Continuous Combined Estrogen Plus Progestin and Endometrial Cancer

The Women's Health Initiative Randomized Trial

R. T. Chlebowski; G. L. Anderson; G. E. Sarto; R. Haque; C. D. Runowicz; A. K. Aragaki; C. A. Thomson; B. V. Howard; J. Wactawski-Wende; C. Chen; T. E. Rohan; M. S. Simon; S. D. Reed; J. E. Manson


J Natl Cancer Inst. 2016;108(3) 

In This Article


Continuous combined estrogen plus progestin use for 5.6 years in postmenopausal women with normal endometrial biopsy at therapy initiation resulted in a statistically significant reduction in endometrial cancer incidence, with the difference becoming statistically significant during longer-term postintervention follow-up. Subgroup analyses suggest a favorable effect of estrogen plus progestin on endometrial cancer risk generally, including in women in the highest BMI groups.

This WHI study is the first randomly assigned, double-blind, placebo-controlled trial to demonstrate that endometrial cancer incidence is statistically significantly lower in women taking continuous combined estrogen plus progestin compared with placebo. Similar findings were reported from the much smaller, randomized Heart and Estrogen/progestin Replacement Study (HERS 2), where fewer endometrial cancers were diagnosed in the estrogen plus progestin group (2 vs 8 case patients, HR = 0.25, 95% CI = 0.01 to 1.18, P = .48).[22] The progestin effect in reducing, rather than just mitigating, the adverse influence of exogenous estrogen on endometrial cancer risk suggests additional progestin effects on endometrial cancer risk related to endogenous estrogen exposure as well.

While case-control studies of continuous combined hormone therapy and endometrial cancer provide somewhat mixed results,[23,24] the current trial findings support results from most cohort studies. Continuous combined hormone therapy has been associated with a statistically significantly lower endometrial cancer incidence in three[3,25,26] of four[27] cohort analyses with a meta-analysis demonstrating an overall lower endometrial cancer risk,[6] often with greatest affect among obese women.[3,26,27] In the current trial, while no interaction between BMI and combined hormone therapy was seen, risk estimates were somewhat suggestive of a larger effect in obese women. One difference from such observational study findings was the identification of several years' lag preceding separation of the incidence rates between randomly assigned groups in the WHI trial, likely the result of the entry requirement for normal endometrial histology, precluding entry of women with existing proliferative endometrial epithelium.

Consideration of the progestin dose, schedule, and duration can explain most study differences. Sequential regimens with fewer days of progestin exposure are less effective in reducing endometrial cancer risk. In a meta-analysis of cohort studies,[6] estrogen plus sequential progestin use for fewer than 10 days per month was associated with higher endometrial cancer risk (odds ratio [OR] = 1.32, 95% CI = 1.06 to 1.65), while progestin sequential use for 10 to 14 days per month was neutral for risk (OR = 1.05, 95% CI = 0.84 to 1.30). In addition, while estrogen regimens that include micronized progesterone have been less strongly associated with breast cancer risk in some studies,[28,29] they also appear to provide limited or no protection against endometrial cancer (HR = 2.42 95% CI = 1.53 to 3.83)[25,30] despite mitigating short term, estrogen-associated endometrial proliferation.[4] These findings suggest that short-term endometrial proliferation change may not be a reliable surrogate for endometrial cancer risk. In the current study, histologic findings did not differ between randomly assigned groups in the 5% subgroup having protocol determined repeat endometrial biopsies at year 3.[13]

The current endometrial cancer findings highlight the completely different influences estrogen plus progestin and estrogen alone have on endometrial cancer and breast cancer.[31,32] In the WHI randomly assigned trial, estrogen plus progestin statistically significantly increased breast cancer incidence[18,21] and, in the current report, reduced endometrial cancer incidence. In contrast, in the separate WHI randomized trial in women with prior hysterectomy, estrogen alone statistically significantly reduced breast cancer incidence.[29,30] Further, in observational studies, estrogen alone use is associated with statistically significantly higher endometrial cancer risk.[3,25]

As previously described,[13,33] participation in the combined hormone therapy compared with the placebo group was associated with more frequent endometrial bleeding[13,33] and more total endometrial biopsies (33% vs 6%, P < .001)[13] during active intervention. Despite this more active surveillance, fewer endometrial cancers were diagnosed in the estrogen plus progestin group. In addition, cumulative hysterectomy rates were not statistically significantly higher in the combined hormone therapy group, hysterectomies were rarely performed for proliferative histologies (in only 2.2%), and the sensitivity analysis adjusting for hysterectomy did not change the endometrial cancer results. Thus, the hysterectomy findings cannot explain the lower endometrial cancer incidence in the combined estrogen plus progestin groups.

This trial assessed one hormone regimen; consequently, the results cannot be extrapolated to other hormone regimens. Whether regimens incorporating lower progestin dosage have similar endometrial cancer influence is unknown. While profound differences in pharmacology and in molecular actions between various progestins are described,[34] clear differences in the clinic for endometrial cancer risk have only emerged for micronized progesterone use.[25]

After the initial WHI report in 2002,[16] combined hormone therapy use rapidly decreased in the United States,[35] followed by an endometrial cancer increase, recently attributed to the hormone therapy decrease.[36] However, rising obesity rates during the same period also could be a factor. Previously, a decrease in breast cancer incidence during the same period was also attributed to the hormone therapy decrease,[37,38,39] a suggestion supported by the preponderance of subsequent reports.[39,40,41] While the directions of changes are opposite, the magnitude of the relative influence on endometrial cancer and breast cancer incidence attributed to the hormone therapy decrease are similar. Consequently, because breast cancers are five times more common than endometrial cancers, a net absolute decrease in cancer incidence likely occurred after the 2002 WHI report,[16] considering both endometrial and breast cancer.

A recent publication has updated the WHI hormone therapy trial findings,[15] which concluded that the estrogen plus progestin effect in decreasing endometrial cancers does not substantially alter the risk and benefit balance of continuous combined hormone therapy use or the recommendation against its use for chronic disease reduction in postmenopausal women.[15]

It is unclear why estrogen and progestin have different influences on epithelial proliferation in the endometrium and the breast. Classically, estrogen drives endometrial epithelial proliferation and progesterone inhibits proliferation and causes cell differentiation.[42,43,44] While estrogen also usually stimulates breast epithelium[45] and inhibits apoptosis,[46] preclinical findings indicate that, after estrogen deprivation, estrogen can act as an apoptosis inducer.[47,48] In contrast to endometrial findings, progestins stimulate mammary epithelial proliferation[49] and stem cell expansion.[50] While differential stromal tissue effects (with substantially more stromal tissue found in the endometrium than in the breast) have been proposed as potential mediator of these differences,[51] full discussion of these complex processes is beyond the present report scope.

As progestins can decrease endometrial epithelial proliferation,[52] progestin use has been proposed as a potential chemoprevention strategy.[53] In this regard, the substantial reduction in endometrial cancers seen with estrogen plus progestin in the current trial in those with high BMIs who are at increased endometrial cancer risk[54,55] may be of relevance. However, more information regarding the overall risks and benefits of progestin alone use is needed before the prevention question is pursued.

Study strengths include the randomly assigned, double-blind, placebo-controlled design with endometrial cancer as a prospectively identified outcome, the large sample size, endometrial biopsy screening to exclude pre-existing endometrial pathology, long postintervention follow-up, the extremely low rate of postintervention hormone therapy use,[56] and high-quality outcome assessment. Limitations include the modest number of endometrial cancers observed and absence of cancer treatment information. Finally, as high-risk women based on endometrial biopsy findings were excluded from trial entry, results in a general population could differ.

In summary, in postmenopausal women, continuous combined estrogen plus progestin use reduces endometrial cancer incidence by 35%. The favorable effects were not limited to any particular histologic subtype and were seen generally, including in women in the highest BMI categories.