The authors of the present study  were interested in evaluating the risk of endometrial cancer (EC) in women using menopausal hormone therapy (MHT). They performed a literature search of the PubMed and Cochrane databases and identified thirty-one studies between 2000 and 2020 that reported on the incidence and prevalence of EC among women using MHT. Of these, twenty studies (ten cohort, eight case-control, two randomized studies) had extrapolatable, individual patient data on EC among women using various forms of MHT. They analyzed various regimens and divided their results into four groups: continuous-combined (cc)MHT with synthetic progestins, sequential-combined (sc)MHT with synthetic progestins, MHT with micronized progesterone, and estrogen-only MHT. A summary of their results showed that there was a significantly reduced risk of EC among continuous-combined (cc)MHT users with synthetic progestins (SPs) in 10/19 studies, with odds ratios (ORs)/hazard ratios (HRs) between 0.24 and 0.71. Only one study documented an increased risk of EC among long-term users (≥10 years), not confirmed in three other sub-group analyses of women with ≥6, ≥5, and >10 years of ccMHT use. There was a significantly increased risk of EC among users of sequential-combined (sc)MHT with synthetic progestins, as demonstrated in 6/12 studies with ORs/HRs between 1.38 and 4.35. The number of days of progestin per month was a significant modulator of EC risk. Two studies documented an increased risk of EC among users of cc/scMHT with micronized progesterone. A significantly increased risk of EC among estrogen-only MHT users was demonstrated in 9/12 studies with ORs/HRs between 1.45 and 4.46. The adverse effect of estrogen-only MHT was most significant among obese women. Thus, they concluded that ccMHT with synthetic progestins reduces the risk of EC, whereas estrogen-only MHT increases the risk. scMHT with synthetic progestins and cc/scMHT with micronized progesterone increase the risk of EC.
This systematic review is extremely comprehensive, and thus lengthy, with many tables, a variety of preparations of MHT, such that it may or may not be applicable to the individual patient that one is treating. Nor, perhaps, should it cause healthcare providers to utilize one method routinely or abandon others. The choice of MHT must be individualized and, if endometrial cancer concerns are paramount, then the results of this review may well come into play. Personally, I fear that, as is often the case, advocates of some formulation will embrace this data if it is favourable to what they like and utilize mostly, while others will discount this data if it conflicts with their preconceived notions. As usual, the correct answer usually lays somewhere in the middle. This review, while not a meta-analysis (and those have their own shortcomings), is a retrospective review of mostly large, long cohort studies and case-controlled studies.
For the purpose of brevity, I have highlighted what I deemed most important. First, unopposed estrogen increases EC risk in almost all studies approximately 1.5-4.5 fold. This is not surprising. Virtually all healthcare providers know and believe this.
Second, there are only two randomized studies, hopefully providing the most reliable data. The first comes from the Women’s Health Initiative (WHI). Chlebowski et al.  carried out a randomized, placebo-controlled trial of 16,608 women on placebo or conjugated equine estrogen 0.625 milligrams with 2.5 milligrams medroxyprogesterone acetate (Prempro®) daily. After 5.6 years’ median intervention and 13 years’ median cumulative follow-up, there were fewer endometrial cancers in the combined hormone therapy group compared with the placebo group (66 vs 95 case-patients), HR = 0.65, 95% confidence interval [CI] = 0.48 to 0.89, P = .007). This correlates well with the composite 10/19 studies in the current paper that showed a decrease in EC with ccMHT. The other randomized but open-label study was by Samsioe et al.  that used either a patch delivering 50 micrograms of estradiol (E2) with 140 micrograms of norethisterone acetate (NETA) per day or oral E2 2 milligrams with NETA 1 milligram daily for 96 weeks in 239 women. They had no cases of EC or endometrial hyperplasia. This is mildly reassuring, although, the study included a smaller number of women in a relatively short time period .The third point involves micronized progesterone, which has become very popular because it is natural and “bioidentical.” Many clinicians believe it can be substituted for synthetic progestins for endometrial protection. The current review cites two studies. The first is by Fournier et al. , which was a French cohort study of 65,630 women with a mean follow up of 10.8 years, in which there were 301 cases of EC. Compared with never use, the use of estrogen + micronized progesterone was associated with an increased risk of endometrial cancer (HR = 1.80, 95% CI: 1.38, 2.34) that was significantly more marked with longer duration of use (for ≤5 years, HR = 1.39 (95% CI: 0.99, 1.97); for >5 years, HR = 2.66 (95% CI: 1.87, 3.77)). However, the dosage or number of days per month was not requested in their questionnaire, so the authors used the phrase, “at doses used in France,” to summarize the patients’ exposure. The second study is by Allen et al.  known as the European Prospective Investigation into Cancer and Nutrition., which included 115,484 women with a mean follow up of 9 years yielding 601 cases of EC. Among users of micronized progesterone, there were 26 cases of EC and 2,231 non-users yielding a hazard ratio of 2.42 (95% CI 1.53-3.83).
To summarize, in terms of EC risk (and EC risk only) unopposed estrogen increases the risk, synthetic progestin is safest and decreases risk, and micronized progesterone seems not to be equivalent to synthetic progestins. However, the power of that statement is not as well studied as for synthetic preparations.
Steven R. Goldstein, MD, CCD, NCMP, FAGCOG, FRCOG (H)
Professor of Obstetrics and Gynecology at New York University School of Medicine and Director of Gynecologic Ultrasound and Co-Director of Bone Densitometry at New York University Medical Center
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