Differential effects of various progestogens on metabolic risk factors for breast cancer

Biological and epidemiological findings suggest that metabolic factors - insulin, insulin-like growth factor-I (IGF-I) and sex hormone-binding globulin (SHBG) - are involved in the development and promotion of breast cancer. Estrogens, particularly if administered orally, counteract metabolic factors that increase breast cancer risk, i.e. they reduce insulin and IGF-I and increase SHBG. This could contribute toward explaining epidemiological data showing that unopposed oral estrogens do not increase breast cancer risk, or do so only modestly. In contrast to natural progesterone and progesterone-derived progestins, progestins endowed with androgenic (or glucocorticoid) activity negatively influence these metabolic factors, counteracting the favorable effects of estrogens. While most biological and epidemiological findings suggest that natural progesterone does not augment breast cancer risk, available data show an increased risk with synthetic progestins - with the possible exception of progesterone-derived dydrogesterone. Different mechanisms for different progestins could possibly be involved. Differences from progesterone with regard to pharmacokinetics and pharmacodynamics, potency, interaction with the two isoforms of the progesterone receptor, and binding to other steroid receptors could all be relevant. These remain theoretical speculations for the time being, but the possibility that some progestins increase breast cancer risk through their negative influence on metabolic factors cannot be rejected.