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Clemens Tempfer, Ziad Hilal, Peter Kern, Ingolf Juhasz-Böss, Günther Rezniczek

• Background: Menopausal hormone therapy (MHT) is an appropriate treatment for women with the climacteric syndrome. The estrogen component of MHT effectively alleviates climacteric symptoms but also stimulates the endometrium and thus may increase the risk of endometrial cancer (EC). Materials and Methods: We performed a systematic literature search of the databases PubMed and Cochrane Central Register of Controlled Trials to identify controlled and uncontrolled clinical trials reporting on the prevalence and/or incidence of EC among women using MHT. Results: 31 publications reporting on 21,306 women with EC diagnosed during or after MHT were identified. A significantly reduced risk of EC among continuous-combined (cc)MHT users with synthetic progestins (SPs) was demonstrated 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 (\(\geq\)10 years), not confirmed in three other sub-group analyses of women with \(\geq\)6, \(\geq\)5, and >10 years of ccMHT use. A significantly increased risk of EC among users of sequential-combined (sc)MHT with SPs was demonstrated in 6/12 studies with ORs/HRs between 1.38 and 4.35. Number of days of progestin per month was a significant modulator of EC risk. A decreased risk of EC was seen in obese women. 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 greatest among obese women. Conclusion: ccMHT with SPs reduces the risk of EC, whereas estrogen-only MHT increases the risk. scMHT with SPs and cc/scMHT with micronized progesterone increase the risk of EC depending on type of progestin, progestin dosage, and duration of MHT use.