{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,8,30]],"date-time":"2025-08-30T00:05:02Z","timestamp":1756512302853,"version":"3.44.0"},"reference-count":18,"publisher":"Pensoft Publishers","issue":"4","license":[{"start":{"date-parts":[[2025,8,29]],"date-time":"2025-08-29T00:00:00Z","timestamp":1756425600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["FM"],"abstract":"<jats:p><jats:bold>Introduction<\/jats:bold>: Human epididymis protein 4 (HE4) is increasingly utilized in diagnosing pelvic masses and monitoring patients with ovarian or endometrial carcinoma. However, various publications and diagnostic kit manufacturers report a wide range of reference and threshold values, complicating accurate clinical interpretation and reducing the marker\u2019s clinical utility. This study aimed to establish reference values for HE4 in the Bulgarian female population and investigate the impact of physiological factors such as age, menopause, and pregnancy, as well as pathological conditions like impaired renal function, on marker levels.<\/jats:p>\n          <jats:p><jats:bold>Materials and methods<\/jats:bold>: The study included 338 women: 246 healthy, nonpregnant women aged 20\u201382 (124 of whom were premenopausal); 52 pregnant women; and 40 women with reduced renal function, as determined by serum creatinine levels. Data were collected on gynecological status, renal and hepatic function, diabetes, and other clinically significant chronic or oncological diseases. Serum HE4 concentrations were measured using an indirect chemiluminescent microparticle immunoassay (CMIA) on the Architect ci8200 system (Abbott Diagnostics). Statistical analyses were performed using SPSS version 25.0, and values were considered statistically significant at <jats:italic>p<\/jats:italic>&amp;lt;0.05.<\/jats:p>\n          <jats:p><jats:bold>Results<\/jats:bold>: The upper reference limit for HE4 in healthy women (95th percentile with 95% confidence interval) was 62.43 (59.02\u201365.45) pmol\/L. For menopausal status, upper reference limits were 53.22 (50.80\u201360.82) pmol\/L for premenopausal women and 65.31 (61.57\u201368.35) pmol\/L for postmenopausal women. In pregnant women, the upper HE4 limit was 50.90 pmol\/L, with values by gestational age of 57.73 pmol\/L (first trimester) and 46.35 pmol\/L (second trimester). None of the women with serum creatinine within the reference range had elevated HE4 levels, whereas all patients with elevated creatinine had HE4 levels above the 95th percentile for their respective age and menopausal status.<\/jats:p>\n          <jats:p><jats:bold>Conclusions<\/jats:bold>: The established reference limits for HE4 in this study significantly differ from those proposed by Abbott Diagnostics that are used to date. Implementing these limits in clinical practice could enhance the marker\u2019s sensitivity and enable earlier detection of gynecological malignancies. The data confirm that HE4 levels depend on age, particularly after 60 years, and on reduced renal function, necessitating cautious interpretation in these patients. No significant differences in HE4 concentrations were observed between pregnant and non-pregnant women, supporting the use of uniform reference values regardless of pregnancy or gestational stage.<\/jats:p>","DOI":"10.3897\/folmed.67.e155013","type":"journal-article","created":{"date-parts":[[2025,8,29]],"date-time":"2025-08-29T11:04:42Z","timestamp":1756465482000},"source":"Crossref","is-referenced-by-count":0,"title":["Reference values of human epididymis protein 4 in the Bulgarian population \u2013 assessment of the influence of age, menopause, pregnancy, and renal function"],"prefix":"10.3897","volume":"67","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9900-708X","authenticated-orcid":true,"given":"Vesselina","family":"Koleva-Topova","sequence":"first","affiliation":[{"name":"Acibadem City Clinic University Hospital Tokuda, Sofia, Bulgaria"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sevim","family":"Shefket","sequence":"additional","affiliation":[{"name":"St Marina University Hospital, Varna, Bulgaria"},{"name":"Prof. Dr Paraskev Stoyanov Medical University, Varna, Bulgaria"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"2258","published-online":{"date-parts":[[2025,8,29]]},"reference":[{"key":"155013_B1","doi-asserted-by":"crossref","unstructured":"1. 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Ovarian tumor marker HE4 is differentially expressed during the phases of the menstrual cycle in healthy young women. Tumor Biol 2010; 31:411\u20135.","DOI":"10.1007\/s13277-010-0049-1"},{"key":"155013_B12","doi-asserted-by":"crossref","unstructured":"12. Moore RG, Miller MC, Eklund EE, et al. Serum levels of the ovarian cancer biomarker HE4 are decreased in pregnancy and increase with age. Am J Obstet Gynecol 2012; 206(4):349.e1\u20137.","DOI":"10.1016\/j.ajog.2011.12.028"},{"key":"155013_B13","unstructured":"13. 3. Abbott Diagnostics. HE4 package insert. November 2015. 600-032 11\/15\/R07."},{"key":"155013_B14","doi-asserted-by":"crossref","unstructured":"14. Tian Y, Wang C, Cheng L, et al. Determination of reference intervals of serum levels of human epididymis protein 4 (HE4) in Chinese women. J Ovarian Res 2015; 8:72.","DOI":"10.1186\/s13048-015-0201-z"},{"key":"155013_B15","doi-asserted-by":"crossref","unstructured":"15. Gasiorowska E, Kluz T, Lipski D, et al. Human epididymis protein 4 (HE4) reference limits in Polish population of healthy women, pregnant women, and women with benign ovarian tumors. Dis Markers 2019; 2019:3890906.","DOI":"10.1155\/2019\/3890906"},{"key":"155013_B16","doi-asserted-by":"crossref","unstructured":"16. Azim SA, Mutz-Dehbalaie I, Wieser V, et al. Influence of pregnancy-related conditions on human epididymis protein 4 serum levels in comparison to CA125\u2014a prospective cohort trial. Geburtshilfe Frauenheilkd 2021;81(9):1047\u201354.","DOI":"10.1055\/a-1475-4296"},{"key":"155013_B17","doi-asserted-by":"crossref","unstructured":"17. Lycke M, Ulfenborg B, Malchau Lauesgaard J, et al. Consideration should be given to smoking, endometriosis, renal function (eGFR) and age when interpreting CA125 and HE4 in ovarian tumor diagnostics. Clin Chem Lab Med 2021; 59(12):1954\u201362.","DOI":"10.1515\/cclm-2021-0510"},{"key":"155013_B18","doi-asserted-by":"crossref","unstructured":"18. Yan S, Lin Y, Tian X. Significantly elevated serum human epididymis protein-4 in chronic kidney disease patients without ovarian cancer: a large-scale retrospective study. 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