BACKGROUND: In 1975, estrogen only was found to be associated with an increased risk of endometrial cancer. In November 2015, NICE guidelines on hormone therapy were published that did not take this risk into account.

AIM: This systematic literature review assesses the safety of estrogen plus progestin therapy according to the risk of endometrial cancer, while considering both regimen and type of progestin.

METHODS: PubMed, EMBASE and the Cochrane Library were searched, resulting in the identification of 527 published articles on menopausal women with intact uteri treated with estrogen only, estrogen plus progestin or tibolone for a minimum of one year. Risk of endometrial cancer was compared to placebo or never users and measured as relative risk, hazard or odds ratio.

RESULTS: 28 studies were included. The observational literature found an increased risk among users of estrogen alone. Continuous combined therapy showed a lower risk than sequential combined therapy. The newer marketed micronized progesterone increased the risk notably, also when administered continuously. In most studies, tibolone was associated with an increased risk.

CONCLUSION: Use of unopposed estrogen, tibolone and sequential combined therapy increases the risk of endometrial cancer. Continuous combined therapy seems risk free, but possibly not when micronized progesterone is used.