Special Feature: Postmenopausal Hormone Therapy and the Risk of Ovarian Cancer
By Leon Speroff, MD
The canceled estrogen-progestin arm of the Women’s Health Initiative reported an increase in ovarian cancer that was not statistically significant, prompting the authors to say: "The possibility of an increased risk of ovarian cancer incidence and mortality remains worrisome and needs confirmation."1
The Kaplan-Meier curves suggested an increasing effect over time, but this, too, was not statistically significant. There were no differences reported in histologic type, stage, or grade (but the small numbers make it essentially impossible to assess subcategories). It is of importance to note that there were 2 endometrioid cancers in the treated group and none in the placebo group.
Although the lifetime risk of ovarian cancer is small, the prevalence of postmenopausal hormone therapy combined with an increase in the risk of ovarian cancer could yield an increase that would be of public health significance. For this reason, it is useful to review the recent epidemiologic data on this important issue. There have been 20 case-control studies and 4 cohort studies assessing the relationship between postmenopausal hormone therapy and the risk of ovarian cancer.2 The relative risks encompass a wide range from below 1.0 to greater than 1.0. Two limitations are immediately apparent. The data reflect largely the use of estrogen without a progestin; only a small number of cases exposed to estrogen-progestin are available. In addition, because this is a relatively infrequent cancer, all studies have been hampered by relatively small numbers.
The studies have found it difficult to control for all of the factors that influence the risk of ovarian cancer. This is because there are multiple factors and information regarding each factor is not readily available.
Factors That Decrease the Risk of Ovarian Cancer
- Use of steroid hormone contraceptives;
- Pregnancy and parity; a greater effect with a recent pregnancy and pregnancy at older age;3
- Hysterectomy and tubal ligation;5
Factors That Increase the Risk of Ovarian Cancer
Two or more eggs per week;10
Family history of ovarian and breast cancer;
Mixed Reports on Decreased Risk;
Mixed Reports on Increased Risk;
Summary: A borderline, significant increase in one meta-analysis with long duration of use; problems with all meta-analyses: assumed that controlling for risk factors was uniform in all studies.
It should also be noted that in one randomized trial and 2 retrospective cohort analyses, no detrimental effect on prognosis after surgery for ovarian cancer could be detected in patients subsequently treated with hormones.26-28
A major problem has been the effect of endometrioid cancers, an ovarian cancer that logically can be expected to be influenced by estrogen therapy. In many of the studies, the overall results are swayed by the increase in endometrioid cancers, a cancer that could originate in hormonally-stimulated endometriosis.29 An accurate analysis requires a separate consideration of endometrioid cancers, but this is difficult because the small numbers do not allow effective sub-categorization.
Another concern is the time line associated with the development of ovarian cancer. The study of ovarian cancer in the atomic bomb survivors documented that the disease increased 25 years later.30 How could postmenopausal hormone therapy produce an effect rapidly, especially because so few women have maintained therapy for many years, unless there is an effect on pre-existing malignant cells?
It is not difficult to review these numbers and conclude that there is no uniform story, that there are studies with both positive and negative results, and that all of the studies struggle with limited power because of small numbers and confounding because of the difficulties in assessing and controlling for risk factors. The case-control and cohort studies irregularly controlled for level of education, parity, OC use, BMI, tubal ligation, and family history of ovarian and breast cancer (not a single study controlled for all known risk factors!). It is appropriate to emphasize the weak associations and the mixed story, but at the same time the seriousness of the specific relationship dictates that postmenopausal hormone therapy and the risk of ovarian cancer remains an unresolved issue.
1. Anderson GL, et al. Effects of estrogen plus progestin on gynecologic cancers and associated diagnostic procedures. The Women’s Health Initiative Randomized Trial. JAMA. 2003;290:1739-1748.
2. Riman T. Hormone replacement therapy and epithelial ovarian cancer: is there an association? J Br Menopause Soc. 2003;June:61-68.
3. Whiteman DC, et al. Timing of pregnancy and the risk of epithelial ovarian cancer. Cancer Epidemiol Biomarkers Prev. 2003;12:42-46.
4. Siskind V, et al. Breastfeeding, menopause, and epithelial ovarian cancer. Epidemiology. 1997;8: 188-191.
5. Green A, et al. Tubal sterilisation, hysterectomy and decreased risk of ovarian cancer, Survey of Women’s Health Study Group. Int J Cancer. 1997;71:948-951.
6. Fairfield KM, et al. Aspirin, other NSAIDs, and ovarian cancer risk (United States). Cancer Causes and Control. 2002;13:535-542.
7. Purdie DM, et al. Body size and ovarian cancer: case-control study and systematic review (Australia). Cancer Causes and Control. 2001;12:855-863.
8. Ness RB, et al. Infertility, fertility drugs, and ovarian cancer: a pooled analysis of case-control studies. Am J Epidemiol. 2002;155:217-24.
9. Goodman MT, et al. Association of caffeine intake and CYP1A2 genotype with ovarian cancer. Nutr Cancer. 2003;46:23-29.
10. Pirozzo S, et al. Ovarian cancer, cholesterol, and eggs: a case-control analysis. Cancer Epidemiol Biomarkers Prev. 2002;11:1112-1114.
11. Goodman MT, Tung KH. Alcohol consumption and the risk of borderline and invasive ovarian cancer. Obstet Gynecol. 2003;101:1221-1228.
12. Green A, et al. Cigarette smoking and risk of epithelial ovarian cancer (Australia). Cancer Causes and Control. 2001;12:713-719.
13. Goodman MT, Tung KH. Active and passive tobacco smoking and the risk of borderline and invasive ovarian cancer (United States). Cancer Causes and Control. 2003;14:569-577.
14. Purdie DW, et al. Hormone replacement therapy and risk of epithelial ovarian cancer. Br J Cancer. 1999;81:559-563.
15. Chiaffarino F, et al. Reproductive and hormonal factors and ovarian cancer. Ann Oncol. 2001;12:337-341.
16. Riman T, et al. Risk factors for epithelial borderline ovarian tumors: results of a Swedish case-control study. Gynecol Oncol. 2001;83:575-585.
17. Riman T, et al. Hormone replacement therapy and the risk of invasive epithelial ovarian cancer in Swedish women. J Natl Cancer Inst. 2002;94:497-504.
18. Sitasy F,et al. Hormone replacement therapy formulations and risk of epithelial ovarian carcinoma. Gynecol Oncol. 2002;86:118-123.
19. Rodriguez C, et al. Estrogen replacement therapy and ovarian cancer mortality in a large prospective study of US women. JAMA. 2001;285:1460-1465.
20. Lacey JV, et al. Menopausal hormone replacement therapy and risk of ovarian cancer. JAMA. 2002;288: 334-341.
21. Negri E, et al. Hormonal therapy for menopause and ovarian cancer in a collaborative re-analysis of European studies. Int J Cancer. 1999;80:848-851.
22. Bosetti C,et al. Relationship between postmenopausal hormone replacement therapy and ovarian cancer. JAMA. 2001;285:3089.
23. Whittemore AS, et al. Characteristics relating to ovarian cancer risk: collaborative analysis of 12 US case-control studies. II: Invasive epithelial ovarian cancers in white women. Am J Epidemiol. 1992;136:1184-1103.
24. Garg PP, et al. Hormone replacement therapy and the risk of epithelial ovarian carcinoma: a meta-analysis. Obstet Gynecol. 1998;92:472-79.
25. Coughlin SS, et al. A meta-analysis of estrogen replacement therapy and risk of epithelial ovarian cancer. J Clin Epidemiol. 2000;53:367-375.
26. Eeles RA, et al. Hormone replacement therapy and survival after surgery for ovarian cancer. Br Med J. 1991;302:259-262.
27. Ursic-Vrscaj M, et al. Hormone replacement therapy after invasive ovarian serous cystadenocarcinoma treatment: the effect on survival. Menopause. 2001; 8:70-75.
28. Hopkins ML, et al. Ovarian cancer patients and hormone replacement therapy: a systematic review. Gynecol Oncol. 2004;92:827-832.
29. Modesitt SC, et al. Ovarian and extraovarian endometriosis-associated cancer. Obstet Gynecol. 2002;100:788-795.
30. Tokuoka S, et al. Malignant and benign ovarian neoplasms among atomic bomb survivors, Hiroshima and Nagasaki, 1950-1980. J Natl Cancer Inst. 1987;79:47-57.
Leon Speroff, MD, Professor of Obstetrics and Gynecology, Oregon Health Sciences University, Portland, and Editor of OB/GYN Clinical Alert.