Individualizing Hormone Therapy to Minimize Risk

Accurate Assessment of Risks and Benefits

Donna Shoupe


Women's Health. 2011;7(4):475-485. 

In This Article

Overall Risks of Estrogen Therapy: Looking at the WHI & other Studies

The original studies published by the WHI study group identified increased risk for a number of diseases that have, in later publications, been substantially changed or clarified. Presentation of the risks as defined by the original WHI data are included in this section. A summary of the risks and benefits of hormone therapy from both the early and later WHI publications is shown in Table 1.

In the original (estrogen plus progestin) WHI study, in the overall study population, women treated with estrogen and progestin had a significant increased risk of blood clots (≥18 per 10,000 women/year) and an increased risk of stroke (≥8 per 10,000/year). Treatment with estrogen plus progestin also resulted in a higher risk of heart disease (≥7 per 10,000/year) and breast cancer (≥8 per 10,000/year) (Table 1).[3,18,19] Combined HRT did not increase endometrial cancer or ovarian cancer risk but did increase the risk of abnormal vaginal bleeding requiring further testing (Table 1).

In the original (estrogen only) WHI study, there was an increased risks of blood clots (+7 per 10,000/year) and stroke (+12 per 10,000/year), no increased risk cardiovascular disease, or ovarian cancer. The use of estrogen only resulted in a lower breast cancer risk (-6 per 10,000/year) that continued to be lower (statistically significant) in a 10-year follow-up study (Table 1).[20]

WHI Substudy

In a separate substudy of the WHI Memory Study (WHIMS) women aged 65 years and older (average age of initiation 71 years of age) reported the combination hormones had a modestly increased risk of developing dementia, compared with those taking placebo (45 per 10,000 vs 22 per 10,000).[21] These findings again clarify the importance of early initiation of therapy and the increased risk (early harm) that can occur when starting hormone therapy in women over 65 years of age.

WHI: Follow-up Studies

In an 11-year follow-up study, the death rate in participants who received estrogen plus progestin for 5 years was 2.6 per 10,000 versus 1.3 per 10,000 per year in the group that took placebo (hazard risk [HR]: 1.96; 95% CI: 1.00–4.04; p = .049). A total of 24 % of the breast cancer patients who took HRT had tumors that spread to the lymph nodes, compared with just 16% of women taking placebos.[22]

Million Women Study

The Million Women Study reported an increased risk of breast cancer in women currently using HRT. Women on current combination hormone therapy were at twofold increased risk of developing breast cancer, and current users of estrogen-only therapy had a 1.3-fold risk. The effects were similar for all doses, patterns of use, delivery methods and types of estrogen and progestogen.[23]

Slovenia Study

In a case–control study carried out in Slovenia, hormone therapy was associated with a reduced risk of breast cancer. A total of 784 cases and 709 controls aged 50–69 years were enrolled in the study. The reduced risk was highest in women on estrogen-only replacement therapy (odds ratio [OR]: 0.51; 95% CI: 0.30–0.87). Longer duration of HRT use did not result in a significant change in risk (1–5 years of HRT use: OR: 0.44; 95% CI: 0.26–0.73; >5 years of HRT use: OR: 0.51; 95% CI: 0.30–0.87). Risk factors for breast cancer identified included obesity, smoking and any first-degree relative with breast or ovarian cancer (Box 3).[24]


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