The relevance of the Women's Health Initiative results on combined hormone replacement therapy in clinical practice.

The results of the Women's Health Initiative's (WHI) large prospective randomized controlled study on the benefits and risks of combined hormone replacement therapy (HRT) have been reported earlier than expected, due to the findings of a small excess in cases of breast cancer, myocardial infarction, cerebrovascular accident, and venous thrombosis, in conjunction with a slight diminution of the number of cases of bone fracture and colon cancer. These results were obtained in a population of women with a mean age of 63 +/- 7 years, many of whom were already presenting relative risks of diseases at randomization. The results provide the best evidence available at present on HRT for prevention of heart disease, and indicate that combined HRT is not indicated for this purpose in the studied population, thus contradicting the reported beneficial effects of HRT on coronary heart disease (CHD) in previous observational studies. Some comments need to be made, particularly with regard to the relevance of the WHI study results to the traditional use of HRT at the beginning of menopause. The results, obtained from a population having a wide age range (50 to 79 years), with only 33% being between the ages of 50 and 59, taking 0.625 mg/day conjugated equine estrogens combined with 2.5 mg/day medroxyprogesterone acetate or placebo, are presented without stratification according to the various decades. Further, 73.9% of the women never took HRT before entering the study; rather, they began HRT several years after menopause. Thus, the age distribution and late start of HRT in the women in the WHI study do not correspond to the traditional use of HRT. The studied population presented numerous risks of diseases related to aging, in particular cardiovascular disease. Except for venous thrombosis, the confidence intervals for outcomes are near the limit of statistical significance, which disappears after adjustment. The accrual of breast cancer cases appearing during the fourth year of observation is similar to that found in previous studies, and remains inferior to the increases related to lifestyle factors reported in other studies. The overall results are being applied to women aged 50 to 60 without specific data for this age group, who are usually considered to be at no or low risk for the traditional use of HRT. There are no data to compare the various formulations actually approved as class labelling (estrogens or estradiol associated or not with a progestin or natural progesterone by the oral or transdermal route) in the various outcomes of the WHI study. Results of the ongoing WHI study on estrogen alone will have to be considered when they become available. The results of the WHI study do not put into question the validity of prescribing combined HRT in early menopause. They are likely to modify somewhat the recommendations of published consensus cautioning the use of HRT. HRT remains an effective and safe intervention when it is prescribed to palliate the signs and symptoms related to estrogen deficiency, mainly in women soon after menopause, but also in women presenting risk factors for osteoporosis but without actual risk factors of cardiovascular disease and without a family history of breast cancer. New mid-term and long-term randomized studies need to be conducted on women starting various formulations of HRT before the age of 60, to evaluate their impact on risk factors and events of cardiovascular disease.