The human ovarian surface epithelium is an androgen responsive tissue

Abstract

The pathogenesis of epithelial ovarian cancer remains unclear. From epidemiological studies raised levels of androgens have been implicated to increase the risk of developing the disease. The purpose of this study was to determine the responses of normal human ovarian surface epithelium to androgens. We have established primary cultures of human ovarian surface epithelium from patients undergoing oophorectomy for benign disease. Total RNA was isolated from these cultures and expression of mRNA encoding for the androgen receptor was demonstrated using reverse transcriptase polymerase chain reaction. The presence of androgen receptor in sections of normal ovary was also investigated using an antibody against androgen receptor. The effects of androgens on DNA synthesis and cell death were determined. Eight out of eight (100%) cultures expressed mRNA encoding the androgen receptor. The presence of androgen receptor in ovarian surface epithelium of sections of normal ovaries was demonstrated in all sections. Mibolerone, a synthetic androgen, caused a significant stimulation of DNA synthesis in 5 out of 9 (55%) cultures when used at a concentration of 1 nM. Mibolerone also caused a significant decrease in cell death in 2 out of 5 (40%) cultures tested. We have demonstrated that the ovarian surface epithelium is an androgen responsive tissue and that androgens can cause an increase in proliferation and a decrease in cell death. These findings have important implications for the pathophysiology of ovarian carcinogenesis.

Height, Age at Menarche, and Risk of Epithelial Ovarian Cancer

“…Progestins may increase apoptosis in ovarian epithelium (28), so women with later menarche may have several extra years of low-level estrogen (or other hormone) stimulation of their ovarian epithelium in the absence of the apoptotic effects of progesterone, possibly increasing the chance of the cells acquiring genetic damage. Androgens, which have been shown to stimulate DNA synthesis and decrease cell death in ovarian cell culture lines (29), are also relatively abundant in girls with later menarche (26). The hormonal milieu associated with later menarche may, therefore, be important in the initiation of neoplastic transformation of the ovarian epithelium, perhaps specifically to the mucinous subtype.…”

Epithelial ovarian cancer: testing the 'androgens hypothesis'

“…Androgen receptors have been detected in normal and neoplastic ovarian epithelial cells (Kuhnel et al 1987, Chadha et al 1993, Ilekis et al 1997, Cardillo et al 1998, Lau et al 1999, Modugno 2004), gonadotropins and androgens that stimulate the proliferation of normal and malignant human ovarian epithelial cells in vitro (Syed et al 2001, Edmondson et al 2002, Modugno 2004, Stewart et al 2004, and ovarian cancer cell growth is inhibited in vitro by antiandrogens (Slotman & Rao 1989). Animal experiments have demonstrated that testosterone can enhance the growth of ovarian epithelial tumours (Sawada et al 1990, Tennent et al 1993, Silva et al 1997.…”

Androgen Receptor Cytosine, Adenine, Guanine Repeats, and Haplotypes in Relation to Ovarian Cancer Risk

“…In phase 2 clinical trials of antiandrogens as a treatment for ovarian cancer, investigators observed that antiandrogens reduced the tumor burden or stabilized the progression of ovarian cancer in some women who had previously failed at least one chemotherapy (5,6). Although data from animal models and cell lines have been less consistent (7)(8)(9), showing both stimulation and inhibition of ovarian cell growth with androgen administration, the epidemiologic and clinical data seem to suggest a role for androgens in ovarian cancer.…”

“…Haplotypes were estimated and evaluated within predetermined haplotype blocks, reported by the National Cancer Institute Cohort Consortium. 7 Haplotype frequencies were estimated in cases and controls together using the expectationmaximization (E-M) algorithm (39). Posterior probabilities of the haplotypes given the observed genotypes were calculated for each individual, as previously described by Zaykin and colleagues (40).…”