997","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"301","DOI":"10.1677\/JME-08-0042","article-title":"Consequences of poly-glutamine repeat length for the conformation and folding of the androgen receptor amino-terminal domain","volume":"41","author":"Davies","year":"2008","journal-title":"J. Mol. Endocrinol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"17319","DOI":"10.1074\/jbc.M400970200","article-title":"Mechanistic relationship between androgen receptor polyglutamine tract truncation and androgen-dependent transcriptional hyperactivity in prostate cancer cells","volume":"279","author":"Wang","year":"2004","journal-title":"J. Biol. Chem."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"85","DOI":"10.1677\/jme.0.0250085","article-title":"Effect of the androgen receptor CAG repeat polymorphism on transcriptional activity: Specificity in prostate and non-prostate cell lines","volume":"25","author":"Beilin","year":"2000","journal-title":"J. Mol. Endocrinol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1002\/pros.10316","article-title":"Effect of a short CAG (glutamine) repeat on human androgen receptor function","volume":"58","author":"Ding","year":"2003","journal-title":"Prostate"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"184","DOI":"10.1038\/ng1093-184","article-title":"Reduced transcriptional regulatory competence of the androgen receptor in X-linked spinal and bulbar muscular atrophy","volume":"5","author":"Mhatre","year":"1993","journal-title":"Nat. Genet."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1677\/JME-06-0072","article-title":"The two most common alleles of the coding GGN repeat in the androgen receptor gene cause differences in protein function","volume":"39","author":"Brockschmidt","year":"2007","journal-title":"J. Mol. Endocrinol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"779","DOI":"10.1111\/bpa.12427","article-title":"RNA toxicity induced by expanded CAG repeats in Huntington\u2019s disease","volume":"26","year":"2016","journal-title":"Brain Pathol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"125","DOI":"10.2147\/nedt.1.2.125.61044","article-title":"Genetic and molecular aspects of spinocerebellar ataxias","volume":"1","author":"Honti","year":"2005","journal-title":"Neuropsychiatr. Dis. Treat."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"285","DOI":"10.1016\/S0361-9230(01)00583-4","article-title":"Cytochrome c oxidase subunit VB interacts with human androgen receptor: A potential mechanism for neurotoxicity in spinobulbar muscular atrophy","volume":"56","author":"Beauchemin","year":"2001","journal-title":"Brain Res. Bull."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"2197","DOI":"10.1093\/hmg\/9.14.2197","article-title":"CREB-binding protein sequestration by expanded polyglutamine","volume":"9","author":"McCampbell","year":"2000","journal-title":"Hum. Mol. Genet."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"459","DOI":"10.1016\/0166-2236(95)94497-S","article-title":"Spinal and bulbar muscular atrophy: A trinucleotide-repeat expansion neurodegenerative disease","volume":"18","author":"Brooks","year":"1995","journal-title":"Trends Neurosci."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"175","DOI":"10.3233\/JHD-200445","article-title":"What is the pathogenic CAG expansion length in Huntington\u2019s disease?","volume":"10","author":"Donaldson","year":"2021","journal-title":"J. Huntingt. Dis."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"516","DOI":"10.3109\/09513590.2011.650744","article-title":"CAG repeat polymorphism of androgen receptor gene and X-chromosome inactivation in daughters of women with polycystic ovary syndrome (PCOS): Relationship with endocrine and metabolic parameters","volume":"28","author":"Maliqueo","year":"2012","journal-title":"Gynecol. Endocrinol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"3484","DOI":"10.1210\/jcem.85.9.6832","article-title":"Androgen receptor gene CAG trinucleotide repeats in anovulatory infertility and polycystic ovaries","volume":"85","author":"Mifsud","year":"2000","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_43","first-page":"73","article-title":"Role of the CAG repeat polymorphism of the androgen receptor gene in polycystic ovary syndrome (PCOS)","volume":"120","author":"Welp","year":"2011","journal-title":"Exp. Clin. Endocrinol. Diabetes"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"693","DOI":"10.1093\/humrep\/dem382","article-title":"The role of sex hormone-binding globulin and androgen receptor gene variants in the development of polycystic ovary syndrome","volume":"23","author":"Xita","year":"2008","journal-title":"Hum. Reprod."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"1271","DOI":"10.1007\/s40618-020-01215-7","article-title":"The role of androgen receptor CAG repeat polymorphism in androgen excess disorder and idiopathic hirsutism","volume":"43","author":"Polat","year":"2020","journal-title":"J. Endocrinol. Investig."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"1939","DOI":"10.1210\/jc.2008-0038","article-title":"Association of androgen receptor CAG repeat polymorphism and polycystic ovary syndrome","volume":"93","author":"Shah","year":"2008","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"107","DOI":"10.1016\/j.jsbmb.2011.11.006","article-title":"CAG repeat polymorphism in androgen receptor gene is not directly associated with polycystic ovary syndrome but influences serum testosterone levels","volume":"128","author":"Skrgatic","year":"2012","journal-title":"J. Steroid. Biochem. Mol. Biol."},{"key":"ref_48","first-page":"925","article-title":"Effects of combined oral contraceptives on the clinical and biochemical parameters of hyperandrogenism in patients with polycystic ovary syndrome: A systematic review and meta-analysis","volume":"44","author":"Morgante","year":"2018","journal-title":"J. Obstet. Gynaecol. Res."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"2","DOI":"10.1080\/09513590.2021.2003326","article-title":"Polycystic ovarian syndrome: Signs and feedback effects of hyperandrogenism and insulin resistance","volume":"38","author":"Barrera","year":"2022","journal-title":"Gynecol. Endocrinol."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"502","DOI":"10.1001\/jamapediatrics.2015.4866","article-title":"Treatment considerations for the cardiometabolic signs of polycystic ovary syndrome: A review of the literature since the 2013 Endocrine Society clinical practice guidelines","volume":"170","author":"Fields","year":"2016","journal-title":"JAMA Pediatr."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"2967","DOI":"10.1093\/humrep\/dem271","article-title":"Efficacy of metformin in obese and non-obese women with polycystic ovary syndrome: A randomized, double-blinded, placebo-controlled cross-over trial","volume":"22","author":"Trolle","year":"2007","journal-title":"Hum. Reprod."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"422","DOI":"10.1007\/s12020-014-0403-y","article-title":"Metformin in women with PCOS, pros","volume":"48","author":"Pasquali","year":"2015","journal-title":"Endocrine"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"4354","DOI":"10.1210\/en.2012-1145","article-title":"Metformin inhibits human androgen production by regulating steroidogenic enzymes HSD3B2 and CYP17A1 and complex I activity of the respiratory chain","volume":"153","author":"Hirsch","year":"2012","journal-title":"Endocrinology"},{"key":"ref_54","doi-asserted-by":"crossref","unstructured":"Chang, K.-J., Chen, J.-H., and Chen, K.-H. (2024). The pathophysiological mechanism and clinical treatment of polycystic ovary syndrome: A molecular and Cellular Review of the literature. Int. J. Mol. Sci., 25.","DOI":"10.3390\/ijms25169037"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"102162","DOI":"10.1016\/j.eclinm.2023.102162","article-title":"Efficacy and safety of anti-androgens in the management of polycystic ovary syndrome: A systematic review and meta-analysis of randomised controlled trials","volume":"63","author":"Alesi","year":"2023","journal-title":"EClinicalMedicine"}],"container-title":["Current Issues in Molecular Biology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1467-3045\/48\/5\/526\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,5,19]],"date-time":"2026-05-19T15:47:28Z","timestamp":1779205648000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1467-3045\/48\/5\/526"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,5,18]]},"references-count":55,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2026,5]]}},"alternative-id":["cimb48050526"],"URL":"https:\/\/doi.org\/10.3390\/cimb48050526","relation":{},"ISSN":["1467-3045"],"issn-type":[{"value":"1467-3045","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,5,18]]}}}