Progestogen breast cancer

Glucocorticoids have inhibitory (apoptotic) effects on lymphocyte proliferation and are used to treat leukemias and lymphomas. Estrogens (fosfestrol) are used to block the effect of androgens in prostate cancer. Progestogens (megestrol, medroxyprogesteroneacetate) have been useful for treating endometrial carcinoma, renal tumors, and breast cancer. 

The continuous combined oral estrogen-progestogen arm of the Women s Health Initiative (WHI) study was terminated prematurely after a mean of 5.2-year follow-up because of the occurrence of a prespecified level of invasive breast cancer. The study also found increased coronary disease events, stroke, and pulmonary embolism. Beneficial effects included decreases in hip fracture and colorectal cancer. 

A subsequent large epidemiologic study found a greater risk for breast cancer with combined estrogen-progestogen use, as well as increased risk for estrogen-only therapy and tibolone, but selection bias was found in the study population. 

In the WHI study, estrogen plus progestogen therapy had an increased risk for invasive breast cancer, which did not appear until after 3 years of study participation. The estrogen-only arm of the WHI showed no increase in risk for breast cancer during the 7-year follow-up. 

The Million Women Study reported that current use of hormone therapy increased breast cancer risk and breast cancer mortality. Increased incidence was observed for estrogen only, estrogen plus progestogen, and for tibolone. 

In a reanalysis of 51 studies, less than 5 years of therapy with combined estrogen and progestogen was associated with a 15% increase in risk for breast cancer, and the risk increased with greater duration of treatment. Five years after discontinuation of hormone replacement therapy, the risk of breast cancer was no longer increased. 

Addition of progestogen to estrogen may increase breast cancer risk beyond that observed with estrogen alone. 

Megestrol acetate Synthetic progestogen Treatment of endometrial carcinoma and some forms of breast cancer... 

Cohort study following up long-term Slight increase in breast cancer, possibly accentuated by progestogens (SED-12, 1027)... 

Link between HRT and breast cancer uncertain, but Nurse s Health Study suggested a relative risk of 1.36 adding a progestogen reduces the risk (163)... 

What the above amounts to is that the absolute excess risks per 10 000 woman-years attributable to the use of an estrogen plus a progestogen were seven more coronary heart disease events, eight more strokes, eight more pulmonary embolisms, and eight more invasive breast cancers, while the risk reductions per 10 000 woman-years were six fewer colorectal cancers and five fewer hip fractures. The absolute excess risk of events included in the global index was 19 per 10 000 woman-years. The overall harms in this study thus clearly exceeded the benefits. Allcause mortality was not affected. 

In women with an intact uterus a progestogen should be added to reduce the risk of endometrial hyperplasia and possible transformation to cancer. However, the addition of a progestogen should be weighed against the increased risk of breast cancer associated with its use. 

Tibolone has combined estrogenic, progestogenic, and androgenic activity. Its effects depend on metabolism and activation in peripheral tissues. Tibolone has beneficial effects on mood and hbido and improves menopausal symptoms and vaginal atrophy. It protects against bone loss and reduces the risk of vertebral fractures. It reduces total cholesterol, triglyceride, lipoprotein (a), and, unfortunately, high-density lipoprotein concentrations. It may increase cardiovascular risk, breast cancer risk, and endometrial cancer risk. 

As far as hormone replacement therapy is concerned (Table 2) one must provisionally conclude, with the authors of a major Canadian study published in 1992, that long-term past use of estrogens is not related to risk, but that current estrogen use increases the risk of breast cancer to a modest degree, and that the addition of progestogens probably does not remove the increased risk resulting from the use of unopposed estrogen (150). 

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