The aim of this study was to assess the balance between uterine and mammary gland effects of two progestins widely used in HRT, progesterone and medroxyprogesterone acetate, in a quantitative mouse model. Ovariectomised mice were treated subcutaneously with either estradiol (100ng) or estradiol plus increasing doses of progesterone or MPA for a period of three weeks. Progestogenic activity in mammary glands was measured using stimulation of side-branching and epithelial cell proliferation. Progestogenic activity in the uterus was assessed by measuring the inhibition of estradiol-activated uterine epithelial cell proliferation. Overall, the study found that the progestins behave differently from one another, favouring the use of natural progesterone over MPA in combined hormone therapy. Estradiol in combination with MPA demonstrated antiproliferative uterine activity and mitogenic activity in the mammary gland at the same dose. Estradiol in combination with natural progesterone demonstrated antiproliferative uterine activity at doses lower than those leading to significant stimulation of epithelial cell proliferation in the mammary gland.