American Association of Clinical Endocrinologists Medical Guidelines for Clinical Practice for the Diagnosis and Treatment of Menopause

AACE Menopause Guidelines Revision Task Force


Endocr Pract. 2006;12(3):315-337. 

In This Article

Review of the WHI

In the discussion in this section, reference will be made to the WHI study[13] (LOE 1), a planned 8.5-year randomized controlled primary prevention trial that enrolled postmenopausal women who were 50 to 79 years old. It involved the following study groups:

  1. The E+P arm consisting of 16,608 women with an intact uterus, who received a daily tablet of conjugated equine estrogen (CEE) (0.625 mg) with MPA (2.5 mg) (N = 8,506) or placebo (N = 8,102)

  2. The estrogen-only arm consisting of 10,379 women who had undergone hysterectomy, who received CEE (0.625 mg) or placebo alone

The primary outcome was CAD (nonfatal MI and CAD-related death), and the primary anticipated adverse outcome was invasive breast cancer. The E+P arm of the WHI trial was terminated near the end of the 5th year because of an apparent increase in the risk of breast cancer and an apparent adverse global index. The factors included in the global index, in addition to an increased risk of breast cancer, were CAD, stroke, and pulmonary embolism. An analysis by the WHI writing group of the complete 5-year period revealed that the increase in breast cancer was not statistically significant and the apparent increase in the cardiovascular hazard risk in year 5 had occurred because of a transient decline in the rates of CAD events in the placebo group, rather than an increase in the estrogen-progestin group.[14] An unequivocal increased risk of VTE was noted in the treated group, which confirms the findings in previous studies of early post-menopausal HT use.

With respect to insights in the management of the menopause and associated symptoms, the major criticism of the results of the WHI trial is the age of the population of postmenopausal women who participated in the study. The mean age at enrollment in the WHI study was 63.3 years. These women were more than a decade older than the age at which most women begin HT. Only 10% of study participants were 50 to 54 years old, and only 16% of the women were less than 5 years after the onset of menopause. Of women randomly assigned in the WHI study, 36% had hypertension, 49% were current or past smokers, and 34% had a body mass index >30 kg/m2. Therefore, the demographics of the WHI population were older postmenopausal women who had significantly increased risk factors for cardiovascular disease. In addition, these women did not have severe postmenopausal symptoms.

The results of the WHI study cannot be generalized to a population of women in early menopause because the WHI was designed to evaluate HT in an older population of aging postmenopausal women.


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