Continuous Combined Postmenopausal Hormone Therapy
October 30, 1999
Continuous Combined Postmenopausal Hormone Therapy May Protect Against Endometrial Cancer
Abstract & Commentary
Synopsis: In this study, the daily continuous use of a progestin for five or more years was associated with an 80% reduced risk of endometrial cancer.
Source: Weiderpass E, et al. J Natl Cancer Inst 1999;91:1131-1137.
Weiderpass and colleagues report the results of a large, nationwide, population-based case-control study in Sweden assessing the effect of adding progestins on the risk of endometrial cancer associated with postmenopausal estrogen therapy. The use of hormone therapy was examined in 709 patients with endometrial cancer compared with 3368 control women. Consistent with previous reports, the use of unopposed estrogen increased the risk of endometrial cancer, reaching a relative risk (RR) of 6.2 for estradiol and other synthetic estrogens and 6.6 for conjugated equine estrogens with five years or longer of treatment, and more than 8 after 10 years.
An increased risk of endometrial cancer in users of combined estrogen and progestin was observed only in women using progestins sequentially for less than 16 days per month (most commonly 10 days). Overall, the daily continuous use of a progestin for five or more years was associated with an 80% reduced risk of endometrial cancer (RR = 0.2; CI = 0.1-0.8). The Swedish study observed a greater degree of protection against endometrial cancer with progestins of the 19-nortestosterone category (norethindrone acetate and levonorgestrel are commonly used in Sweden) compared with 17-hydroxyprogestins (like medroxyprogesterone acetate). However, this analysis was limited by a small number of 17-hydroxyprogesterone users.
COMMENT BY LEON SPEROFF, MD
Estrogen normally promotes mitotic growth of the endometrium. Abnormal progression of growth through simple hyperplasia, complex hyperplasia, atypia, and early carcinoma has been associated with unopposed estrogen activity, administered either continuously or in cyclic fashion. Only one year of treatment with unopposed estrogen (0.625 mg conjugated estrogens or the equivalent) will produce a 20% incidence of hyperplasia, largely simple hyperplasia; in the three-year PEPI trial, 30% of the women on unopposed estrogen developed adenomatous or atypical hyperplasia.1-3
Approximately 40 case-control and cohort studies have estimated that the risk of endometrial cancer in women on estrogen therapy (unopposed by a progestational agent) is increased by a factor of somewhere from two to 10 times the normal incidence of one per 1000 postmenopausal women per year.4,5 The risk increases with the dose of estrogen and with the duration of exposure (reaching a 10-fold increase with 10-15 years of use, and perhaps an incidence of 1 in 10 with long-term use), and an aspect often unappreciated by clinicians, lingers for up to 10 years after estrogen is discontinued.6 It is important to note that in the current Swedish study, no increase in risk was observed after the cessation of use of combined estrogen/progestin.
Reports of the clinical effect of adding progestin in sequence with estrogen include both the reversal of hyperplasia and a diminished incidence of endometrial cancer.7-11 The protective action of progestational agents operates via a mechanism that requires time in order to reach its maximal effect. For that reason, the duration of exposure to the progestin each month is critical. While one standard method incorporated the addition of a progestational agent for the last 10 days of estrogen exposure, most have argued in favor of 12 or 14 days. Studies indicate that the minimal requirement is a monthly exposure of at least 10 days duration.12-14 About 2-3% of women per year develop endometrial hyperplasia when the progestin is administered for less than 10 days monthly.
A case-control study from Seattle reported that the use of combined estrogen-progestin (essentially all sequential and oral) for five or more years was associated with an increased RR of endometrial cancer, even with 10-21 days of added progestin per month.15 However, the increased risk was confined to those women who had been previously exposed to unopposed estrogen treatment. Remember, after discontinuing unopposed estrogen treatment, the risk of endometrial cancer lingers for up to 10 years, even if a subsequent regimen includes a progestin. In the Swedish prospective cohort in Uppsala, a reduced risk of mortality due to endometrial cancer was observed in women receiving an estrogen-progestin combination; however, there were only two deaths, precluding statistical significance.16 A case-control study from Los Angeles found no increased risk of endometrial cancer with the continuous combined estrogen-progestin regimen or when at least 10 days of progestin were provided in a sequential regimen.14
An attractive idea is that protection against endometrial cancer requires shedding of the endometrium. However, we know that at least one-third and up to one-half of the functioning endometrium is not lost during withdrawal bleeding, and it has not been established that endometrial shedding is essential to protect against cancer.17 It is just as logical to believe that prevention of growth and development of atrophic endometrium are protective. There is good reason to believe that both the sequential regimens (with appropriate dose and duration of progestin administration) and the continuous combined regimens offer protection against endometrial cancer. The degree of protection and comparable performance will ultimately be determined by the long-term, randomized, currently ongoing clinical trials.
In the meantime, the results from this Swedish case-control study provide us with the latest epidemiologic assessment of combined estrogen/progestin therapy, and the data indicate an emerging benefit of daily, continuous treatment. Because the use of a daily, continuous, combined regimen is relatively recent in clinical practice (at least in an epidemiologic time frame), it is only now that epidemiologic studies can begin to assess the effect. A protective effect by daily exposure to a progestin is not unexpected because a similar experience with oral contraceptives yields the same result. I fully expect that protection against endometrial cancer will become a proven benefit of the estrogen/progestin daily regimens. This will be a powerful piece of information to use when counseling patients who are experiencing breakthrough bleeding on these regimens. (Dr. Speroff is Professor of Obstetrics and Gynecology, Oregon Health Sciences University, Portland.)
References
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2. The Writing Group for the PEPI Trial. JAMA 1995; 273:199-208.
3. The Writing Group for the PEPI Trial. JAMA 1996; 275:370-375.
4. Grady D, et al. Obstet Gynecol 1995;85:304-313.
5. Weiss NS, et al. Maturitas 1996;23:235-239.
6. Green PK, et al. Cancer Causes Control 1996;7: 575-580.
7. Thom MH, et al. Lancet 1979;ii:455-457.
8. Whitehead MI, et al. N Engl J Med 1981;305: 1599-1605.
9. Gambrell RD Jr, et al. Am J Obstet Gynecol 1983; 146:696-707.
10. Persson I, et al. BMJ 1989;298:147-151.
11. Voigt LF, et al. Lancet 1991;338:274-277.
12. Varma TR, et al. Acta Obstet Gynecol Scand 1985; 64:41-46.
13. Feldman S, et al. Gynecol Oncol 1994;55:56-59.
14. Pike MC, et al. J Natl Cancer Inst 1997;89: 1110-1116.
15. Beresford SA, et al. Lancet 1997;349:458-461.
16. Schairer C, et al. Epidemiology 1997;8:59-65.
17. Flowers CE, et al. Obstet Gynecol 1983;61: 135-143.
The following statements are true regarding postmenopausal hormone therapy and the risk of endometrial cancer except:
a. Sequential postmenopausal hormone regimens should use more than 10 days of progestin monthly.
b. The increased risk of endometrial cancer associated with the use of unopposed estrogen treatment is dissipated five years after cessation of use.
c. Protection against endometrial cancer does not require hormonal withdrawal shedding of the endometrium.
d. Synthetic estrogens and conjugated equine estrogens have the same increased risk of endometrial cancer when used without a progestational agent.
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