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Examining the Evidence

Q.Does menopausal HRT increase the risk of ovarian cancer?

July 2007 · Vol. 19, No. 07

<huc>A.</huc>Maybe. Current users of hormone replacement therapy (HRT) were significantly more likely to develop ovarian cancer, and to die from it, than never users were. Specifically, 5 or more years of current HRT use resulted in 1 additional case of incident ovarian cancer for every 2,500 users and 1 additional death from ovarian cancer for every 3,300 users. Past HRT users had no elevation in risk.

Expert Commentary

Although rare, ovarian cancer usually is diagnosed late; for this reason, it is the most lethal gynecologic cancer in the US. In the Million Women Study, a massive cohort study carried out in the United Kingdom, roughly 950,000 postmenopausal women were surveyed between 1996 and 2001 and approximately 3 years later. Participants had no history of bilateral oophorectomy or ovarian cancer upon entry into the trial. Of these women, 50% had never used HRT, 30% were current users, and 20% had used it in the past. Over the course of the trial, 2,273 ovarian cancers were diagnosed, and 1,593 women died from the disease.

Elevated risk after 5 years of use

Compared with never users, women who had currently used HRT for longer than 5 years had a higher risk of 1) being given a diagnosis of (relative risk [RR], 1.20; 95% confidence interval [CI], 1.09–1.32) and 2) dying from (RR, 1.23; 95% CI, 1.09–1.38) ovarian cancer. However, current users with less than 5 years of use had no significantly elevated risk.

Other studies have suggested an association between HRT and ovarian cancer, but most have lacked power to determine the incidence of this rare malignancy. Although both estrogen-only and combination HRT were associated with ovarian cancer in current users in this trial, the findings are otherwise similar to those in regard to HRT and incident breast cancer.1 In the WHI, there was no elevated risk of breast cancer when a woman used combination HRT for less than 5 years.2

Some will choose to counsel women about possible elevated risk

Because the Million Women Study is an observational study, with HRT exposure reported by participants, selection bias is possible (ie, respondents with ovarian cancer may be more likely to report HRT use). With this caveat, some clinicians may choose to counsel women that more than 5 years of unopposed estrogen or combination HRT may increase the risk of ovarian cancer, just as combination HRT raises the risk of breast cancer. A shorter duration of HRT does not appear to increase the risk of ovarian cancer and will probably serve the needs of many symptomatic, newly menopausal women.


1. Collins JA, Blake JM, Crosinani PG. Breast cancer risk with postmenopausal hormonal treatment. Hum Reprod Update. 2005;11:545-560.

2. Anderson GL, Chlebowski RT, Rossouw JE, et al. Prior hormone therapy and breast cancer risk in the Women’s Health Initiative randomized trial of estrogen plus progestin. Maturitas. 2006;55:103-115.

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