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[Cancer Research 61, 6768-6776, September 15, 2001]
© 2001 American Association for Cancer Research

Endocrinology

Expression of Gonadotropin Receptor and Growth Responses to Key Reproductive Hormones in Normal and Malignant Human Ovarian Surface Epithelial Cells1

Viqar Syed, Gregory Ulinski, Samuel C. Mok, Gary K. Yiu and Shuk-Mei Ho2

Department of Surgery, Division of Urology [V. S., G. U., S-M. H.] and Department of Cell Biology [S-M. H.], University of Massachusetts Medical School, Worcester, Massachusetts 01655, and Laboratory of Gynecologic Oncology, Department of Obstetrics, Gynecology and Reproductive Biology, Brigham and Women’s Hospital, Harvard Medical School Boston, Massachusetts 02115 [S. C. M., G. K. Y.]

Epidemiological data have implicated reproductive hormones as probable risk factors for ovarian cancer (OCa) development. Although pituitary and sex hormones have been reported to regulate OCa cell growth, no information is available regarding whether and how they influence normal ovarian surface epithelial (OSE) cell proliferation. To fill this data gap, this study has compared cell growth responses to gonadotropins and sex steroids in primary cultures of human OSE (HOSE) cells with those observed in immortalized, nontumorigenic HOSE cells and in OCa cell lines. Both malignant and normal cell lines/cultures responded equally well to the stimulatory actions of luteinizing hormone and follicle-stimulating hormone and to 17ß-estradiol and estrone, although the latter estrogen has a much lower affinity for estrogen receptor than does the former estrogen. In normal HOSE cell cultures/lines, 5{alpha}-dihydrotestosterone was found to be more effective than testosterone in stimulating cell growth, but in OCa cell lines, 5{alpha}-dihydrotestosterone and testosterone are equally potent. One OCa cell line, OVCA 433, was found to be nonresponsive to androgen stimulation. In general, primary cultures of normal HOSE cells exhibited the greatest hormone-stimulated growth responses (>10-fold enhancement), followed by immortalized HOSE cell lines (4–5-fold enhancement) and by OCa cell lines (2–4-fold enhancement). Interestingly, progesterone (P4), at low concentrations (10-11 to 10-10 M), was stimulatory to HOSE and OCa cell growth, but at high doses (10-8 to 10-6 M), P4 exerted marked inhibitory effects. In all cases, cotreatment of a cell culture/line with a hormone and its specific antagonist blocked the effect of the hormone, confirming specificity of the hormonal action. Taken together, these data support the hypothesis that reproductive states associated with rising levels of gonadotropins, estrogen, and/or androgen promote cell proliferation in the normal OSE, which favors neoplastic transformation. Conversely, those states attended by high levels of circulating P4, such as that seen during pregnancy, induce OSE cell loss and offer protection against ovarian carcinogenesis.




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