11-Oxygenated estrogens are a novel class of human estrogens but do not contribute to the circulating estrogen pool
Open accessAbstract
Androgens are the obligatory precursors of estrogens. In humans, classic androgen biosynthesis yields testosterone, thought to represent the predominant circulating active androgen both in men and women. However, recent work has shown that 11-ketotestosterone, derived from the newly described 11-oxygenated androgen biosynthesis pathway, makes a substantial contribution to the active androgen pool in women. Considering that classic androgens are the obligatory substrates for estrogen biosynthesis catalyzed by cytochrome P450 aromatase, we hypothesized that 11-oxygenated androgens are aromatizable. Here we use steroid analysis by tandem mass spectrometry to demonstrate that human aromatase generates 11-oxygenated estrogens from 11-oxygenated androgens in 3 different cell-based aromatase expression systems and in human ex vivo placenta explant cultures. We also show that 11-oxygenated estrogens are generated as a byproduct of the aromatization of classic androgens. We show that 11β-hydroxy-17β-estradiol binds and activates estrogen receptors α and β and that 11β-hydroxy-17β-estradiol and the classic androgen pathway-derived active estrogen, 17β-estradiol, are equipotent in stimulating breast cancer cell line proliferation and expression of estrogen-responsive genes. 11-oxygenated estrogens were, however, not detectable in serum from individuals with high aromatase levels (pregnant women) and elevated 11-oxygenated androgen levels (patients with congenital adrenal hyperplasia or adrenocortical carcinoma). Our data show that while 11-oxygenated androgens are aromatizable in vitro and ex vivo, the resulting 11-oxygenated estrogens are not detectable in circulation, suggesting that 11-oxygenated androgens function primarily as androgens in vivo.
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The intermediate 11-ketoandrostenedione but not 11OH-androstenedione is a much better substrate for AKR1C3 than androstenedione itself, which explains why 11KT is the second-most abundant circulating 11-oxo-androgen in both 21OHD patients and unaffected individuals.
“The intermediate 11-ketoandrostenedionebut not 11OHandrostenedioneis a much better substrate for AKR1C3 than androstenedione itself (127), which explains why 11KT is the second-most abundant circulating 11-oxo-androgen in both 21OHD patients and unaffected individuals.”
From Congenital Adrenal Hyperplasia—Current Insights in Pathophysiology, Diagnostics, and Management (2022) · cites this paper as [127]
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Congenital Adrenal Hyperplasia—Current Insights in Pathophysiology, Diagnostics, and Management
Claahsen - van der Grinten, H. L., Speiser, P. W., Ahmed, S. F., Arlt, W., Auchus, R. J., Falhammar, H., Flück, C. E., Guasti, L., Huebner, A., Kortmann, B. B. M., et al. (2022) · Endocrine Reviews · doi:10.1210/endrev/bnab016 · Cited by 556 · see citing works
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Self-citation
- Authors
- Barnard, L., Schiffer, L., Louw du-Toit, R., Tamblyn, J. A., Chen, S., Africander, D., Arlt, W., Foster, P. A., & Storbeck, K.-H.
- Affiliations
- Stellenbosch University (ZA)
- University of Birmingham (GB)
- Department of Biochemistry, Stellenbosch University, Matieland, South Africa
- University Hospitals Birmingham NHS Foundation Trust (GB)
- Beckman Research Institute (US)
- Corresponding author
- Storbeck, Karl-Heinz
- ORCID
- Venue
- Endocrinology
- Publisher
- The Endocrine Society
- Published
- 2020-12-19
- Volume
- 162
- Issue
- 3
- ISSN
- 0013-7227 (ISSN-L)
- 1945-7170
- PMC
- PMC7814299
- OpenAlex
- W3113634989
- Cited by
- 27
- References
- 33
- Citations by year
- 2026: 4 · 2025: 2 · 2024: 2 · 2023: 5 · 2022: 6 · 2021: 8
- FWCI
- 2.79
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Endocrinology (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- University of Birmingham Research Portal (University of Birmingham) (submittedVersion, cc-by)
- Spiral (Imperial College London) (submittedVersion, cc-by)
- Funders
- Academy of Medical Sciences (NAF004\1002)
- Wellcome Trust (WT209492/Z/17/Z)
- National Research Foundation (111622)
- National Institutes of Health (U01ES026137, P30CA033572)
- University of Birmingham (BRC-1215-20009)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Estrogen and related hormone effects
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Steroid Chemistry and Biochemistry
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Sexual Differentiation and Disorders
- Keywords
- 11-ketotestosterone, aromatase, estrogen synthesis, 11-oxygenated androgens, androgen production, estrogen receptor activation, breast cancer cell proliferation, placenta, congenital adrenal hyperplasia, adrenocortical carcinoma
- MeSH terms
- Animals, Aromatase, Chlorocebus aethiops, Estradiol, Estrogens, Female, Fetal Blood, Humans, Infant, Newborn, Oxygen, Placenta, Pregnancy, Protein Binding, Receptors, Estrogen, Testosterone, COS Cells, Cell Line, Tumor, HEK293 Cells, MCF-7 Cells
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