Postmenopausal Hormone Therapy and the Risk of Endometrial Cancer
Abstract & Commentary
By Leon Speroff, MD, Editor, Professor of Obstetrics and Gynecology, Oregon Health and Science University, Portland, is Editor for OB/GYN Clinical Alert
Synopsis: Both estrogen plus progestin regimens significantly increased endometrial carcinoma risk in this study. Risks among unopposed estrogen users remained elevated long after last use. The prospect that all estrogen plus progestin regimens increase endometrial carcinoma risk deserves continued research.
Source:Lacey JV Jr, et al. Endometrial carcinoma risks among menopausal estrogen plus progestin and unopposed estrogen users in a cohort of postmenopausal women. Cancer Epidemiol Biomarkers Prev. 2005;14:1724-1731.
Lacey and colleagues from the National Cancer Institute report the risks of endometrial cancer in users of combined estrogen-progestin regimens. The data were collected from the follow-up of the women in the Breast Cancer Detection Demonstration Project that began in 1979. Follow-up consisted of telephone interviews and self-administered mailed questionnaires. Over the time of the study the questions asked regarding hormone therapy varied regarding type and duration. After exclusions, 30,379 women were available for analysis, with an average follow-up of 13 years. The final group of endometrial cancers totaled 541 women, identified from a combination of medical records, registry data, death certificates, and self-reports. The results below excluded women who had previously used unopposed estrogen.
Lacey et al reported an increasing risk with increasing duration of use of estrogen-progestin. They found 43 cases of endometrial cancer in users of unopposed estrogen 5-9 years previously, RR = 2.2 (1.4-3.4) and in users for 10 or more years, the increased risk did not achieve statistical significance, RR = 1.5 (1.0-2.1).
Commentary
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 2 to 10 times the normal incidence of 1 per 1,000 postmenopausal women per year.1,2 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, perhaps an incidence of 1 in 10 with very long-term use), and lingers for up to 10 years after estrogen is discontinued. The current study supports this conclusion.
Reports of the clinical impact of adding progestin in sequence with estrogen include both the reversal of hyperplasia and a diminished incidence of endometrial cancer.3-7 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. Studies indicate that the minimal requirement is a monthly exposure of at least 10 days’ duration.8-10 About 2-3% of women per year develop endometrial hyperplasia when the progestin is administered for less than 10 days monthly. Although the older standard method incorporated the addition of a progestational agent for the last 10 days of estrogen exposure, most evidence has argued in favor of 12 or 14 days.
Important unanswered questions are the following: What will be the actual incidence of endometrial cancer in long-term users of postmenopausal hormone therapy, and will there be differences among the various regimens and routes of administration? A case-control study from Seattle reported that the use of combined estrogen-progestin (essentially all sequential and oral) for 5 or more years was associated with an increased relative risk of endometrial cancer, even with 10-21 days of added progestin per month.11 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 2 deaths, precluding statistical significance.12 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.10
Case-control studies have indicated that not only is the excess risk associated with unopposed estrogen prevented by continuous, combined regimens but with increasing duration of use, the risk of endometrial cancer is lower than that in never users.13,14 In a small number of women who developed hyperplasia on a sequential regimen, conversion to continuous, combined treatment produced a return to normal endometrium, and in 345 women who completed 5 years of treatment with a continuous, combined regimen not a single case of hyperplasia was detected.15
The Women’s Health Initiative reported the following results with endometrial cancer in the canceled estrogen-progestin arm after 5 years of this clinical trial:16
The WHI concluded that combined estrogen-progestin treatment prevented the increase in endometrial cancer associated with unopposed estrogen. Note that adenocarcinoma of the endometrium (the cancer most likely to be affected by estrogen-progestin therapy) accounted for only 8 cases in the treated group of 8,506 subjects and 9 in the placebo group of 8,102 subjects, small numbers that make confident conclusions difficult. The literature on hormone therapy and the risk of endometrial cancer does not suggest that a beneficial reduction in risk with estrogen-progestin combined treatment should be expected within a time period of a few years, and if the estrogen-progestin arm of the WHI had not been canceled, a reduced risk could have achieved statistical significance.
What does the current study add to this state of affairs? The most important concern is that these data do not agree with previous studies supporting the protection by adequate exposure to progestational agents. Lacey et al appropriately and apparently effectively removed the influencing factor of previous exposure to unopposed estrogens. But there are still limitations.
As time went on, the percentage of women who completed interviews dropped from 86.4% to 72.6%. The loss of subjects is important when case numbers are small. The estimates on the impact of increasing duration of use are limited by very small numbers (for example, with use 5-9 years previously, there were 10 cases in the sequential group and 5 in the continuous group). Indeed, only the numbers for any use are respectable.
Most problematic is the method of classifying hormone use, a method made necessary by the impreciseness of the follow-up design of the study. Sequential estrogen-progestin classification required the use of a progestin for less than 15 days per month. Estrogen-progestin users were classified as continuous users if the progestin had been used for 15 or more days per month. Too few of the women used a combination E-P single pill to allow greater accuracy. Thus the data on continuous estrogen-progestin actually are compromised by not excluding those who took combination estrogen-progestin less than daily.
The current study raises a warning signal. Although the protective effect of progestin is considerable and predictable, it is unwise to expect all patients on estrogen-progestin therapy to never develop endometrial cancer. Appropriate monitoring of patients cannot be disregarded. Although routine assessments are not cost-effective, interventions directed by clinical responses are prudent and necessary.
References
- Grady D, et al. Hormone replacement therapy and endometrial cancer risk: a meta-analysis. Obstet Gynecol. 1995;85:304-313.
- Weiss NS, Hill DA. Postmenopausal estrogens and progestins and the incidence of gynecologic cancer. Maturitas. 1996;23:235-239.
- Thom MH, et al. Prevention and treatment of endometrial disease in climacteric women receiving oestrogen therapy. Lancet. 1979;2:455-457.
- Whitehead MI, et al. Effects of estrogens and progestins on the biochemistry and morphology of the postmenopausal endometrium. N Engl J Med. 1981;305:1599-1605.
- Gambrell RD Jr, et al. Role of estrogens and progesterone in the etiology and prevention of endometrial cancer: a review. Am J Obstet Gynecol. 1983;146:696-707.
- Persson I, et al. Risk of endometrial cancer after treatment with oestrogens alone or in conjunction with progestogens: results of a prospective study. BMJ. 1989;298:147-151.
- Voigt LF, et al. Progestagen supplementation of exogenous oestrogens and risk of endometrial cancer. Lancet. 1991;338:274-277.
- Varma TR. Effect of long-term therapy with estrogen and progesterone on the endometrium of postmenopausal women. Acta Obstet Gynecol Scand. 1985;64:41-46.
- Feldman S, et al. Two-year follow-up of 263 patients with post/perimenopausal vaginal bleeding and negative initial biopsy. Gynecol Oncol. 1994;55:56-59.
- Pike MC, et al. Estrogen-progestin replacement therapy and endometrial cancer. J Natl Cancer Inst. 1997;89:1110-1116.
- Beresford SA, et al. Risk of endometrial cancer in relation to use of oestrogen combined with cyclic progestagen therapy in postmenopausal women. Lancet. 1997;349:458-461.
- Schairer C, et al. Cause-specific mortality in women receiving hormone replacement therapy. Epidemiology. 1997;8:59-65.
- Weiderpass E, et al. Risk of endometrial cancer following estrogen replacement with and without progestins. J Natl Cancer Inst. 1999;91:1131-1137.
- Hill DA, et al. Continuous combined hormone replacement therapy and risk of endometrial cancer. Am J Obstet Gynecol. 2000;183:1456-1461.
- Wells M, et al. Effect on endometrium of long term treatment with continuous combined oestrogen-progestogen replacement therapy: follow up study. BMJ. 2002;325:239.
- Anderson GL, et al. Effects of estrogen plus progestin on gynecologic cancers and associated diagnostic procedures. The Women’s Health Initiative randomized trial. JAMA. 2003;290:1739-1748.
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