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. 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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    ABSTRACT: Focusing on information behavior in a context where medical evidence is explicitly evolving (management of the menopause transition), this investigation explored how women interact with and make sense of uncertain health information mediated by formal and informal sources. Based on interviews with 28 information seekers and 12 health professionals (HPs), findings demonstrate that participants accessed and valued a wide range of information sources, moved fluidly between formal and informal sources, and trust was strengthened through interaction and referral between sources. Participants were motivated to seek informa-tion to prepare for formal encounters with HPs, evaluate and/or supplement information already gathered, estab-lish that they were "normal," understand and address the physical embodiment of their experiences, and prepare for future information needs. Findings revealed four strategies used to construct sense from health information mediated by the many information sources encountered and accessed on an everyday basis: women assumed analytic and experiential "postures"; they valued social contexts for learning and knowledge construction; information consistency was used as a heuristic representing accuracy and credibility; and an important feature of sense making was source comple-mentarity. Implications for health information literacy and patient education are discussed.
    Journal of the American Society for Information Science 08/2012; 63(8):1553–1566. DOI:10.1002/asi.22691 · 2.01 Impact Factor
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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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    ABSTRACT: Over the past two decades, there has been a significant amount of research investigating the risks and benefits of hormone replacement therapy (HRT) with regards to neurodegenerative disease. Here, we review basic science studies, randomized clinical trials, and epidemiological studies, and discuss the putative neuroprotective effects of HRT in the context of Alzheimer's disease, Parkinson's disease, frontotemporal dementia, and HIV-associated neurocognitive disorder. Findings to date suggest a reduced risk of Alzheimer's disease and improved cognitive functioning of postmenopausal women who use 17β-estradiol. With regards to Parkinson's disease, there is consistent evidence from basic science studies for a neuroprotective effect of 17β-estradiol; however, results of clinical and epidemiological studies are inconclusive at this time, and there is a paucity of research examining the association between HRT and Parkinson's-related neurocognitive impairment. Even less understood are the effects of HRT on risk for frontotemporal dementia and HIV-associated neurocognitive disorder. Limits to the existing research are discussed, along with proposed future directions for the investigation of HRT and neurodegenerative diseases.
    04/2012; 2012:258454. DOI:10.1155/2012/258454
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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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    ABSTRACT: The primary objective of this study was measurement of the systemic bioavailability of DHEA and its metabolites following daily intravaginal application of the sex steroid precursor. Forty postmenopausal women were randomized to receive a daily dose of one ovule of the following DHEA concentrations: 0.0%, 0.5%, 1.0% or 1.8%. After only 7 days of treatment, the maturation value of the vaginal epithelial cells was significantly increased while the vaginal pH was significantly decreased at all DHEA doses. These important local effects were observed while the serum concentrations of estradiol and testosterone remained within the values found in normal postmenopausal women at all DHEA doses. Similar observations were made for serum androstenedione, estrone, estrone-sulfate and DHEA-sulfate. Even at the highest 1.8% DHEA dose, serum DHEA was increased at the levels found in normal premenopausal women. The present data show that the intravaginal administration of DHEA permits to rapidly achieve the local beneficial effects against vaginal atrophy without significant changes in serum estrogens, thus avoiding the increased risk of breast cancer associated with the current intravaginal or systemic estrogenic formulations. In addition, the recent observation that DHEA is transformed into both androgens and estrogens in the vagina permits to exert benefits on all the three layers of the vaginal wall.
    The Journal of Steroid Biochemistry and Molecular Biology 07/2008; 111(3-5):178-94. DOI:10.1016/j.jsbmb.2008.06.003 · 4.05 Impact Factor
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