© 1999 by Oxford University Press
Journal of the National Cancer Institute, Vol. 91, No. 7, 650-651,
April 7, 1999
© 1999 Oxford University Press
CORRESPONDENCE |
RESPONSE - Re: Hormonal Etiology of Epithelial Ovarian Cancer, With a Hypothesis Concerning the Role of Androgens and Progesterone
Correspondence to: Harvey A. Risch, M.D., Ph.D., Department of Epidemiology and Public Health, Yale University School of Medicine, 60 College St., P. O. Box 208034, New Haven, CT 06520-8034.
Dr. Hamilton makes a number of interesting observations. First, with regard to a possible temporal nonlinearity of incessant ovulation: Given an average latency for the development of ovarian cancer of some 25 years, a year of anovulation around 25 years in the past should be more influential than one at other times in life. Perhaps that is why each pregnancy appears threefold more protective than would be expected solely on the basis of its duration of anovulation. However, as we have pointed out in our review and elsewhere (1), this reasoning cannot account for the substantial disparity in risk between one full-term pregnancy and 1 year of oral contraceptive use; thus, some factor in addition to anovulation must be involved. Whether this factor is more important than incessant ovulation cannot be determined from the present evidence.
Second, we attempted to present a range of evidence bearing upon the incessant ovulation and gonadotropin hypotheses. To date, experimental evidence for a role of the gonadotropins is relatively scanty, but it does include the excess gonadotropin-related production in animals of tubular adenomas, which are destructive epithelial neoplasms of the ovary. Nevertheless, as we stated, the totality of evidence for direct gonadotropin involvement in the etiology of ovarian cancer in humans is fairly weak, especially considering the lack of positive association seen in the study by Helzlsouer et al. (2).
Third, our understanding of the nature of hormone receptors in normal ovarian surface
epithelial cells continues to evolve. As we pointed out, androgen—and particularly
progesterone—receptors appear to be present. Follicle stimulating hormone receptors may
also be present (3). The existence of estrogen receptors (ERs) in the
surface epithelium of the rat ovary has been inferred (4), and studies of
human ovaries have now also identified both ER-
and ER-ß in normal epithelium, but
apparently only at quite low levels of expression (5-7).
Finally, I am in agreement with Dr. Hamilton that the research community interested in the etiology and primary prevention of ovarian cancer is very small. This situation seems remarkable because ovarian cancer is the fourth most frequent cause of cancer death among women in North America and because, after more than two decades of research on ovarian cancer, we have consistently identified the protective effects of increasing parity and use of oral contraceptives, yet we still have no basic understanding of how these factors are involved in the disease process.
REFERENCES
1
Risch HA, Weiss NS, Lyon JL, Daling JR, Liff JM. Events of
reproductive life and the incidence of epithelial ovarian cancer. Am J Epidemiol 1983;117:128-39.
2
Helzlsouer KJ, Alberg AJ, Gordon GB, Longcope C, Bush TL,
Hoffman SC, et al. Serum gonadotropins and steroid hormones and the development of ovarian
cancer. JAMA 1995;274:1926-30.
3 Zheng W, Magid MS, Kramer EE, Chen YT. Follicle-stimulating hormone receptor is expressed in human ovarian surface epithelium and fallopian tube. Am J Pathol 1996;148:47-53.[Abstract]
4
Hamilton TC, Davies P, Griffiths K. Oestrogen receptor-like
binding in the surface germinal epithelium of the rat ovary. J Endocrinol 1982;95:377-85.
5 Isola J, Kallioniemi OP, Korte JM, Wahlstrom T, Aine R, Helle R, et al. Steroid receptors and Ki-67 reactivity in ovarian cancer and in normal ovary: correlation with DNA flow cytometry, biochemical receptor assay, and patient survival. J Pathol 1990;162:295-301.[CrossRef][Web of Science][Medline]cancerlit;91147983
6
Brandenberger AW, Tee MK, Jaffe RB. Estrogen receptor alpha
(ER-) and beta (ER-ß) mRNAs in normal ovary, ovarian serous cystadenocarcinoma
and ovarian cancer cell lines: down-regulation of ER-ß in neoplastic tissues. J Clin
Endocrinol Metab 1998;83:1025-8.
7
Hillier SG, Anderson RA, Williams AR, Tetsuka M. Expression
of oestrogen receptor alpha and beta in cultured human ovarian surface epithelial cells. Mol Hum Reprod 1998;4:811-5.
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