In situ androgen and estrogen biosynthesis in endometrial cancer: focus on androgen actions and intratumoral production

Abstract

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.

Blocking 17β‐hydroxysteroid dehydrogenase type 1 in endometrial cancer: a potential novel endocrine therapeutic approach

“…Local steroid metabolism and intracrinology offer opportunities for novel drug targets and prognosis markers in hormone-dependent conditions such as EC [15,22,[35][36][37][38][39]. At the same time, however, intracrine networks are complex; can convert adrenal steroid precursors into androgens and estrogens; and can interconvert androgens, estrogens, active and inactive compounds, and protective and cancer-promoting compounds.…”

Cancer in Transgender People: Evidence and Methodological Considerations

“…Testosterone can be converted to DHT by 5α-reductase or to estradiol by aromatase. Although DHT has been shown to have antiproliferative effects on endometrial cancer cells, aromatase may decrease DHT production by depleting testosterone and increasing estrogen levels, which may stimulate proliferation of the endometrial epithelium (93). In addition, both testosterone and DHT interact with endometrial epidermal growth factor receptor (94).…”

Prostaglandin E2 triggers cytochrome P450 17α hydroxylase overexpression via signal transducer and activator of transcription�3 phosphorylation and promotes invasion in endometrial cancer

“…This group of hormones includes sex hormones, such as androgen and estrogen, which are required for normal sexual development and reproduction. The CYP17 enzyme performs two important reactions in this process, and existing evidence indicates that unopposed androgens contribute to the tumorigenesis and promotion of endometrial cancer (34,35). Patients with polycystic ovary syndrome, who usually have high androgen levels, have an increased risk of developing endometrial cancer (35,36).…”