Experimental mouse model of hormonal therapy effects on the postmenopausal mammary gland

Menopausal hormone therapy, in particular estrogen plus progestin therapy, has been associated with increased breast cancer risk. In order to understand the basis for increased breast cancer risk, more information is needed about the effects of menopausal hormone therapies on the breast. In this review we describe studies carried out in a mouse model of early vs. late postmenopausal states. We investigated the effects of 1) estrogen alone, 2) combined continuous estrogen + progestin, 3) systemically vs. locally administered estrogen and progestin, and 4) the effect of pregnancy on the response to hormonal therapies. We analysed the effects on mammary gland morphology and proliferation. Estrogen therapy started in late postmenopause caused a greater proliferative response than when started in early postmenopause. In parous, late postmenopausal mice the greater proliferative response to estrogen was not observed. Overall, the greatest proliferative response was observed with combined continuous estrogen + progestin hormone therapy and did not differ significantly in early vs. late nulliparous or parous postmenopausal mice. Both estrogen and progestin were found to act directly on the mammary gland rather than through systemically mediated effects. The possible implications of these findings for menopausal hormone therapy in women and breast cancer risk are discussed.