11-Oxygenated estrogens are a novel class of human estrogens but do not contribute to the circulating estrogen pool
File(s)
Published version
Author(s)
Type
Journal Article
Abstract
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.
Date Issued
2021-03-01
Date Acceptance
2020-12-01
Citation
Endocrinology, 2021, 162 (3)
ISSN
0013-7227
Publisher
Oxford University Press
Journal / Book Title
Endocrinology
Volume
162
Issue
3
Copyright Statement
© The Author(s) 2020. Published by Oxford University Press on behalf of the Endocrine Society. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http:// creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.
License URL
Identifier
https://www.ncbi.nlm.nih.gov/pubmed/33340399
PII: 6042237
Subjects
11-ketoestradiol
11-ketoestrone
11-ketotestosterone
11-oxygenated androgens
11-oxygenated estrogens
19-CARBON STEROIDS
ANDROGENS
AROMATASE
ASSAY
C19 STEROIDS
CELLS
cytochrome P450 aromatase
Endocrinology & Metabolism
ESTRADIOL
INHIBITOR
Life Sciences & Biomedicine
METABOLISM
Science & Technology
Publication Status
Published
Coverage Spatial
United States
Article Number
bqaa231
Date Publish Online
2020-12-19