Establishment of harmonized international reference ranges for plasma estradiol concentrations in postmenopausal women
Year: 2026
Type: article
Study design: Observational Study
Abstract: CONTEXT: Prior reports of plasma estradiol concentrations and their reference ranges in postmenopausal women identified marked variation, in part due to assay method and body mass index (BMI). OBJECTIVE: To develop an international reference range for plasma estradiol in postmenopausal women, support accurate assessment of concentrations during systemic and local (eg, vaginal) estradiol therapy, and improve risk prediction for diseases, including osteoporosis, breast, and endometrial cancers. METHODOLOGY: Estradiol concentrations were measured using primarily liquid chromatography-tandem mass spectrometry (LC-MS/MS) assays in 5 international cohorts of community-dwelling, postmenopausal women of primarily European ancestry aged 38-100 years who were not using exogenous estrogens (n = 7206). Measurements were harmonized to the Centers for Disease Control and Prevention (CDC) reference measurement procedure (RMP) by re-assaying a subset of samples for each cohort and generating recalibration equations. Reference intervals were determined for all women, non-obese women, and specific BMI categories. RESULTS: Estradiol concentrations from separate LC-MS/MS assays correlated closely with the CDC RMP, and harmonization minimized inter-assay variability. Estradiol concentrations correlated with BMI but not with chronological age. The reference range (2.5th-97.5th percentile) was 1.1-18.2 pg/mL (4.0-66.8 pmol/L) with median of 4.9 pg/mL (18.0 pmol/L) for all postmenopausal women and 1.1-12.5 pg/mL (4.0-45.9 pmol/L) with median of 4.1 pg/mL (15.1 pmol/L) for non-obese women (BMI < 30). Reference ranges increased progressively with higher BMI categories. CONCLUSION: Cross-calibration of estradiol measurements with the CDC RP enabled the development of harmonized plasma estradiol reference ranges for postmenopausal women who were not using exogenous estrogens, suitable for future studies to establish clinical utility. Increasing obesity in postmenopausal women was associated with increasing estradiol concentration and BMI category-specific reference ranges.
Authors: Jinghan Cui, Susan E Hankinson, Alvin M Matsumoto, Richard J Santen, Maegan E Boutot, Jeffrey R Budd, Mitch Dowsett, Matthew P Goetz, Catherine Guranich, Serena Houghton, James N Ingle, Micheal E Jones, Sabina Rinaldi, Bernard Rosner, Minouk J Schoemaker, Ravinder J Singh, Hubert W Vesper, A Heather Eliassen, Roger L Milne, Anthony J Swerdlow, Celine M Vachon, Harriet Richardson, Jing Qian
Institutions: University of Massachusetts Amherst, University of Washington, VA Puget Sound Health Care System, University of Virginia, Royal Marsden Hospital, Mayo Clinic, Institute of Cancer Research, Centre international de recherche sur le cancer, Brigham and Women's Hospital, Harvard University, Centers for Disease Control and Prevention, The University of Melbourne, Cancer Council Victoria, Monash Health, Monash University, Queen's University, Canadian Cancer Trials Group
Language: English
Subfield: Endocrinology, Diabetes and Metabolism
Field: Medicine
Domain: Health Sciences
Open Access status: green
Funders: American Society for Reproductive Medicine, North American Menopause Society, American Society for Bone and Mineral Research, World Cancer Research Fund International, Novo Nordisk, National Institutes of Health, World Cancer Research Fund, National Health and Medical Research Council, Cancer Council Victoria, National Cancer Institute
Awards: G1892169571, Health 2020, Epidemiology of Chronic Disease, Health Interventions and DNA Studies, Precision Public Health for major cancers - novel approaches to building the genetic, epigenetic and lifestyle knowledge base for assessing risk and prognosis, Endogenous hormones and postmenopausal breast cancer: Etiologic insights and improving risk prediction, Long Term Multidisciplinary Study of Cancer in Women: The Nurses Health Study, Mayo Clinic Breast Cancer SPORE
OpenAlex ID: W7161049332