Postmenopausal Hormone Therapy Trial Research Articles

Estrogen Replacement in Young Hypogonadal Women-Transferrable Lessons From the Literature Related to the Care of Young Women With Premature Ovarian Failure and Transgender Women.

Nearly two decades have passed since the release of Women's Health Initiative (WHI) postmenopausal hormone therapy trial findings, yet the medical community, and general public remain unsettled by ongoing debate over the benefits and safety of sex hormone replacement therapy (HRT). Among the contentious issues is the elevated risk of venous thromboembolism (VTE) and stroke observed in HRT users (1). While major guidelines rightly recommend the use of transdermal estradiol in women with risk factors, little attention has been given to the potential impact of the type of estrogen molecule. This review aims to highlight the importance of selecting appropriate estrogen therapy to enhance safety.

Prevalence and risk factors of urinary incontinence among Estonian postmenopausal women

AimsTo estimate the prevalence of urinary incontinence (UI) and to assess its risk factors among postmenopausal Estonian women.MethodsIn 2004, 1363 women participating in the Estonian Postmenopausal Hormone Therapy Trial were asked at the closure visit to the trial physician about symptoms of UI. The type of incontinence was assessed with the help of a questionnaire, based on recommendations from the working group set up by the Finnish Gynaecological Association. Frequency characteristics were analysed by descriptive statistics. Risk factors were examined using logistic regression.ResultsMean age of study women was 53.3 years (min = 48, max = 67; SD 4.0). The prevalence of UI was 18.12% (95% CI: 16.07 - 20.17). Stress incontinence was diagnosed in 78.83% (95% CI: 73.32 - 84.33) and urge or mixed incontinence in 21.17% (95% CI: 15.67 - 26.68) of women who reported incontinence. Prevalence of UI slightly increased with age. Women who used hormone therapy (HT) (OR 1.67; 95% CI: 1.17 - 2.39), had had hysterectomy (1.73, 95% CI: 1.06 - 2.83), and those with secondary education (OR 1.87, 95% CI: 1.23 - 2.82) or basic education (OR 3.29, 95% CI: 1.80 - 6.02) had a higher risk for UI. Parity, having a BMI over 30 kg/m2, being a smoker or a former smoker, having diabetes and being physically or sexually active, tended to increase the risk of UI.ConclusionsAbout one in five postmenopausal women in Estonia reported to have UI. Risk factors linked with UI, its prevalence in other age groups and the impact of UI on quality of life deserve more research.Trial registrationNumber: ISRCTN35338757

Variability of bothersome menopausal symptoms over time – a longitudinal analysis using the Estonian postmenopausal hormone therapy trial (EPHT)

BackgroundVery little data are available on the natural course or level of disturbance of vasomotor symptoms among middle-aged women. Using readily collected trial data we studied the persistence of vasomotor symptoms among untreated women.MethodsIn a trial comparing combined hormone therapy to placebo or no treatment (control groups), a cohort of women aged 50–59 at recruitment were followed annually by questionnaires. Women in the control groups (n = 486) were grouped by the number of years followed, with the prevalence and severity of symptoms calculated both cross-sectionally and longitudinally.ResultsAbout two thirds of the women (67%) reported vasomotor symptoms and half (46%) bothersome symptoms at recruitment. In the cross-sectional analysis, their prevalence declined between recruitment and 1-year follow-up (32% bothersome symptoms) and 2-year follow-up (27%). Thereafter it remained about the same level. In the longitudinal analysis, there was a notable variation in the prevalence of disturbing vasomotor symptoms over time, time entering the study and the compliance to the surveys. In the two groups having most follow-up times, the proportion of women with bothersome symptoms first increased and then decreased.ConclusionsThere was a notable variability in the development of disturbing vasomotor symptoms over time in a selected group of women aged 50–59. Population-based follow-up studies of untreated women would be useful to estimate the symptom burden.

The effect of hormone therapy on women's quality of life in the first year of the Estonian Postmenopausal Hormone Therapy trial

BackgroundFor postmenopausal women, the main reason to start hormone therapy (HT) is to reduce menopausal symptoms and to improve quality of life (QOL). The aim of this study was to analyse the impact of HT on different aspects of symptom experience and QOL during a randomised trial.A total of 1823 postmenopausal women were recruited into the Estonian Postmenopausal Hormone Therapy (EPHT) trial in 1999–2001. Women were randomised to blind HT, open-label HT, placebo or non-treatment arm. After one year in the trial, a questionnaire was mailed and 1359 women (75%) responded, 686 in the HT arms and 673 in the non-HT arms. Mean age at filling in the questionnaire was 59.8 years. The questionnaire included Women's Health Questionnaire (WHQ) to assess menopause specific QOL of middle-aged women together with a 17-item questionnaire on symptoms related to menopause, a question about painful intercourse, and a question about women's self-rated health.ResultsAfter one year in the trial, fewer women in the HT arms reported hot flashes, trouble sleeping, and sweating on the symptom questionnaire. According to WHQ, women in the HT arms had fewer vasomotor symptoms, sleep problems, and problems with sexual behaviour, but more menstrual symptoms; HT had no effect on depression, somatic symptoms, memory, attractiveness, or anxiety. A smaller proportion of women reported painful intercourse in the HT arms. There were no significant differences between the trial arms in women’s self-rated subjective health.ConclusionsThe results from the EPHT trial confirm that HT is not justified for treating symptoms, other than vasomotor symptoms, among postmenopausal women. WHQ proved to be a useful and sensitive tool to assess QOL in this age group of women.

Tissue Factor Pathway Inhibitor, Activated Protein C Resistance, and Risk of Ischemic Stroke due to Postmenopausal Hormone Therapy

To test whether changes in plasma tissue factor pathway inhibitor (TFPI) levels or activated protein C resistance (normalized activated protein C resistance ratio [nAPCsr]) modify the increased risk of ischemic stroke due to postmenopausal hormone therapy. Nested case-control study of 455 cases of ischemic stroke and 565 matched control subjects in the Women's Health Initiative trials of postmenopausal hormone therapy. Baseline free TFPI was associated with ischemic stroke risk (OR per SD increase, 1.17; 95% CI, 1.01-1.37; P=0.039), but baseline nAPCsr was not (OR per SD increase, 0.89; 95% CI, 0.75-1.05; P=0.15). Baseline TFPI levels and nAPCsr did not modify the effect of postmenopausal hormone therapy on ischemic stroke. Treatment-induced mean changes of -28% in free TFPI and +65% in nAPCsr did not change the risk of ischemic stroke (interaction P=0.452 and 0.971, respectively). In subgroup analyses, baseline nAPCsr was inversely associated with lacunar strokes (OR per SD increase, 0.74; 95% CI, 0.57-0.96; P=0.025) and baseline free TFPI interacted with treatment to increase large vessel atherosclerotic strokes (P=0.008). Procoagulant changes in TFPI or nAPCsr do not modify the increased ischemic stroke risk due to postmenopausal hormone therapy. Clinical Trial Registration- URL: www.clinicaltrials.gov. Unique identifier: NCT 00000611.

Invited Commentary on Pearl and Principal Stratification

Pearl (2011) posed the question of whether confinement of clinical trial analyses involving post-randomization variables to the principal stratum "framework" of Frangakis and Rubin (2002) unduly restricts the scientific questions that can be asked. Frangakis and Rubin illustrated their proposal through examples involving compliance, mediation, and surrogacy. Here the utility of the principal stratum framework, and the potential outcomes formulation from which it derives, are considered for these topics in the specific setting of the Women's Health Initiative randomized, placebo controlled trials of postmenopausal hormone therapy. It is argued that the essential issues related to study reliability and causal interpretation involve the avoidance of context-specific biases that are typically not closely related to whether or not treatment effects have a representation in terms of potential outcomes contrasts. Also, while the questions posed within principal strata may be of interest, some key questions in the hormone therapy setting would not be addressed if restricted to contrasts within principal strata.

Estrogen Receptor Polymorphisms and the Vascular Effects of Hormone Therapy

To test whether estrogen receptor polymorphisms modify the effects of postmenopausal hormone therapy on biomarkers and on risk of coronary heart disease events, stroke, or venous thromboembolism. The design was a nested case-control study in the Women's Health Initiative trials of postmenopausal hormone therapy. The study included all cases in the first 4 years: 359 cases of coronary heart disease, 248 of stroke, and 217 of venous thromboembolism. Six estrogen receptor-α polymorphisms and 1 estrogen receptor-β polymorphism were genotyped; 8 biomarkers known to be affected by hormone therapy were measured at baseline and 1 year after randomization. The polymorphisms were not associated with risk of vascular events and did not modify the increased risks of coronary heart disease, stroke, or venous thromboembolism due to hormone therapy. However, a reduced response of plasmin-antiplasmin to hormone therapy was noted for estrogen receptor-1 IVS1 (intron number 1)-354 (interaction P<0.0001, corrected for multiple comparisons P=0.014) and estrogen receptor-1 IVS1-1415 (interaction P<0.0001, corrected P=0.014). Estrogen receptor polymorphisms reduce the effect of postmenopausal hormone therapy on plasmin-antiplasmin, a marker of coagulation and fibrinolysis. However, screening for estrogen receptor polymorphisms to identify women at less risk of adverse cardiovascular outcomes is not likely to be useful in making decisions about hormone therapy treatment.

Hot flushes and quality of life during menopause

Menopausal health is important since this stage of life is not to be avoided. A recent article in BMC Women's Health from the Estonian Postmenopausal Hormone Therapy trial has concluded that quality of life is not related to hormonal therapy use. The commentary article discusses this finding and considers other factors related to symptoms and quality of life during menopause. Important factors known to affect hot flushes and quality of life are smoking and high body weight. Since both these factors are modifiable, menopause is a suitable area for health promotion. However, evidence concerning lifestyle changes in symptom relief or increase of quality of life is weak. More trials in this area are needed before women may consider non-pharmacological treatment of symptoms as a reliable option for menopausal symptom cure.

Postmenopausal estrogen and progestin effects on the serum proteome

BackgroundWomen's Health Initiative randomized trials of postmenopausal hormone therapy reported intervention effects on several clinical outcomes, with some important differences between estrogen alone and estrogen plus progestin. The biologic mechanisms underlying these effects, and these differences, have yet to be fully elucidated.MethodsBaseline serum samples were compared with samples drawn 1 year later for 50 women assigned to active hormone therapy in both the estrogen-plus-progestin and estrogen-alone randomized trials, by applying an in-depth proteomic discovery platform to serum pools from 10 women per pool.ResultsIn total, 378 proteins were quantified in two or more of the 10 pooled serum comparisons, by using strict identification criteria. Of these, 169 (44.7%) showed evidence (nominal P < 0.05) of change in concentration between baseline and 1 year for one or both of estrogen-plus-progestin and estrogen-alone groups. Quantitative changes were highly correlated between the two hormone-therapy preparations. A total of 98 proteins had false discovery rates < 0.05 for change with estrogen plus progestin, compared with 94 for estrogen alone. Of these, 84 had false discovery rates <0.05 for both preparations. The observed changes included multiple proteins relevant to coagulation, inflammation, immune response, metabolism, cell adhesion, growth factors, and osteogenesis. Evidence of differential changes also was noted between the hormone preparations, with the strongest evidence in growth factor and inflammation pathways.ConclusionsSerum proteomic analyses yielded a large number of proteins similarly affected by estrogen plus progestin and by estrogen alone and identified some proteins and pathways that appear to be differentially affected between the two hormone preparations; this may explain their distinct clinical effects.

Inflammatory, Lipid, Thrombotic, and Genetic Markers of Coronary Heart Disease Risk in the Women's Health Initiative Trials of Hormone Therapy

Clinical trials of postmenopausal hormone therapy (HT) have shown increased risk of coronary heart disease (CHD) in the first few years after initiation of therapy and no overall benefit. This nested case-control study evaluates a range of inflammatory, lipid, thrombotic, and genetic markers for their association with CHD in the 4 years after randomization and assesses whether any of these markers modified or mediated the initially increased risk associated with HT in postmenopausal women aged 50 to 79 years at baseline. Conjugated equine estrogens, 0.625 mg/d, or placebo was given to 10 739 hysterectomized women, and the same estrogen plus medroxyprogesterone acetate, 2.5 mg/d, was given to 16 608 women with an intact uterus. In multivariate-adjusted analyses of 359 cases and 820 controls in the combined trials, baseline levels of 12 of the 23 biomarkers studied were associated with CHD events: interleukin 6, matrix metalloproteinase 9, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, total cholesterol, triglycerides, D-dimer, factor VIII, von Willebrand factor, leukocyte count, homocysteine, and fasting insulin. Biomarkers tended to be more strongly associated with CHD in the initial 2 years after randomization. The genetic polymorphism glycoprotein IIIa leu33pro was significantly associated with CHD. Baseline low-density lipoprotein cholesterol interacted significantly with HT so that women with higher levels were at higher risk for CHD when given HT (P = .03 for interaction). The levels of several biomarkers were changed by HT, but these changes did not seem to be associated with future CHD events. Several thrombotic, inflammatory, and lipid biomarkers were associated with CHD events in postmenopausal women, but only low-density lipoprotein cholesterol modified the effect of HT. Further research is needed to identify the mechanisms by which HT increases the risk of CHD. clinicaltrials.gov Identifier: NCT00000611.

Reassessing Benefits and Risks of Hormone Therapy

Recent randomized clinical trials of postmenopausal hormone therapy have informed clinical decision making and provided insights that help identify appropriate candidates for treatment. A decline in the use of hormone therapy began precipitously in 2002 with publication of data from the Women's Health Initiative. This review examines the scientific literature surrounding this major change in practice and comments on the equilibrating process now taking place. Notably, the incidence of most of the medical conditions adversely affected by hormone therapy increases with age. As a result, recently menopausal women—those most interested in using hormone therapy—are at lower absolute risk of adverse events than older women. A critical mass of data now suggests that age and time since menopause may also modify relative risks of selected outcomes with use of hormone therapy, but this warrants further study. Duration of hormone therapy use also appears to influence risk, with the occurrence of certain outcomes (such as venous thrombosis) being highest in the first 1 or 2 years of hormone therapy use and others (such as breast cancer) increasing with longer duration of hormone therapy use. The conflicting results for some outcomes from the estrogen arm and the estrogen-progestin arm of the Women's Health Initiative suggest that progestins influence risk of several diseases, particularly breast cancer. Quantifying the benefits and risks of estrogen and estrogen-progestin by age group makes it possible to discuss pros and cons of hormone therapy in a more clinically relevant manner with patients. Hormone therapy remains a viable short-term option for the management of moderate to severe vasomotor symptoms in recently menopausal women who are in generally good health. However, due to known risks, it should not be initiated or continued for the express purpose of preventing cardiovascular disease or other chronic diseases.

Experiences of a long-term randomized controlled prevention trial in a maiden environment: Estonian Postmenopausal Hormone Therapy trial

BackgroundPreventive drugs require long-term trials to show their effectiveness or harms and often a lot of changes occur during post-marketing studies. The purpose of this article is to describe the research process in a long-term randomized controlled trial and discuss the impact and consequences of changes in the research environment.MethodsThe Estonian Postmenopausal Hormone Therapy trial (EPHT), originally planned to continue for five years, was planned in co-operation with the Women's International Study of Long-Duration Oestrogen after Menopause (WISDOM) in the UK. In addition to health outcomes, EPHT was specifically designed to study the impact of postmenopausal hormone therapy (HT) on health services utilization.ResultsAfter EPHT recruited in 1999–2001 the Women's Health Initiative (WHI) in the USA decided to stop the estrogen-progestin trial after a mean of 5.2 years in July 2002 because of increased risk of breast cancer and later in 2004 the estrogen-only trial because HT increased the risk of stroke, decreased the risk of hip fracture, and did not affect coronary heart disease incidence. WISDOM was halted in autumn 2002. These decisions had a major influence on EPHT.ConclusionChanges in Estonian society challenged EPHT to find a balance between the needs of achieving responses to the trial aims with a limited budget and simultaneously maintaining the safety of trial participants. Flexibility was the main key for success. Rapid changes are not limited only to transiting societies but are true also in developed countries and the risk must be included in planning all long-term trials.The role of ethical and data monitoring committees in situations with emerging new data from other studies needs specification. Longer funding for preventive trials and more flexibility in budgeting are mandatory. Who should prove the effectiveness of an (old) drug for a new preventive indication? In preventive drug trials companies may donate drugs but they take a financial risk, especially with licensed drugs. Public funding is crucial to avoid commercial biases. Legislation to share the costs of large post-marketing trials as well as regulation of manufacturer's participation is needed. [ISRCTN35338757]

Symptom reporting and quality of life in the Estonian Postmenopausal Hormone Therapy Trial.

BackgroundThe aim of the study was to determine the effect of postmenopausal hormone therapy on women's symptom reporting and quality of life in a randomized trial.Methods1823 women participated in the Estonian Postmenopausal Hormone Therapy (EPHT) Trial between 1999 and 2004. Women were randomized to open-label continuous combined hormone therapy or no treatment, or to blind hormone therapy or placebo. The average follow-up period was 3.6 years. Prevalence of symptoms and quality of life according to EQ-5D were assessed by annually mailed questionnaires.ResultsIn the hormone therapy arms, less women reported hot flushes (OR 0.20; 95% CI: 0.14–0.28), sweating (OR 0.56; 95% CI: 0.44–0.72), and sleeping problems (OR 0.66; 95% CI: 0.52–0.84), but more women reported episodes of vaginal bleeding (OR 19.65; 95% CI: 12.15–31.79). There was no difference between the trial arms in the prevalence of other symptoms over time. Quality of life did not depend on hormone therapy use.ConclusionPostmenopausal hormone therapy decreased vasomotor symptoms and sleeping problems, but increased episodes of vaginal bleeding, and had no effect on quality of life.Trial registration numberISRCTN35338757

Coagulation Factors, Postmenopausal Hormone Replacement Therapy and the Risk of Venous Thrombosis: The WHI Clinical Trials of Postmenopausal Hormone Therapy.

Background. Postmenopausal estrogen (E) therapy, especially in combination with progestin (P) doubles the relative risk of venous thrombosis (VTE). Risk with hormones is higher with increasing age, obesity and with factor V Leiden. We studied coagulation markers as susceptibility factors for postmenopausal hormone-related VTE.Methods. The Women's Health Initiative program included two placebo-controlled double-blind randomized trials of two E regimens, E (conjugated equine estrogens) or E+P (E + medroxyprogesterone acetate), in 16,608 postmenopausal women aged 50–79. We performed a nested case control study that measured baseline levels of coagulation markers in 215 women who developed VTE during follow up and 867 age-matched controls. The joint effects of treatment assignment to either E regimen vs placebo and prespecified abnormal levels of each coagulation factor on relative risk of VTE were estimated by logistic regression adjusting for age, race, body-mass index and type of E regimen.Results. Low levels of protein C and free protein S (<5th percentile), high D-dimer (top quartile), and high plasmin antiplasmin complex (PAP) and prothrombin fragment 1–2 (top decile) were all associated with risk of VTE with adjusted odds ratios (95% CI) of 2.0 (1.0–4.1), 2.9 (1.5–5.6), 2.8 (2.0–4.0), 2.5 (1.6–4.0) and 1.9 (1.2–3.1), respectively. Elevated factors II, VIII, IX and fibrinogen were not VTE risk factors. Compared to women with normal coagulation marker levels assigned to placebo, the joint odds of VTE with either E regimen plus an abnormal coagulation marker were more than additive compared to the separate effects of hormones and coagulation abnormalities for low protein C, low free protein S, and elevated D-dimer, PAP and F1–2. The odds ratios of VTE with the combination of an abnormal coagulation factor and assignment to hormones were (in order listed in prior sentence), 4.5 (95% CI 2.0–10.2), 6.7 (3.0–14.5), 6.1 (3.7–10), 5.8 (3.2–10.5) and 4.4 (2.4–7.7).Conclusions. We report new findings of elevated F1-2 and PAP as VTE risk factors in women in this prospective study nested in trials of E or E+P versus placebo. Protein C or S values below the 5th percentile were also clinically relevant even though they do not represent inherited deficiency. Lower protein C and free protein S, and higher D-dimer, F1-2 and PAP all identified women at increased risk of VTE with hormones. If our findings are confirmed in management studies, measurement of these factors might assist women with decision-making on safety of E or E+P.

Observational studies, clinical trials, and the women’s health initiative

The complementary roles fulfilled by observational studies and randomized controlled trials in the population science research agenda is illustrated using results from the Women's Health Initiative (WHI). Comparative and joint analyses of clinical trial and observational study data can enhance observational study design and analysis choices, and can augment randomized trial implications. These concepts are described in the context of findings from the WHI randomized trials of postmenopausal hormone therapy and of a low-fat dietary pattern, especially in relation to coronary heart disease, stroke, and breast cancer. The role of biomarkers of exposure and outcome, including high-dimensional genomic and proteomic biomarkers, in the elucidation of disease associations, will also be discussed in these same contexts.

Major changes in breast cancer incidence in the United States over the period 2002 to 2004

1533 Background: We have recently reported that a steep decrease in the incidence of breast cancer occurred in the United States in 2003 relative to 2002 (BCRT 100: S5, 2006). This decrease was most evident in patients older than 50, and largely occurred because of a decrease in the incidence of estrogen receptor positive breast cancer. This decrease occurred after the report in 2002 of the results of first of the Women s Health Initiative trials of postmenopausal hormone therapy (HT). This publication showed that use of a combined estrogen/progestin combination was associated with increased risk of breast cancer and heart disease and led to an immediate and substantial decrease in the use of HT in the US. Dramatic shifts in breast cancer incidence are unusual, and provide unique opportunities to test models that have been developed to explain trends in breast cancer incidence and mortality. We have been engaged in modeling trends in breast cancer incidence and mortality, in collaborative effects such as the Cancer Intervention and Surveillance Modeling Network (CISNET), to understand these and other processes (NEJM 353:1784–1792,2005). These models have practical implications for understanding the impact of changes in risk factors, use of prevention strategies, screening, and treatment of breast cancer. Methods: SEER public use incidence data from 1990 to the end of 2003 will be updated with information from the release in the spring of 2007 of incidence data for 2004. We will analyze the full data set through 2004 and report on the trends in incidence of breast cancer in the population as a whole and by subsets (such as age, estrogen receptor status, stage etc). We will also use the most recent and detailed data about HT use and screening mammography during this period as part of modeling. Results: We are awaiting SEER data from 2004 which will be released by April of 2007. Conclusions: Our first SEER based multi-year analysis of breast cancer incidence following the change in HT use in the US will be presented. Modeling of these trends in incidence will be discussed in the context of understanding the role of various contributors to the change in breast cancer incidence and what insights on the evolution of preclinical disease might be possible. No significant financial relationships to disclose.

Implications of Recent Clinical Trials of Postmenopausal Hormone Therapy for Management of Cardiovascular Disease

Estrogen therapy, originally used for the treatment of menopausal vasomotor symptoms, had by 1990 become a mainstay for the prevention of coronary heart disease (CHD) in postmenopausal women. The recommendations for use of estrogen in CHD were based on epidemiologic, animal, and laboratory data. However, a series of clinical trials published from 1998 onward have failed uniformly to confirm a CHD benefit. When the disappointing results of the secondary prevention trials were announced, there was widespread anticipation of more promising results from the primary prevention trials of the Women's Health Initiative (WHI). The WHI trials in generally healthy women also did not provide evidence of benefit, and the use of HT for disease prevention is now discouraged. In response, some commentators have incorrectly stated that the WHI was not a true primary prevention trial. A more appropriate way to frame the question is whether the effects of HT on cardiovascular disease (CVD) differ by age or years since menopause. Some preliminary data suggest that more recently menopausal women starting HT could be at lower risk of CHD (but not stroke) than women more distant from the menopause. However, even if ongoing studies provide evidence that HT can slow the initiation of early atherosclerosis in younger women, this is unlikely to translate into a reconsideration of the use of HT for the prevention of disease, because the long-term effects on cardiovascular events are unknown and unknowable, HT has other adverse effects, and there are more effective and safer ways of preventing cardiovascular disease.

Results from the Estonian postmenopausal hormone therapy trial [ISRCTN35338757

Objectives At present the Women's Health Initiative trial is the only reported randomised controlled trial studying the effects of hormone therapy among healthy postmenopausal women. The Women's Health Initiative reports have been criticized for lacking in generalisability, due to the characteristics of the trial population. We aimed to compare the health effects of oral continuous combined hormone therapy with a placebo and non-treatment among healthy Estonian women. Methods Eligible women were randomised into a blind group of hormone therapy versus placebo and into a non-blind group of open label hormone therapy versus non-treatment. One thousand seven hundred and seventy-eight postmenopausal women aged 50–64 at the time of sampling were recruited in 1999–2001 at three clinical centers in Estonia. Participants received conjugated equine oestrogens, 0.625 mg/d, plus medroxyprogesterone acetate, 2.5 mg/d, or conjugated equine oestrogens, 0.625 mg/d, plus medroxyprogesterone acetate, 5 mg/d, if less than 3 years had passed since menopause at recruitment, or matched placebo or non-treatment. Trial treatment was stopped gradually from 1 January 2004 to 31 May 2004. Results After a follow-up period from 2.0 to 5.0 years the combined hazard ratio, stratified by blinding and adjusted for age at recruitment and former oral contraceptive use was 1.12 (95% confidence interval [CI]: 0.90–1.40) for coronary heart disease, 1.24 (95% CI: 0.85–1.82) for cerebrovascular disease, 1.36 (95% CI: 0.73–2.52) for total cancer, and 0.61 (95% CI: 0.42 to 0.89) for bone fractures. Conclusions The results from the Estonian Postmenopausal Hormone Therapy randomised trial are consistent with the Women's Health Initiative findings.

Changes in newspaper coverage about hormone therapy with the release of new medical evidence

Results of 2 trials of postmenopausal hormone therapy (HT) challenged established practice patterns; 1 was not associated with changes in HT use, whereas the other was associated with substantial decline. Differential coverage by lay newspapers may have contributed to the differential impact. To examine newspaper coverage of HT before and after the publication of the Heart and Estrogen Replacement Study (HERS) in August 1998, and the main findings of the estrogen plus progestin therapy arm of the Women's Health Initiative (EPT-WHI) in July 2002. Longitudinal review of newspaper articles, 1998 to 2003 (n=663). Twenty local and 6 regional/national newspapers. Number and content of articles about HT. The average number of articles about HT published during the month of the publication of the EPT-WHI was at least 8-fold greater than the number of articles published on the topic during any prior period. While the majority of articles in all periods presented information about the potential benefits of HT, information about harms became more common than information about benefits during the 2 months before the publication of the EPT-WHI, when the trial participants were notified of the early termination of the study. The presentation of specific health harms was more common after the publication of the EPT-WHI than after the publication of HERS. Few articles in any period used visual aids. The publication of the EPT-WHI was associated with a change in both the volume and content of newspaper coverage about HT.

Who wants to join preventive trials? – Experience from the Estonian Postmenopausal Hormone Therapy Trial [ISRCTN35338757

BackgroundThe interest of patients in participating in randomized clinical trials involving treatments has been widely studied, but there has been much less research on interest in preventive trials. The objective of this study was to find out how many women would be interested in a trial involving postmenopausal hormone therapy (PHT) and how the women's background characteristics and opinions correlated to their interest.MethodsThe data come from recruitment questionnaires (n = 2000) sent to women in Estonia in 1998. A random sample of women aged 45 to 64 was drawn from the Population Registry. The trial is a two-group randomized trial comparing estrogen-progestogen therapy with placebo or no drugs. A brief description of the study was attached to the questionnaires. Women were not told at this stage of the recruitment which group they would be assigned to, however, they were told of the chance to receive either hormone, placebo or no treatment.ResultsAfter two reminders, 1312 women (66%) responded. Eleven percent of the women approached (17% of the respondents) were interested in joining the trial, and 8% wanted more information before deciding. When the 225 women who stated clearly that they were interested in joining and the 553 women who said they were not interested were compared, it was found that interested women were younger and, adjusting for age, that more had given birth; in other respects, the sociodemographic characteristics and health habits of the interested women were similar to those of the non-interested women. The interested women had made more use of more health services, calcium preparations and PHT, they were more often overweight, and more had chronic diseases and reported symptoms. Interested women's opinions on the menopause were more negative, and they favoured PHT more than the non-interested women.ConclusionUnlike the situation described in previous reports on preventive trials, in this case Estonian women interested in participating in a PHT trial were not healthier than other women. This suggests that trials involving PHT are more similar to treatment trials than to preventive trials. In a randomized controlled trial, more information should be obtained from those women who decline to participate.