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Menopausal women who have taken hormone therapy with conjugated equine estrogen (CEE) alone may have an increased risk of developing and dying from ovarian cancer. However, those who have taken CEE combined with medroxyprogesterone acetate (MPA) do not incur an increased risk and may reduce their risk of developing uterine cancer.

Menopausal hormone therapy's influence on ovarian and endometrial cancers remains unsettled. In the , Rowan T. Chlebowski, MD, PhD, of the Lundquist Institute in Torrance, California, and colleagues compared the long-term influence of CEE+MPA and CEE alone on ovarian and endometrial cancer incidence and mortality in the Women's Health Initiative (WHI) randomized, placebo-controlled clinical trials.

The following Q&A includes additional details. (None of the authors were available for comment, and the answers here are from the text of the report.)

What does the study add to the literature?

The current report updates findings with 20-year follow-up from the WHI randomized trial evaluating CEE plus MPA regarding ovarian and endometrial cancer incidence and mortality, and to our knowledge, for the first time reports findings from the WHI randomized trial evaluating CEE alone on ovarian cancer incidence and mortality.

Postmenopausal women ages 50-79 were entered on two randomized clinical trials evaluating different menopausal hormone therapy regimens. In 16,608 women with a uterus, 8,506 were randomly assigned to once daily 0.625 mg of CEE plus 2.5 mg once daily of MPA, and 8,102 received placebo.

In 10,739 women with previous hysterectomy, 5,310 were randomly assigned to once-daily 0.625 mg of CEE alone and 5,429 received placebo. The intervention was stopped for cause before the planned 8.5-year intervention after 5.6 years (CEE+MPA) and 7.2 years (CEE alone).

What were the main highlights?

After 20 years of follow-up, CEE alone versus placebo significantly increased ovarian cancer incidence (35 vs 17 cases, HR 2.04) and ovarian cancer mortality. By contrast, CEE+MPA vs placebo did not increase ovarian cancer incidence (75 vs 63 cases, HR 1.14) or ovarian cancer mortality, but did significantly lower endometrial cancer incidence (106 vs 140 cases, HR 072).

The findings of CEE alone having an adverse influence on ovarian cancer incidence are consistent with most observational studies and we now add new, randomized trial information regarding CEE-alone increasing ovarian cancer mortality. The CEE+MPA findings on endometrial cancer incidence are consistent with observational studies.

By contrast, although observational studies generally associate use of combined hormone therapy with higher ovarian cancer incidence and ovarian cancer mortality, CEE+MPA use in the WHI randomized trial did not significantly increase ovarian cancer incidence or ovarian cancer mortality.

Regarding ovarian cancer, in the WHI randomized, placebo-controlled trial, CEE alone in women with previous hysterectomy significantly increased ovarian cancer incidence and significantly increased ovarian cancer mortality. The current report does not provide evidence for CEE+MPA adverse effects on ovarian cancer incidence or mortality.

How should the results impact the decision to take menopausal hormone therapy for symptomatic relief of menopausal symptoms?

A number of recent observational studies have suggested that menopausal hormone therapy users before diagnosis of ovarian cancer have longer survival compared with those not using hormone therapy. A concluded that despite a lack of level I evidence, the risk/benefit profile of hormone therapy appears favorable in many women with a history of high-grade serous ovarian cancer.

It is unclear how the WHI findings, which suggest that CEE alone has an adverse influence on ovarian cancer in postmenopausal women, relate to younger premenopausal ovarian cancer survivors.

However, in both the WHI randomized trial and in ovarian cancer survivors' status after oophorectomy, estrogen alone is used in a low-estrogen environment. As the short-term consequences of ovarian cancer recurrence are grave, perhaps reconsideration of the evidence regarding general recommendation of estrogen-alone use in ovarian cancer survivors should be considered.

The findings should inform decisions regarding hormone therapy use and suggest reconsideration of guideline recommendations of estrogen-alone use in ovarian cancer survivors.

What are other considerations?

The current findings regarding CEE+MPA effects on ovarian cancer are neutral and those on endometrial cancer are favorable. However, there are other considerations regarding estrogen plus progestin use. CEE+MPA use increases breast density, abnormal mammogram frequency, delays breast cancer detection, significantly increases breast cancer incidence through 20 years, and increases breast cancer mortality through 11 years.

In addition, women required more endometrial biopsies (33% vs 6%) and diagnostic ultrasound examinations (13% vs 4%), largely related to vaginal bleeding.

What is your main message for practicing oncologists?

The different impacts of the types of menopausal hormone therapies on ovarian and endometrial cancer incidence and mortality point to the importance of evaluating the risks versus benefits in the use of estrogen-alone and the combination of progesterone with estrogen.

Read the study here.