Ito Kiyoshi, Miki Yasuhiro, Suzuki Takashi, McNamara Keely May, Sasano Hironobu
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
Department of Disaster Obstetrics and GynecologyInternational Research Institute of Disaster Science (IRIDeS), Tohoku University, Sendai, Japan.
Endocr Relat Cancer. 2016 Jul;23(7):R323-35. doi: 10.1530/ERC-15-0470. Epub 2016 Jun 10.
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.
原位雌激素生物合成被认为在人类子宫内膜癌的发生和发展中起关键作用。然而，雄激素的生物学作用几乎仍不为人知。各种流行病学研究表明，血清雄激素水平升高通常与子宫内膜癌发生风险增加相关；然而，直接检测癌组织中雄激素的研究相对较少，总结此类信息的综述也很匮乏。因此，我们总结了近期关于子宫内膜癌中雄激素的研究，尤其关注雄激素作用和原位雄激素生物合成。在雄激素局部生物合成所需的酶中，17β-羟类固醇脱氢酶5型（将雄烯二酮转化为睾酮）和5α-还原酶（将睾酮还原为二氢睾酮（DHT））是参与形成生物活性最强的雄激素DHT的主要酶。这两种酶和雄激素受体均在子宫内膜癌组织中表达，并且据报道子宫内膜癌组织中存在DHT的原位产生。然而，睾酮不仅是DHT产生的前体，也是作为芳香化酶底物的雌二醇合成的前体。因此，芳香化酶可能是另一种关键酶，通过减少前体数量来作为DHT原位产生的负调节因子。在一项体外研究中，据报道DHT对子宫内膜癌细胞具有抗增殖作用。然而，雄激素的内分泌机制、与抗癌进展直接相关的AR下游信号以及DHT-AR途径在子宫内膜癌患者中的临床意义尚未完全阐明。
