Ovarian epithelial tumor growth promotion by follicle-stimulating hormone and inhibition of the effect by luteinizing hormone

Objectives. The role of gonadotropins in ovarian epithelial cancer developm ent is still controversial. Follicle-stimulating hormone receptor (FSHR) st atus in ovarian epithelial tumors (OETs) and their presumed precursor lesio ns has never been studied in detail. The objective of this study was to exa mine whether FSHR is expressed in OETs and to investigate the possible diff erent roles of the gonadotropins in ovarian cancer development. Methods. Twenty ovarian epithelial inclusions (entrapments or imaginations of ovarian surface epithelium) from benign ovaries and 60 OETs including 12 cystadenomas, 18 borderline tumors, and 30 carcinomas were examined for FS HR expression by using reverse transcription polymerase chain reaction (RT- PCR), in situ hybridization (ISH), and immunohistochemistry (IHC). We also studied the mitogenic activity of FSH on two FSH and luteinizing hormone (L H) receptor-positive ovarian epithelial carcinoma cell lines (AO and 3AO) a nd on the modifying effect of LH on this activity. Growth-stimulating effec ts of the gonadotropins were tested in vitro with measurement of cell numbe rs, S-phase by flow cytometry, and changes in the cellular proliferative ma rker Ki-67. Results. Positive FSHR mRNA expression by RT-PCR (the most sensitive method ) was found in 100% of epithelial inclusions, 100% of cystadenomas, 94% of borderline tumors, and 60% of carcinomas. There was a nonstatistically sign ificant trend of decreasing positivity with increasing carcinoma grade, ISH and IHC gave similar, but somewhat less sensitive, results. A dose-respons e effect was seen with FSH, with a 1.6-fold increase in cell numbers with a maximally stimulating FSH concentration of 40 IU/L for a period of 48 h. T hese proliferative cellular effects were not observed when the cells were s timulated by LH in the range 1 to 100 IU/L. Most significantly, the growth stimulating effects of FSH could be blocked by the simultaneous administrat ion of LH. Conclusions. FSHR is present in the majority of ovarian epithelial inclusio ns and OETs. The steady decline of FSHR expression from benign cystadenoma to borderline tumor to carcinoma suggests that FSH may be needed in early o varian cancer development. Gonadotropins, FSH and LH, may have different ro les in ovarian cancer cell proliferation. FSN, not LH, may be an important ovarian epithelial cell growth-promoting factor. The "'opposing" effect of LH on FSH stimulation may explain why high FSH levels at postmenopausal age s are not associated with great increases in ovarian cancer risk. (C) 2000 Academic Press.