Endometrial Cancer in Postmenopausal Women
Gambrell presented a review of the literature and his own clinical experience at the 1997 meeting of the South Atlantic Association of Obstetricians and Gynecologists. He first reviewed the incidence of endometrial cancer in the United States, pointing out a peak in the late 1970s that has since declined after the recognition that unopposed estrogen therapy is associated with an increased risk of endometrial cancer.
Gambrell reviews the methods to characterize the endometrium of postmenopausal women and makes a strong case that the progestin challenge test will effectively identify women who need biopsy. This test prescribes either 10 mg medroxyprogesterone acetate or norethindrone acetate 2.5 mg or 5 mg for 13 days. Those patients who demonstrate withdrawal bleeding undergo biopsy. A series of reports in the literature was reviewed validating this approach.
The most important part of this report is Gambrell’s contention that there are no cases of endometrial cancer with sequential estrogen-progestin therapy as long as 12-14 days of progestin are administered monthly. In contrast, he reviews 15 reported cases of endometrial cancer with the continuous combined method of estrogen-progestin therapy and states his belief that a cyclic sequential regimen will protect the endometrium better because shedding of the endometrium is necessary to protect against endometrial cancer. (Gambrell RD, Jr. Am J Obstet Gynecol 1997;177:1196-1207.)
COMMENT BY LEON SPEROFF, MD
Gambrell deserves kudos for his pioneering studies in the 1970s at Willford Hall, U.S. Air Force Medical Center, demonstrating that the addition of progestational agents to postmenopausal hormone therapy could protect the uterus against endometrial cancer. He further developed the progestin challenge test as a low-cost and effective means of identifying patients for further and more costly assessment of the endometrium. I, for one, was reluctant over the years to accept the progestin challenge test because there was a lack of validating data. The studies reviewed by Gambrell in this report substantially support the progestin challenge test as effective and reliable. There lingers, however, a concern regarding the false-negative rate. However, the available data indicate that most, if not nearly all, women with endometrial proliferation, hyperplasia, and even cancer will respond with a withdrawal bleed after the progestin challenge, and ultrasonography measurement of the endometrial thickness will demonstrate a thickness greater than 5 mm.
My concern with the Gambrell report focuses on the promotion of an idea that is based upon anecdotal experience. Gambrell argues that the sequential method protects the endometrium in a superior fashion as long as the doses of the estrogen and progestin are appropriate and the progestin is given in a sufficient duration of 12 or more days per month. He believes that a significant part of the protection against endometrial cancer requires shedding of the endometrium. He argues that the way that oral contraceptives decrease the risk of endometrial cancer is, to a significant degree, by inducing withdrawal bleeding. However, we know that at least one-third of the functioning endometrium is not lost during withdrawal bleeding. By no means, is it a clearly demonstrated principle that shedding of the endometrium is essential to protect the endometrium against endometrial cancer. It is just as logical to believe that prevention of growth and development of a decidualized atrophic endometrium can be fully protective. Gambrell further asserts that his cyclic combined regimen is clinically superior in producing amennorrhea in patients when compared to the continuous combination method. A conclusion such as this can only be established in an appropriately designed comparative epidemiologic clinical trial.
In Gambrell’s report and the discussion comments by Donald L. Fylstra, MD, that follow the report, it is pointed out that most patients who develop endometrial cancer when they are taking a regimen of estrogen and progestin have predisposing reasons. Among them is the existence of hyperplasia prior to treatment, as well as exposure to unopposed estrogen prior to treatment. This emphasizes that patients at high risk for endometrial cancer require more aggressive surveillance of the endometrium. Furthermore, it is impossible to compensate for predisposing factors in anecdotal experience and thus make accurate epidemiologic conclusions.
We can even make the counter argument that the sequential method does not protect against endometrial cancers as well as the continuous combined method. For example, in Lancet, a case-control study from Seattle concluded that there was still an increased relative risk of endometrial cancer with sequential estrogen and progestin even when the progestin was given for more than 10 days per month (Lancet 1997;349:458-461). Even in that study, however, the majority, if not all, of the cases of cancer were in women who had been previously exposed to unopposed estrogen therapy. At the FIGO meeting last August in Copenhagen, I heard a report from an ongoing clinical trial in England. In this trial, women coming off of long-term sequential estrogen-progestin therapy had a 6% incidence of endometrial hyperplasia. About a year and a half ago, I heard a report in Europe that documented 15 and more years of current use of a daily estrogen-progestin combination, and after more than 7 million women’s years of use, there were only seven cases of endometrial cancerfour of which had hyperplasia before beginning treatment.
Certainly, it is appropriate to be concerned regarding what the long-term actual incidence will be of endometrial cancer on various postmenopausal hormone therapy regimens. The short-term trials have been very reassuring. Nevertheless, even a trial that is as long as three years must be considered short-term. At the present time, I believe that there is good reason to indicate that both the sequential regimen and the daily continuous combination regimen of estrogen-progestin therapy offer protection against endometrial cancer. Whether one is better than another will only be determined when we have the results of long-term randomized clinical trials such as the Women’s Health Initiative. Both Gambrell’s concerns and his recommendations are based upon his anecdotal experience. This does not equate to the kind of epidemiologic evidence that we need in order to make clinical decisions.
Another example of Gambrell’s anecdotal recommendations is his conclusion that to fully protect the endometrium, 300 mg of oral micronized progesterone must be given daily for 12-14 days. In fact, there are no dose response studies with oral micronized progesterone. The minimal effective dose is not known, nor are there any long-term studies regarding ultimate safety and efficacy.
This discussion reminds us that it is unlikely we will prevent every case of endometrial cancer with postmenopausal hormone therapy. Aggressive endometrial surveillance and appropriate diagnostic interventions continue to be our obligations as clinicians when we administer therapy regardless of its schedule and design.
The following statements are true of endometrial cancer and postmenopausal hormone therapy except:
a. the addition of progestational agents to postmenopausal estrogen therapy clearly reduces the risk of endometrial cancer.
b. the progestin challenge test identifies most patients, but it is not certain whether it identifies all patients who require endometrial assessment.
c. epidemiologic studies have demonstrated that a sequential method of postmenopausal hormone therapy with withdrawal bleeding is necessary to protect the endometrium against cancer.
d. short-term studies of postmenopausal hormone regimens have not detected a difference in endometrial protection comparing sequential to continuous combination methods.
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