The choice of progestogen for HRT in menopausal women: breast cancer risk is a major issue.

Doctors and patients fear the risk of breast cancer when using hormone replacement therapy (HRT). This review focuses on the choice of progestogen for HRT in menopausal. The Women's Health Initiative (WHI) has been the only large double-blind placebo-controlled study testing the risk of breast cancer (BC) using HRT. No increased risk using estrogen (E)-only was seen, there was a significant decrease in mortality due to BC after the use of HRT which persisted during the recent 18-year follow-up of the WHI. In contrast in the combined arm the risk increased. In about 20 observational studies using mostly medroxyprogesterone acetate (MPA) or estradiol-norethisterone acetate (NETA) an increased BC-risk was observed comparable with the WHI. Only for natural progestogen, progesterone and for dydrogesterone (retro-isomer of progesterone) was no increased risk seen for up to 5-8 years, when compared directly with other progestogens, but for longer treatment an increased risk cannot be excluded. In contrast, the mortality due to BC after use of E-only and combined HRT decreased in about a dozen observational studies, and was very recently confirmed in a Finnish study evaluating 490,000 women using estradiol (E2) plus different progestogens. There have been already more than 70 studies evaluating the risk of BC during HRT, and still there are many open questions. Therefore, this review covers our own and other experimental research which could answer important questions. Experimental research has demonstrated that certain synthetic progestogens, but not progesterone and to some extent also not dydrogesterone, can accelerate the proliferation of breast cancer cells in vitro and in animal studies via special cell membrane components which we recently also detected in patients with BC, and we found differences comparing all available synthetic progestogens. Derived from these mechanisms future research may provide screening for patients at risk and predict the prognosis of possible BC.