Article

Health risks and benefits 3 years after stopping randomized treatment with estrogen and progestin

University of North Carolina, School of Public Health, Department of Epidemiology, Chapel Hill, NC 27514-3628, USA.
JAMA The Journal of the American Medical Association (Impact Factor: 30.39). 04/2008; 299(9):1036-45. DOI: 10.1001/jama.299.9.1036
Source: PubMed

ABSTRACT The Women's Health Initiative (WHI) trial of estrogen plus progestin vs placebo was stopped early, after a mean 5.6 years of follow-up, because the overall health risks of hormone therapy exceeded its benefits.
To report health outcomes at 3 years (mean 2.4 years of follow-up) after the intervention was stopped.
The intervention phase was a double-blind, placebo-controlled, randomized trial of conjugated equine estrogens (CEE) 0.625 mg daily plus medroxyprogesterone acetate (MPA) 2.5 mg daily, in 16,608 women aged 50 through 79 years, recruited by 40 centers from 1993 to 1998. The postintervention phase commenced July 8, 2002, and included 15 730 women.
Semi-annual monitoring and outcomes ascertainment continued per trial protocol. The primary end points were coronary heart disease and invasive breast cancer. A global index summarizing the balance of risks and benefits included the 2 primary end points plus stroke, pulmonary embolism, endometrial cancer, colorectal cancer, hip fracture, and death due to other causes.
The risk of cardiovascular events after the intervention was comparable by initial randomized assignments, 1.97% (annualized rate) in the CEE plus MPA (343 events) and 1.91% in the placebo group (323 events). A greater risk of malignancies occurred in the CEE plus MPA than in the placebo group (1.56% [n = 281] vs 1.26% [n = 218]; hazard ratio [HR], 1.24; 95% confidence interval [CI], 1.04-1.48). More breast cancers were diagnosed in women who had been randomly assigned to receive CEE plus MPA vs placebo (0.42% [n = 79] vs 0.33% [n = 60]; HR, 1.27; 95% CI, 0.91-1.78) with a modest trend toward a lower HR during the follow-up after the intervention. All-cause mortality was somewhat higher in the CEE plus MPA than in the placebo group (1.20% [n = 233] vs 1.06% [n = 196]; HR, 1.15; 95% CI, 0.95-1.39). The global index of risks and benefits was unchanged from randomization through March 31, 2005 (HR, 1.12; 95% CI, 1.03-1.21), indicating that the risks of CEE plus MPA exceed the benefits for chronic disease prevention.
The increased cardiovascular risks in the women assigned to CEE plus MPA during the intervention period were not observed after the intervention. A greater risk of fatal and nonfatal malignancies occurred after the intervention in the CEE plus MPA group and the global risk index was 12% higher in women randomly assigned to receive CEE plus MPA compared with placebo.
clinicaltrials.gov Identifier: NCT00000611.

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    • "Not only were standards of practice related to menopause management unexpectedly and dramatically rendered outdated by the WHI, but also uncertainty about translating these new findings into practice persists (Holloway, 2010; Wathen, 2006a). Furthermore, although practice guidelines suggest that HT for menopausal symptom relief is safe for up to five years (Pines, 2009), reputable sources contest the safety of these guidelines (Heiss et al., 2008; National Institutes of Health, 2008). Ongoing confusion about managing this life transition has resulted in the view that HPs are not meeting women's needs for information and guidance (Ma, Drieling, & Stafford, 2006) and women are turning to other information sources, including the media and the Internet (Archer, 2007). "
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    • "In fact, it is claimed that combined HRT with estrogen plus progestin is a cause for breast cancer. However, while followup analysis approximately three years after termination of the WHI study demonstrated an increased risk for " all-cause cancer " for participants in the CEE + MPA trial compared to the placebo group [158], the risk for breast cancer and other types of cancer did not differ between groups. Similarly, recent retrospective analyses of the WHI data found insufficient evidence that estrogen plus progestin increased risk of breast cancer [159]. "
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    • "Since serum DHEA is the predominant source of androgens in women, the 60% decrease in circulating DHEA leads to a similar 60% decrease in the total androgen pool in women by time of menopause [18]. Although intravaginal estrogen formulations were developed to avoid systemic exposure to estrogens, a series of studies have clearly demonstrated that such preparations intended for exclusive local action lead to relatively high serum estrogen levels [19] [20] [21] [22] clearly indicating that their use is an issue related to an increased risk of breast and possibly also uterine cancer [23] [24] [25] [26] [27]. It is well known that atrophic vaginitis in postmenopausal women can be worsened or induced by the use of aromatase inhibitors for the treatment of breast cancer. "
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