Breast Cancer in Postmenopausal Women After Hormone Therapy

To the Editor: The increase in risk for breast cancer incidence and mortality observed in the WHI¹ is specific to the estrogen and progestin formulation used in the study (Prempro; Wyeth Ayerst, Collegeville, Pennsylvania), and therefore conclusions cannot be extrapolated to progesterone, alone or in combination with estrogen. Chemical and biological distinctions exist between synthetic progestin (medroxyprogesterone), a C₂₄ androgenic vasoconstrictor, and endogenous progesterone, a C₂₁ antiandrogenic vasodilator.² Progesterone is the only steroid hormone that has been shown to be free of carcinogenicity in controlled clinical studies.³ Dr Chlebowski and colleagues state that “[r]eproductive hormones, especially progestin, are potent stimulators of angiogenesis.” However, low physiological levels of progesterone inhibit angiogenesis through binding to progesterone receptor A, while higher-dose synthetic progestin stimulates angiogenesis through binding to progesterone receptor B.⁴ Deficits of progesterone are associated with significantly increased medical risk in postmenopausal women.⁵ No prospective study that replaced the deficiency of progesterone, either alone or with estrogen, has been carried out. We believe such a study is critically needed.