11-oxygenated estrogens are a novel class of human estrogens but do not contribute to the circulating estrogen pool

Research output: Contribution to journalArticlepeer-review

Authors

  • Lise Barnard
  • Renate Louw Du-Toit
  • Shiuan Chen
  • Donita Africander

Colleges, School and Institutes

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.

Details

Original languageEnglish
Article numberbqaa231
JournalEndocrinology
Volume162
Issue number3
Early online date19 Dec 2020
Publication statusPublished - Mar 2021

Keywords

  • 11-ketoestradiol, 11-ketoestrone, 11-ketotestosterone, 11-oxygenated androgens, 11-oxygenated estrogens, cytochrome P450 aromatase

ASJC Scopus subject areas