{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,27]],"date-time":"2026-06-27T04:46:10Z","timestamp":1782535570021,"version":"3.54.5"},"reference-count":39,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2026,6,14]],"date-time":"2026-06-14T00:00:00Z","timestamp":1781395200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Medical University-Sofia","award":["200"],"award-info":[{"award-number":["200"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JCM"],"abstract":"<jats:p>Background: Polycystic ovarian syndrome (PCOS) and the non-classic form of congenital adrenal hyperplasia (NC-CAH) are hyperandrogenic conditions with overlapping clinical symptoms but different genetic backgrounds. The possible interrelationships between the two conditions remain unclear; thus, the present study aims to investigate the prevalence of CYP21A2 exon 7 genetic variants in patients with PCOS and to explore the possible associations of the polymorphisms with adrenocortical hormonal production. Methods: The CYP21A2 exon 7 region was genotyped in 80 unrelated female patients with PCOS and 12 women with NC-CAH. The associations between genetic variants, clinical characteristics, and adrenocortical hormones were investigated. Results: The pathogenic CYP21A2 NC-CAH variant c.844G&gt;T; p.(Val282Leu) was found in 66.7% (8\/12) of patients with NC-CAH but in none of the individuals with PCOS. The benign rs1554305325, rs6465, rs6472, and rs6477 genetic polymorphisms were not related to clinical hyperandrogenism. The rs6472 polymorphic alleles were associated with increased adrenocorticotropic hormone (ACTH) (5.5 vs. 3.4 pmol\/L, p = 0.022) and cortisol (460.5 vs. 366.5 nmol\/L, p = 0.016) levels. The rs6465 variant alleles were significantly associated with lower pregnenolone (1.43 vs. 3.1 ng\/mL, p = 0.031) and ACTH (2.5 vs. 4.5 pmol\/L, p = 0.030) levels in the unadjusted model but not after adjustment for potential confounders (p &gt; 0.05). Conclusions: The p.(Val282Leu) variant is very common among Bulgarian patients with NC-CAH but it has not been found in our cohort of women with PCOS. The CYP21A2 exon 7 polymorphisms might be associated with cortisol levels in the patients with PCOS. Further larger studies are needed to confirm or reject the current findings in different ethnic groups.<\/jats:p>","DOI":"10.3390\/jcm15124626","type":"journal-article","created":{"date-parts":[[2026,6,15]],"date-time":"2026-06-15T08:57:58Z","timestamp":1781513878000},"page":"4626","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Some CYP21A2 Polymorphisms in the Exon 7 Region Might Be Associated with Cortisol Secretion in Polycystic Ovary Syndrome"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4007-9713","authenticated-orcid":false,"given":"Ralitsa","family":"Robeva","sequence":"first","affiliation":[{"name":"Department of Endocrinology, Faculty of Medicine, Medical University-Sofia, USHATE \u201cAcad. Iv. Penchev\u201d, 1000 Sofia, Bulgaria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Silvia","family":"Andonova","sequence":"additional","affiliation":[{"name":"Genetic Medico-Diagnostic Laboratory \u201cGenica\u201d, 1000 Sofia, Bulgaria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6535-5409","authenticated-orcid":false,"given":"Georgi","family":"Kirilov","sequence":"additional","affiliation":[{"name":"Department of Endocrinology, Faculty of Medicine, Medical University-Sofia, USHATE \u201cAcad. Iv. Penchev\u201d, 1000 Sofia, Bulgaria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Iglika","family":"Yordanova","sequence":"additional","affiliation":[{"name":"Genetic Medico-Diagnostic Laboratory \u201cGenica\u201d, 1000 Sofia, Bulgaria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Silvia","family":"Vandeva","sequence":"additional","affiliation":[{"name":"Department of Endocrinology, Faculty of Medicine, Medical University-Sofia, USHATE \u201cAcad. Iv. Penchev\u201d, 1000 Sofia, Bulgaria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Atanaska","family":"Elenkova","sequence":"additional","affiliation":[{"name":"Department of Endocrinology, Faculty of Medicine, Medical University-Sofia, USHATE \u201cAcad. Iv. Penchev\u201d, 1000 Sofia, Bulgaria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexey","family":"Savov","sequence":"additional","affiliation":[{"name":"National Genetic Laboratory, Medical Faculty, Medical University-Sofia, University Hospital of Obstetrics and Gynecology \u201cMaichin Dom\u201d, 1000 Sofia, Bulgaria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tihomir","family":"Todorov","sequence":"additional","affiliation":[{"name":"Genetic Medico-Diagnostic Laboratory \u201cGenica\u201d, 1000 Sofia, Bulgaria"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,6,14]]},"reference":[{"key":"ref_1","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_2","doi-asserted-by":"crossref","unstructured":"Sadeghi, H.M., Adeli, I., Calina, D., Docea, A.O., Mousavi, T., Daniali, M., Nikfar, S., Tsatsakis, A., and Abdollahi, M. (2022). Polycystic Ovary Syndrome: A Comprehensive Review of Pathogenesis, Management, and Drug Repurposing. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23020583"},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Rotterdam ESHRE\/ASRM-Sponsored PCOS Consensus Workshop Group (2004). Revised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome (PCOS). Hum. Reprod., 19, 41\u201347.","DOI":"10.1093\/humrep\/deh098"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"767","DOI":"10.1016\/j.fertnstert.2023.07.025","article-title":"Recommendations from the 2023 International Evidence-based Guideline for the Assessment and Management of Polycystic Ovary Syndrome","volume":"120","author":"Teede","year":"2023","journal-title":"Fertil. Steril."},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Uslar, T., Olmos, R., Mart\u00ednez-Aguayo, A., and Baudrand, R. (2023). Clinical Update on Congenital Adrenal Hyperplasia: Recommendations from a Multidisciplinary Adrenal Program. J. Clin. Med., 12.","DOI":"10.3390\/jcm12093128"},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Papadakis, G., Kandaraki, E.A., Tseniklidi, E., Papalou, O., and Diamanti-Kandarakis, E. (2019). Polycystic Ovary Syndrome and NC-CAH: Distinct Characteristics and Common Findings. A Systematic Review. Front. Endocrinol., 10.","DOI":"10.3389\/fendo.2019.00388"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"4043","DOI":"10.1210\/jc.2018-01865","article-title":"Congenital Adrenal Hyperplasia Due to Steroid 21-Hydroxylase Deficiency: An Endocrine Society Clinical Practice Guideline","volume":"103","author":"Speiser","year":"2018","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"467","DOI":"10.1210\/er.2015-1104","article-title":"The Pathogenesis of Polycystic Ovary Syndrome (PCOS): The Hypothesis of PCOS as Functional Ovarian Hyperandrogenism Revisited","volume":"37","author":"Rosenfield","year":"2016","journal-title":"Endocr. Rev."},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"G\u00f3ral, A., \u017bywot, K., Zalewski, W., Jagodzi\u0144ski, A., and Murawski, M. (2024). Polycystic Ovary Syndrome and Eating Disorders-A Literature Review. J. Clin. Med., 14.","DOI":"10.3390\/jcm14010027"},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Karakas, S.E. (2023). Reactive Hypoglycemia: A Trigger for Nutrient-Induced Endocrine and Metabolic Responses in Polycystic Ovary Syndrome. J. Clin. Med., 12.","DOI":"10.20944\/preprints202309.2148.v1"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"252","DOI":"10.1186\/s13048-025-01824-x","article-title":"Long-read sequencing analysis of non-classical congenital adrenal hyperplasia prevalence and carrier frequency in Chinese polycystic ovarian syndrome patients","volume":"18","author":"Huang","year":"2025","journal-title":"J. Ovarian Res."},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Robeva, R., Andonova, S., Todorov, T., Feyzullova, A., Elenkova, A., Kirilov, G., Savov, A., Zacharieva, S., and Todorova, A. (2024). CYP21A2 Intron 2 Genetic Variants Might Be Associated with the Clinical Characteristics of Women with PCOS. Biomedicines, 12.","DOI":"10.3390\/biomedicines12071528"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"611","DOI":"10.1073\/pnas.1300057110","article-title":"Genotype-phenotype correlation in 1,507 families with congenital adrenal hyperplasia owing to 21-hydroxylase deficiency","volume":"110","author":"New","year":"2013","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Pignatelli, D., Carvalho, B.L., Palmeiro, A., Barros, A., Guerreiro, S.G., and Macut, D. (2019). The Complexities in Genotyping of Congenital Adrenal Hyperplasia: 21-Hydroxylase Deficiency. Front. Endocrinol., 10.","DOI":"10.3389\/fendo.2019.00432"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"427","DOI":"10.1111\/j.1365-2265.2011.04123.x","article-title":"Steroid 21-hydroxylase gene mutational spectrum in 454 Argentinean patients: Genotype-phenotype correlation in a large cohort of patients with congenital adrenal hyperplasia","volume":"75","author":"Marino","year":"2011","journal-title":"Clin. Endocrinol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"181","DOI":"10.1007\/BF03347422","article-title":"In the Sicilian ethnic group, non-classical congenital adrenal hyperplasia is frequently associated with a very mild genotype","volume":"30","author":"Wasniewska","year":"2007","journal-title":"J. Endocrinol. Investig."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"543","DOI":"10.1111\/cen.12543","article-title":"The spectrum of clinical, hormonal, and molecular findings in 280 individuals with nonclassical congenital adrenal hyperplasia caused by mutations of the CYP21A2 gene","volume":"82","author":"Livadas","year":"2015","journal-title":"Clin. Endocrinol."},{"key":"ref_18","first-page":"447","article-title":"Distribution of the V281L mutation of the CYP21 gene in Israeli congenital adrenal hyperplasia patients and its association with HLA- B14","volume":"3","author":"Israel","year":"2006","journal-title":"Pediatr. Endocrinol. Rev."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"106156","DOI":"10.1016\/j.jsbmb.2022.106156","article-title":"Genetic analysis and novel variation identification in Chinese patients with congenital adrenal hyperplasia due to 21-hydroxylase deficiency","volume":"222","author":"Xia","year":"2022","journal-title":"J. Steroid. Biochem. Mol. Biol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1021","DOI":"10.1507\/endocrj.K07-028","article-title":"Nonclassic Steroid 21-Hydroxylase Deficiency due to a Homozygous V281L Mutation in CYP21A2 Detected by the Neonatal Mass-Screening Program in Japan","volume":"54","author":"Shinagawa","year":"2007","journal-title":"Endocr. J."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"20916","DOI":"10.1016\/S0021-9258(17)45304-X","article-title":"Determination of functional effects of mutations in the steroid 21-hydroxylase gene (CYP21) using recombinant vaccinia virus","volume":"265","author":"Traktman","year":"1990","journal-title":"J. Biol. Chem."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"519","DOI":"10.1172\/JCI115334","article-title":"Mutations of P450c21 (steroid 21-hydroxylase) at Cys428, Val281, and Ser268 result in complete, partial, or no loss of enzymatic activity, respectively","volume":"88","author":"Wu","year":"1991","journal-title":"J. Clin. Investig."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1425","DOI":"10.1080\/07391102.2019.1607560","article-title":"Measuring the structural impact of mutations on cytochrome P450 21A2, the major steroid 21-hydroxylase related to congenital adrenal hyperplasia","volume":"38","year":"2020","journal-title":"J. Biomol. Struct. Dyn."},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Prado, M.J., Singh, S., Ligabue-Braun, R., Meneghetti, B.V., Rispoli, T., Kopacek, C., Monteiro, K., Zaha, A., Rossetti, M.L.R., and Pandey, A.V. (2021). Characterization of Mutations Causing CYP21A2 Deficiency in Brazilian and Portuguese Populations. Int. J. Mol. Sci., 23.","DOI":"10.20944\/preprints202112.0144.v1"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"20420188251388397","DOI":"10.1177\/20420188251388397","article-title":"Assessing cortisol levels in non-classical congenital adrenal hyperplasia: Focus on the V281L variant","volume":"16","author":"Bilici","year":"2025","journal-title":"Ther. Adv. Endocrinol. Metab."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"bvae163.137","DOI":"10.1210\/jendso\/bvae163.137","article-title":"Characterizing The Presentation of Non-Classical Congenital Adrenal Hyperplasia","volume":"8","author":"Patel","year":"2024","journal-title":"J. Endocr. Soc."},{"key":"ref_27","first-page":"965","article-title":"Characteristics and prevalence of non-classical congenital adrenal hyperplasia with a V2811 mutation in patients with premature pubarche","volume":"24","author":"Berberoglu","year":"2011","journal-title":"J. Pediatr. Endocrinol. Metab."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"S72","DOI":"10.4103\/2230-8210.145077","article-title":"Phenotypic variability of hyperandrogenemia in females heterozygous for CYP21A2 mutations","volume":"18","author":"Neocleous","year":"2014","journal-title":"Indian J. Endocrinol. Metab."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"645","DOI":"10.1111\/j.1365-2265.2006.02521.x","article-title":"Hyperandrogenism in carriers of CYP21 mutations: The role of genotype","volume":"64","author":"Admoni","year":"2006","journal-title":"Clin. Endocrinol."},{"key":"ref_30","first-page":"1017","article-title":"Steroid 21-hydroxylase (P450c21) naturally occurring mutants I172N, V281L, and I236n\/V237E\/M239K exert a dominant negative effect on enzymatic activity when co-expressed with the wild-type protein","volume":"16","author":"Riba","year":"2003","journal-title":"J. Pediatr. Endocrinol. Metab."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"596","DOI":"10.3109\/09513591003649849","article-title":"Lack of association between CYP21 V281L variant and polycystic ovary syndrome in Italian women","volume":"26","author":"Pucci","year":"2010","journal-title":"Gynecol. Endocrinol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"371","DOI":"10.1016\/j.fertnstert.2004.10.027","article-title":"Prevalence of CYP21 mutations and IRS1 variant among women with polycystic ovary syndrome and adrenal androgen excess","volume":"83","author":"Witchel","year":"2005","journal-title":"Fertil. Steril."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"383","DOI":"10.1055\/s-0033-1333727","article-title":"CYP21A2 mutations in women with polycystic ovary syndrome (PCOS)","volume":"45","author":"Settas","year":"2013","journal-title":"Horm. Metab. Res."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"665","DOI":"10.1007\/s12020-019-02104-7","article-title":"The prevalence of heterozygous CYP21A2 deficiency in patients with idiopathic acne, hirsutism, or both","volume":"67","author":"Gao","year":"2020","journal-title":"Endocrine"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"313","DOI":"10.2147\/CCID.S293171","article-title":"The Associations of Androgen-Related Genes CYP21A2 and CYP19A1 with Severe Acne Vulgaris in Patients from Southwest China","volume":"14","author":"Yang","year":"2021","journal-title":"Clin. Cosmet. Investig. Dermatol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"743","DOI":"10.1530\/EJE-14-0432","article-title":"CYP21A2 polymorphisms in patients with autoimmune Addison\u2019s disease, and linkage disequilibrium to HLA risk alleles","volume":"171","author":"Skinningsrud","year":"2014","journal-title":"Eur. J. Endocrinol."},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Doleschall, M., Szab\u00f3, J.A., P\u00e1zm\u00e1ndi, J., Szil\u00e1gyi, \u00c1., Koncz, K., Farkas, H., T\u00f3th, M., Igaz, P., Gl\u00e1z, E., and Proh\u00e1szka, Z. (2014). Common genetic variants of the human steroid 21-hydroxylase gene (CYP21A2) are related to differences in circulating hormone levels. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0107244"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"48","DOI":"10.1093\/humupd\/dmae028","article-title":"Evaluating the diagnostic accuracy of androgen measurement in polycystic ovary syndrome: A systematic review and diagnostic meta-analysis to inform evidence-based guidelines","volume":"31","author":"Bizuneh","year":"2025","journal-title":"Hum. Reprod. Update"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1059","DOI":"10.1016\/j.fertnstert.2022.01.014","article-title":"Changes in individual polycystic ovary syndrome phenotypical characteristics over time: A long-term follow-up study","volume":"117","author":"Louwers","year":"2022","journal-title":"Fertil. Steril."}],"container-title":["Journal of Clinical Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2077-0383\/15\/12\/4626\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,6,27]],"date-time":"2026-06-27T04:12:18Z","timestamp":1782533538000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2077-0383\/15\/12\/4626"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,6,14]]},"references-count":39,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2026,6]]}},"alternative-id":["jcm15124626"],"URL":"https:\/\/doi.org\/10.3390\/jcm15124626","relation":{},"ISSN":["2077-0383"],"issn-type":[{"value":"2077-0383","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,6,14]]}}}