Breast cancer and menopausal hormone therapy: does the progestogen matter?

It is established that the adjunction of a progestogen to the estrogenic component of menopausal hormone therapy (MHT) is not neutral regarding breast cancer risk, and even constitutes a central factor. Estrogen–progestogen MHT has now been classified as carcinogenic to the human breast. Should we thus conclude that there exists a class effect related to all progestogens? Or is there a possibility that different molecules or doses, for example, bear different risks? It is only quite recently that progestogens have become a key topic of investigation concerning the relation between breast cancer and MHT. Therefore, many aspects of this relation remain unresolved, some of them having been barely investigated. However, data exist suggesting that the choice of the progestogen molecule is able to impact the risk of breast cancer. In particular, in the French E3 N cohort, MHT-containing progesterone or its isomer, dydrogesterone, were associated with a lower risk than those containing other progestogens. The question of whether the number of days the progestogen is used per month modulates the risk produced so far divergent results. The observation that risk differences between sequential and continuous-combined regimens are generally more marked in studies conducted in Northern Europe than in the USA or in the UK is puzzling. This apparent discrepancy is resolved if the hypothesis that the cumulative monthly dose of progestogen is implicated in breast cancer risk holds true. Indeed, in Northern Europe, the daily dose of progestogen is often the same in both continuous-combined and sequential regimens, so that the total monthly dose in the former ismore elevated than in the latter, which is generally not the case in the USA or in the UK. Finally, the route of administration of the progestogen (oral, transdermal, vaginal, . . .) mayalso intervene regarding breast cancer risk, but there is so far no epidemiological data on this subject. By considering the available epidemiological evidence, it therefore seems likely that breast cancer risk varies according to the characteristics of the progestogen component of MHT. As it is the most effective treatment to alleviate climacteric symptoms, MHT remains widely used, and the administration of a progestogen is mandatory in hysterectomized women to protect the endometrium against the development of estrogen-induced hyperplasia. Therefore, for these women who need estrogen–progestogen MHT, the issue of progestogens must remain a very active area of research, aiming at identifying treatment modalities that have the least potential for exerting adverse effects. In particular, future studies should be designed to disentangle the effects of various progestogen-related parameters: the molecule, the dosage, the regimen and the route of administration.