Human chorionic gonadotropin suppresses ovarian epithelial neoplastic cell proliferation in vitro.

OBJECTIVE: To quantify the in vitro effects of gonadotropins on benign, borderline, and malignant ovarian cell lines. DESIGN: In vitro cell culture. SETTING: Research laboratory. PATIENT(S): None. INTERVENTION(S): Three hormonally sensitive ovarian neoplastic cell lines were exposed to control medium, FSH (40 mIU/mL), hCG (200 mIU/mL), and a combination of FSH and hCG. MAIN OUTCOME MEASURE(S): Cellular proliferation measured by a colorimetric (MTT) assay. RESULT(S): Growth of the cell lines was similar when exposed to control or FSH. In the presence of hCG alone, the cell lines demonstrated decreased proliferation when compared to control or FSH alone. When hCG was given in combination with FSH, there was decreased proliferation of the cell lines compared to control or FSH alone. CONCLUSION(S): Growth of benign, borderline, and malignant ovarian epithelial cell lines is inhibited by hCG at levels, which are commonly achieved with hCG administration during ovulation induction or as a result of trophoblastic production in early pregnancy.

VEGF expression and enhanced production by gonadotropins in ovarian epithelial tumors.

Vascular endothelial growth factor (VEGF) is a heparin-binding, dimeric polypeptide with potent mitogenic effects on endothelial cells. VEGF expression has also been reported in ovarian epithelial tumors (OETs), which may be associated with gonadotropin stimulatioin. We recently reported that most OETs, including OET cell lines, express gonadotropin receptors. Here we studied VEGF mRNA expression in 141 OET and 35 benign ovarian samples using reverse transcriptase polymerase chain reaction and in situ hybridization (ISH). We also studied VEGF production by OET cell lines under stimulation of gonadotropins. AO (serous carcinoma), low malignant potential (LMP; SV40-transformed borderline tumor) and ML-5 (SV40-transformed cystadenoma) cells were examined for VEGF protein production under the regulation of gonadotropins in vitro. The biologic function of VEGF was confirmed by using bovine endothelial growth assay. Whereas VEGF was not detected in benign ovarian surface epithelium or in ovarian epithelial inclusions, it was detected in both epithelial and stromal compartments of OETs. For VEGF epithelial expression, only 5% of ovarian cystadenomas and 30% of borderline tumors were positive for VEGF detection by ISH, whereas VEGF mRNA signal was detected in 80% of ovarian carcinoma cases. This increment of VEGF expression in ovarian carcinomas was statistically significant compared with benign and borderline tumors. Within ovarian carcinomas, the percentage of VEGF-positive cells was significantly associated with the grade of cancer but not with cancer cell types or cancer stages. Both follicle-stimulating hormone (FSH) and luteinizing hormone (LH) stimulated the expression of VEFG(165) in AO cells in a dose-dependent manner. Maximal induction was obtained for FSH at dose of 40 mIU/ml and for LH at 50 mIU/ml after 48 hr of culture. Compared with the nonstimulated cells, VEGF level was significantly elevated in both LMP and AO cells after stimulation of gonadotropins. Furthermore, the induction of VEGF expression was significantly stronger in carcinoma cells than in borderline OET cells. These observations suggest that VEGF may play a role in the development of ovarian cancer and that the elevated gonadotropins, as found in menopause and in most ovarian cancer patients after surgery, could accelerate tumor growth and tumor recurrence by inducing VEGF expression in OETs.