Post-Menopausal Hormone Therapy and Ovarian Cancer Risk
Post-Menopausal Hormone Therapy and Ovarian Cancer Risk
Abstract & Commentary
By Leon Speroff, MD, Editor, Professor of Obstetrics and Gynecology, Oregon Health and Science University, Portland, is Editor for OB/GYN Clinical Alert.
Synopsis: A National Cancer Institute cohort study reported an increased risk of ovarian cancer associated with long-term use of post-menopausal hormone therapy.
Source: Lacey JV, et al. Menopausal hormone therapy and ovarian cancer risk in the National Institutes of Health-AARP Diet and health Study cohort. J Natl Cancer Inst. 2006;98:1397-1405.
Lacey and colleagues from the National Cancer Institute reported the results of postmenopausal hormone exposure in a cohort study with 214 cases of ovarian cancer.1 The over-all cohort of 97,368 women constituted the NIH-AARP Diet and Health Study. The baseline information was derived from two questionnaires in 1995-1997, and the cases of ovarian cancer were identified through the year 2000 from state registries. The statistically significant findings were as follows:
| Unopposed estrogen for 10 or more years: 56 cases RR=1.89 (CI=1.22-2.95) Sequential E-P for 5 or more years: 13 cases RR=3.09 (CI=1.68-5.68) Continuous E-P for 5 or more years: 15 cases RR=1.82 (CI=1.03-3.23) |
The authors concluded that long durations of unopposed estrogen therapy increase the risk of ovarian cancer, and that sequential regimens of estrogen-progestin have a greater increase in risk.
This report has two major strengths. The overall incidence of ovarian cancer was consistent with the number predicted by U.S. national data, and the ovarian cancer risk was influenced by recognized risk factors (increased by a family history of breast cancer, decreased with oral contraceptive use and parity, and no effects of BMI, smoking, age at menopause). But this report has several problems that are commonly found in observational studies of this subject.
How representative is the population sample? Of an initial 337,076 respondents, only 59.5% completed the baseline questionnaire, leaving 136,409 women potentially eligible. Exclusions yielded the final number of 97,638 for analysis. Approximately 5% of cancers were probably not identified through the cancer registries. The authors stated that they considered "most known ovarian cancer risk factors," but the relative risks were adjusted only for age, race, duration of oral contraceptive use, and BMI.
The importance of these problems is appreciated by a review of the recent studies. Up to 2004, there had 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 encompassed 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 have been available. In addition, because this is a relatively infrequent cancer, all studies have been hampered by relatively small numbers.
The canceled estrogen-progestin arm of the Women's Health Initiative reported an increase in ovarian cancer that was not statistically significant (Hazard ratio-1.58, CI-0.77-3.24), prompting the authors to say: "The possibility of an increased risk of ovarian cancer incidence and mortality remains worrisome and needs confirmation."3 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 made it essentially impossible to assess subcategories).
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
Factors That Increase the Risk of Ovarian Cancer
Mixed Reports on Decreased Risk Mixed Reports on Increased Risk |
Because of the many factors that influence the risk of ovarian cancer, case-control and cohort studies have found it difficult (in fact, impossible) to match cases and controls. It has been found that hormone users have used more oral contraceptives, have had fewer children, are more educated, and thinner. Adjustments have been made only for major factors, such as oral contraceptive use. The technique of meta-analysis is especially hampered by these confounding issues. The authors of the published meta-analyses15-17 have inappropriately assumed that controlling for risk factors was uniformly accomplished in all studies.
A major problem has been the impact 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.18 An accurate analysis requires a separate consideration of endometrioid cancers, but this is difficult because the small numbers do not allow effective sub-categorization.
An Australian case-control study reported a statistically significant increase only in the 18 cases with endometrioid cancer.19 A Swedish case-control study reported a small but significant increase in risk with unopposed estrogen and with sequential estrogen-progestin, but 49% of the cases were endometrioid cancers.20 In a cohort report from the Breast Cancer Detection Demonstration Project, only endometrioid cancer was significantly increased.21 In the current NCI report, there were 18 endometrioid cancers (and perhaps a few more in the 26 cases of "unclassified types"), and excluding these cases would have altered the overall conclusions. In the WHI, there were 2 endometrioid cancers in the treated group and none in the placebo group.
It should also be noted that in one randomized trial and two retrospective cohort analyses, no detrimental effect on prognosis after surgery for ovarian cancer could be detected in patients subsequently treated with hormones.22-24
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 are 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 a real possibility that there exists an increased risk for the hormonally sensitive ovarian cancer of the endometrioid type, and studies should carefully segregate this cancer for separate analysis. 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.
References
- Lacey JV, et al. Menopausal hormone therapy and ovarian cancer risk in the National Institutes of Health—AARP Diet and health Study cohort. J Natl Cancer Inst. 2006;98:1397-1405.
- Riman T. Hormone replacement therapy and epithelial ovarian cancer: is there an association? J Br Menopause Soc. 2003;61-68.
- 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.
- Whiteman DC, et al. Timing of pregnancy and the risk of epithelial ovarian cancer. Cancer Epidemiol Biomarkers Prev. 2003;12:42-46.
- Siskind V, et al. Breastfeeding, menopause, and epithelial ovarian cancer. Epidemiology. 1997;8:188-191.
- 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.
- Fairfield KM, et al. Aspirin, other NSAIDs, and ovarian cancer risk (United States). Cancer Causes and Control. 2002;13:535-542.
- Purdie DM, et al. Body size and ovarian cancer: case-control study and systematic review (Australia). Cancer Causes and Control. 2001;12:855-863.
- Ness RB, et al. Infertility, fertility drugs, and ovarian cancer: a pooled analysis of case-control studies. Am J Epidemiol.2002;155:217-224.
- Goodman MT, et al. Association of caffeine intake and CYP1A2 genotype with ovarian cancer. Nutr Cancer. 2003;46:23-29.
- Pirozzo S, et al. Ovarian cancer, cholesterol, and eggs: a case-control analysis. Cancer Epidemiol Biomarkers Prev. 2002;11:1112-1114.
- Goodman MT, et al. Alcohol consumption and the risk of borderline and invasive ovarian cancer. Obstet Gynecol. 2003;101:1221-1228.
- Green A, et al. Cigarette smoking and risk of epithelial ovarian cancer (Australia). Cancer Causes and Control. 2001;12:713-719.
- 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.
- 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. The Collaborative Ovarian Cancer Group. Am J Epidemiol. 1992;136:1184-1203.
- Garg, PP, et al. Hormone replacement therapy and the risk of epithelial ovarian carcinoma: a meta-analysis. Obstet Gynecol. 1998;92:472-479.
- Coughlin, SS, et al. A meta-analysis of estrogen replacement therapy and risk of epithelial ovarian cancer. J Clin Epidemiol. 2000;53:367-375.
- Modesitt, et al. Ovarian and extraovarian endometriosis-associated cancer. Obstet Gynecol. 2002;100:788-795.
- Purdie DW, et al. Hormone replacement therapy and risk of epithelial ovarian cancer. Br J Cancer. 1999;81:559-563.
- 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.
- Lacey JV Jr., et al. Menopausal hormone replacement therapy and risk of ovarian cancer. JAMA. 2002;288:334-341.
- Eeles RA, et al. Hormone replacement therapy and survival after surgery for ovarian cancer. Br Med J. 1991;302:259-262.
- Ursic-Vrscaj M, et al. Hormone replacement therapy after invasive ovarian serous cystadenocarcinoma treatment: the effect on survival. Menopause. 2001;8:70-75.
- Hopkins ML, et al. Ovarian cancer patients and hormone replacement therapy: a systematic review. Gynecol Oncol. 2004;92:827-832.
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