Failure of estrogen plus progestin therapy for prevention.

PPROXIMATELY 38% OF POSTMENOPAUSAL WOMEN in the United States use hormone replacement therapy. 1 In 2000, 46 million prescriptions were written for Premarin (conjugated estrogens), making it the second most frequently prescribed medication in the United States and accounting for more than $1 billion in sales, and 22.3 million prescriptions were written for Prempro (conjugated estrogens plus medroxyprogesterone acetate). 2 While US Food and Drug Administration– approved indications for hormone therapy include relief of menopausal symptoms and prevention of osteoporosis, longterm use has been in vogue to prevent a range of chronic conditions, especially heart disease. Estrogen alone was the dominant hormone until the increased risk of endometrial cancer led to the addition of progestins for women with an intact uterus. Since the mid-1980s, combined estrogen/ progestin use has steadily increased. 3 Evidence on the potential risks and benefits of combined estrogen/progestin has slowly accumulated, suggesting that the combination acts differently than estrogen alone. Several studies found a link between duration of estrogen/ progestin use and breast cancer risk. 4-8 Addition of progestins may increase risk above that observed with estrogen alone, as mitotic activity in the breast during normal menstrual cycles is greatest when progesterone levels are highest. 9 Early evidence from studies of unopposed estrogen suggested it lowered risk of cardiovascular disease, consistent with results from studies of intermediate markers that showed beneficial changes. 10 However, recent evidence from secondary prevention trials and observational studies using combined estrogen/progestin therapy showed increased risk of coronary heart disease in the first year. 11-13 This may reflect prothrombotic and proinflammatory effects of progestins that outweigh any effects of estrogens on atherogenesis and vasodilatation. Now, the surprising results of the Women’s Health Initiative (WHI) are reported in this issue of THE JOURNAL. 14 The WHI is the first randomized primary prevention trial of postmenopausal hormones, and the part of the study that compared estrogen/progestin with placebo was terminated early. The data and safety monitoring board (DSMB) recommended stopping the trial because women receiving the active drug had an increased risk of invasive breast cancer (hazard ratio [HR], 1.26; 95% confidence interval [CI], 1.001.59), and an overall measure suggested that the treatment was causing more harm than good (global index, 1.15; 95% CI, 1.03-1.28). The decision to stop the trial after an average follow-up of 5.2 years (planned duration, 8.5 years) was made when these results met predetermined levels of harm. However, several other outcomes also suggested harm, including increased coronary heart disease (HR, 1.29; 95% CI, 1.02-1.63), stroke (HR, 1.41; 95% CI, 1.07-1.85), and pulmonary embolism (HR, 2.13; 95% CI, 1.39-3.25). Beneficial results included decreases in colorectal cancer (HR, 0.63, 95% CI, 0.43-0.92) and hip fracture (HR, 0.66; 95% CI, 0.45-0.98). Numbers of overall deaths in the estrogen/