Rowan T Chlebowski, MD, PhD
Professor of Medicine, David Geffen School of Medicine at UCLA Chief, Division of Medical Oncology and Hematology, Harbor-UCL Medical Center

Edited comments by Dr Chlebowski

Terminology: Hormone replacement therapy versus menopausal hormone therapy

The FDA and the NIH have removed hormone replacement therapy from their lexicon. The preferred term is menopausal hormone therapy or hormone therapy. Menopausal hormone therapy is probably more descriptive, because hormone therapy could include oral contraceptives.

Women's Health Initiative (WHI) trial

The Women's Health Initiative trial randomized 16,608 healthy postmenopausal women to conjugated equine estrogens plus medroxyprogesterone acetate (PremproTM) or placebo.

Overall results

The estrogen/progestin part of the WHI trial was prematurely stopped after 5.2 years of follow-up because the global index, which involved life-threatening conditions, suggested that there was risk associated with estrogen plus progestin. The adverse effects included a 29 percent increase in coronary heart disease and a 26 percent increase in breast cancer. The incidence of stroke and pulmonary embolus was also substantially increased. On the favorable side, colorectal cancer and hip fractures were significantly decreased by menopausal hormone therapy. However overall, there were still 19 more adverse events per 10,000 women per year of use of estrogen/progestin therapy.

Influence of menopausal hormone therapy on breast cancer risk

After a mean follow-up of 5.6 years, 349 cases of invasive breast cancer were detected - 150 in the placebo group and 199 in the estrogen plus progestin group.

In contrast to observational studies suggesting that the tumors in the estrogen plus progestin group would be low grade and easy to treat, we found these tumors to have identical histology and grade, but a more advanced stage. The tumors in the estrogen plus progestin group were larger (mean size of 1.7 versus 1.5 cm, P = 0.04) and more likely to have positive nodes (26 percent versus 16 percent, P = 0.03), which were statistically significant findings.

The cancers that developed in the estrogen plus progestin group included ER-positive and ER-negative cancers. The number of ER-positive and ER-negative cancers increased by the same amount with hormone therapy use. This indicates that estrogen plus progestin can stimulate breast cancer growth.

Influence of menopausal hormone therapy on mammograms

The mammogram results were probably the most surprising finding. After one year of estrogen and progestin use, there was a four percent absolute increase in the frequency of abnormal mammograms. A woman would have a 1-in-25 chance of having an otherwise avoidable abnormal mammogram by taking estrogen and progestin for just one year.

The difference persisted throughout the study, and at the end, the women in the estrogen plus progestin group had a 30 percent chance of having an abnormal mammogram compared to about a 20 percent chance for the women in the placebo group. Previously, it was believed that there were no consequences from one or two years of estrogen plus progestin use. Now, women must consider the 1-in-25 or 1-in-10 chance of having an abnormal mammogram.

The women in the estrogen plus progestin group had more advanced-stage cancers diagnosed, even though they were the same grade, because the abnormal mammograms hindered the diagnosis. For the first three years there were fewer cancers diagnosed in the estrogen plus progestin group than the placebo group, and it looked like the breast cancer incidence decreased. In actuality, it was just harder to find the cancers.

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