The pendulum swings from fear to understanding

They reported a significant trend between increasing risk of mortality and increasing mean age of the women using hormone therapy—raising the possibility of a health benefit for younger postmenopausal women.

The studies included in the metaanalysis varied in entry criteria, outcomes assessed, number of subjects, and HT type and dosage. Furthermore, because age groups were defined by mean age in each trial rather than actual age of pooled participants, some overlap in ages likely occurred between the analyses of younger and older women.

In postmenopausal women younger than 60, the total mortality rate was reduced by 39% in women taking estrogen-containing hormone therapy, which was significant; in women older than 60, there was no significant effect on total mortality.

The data were from 30 randomized, controlled clinical trials published between 1966 and 2002, and included 26,708 women taking estrogen (ET) or estrogen plus progestogen (EPT). Data were pooled to determine total mortality and mortality due to specific causes such as cardiovascular disease and cancer. The mean trial duration was 4.5 years, and the mean age was 62.2 years.

When the study population was divided into younger and older age groups based on mean ages, it was found that those younger than 60 (mean age, 53.9) had a significantly reduced OR for total mortality of 0.61 (95% CI, 0.39–0.95) and those older than age 60 (mean age, 64.6) had an OR of 1.03 (95% CI, 0.90–1.18).

For specific causes, the OR for cardiovascular disease mortality associated with ET/EPT was 1.10 (95% CI, 0.90–1.34). For overall cancer mortality, the OR was 1.03 (95% CI, 0.82–1.29) and for breast cancer mortality, the OR was 1.03 (95% CI, 0.29–3.67).

For causes other than cardiovascular disease or cancer, mortality was significantly lower in women on HT: OR 0.67 (95% CI, 0.51–0.88). When divided into younger and older age groups, ET/EPT was not associated with a significant change in mortality, with the exception of reduced mortality from causes other than cardiovascular disease and cancer in the older age group (OR, 0.68; 95% CI, 0.56–0.91).

Does HT improve insulin resistance?

Margolis KL, Bonds DE, Rodabough RJ, et al, for the Women’s Health Initiative Investigators. Effect of oestrogen plus progestin on the incidence of diabetes in postmenopausal women: results from the Women’s Health Initiative Hormone Trial. Diabetologia. 2004;47:1175–1187. LEVEL 1 EVIDENCE: Randomized, controlled trial

Hormone therapy, compared with placebo, was associated with 15 fewer cases of diabetes per 10,000 women per year. Fasting glucose and insulin decreased compared with placebo, and may suggest improved insulin resistance. Although others have reported similar results, it is unlikely that hormone therapy will be prescribed to prevent diabetes, given its greater risk than benefit for other outcomes observed in other WHI analyses.

In the EPT part of WHI, a total of 15,641 postmenopausal women aged 50 to 79 were assigned to placebo or continuous-combined EPT (0.625 mg/day conjugated equine estrogens plus 2.5 mg/day medroxyprogesterone acetate). The incidence of diabetes was based on self-reports of insulin or oral diabetes drug treatment. Fasting glucose, insulin, and lipoproteins were measured at 1 and 3 years. After 5.6 years, the incidence of treated diabetes was 3.5% in the EPT group and 4.2% in the placebo group (hazard ratio, 0.79; 95% CI, 0.67–0.93; P= 0.004). Decreases in fasting glucose and insulin, suggesting decreased insulin resistance, were significant at 1 year in EPT users compared with placebo. The authors concluded that EPT reduces the incidence of diabetes possibly through a decrease in insulin resistance.

To be sure that a drug prevents a disease, everyone with the disease should be excluded at baseline, and at the end of the trial, everyone should be tested for the disease—if it is commonly undiagnosed. To study the incidence of new diabetes, all women (6%) with self-reported diabetes at baseline were excluded, and correctly so. But half of US adults with diabetes are undiagnosed. The WHI 6% prevalence is half of the assumed 12% prevalence in older overweight women. In the WHI, average age was 63 years and average body mass index was 28. Thus, it is not certain that the reduced risk occurred in women who were diabetes-free at baseline.