To the Editor: Dr Lacey and colleagues1 reported an increased risk of ovarian cancer in women who used unopposed estrogen, but not among women who used an estrogen-progestin combination. However, the histology of these tumors was described for only one third of the cases. A significant difference was found only for endometrioid cancers. Another study had similar findings, with only a significant increase in endometrioid and clear cell epithelial cancers among women receiving unopposed estrogen.2 In that study, the risk was greater in women who had received a tubal ligation or a hysterectomy, thus suggesting a possible role of estrogen-stimulating endometriosis.

However, the data concerning the risk of estrogen and ovarian cancer are not consistent. A recent meta-analysis did not find an association between estrogen replacement therapy (ERT) and ovarian cancer.3 The literature suggests that the risk, if any, may be confined to specific histologic subgroups of ovarian cancer.

There are several reasons to assume that estrogen may selectively increase the risk of epithelial cancer. It has been observed that tumors with a high expression of estrogen receptors and an increase in proliferation in areas of high estrogen-receptor density have less apoptotic activity.4 An inhibition of apoptosis by estradiol may be due to an increase of Bcl-2 messenger RNA and protein levels.5 The surface epithelium of these tumors secretes estradiol and aromatase is functionally expressed, playing an active role in altering its own hormonal environment and promoting tumor progression. Estrogen also induces other factors that may increase cancer risk.6

Conversely, high levels of progesterone appear to exert marked inhibitory effects on ovarian epithelium. Progestins induce differential regulation of transforming growth factor , a change in expression that is highly associated with apoptosis.7

Kenneth Burry, MD; Joanna M. Cain, MD
Department of Obstetrics and Gynecology
Oregon Health and Science University
Portland

1. Lacey JV, Mink PJ, Lubin JH, et al. Menopausal hormone replacement therapy and risk of ovarian cancer. JAMA. 2002;288:334-341. ABSTRACT/FULL TEXT
2. Purdie DM, Bain CJ, Siskind V, et al. Hormone replacement therapy and risk of epithelial ovarian cancer. Br J Cancer. 1999;81:559-563. CrossRef | ISI | MEDLINE
3. Coughlin SS, Giustozzi A, Smith SJ, Lee NC. A meta-analysis of estrogen replacement therapy and risk of epithelial ovarian cancer. J Clin Epidemiol. 2000;53:367-375. CrossRef | ISI | MEDLINE
4. Lindgren P, Backstrom T, Mahlck CG, Ridderheim M, Cajander S. Steroid receptors and hormones in relation to cell proliferation and apoptosis in poorly differentiated epithelial ovarian tumors. Int J Oncol. 2001;19:31-38. ISI | MEDLINE
5. Choi KC, Kang SK, Tai CJ, et al. Estradiol up-regulates antiapoptotic Bcl-2 messenger ribonucleic acid and protein in tumorigenic ovarian surface epithelium cells. Endocrinology. 2001;142:2351-2360. ABSTRACT/FULL TEXT
6. Moll F, Katsaros D, Lazennec G, et al. Estrogen induction and overexpression of fibulin-1C mRNA in ovarian cancer cells. Oncogene. 2002;21:1097-1107. CrossRef | ISI | MEDLINE
7. Rodriguez GC, Nagarsheth NP, Lee KL, et al. Progestin-induced apoptosis in the Macaque ovarian epithelium: differential regulation of transforming growth factor-beta. J Natl Cancer Inst. 2002;94:50-60.