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: 35.29). 04/2008; 299(9):1036-45. DOI: 10.1001/jama.299.9.1036
Source: PubMed


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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    • "Experiments in PR knock-out mice demonstrated that progestins promote mammary tumor progression and growth [2], [5], [6]. Two large clinical studies in women [7], [8] have also provided supporting evidence for a tumorigenic role of progesterone in the mammary tissue. In vitro studies have confirmed that progestin treatment affects important cellular programs, such as proliferation, apoptosis and differentiation [3], [9], all of which have the potential to lead to a malignant phenotype when deregulated. "
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    ABSTRACT: Despite the pleiotropic effects of the progesterone receptor in breast cancer, the molecular mechanisms in play remain largely unknown. To gain a global view of the PR-orchestrated networks, we used next-generation sequencing to determine the progestin-regulated transcriptome in T47D breast cancer cells. We identify a large number of PR target genes involved in critical cellular programs, such as regulation of transcription, apoptosis, cell motion and angiogenesis. Integration of the transcriptomic data with the PR-binding profiling of hormonally treated cells identifies numerous components of the small-GTPases signaling pathways as direct PR targets. Progestin-induced deregulation of the small GTPases may contribute to the PR's role in mammary tumorigenesis. Transcript expression analysis reveals significant expression changes of specific transcript variants in response to the extracellular hormonal stimulus. Using the NET1 gene as an example, we show that the PR can dictate alternative promoter usage leading to the upregulation of an isoform that may play a role in metastatic breast cancer. Future studies should aim to characterize these selectively regulated variants and evaluate their clinical utility in prognosis and targeted therapy of hormonally responsive breast tumors.
    PLoS ONE 06/2014; 9(6):e98404. DOI:10.1371/journal.pone.0098404 · 3.23 Impact Factor
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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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    • "Forty-six trials adjusted for treatment protocol deviations by carrying out analysis based on PP analysis (total not shown in Table 4), by censoring or excluding participants who had violated the treatment protocol in some way, but half of these analyses were labelled as ITT or modified ITT analyses. Only one trial [35] aimed to address the bias introduced from potentially informative censoring of patients at the point of deviation from treatment protocol, by weighting their censoring by the inverse of their estimated probability of adhering, as advocated by Robins and Finkelstein [36]. Other analysis methods that dealt with departures from randomised treatment included treating discontinuation of treatment (or starting disallowed or rescue medication) as a treatment failure in analysis (three trials), AT analyses (analysing participants according to the actual treatment received regardless of randomisation allocation) (three trials) and analysing outcomes concerned with time to discontinuation of trial drug (four trials). "
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    ABSTRACT: This review aimed to ascertain the extent to which nonadherence to treatment protocol is reported and addressed in a cohort of published analyses of randomised controlled trials (RCTs). One hundred publications of RCTs, randomly selected from those published in BMJ, New England Journal of Medicine, the Journal of the American Medical Association and The Lancet during 2008, were reviewed to determine the extent and nature of reported nonadherence to treatment protocol, and whether statistical methods were used to examine the effect of such nonadherence on both benefit and harms analyses. We also assessed the quality of trial reporting of treatment protocol nonadherence and the quality of reporting of the statistical analysis methods used to investigate such nonadherence. Nonadherence to treatment protocol was reported in 98 of the 100 trials, but reporting on such nonadherence was often vague or incomplete. Forty-two publications did not state how many participants started their randomised treatment. Reporting of treatment initiation and completeness was judged to be inadequate in 64% of trials with short-term interventions and 89% of trials with long-term interventions. More than half (51) of the 98 trials with treatment protocol nonadherence implemented some statistical method to address this issue, most commonly based on per protocol analysis (46) but often labelled as intention to treat (ITT) or modified ITT (23 analyses in 22 trials). The composition of analysis sets for their benefit outcomes were not explained in 57% of trials, and 62% of trials that presented harms analyses did not define harms analysis populations. The majority of defined harms analysis populations (18 out of 26 trials, 69%) were based on actual treatment received, while the majority of trials with undefined harms analysis populations (31 out of 43 trials, 72%) appeared to analyse harms using the ITT approach. Adherence to randomised intervention is poorly considered in the reporting and analysis of published RCTs. The majority of trials are subject to various forms of nonadherence to treatment protocol, and though trialists deal with this nonadherence using a variety of statistical methods and analysis populations, they rarely consider the potential for bias introduced. There is a need for increased awareness of more appropriate causal methods to adjust for departures from treatment protocol, as well as guidance on the appropriate analysis population to use for harms outcomes in the presence of such nonadherence.
    Trials 06/2012; 13(1):84. DOI:10.1186/1745-6215-13-84 · 1.73 Impact Factor
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