11-Oxygenated Estrogens Are a Novel Class of Human Estrogens but Do not Contribute to the Circulating Estrogen Pool

Area of Science:

• Endocrinology
• Steroid Biochemistry

Background:

• Androgens are precursors to estrogens, with testosterone being the primary active androgen.
• 11-oxygenated androgens, like 11-ketotestosterone, are increasingly recognized as significant contributors to the active androgen pool, especially in women.

Purpose of the Study:

• To investigate whether 11-oxygenated androgens can be aromatized into estrogens by human aromatase.
• To characterize the biological activity of these potential 11-oxygenated estrogens.

Main Methods:

• Steroid analysis using tandem mass spectrometry.
• In vitro studies using cell-based aromatase expression systems.
• Ex vivo studies using human placenta explant cultures.
• Estrogen receptor binding and activation assays.
• Cell proliferation and gene expression assays using breast cancer cell lines.

Main Results:

• Human aromatase converts 11-oxygenated androgens into 11-oxygenated estrogens in vitro and ex vivo.
• 11-oxygenated estrogens are also generated as byproducts from classic androgen aromatization.
• 11β-hydroxy-17β-estradiol binds and activates estrogen receptors α and β.
• 11β-hydroxy-17β-estradiol and 17β-estradiol exhibit equipotent stimulation of breast cancer cell proliferation and gene expression.
• Despite in vitro aromatizability, 11-oxygenated estrogens were undetectable in serum from individuals with high aromatase or elevated 11-oxygenated androgen levels.

Conclusions:

• 11-oxygenated androgens are indeed aromatizable, yielding biologically active 11-oxygenated estrogens.
• The absence of circulating 11-oxygenated estrogens suggests they do not significantly contribute to the estrogen pool in vivo.
• 11-oxygenated androgens likely function predominantly as androgens in the human body.