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Published on: August 13, 2019
Establishment of harmonized international reference ranges for plasma estradiol concentrations in postmenopausal
Jinghan Cui1, Susan E Hankinson1, Alvin M Matsumoto2
1Department of Biostatistics and Epidemiology, School of Public Health and Health Sciences, University of Massachusetts, Amherst, MA 01003, USA.
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, to support accurate assessment of concentrations during systemic and local (e.g., vaginal) estradiol therapy, and to 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 five 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.