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Published on: October 7, 2020
11-Ketotestosterone Is a Major Androgen Produced in Human Gonads
Yoshitaka Imamichi1, Koh-Ichi Yuhki1, Makoto Orisaka1
1Departments of Pharmacology (Y.I., K.-i.Y., F.U.) and Biochemistry (T.T., T.Y.), Asahikawa Medical University, Hokkaido 078-8510, Japan; Departments of Biochemistry (Y.I., K.Mi.) and Obstetrics and Gynecology (M.O.), Faculty of Medical Sciences, University of Fukui, Fukui 910-1193, Japan; Department of Materials and Life Science (T.K.), Graduate School of Science and Technology, Kumamoto University, Kumamoto 860-8555, Japan; Department of Biochemistry and Medical Education Center (K.Mu.), Keio University School of Medicine, Tokyo 160-8582, Japan; and Department of Reproduction (A.U.), National Research Institute for Child Health and Development, Tokyo 157-8535, Japan.
Context:
11-ketotestosterone (11-KT) is a novel class of active androgen. However, the detail of its synthesis remains unknown for humans.
Objective:
The objective of this study was to clarify the production and properties of 11-KT in human. Design, Participants, and Methods: Expression of cytochrome P450 and 11β-hydroxysteroid dehydrogenase types 1 and 2 (key enzymes involved in the synthesis of 11-KT) were investigated in human gonads. The production of 11-KT was investigated in Leydig cells. Plasma concentrations of testosterone and 11-KT were measured in 10 women and 10 men of reproductive age. Investigation of its properties was performed using breast cancer-derived MCF-7 cells.
Results:
Cytochrome P450 and 11β-hydroxysteroid dehydrogenase types 1 and 2 were detected in Leydig cells and theca cells. Leydig cells produced 11-KT, and relatively high levels of plasma 11-KT were measured in both men and women. There was no sexual dimorphism in the plasma levels of 11-KT, even though testosterone levels were more than 20 times higher in men than in women. It is noteworthy that the levels of testosterone and 11-KT were similar in women. In a luciferase reporter system, 11-KT activated human androgen receptor-mediated transactivation. Conversely, 11-KT did not activate estrogen receptor-mediated transactivation in aromatase-expressed MCF-7 cells, whereas testosterone did following conversion to estrogen. 11-KT did not affect the estrogen/estrogen receptor -mediated cell proliferation of MCF-7 cells. Furthermore, it significantly inhibited cell proliferation when androgen receptor was transfected into MCF-7 cells.
Conclusions:
The current study indicates that 11-KT is produced in the gonads and represents a major androgen in human. It can potentially serve as a nonaromatizable androgen.
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