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PURPOSE: Menopausal hormone therapy's influence on ovarian and endometrial cancers remains unsettled. Therefore, we assessed the long-term influence of conjugated equine estrogen (CEE) plus medroxyprogesterone acetate (MPA) and CEE-alone on ovarian and endometrial cancer incidence and mortality in the Women's Health Initiative randomized, placebo-controlled clinical trials. MATERIALS AND METHODS: Postmenopausal women, age 50-79 years, were entered on two randomized clinical trials evaluating different menopausal hormone therapy regimens. In 16,608 women with a uterus, 8,506 were randomly assigned to once daily 0.625 mg of CEE plus 2.5 mg once daily of MPA and 8,102 placebo. In 10,739 women with previous hysterectomy, 5,310 were randomly assigned to once daily 0.625 mg of CEE-alone and 5,429 placebo. Intervention was stopped for cause before planned 8.5-year intervention after 5.6 years (CEE plus MPA) and after 7.2 years (CEE-alone). Outcomes include incidence and mortality from ovarian and endometrial cancers and deaths after these cancers. RESULTS: After 20-year follow-up, CEE-alone, versus placebo, significantly increased ovarian cancer incidence (35 cases [0.041%] v 17 [0.020%]; hazard ratio [HR], 2.04 [95% CI, 1.14 to 3.65]; P = .014) and ovarian cancer mortality (P = .006). By contrast, CEE plus MPA, versus placebo, did not increase ovarian cancer incidence (75 cases [0.051%] v 63 [0.045%]; HR, 1.14 [95% CI, 0.82 to 1.59]; P = .44) or ovarian cancer mortality but did significantly lower endometrial cancer incidence (106 cases [0.073%] v 140 [0.10%]; HR, 0.72 [95% CI, 0.56 to 0.92]; P = .01). CONCLUSION: In randomized clinical trials, CEE-alone increased ovarian cancer incidence and ovarian cancer mortality, while CEE plus MPA did not. By contrast, CEE plus MPA significantly reduced endometrial cancer incidence.
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Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported.We report long-term colorectal cancer findings from the Women's Health Initiative trial where 16,608 postmenopausal women with a uterus were randomly assigned to daily conjugated equine estrogen (CEE) 0.625 mg, plus medroxyprogesterone acetate (MPA) 2.5 mg, or placebo. When intervention ended after 5.6 years, although there were 44% fewer colorectal cancers in the intervention group (43 v 72, P = .003), the cancers were more commonly lymph node-positive (59.0% v 29.4%, P = .003). Now after cumulative 24-year follow-up, with 431 colorectal cancers, CEE plus MPA no longer influenced colorectal cancer incidence (215 [0.15, annualized rate %] v 216 [0.15], hazard ratio [HR], 0.95 [95% CI, 0.79 to 1.15]). Although not statistically significant, there were more colorectal cancer deaths with CEE plus MPA (87 [0.049] v 69 [0.041] deaths, HR, 1.20 [95% CI, 0.87 to 1.65], P = .26). Vaginal bleeding (54.1% v 5.2% at 6 months) and breast changes were more frequent in the intervention group. After adjusting for postrandomization vaginal bleeding and breast changes, bowel examinations were significantly delayed in intervention group participants (P = .005), potentially contributing to diagnostic delay. Taken together, the findings suggest no clinically meaningful benefit for about 5 years of CEE plus MPA use on colorectal cancer outcome.
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BACKGROUND: In the Women's Health Initiative (WHI) randomized trial, dietary intervention significantly reduced breast cancer mortality, especially in women with more metabolic syndrome (MetS) components. Therefore, this study investigated the associations of MetS and obesity with postmenopausal breast cancer after long-term follow-up in the WHI clinical trials. METHODS: A total of 68,132 postmenopausal women, without prior breast cancer and with normal mammogram, were entered into WHI randomized clinical trials; 63,330 women with an entry MetS score comprised the study population. At entry, body mass index (BMI) was determined; MetS score (0, 1-2, and 3-4) included the following: (1) high waist circumference (≥88 cm), (2) high blood pressure (systolic ≥130 mm Hg and/or diastolic ≥85 mm Hg, or hypertension history), (3) high-cholesterol history, and (4) diabetes history. Study outcomes included breast cancer incidence, breast cancer mortality, deaths after breast cancer, and results by hormone receptor status. RESULTS: After a >20-year mortality follow-up, a higher MetS score (3-4), adjusted for BMI, was significantly associated with more poor prognosis, estrogen receptor (ER)-positive, progesterone receptor (PR)-negative cancers (p = .03), 53% more deaths after breast cancer (p < .001), and 44% higher breast cancer mortality (p = .03). Obesity status, adjusted for MetS score, was significantly associated with more good prognosis, ER-positive, PR-positive cancers (p < .001), more total breast cancers (p < .001), and more deaths after breast cancer (p < .001), with higher breast cancer mortality only in women with severe obesity (BMI, ≥35 kg/m2; p < .001). CONCLUSIONS: MetS and obesity status have independent, but differential, adverse associations with breast cancer receptor subtypes and breast cancer mortality risk. Both represent separate targets for breast cancer prediction and prevention strategies.
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Importance: Approximately 55 million people in the US and approximately 1.1 billion people worldwide are postmenopausal women. To inform clinical practice about the health effects of menopausal hormone therapy, calcium plus vitamin D supplementation, and a low-fat dietary pattern, the Women's Health Initiative (WHI) enrolled 161â¯808 postmenopausal US women (N = 68â¯132 in the clinical trials) aged 50 to 79 years at baseline from 1993 to 1998, and followed them up for up to 20 years. Observations: The WHI clinical trial results do not support hormone therapy with oral conjugated equine estrogens plus medroxyprogesterone acetate for postmenopausal women or conjugated equine estrogens alone for those with prior hysterectomy to prevent cardiovascular disease, dementia, or other chronic diseases. However, hormone therapy is effective for treating moderate to severe vasomotor and other menopausal symptoms. These benefits of hormone therapy in early menopause, combined with lower rates of adverse effects of hormone therapy in early compared with later menopause, support initiation of hormone therapy before age 60 years for women without contraindications to hormone therapy who have bothersome menopausal symptoms. The WHI results do not support routinely recommending calcium plus vitamin D supplementation for fracture prevention in all postmenopausal women. However, calcium and vitamin D are appropriate for women who do not meet national guidelines for recommended intakes of these nutrients through diet. A low-fat dietary pattern with increased fruit, vegetable, and grain consumption did not prevent the primary outcomes of breast or colorectal cancer but was associated with lower rates of the secondary outcome of breast cancer mortality during long-term follow-up. Conclusions and Relevance: For postmenopausal women, the WHI randomized clinical trials do not support menopausal hormone therapy to prevent cardiovascular disease or other chronic diseases. Menopausal hormone therapy is appropriate to treat bothersome vasomotor symptoms among women in early menopause, without contraindications, who are interested in taking hormone therapy. The WHI evidence does not support routine supplementation with calcium plus vitamin D for menopausal women to prevent fractures or a low-fat diet with increased fruits, vegetables, and grains to prevent breast or colorectal cancer. A potential role of a low-fat dietary pattern in reducing breast cancer mortality, a secondary outcome, warrants further study.
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Neoplasias da Mama , Doenças Cardiovasculares , Suplementos Nutricionais , Terapia de Reposição de Estrogênios , Saúde da Mulher , Idoso , Feminino , Humanos , Pessoa de Meia-Idade , Neoplasias da Mama/prevenção & controle , Cálcio/uso terapêutico , Cálcio/administração & dosagem , Cálcio da Dieta/administração & dosagem , Doenças Cardiovasculares/prevenção & controle , Dieta com Restrição de Gorduras , Terapia de Reposição de Estrogênios/efeitos adversos , Estrogênios Conjugados (USP)/uso terapêutico , Estrogênios Conjugados (USP)/administração & dosagem , Estrogênios Conjugados (USP)/efeitos adversos , Fogachos/tratamento farmacológico , Acetato de Medroxiprogesterona/administração & dosagem , Acetato de Medroxiprogesterona/uso terapêutico , Acetato de Medroxiprogesterona/efeitos adversos , Osteoporose Pós-Menopausa/prevenção & controle , Osteoporose Pós-Menopausa/tratamento farmacológico , Pós-Menopausa , Ensaios Clínicos Controlados Aleatórios como Assunto , Vitamina D/uso terapêutico , Vitamina D/administração & dosagem , Estados UnidosRESUMO
PURPOSE: In the Women's Health initiative (WHI) randomized clinical trial, conjugated equine estrogen (CEE)-alone significantly reduced breast cancer incidence (P = 0.005). As cohort studies had opposite findings, other randomized clinical trials were identified to conduct a meta-analysis of estrogen-alone influence on breast cancer incidence. METHODS: We conducted literature searches on randomized trials and: estrogen, hormone therapy, and breast cancer, and searches from a prior meta-analysis and reviews. In the meta-analysis, for trials with published relative risks (RR) and 95% confidence intervals (CI), each log-RR was multiplied by weight = 1/V, where V = variance of the log-RR, and V was derived from the corresponding 95% CI. For smaller trials with only breast cancer numbers, the corresponding log-RR = (O - E)/weight, where O is the observed case number in the oestrogen-alone group and E the corresponding expected case number, E = nP. RESULTS: Findings from 10 randomized trials included 14,282 participants and 591 incident breast cancers. In 9 smaller trials, with 1.2% (24 of 2029) vs 2.2% (33 of 1514) randomized to estrogen-alone vs placebo (open label, one trial) (RR 0.65 95% CI 0.38-1.11, P = 0.12). For 5 trials evaluating estradiol formulations, RR = 0.63 95% CI 0.34-1.16, P = 0.15. Combining the 10 trials, 3.6% (262 of 7339) vs 4.7% (329 of 6943) randomized to estrogen-alone vs placebo (overall RR 0.77 95% CI 0.65-0.91, P = 0.002). CONCLUSION: The totality of randomized clinical trial evidence supports a conclusion that estrogen-alone use significantly reduces breast cancer incidence.
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Neoplasias da Mama , Estrogênios , Ensaios Clínicos Controlados Aleatórios como Assunto , Humanos , Neoplasias da Mama/epidemiologia , Feminino , Incidência , Estrogênios/uso terapêutico , Terapia de Reposição de Estrogênios/efeitos adversos , Estrogênios Conjugados (USP)/uso terapêutico , Estrogênios Conjugados (USP)/efeitos adversos , Estrogênios Conjugados (USP)/administração & dosagemRESUMO
BACKGROUND: The association of total energy intake (EI) with all-cause mortality is uncertain as are the dependencies of this association on age and weight change history. OBJECTIVES: To identify an EI biomarker suitable for use in epidemiologic association studies and to study EI associations with total mortality in a Women's Health Initiative (WHI) cohort of postmenopausal United States females (1993-present). METHODS: EI biomarkers were developed based on doubly labeled water (DLW) total energy expenditure (TEE) and weight variation during the 2-wk DLW protocol period using the energy balance method in an embedded feeding study (n = 153). This along with 2 earlier WHI nutrition biomarker studies having TEE assessments (n = 1131 total), with 14.6 y (median) follow-up, constituted a prospective cohort for the study of EI and all-cause mortality. RESULTS: An empirical biomarker for log(EI) was developed that had a correlation of 0.73 with log(feeding study-consumed EI). The overall association between EI and mortality was nonsignificant. The association, however, depended on age (P = 0.009), with lower EI associated with lower mortality at younger ages, and also on preceding weight change history (P = 0.03). Among participants with stable or increasing weight, mortality hazard ratios (95% confidence intervals [CIs]) for a 12% lower EI were 0.66 (95% CI: 0.51, 0.87) at age 60, 0.84 (95% CI: 0.72, 0.98) at age 70, and 1.06 (95% CI: 0.87, 1.29) at age 80. Corresponding values for participants having preceding weight loss were 0.83 (95% CI: 0.61, 1.12) at age 60, 1.05 (95% CI: 0.87, 1.26) at age 70, and 1.33 (95% CI: 1.08, 1.63) at age 80. A previously considered EI biomarker, using a theoretical model for variation in body fat and fat-free mass components over time, gave similar results following rescaling. CONCLUSIONS: Lower EI is associated with lower all-cause mortality among younger postmenopausal females with stable or increasing weight and with higher mortality among older females with weight loss. This study was registered with clinicaltrials.gov as NCT00000611.
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Biomarcadores , Ingestão de Energia , Metabolismo Energético , Pós-Menopausa , Humanos , Feminino , Biomarcadores/sangue , Pessoa de Meia-Idade , Idoso , Estudos Prospectivos , Estudos de Coortes , Mortalidade , Estados Unidos/epidemiologia , SeguimentosRESUMO
BACKGROUND: Although calcium and vitamin D (CaD) supplementation may affect chronic disease in older women, evidence of long-term effects on health outcomes is limited. OBJECTIVE: To evaluate long-term health outcomes among postmenopausal women in the Women's Health Initiative CaD trial. DESIGN: Post hoc analysis of long-term postintervention follow-up of the 7-year randomized intervention trial of CaD. (ClinicalTrials.gov: NCT00000611). SETTING: A multicenter (n = 40) trial across the United States. PARTICIPANTS: 36 282 postmenopausal women with no history of breast or colorectal cancer. INTERVENTION: Random 1:1 assignment to 1000 mg of calcium carbonate (400 mg of elemental calcium) with 400 IU of vitamin D3 daily or placebo. MEASUREMENTS: Incidence of colorectal, invasive breast, and total cancer; disease-specific and all-cause mortality; total cardiovascular disease (CVD); and hip fracture by randomization assignment (through December 2020). Analyses were stratified on personal supplement use. RESULTS: For women randomly assigned to CaD versus placebo, a 7% reduction in cancer mortality was observed after a median cumulative follow-up of 22.3 years (1817 vs. 1943 deaths; hazard ratio [HR], 0.93 [95% CI, 0.87 to 0.99]), along with a 6% increase in CVD mortality (2621 vs. 2420 deaths; HR, 1.06 [CI, 1.01 to 1.12]). There was no overall effect on other measures, including all-cause mortality (7834 vs. 7748 deaths; HR, 1.00 [CI, 0.97 to 1.03]). Estimates for cancer incidence varied widely when stratified by whether participants reported supplement use before randomization, whereas estimates on mortality did not vary, except for CVD mortality. LIMITATION: Hip fracture and CVD outcomes were available on only a subset of participants, and effects of calcium versus vitamin D versus joint supplementation could not be disentangled. CONCLUSION: Calcium and vitamin D supplements seemed to reduce cancer mortality and increase CVD mortality after more than 20 years of follow-up among postmenopausal women, with no effect on all-cause mortality. PRIMARY FUNDING SOURCE: National Heart, Lung, and Blood Institute of the National Institutes of Health.
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Doenças Cardiovasculares , Fraturas do Quadril , Neoplasias , Feminino , Humanos , Estados Unidos/epidemiologia , Idoso , Cálcio/uso terapêutico , Seguimentos , Distribuição Aleatória , Cálcio da Dieta , Suplementos Nutricionais , Vitamina D/uso terapêutico , Vitaminas/uso terapêutico , Neoplasias/epidemiologia , Doenças Cardiovasculares/epidemiologia , Doenças Cardiovasculares/prevenção & controle , Doenças Cardiovasculares/tratamento farmacológico , Fraturas do Quadril/epidemiologia , Fraturas do Quadril/prevenção & controleRESUMO
BACKGROUND: In the Women's Health Initiative Dietary Modification randomized trial, the dietary intervention reduced breast cancer mortality by 21% (P = .02) and increased physical activity as well. OBJECTIVE: Therefore, the aim was to examine whether or not these lifestyle changes attenuated age-related physical functioning decline. DESIGN: In a randomized trial, the influence of 8 years of a low-fat dietary pattern intervention was examined through 20 years of cumulative follow-up. PARTICIPANTS AND SETTING: From 1993 to 1998, 48,835 postmenopausal women, ages 50 to 79 years with no prior breast cancer and negative baseline mammogram were randomized at 40 US clinical centers to dietary intervention or usual diet comparison groups (40 out of 60). The intervention significantly reduced fat intake and increased vegetable, fruit, and grain intake. MAIN OUTCOME MEASURES: In post hoc analyses, physical functioning, assessed using the RAND 36-Item Short Form Health Survey, evaluated quality or limitations of 10 hierarchical physical activities. Longitudinal physical functioning, reported against a disability threshold (when assistance in daily activities is required) was the primary study outcome. STATISTICAL ANALYSES PERFORMED: Semiparametric linear mixed effect models were used to contrast physical functioning trajectories by randomization groups. RESULTS: Physical functioning score, assessed 495,317 times with 11.0 (median) assessments per participant, was significantly higher in the intervention vs comparison groups through 12 years of cumulative follow-up (P = .001), representing a reduction in age-related functional decline. The intervention effect subsequently attenuated and did not delay time to the disability threshold. Among women in the dietary intervention vs comparison groups, aged 50 to 59 years, who were physically inactive at entry, a persistent, statistically significant, favorable influence on physical functioning with associated delay in crossing the disability threshold by approximately a year was seen (P value for interaction = .007). CONCLUSIONS: In the Women's Health Initiative Dietary Modification randomized trial, a dietary intervention that significantly reduced breast cancer mortality also significantly reduced age-related functional decline through 12 years, which was attenuated with longer follow-up.
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PURPOSE: Over the past half century, the annual age-adjusted breast cancer incidence in the USA has fluctuated, potentially influenced by changes in mammography screening, obesity, and menopausal hormone therapy. As the relative contributions of these factors on breast cancer incidence have not been resolved, we assembled reliable sources of year-to-year changes in mammography, obesity, and hormone therapy to graphically display their relationship to breast cancer incidence through 50 years. METHODS: Year-to-year trends were assembled: for mammography from the Center for Disease Control National Health Interviews; for hormone therapy from the Collaborative Group on Hormonal Factors in Breast Cancer report; for obesity from the NCD (Non-Communicable Diseases) Risk Factor Collaboration; and for breast cancer for US women 50-64 years of age from Surveillance, Epidemiology, and End Results (SEER) registry findings. RESULTS: Increases in age-adjusted breast cancer incidence trend from about 1982 to 2002 track both mammography and hormone therapy use but not obesity. However, the sudden decrease in breast cancer incidence in 2003, subsequently sustained at a lower incidence level, only tracks the parallel reduction in hormone therapy use. CONCLUSION: The sustained reduction in hormone therapy use from 2003 provides a plausible explanation for most of the lower breast cancer incidence seen in US postmenopausal women during the last two decades. The strong observational study obesity association with higher breast cancer risk is not reflected in breast cancer incidence trends.
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Neoplasias da Mama , Feminino , Humanos , Neoplasias da Mama/diagnóstico por imagem , Neoplasias da Mama/epidemiologia , Neoplasias da Mama/prevenção & controle , Incidência , Mamografia , Obesidade/complicações , Obesidade/epidemiologia , Menopausa , HormôniosRESUMO
BACKGROUND: A substantial observational literature relating specific fatty acid classes to chronic disease risk may be limited by its reliance on self-reported dietary data. OBJECTIVES: We aimed to develop biomarkers for saturated (SFA), monounsaturated (MUFA), and polyunsaturated (PUFA) fatty acid densities, and to study their associations with cardiovascular disease (CVD), cancer, and type 2 diabetes (T2D) in Women's Health Initiative (WHI) cohorts. METHODS: Biomarker equations were based primarily on serum and urine metabolomics profiles from an embedded WHI human feeding study (n = 153). Calibration equations were based on biomarker values in a WHI nutritional biomarker study (n = 436). Calibrated intakes were assessed in relation to disease incidence in larger WHI cohorts (n = 81,894). Participants were postmenopausal women, aged 50-79 when enrolled at 40 United States Clinical Centers (1993-1998), with a follow-up period of â¼20 y. RESULTS: Biomarker equations meeting criteria were developed for SFA, MUFA, and PUFA densities. That for SFA density depended somewhat weakly on metabolite profiles. On the basis of our metabolomics platforms, biomarkers were insensitive to trans fatty acid intake. Calibration equations meeting criteria were developed for SFA and PUFA density, but not for MUFA density. With or without biomarker calibration, SFA density was associated positively with risk of CVD, cancer, and T2D, but with small hazard ratios, and CVD associations were not statistically significant after controlling for other dietary variables, including trans fatty acid and fiber intake. Following this same control, PUFA density was not significantly associated with CVD risk, but there were positive associations for some cancers and T2D, with or without biomarker calibration. CONCLUSIONS: Higher SFA and PUFA diets were associated with null or somewhat higher risk for clinical outcomes considered in this population of postmenopausal United States women. Further research is needed to develop even stronger biomarkers for these fatty acid densities and their major components. This study is registered with clinicaltrials.gov identifier: NCT00000611.
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Doenças Cardiovasculares , Diabetes Mellitus Tipo 2 , Neoplasias , Ácidos Graxos trans , Humanos , Feminino , Ácidos Graxos , Diabetes Mellitus Tipo 2/complicações , Pós-Menopausa , Biomarcadores , Doença Crônica , Gorduras na DietaRESUMO
BACKGROUND: The Women's Health Initiative (WHI) randomized, controlled Dietary Modification (DM) trial of a low-fat dietary pattern suggested intervention benefits related to breast cancer, coronary heart disease (CHD), and diabetes. Here, we use WHI observational data for further insight into the chronic disease implications of adopting this type of low-fat dietary pattern. OBJECTIVES: We aimed to use our earlier work on metabolomics-based biomarkers of carbohydrate and protein to develop a fat intake biomarker by subtraction, to use the resulting biomarker to develop calibration equations that adjusts self-reported fat intake for measurement error, and to study associations of biomarker-calibrated fat intake with chronic disease risk in WHI cohorts. Corresponding studies for specific fatty acids will follow separately. METHODS: Prospective disease association results are presented using WHI cohorts of postmenopausal women, aged 50-79 y when enrolled at 40 United States clinical centers. Biomarker equations were developed using an embedded human feeding study (n = 153). Calibration equations were developed using a WHI nutritional biomarker study (n = 436). Calibrated intakes were associated with cancer, cardiovascular diseases, and diabetes incidence in WHI cohorts (n = 81,954) over an approximate 20-y follow-up period. RESULTS: A biomarker for fat density was developed by subtracting protein, carbohydrate, and alcohol densities from one. A calibration equation was developed for fat density. Hazard ratios (95% confidence intervals) for 20% higher fat density were 1.16 (1.06, 1.27) for breast cancer, 1.13 (1.02, 1.26) for CHD, and 1.19 (1.13, 1.26) for diabetes, in substantial agreement with findings from the DM trial. With control for additional dietary variables, especially fiber, fat density was no longer associated with CHD, with hazard ratio (95% confidence interval) of 1.00 (0.88, 1.13), whereas that for breast cancer was 1.11 (1.00, 1.24). CONCLUSIONS: WHI observational data support prior DM trial findings of low-fat dietary pattern benefits in this population of postmenopausal United States women. TRIAL REGISTRATION NUMBER: This study is registered with clinicaltrials.gov identifier: NCT00000611.
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Neoplasias da Mama , Doença das Coronárias , Diabetes Mellitus , Feminino , Humanos , Estados Unidos/epidemiologia , Gorduras na Dieta , Estudos Prospectivos , Pós-Menopausa , Saúde da Mulher , Neoplasias da Mama/epidemiologia , Dieta com Restrição de Gorduras , Biomarcadores , Doença das Coronárias/epidemiologia , Carboidratos , Doença Crônica , Fatores de RiscoRESUMO
BACKGROUND: The association of TEE with all-cause mortality is uncertain, as is the dependence of this association on age. OBJECTIVES: To examine the association between TEE and all-cause mortality, and its age interaction, in a Women's Health Initiative (WHI) cohort of postmenopausal United States women (1992-present). METHODS: A cohort of 1131 WHI participants having DLW TEE assessment of â¼10.0 y (median) following WHI enrollment with â¼13.7 y (median) of subsequent follow-up, was used to study the EE associations with all-cause mortality. To enhance the comparability of TEE and total EI, key analyses excluded participants having >5% weight change between WHI enrollment and DLW assessment. The influence of participant age on mortality associations was examined, as was the ability of concurrent and earlier weight and height measurements to explain the results. RESULTS: There were 308 deaths following the TEE assessment through 2021. TEE was unrelated to overall mortality (P = 0.83) in this cohort of generally healthy, older (mean 71 y at TEE assessment) United States women. However, this potential association varied with age (P = 0.003). Higher TEE was associated with a higher mortality rate at the age of 60 y and a lower mortality rate at the age of 80 y. Within the weight-stable subset (532 participants, 129 deaths), TEE was weakly positively related to overall mortality (P = 0.08). This association also varied with age (P = 0.03), with mortality HRs (95% CIs) for a 20% increment in TEE of 2.33 (1.24, 4.36) at the age of 60 y, 1.49 (1.10, 2.02) at 70 y of age, and 0.96 (0.66, 1.38) at 80 y of age. This pattern remained, although was somewhat attenuated, following control for baseline weight and weight changes between WHI enrollment and TEE assessment. CONCLUSIONS: Higher EE is associated with higher all-cause mortality among younger postmenopausal women, only partially explained by weight and weight change. This study is registered with clinicaltrials.gov identifier: NCT00000611.
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Ingestão de Energia , Água , Humanos , Feminino , Lactente , Pós-Menopausa , Metabolismo Energético , Peso CorporalAssuntos
Doença Crônica , Terapia de Reposição Hormonal , Hormônios , Pós-Menopausa , Feminino , Humanos , Doença Crônica/prevenção & controle , Terapia de Reposição de Estrogênios/métodos , Terapia de Reposição Hormonal/métodos , Hormônios/farmacologia , Hormônios/uso terapêutico , Osteoporose Pós-Menopausa/prevenção & controle , Pós-Menopausa/efeitos dos fármacosRESUMO
IMPORTANCE AND OBJECTIVE: The menopausal hormone therapy (MHT) association with breast cancer has been controversial for more than 40 years. Most recently, findings from cohort studies have been discordant compared with those from the Women's Health Initiative (WHI) randomized trials. In cohort studies, both estrogen therapy and estrogen plus progestin were associated with higher breast cancer incidence. In contrast, in the WHI randomized trials, findings for estrogen plus progestin are concordant with cohort study reports, whereas estrogen therapy significantly reduced breast cancer incidence. In addition, concerns have been raised regarding the WHI findings from both trials. In this report, we briefly summarize findings for MHT on breast cancer from cohort studies and the WHI randomized trials. The report focus is addressing, point-by-point, concerns raised regarding the WHI findings. METHODS: For cohort studies, we relied on the latest findings from (1) the meta-analysis of the Collaborative Group on Hormonal Factors in Breast Cancer and (2) the Million Women's Study. To identify commentaries and editorials, "Menopause" and "Climacteric" were searched from 2002 to present; PubMed and Google Scholar were searched for commentaries, editorials, and breast cancer, MHT, estrogen, conjugated equine estrogen, estradiol, "hormone replacement therapy," and "HRT." DISCUSSION AND CONCLUSIONS: Thirty commentaries challenging WHI findings were identified. All were reviewed, and issues needing response were identified. Findings from the meta-analysis from the Collaborative Group on Hormonal Factors in Breast Cancer and the Million Women Study were summarized and compared with finding in the two WHI randomized trials evaluating estrogen therapy and estrogen plus progestin. Based on the randomized clinical trials, estrogen therapy, for women with prior hysterectomy, decreases breast cancer incidence and mortality. In contrast, estrogen plus progestin increases breast cancer incidence, which persists through two decades. Women considering estrogen plus progestin use for vasomotor symptoms should understand the breast cancer risk.
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Neoplasias da Mama , Neoplasias , Humanos , Feminino , Progestinas/efeitos adversos , Estudos de Coortes , Terapia de Reposição de Estrogênios/efeitos adversos , Ensaios Clínicos Controlados Aleatórios como Assunto , Saúde da Mulher , Menopausa , Estrogênios/efeitos adversos , Neoplasias da Mama/induzido quimicamente , Neoplasias da Mama/epidemiologia , Neoplasias da Mama/tratamento farmacológicoRESUMO
OBJECTIVE: The objective of this study was to assess the effect of menopausal hormone therapy (HT) on blood pressure control in postmenopausal women with hypertension. METHODS: The Women's Health Initiative HT clinical trials were double-blinded, randomized, placebo-controlled studies of women aged 50 to 79 years testing the effects of HT (conjugated equine estrogens [CEE, 0.625 mg/d] or CEE + medroxyprogesterone acetate [MPA; 2.5 mg/d]) on risks for coronary heart disease and invasive breast cancer, the primary outcomes for efficacy and safety, respectively. This secondary analysis of the Women's Health Initiative HT trials examined a subsample of 9,332 women with hypertension (reported ever taking pills to treat hypertension or were taking antihypertensive medication) at baseline. Blood pressure was measured at baseline and up to 10 annual follow-up visits during the planned study phase. Antihypertensive medications were inventoried at baseline and years 1, 3, 6, and 9 during the study, and self-reported during extended follow-up: 2009-2010 and 2012-2013, which occurred median of 13 and 16 years after randomization, respectively. The intervention effect was estimated through year 6. Cumulative follow-up included all visits. RESULTS: Compared with placebo, CEE-alone had significantly ( P = 0.02) higher systolic blood pressure (SBP) by mean (95% confidene interval [CI]) = 0.9 (0.2-1.5) mm Hg during the intervention phase. For cumulative follow-up, the CEE arm was associated with increased SBP by mean (95% CI) = 0.8 (0.1-1.4) mm Hg ( P = 0.02). Furthermore, CEE + MPA relative to placebo was associated with increased SBP by mean (95% CI) = 1.8 (1.2-2.5) mm Hg during the intervention phase ( P < 0.001). For cumulative follow-up, the CEE + MPA arm was associated with increased SBP by mean (95% CI) = 1.6 (1.0-2.3) mm Hg ( P < 0.001). The mean number of antihypertensive medications taken at each follow-up visit did not differ between randomization groups during the intervention or long-term extended follow-up of 16 years. CONCLUSION: There was a small but statistically significant increase in SBP in both CEE-alone and CEE + MPA arms compared with placebo during both the intervention and cumulative follow-up phases among postmenopausal women with hypertension at baseline. However, this increase in SBP was not associated with an increased antihypertensive medication use over time among women randomized to HT compared with placebo.
Assuntos
Anti-Hipertensivos , Hipertensão , Feminino , Humanos , Anti-Hipertensivos/uso terapêutico , Pressão Sanguínea , Terapia de Reposição de Estrogênios , Estrogênios Conjugados (USP) , Hipertensão/tratamento farmacológico , Acetato de Medroxiprogesterona , Pós-Menopausa , Saúde da Mulher , Pessoa de Meia-Idade , IdosoRESUMO
OBJECTIVE: The aim of this study was to examine the association between common menopausal symptoms (MS) and long-term cardiovascular disease (CVD) and all-cause mortality. METHODS: In an observational cohort of 80,278 postmenopausal women with no known CVD at baseline from the Women's Health Initiative, we assessed individual MS severity (mild vs none; moderate/severe vs none) for night sweats, hot flashes, waking up several times at night, joint pain or stiffness, headaches or migraines, vaginal or genital dryness, heart racing or skipping beats, breast tenderness, dizziness, tremors (shakes), feeling tired, forgetfulness, mood swings, restless or fidgety, and difficulty concentrating. Outcomes included total CVD events (primary) and all-cause mortality (secondary). Associations between specific MS, their severity, and outcomes were assessed during a median of 8.2 years of follow-up. All results were multivariable adjusted, and individual associations were Bonferroni corrected to adjust for multiple comparisons. A machine learning approach (least absolute shrinkage and selection operator) was used to select the most parsimonious set of MS most predictive of CVD and all-cause mortality. RESULTS: The severity of night sweats, waking up several times at night, joint pain or stiffness, heart racing or skipping beats, dizziness, feeling tired, forgetfulness, mood swings, restless or fidgety, and difficulty concentrating were each significantly associated with total CVD. The largest hazard ratio (HR) for total CVD was found for moderate or severe heart racing or skipping beats (HR, 1.55; 95% confidence interval [CI], 1.29-1.86). The individual severities of heart racing or skipping beats, dizziness, tremors (shakes), feeling tired, forgetfulness, mood swings, restless or fidgety, and difficulty concentrating were associated with increased all-cause mortality. Moderate or severe dizziness had the largest HR (1.58; 95% CI, 1.24-2.01). Multiple symptom modeling via least absolute shrinkage and selection operator selected dizziness, heart racing, feeling tired, and joint pain as most predictive of CVD, whereas dizziness, tremors, and feeling tired were most predictive of all-cause mortality. CONCLUSION: Among postmenopausal women with no known CVD at baseline, the severity of specific individual MS was significantly associated with incident CVD and mortality. Consideration of severe MS may enhance sex-specific CVD risk predication in future cohorts, but caution should be applied as severe MS could also indicate other health conditions.