Postmenopausal hormone therapy and breast cancer: What is the problem?

Abstract

Observational studies provide evidence that breast cancer risk is increased with long-term oral use of postmenopausal estrogen replacement therapy (ET). Various large cohort studies have shown that the addition of a progestogen in combined hormone replacement therapy (EPT) increases this risk further. Prospective, randomized controlled trials have confirmed this for the continuous combined regimen. So, why not tell our patients, “Stop using ET and EPT, it is dangerous to your health!”? The answer is: there are too many problems to allow such an oversimplified, definite statement. What is the problem? There is more than one! The problems are as follows: • There are many observational studies, but these are not consistent in their results. • Relative risk increases, if any, are small and thus often statistically non-significant. • Observational studies have inherent biases that cannot be corrected for; therefore evidence should come from randomized clinical trials (RCTs). • There are no RCTs that provide evidence as to the breast cancer risk with ET, compared to EPT in the same study population. • In the three large RCTs available, the populations studied are: not representative, too old and without climacteric complaints, and therefore lacking any indication for postmenopausal hormone therapy (HT). • The data obtained thus far do not apply to non-oral routes, neglect the difference in progestogens, and do not address tibolone, a valuable alternative to classical HT in Europe. • And finally, are these epidemiological findings biologically plausible? Can estrogens cause breast cancer and why then does the Women's Health Initiative (WHI) RCT not find this? And how can the addition of a progestogen increase the ET risk further as progestogens are pro-apoptotic and down-regulate estrogen receptors as well as local estrogen biosynthesis? In conclusion, we have a problem as we cannot formulate any general advice that holds for the majority of European postmenopausal women due to lack of consistency, lack of biological plausibility, and lack of relevance of randomized clinical trial data to our daily practical work. So, we have a problem and not a firm basis for undisputable statements.