Mechanisms for differential effects between natural progesterone and synthetic progestogens on normal breast tissue

Both epidemiological studies and experimental data on normal breast tissue suggest increased cancer risk, proliferation and mammographic breast density (MD) during hormone therapy (HT) containing synthetic progestogens in traditional doses, and the relative risk or RR is approximately 1.5-3 (for women treated vs. untreated with the above therapies), proliferation levels of normal breast epithelial cells of around 10% and increase in MD in up to around 50% of women during treatment. Dose-response relationships have been inferred by correlations between progestogens as levonorgestrel, norethisterone acetate and medroxyprogesterone acetate on the one hand and proliferation and/or MD on the other hand, and of indications of lower relative risk of breast cancer with modern low or ultra-low dose HT. In contrast, natural progesterone endogenously during the menstrual cycle has a weak effect and exogenous estrogen in combination with oral micronized progesterone in HT has shown to yield an indifferent effect on proliferation. Furthermore, in epidemiological studies such as the French E3N cohort, these combinations have not shown any risk increase for breast cancer for at least 5 years of treatment. Experimental data supporting or not supporting the view that the main proliferative mechanism for natural progesterone is through binding to its nascent progesterone receptors is discussed as well as the pros and cons that the non-physiological higher proliferation levels induced by synthetic progestogens is mainly mediated through interaction with potent growth factors and their paracrine and/or cell signaling pathways.