Androgenic progestins amplify the breast cancer risk associated with hormone replacement therapy by boosting IGF-I activity.

Recent epidemiology indicates that unopposed oral estrogen replacement therapy has a surprisingly small impact on breast cancer risk--little if any in overweight women--whereas combined regimens featuring synthetic progestins are attended by a much larger increase in this risk. These findings may reflect the fact that oral estrogen acts on the liver to down-regulate systemic IGF-I activity, whereas concurrent administration of androgens--including the androgenic progestins often used in replacement therapy--abrogates this effect. Increased systemic IGF-I activity has been linked to increased breast cancer risk, and may be largely responsible for the greater incidence of breast cancer in overweight postmenopausal women--who thus should have the most to gain from suppression of IGF-I activity by oral estrogen. Down-regulation of IGF-I may likewise account for the marked reduction in colon cancer risk associated with current estrogen replacement therapy. Fortunately, natural progesterone--now available in micronized oral preparations--does not oppose the hepatic effects of oral estrogen, and moreover may be preferable to androgenic progestins with respect to vascular function. Oral replacement therapy featuring micronized progesterone, if administered throughout postmenopausal life, can be expected to have a highly positive impact on vascular health, bone density, and risks for Alzheimer's disease and colon cancer--benefits which, in most women, may vastly outweigh the associated increase in risk for breast and endometrial cancers.