Sex-specific estrogen levels and reference intervals from infancy to late adulthood determined by LC-MS/MS
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Abstract Context The lack of sensitive and robust analytical methods has hindered the reliable quantification of estrogen metabolites in subjects with low concentrations. Objective To establish sex-specific reference ranges for estrone (E1) and estradiol (E2) throughout life and to evaluate sex-differences using the state-of-the-art liquid chromatography tandem mass spectrometry (LC-MS/MS) method for quantification of E1, E2, and estriol (E3). Design LC-MS/MS method development and construction of estrogen reference ranges. Settings Population-based cross-sectional cohorts from the greater Copenhagen and Aarhus areas. Participants Healthy participants aged 3 months to 61 years (n = 1838). Results An isotope diluted LC-MS/MS method was developed and validated for measurements of serum E1, E2, and E3. Limits of detections (LODs) were 3 pmol/L (E1), 4 pmol/L (E2), and 12 pmol/L (E3), respectively. This sensitive method made it possible to differentiate between male and female concentration levels of E1 and E2 in children. In girls, E2 levels ranged from Conclusion Reference ranges of simultaneous quantification of E1 and E2 by this novel specific and highly sensitive LC-MS/MS method provide an invaluable tool in clinical practice and in future research studies.
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The authors previously reported age- and sex-specific reference intervals for E1 and E2 from 1838 subjects aged 0-65 years.
“Likewise, we reported age- and sexspecific reference intervals for E1 and E2 from 1838 subjects aged 0 -65 years [1].”
From Sex- and age-specific reference intervals of 16 steroid metabolites quantified simultaneously by LC-MS/MS in sera from 2458 healthy subjects aged 0 to 77 years (2024) · cites this paper as [1]
The Discussion reports sex- and age-stratified reference ranges for E1 and E2, and Materials and Methods (Subjects) reports 1,838 participants. The age range is misstated: the paper describes participants aged 3 months to 61 years, not 0 to 65 years. (LLM, conf=0.90)
Experimental — accuracy not yet measuredSerum steroid concentrations may change significantly throughout life, with some increasing from picomolar to micromolar concentrations, like progesterone and estradiol in women, and especially during pregnancy.
“In addition, serum steroid concentrations may change significantly throughout life with some increasing from picomolar to micromolar concentrations, like progesterone (PROG) and estradiol (E2) in women, and especially during pregnancy [1].”
From Sex- and age-specific reference intervals of 16 steroid metabolites quantified simultaneously by LC-MS/MS in sera from 2458 healthy subjects aged 0 to 77 years (2024) · cites this paper as [1]
The Results (Association to menstrual cycle; page unavailable) report significant changes in estradiol and progesterone across menstrual-cycle phases, and the Results (Menopausal status; page unavailable) report age-related differences in estradiol. The paper does not show progesterone or estradiol rising from picomolar to micromolar concentrations, particularly during pregnancy; its pregnancy example in the Results (Estrogen LC-MS/MS method validation; page unavailable) is a chromatogram, not evidence of that increase. (LLM, conf=0.88)
Experimental — accuracy not yet measuredReference intervals have been published for women with known menstrual cycle timing at blood sampling.
“as well as in women with known menstrual cycle timing at blood sampling [1,13,22].”
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References 54 · Cited by 211
- Authors
- Frederiksen, H., Johannsen, T. H., Andersen, S. E., Albrethsen, J., Landersoe, S. K., Petersen, J. H., Andersen, A. N., Vestergaard, E. T., Schorring, M. E., Linneberg, A., Main, K. M., Andersson, A.-M., & Juul, A.
- Affiliations
- University of Copenhagen (DK)
- The Fertility Clinic, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
- Aarhus University Hospital (DK)
- Paediatrics and Adolescent Medicine, Aarhus University Hospital, Aahus, Denmark
- Corresponding author
- Frederiksen, Hanne
- ORCID
- Venue
- The Journal of Clinical Endocrinology & Metabolism
- Publisher
- The Endocrine Society
- Published
- 2019-11-13
- Volume
- 105
- Issue
- 3
- Pages
- 754-768
- ISSN
- 0021-972X (ISSN-L)
- 1945-7197
- PMC
- PMC7007877
- OpenAlex
- W2983800014
- Cited by
- 211
- References
- 54
- Citations by year
- 2026: 38 · 2025: 51 · 2024: 39 · 2023: 26 · 2022: 26 · 2021: 22 · 2020: 8 · 2019: 1
- FWCI
- 8.58
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- The Journal of Clinical Endocrinology & Metabolism (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Research at the University of Copenhagen (University of Copenhagen) (publishedVersion, cc-by)
- Figshare (submittedVersion, cc-by)
- Figshare (cc-by)
- Funders
- Innovation Fund Denmark (14-2013-4)
- ReproUnion collaboration (NYPS 20201846)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Estrogen and related hormone effects
- Physical Sciences › Environmental Science › Health, Toxicology and Mutagenesis › Effects and risks of endocrine disrupting chemicals
- Health Sciences › Medicine › Physiology › Clinical Laboratory Practices and Quality Control
- Keywords
- estrone, estradiol, estriol, estrogen metabolites, LC-MS/MS method validation, isotope dilution, sex differences, life course, children, healthy adults
- MeSH terms
- Adolescent, Adult, Child, Child, Preschool, Chromatography, Liquid, Estradiol, Estrone, Female, Humans, Infant, Male, Middle Aged, Reference Values, Sensitivity and Specificity, Sex Factors, Tandem Mass Spectrometry, Young Adult, Healthy Volunteers
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