In situ androgen and estrogen biosynthesis in endometrial cancer: focus on androgen actions and intratumoral production.
In situ estrogen biosynthesis is considered to play pivotal roles in the development and progression of human endometrial carcinoma. However, the biological roles of androgen have remained virtually unknown. Various epidemiological studies have revealed that elevated serum androgen levels are generally associated with an increased risk of developing endometrial carcinoma; however, studies directly examining androgens in carcinoma tissues are relatively rare and reviews summarizing this information are scarce. Therefore, we summarized recent studies on androgens in endometrial carcinoma, especially focusing androgen actions and in situ androgen biosynthesis. Among the enzymes required for local biosynthesis of androgen, 17β-hydroxysteroid dehydrogenase type 5 (conversion from androstenedione to testosterone) and 5α-reductase (reduction of testosterone to dihydrotestosterone (DHT)) are the principal enzymes involved in the formation of biologically most potent androgen, DHT. Both enzymes and androgen receptor were expressed in endometrial carcinoma tissues, and in situ production of DHT has been reported to exist in endometrial carcinoma tissues. However, testosterone is not only a precursor of DHT production, but also a precursor of estradiol synthesis, as a substrate of the aromatase enzyme. Therefore, aromatase could be another key enzyme serving as a negative regulator for in situ production of DHT by reducing amounts of the precursor. In an in vitro study, DHT was reported to exert antiproliferative effects on endometrial carcinoma cells. Intracrine mechanisms of androgens, the downstream signals of AR, which are directly related to anticancer progression, and the clinical significance of DHT-AR pathway in the patients with endometrial carcinoma have, however, not been fully elucidated.
Department of Disaster Obstetrics and GynecologyInternational Research Institute of Disaster Science (IRIDeS), Tohoku University, Sendai, Japan Department of Disaster Obstetrics and GynecologyTohoku University Graduate School of Medicine, Sendai, Japan kito@med.tohoku.ac.jp.
Kiyoshi
K
Ito
Department of Disaster Obstetrics and GynecologyInternational Research Institute of Disaster Science (IRIDeS), Tohoku University, Sendai, Japan.
Yasuhiro
Y
Miki
Department of Pathology and HistotechnologyTohoku University Graduate School of Medicine, Sendai, Japan.
Takashi
T
Suzuki
Department of PathologyTohoku University Graduate School of Medicine, Sendai, Japan.
Keely May
KM
McNamara
Department of PathologyTohoku University Graduate School of Medicine, Sendai, Japan.
Hironobu
H
Sasano
D000728:Androgens / Q000096:biosynthesis* / Q000097:blood; D000818:Animals; D016889:Endometrial Neoplasms / Q000378:metabolism*; D004967:Estrogens / Q000096:biosynthesis*; D005260:Female; D006801:Humans; D011944:Receptors, Androgen / Q000378:metabolism
D000728:Androgens; D004967:Estrogens; D011944:Receptors, Androgen
5α-dihydrotestosterone; 5α-reductase; androgen; androgen receptor; aromatase; endometrial carcinoma