Hormone Therapy and Ovarian Cancer: Another Affirmation
Hormone Therapy and Ovarian Cancer: Another Affirmation
Abstract & Commentary
By Robert L. Coleman, MD, Professor, University of Texas; M.D. Anderson Cancer Center, Houston, is Associate Editor for OB/GYN Clinical Alert.
Synopsis: Several large prospective cohort studies, including the Nurse's Health Study and the Million Women Study have examined the risk of ovarian cancer among those who have taken steroidal menopausal replacement. The consistency of results supports the global conclusion that a small, but real risk is assumed in ever-takers. The current study adds another nearly 1 million women to this research question. Many of its conclusions affirm previous reports; however, the limitations in bias from the Danish registry provide the clearest observation of this risk, including examination of formulation, dose, progestin type, and route of administration.
Source: Morch LS, et al. Hormone therapy and ovarian cancer. JAMA 2009;302:298-305.
Previous studies have suggested that menopausal hormone therapy is associated with the risk of developing epithelial ovarian cancer. The strongest association comes from examining "ever use" against those never exposed. However, great variations in formulation, route of administration, and regimen have limited detailed analyses of these important modifiers. To address these questions, a large cohort of perimenopausal and menopausal Danish women, aged 50-79 were followed prospectively from 1995 through 2005. Cross-referencing and linkage to other national registries provided important confirmatory information on specific type of regimen and usage, as well as accurate histology at diagnosis. In all, 909,946 women without a hormone-sensitive cancer and with at least 1 intact ovary were identified and followed a median of 8 years. Epithelial ovarian cancer was identified in 2681 women (87% of all ovarian cancers). The incidence rate ratio for women with epithelial ovarian cancer who were classified as current users was 1.44 (95% confidence interval [CI], 1.30-1.58) compared to never-users. The risk for all forms of ovarian malignancy diagnosed in the study was similarly elevated among current users. Risk declined over time once usage stopped but remained elevated relative to never-users for 6 years. The elevated incidence risk was unaltered by formulation, including synthetic steroids, schedule (continuous vs cyclic), or duration of use. Vaginal and transdermal routes of administration were associated with numerically lower risks, but were not statistically different from the risk associated the oral administration. The absolute rate of increased incidence risk was 0.12 per 1000 years, or about 1 extra ovarian cancer per 8300 women taking hormone therapy each year. The authors conclude that menopausal estrogen replacement is associated with an increased incidence risk of ovarian cancer. The risk is unaffected by regimen, route, schedule, dose, or duration of use.
Commentary
While the current study confirms the general consensus that menopausal hormone replacement therapy is associated with an increased incidence risk of ovarian cancer, it provides some clarity on other controversial aspects related to the type of replacement, schedule, formulation, and dose. In previous studies and in a meta-analysis on the subject, a protective or risk-nullifying effect of progesterone had been suggested. The current study, bolstered by indexing from a national pharmacy database, suggests this is not the case and is unaltered by type of progestin used. The relative risk for women taking estrogen and progestin-based hormone replacement was 1.5 and not significantly different from those taking estrogen alone. Similarly, contradicting findings have been previously reported in women taking either cyclic or continuous hormone replacement. The current study suggests these risks in ever-takers is unaffected by schedule. While the attributable risks of hormone replacement in this study appear small, the number of extra ovarian cancer cases, if the association is causal, amounted to about 140 over the 8 years of median follow-up. Unfortunately, the number is probably greater because the study was unable to completely control for family history (which is associated with lower hormone replacement use), history and duration of oral contraceptive use (associated with higher use of hormone replacement therapy, yet also associated with ovarian cancer protective effects), age at menopause (higher use associated with early natural menopause), and surgical procedures in older women (hysterectomy and oophorectomy performed later in the study would reduce the risk of ovarian cancer). Given the mortality associated with the disease, any attributable increased risk must be carefully weighed against the potential benefits, which largely remain symptomatic. In the absence of detailed patient-reported outcomes and quality-of-life assessments in these patients, we are left to trial and error, with the goal being the lowest dose of hormone replacement for the shortest duration.
Suggested Readings
- Greiser CM, et al. Menopausal hormone therapy and risk of ovarian cancer: Systematic review and meta-analysis. Hum Reprod Update 2007;13:453-463.
- Danforth KN, et al. A prospective study of postmenopausal hormone use and ovarian cancer risk. Br J Cancer 2007;96:151-156.
- Beral V, et al; Million Women Study Collaborators. Million Women Study Collaborators. Ovarian cancer and hormone replacement therapy in the Million Women Study. Lancet 2007;369:1703-1710.
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