TY - JOUR
T1 - Ovarian epithelial tumor growth promotion by follicle-stimulating hormone and inhibition of the effect by luteinizing hormone
AU - Zheng, Wenxin
AU - Lu, Jean J.
AU - Luo, Feng
AU - Zheng, Yu
AU - Feng, You Ji
AU - Felix, Juan C.
AU - Lauchlan, Stuart C.
AU - Pike, Malcolm C.
N1 - Funding Information:
The insightful discussion with and critical review by Dr. Robert E. Scully (Massachusetts General Hospital, Harvard Medical School, Boston, MA) were valuable contributions to this work. This study was partially supported by grants from the James H. Zumberge Faculty Research and Innovation Fund, the American Cancer Society (No. IRG-21-37), the Robert E. and May R.
Funding Information:
Wright Foundation, the American Association of Chinese Physician—California Research Fund, and the National Cancer Institute (No. 5 P30 CA14089-21). We thank Dr. A. F. Parlow of the NIH National Hormone and Pituitary Program for providing human FSH and LH for these studies, and the Academic Partners Program of BioGenex Laboratories (San Ramon, CA) for providing the immunostaining reagents.
PY - 2000/1
Y1 - 2000/1
N2 - Objectives. The role of gonadotropins in ovarian epithelial cancer development is still controversial. Follicle-stimulating hormone receptor (FSHR) status in ovarian epithelial tumors (OETs) and their presumed precursor lesions has never been studied in detail. The objective of this study was to examine whether FSHR is expressed in OETs and to investigate the possible different roles of the gonadotropins in ovarian cancer development. Methods. Twenty ovarian epithelial inclusions (entrapments or invaginations of ovarian surface epithelium) from benign ovaries and 60 OETs including 12 cystadenomas, 18 borderline tumors, and 30 carcinomas were examined for FSHR 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 (LH) receptor-positive ovarian epithelial carcinoma cell lines (AO and 3AO) and on the modifying effect of LH on this activity. Growth-stimulating effects of the gonadotropins were tested in vitro with measurement of cell numbers, S- phase by flow cytometry, and changes in the cellular proliferative marker 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 significant trend of decreasing positivity with increasing carcinoma grade. ISH and IHC gave similar, but somewhat less sensitive, results. A dose- response 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. These proliferative cellular effects were not observed when the cells were stimulated by LH in the range 1 to 100 IU/L. Most significantly, the growth stimulating effects of FSH could be blocked by the simultaneous administration of LH. Conclusions. FSHR is present in the majority of ovarian epithelial inclusions and OETs. The steady decline of FSHR expression from benign cystadenoma to borderline tumor to carcinoma suggests that FSH may be needed in early ovarian cancer development. Gonadotropins, FSH and LH, may have different roles in ovarian cancer cell proliferation. FSH, 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 ages are not associated with great increases in ovarian cancer risk.
AB - Objectives. The role of gonadotropins in ovarian epithelial cancer development is still controversial. Follicle-stimulating hormone receptor (FSHR) status in ovarian epithelial tumors (OETs) and their presumed precursor lesions has never been studied in detail. The objective of this study was to examine whether FSHR is expressed in OETs and to investigate the possible different roles of the gonadotropins in ovarian cancer development. Methods. Twenty ovarian epithelial inclusions (entrapments or invaginations of ovarian surface epithelium) from benign ovaries and 60 OETs including 12 cystadenomas, 18 borderline tumors, and 30 carcinomas were examined for FSHR 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 (LH) receptor-positive ovarian epithelial carcinoma cell lines (AO and 3AO) and on the modifying effect of LH on this activity. Growth-stimulating effects of the gonadotropins were tested in vitro with measurement of cell numbers, S- phase by flow cytometry, and changes in the cellular proliferative marker 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 significant trend of decreasing positivity with increasing carcinoma grade. ISH and IHC gave similar, but somewhat less sensitive, results. A dose- response 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. These proliferative cellular effects were not observed when the cells were stimulated by LH in the range 1 to 100 IU/L. Most significantly, the growth stimulating effects of FSH could be blocked by the simultaneous administration of LH. Conclusions. FSHR is present in the majority of ovarian epithelial inclusions and OETs. The steady decline of FSHR expression from benign cystadenoma to borderline tumor to carcinoma suggests that FSH may be needed in early ovarian cancer development. Gonadotropins, FSH and LH, may have different roles in ovarian cancer cell proliferation. FSH, 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 ages are not associated with great increases in ovarian cancer risk.
KW - Follicle-stimulating hormone
KW - Gonadotropin receptors
KW - Luteinizing hormone
KW - Ovarian cancer
KW - Ovarian epithelial tumor
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U2 - 10.1006/gyno.1999.5628
DO - 10.1006/gyno.1999.5628
M3 - Article
C2 - 10620446
AN - SCOPUS:0033971972
SN - 0090-8258
VL - 76
SP - 80
EP - 88
JO - Gynecologic Oncology
JF - Gynecologic Oncology
IS - 1
ER -