Observational and randomized controlled trial data have extensively examined the relationship between menopausal
hormone therapy (
MHT) and risk of developing
breast cancer. A highly influential study from the Women's Health Initiative (WHI) in 2002 reported that a
MHT regimen of
conjugated equine estrogens and
medroxyprogesterone acetate increased the risk of
breast cancer by 26%. Later reports from the WHI indicated that a
MHT regimen with
conjugated equine estrogens alone decreased the risk of
breast cancer by 23%. Critical re-examination of the WHI study noted that the average participant age was 63, that few women had symptoms, and that the WHI results might not apply to younger, symptomatic women shortly after menopause. Since the original publications, several post hoc analyses and observational studies have stimulated reconsideration of the WHI findings. Emphasis has been directed toward risks in younger women just entering the menopause, the subgroup who are most likely to be considering
MHT use. The goal of this treatise is to integrate available mechanistic and clinical information related to the use of
estrogen alone or
estrogen plus a
progestogen for five years or less. These data suggest that
estrogen alone neither decreases nor increases risk in younger women initiating
therapy close to the time of menopause but decreases risk in older women. Both younger and older women experience an excess risk with
estrogen plus a
progestogen. The attributable risk in younger women is less in those with a low underlying Gail Model risk score. Effects of
MHT on risk largely reflect actions on pre-existing, occult, undiagnosed breast
cancers.
Tumor kinetic models suggest that the pro-proliferative effects of
estrogen plus a
progestogen on occult
tumors provide a mechanistic explanation for the increased risk with this
therapy. Pro-apoptotic effects of
estrogen alone may explain the reduction of
breast cancer in women starting this
therapy at an average age of 63 as reported in the WHI study. This article is part of a Special Issue entitled 'Menopause'.