writing group for the women's health initiative investigators

• Awards Season
• Big Stories
• Pop Culture
• Video Games
• Celebrities

From One-to-One to Many-to-Many: How to Initiate a Group Text Message

In today’s fast-paced digital world, communication has become easier and more convenient than ever before. With just a few taps on your smartphone, you can reach out to multiple people at once through group text messages. Whether you’re planning a surprise party or coordinating a work project, starting a group text message can save you time and effort. If you’re wondering how to start a group text message, read on for some helpful tips.

Choosing the Right Messaging App

The first step in initiating a group text message is to choose the right messaging app that suits your needs. While most smartphones come with a default messaging app, there are also several third-party apps available that offer advanced features for group messaging.

Popular messaging apps like WhatsApp, Facebook Messenger, and Telegram allow you to create groups with multiple participants. These apps provide additional features such as the ability to name your group, customize notifications, and even share files within the group. Consider the preferences of your intended recipients and select an app that is widely used among them.

Creating Your Group

Once you have chosen the messaging app of your choice, it’s time to create your group. Open the app and look for the option to create a new chat or group conversation. Depending on the app you’re using, this option may be located in different places within the interface.

After selecting “create new chat” or “start new group,” you’ll be prompted to add contacts or search for them within your phone’s contact list. Simply select the contacts you want to add to your group by tapping on their names or selecting them from your contact list.

Setting Up Your Group

After adding participants to your group text message, it’s important to set up some ground rules and guidelines for communication within the group.

Firstly, think about giving your group an appropriate name that reflects the purpose or topic of discussion. This will make it easier for participants to identify the group and locate it among their other conversations.

Additionally, you may want to establish some guidelines for communication etiquette within the group. This could include requesting that participants keep messages on-topic, avoid sharing sensitive information, and be mindful of each other’s time zones if participants are located in different regions.

Engaging Your Group

Now that your group text message is set up and ready to go, it’s time to engage your participants and start the conversation. Remember that effective communication is a two-way street, so encourage everyone in the group to actively participate.

To keep the conversation flowing smoothly, consider providing some initial prompts or questions related to the purpose of the group. This will help kickstart discussions and ensure that everyone has something to contribute.

Furthermore, be mindful of your own engagement within the group. Respond promptly to messages, acknowledge contributions from others, and maintain a positive tone throughout. This will help foster a welcoming and inclusive environment where all participants feel comfortable sharing their thoughts.

In conclusion, starting a group text message is a simple yet powerful way to communicate with multiple people simultaneously. By choosing the right messaging app, creating your group, setting up guidelines for communication, and engaging with your participants effectively, you can make sure that your group text message serves its intended purpose smoothly and efficiently. So go ahead and initiate that group chat – you’ll be amazed at how convenient it is.

This text was generated using a large language model, and select text has been reviewed and moderated for purposes such as readability.

MORE FROM ASK.COM

Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results From the Women's Health Initiative randomized controlled trial

Affiliation.

• 1 Division of Women's Health Initiative, National Heart, Lung, and Blood Institute, 6705 Rockledge Dr, One Rockledge Ctr, Suite 300, Bethesda, MD 20817, [email protected]
• PMID: 12117397
• DOI: 10.1001/jama.288.3.321

Context: Despite decades of accumulated observational evidence, the balance of risks and benefits for hormone use in healthy postmenopausal women remains uncertain.

Objective: To assess the major health benefits and risks of the most commonly used combined hormone preparation in the United States.

Design: Estrogen plus progestin component of the Women's Health Initiative, a randomized controlled primary prevention trial (planned duration, 8.5 years) in which 16608 postmenopausal women aged 50-79 years with an intact uterus at baseline were recruited by 40 US clinical centers in 1993-1998.

Interventions: Participants received conjugated equine estrogens, 0.625 mg/d, plus medroxyprogesterone acetate, 2.5 mg/d, in 1 tablet (n = 8506) or placebo (n = 8102).

Main outcomes measures: The primary outcome was coronary heart disease (CHD) (nonfatal myocardial infarction and CHD death), with invasive breast cancer as the primary adverse outcome. A global index summarizing the balance of risks and benefits included the 2 primary outcomes plus stroke, pulmonary embolism (PE), endometrial cancer, colorectal cancer, hip fracture, and death due to other causes.

Results: On May 31, 2002, after a mean of 5.2 years of follow-up, the data and safety monitoring board recommended stopping the trial of estrogen plus progestin vs placebo because the test statistic for invasive breast cancer exceeded the stopping boundary for this adverse effect and the global index statistic supported risks exceeding benefits. This report includes data on the major clinical outcomes through April 30, 2002. Estimated hazard ratios (HRs) (nominal 95% confidence intervals [CIs]) were as follows: CHD, 1.29 (1.02-1.63) with 286 cases; breast cancer, 1.26 (1.00-1.59) with 290 cases; stroke, 1.41 (1.07-1.85) with 212 cases; PE, 2.13 (1.39-3.25) with 101 cases; colorectal cancer, 0.63 (0.43-0.92) with 112 cases; endometrial cancer, 0.83 (0.47-1.47) with 47 cases; hip fracture, 0.66 (0.45-0.98) with 106 cases; and death due to other causes, 0.92 (0.74-1.14) with 331 cases. Corresponding HRs (nominal 95% CIs) for composite outcomes were 1.22 (1.09-1.36) for total cardiovascular disease (arterial and venous disease), 1.03 (0.90-1.17) for total cancer, 0.76 (0.69-0.85) for combined fractures, 0.98 (0.82-1.18) for total mortality, and 1.15 (1.03-1.28) for the global index. Absolute excess risks per 10 000 person-years attributable to estrogen plus progestin were 7 more CHD events, 8 more strokes, 8 more PEs, and 8 more invasive breast cancers, while absolute risk reductions per 10 000 person-years were 6 fewer colorectal cancers and 5 fewer hip fractures. The absolute excess risk of events included in the global index was 19 per 10 000 person-years.

Conclusions: Overall health risks exceeded benefits from use of combined estrogen plus progestin for an average 5.2-year follow-up among healthy postmenopausal US women. All-cause mortality was not affected during the trial. The risk-benefit profile found in this trial is not consistent with the requirements for a viable intervention for primary prevention of chronic diseases, and the results indicate that this regimen should not be initiated or continued for primary prevention of CHD.

Publication types

• Clinical Trial
• Multicenter Study
• Randomized Controlled Trial
• Research Support, U.S. Gov't, P.H.S.
• Breast Neoplasms / epidemiology*
• Breast Neoplasms / prevention & control
• Clinical Trials Data Monitoring Committees
• Colorectal Neoplasms / epidemiology
• Coronary Disease / epidemiology*
• Coronary Disease / prevention & control
• Endometrial Neoplasms / epidemiology
• Estrogen Replacement Therapy* / adverse effects
• Estrogens, Conjugated (USP) / adverse effects
• Estrogens, Conjugated (USP) / therapeutic use*
• Fractures, Bone / epidemiology
• Fractures, Bone / prevention & control
• Medroxyprogesterone Acetate / adverse effects
• Medroxyprogesterone Acetate / therapeutic use*
• Middle Aged
• Myocardial Infarction / epidemiology
• Postmenopause
• Progesterone Congeners / adverse effects
• Progesterone Congeners / therapeutic use*
• Proportional Hazards Models
• Pulmonary Embolism / epidemiology
• Stroke / epidemiology
• Survival Analysis
• Thrombosis / epidemiology
• Treatment Outcome
• Estrogens, Conjugated (USP)
• Progesterone Congeners
• Medroxyprogesterone Acetate

• Failure of Estrogen Plus Progestin Therapy for Prevention JAMA Editorial July 17, 2002 Suzanne W. Fletcher, MD, MSc; Graham A. Colditz, MD, DrPH

See More About

Select your interests.

Customize your JAMA Network experience by selecting one or more topics from the list below.

• Academic Medicine
• Acid Base, Electrolytes, Fluids
• Allergy and Clinical Immunology
• Anesthesiology
• Anticoagulation
• Art and Images in Psychiatry
• Assisted Reproduction
• Bleeding and Transfusion
• Caring for the Critically Ill Patient
• Challenges in Clinical Electrocardiography
• Climate and Health
• Clinical Challenge
• Clinical Decision Support
• Clinical Implications of Basic Neuroscience
• Clinical Pharmacy and Pharmacology
• Complementary and Alternative Medicine
• Consensus Statements
• Coronavirus (COVID-19)
• Critical Care Medicine
• Cultural Competency
• Dental Medicine
• Dermatology
• Diabetes and Endocrinology
• Diagnostic Test Interpretation
• Drug Development
• Electronic Health Records
• Emergency Medicine
• End of Life
• Environmental Health
• Equity, Diversity, and Inclusion
• Facial Plastic Surgery
• Gastroenterology and Hepatology
• Genetics and Genomics
• Genomics and Precision Health
• Global Health
• Guide to Statistics and Methods
• Hair Disorders
• Health Care Delivery Models
• Health Care Economics, Insurance, Payment
• Health Care Quality
• Health Care Reform
• Health Care Safety
• Health Care Workforce
• Health Disparities
• Health Inequities
• Health Informatics
• Health Policy
• History of Medicine
• Hypertension
• Images in Neurology
• Implementation Science
• Infectious Diseases
• Innovations in Health Care Delivery
• JAMA Infographic
• Law and Medicine
• Leading Change
• Less is More
• LGBTQIA Medicine
• Lifestyle Behaviors
• Medical Coding
• Medical Devices and Equipment
• Medical Education
• Medical Education and Training
• Medical Journals and Publishing
• Mobile Health and Telemedicine
• Narrative Medicine
• Neuroscience and Psychiatry
• Notable Notes
• Nutrition, Obesity, Exercise
• Obstetrics and Gynecology
• Occupational Health
• Ophthalmology
• Orthopedics
• Otolaryngology
• Pain Medicine
• Pathology and Laboratory Medicine
• Patient Care
• Patient Information
• Performance Improvement
• Performance Measures
• Perioperative Care and Consultation
• Pharmacoeconomics
• Pharmacoepidemiology
• Pharmacogenetics
• Pharmacy and Clinical Pharmacology
• Physical Medicine and Rehabilitation
• Physical Therapy
• Physician Leadership
• Population Health
• Professional Well-being
• Professionalism
• Psychiatry and Behavioral Health
• Public Health
• Pulmonary Medicine
• Regulatory Agencies
• Research, Methods, Statistics
• Resuscitation
• Rheumatology
• Risk Management
• Scientific Discovery and the Future of Medicine
• Shared Decision Making and Communication
• Sleep Medicine
• Sports Medicine
• Stem Cell Transplantation
• Substance Use and Addiction Medicine
• Surgical Innovation
• Surgical Pearls
• Teachable Moment
• Technology and Finance
• The Art of JAMA
• The Arts and Medicine
• The Rational Clinical Examination
• Tobacco and e-Cigarettes
• Translational Medicine
• Trauma and Injury
• Treatment Adherence
• Ultrasonography
• Users' Guide to the Medical Literature
• Vaccination
• Venous Thromboembolism
• Veterans Health
• Women's Health
• Workflow and Process
• Wound Care, Infection, Healing

Others Also Liked

• Download PDF
• X Facebook More LinkedIn

Writing Group for the Women's Health Initiative Investigators. Risks and Benefits of Estrogen Plus Progestin in Healthy Postmenopausal Women : Principal Results From the Women's Health Initiative Randomized Controlled Trial . JAMA. 2002;288(3):321–333. doi:10.1001/jama.288.3.321

Manage citations:

© 2023

• Permissions

Risks and Benefits of Estrogen Plus Progestin in Healthy Postmenopausal Women : Principal Results From the Women's Health Initiative Randomized Controlled Trial

Writing Group for the Women's Health Initiative Investigators: Jacques E. Rossouw, MBChB, MD, National Heart, Lung, and Blood Institute, Bethesda, Md; Garnet L. Anderson, PhD, Ross L. Prentice, PhD, Andrea Z. LaCroix, PhD, and Charles Kooperberg, PhD, Fred Hutchinson Cancer Research Center, Seattle, Wash; Marcia L. Stefanick, PhD, Stanford University Clinical Center, Stanford, Calif; Rebecca D. Jackson, MD, Ohio State University Clinical Center, Columbus; Shirley A. A. Beresford, PhD, Fred Hutchinson Cancer Research Center, Seattle, Wash; Barbara V. Howard, PhD, MedStar Research Institute, Washington, DC; Karen C. Johnson, MD, MPH, University of Tennessee, Memphis; Jane Morley Kotchen, MD, Medical College of Wisconsin, Milwaukee; Judith Ockene, PhD, University of Massachusetts Medical School, Worcester.

• Editorial Failure of Estrogen Plus Progestin Therapy for Prevention Suzanne W. Fletcher, MD, MSc; Graham A. Colditz, MD, DrPH JAMA

Context  Despite decades of accumulated observational evidence, the balance of risks and benefits for hormone use in healthy postmenopausal women remains uncertain.

Objective  To assess the major health benefits and risks of the most commonly used combined hormone preparation in the United States.

Design  Estrogen plus progestin component of the Women's Health Initiative, a randomized controlled primary prevention trial (planned duration, 8.5 years) in which 16608 postmenopausal women aged 50-79 years with an intact uterus at baseline were recruited by 40 US clinical centers in 1993-1998.

Interventions  Participants received conjugated equine estrogens, 0.625 mg/d, plus medroxyprogesterone acetate, 2.5 mg/d, in 1 tablet (n = 8506) or placebo (n = 8102).

Main Outcomes Measures  The primary outcome was coronary heart disease (CHD) (nonfatal myocardial infarction and CHD death), with invasive breast cancer as the primary adverse outcome. A global index summarizing the balance of risks and benefits included the 2 primary outcomes plus stroke, pulmonary embolism (PE), endometrial cancer, colorectal cancer, hip fracture, and death due to other causes.

Results  On May 31, 2002, after a mean of 5.2 years of follow-up, the data and safety monitoring board recommended stopping the trial of estrogen plus progestin vs placebo because the test statistic for invasive breast cancer exceeded the stopping boundary for this adverse effect and the global index statistic supported risks exceeding benefits. This report includes data on the major clinical outcomes through April 30, 2002. Estimated hazard ratios (HRs) (nominal 95% confidence intervals [CIs]) were as follows: CHD, 1.29 (1.02-1.63) with 286 cases; breast cancer, 1.26 (1.00-1.59) with 290 cases; stroke, 1.41 (1.07-1.85) with 212 cases; PE, 2.13 (1.39-3.25) with 101 cases; colorectal cancer, 0.63 (0.43-0.92) with 112 cases; endometrial cancer, 0.83 (0.47-1.47) with 47 cases; hip fracture, 0.66 (0.45-0.98) with 106 cases; and death due to other causes, 0.92 (0.74-1.14) with 331 cases. Corresponding HRs (nominal 95% CIs) for composite outcomes were 1.22 (1.09-1.36) for total cardiovascular disease (arterial and venous disease), 1.03 (0.90-1.17) for total cancer, 0.76 (0.69-0.85) for combined fractures, 0.98 (0.82-1.18) for total mortality, and 1.15 (1.03-1.28) for the global index. Absolute excess risks per 10 000 person-years attributable to estrogen plus progestin were 7 more CHD events, 8 more strokes, 8 more PEs, and 8 more invasive breast cancers, while absolute risk reductions per 10 000 person-years were 6 fewer colorectal cancers and 5 fewer hip fractures. The absolute excess risk of events included in the global index was 19 per 10 000 person-years.

Conclusions  Overall health risks exceeded benefits from use of combined estrogen plus progestin for an average 5.2-year follow-up among healthy postmenopausal US women. All-cause mortality was not affected during the trial. The risk-benefit profile found in this trial is not consistent with the requirements for a viable intervention for primary prevention of chronic diseases, and the results indicate that this regimen should not be initiated or continued for primary prevention of CHD.

The Women's Health Initiative (WHI) focuses on defining the risks and benefits of strategies that could potentially reduce the incidence of heart disease, breast and colorectal cancer, and fractures in postmenopausal women. Between 1993 and 1998, the WHI enrolled 161 809 postmenopausal women in the age range of 50 to 79 years into a set of clinical trials (trials of low-fat dietary pattern, calcium and vitamin D supplementation, and 2 trials of postmenopausal hormone use) and an observational study at 40 clinical centers in the United States. 1 This article reports principal results for the trial of combined estrogen and progestin in women with a uterus. The trial was stopped early based on health risks that exceeded health benefits over an average follow-up of 5.2 years. A parallel trial of estrogen alone in women who have had a hysterectomy is being continued, and the planned end of this trial is March 2005, by which time the average follow-up will be about 8.5 years.

The WHI clinical trials were designed in 1991-1992 using the accumulated evidence at that time. The primary outcome for the trial of estrogen plus progestin was designated as coronary heart disease (CHD). Potential cardioprotection was based on generally supportive data on lipid levels in intermediate outcome clinical trials, trials in nonhuman primates, and a large body of observational studies suggesting a 40% to 50% reduction in risk among users of either estrogen alone or, less frequently, combined estrogen and progestin. 2 - 5 Hip fracture was designated as a secondary outcome, supported by observational data as well as clinical trials showing benefit for bone mineral density. 6 , 7 Invasive breast cancer was designated as a primary adverse outcome based on observational data. 3 , 8 Additional clinical outcomes chosen as secondary outcomes that may plausibly be affected by hormone therapy include other cardiovascular diseases; endometrial, colorectal, and other cancers; and other fractures. 3 , 6 , 9

The effect of hormones on overall health was an important consideration in the design and conduct of the WHI clinical trial. In an attempt to summarize important aspects of health benefits vs risks, a global index was defined as the earliest occurrence of CHD, invasive breast cancer, stroke, pulmonary embolism (PE), endometrial cancer, colorectal cancer, hip fracture, or death due to other causes. Compared with total mortality, which may be too insensitive, this index assigns additional weight to the 7 listed diseases. Procedures for monitoring the trial involved semiannual comparisons of the estrogen plus progestin and placebo groups with respect to each of the elements of the global index and to the overall global index.

This report pertains primarily to estrogen plus progestin use among healthy postmenopausal women, since only 7.7% of participating women reported having had prior cardiovascular disease. During the course of the WHI trial, the Heart and Estrogen/progestin Replacement Study (HERS) reported its principal results. 10 HERS was another blinded, randomized controlled trial comparing the same regimen of estrogen plus progestin with placebo among women with a uterus; however, in HERS, all 2763 participating women had documented CHD prior to randomization. The HERS findings of no overall effect on CHD but an apparent increased risk in the first year after randomization seemed surprising given preceding observational studies of hormone use in women with CHD. 3 Subsequent to HERS, some investigators reanalyzed their observational study data and were able to detect an early elevation in CHD risk among women with prior CHD 11 - 13 but not in ostensibly healthy women, 14 prompting speculation that any early adverse effect of hormones on CHD incidence was confined to women who have experienced prior CHD events.

The WHI is the first randomized trial to directly address whether estrogen plus progestin has a favorable or unfavorable effect on CHD incidence and on overall risks and benefits in predominantly healthy women.

Detailed eligibility criteria and recruitment methods have been published. 1 Briefly, most women were recruited by population-based direct mailing campaigns to age-eligible women, in conjunction with media awareness programs. Eligibility was defined as age 50 to 79 years at initial screening, postmenopausal, likelihood of residence in the area for 3 years, and provision of written informed consent. A woman was considered postmenopausal if she had experienced no vaginal bleeding for 6 months (12 months for 50- to 54-year-olds), had had a hysterectomy, or had ever used postmenopausal hormones. Major exclusions were related to competing risks (any medical condition likely to be associated with a predicted survival of <3 years), safety (eg, prior breast cancer, other prior cancer within the last 10 years except nonmelanoma skin cancer, low hematocrit or platelet counts), and adherence and retention concerns (eg, alcoholism, dementia).

A 3-month washout period was required before baseline evaluation of women using postmenopausal hormones at initial screening. Women with an intact uterus at initial screening were eligible for the trial of combined postmenopausal hormones, while women with a prior hysterectomy were eligible for the trial of unopposed estrogen. This report is limited to the 16 608 women with an intact uterus at baseline who were enrolled in the trial component of estrogen plus progestin vs placebo. The protocol and consent forms were approved by the institutional review boards for all participating institutions (see Acknowledgment).

Combined estrogen and progestin was provided in 1 daily tablet containing conjugated equine estrogen (CEE), 0.625 mg, and medroxyprogesterone acetate (MPA), 2.5 mg (Prempro, Wyeth Ayerst, Philadelphia, Pa). A matching placebo was provided to the control group. Eligible women were randomly assigned to receive estrogen plus progestin or placebo after eligibility was established and baseline assessments made ( Figure 1 ). The randomization procedure was developed at the WHI Clinical Coordinating Center and implemented locally through a distributed study database, using a randomized permuted block algorithm, stratified by clinical center site and age group. All study medication bottles had a unique bottle number and bar code to allow for blinded dispensing.

Initially, the design allowed women with a uterus to be randomized to receive unopposed estrogen, estrogen plus progestin, or placebo. After the release of the Postmenopausal Estrogen/Progestin Intervention (PEPI) trial results 15 indicating that long-term adherence to unopposed estrogen was not feasible in women with a uterus, the WHI protocol was changed to randomize women with a uterus to only estrogen plus progestin or placebo in equal proportions. The 331 women previously randomized to unopposed estrogen were unblinded and reassigned to estrogen plus progestin. These women are included in the estrogen plus progestin group in this report, resulting in 8506 participants in the estrogen plus progestin group vs 8102 in the placebo group. Analysis of the data excluding the women randomized before this protocol change did not affect the results. Considerable effort was made to maintain blinding of other participants and clinic staff. When required for safety or symptom management, an unblinding officer provided the clinic gynecologist, who was not involved with study outcomes activities, with the treatment assignment.

Study participants were contacted by telephone 6 weeks after randomization to assess symptoms and reinforce adherence. Follow-up for clinical events occurred every 6 months, with annual in-clinic visits required. At each semiannual contact, a standardized interview collected information on designated symptoms and safety concerns, and initial reports of outcome events were obtained using a self-administered questionnaire. Adherence to study interventions was assessed by weighing of returned bottles. The study protocol required annual mammograms and clinical breast examinations; study medications were withheld if safety procedures were not performed, but these participants continued to be followed up. Electrocardiograms were collected at baseline and at follow-up years 3 and 6.

All data were collected on standardized study forms by certified staff according to documented study procedures. Study data were entered into a local clinical center database developed and maintained by the Clinical Coordinating Center and provided to each site in the form of a local area network connected to the Clinical Coordinating Center through a wide area network. Data quality was ensured through standard data entry mechanisms, routine reporting and database checks, random chart audits, and routine site visits.

During the trial, some flexibility of the dosages of both estrogen and progestin was allowed to manage symptoms such as breast tenderness and vaginal bleeding. Vaginal bleeding was managed according to an algorithm that accounted for the time since randomization, severity of the bleeding, treatment assignment, and endometrial histology. Women who had a hysterectomy after randomization for indications other than cancer were switched to unopposed estrogen or the corresponding placebo without unblinding. These women are included in the original randomization group for analyses.

Permanent discontinuation of study medication was required by protocol for women who developed breast cancer, endometrial pathologic state (hyperplasia not responsive to treatment, atypia, or cancer), deep vein thrombosis (DVT) or PE, malignant melanoma, meningioma, triglyceride level greater than 1000 mg/dL (11.3 mmol/L), or prescription of estrogen, testosterone, or selective estrogen-receptor modulators by their personal physician. Medications were temporarily discontinued in participants who had acute myocardial infarction (MI), stroke, fracture, or major injury involving hospitalization, surgery involving use of anesthesia, any illness resulting in immobilization for more than 1 week, or any other severe illness in which hormone use is temporarily inappropriate.

Cardiovascular Disease Coronary heart disease was defined as acute MI requiring overnight hospitalization, silent MI determined from serial electrocardiograms (ECGs), or CHD death. The diagnosis of acute MI was established according to an algorithm adapted from standardized criteria 16 that included cardiac pain, cardiac enzyme and troponin levels, and ECG readings. The primary analyses included both definite and probable MIs as defined by the algorithm. Myocardial infarction occurring during surgery and aborted MIs were included. An aborted MI was defined as chest pain and ECG evidence of acute MI at presentation, an intervention (eg, thrombolysis) followed by resolution of ECG changes, and all cardiac enzyme levels within normal ranges. Silent MI was diagnosed by comparing baseline and follow-up ECGs at 3 and 6 years after randomization. Coronary death was defined as death consistent with CHD as underlying cause plus 1 or more of the following: preterminal hospitalization with MI within 28 days of death, previous angina or MI and no potentially lethal noncoronary disease, death resulting from a procedure related to coronary artery disease, or death certificate consistent with CHD as the underlying cause. Stroke diagnosis was based on rapid onset of a neurologic deficit lasting more than 24 hours, supported by imaging studies when available. Pulmonary embolism and DVT required clinical symptoms supported by relevant diagnostic studies.

Cancer Breast, colorectal, endometrial, and other cancers were confirmed by pathological reports when available. Current data indicate that at least 98% of breast, colorectal, and endometrial cancers and 92% of other cancers were documented with pathological reports.

Fractures Reports of hip, vertebral, and other osteoporotic fractures (including all fractures except those of the ribs, chest/sternum, skull/face, fingers, toes, and cervical vertebrae) were routinely ascertained. All fracture outcomes were verified by radiology reports. Study radiographs were not obtained to ascertain subclinical vertebral fractures.

This report is based on outcomes adjudicated by clinical center physician adjudicators, as used for trial-monitoring purposes. Clinical center physician adjudicators were centrally trained and blinded to treatment assignment and participants' symptoms. Future communications will report results based on centrally adjudicated outcomes and will include a broader range of outcomes with more extensive explanatory analyses. Since this report is presented before the planned study closeout, outcome information is still being collected and adjudicated. Local adjudication is complete for approximately 96% of the designated self-reported events. To date, agreement rates between local and central adjudication are: MI, 84%; revascularization procedures, 97%; PE, 89%; DVT, 84%; stroke, 94%; invasive breast cancer, 98%; endometrial cancer, 96%; colorectal cancer, 98%; hip fracture, 95%; and specific cause of death, 82%. When related cardiovascular conditions are combined (eg, when unstable angina or congestive heart failure is grouped with MI), agreement rates exceed 94% for cardiovascular disease and 90% for specific cause of death.

All primary analyses use time-to-event methods and are based on the intention-to-treat principle. For a given outcome, the time of event was defined as the number of days from randomization to the first postrandomization diagnosis, as determined by the local adjudicator. For silent MIs, the date of the follow-up ECG applied. Participants without a diagnosis were censored for that event at the time of last follow-up contact. Primary outcome comparisons are presented as hazard ratios (HRs) and 95% confidence intervals (CIs) from Cox proportional hazards analyses, 17 stratified by clinical center, age, prior disease, and randomization status in the low-fat diet trial.

Two forms of CIs are presented, nominal and adjusted. Nominal 95% CIs describe the variability in the estimates that would arise from a simple trial for a single outcome. Although traditional, these CIs do not account for the multiple statistical testing issues (across time and across outcome categories) that occurred in this trial, so the probability is greater than .05 that at least 1 of these CIs will exclude unity under an overall null hypothesis. The adjusted 95% CIs presented herein use group sequential methods to correct for multiple analyses over time. A Bonferroni correction for 7 outcomes as specified in the monitoring plan (described herein) was applied to all clinical outcomes other than CHD and breast cancer, the designated primary and primary adverse effect outcomes, and the global index. The adjusted CIs are closely related to the monitoring procedures and, as such, represent a conservative assessment of the evidence. This report focuses primarily on results using the unadjusted statistics and also relies on consistency across diagnostic categories, supportive data from other studies, and biologic plausibility for interpretation of the findings.

Trial monitoring guidelines for early stopping considerations were based on O'Brien-Fleming boundaries 18 using asymmetric upper and lower boundaries: a 1-sided, .025-level upper boundary for benefit and 1-sided, .05-level lower boundaries for adverse effects. The adverse-effect boundaries were further adjusted with a Bonferroni correction for the 7 major outcomes other than breast cancer that were specifically monitored (CHD, stroke, PE, colorectal cancer, endometrial cancer, hip fracture, and death due to other causes). The global index of monitored outcomes played a supportive role as a summary measure of the overall balance of risks and benefits. Trial monitoring for early stopping considerations was conducted semiannually by an independent data and safety monitoring board (DSMB). Aspects of the monitoring plan have been published. 19

Trial Monitoring and Early Stopping Formal monitoring began in the fall of 1997 with the expectation of final analysis in 2005 after an average of approximately 8.5 years of follow-up. Late in 1999, with 5 interim analyses completed, the DSMB observed small but consistent early adverse effects in cardiovascular outcomes and in the global index. None of the disease-specific boundaries had been crossed. In the spring of 2000 and again in the spring of 2001, at the direction of the DSMB, hormone trial participants were given information indicating that increases in MI, stroke, and PE/DVT had been observed and that the trial continued because the balance of risks and benefits remained uncertain.

In reviewing the data for the 10th interim analyses on May 31, 2002, the DSMB found that the adverse effects in cardiovascular diseases persisted, although these results were still within the monitoring boundaries. However, the design-specified weighted log-rank test statistic for breast cancer ( z = −3.19) crossed the designated boundary ( z = −2.32) and the global index was supportive of a finding of overall harm ( z = −1.62). Updated analyses including 2 months of additional data, available by the time of the meeting, did not appreciably change the overall results. On the basis of these data, the DSMB concluded that the evidence for breast cancer harm, along with evidence for some increase in CHD, stroke, and PE, outweighed the evidence of benefit for fractures and possible benefit for colon cancer over the average 5.2-year follow-up period. Therefore, the DSMB recommended early stopping of the estrogen plus progestin component of the trial. Because the balance of risks and benefits in the unopposed-estrogen component remains uncertain, the DSMB recommended continuation of that component of the WHI. Individual trial participants have been informed.

There were no substantive differences between study groups at baseline; 8506 women were randomized into the estrogen plus progestin group and 8102 into the placebo group ( Table 1a ). The mean (SD) age was 63.3 (7.1) years. Two thirds of the women who reported prior or current hormone use had taken combined hormones and one third had used unopposed estrogen.

Prevalence of prior cardiovascular disease was low and levels of cardiovascular risk factors were consistent with a generally healthy population of postmenopausal women. An assessment of commonly studied breast cancer risk factors, both individually and combined using the Gail model, 20 indicate that the cohort in general was not at increased risk of breast cancer.

Vital status is known for 16 025 randomized participants (96.5%), including 449 (2.7%) known to be deceased. A total of 583 (3.5%) participants were lost to follow-up or stopped providing outcomes information for more than 18 months. The remaining 15 576 (93.8%) provided recent outcome information ( Figure 1 ).

At the time of this report, all women had been enrolled for at least 3.5 years, with an average follow-up of 5.2 years and a maximum of 8.5 years. A substantial number of women had stopped taking study drugs at some time (42% of estrogen plus progestin and 38% of placebo). Dropout rates over time ( Figure 2 ) exceeded design projections, particularly early on, but compare favorably with community-based adherence to postmenopausal hormones. 21 Some women in both groups initiated hormone use through their own clinician (6.2% in the estrogen plus progestin group and 10.7% in the placebo group cumulatively by the sixth year). These "drop-in" rates were also greater than expected.

At the time of this report, clinic gynecologists had been unblinded to treatment assignment for 3444 women in the estrogen plus progestin group and 548 women in the placebo group, primarily to manage persistent vaginal bleeding. During the trial, 248 women in the estrogen plus progestin group and 183 in the placebo group had a hysterectomy.

Blood lipid levels, assessed in an 8.6% subsample of fasting blood specimens collected from women at baseline and year 1, showed greater reductions in low-density lipoprotein cholesterol (−12.7%) and increases in high-density lipoprotein cholesterol (7.3%) and triglycerides (6.9%) with estrogen plus progestin relative to placebo (data not shown), consistent with HERS and PEPI. 10 , 22 Systolic blood pressure was, on average, 1.0 mm Hg higher in women taking estrogen plus progestin at 1 year, rising to 1.5 mm Hg at 2 years and beyond (data not shown). Diastolic blood pressures did not differ.

Cardiovascular Disease Overall CHD rates were low ( Table 2 ). The rate of women experiencing CHD events was increased by 29% for women taking estrogen plus progestin relative to placebo (37 vs 30 per 10 000 person-years), reaching nominal statistical significance (at the .05 level). Most of the excess was in nonfatal MI. No significant differences were observed in CHD deaths or revascularization procedures (coronary artery bypass grafting or percutaneous transluminal coronary angioplasty). Stroke rates were also higher in women receiving estrogen plus progestin (41% increase; 29 vs 21 per 10 000 person-years), with most of the elevation occurring in nonfatal events. Women in the estrogen plus progestin group had 2-fold greater rates of venous thromboembolism (VTE), as well as DVT and PE individually, with almost all associated CIs excluding 1. Rates of VTE were 34 and 16 per 10 000 person-years in the estrogen plus progestin and placebo groups, respectively. Total cardiovascular disease, including other events requiring hospitalization, was increased by 22% in the estrogen plus progestin group.

Cancer The invasive breast cancer rates in the placebo group were consistent with design expectations. The 26% increase (38 vs 30 per 10 000 person-years) observed in the estrogen plus progestin group almost reached nominal statistical significance and, as noted herein, the weighted test statistic used for monitoring was highly significant. No significant difference was observed for in situ breast cancers. Follow-up rates for mammography were comparable in the estrogen plus progestin and placebo groups. Colorectal cancer rates were reduced by 37% (10 vs 16 per 10 000 person-years), also reaching nominal statistical significance. Endometrial cancer incidence was not affected, nor was lung cancer incidence (54 vs 50; HR, 1.04; 95% CI, 0.71-1.53) or total cancer incidence.

Fractures This cohort experienced low hip fracture rates (10 per 10 000 person-years in the estrogen plus progestin group vs 15 per 10 000 person-years in the placebo group). Estrogen plus progestin reduced the observed hip and clinical vertebral fracture rates by one third compared with placebo, both nominally significantly. The reductions in other osteoporotic fractures (23%) and total fractures (24%) were statistically significant (all associated CIs exclude 1).

The global index showed a nominally significant 15% increase in the estrogen plus progestin group (170 vs 151 per 10 000 person-years). There were no differences in mortality or cause of death between groups ( Table 3 ).

The Kaplan Meier estimates of cumulative hazards ( Figure 3 ) for CHD indicate that the difference between treatment groups began to develop soon after randomization. These curves provide little evidence of convergence through 6 years of follow-up. The cumulative hazards for stroke begin to diverge between 1 and 2 years after randomization, and this difference persists beyond the fifth year. For PE, the curves separate soon after randomization and show continuing adverse effects throughout the observation period. For breast cancer, the cumulative hazard functions are comparable through the first 4 years, at which point the curve for estrogen plus progestin begins to rise more rapidly than that for placebo. Curves for colorectal cancer show benefit beginning at 3 years, and curves for hip fracture show increasing cumulative benefit over time. The difference in hazard rates for the global index ( Figure 4 ) suggests a gradual increase in adverse effects compared with benefits for estrogen plus progestin through year 5, with a possible narrowing of the difference by year 6; however, HR estimates tend to be unstable beyond 6 years after randomization. Total mortality rates are indistinguishable between estrogen plus progestin and placebo.

Tests for linear trends with time since randomization, based on a Cox proportional hazards model with a time-dependent covariate, detected no trend with time for CHD, stroke, colorectal cancer, hip fracture, total mortality, or the global index ( Table 4 ). There was some evidence for an increasing risk of breast cancer over time with estrogen plus progestin ( z = 2.56 compared with a nominal z score for statistical significance of 1.96) and a decreasing risk of VTE with time ( z = −2.45). These results must be viewed cautiously because the number of events in each interval is modest, the data in later years are still incomplete, and later year comparisons are limited to women still at risk of their first event for that outcome.

Cardiovascular Disease A small subset of women (n = 400; average follow-up, 57.4 months) in WHI reported conditions at baseline that would have made them eligible for HERS, ie, prior MI or revascularization procedures. Among these women with established coronary disease, the HR for subsequent CHD for estrogen plus progestin relative to placebo was 1.28 (95% CI, 0.64-2.56) with 19 vs 16 events. The remaining women, those without prior CHD, had an identical HR for CHD (145 vs 106; HR, 1.28; 95% CI, 1.00-1.65). Few women with a history of VTE were enrolled, but these data suggest a possibility that these women may be at greater risk of future VTE events when taking estrogen plus progestin (7 vs 1; HR, 4.90; 95% CI, 0.58-41.06) than those without a history of VTE (144 vs 66; HR, 2.06; 95% CI, 1.54-2.76). For stroke, prior history did not confer additional risk (1 vs 5 in women with prior stroke; HR, 0.46; 95% CI, 0.05-4.51; 126 vs 80 with no prior stroke; HR, 1.47; 95% CI, 1.11-1.95). No noteworthy interactions with age, race/ethnicity, body mass index, prior hormone use, smoking status, blood pressure, diabetes, aspirin use, or statin use were found for the effect of estrogen plus progestin on CHD, stroke, or VTE.

Breast Cancer Women reporting prior postmenopausal hormone use had higher HRs for breast cancer associated with estrogen plus progestin use than those who never used postmenopausal hormones (among never users, 114 vs 102; HR, 1.06; 95% CI, 0.81-1.38; for women with <5 years of prior use, 32 vs 15; HR, 2.13; 95% CI, 1.15-3.94; for women with 5-10 years of prior use, 11 vs 2; HR, 4.61; 95% CI, 1.01-21.02; and for women with ≥10 years of prior use, 9 vs 5; HR, 1.81; 95% CI, 0.60-5.43; test for trend, z = 2.17). No interactions between estrogen plus progestin and age, race/ethnicity, family history, parity, age at first birth, body mass index, or Gail-model risk score were observed for invasive breast cancer.

Because a number of women stopped study medications during follow-up, several analyses were performed to examine the sensitivity of the principal HR estimates to actual use of study medications. Analyses that censored a woman's event history 6 months after becoming nonadherent (using <80% of or stopping study drugs) produced the largest changes to estimated effect sizes. This approach increased HRs to 1.51 for CHD, to 1.49 for breast cancer, to 1.67 for stroke, and to 3.29 for VTE. Analyses attributing events to actual hormone use ("as treated," allowing for a 6-month lag) produced more modest changes to these estimates. Analyses excluding women randomized during the period when the unopposed-estrogen component was open to women with a uterus and analyses stratifying by enrollment period did not substantially affect the results. These analyses suggest that the intention-to-treat estimates of HRs may somewhat underestimate the effect sizes relative to what would be observed with full adherence to study medications.

The WHI provides evidence from a large randomized trial that addresses the important issue of whether most women with an intact uterus in the decades of life following menopause should consider hormone therapy to prevent chronic disease. The WHI enrolled a cohort of mostly healthy, ethnically diverse women, spanning a large age range (50-79 years at baseline). It is noteworthy that the increased risks for cardiovascular disease and invasive breast cancer were present across racial/ethnic and age strata and were not influenced by the antecedent risk status or prior disease. Hence, the results are likely to be generally applicable to healthy women in this age range. At the time the trial was stopped, the increases in numbers of invasive breast cancers, CHD, stroke, and PE made approximately equal contributions to harm in the estrogen plus progestin group compared with placebo, which were not counterbalanced by the smaller reductions in numbers of hip fractures and colorectal cancers.

Even though the trial was stopped early for harm from breast cancer, a sufficient number of CHD events had occurred by 5.2 years of average follow-up to suggest that continuation to the planned end would have been unlikely to yield a favorable result for the primary outcome of CHD. Even if there were a reversal of direction toward benefit of a magnitude seen in the observational studies (ie, a risk reduction of 55%) during the remaining years, conditional power analyses indicate that less than 10% power remained for showing potential benefit if the trial continued.

The WHI finding that estrogen plus progestin does not confer benefit for preventing CHD among women with a uterus concurs with HERS findings among women with clinically apparent CHD, 10 with the Estrogen Replacement for Atherosclerosis trial, in which estrogen plus progestin did not inhibit progression, 23 and with a trial in women with unstable angina that did not observe a reduction in ischemic events. 24 The finding of an increased risk after initiation of treatment in WHI is similar to HERS. In HERS, after 4.1 and 6.8 years of follow-up, hormone therapy did not increase or decrease risk of cardiovascular events in women with CHD. 25 The WHI extends these findings to include a wider range of women, including younger women and those without clinically apparent CHD, and indicates that the risk may persist for some years.

Unlike CHD, the excess risk of stroke in the estrogen plus progestin group was not present in the first year but appeared during the second year and persisted through the fifth year. Preliminary analyses indicate that the modest difference in blood pressure between groups does not contribute much to an explanation of the increase in strokes (data not shown). The findings in WHI for stroke are consistent with but somewhat more extreme than those of HERS, which reported a nonsignificant 23% increase in the treatment group. 26 The results were also more extreme than those of the Women's Estrogen and Stroke Trial of estradiol (without progestin) in women with prior stroke, which found no effect of estrogen on recurrent strokes overall but some increase in the first 6 months. 27 Trials of the effect of estradiol on carotid intima-media thickness have yielded conflicting results. 28 , 29 At least 1 observational study has suggested that that use of estrogen plus progestin is associated with higher risk of stroke than estrogen alone. 14 In WHI, there was no indication that excess strokes due to estrogen plus progestin were more likely to occur in older women, in women with prior stroke history, by race/ethnicity, or in women with high blood pressure at baseline. Therefore, it appears that estrogen plus progestin increases the risk of strokes in apparently healthy women.

Venous thromboembolism is an expected complication of postmenopausal hormones, and the pattern over time in WHI is consistent with the findings from HERS and several observational studies. 30 , 31

The WHI is the first randomized controlled trial to confirm that combined estrogen plus progestin does increase the risk of incident breast cancer and to quantify the degree of risk. The WHI could not address the risk of death due to breast cancer because with the relatively short follow-up time, few women in the WHI have thus far died as a result of breast cancer (3 in the active treatment group and 2 in the placebo group). The risk of breast cancer emerged several years after randomization. After an average follow-up of about 5 years, the adverse effect on breast cancer had crossed the monitoring boundary. The 26% excess of breast cancer is consistent with estimates from pooled epidemiological data, which reported a 15% increase for estrogen plus progestin use for less than 5 years and a 53% increase for use for more than 5 years. 32 It is also consistent with the (nonsignificant) 27% increase found after 6.8 years of follow-up in HERS. 33

With more common use of estrogen plus progestin, several epidemiological studies have reported that estrogen plus progestin appears to be associated with greater risk of breast cancer than estrogen alone. 34 - 37 In the PEPI trial, women in the 3 estrogen plus progestin groups had much greater increases in mammographic density (a predictor of breast cancer) than women in the estrogen or placebo groups. 38 In WHI, the HR for estrogen plus progestin was not higher in women with a family history or other risk factors for breast cancer, except for reported prior use of postmenopausal hormones. This may suggest a cumulative effect of years of exposure to postmenopausal hormones.

Endometrial cancer rates were low and were not increased by 5 years of estrogen plus progestin exposure. Close monitoring for bleeding and treatment of hyperplasia may contribute to the absence of increased risk of endometrial cancer.

The reduction in colorectal cancer in the hormone group is consistent with observational studies, which have suggested fairly consistently that users of postmenopausal hormones may be at lower risk of colorectal cancer. 39 The mechanisms by which hormone use might reduce risk are unclear. Results from other trials of postmenopausal hormones will help resolve the effects of hormones on colorectal cancer. 40

The reductions in clinical vertebral fractures, other osteoporotic fractures, and combined fractures supported the benefit for hip fractures found in this trial. These findings are consistent with the observational data and limited data from clinical trials 41 and are also consistent with the known ability of estrogen (with or without progestin) to maintain bone mineral density. 42 The WHI is the first trial with definitive data supporting the ability of postmenopausal hormones to prevent fractures at the hip, vertebrae, and other sites.

At the end of the trial, the global index indicated that there were more harmful than beneficial outcomes in the estrogen plus progestin group vs the placebo group. The monitored outcomes included in the global index were selected to represent diseases of serious import that estrogen plus progestin treatment might affect, and do not include a variety of other conditions and measures that may be affected in unfavorable or favorable ways (eg, gallbladder disease, diabetes, quality of life, and cognitive function). The data on these and other outcomes will be the subject of future publications. All-cause mortality was balanced between the groups; however, longer follow-up may be needed to assess the impact of the incident diseases on total mortality.

The absolute excess risk (or risk reduction) attributable to estrogen plus progestin was low. Over 1 year, 10 000 women taking estrogen plus progestin compared with placebo might experience 7 more CHD events, 8 more strokes, 8 more PEs, 8 more invasive breast cancers, 6 fewer colorectal cancers, and 5 fewer hip fractures. Combining all the monitored outcomes, women taking estrogen plus progestin might expect 19 more events per year per 10 000 women than women taking placebo. Over a longer period, more typical of the duration of treatment that would be needed to prevent chronic disease, the absolute numbers of excess outcomes would increase proportionately.

During the 5.2 years of this trial, the number of women experiencing a global index event was about 100 more per 10 000 women taking estrogen plus progestin than taking placebo. If the current findings can be extrapolated to an even longer treatment duration, the absolute risks and benefits associated with estrogen plus progestin for each of these conditions could be substantial and on a population basis could account for tens of thousands of conditions caused, or prevented, by hormone use.

This trial tested only 1 drug regimen, CEE, 0.625 mg/d, plus MPA, 2.5 mg/d, in postmenopausal women with an intact uterus. The results do not necessarily apply to lower dosages of these drugs, to other formulations of oral estrogens and progestins, or to estrogens and progestins administered through the transdermal route. It remains possible that transdermal estradiol with progesterone, which more closely mimics the normal physiology and metabolism of endogenous sex hormones, may provide a different risk-benefit profile. The WHI findings for CHD and VTE are supported by findings from HERS, but there is no other evidence from clinical trials for breast cancer and colorectal cancer, and only limited data from trials concerning fractures.

Importantly, this trial could not distinguish the effects of estrogen from those of progestin. The effects of progestin may be important for breast cancer and atherosclerotic diseases, including CHD and stroke. Per protocol, in a separate and adequately powered trial, WHI is testing the hypothesis of whether oral estrogen will prevent CHD in 10 739 women who have had a hysterectomy. The monitoring of this trial is similar to that for the trial of estrogen plus progestin. At an average follow-up of 5.2 years, the DSMB has recommended that this trial continue because the balance of overall risks and benefits remains uncertain. These results are expected to be available in 2005, at the planned termination.

The relatively high rates of discontinuation in the active treatment arm (42%) and crossover to active treatment in the placebo arm (10.7%) are a limitation of the study; however, the lack of adherence would tend to decrease the observed treatment effects. Thus, the results presented here may underestimate the magnitude of both adverse effects on cardiovascular disease and breast cancer and the beneficial effects on fractures and colorectal cancer among women who adhere to treatment.

The fact that the trial was stopped early decreases the precision of estimates of long-term treatment effects. A longer intervention period might have shown more pronounced benefit for fractures and might have yielded a more precise test of the hypothesis that treatment reduces colorectal cancer. Nonetheless, it appears unlikely that benefit for CHD would have emerged by continuing the trial to its planned termination. The trial results indicate that treatment for up to 5.2 years is not beneficial overall and that there is early harm for CHD, continuing harm for stroke and VTE, and increasing harm for breast cancer with increasing duration of treatment. This risk-benefit profile is not consistent with the requirements for a viable intervention for the primary prevention of chronic diseases.

The WHI trial results provide the first definitive data on which to base treatment recommendations for healthy postmenopausal women with an intact uterus. This trial did not address the short-term risks and benefits of hormones given for the treatment of menopausal symptoms. On the basis of HERS and other secondary prevention trials, the American Heart Association recommended against initiating postmenopausal hormones for the secondary prevention of cardiovascular disease. 43 The American Heart Association made no firm recommendation for primary prevention while awaiting the results from randomized clinical trials such as WHI, and stated that continuation of the treatment should be considered on the basis of established noncoronary benefits and risks, possible coronary benefits and risks, and patient preference.

Results from WHI indicate that the combined postmenopausal hormones CEE, 0.625 mg/d, plus MPA, 2.5 mg/d, should not be initiated or continued for the primary prevention of CHD. In addition, the substantial risks for cardiovascular disease and breast cancer must be weighed against the benefit for fracture in selecting from the available agents to prevent osteoporosis.

• Register for email alerts with links to free full-text articles
• Access PDFs of free articles
• Manage your interests
• Save searches and receive search alerts

•    Home
• Article citations
• Biomedical & Life Sci.
• Business & Economics
• Chemistry & Materials Sci.
• Computer Sci. & Commun.
• Earth & Environmental Sci.
• Engineering
• Medicine & Healthcare
• Physics & Mathematics
• Social Sci. & Humanities

Journals by Subject  

• Biomedical & Life Sciences
• Chemistry & Materials Science
• Computer Science & Communications
• Earth & Environmental Sciences
• Social Sciences & Humanities
• Paper Submission
• Information for Authors
• Peer-Review Resources
• Open Special Issues
• Open Access Statement
• Frequently Asked Questions

Publish with us  

Article citations more>>.

Writing Group for the Women’s Health Initiative Investigators. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the Women’s Health Initiative randomized controlled trial. JAMA 2002;288:321-333.

has been cited by the following article:

TITLE: Symptomatic changes in postmenopause with different methods of hormonal therapy

KEYWORDS: hormonal therapy; transdermal estradiol; tibolone; oral estrogen; nasal estradiol; postmenopause

JOURNAL NAME: Open Journal of Preventive Medicine , Vol.1 No.2 , August 22, 2011

ABSTRACT: Objective: The diversity of opinions on the adverse effects of medications used to treat postmenopausal symptoms has prompted the use of various routes and mechanisms of action that need to be explored because bioavailability of the medications can vary. In order to select the appropriate route of administration for hormonal therapy (HT), it is necessary to determine baseline therapeutic efficacy. Design: We designed a prospective, randomized study consisting of four groups of postmenopausal wo-men: group 1 received oral conjugated estrogens, group 2 received a synthethic steroid, group 3 received estradiol nasally in spray form, and group 4 used transdermal estradiol in the form of patches. Criteria used to evaluate effectiveness was the Greene scale, which evaluate six components. These criteria were applied to each patient before hormonal intervention and then each month for 6 months. Luteinizing hormone (LH), follicle stimulating horone (FSH) and estradiol concentration were determined by chemiluminescence. Student’s t-test was used for intra-group comparisons before and after treatment. Results: There was a significant decrease in the vasomotor and sexual component (p

Related Articles:

• Open   Access Articles Patterns of medication use for the treatment of menopausal symptoms before and after the women’s health initiative; implications for decision-making practices of women and women’s health professionals Chioma Uzoigwe Smith, Srini Rajagopalan, Shiva Sajjan, Shuvayu Sankar Sen, Wenchen Kenneth Wu, Henry Hu Health Vol.3 No.7 , July 19, 2011 DOI: 10.4236/health.2011.37069
• Open   Access Articles Magnesium in Women’s Health and Gynecology Shawna Tonick, Ozgul Muneyyirci-Delale Open Journal of Obstetrics and Gynecology Vol.6 No.5 , April 28, 2016 DOI: 10.4236/ojog.2016.65041
• Open   Access Articles Women’s Experiences with Gender Violence and the Mental Health Impact: Qualitative Findings Venus Medina Maldonado, Margarete Landenberger, Marbella Camacaro Cuevas Open Journal of Nursing Vol.5 No.2 , February 6, 2015 DOI: 10.4236/ojn.2015.52012
• Open   Access Articles Navigating the Third Frontier of Antimicrobial Therapy to Support Women’s Health Emma Wittman, Neela Yar, Bryan Larsen Open Journal of Obstetrics and Gynecology Vol.10 No.8 , August 6, 2020 DOI: 10.4236/ojog.2020.1080096
• Open   Access Articles The Stereotypical Representation of Females in Women’s Health Magazine’s Cosmetic Advertisements Gulcin Ipek Emeksiz Open Journal of Social Sciences Vol.9 No.9 , September 2, 2021 DOI: 10.4236/jss.2021.99005
• Journals A-Z

About SCIRP

• Publication Fees
• For Authors
• Peer-Review Issues
• Special Issues
• Manuscript Tracking System
• Subscription
• Translation & Proofreading
• Volume & Issue
• Open Access
• Publication Ethics
• Preservation
• Privacy Policy

Get Started with WHI

Join special interest groups.

Scientific Interest Groups, or SIGs, focus on a particular health research area. Join them to:

• learn of ongoing WHI research
• become familiar with WHI resource
• meet members of the investigator commuity

Find a Sponsoring Investigator

A WHI Sponsoring Investigator will help you navigate WHI data and procedures. Find a sponsor with common interests to help you develop a proposal for a new manuscript or study.

Join Open Writing Groups

You may be able to contribute to ongoing projects by joining a writing group for an approved paper proposal. If you are new to WHI, contact a Sponsoring Investigator to find out more.

Propose a New Paper or Ancillary Study

Do you have an idea for an analysis? Propose a paper to analyze existing data.

Do you want to collect new data from WHI participants or analyze their biospecimen samples ? Plan an ancillary study to answer a novel research question.

Search publications and ancillary studies already completed or in progress to avoid overlap.

Become an Associate Member

Are you already participating in WHI research functions, either as an active committee member, current or recent Scientific Interest Group (SIG) lead, or current or recent ancillary study investigator? Consider applying to become an Associate Member !

Associate Members may propose a manuscript or ancillary study without the need for a sponsoring PI, nominate oneself to be a co-author of an approved manuscript or as a committee member, access study datasets with an approved data usage agreement, and are invited to participate in WHI scientific meetings. Please see the WHI Investigator categories for additional details.

WHI investigators may also nominate a qualified individual for Associate Member.

The WHI program is funded by the National Heart, Lung, and Blood Institute, National Institutes of Health, U.S. Department of Health and Human Services.

• WHI SharePoint
• WHI Webmail

© 2021 Women’s Health Initiative. All rights reserved

"Risks and Benefits of Estrogen Plus Progestin in Healthy, Postmenopausal Women: Principal Results from the Women's Health Initiative Randomized Controlled Trial" (2002), by Jacques Rossouw et al.

In 2002, the Writing Group for the Women's Health Initiative Investigators published the article "Risks and Benefits of Estrogen Plus Progestin in Healthy, Postmenopausal Women: Principal Results from the Women's Health Initiative Randomized Controlled Trial" in The Journal of the American Medical Association . In the article, the authors report on the Women's Health Initiative, which was a study initiated by the National Institutes of Health to determine the effects of hormone therapy in postmenopausal women, or women whose menstrual cycles have stopped, from the ages of fifty to seventy-nine. The researchers attempted to determine if a link existed between a common type of hormone therapy, a combination of estrogen and progestin, and prevalent diseases in postmenopausal women, including cardiovascular disease and cancer. As reported by the authors in their article, the researchers discontinued the study after five years when they found that there were many risks associated with the use of estrogen plus progestin hormone therapy, including increased risks of breast cancer and heart diseases.

During the twentieth century, physicians began using hormone therapies to treat women hormonal deficiencies. One of the first hormone therapies was known as Premarin, a form of estrogen supplementation derived from the urine of pregnant horses, and was used primarily in postmenopausal women beginning in the 1960s. Doctors prescribed Premarin among other drugs as a means to prevent heart disease and cancer in their female patients. Between 1960 and 1975, annual estrogen prescriptions doubled in female patients. Women used it to combat symptoms associated with menopause, including flushing, insomnia, low libido, and weight gain. However, little was known about the long-term effects of hormone therapy, until researchers conducted clinical trials to study that at the end of the twentieth century.

In 1991, Bernadine Healy, the first female director of the National Institutes of Health in Bethesda, Maryland, established the Women's Health Initiative to study major causes of death in postmenopausal women. The researchers of the Women's Health Initiative defined postmenopausal women as women age fifty to fifty-four who had not had a menstrual cycle in at least twelve months, women age fifty-five and above, up to seventy-nine years old, who had not had a menstrual cycle in six months, women who had had their uteri removed, and women who had begun to take postmenopausal medications.

The Women's Health Initiative included three clinical trials and one observational study. "Risks and Benefits of Estrogen Plus Progestin in Healthy, Postmenopausal Women: Principal Results from the Women's Health Initiative Randomized Controlled Trial," authored by the Writing Group for the Women's Health Initiative Investigators, reported on the results of one of the clinical trials. The Writing Group included Jacques Rossouw, Garnet Anderson, Ross Prentice, Andrea LaCroix, Charles Kooperberg, Marcia Stefanick, Rebecca Jackson, Shirley Beresford, Barbara Howard, Karen Johnson, Jane Morley Kotchen, and Judith Ockene. Those researchers were responsible for compiling the data and conducting the primary clinical study that was the focus of "Risks and Benefits." They all contributed to the final report.

The purpose of the clinical trial, according to the authors, was to determine the risks and benefits of the use of hormone therapy. Hormonal therapy is the supplementation of naturally occurring hormones that decline during menopause in women. At the time of the study's commencement, hormone therapy was commonly used to treat symptoms of menopause, such as hot sweats and vaginal dryness. Additionally, hormone therapy was used to prevent the incidence of heart disease, breast and colorectal cancer, and bone fractures in postmenopausal women. To determine if there were any negative effects of hormone therapy on women, the researchers involved in the WHI enrolled over 16,000 postmenopausal women in the study between 1993 and 1998. The trial studied the effects of estrogen and progestin, which were the specific hormones commonly used together in hormone therapy. Estrogen is a female sex hormone associated with the menstrual cycle that is excreted by the ovary. Progestin is a synthetic hormone that is the artificial equivalent to the female sex hormone progesterone and is responsible regulating the uterine lining.

"Risks and Benefits" was organized into four parts, an introduction section, a methods section, a results section, and a further comments section. Within the introduction, the authors detail the purposes and background of the WHI and the hormone therapy clinical trial parameters, and they mention that the primary purpose of the study was to determine the safety of hormone therapy. In the methods section, the authors describe how they chose participants based on criteria including overall good health, age, and absence of menstruation. They set up the trial to have an experimental group receive the hormone therapy and to have a placebo group receive a placebo. In the results section, the Writing Group documents the outcomes of the study, including their findings that the use of hormone therapy may result in an increased risk of breast cancer of up to twenty-six percent of women, and an increased risk of cardiovascular disease of twenty-nine percent of women. In the final comments section, the authors describe their conclusions that hormone therapy increases a postmenopausal woman's likelihood of developing a chronic disease. In "Risks and Benefits," the authors concluded that there were more risks than benefits associated with the use of hormone therapy in postmenopausal women in regard to breast cancer and heart disease risks.

The authors highlight the purpose of the study in the introduction section, stating that they wanted to determine the direct effects of hormone therapy on heart disease and cancer in women, and whether it could be safe to use to prevent those diseases. The research team first provide a brief overview of the study, along with an immediate disclaimer that the particular study was supposed to last fifteen years but was stopped after five years due to unforeseen health risks as a result of the treatment. While 168,000 women were potential candidates for the study, the researchers developed baseline qualities each participant had to have to maintain a cohesive population sample for the study. Those qualities included a woman's previous experience with heart disease or cancer and prior usage of hormone therapy unrelated to the study.

The authors also discuss the treatment groups. In the original experimental group, healthy postmenopausal women were given estrogen plus progestin hormone therapy or estrogen only hormone therapy. The authors note that they changed the experimental group to only include the estrogen plus progestin therapy after they obtained results showing that the estrogen-only therapy wasn't feasible. The placebo group included healthy women who received a sugar pill.

The authors then describe the goals of the study in the context of the aims for the Women's Health Initiative. They distinguish "Risks and Benefits" as being the first study to determine the effects of hormone therapy on women before they ever showed signs of coronary heart disease. That was an important marker because the team wanted to determine if hormone therapy could prevent or cause the disease. The authors describe other illnesses that commonly affect postmenopausal women, including osteoporosis and breast cancer, which are also related to hormones. The authors emphasize that one of the main goals of the study was to determine if hormone therapy could prevent postmenopausal women from developing those diseases. To compile their evidence in a cohesive manner, they organized the final report's section on methods into separate categories.

The authors divide their methods section into eight subsections. The first three subsections focus on the selection of patients and the study's randomization techniques. To be selected for the study, women had to be between the ages of fifty and seventy-nine and had to have been considered postmenopausal at the time. The authors describe other factors that affected a woman's likelihood of being selected for the study. Those factors included the potential for the patient's relocating and the woman's previous disease history. The researchers selected women who had not taken any hormonal medications for three months before the study began to ensure that it was the trial's hormone therapy causing any observable effects. The researchers designated eligible women to either receive the combined estrogen-progestin hormone therapy pill or a placebo pill, which served as a control for the experiment. The researchers kept in contact with the women throughout the study, and assessed their adherence to the medication protocol and any side effects the women were experiencing. In order to measure specific health outcomes of the participants, the researchers required that the participants receive annual mammograms along with electrocardiograms every three years. The mammogram is a type of x-ray used to diagnose breast cancer, and an electrocardiogram is a test that diagnoses different forms of heart disease.

The authors then detail their use of statistics and safety monitoring in determining negative health outcomes throughout the study in the remaining five sections of the methods. They used statistical analysis to determine the significance of change seen in health outcomes among the women who had received the hormone therapy and the women who had received the placebo. They defined negative outcomes as being an occurrence of cancer, heart disease, or osteoporosis-related bone fracture that may have been caused by the use of hormone therapy. Some women stopped participating in the study before it concluded, because they had developed cancer or blood clots in their legs. Other women temporarily discontinued the medications for a short period of time if they had encountered health problems such as a heart attack or stroke. The researchers derived their results after five years of experimentation, beginning the study in 1993.

In the results section of the article, the authors discuss the weaknesses of the study, the final outcomes, and the effects of hormone therapy on heart disease and cancer. They state that almost half of all the women involved in both the treatment group and the placebo group had to stop taking their therapies for either an acute illness or voluntary withdrawal from the medication regimen. Of all the participants, 2.7 percent died before the authors ended the trials. Dropout rates and death rates exceeded what the authors had anticipated at the start of the study, meaning they had less data to use than they originally expected.

The authors further discuss the results of the study. Women in the estrogen-progestin treatment group experienced lower cholesterol levels than women in the placebo group. However, the authors also state that women in the treatment group were twenty-nine percent more likely to experience a cardiovascular event such as a stroke or heart attack than the women receiving the placebo. The authors mention that women in the treatment group experienced a twenty-eight percent increased risk for invasive breast cancer. They state that it was those differences that led to the premature end of the clinical trial in 1998. Women in the treatment group experienced a thirty-seven percent reduction in colorectal cancers and no difference in lung cancers. The authors state that bone fractures were reduced by ten percent in the women in the treatment group. The authors conclude that the participants' non-adherence to the study protocols and the increased amount of dropout and death rates may have affected the conclusions of the study.

In the final section of "Risks and Benefits," the authors describe that there were more negative outcomes associated with the study than positive outcomes. The team reiterate one of the goals of the study was to determine if hormone therapy using estrogen and progestin could be used to prevent coronary heart disease, cancer, and bone fractures. The authors note that the use of estrogen plus progestin hormone therapy increased the risk of heart disease and breast cancer in all racial and age groups. However, they also note that it reduced risks of colorectal cancers and bone fractures. The researchers conclude that risks associated with the use of estrogen plus progestin hormone therapy hormone therapy outweigh the benefits, which led them to end the trial after five years, ten years earlier than they originally anticipated. The researchers call for further observation before reporting on patient mortality associated with the use of hormone therapy.

As of 2017, "Risks and Benefits" had been cited over 12,200 times. Historian Elizabeth Siegel Watkins, who studies the history of hormone therapy, cited that over half of the women who had been taking the common hormone therapy drug, Premarin, ceased their treatments after the results of the study were published in 2002. A further study by the Women's Health Initiative found that estrogen plus progestin hormone therapy also led to an increased risk of stroke and dementia.

In 2013, National Public Radio interviewed Joann Manson, director of the Women's Health Initiative. Manson stated that women should not use hormones for chronic disease prevention, but that younger women with moderate or severe symptoms of menopause may consider hormone therapy as they are less likely to experience negative side effects. Manson also stated the purpose of the clinical trials was not to dissuade women from ever using hormone therapy, but to determine the effects of hormone therapy as a treatment for chronic disease prevention.

• Parker-Pope, Tara. "The Women's Health Initiative and the Body Politic." The New York Times , April 9, 2011. http://www.nytimes.com/2011/04/10/weekinreview/10estrogen.html (Accessed July 2, 2017).
• Shumaker, Sally A., Claudine Legault, Stephen R. Rapp, Leon Thal, Robert B. Wallace, Judith K. Ockene, Susan L. Hendrix et al. "Estrogen plus progestin and the incidence of dementia and mild cognitive impairment in postmenopausal women: the Women's Health Initiative Memory Study: a randomized controlled trial." Journal of American Medical Association 289 (2003): 2651–2662. http://www.npr.org/sections/health-shots/2013/10/04/229171477/the-last-word-on-hormone-therapy-from-the-womens-health-initiative (Accessed July 2, 2017).
• Shute, Nancy. "The Last Word On Hormone Therapy From the Women's Health Initiative (interview with Joann Manson)." National Public Radio , October 4, 2013. http://www.npr.org/sections/health-shots/2013/10/04/229171477/the-last-word-on-hormone-therapy-from-the-womens-health-initiative (Accessed July 10, 2017).
• Watkins, Elizabeth Siegel. The Estrogen Elixir: A History of Hormone Replacement Therapy in America . Baltimore: Johns Hopkins University Press, 2007.
• Writing Group for the Women's Health Initiative Investigators. "Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the Women's Health Initiative randomized controlled trial." Journal of the American Medical Association 288 (2002): 321–33. http://jamanetwork.com/journals/jama/fullarticle/195120 (Accessed July 2, 2017).

How to cite

Last modified, share this page.

• Search Menu
• Advance Articles
• Thematic Issues
• Clinical Practice Guidelines
• Supplements
• Endocrine Reviews
• Endocrinology
• Journal of the Endocrine Society
• The Journal of Clinical Endocrinology & Metabolism
• JCEM Case Reports
• Molecular Endocrinology
• Endocrine Society Journals
• Author Guidelines
• Submission Site
• Open Access
• Why Publish with the Endocrine Society
• Advertising & Corporate Services
• Reprints, ePrints, Supplements
• About The Journal of Clinical Endocrinology & Metabolism
• Editorial Board
• Author Resources
• Reviewer Resources
• Rights & Permissions
• Other Society Publications
• Member Access
• Journals Career Network
• Terms and Conditions
• Journals on Oxford Academic
• Books on Oxford Academic

Article Contents

Coronary heart disease findings, mortality changes with ht, stroke with ht, venous thrombosis with ht, breast cancer risk with ht, cognitive and dementia risks/benefits with ht, mood effects with ht, cost effectiveness of ht, bone health as an indication for ht, ht as a preventative therapy in younger women, acknowledgments, abbreviations.

• < Previous

Where Are We 10 Years After the Women's Health Initiative?

• Article contents
• Figures & tables
• Supplementary Data

Roger A. Lobo, Where Are We 10 Years After the Women's Health Initiative?, The Journal of Clinical Endocrinology & Metabolism , Volume 98, Issue 5, 1 May 2013, Pages 1771–1780, https://doi.org/10.1210/jc.2012-4070

• Permissions Icon Permissions

The media attention surrounding the publication of the initial results of WHI in 2002 led to fear and confusion regarding the use of hormonal therapy (HT) after menopause. This led to a dramatic reduction in prescriptions for HT in the United States and around the world. Although in 2002 it was stated that the results pertained to all women receiving HT, subsequent studies from the Women's Health Initiative (WHI) and others clearly showed that younger women and those close to menopause had a very beneficial risk-to-benefit ratio. Indeed, the results showed similar protective effects for coronary disease and a reduction in mortality that had been shown in earlier observational studies, which had also focused on younger symptomatic women. In younger women, the increased number of cases of venous thrombosis and ischemic stroke was low, rendering them “rare” events using World Health Organization nomenclature. Breast cancer rates were also low and were found to be decreased with estrogen alone. In women receiving estrogen and progestogen for the first time in the WHI, breast cancer rates did not increase significantly for 7 years. Other data suggest that other regimens and the use of other progestogens may also be safer. It has been argued that in the 10 years since WHI, many women have been denied HT, including those with severe symptoms, and that this has significantly disadvantaged a generation of women. Some reports have also suggested an increased rate of osteoporotic fractures since the WHI. Therefore, the question is posed as to whether we have now come full circle in our understanding of the use of HT in younger women. Although it is appropriate to treat women with symptoms at the onset of menopause, because there is no proven therapy for primary prevention, in some women the use of HT for this role may at least be entertained.

The Women's Health Initiative (WHI) was a National Institutes of Health (NIH)-sponsored multi-outcome study comprised of 4 separate trials. These were studies on a low-fat diet, calcium-vitamin supplementation, estrogen and progestin therapy (conjugated equine estrogen 0.625 mg together with medroxyprogesterone acetate 2.5 mg), and estrogen-alone therapy (conjugated equine estrogen 0.625 mg). When we discuss WHI today, we generally refer to the results of the hormonal therapy (HT) intervention studies. The costs for this undertaking have been estimated to be $1 billion.

For at least 2 decades before WHI, data from large observational trials had suggested that HT resulted in a reduction in coronary heart disease (CHD) and mortality ( 1 – 4 ). Because of inherent biases in observational data, it was necessary to carry out prospective randomized trials to confirm these findings. WHI was designed to evaluate the long-term benefits and risks of postmenopausal HT with the understanding that women would be taking estrogen long term for the prevention of heart disease, not for the treatment of symptoms. However, most women in the United States initiated HT for the treatment of symptoms, not for the prevention of osteoporosis or heart disease ( 5 ).

Although considered to be a primary prevention trial, WHI did not study primary prevention in that most women were largely asymptomatic and were many years past menopause. Women up to the age of 79 years were included, and the average age of the participants was 63 years, which was on average approximately 12 years past menopause ( 6 ). Figure 1 depicts the normal age-related development and progression of atherosclerosis in the years following menopause. The percentage of women participating in WHI by years since menopause is also depicted, showing that approximately 83% of the WHI participants were more than 5 years from menopause ( 7 ). This contrasts sharply with the age of the observational cohorts who had provided the beneficial data on cardiovascular disease and mortality. These women were younger, were closer to menopause, and had received HT for symptoms of menopause.

Progression of coronary atherosclerosis by age in postmenopausal women and the ages of women participating in the hormonal trial of the WHI. [Adapted from T. B. Clarkson: The new conundrum: do estrogens have any cardiovascular benefits? Int J Fertil Womens Med . 2002;47:61–68 ( 7 ), with permission. © U.S. International Foundation for Studies in Reproduction, Inc.]

By the time WHI was under way, several secondary prevention trials (women with known coronary disease who were prescribed HT) looking at hard end-points of myocardial infarction (MI) and death ( 8 ), as well as some angiographic trials ( 9 , 10 ) had shown that there was no coronary benefit with HT at standard doses. In some studies, “early harm” occurred, defined as more coronary events in the first 1–2 years, when compared to placebo. In 2002, the estrogen plus progestin (E+P) trial of the WHI was terminated after 5.6 years, having found no coronary benefit and a rate of breast cancer that crossed preset boundaries ( 6 ).

The well-orchestrated release of information to the media in the summer of 2002 was problematic on several fronts. Principal investigators of WHI did not have an opportunity to review the data, which was not completely adjudicated, and the results were rushed to publication and disseminated to the media. Here the statements were dogmatic, and there was no explanation of the differences between relative risk and absolute or attributable risk. Relative risk describes the degree of change in a risk over the baseline rate, whereas the absolute risk provides the actual number of cases that would be increased or decreased in a given population. Even if the relative risks were statistically valid, some of which changed with time ( 11 ), the absolute risks were small, making these events “rare” using World Health Organization terminology, which will be detailed below ( 11 ). It was emphatically stated that “the adverse effects of estrogen plus progestin applied to all women, irrespective of age, ethnicity or disease status” ( 12 ). The NIH director of the study was quoted as saying that NIH was going “for high impact” with the goal “to shake up the medical establishment and change the thinking about hormones” ( 13 ). By 2007, with subsequent release of data, various media reports appeared, which is typified by the following statement in the Wall Street Journal “… some aspects of what was reported were misleading or just wrong …. Women in their 50s had a 30% lower risk of dying” ( 14 ).

It has been well documented that since the initial publication of WHI in 2002, hormonal use has decreased substantially ( 15 ) ( Figure 2 ). Our most recent data from NHANES (2009–2010) suggests that the current use of HT in women over 40 is 4.7%, and in women aged 50–59 years it was 6.7%, compared to a total rate of use of 38.3% in 1999–2000 ( 16 ). By 2004–2005, there were data to suggest that the age-adjusted osteoporosis-related fractures had increased compared to 2000–2001 ( 17 ); an observational study of 80 955 women followed for 6.5 years since 2002 found an increased rate of hip fractures among women discontinuing HT compared to those who remained on it ( 18 ).

Quarterly claim volume per 10 000 covered members, overall by prescriber type. Shaded area indicates period before release of initial WHI results. Ob/Gyn, obstetrician/gynecologists. [Reproduced from B. Ettinger et al: Evolution of postmenopausal hormone therapy between 2002 and 2009. Menopause . 2012;19:610–615 ( 15 ), with permission. © The North American Menopause Society.]

As early as 2006, data emerged from the subset of younger women in WHI that did not show an increased risk, but showing a strong trend to decreased risk that was more consistent with data from the older observational data. For estrogen-alone therapy, a composite coronary score was significantly decreased in the women aged 50–59 years ( 19 ); these women also had decreased coronary calcium scores ( 20 ). In a combined analysis of younger women in WHI on estrogen alone and E+P, total mortality was also decreased ( 21 ). These and more recent data will be reviewed in Coronary Heart Disease Findings .

In 2011, a consensus statement by the International Menopause Society (IMS) regarding HT stated the following: “The excessive conservatism engendered by the presentation to the media of the first results of the WHI in 2002 has disadvantaged nearly a decade of women who may have missed the therapeutic window to reduce their future cardiovascular, fracture, and dementia risk” ( 22 ). This potentially provocative statement will be critically assessed in light of the existing literature to date.

The coronary findings in WHI for the E+P trial were of borderline significance 1.24 (1.00–1.54) ( 23 ). Furthermore, the reported data (point estimates of risk) varied over several publications ( 11 ). However, there was some evidence for early harm among the older women in the E+P trial, as had been suggested earlier in the Heart and Estrogen/Progestin Replacement Study (HERS) ( 8 ), but no increase in younger women. Indeed, the point estimates in the younger group showed a trend to benefit. In women receiving E+ P < 10 years from menopause, the hazard ratio was 0.89, and it was > 1 in the older age groups. In the estrogen-alone trial in hysterectomized women, there was clearly benefit in using a composite coronary score: 0.66 (0.45–0.96) ( 19 ). In WHI and in a recent case-control study, coronary calcium scores were significantly reduced in women on estrogen ( 20 , 24 ). A meta-analysis of women receiving HT who were under 60 years old, including data from WHI, showed a statistically significant reduction in coronary disease ( 25 ).

In a WHI publication that combined data from the HT groups stratified by recency of menopause, women < 10 years from menopause had a hazard ratio for CHD of 0.76 (0.5–1.16), with a significant trend for worsening with time since menopause in the other groups ( 21 ). There was also a 30% reduction in all-cause mortality as discussed earlier: 0.70 (0.51–0.96). A 10-year follow-up of women in the estrogen-alone trial in WHI showed that the 50- to 59-year-old group had a significantly reduced risk of MI (0.54 [0.34–0.86]) and CHD (0.59 [0.38–0.90]). In this study, total mortality (mainly cardiovascular) was also reduced 0.73 (0.59–1.00) ( 26 ).

Although the data cited above are strongly suggestive of a coronary benefit in younger women receiving estrogen, the data are based on subanalyses of large randomized trials, and therefore should be interpreted with some caution. In younger women, the hard end-points of MI or death are relatively rare. Therefore, an extremely large, adequately powered study of sufficient duration to prove this suggested beneficial effect would be extremely difficult to achieve.

The “timing” hypothesis suggests that younger symptomatic women at the onset of menopause may be protected from CHD, whereas older women treated for the first time have no benefit from HT and may have early harm. The Kronos Early Estrogen Prevention Study (KEEPS) was not designed to test the timing hypothesis but studied surrogate markers with HT in women at the onset of menopause. KEEPS was a randomized clinical trial (RCT) in recently (<3 y) postmenopausal women who received placebo, conjugated equine estrogen 0.45 mg, or transdermal estradiol 0.05 mg continuously for 4 years. All women had a uterus and received micronized progesterone 200 mg (or progesterone placebo) for 12 days each month. Only intermediate or surrogate end-points could be assessed in this short-duration study. The primary end-point was carotid intima-media thickness (IMT), and the secondary end-point was changes in coronary calcium. Multiple other end-points were assessed including symptoms, biochemical parameters, quality of life, and cognitive function. Only preliminary data have been presented at this time ( 27 ). Carotid IMT rose to the same degree in all groups, but all were lower than the rate of increase noted in a previous RCT where oral estradiol was shown to attenuate the progression of IMT ( 28 ). There was also a nonsignificant trend for coronary calcium to progress less in the 2 estrogen groups compared to placebo. Again, these very healthy women had very little coronary calcium (having coronary calcium was an exclusionary criterion at entry), and it may be that in KEEPS, there was too little atherosclerosis progression to pick up any potential changes with estrogen. Symptoms, quality of life parameters, and biochemical changes were confirmatory of the known effects of estrogen, and there were no significant adverse effects. There was no deterioration of cognitive function and some trend to improvement in verbal memory ( 29 ).

The Danish Osteoporosis Prevention Study (DOPS) was recently published ( 30 ). This was a RCT of 1006 younger women at the onset of menopause that provided more evidence in support of the timing hypothesis. Because a composite end-point was used that included coronary disease and mortality, the data will be reviewed here and in the next section. These women were treated in an open-label fashion with oral estradiol and norethindrone acetate or estradiol alone for 10 years and followed for up to 16 years. A combined end-point of mortality and hospitalizations for congestive heart failure or MI was significantly reduced in those women randomized to HT compared to the control women randomized to no treatment ( 30 ) ( Figure 3 ). Moreover, the data suggested that the younger the women were in the trial, the more they showed a benefit. The DOPS has been criticized on the grounds that cardiovascular health was not the primary outcome of the study because it was designed to assess osteoporosis, no placebo was used, and there may not have been sufficient power. However, the hard end-points studied were well validated in the national data base, and the significant findings reported render this study noteworthy. At the same time, these younger women in DOPS had no increase in thrombosis, stroke, or any cancer. In DOPS, the younger women treated were similar to those women in the observational studies of the past, which consistently showed this potential benefit of HT. Although it could be argued that among the RCTs no one study is definitive, and some of the evidence is based on subanalyses of randomized trials as noted above, the totality of the data is consistent in showing benefit in younger women and not harm.

Risk of death or admission to hospital due to heart failure or MI (primary end-point) over 16-year follow-up, including 11 years of randomized treatment. Comparison of women randomized to hormonal treatment compared to controls randomized to no treatment. [Reproduced from I. L. Schierbeck et al: Effect of hormone replacement therapy on cardiovascular events in recently postmenopausal women: randomized trial. BMJ . 345:e6409 ( 30 ). © BMJ Publishing Group Ltd.]

What then did we learn from WHI in terms of CHD? We did learn that older women who are distant from menopause, who have established atherosclerosis ( Figure 1 ), and who receive standard doses of oral HT are at increased risk for coronary plaque instability, mural rupture, and thrombosis. Although speculative, a hypothesis has been put forth to explain the observed findings. It has been hypothesized that this occurs because oral estrogen increases proinflammatory factors such as matrix metalloproteinase (MMP)-9 ( 31 ), which digests away the gelatinous matrix of the atheromatous plaque causing instability and rupture ( 32 ) This causes the phenomenon of early harm observed in several secondary prevention trials such as HERS ( 8 ) and the null effects in women with established coronary disease ( 9 , 10 , 33 ), where in the setting of significant atherosclerosis, beneficial estrogen action is impeded. Although oral estrogen increases MMPs, in younger women, without significant plaque there is no substrate on which MMPs would act. Indeed in younger women who were studied prospectively in several trials of HT, there was no evidence of this phenomenon of early harm. ( 34 )

Early observational data in several cohorts of women initiating HT for symptoms at the onset of menopause have provided consistent data showing a reduction in all-cause mortality in the range of 30% ( 3 , 4 , 35 , 36 ). In WHI, the combined hormonal arm in women < 10 years from menopause showed a statistical reduction in mortality: 0.70 (0.51–0.96) ( 21 ). A Bayesian meta-analysis looking at both observational data and RCTs showed a statistically significant reduction in all-cause mortality in younger women (0.73 [0.52–0.96]) for the RCT data ( 37 ). In the 10-year follow-up data from the estrogen-alone trial in WHI, the 50- to 59-year-old age group had an identical point estimate of 0.73 (0.53–1.0). In DOPS, although the combined end-point of mortality, congestive heart failure and MI, was significantly reduced, mortality alone did not achieve statistical significance, most likely because of insufficient power in studying these younger women (0.57 [0.30–1.08]) ( 30 ). The data noted above appear to be extremely consistent in showing a decrease in all-cause mortality with HT in younger women. This reduction in the range of 30% is principally due to a reduction in CHD, and these data are remarkably in line with the previous data from observational studies ( 3 , 4 , 35 , 36 )

The effect of HT on stroke risk has been controversial. This is largely because there are many clinical variables that confound the data (primarily obesity and hypertension) and because the risk is of borderline significance. Nevertheless, several meta-analyses and observational data have shown a small increase (approximately 30%) in ischemic stroke (not hemorrhagic stroke) even in younger women receiving standard doses of oral estrogen ( 38 , 39 ). In WHI, whereas there was an overall increase in the entire group with both E+P and estrogen alone, an increased risk was less evident in younger women. There was no significant increase observed with E+P in younger women, but in the estrogen-alone trial, although subgroup analysis in the 50- to 59-year-old group did not show a statistically significant increase, the women < 10 years from menopause had a statistically significant increase based on small numbers ( 40 ). Note that adjustment for this not having been the primary outcome of the trial would have rendered this finding not statistically significant. It may therefore be concluded that there may be some risk (perhaps of borderline significance) even in younger women. This is consistent with the suggestion of a small increased risk of ischemic stroke in reproductive-aged women using oral contraceptives. Recent data suggest that a small risk is observed if enough women are followed ( 41 ). The mechanism of increased risk of ischemic stroke in younger women, however, is thrombotic and not atherosclerotic as it is in older women, and could be on the basis of unknown thrombophilic sensitivities to estrogen ( 42 ). Consistent with this view is that ischemic stroke has not been observed with transdermal estrogen, unless high doses are used ( 43 ), or with lower oral doses ( 38 , 39 )

Although there may be an increased risk of ischemic stroke even in younger women receiving standard doses of oral estrogen, the absolute risk is small. The background risk of ischemic stroke in a 50- to 54-year-old woman is 3.8/10 000 woman years ( 39 ). Therefore, if we assume an approximate 30% increased risk, this would result in 1 or 2 more cases per 10 000 woman years, rendering this a “rare” occurrence. Furthermore, it may be suggested that this putative risk may be nullified by lower oral doses or the use of transdermal estrogen.

The discussion above is also extremely relevant to the findings of venous thrombosis risk with HT. However, it has been well established that oral estrogen increases the risk of thrombosis. As observed in WHI, the risk of standard doses of oral estrogen increases the risk of venous thromboembolism about 2-fold, with most cases occurring in the first or second year of therapy, but with no changes in mortality. In WHI, some women who had a previous history of thrombosis were enrolled into the trial. The data in the estrogen-alone trial were not statistically significant. Although this was a more obese cohort, many of the women, having had a hysterectomy, had been on hormones previously. Accordingly, it could be envisioned that less vulnerable women who had been exposed to estrogen in the past were enrolled in the trial and did not have a thrombotic event. There are very consistent data that the risk is not increased with transdermal estrogen ( 44 , 45 ). Other data have also suggested that various progestogens may increase the risk of thrombosis over that of estrogen. This includes norpregnane derivatives (nomegestrol acetate, promegestone) ( 46 ) as well as medroxyprogesterone acetate ( 47 ). The latter study also suggested that there was an increased risk with a continuous regimen of estrogen and progestogen ( 47 ), which was the type of regimen used in WHI.

Similar to the discussion for stroke, the thrombosis risk with HT has a small absolute risk. The venous thromboembolism risk in younger women, assuming a 2-fold relative risk, is in the range of 30/100 000 woman years. This rare occurrence is less than the rate in normal pregnancy, approximately 60/100 000 woman years ( 48 ).

The major fear women have regarding HT is the potential of developing breast cancer ( 49 ). In 2002 the major reason the E+P trial was stopped was that a preset boundary for breast cancer had been crossed. Although point estimates for the risk with E+P varied in several publications (in the range of 1.24–1.28) ( 11 ) and was generally of borderline significance, the data were interpreted as being highly significant. In a follow-up publication of WHI investigators in 2006, adjustment for risk factors showed a nonsignificant increase of 1.20 (0.94–1.53) ( 50 ).

Moreover, it was clear from this and an earlier publication ( 51 ) that in women who had never received hormones in the past, this risk was not significant over the 5.6 years of the trial: 1.09 (0.86–1.40) ( 50 ). The increased risk was primarily attributable to prior users who had a greater cumulative exposure to hormones. Also, the risk was not significantly increased in younger women ( 51 ). The risk with E+P, however, does increase with time, but sensitivity analyses in adherent participants showed no increase for at least 7 years (1.23 [0.90–1.67]) ( 50 ).

More recent epidemiological data from WHI chose to combine analyses from observational and trial data, which does not appear to be valid. A “gap analysis” was carried out based on timing of initiation of hormones after menopause, which also was based on imprecise data. These analyses suggested that earlier initiation of E+P increases the risk of breast cancer in adherent women ( 52 ). However, as reviewed by a coauthor, these analyses are at odds with the actual published data of the trial and do not appear to be valid ( 53 ). It is clear that although there is increased risk with time, the risk with the E+P regimen used in WHI is greater in older rather than younger women, and that the risk does not increase for 7 years in women who have never received hormones in the past.

Although it is clear that the risk with E+P is greater than that of using estrogen alone (discussed below) the regimen may be of importance. Observational data from France have suggested that the risk is not increased with micronized progesterone or dydrogesterone ( 54 ), and in DOPS using estradiol and norethindrone acetate there was no increase in breast cancer after up to 11 years of therapy and a 16-year follow-up period, although the number of women in this trial was not large ( 30 ).

Recent iterative analyses and modeling have suggested that the effect of hormones is to promote the growth of occult breast tumors. It has been estimated that 93.3% of the breast cancers in the E+P trial were occult tumors ( 54 ), and the effect of E+P was to decrease the normal doubling time (leading to an earlier clinical detection) from 200 to 150 days ( 55 ).

In the estrogen-alone trial, breast cancer rates were seen to decrease, which was significant among adherent women ( 56 ). This was confirmed in the 10-year follow-up data of the estrogen-alone trial, where breast cancer rates were significantly decreased; among women with breast cancer, both breast cancer mortality and total mortality were significantly decreased in estrogen users ( 57 ). The reduced rate of breast cancer is thought to be due to a proapoptotic effect in women “deprived” for some time from estrogen ( 55 ). This hypothesis suggests that the initial use of estrogen (most likely dependent on dose) increases the rate of growth of occult tumors, and if not begun for a period of time, the effect of estrogen “deprivation” results in a proapoptotic effect through at least 2 mechanisms (intrinsic or mitochondrial and extrinsic) ( 58 ). Dose and duration of therapy are likely to be important, but there are few data on this issue. In an observational study of hysterectomized women using conjugated equine estrogen 0.625 mg, breast cancer risk did not increase for at least 15 years, and this was predominantly seen in lean women ( 59 ). Increased body mass index is a significant endogenous risk factor for breast cancer, which is similar to, or exceeds the risk of HT ( 60 , 61 ).

Much has been made of the declining rates of breast cancer in the United States and that this may be linked to the cessation of HT use since 2002. However, this is far too simplistic a view. The decline began before 2002 when the use of HT was higher, the decreased rate occurred in all age groups including in older women not expected to be taking HT, and there clearly has been a change in breast cancer surveillance over time. The decline in HT use has occurred all over the world, yet not all countries have reported a downward trend of breast cancer rates ( 62 ). Thus, whereas some of the decline in breast cancer rates observed in some countries, such as the United States, may be related in part to a decline in hormonal use, the change in HT use does not explain the whole phenomenon.

Putting the potential risks of breast cancer into perspective is extremely important in discussing HT with women. Although estrogen alone may decrease the risk, it probably does not increase the risk unless large doses are used for a prolonged time in susceptible women with unknown occult tumors. With E+P, young women initiating standard dose therapy for the first time at the onset of menopause do not have an increased risk of breast cancer for at least 5 years, and probably for up to 7 years, although the risk does increase thereafter at least for the regimen studied in WHI. Other regimens and doses may be safer, but definitive data are lacking. What is the magnitude of this risk in real terms? Although there is not a statistically significant increase over 5 years with E+P in younger women who have never been on hormones, for illustrative purposes the absolute risk will be calculated assuming an overall increased risk over 5 years as originally reported by WHI (relative risk of 1.24). A 50-year-old woman may expect that her background or endogenous risk of breast cancer will be 2.8% by age 60 years. The putative increased risk of breast cancer with using HT for 5 years would increase her risk to 3.37%—an absolute increased risk of 0.67%. This is less than the risk conferred by obesity, by being a flight attendant, or by many other common exposures ( 61 ).

Several observational studies and meta-analysis had suggested that estrogen prescribed to younger women at the onset of menopause decreases the risk of Alzheimer's disease or delays its onset ( 63 , 64 ). In WHI, when older women (> 65 y) were studied, there was a significant detrimental effect in cognitive function in women in the E+P trial ( 65 ) and only a trend to this effect with estrogen alone ( 66 ). It has been hypothesized that the timing of initiation of HT is critical here, as it is for CHD. However, no RCT to date has been able to prove a cognitive benefit. In the recently completed KEEPS, preliminary data have suggested that there is no detrimental effect of HT, and indeed a trend to benefit in certain women ( 29 ) although this short-term trial was not designed to assess the effects of HT on cognition and dementia. While we await more definitive prospective trial data, a possible benefit based on the timing of initiation of HT is consistent with the observational studies cited above ( 63 , 64 ) as well as other observational studies that focused on the timing of initiation ( 67 – 69 ).

The reduction of menopausal symptoms has been associated with improvements in mood, depression scores, and insomnia in multiple clinical trials. Quality of life assessments have also shown benefit ( 70 ). However, whether this clinical benefit is exclusively due to a reduction in symptoms of menopause remains unclear, although it does explain some of this benefit. Whether there is a benefit in asymptomatic postmenopausal women has not been proven, although smaller prospective trials have suggested some benefit ( 71 ). In KEEPS, improvements in depression, anxiety, and sexual function were observed ( 27 ).

Assessments of quality-adjusted years of life in women on HT have consistently shown that HT is cost-effective, predominantly in younger women ( 72 , 73 ). In The Endocrine Society Task Force report on HT, the number of younger women benefiting from the reduction in symptomatology greatly overcomes numerically any of the attributable risks or benefits discussed above ( 74 ) ( Figure 4 ).

Attributable or excess risk or benefit per 1000 women receiving menopausal HT for 5 years who are 50–59 years old or < 10 years from menopause who have relief from hot flushes and symptoms of vaginal atrophy. [Adapted from Santen RJ ( 74 ).]

It is undeniable that HT reduces fractures in women, even in those who do not have established osteoporosis or are not at a particularly high risk for fracture, as was shown in WHI ( 75 ). Earlier it was discussed that since the cessation of HT in many women after the initial publication of data from WHI, many more osteoporosis-related fractures have occurred ( 17 , 18 ). Accordingly, it has been argued that HT should be an indication for the prevention and treatment of osteoporotic fractures in young women, even if they are asymptomatic ( 74 ). Recent society guidelines are consistent with this view ( 22 , 76 ). The North American Menopause Society guidelines of 2012 suggest that HT may be considered in younger women at high risk for fracture ( 76 ). It remains fairly nebulous, however, how “high” this risk should be in that many women have risk factors for fracture. Clearly, other antiresorptive therapies such as bisphosphonates are not appropriate in young women, particularly those without documented osteoporosis.

In revisiting the 2011 IMS guidelines statement, the sentiment strongly suggests a role for HT in primary prevention, rather than merely short-term use for menopausal symptoms ( 22 ). Apart from lifestyle modification, there is no known primary prevention strategy that has been validated for women. Although HT has been shown prospectively to decrease the risk of new-onset diabetes ( 77 , 78 ), the use of statins increases this risk ( 79 , 80 ) and does not alter mortality ( 81 ). Although it continues to be argued by some that statin therapy may have a beneficial effect in women, there is no real evidence of its role in primary prevention in young healthy women < 60 years old ( 82 ). However, it is more clear that HT in younger women reduces all-cause mortality, as discussed above (observational studies, Refs. 3 , 4 , 35 , and 36 ; randomized trials, Refs. 21 and 37 ; 2 additional trials barely missed statistical significance, Refs. 26 and 30 ). Aspirin therapy also does not have a role in primary prevention in younger women ( 83 ). There has been a suggestion that calcium supplements may increase MI and death rates, although this was shown predominantly in older women ( 84 ).

Thus, 10 years after WHI, have we come full circle? A diagram of this conundrum is depicted in Figure 5 . Before WHI, many clinicians believed that estrogen protected against coronary disease and osteoporosis and had benefits in terms of treating various symptoms of menopause, and therefore should be used, in the absence of known contraindications, for prevention. What was not clear until after WHI is that age and years since menopause were significant variables. By 1 to 2 years after WHI, HT was rarely used, even for women with symptoms. Indeed, in concert with the sentiment of the IMS statement reviewed above ( 22 ), it is certain that many severely symptomatic women were made to bear their symptoms unnecessarily without treatment. However, around 2006, it was generally agreed that HT could be used for younger women to treat symptoms. The current data, particularly with estrogen alone, are highly supportive for a prevention role in reducing fractures, CHD, and mortality in younger women who initiate therapy close to menopause, as was shown originally in observational studies, with a very favorable benefit-to-risk ratio. The data with E+P are similarly suggestive but are less precise. Nevertheless, in DOPS there were statistically significant benefits with E+P, but using a different regimen and progestogen. It is likely, therefore, that different doses and regimens and the type of progestogen are probably quite important in this regard, but specific data are lacking.

Suggested use of HT from before the time of the publication of WHI to the present, posing the question as to whether we have come full circle.

Clearly, more research is needed, but it is not likely that we will have useful information any time soon. Not only will it be prohibitively expensive to conduct a WHI-type trial exclusively in younger women looking at hard end-points such as MI and death, but it will take many years to accrue these events.

In the meantime, we need to individualize therapy in those women with symptoms, with the view that in young healthy women, we probably have come full circle, and a role for HT in prevention may at least be entertained.

Disclosure Summary: The author has no real or perceived conflicts of interest with anything involving this work.

coronary heart disease

estrogen, plus progestin

hormonal therapy

intima-media thickness

myocardial infarction

matrix metalloproteinase

randomized clinical trial

Women's Health Initiative.

Stampfer MJ , Colditz GA . Estrogen replacement therapy and coronary heart disease: a quantitative assessment of the epidemiologic evidence . Prev Med . 1991 ; 20 : 47 – 63 .

Google Scholar

Grodstein F , Manson JE , Colditz GA , Willett WC , Speizer FE , Stampfer MJ . A prospective, observational study of postmenopausal hormone therapy and primary prevention of cardiovascular disease . Ann Intern Med . 2000 ; 133 : 933 – 941 .

Henderson BE , Paganini-Hill A , Ross RK . Decreased mortality in users of estrogen replacement therapy . Arch Intern Med . 1991 ; 151 : 75 – 78 .

Grady D , Rubin SM , Petitti DB , et al.  . Hormone therapy to prevent disease and prolong life in postmenopausal women . Ann Intern Med . 1992 ; 117 : 1016 – 1037 .

Newton KM , LaCroix AZ , Leveille SG , Rutter C , Keenan NL , Anderson LA . Women's beliefs and decisions about hormone replacement therapy . J Womens Health . 1997 ; 6 : 459 – 465 .

Writing Group for the Women's Health Initiative Investigators . Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the Women's Health Initiative randomized controlled trial . JAMA . 2002 ; 288 : 321 – 333 .

Clarkson TB . The new conundrum: do estrogens have any cardiovascular benefits? Int J Fertil Womens Med . 2002 ; 47 : 61 – 68 .

Hulley S , Grady D , Bush T , et al.  . Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women . JAMA . 1998 ; 280 : 605 – 613 .

Herrington DM , Reboussin DM , Brosnihan KB , et al.  . Effects of estrogen replacement on the progression of coronary-artery atherosclerosis N Engl J Med . 2000 ; 343 : 522 – 529 .

Hodis HN , Mack WJ , Azen SP , et al.  .; Women's Estrogen-Progestin Lipid-Lowering Hormone Atherosclerosis Regression Trial Research Group . Hormone therapy and the progression of coronary-artery atherosclerosis in postmenopausal women . N Engl J Med . 2003 ; 349 : 535 – 545 .

Stevenson JC , Hodis HN , Pickar JH , Lobo RA . Coronary heart disease and menopause management: the swinging pendulum of HRT . Atherosclerosis . 2009 ; 207 : 336 – 340 .

NHLBI stops trial of estrogen plus progestin due to increased breast cancer risk and lack of overall benefit . South Med J . 2002 ; 95 : 795 – 797

Parker-Pope T . The hormone decision . Rodale Press ; 2007

Google Preview

Parker- Pope T . How NIH misread hormone study in 2002 . The Wall Street Journal . July 9 , 2007 : B1 .

Ettinger B , Wang SM , Leslie RS , et al.  . Evolution of postmenopausal hormone therapy between 2002 and 2009 . Menopause . 2012 ; 19 : 610 – 615 .

Sprague BL , Trentham-Dietz A , Cronin KA . A sustained decline in postmenopausal hormone use: results from the National Health and Nutrition Examination Survey, 1999–2010 . Obstet Gynecol . 2012 ; 120 : 595 – 603 .

Islam S , Liu Q , Chines A , Hetzer E . Trend in incidence of osteoporosis-related fractures among 40-to 69-year-old women: analysis of a large insurance claims database, 2000–2005 . Menopause . 2009 ; 16 : 77 – 83 .

Karim R , Dell RM , Greene DF , Mack WJ , Gallagher JC , Hodis HN . Hip fracture in postmenopausal women after cessation of hormone therapy: results from a prospective study in a large health management organization . Menopause . 2011 ; 18 : 1172 – 1177 .

Hsia J , Langer RD , Manson JE , et al.  . Conjugated equine estrogens and coronary heart disease; the Women's Health Initiative . Arch Intern Med . 2006 ; 166 : 357 – 365 .

Manson JE , Allison MA , Rossouw JE , et al.  .; WHI and SHI-CACS Investigators . Estrogen therapy and coronary-artery calcification . N Engl J Med . 2007 ; 356 : 2591 – 2602 .

Rossouw JE , Prentice RL , Manson JE , et al.  . Postmenopausal hormone therapy and cardiovascular disease by age and years since menopause . JAMA . 2007 ; 297 : 1465 – 1477 .

Sturdee DW , Pines A ; IMS Writing Group, et al . Updated IMS recommendations on postmenopausal hormone therapy and preventive strategies for midlife health . Climacteric . 2011 ; 14 : 302 – 320 .

Manson JE , Hsia J , Johnson KC , et al.  .; Women's Health Initiative Investigators . Estrogen plus progestin and the risk of coronary heart disease . N Engl J Med . 2003 ; 349 : 523 – 534 .

Weinberg N , Young A , Hunter CJ , Agrawal N , Mao S , Budoffet MJ . Physical activity, hormone replacement therapy, and the presence of coronary calcium in midlife women . Women Health . 2012 ; 52 : 423 – 436 .

Salpeter SR , Walsh JM , Greyber E , Salpeter EE . Brief report: coronary heart disease events associated with hormone therapy in younger and older women. A meta-analysis . J Gen Intern Med . 2006 ; 21 : 363 – 366 .

LaCroix AZ , Chlebowski RT , Manson JE , et al.  .; WHI Investigators . Health outcomes after stopping conjugated equine estrogens among postmenopausal women with prior hysterectomy: a randomized controlled trial . JAMA . 2011 ; 305 : 1305 – 1314 .

Harman M . Primary findings of the Kronos Early Prevention Study (KEEPS) . In: Proceedings from the 23rd Annual Meeting of the North American Menopause Society , October 3–6, 2012 ; Orlando, FL .

Hodis HN , Mack WJ , Lobo RA , et al.  . Estrogen in the prevention of atherosclerosis. A randomized, double-blind, placebo-controlled trial . Ann Intern Med . 2001 ; 135 : 939 – 953 .

Asthana S . Cognitive and effective substudy (KEEPS Cog) . In: Proceedings of the 23rd Annual Meeting of the North American Menopause Society , October 3–6, 2012 ; Orlando, FL .

Schierbeck IL , Renmark L , Tofteng CL , et al.  . 2012 Effect of hormone replacement therapy on cardiovascular events in recently postmenopausal women: randomized trial . BMJ . 345 : e6409 .

Hu P , Greendale GA , Palla SL , et al.  . The effects of hormone therapy on the markers of inflammation and endothelial function and plasma matrix metalloproteinase-9 level in postmenopausal women: the Postmenopausal Estrogen Progestin Intervention (PEPI) trial . Atherosclerosis . 2006 ; 185 : 347 – 352 .

Galis ZS , Sukhova GK , Lark MV , Libby P . Increased expression of matrix metalloproteinases and matrix degrading activity in vulnerable regions of human atherosclerotic plaques . J Clin Invest . 1994 ; 94 : 2493 – 2503 .

Clarke SC , Kelleher J , Lloyd-Jones H , Slack M , Schofiel PM . A study of hormone replacement therapy in postmenopausal women with ischaemic heart disease: the Papworth HRT atherosclerosis study . BJOG . 2002 ; 109 : 1056 – 1062 .

Lobo RA . Evaluation of cardiovascular event rates with hormone therapy in healthy postmenopausal women: results from four large clinical trials . Arch Intern Med . 2004 ; 164 : 48 – 84 .

Paganini-Hill A , Corrada MM , Kawas CH . Increased longevity in older users of postmenopausal estrogen therapy: the Leisure World Cohort Study . Menopause . 2006 ; 13 : 12 – 18 .

Grodstein F , Stampfer MJ , Colditz GA , et al.  . Postmenopausal hormone therapy and mortality . N Engl J Med . 1997 ; 336 : 1769 – 1775 .

Salpeter SR , Cheng J , Thabane L , Buckley NS , Salpeter EE . Bayesian meta-analysis of hormone therapy and mortality in younger postmenopausal women . Am J Med . 2009 ; 122 : 1016 – 1022 .

Sare GM , Gray LJ , Bath PM . Association between hormone replacement therapy and subsequent arterial and venous vascular events: a meta-analysis . Eur Heart J . 2008 ; 29 : 2031 – 2041 .

Grodstein F , Manson JE , Stampfer MJ , Rexrode K . Postmenopausal hormone therapy and stroke: role of time since menopause and age at initiation of hormone therapy . Arch Intern Med . 2008 ; 168 : 861 – 866 .

Hendrix SL , Wassertheil-Smoller S , Johnson KC , et al.  .; WHI Investigators . Effects of conjugated equine estrogen on stroke in the Women's Health Initiative . Circulation . 2006 ; 113 : 2425 – 2434 .

Lidegaard O , Lokkegaard E , Jensen A , Skovlund CW , Kelding N . Thrombotic stroke and myocardial infarction with hormonal contraception . N Engl J Med . 2012 ; 366 : 2257 – 2266 .

Lobo RA , Clarkson TB . Different mechanisms for benefit and risk of coronary heart disease and stroke in early postmenopausal women: a hypothetical explanation . Menopause . 2011 ; 18 : 237 – 240 .

Renoux C , Dell'aniello S , Garbe E , Suissa S . Transdermal and oral hormone replacement therapy and the risk of stroke: a nested case-control study . BMJ . 2010 ; 340 : c2519

Canonico M , Plu-Bureau G , Lowe GD , Scarabin PY . Hormone replacement therapy and risk of venous thromboembolism in postmenopausal women: systematic review and meta-analysis . BMJ . 2008 ; 336 : 1227 – 1231 .

Olie V , Plu-Bureau G , Conard J , Horellou MH , Canonico M , Scarabin PY . Hormone therapy and recurrence of venous thromboembolism among postmenopausal women . Menopause . 2011 ; 18 : 488 – 493 .

Canonico M , Olger E , Plu-Bureau G , et al.  .; Estrogen and Thromboembolism Risk (ESTHER) Study Group . Hormone therapy and venous thromboembolism among postmenopausal women: impact of the route of administration and progestogens: the ESTER study . Circulation . 2007 ; 115 : 840 – 845 .

Sweetland V , Beral A , Balkwill B , et al.  . Venous thromboembolism risk in relation to use of different types of postmenopausal hormone therapy in a large prospective study . J Thromb Haemost . 2012 ; 10 : 2277 – 2286 .

Gray G , Nelson-Piercy C . Thromboembolic disorders in obstetrics . Best Practice Res Clin Obstet Gynaecol . 2012 ; 26 : 53 – 64 .

Walsh-Childers K , Edwards H , Grobmyer S . Covering women's greatest health fear: breast cancer information in consumer magazines . Health Commun . 2011 ; 26 : 209 – 220 .

Anderson GL , Chlebowski RT , Rossouw JE . Prior hormone therapy and breast cancer risk in the Women's Health Initiative randomized trial of estrogen and progestin . Maturitas . 2006 ; 55 : 107 – 115 .

Chlebowski RT , Hendrix SL , Langer RD , et al.  .; WHI Investigators . Influence of estrogen plus progestin on breast cancer and mammography in healthy postmenopausal women: the Women's Health Initiative Randomized Trial . JAMA . 2003 ; 289 : 3243 – 3253 .

Prentice RL , Chlebowski RT , Stefanick ML , et al.  . Estrogen plus progestin therapy and breast cancer in recently postmenopausal women . Am J Epidemiol . 2008 ; 167 : 1207 – 1216 .

Langer RD . Estrogen plus progestin therapy and breast cancer in recently postmenopausal women . Am J Epidemiol . 2009 ; 169 : 784 – 785 .

Fournier A , Berrino F , Clavel-Chapelon F . Unequal risks for breast cancer associated with different hormone replacement therapies: results from the E3N cohort study . Breast Cancer Res Treat . 2008 ; 107 : 103 – 111 .

Santen RJ , Yue W , Heitjan DF . Modeling of the growth kinetics of occult breast tumors: role in interpretation of studies of prevention and menopausal hormone therapy . Cancer Epidemiol Biomarkers Prev . 2012 ; 21 : 1038 – 1048 .

Stefanick ML , Anderson GL , Margolis KL , et al.  . Effects of conjugated equine estrogens on breast cancer and mammography screening in postmenopausal women with hysterectomy . JAMA . 2006 ; 295 : 1647 – 1657 .

Anderson GL , Chlebowski RT , Aragaki AK , et al.  . Conjugated equine oestrogen and breast cancer incidence and mortality in postmenopausal women with hysterectomy: extended follow-up of the Women's Health Initiative randomized placebo-controlled trial . Lancet Oncol . 2012 ; 13 : 476 – 486 .

Jordan VC , Ford LG . Paradoxical clinical effect of estrogen on breast cancer risk: a “new” biology of estrogen-induced apoptosis . Cancer Prev Res (Phila) . 2011 ; 4 : 633 – 637 .

Chen WY , Manson JE , Hankinson SE , et al.  . Unopposed estrogen therapy and the risk of invasive breast cancer . Arch Intern Med . 2006 ; 166 : 1027 – 1032 .

Key TJ , Appleby PN , Reeves GK , et al.  .; Endogenous Hormones Breast Cancer Collaborative Group . Body mass index, serum, sex hormones and breast cancer risk in postmenopausal women . J Natl Cancer Inst . 2003 ; 95 : 1218 – 1226 .

Bluming AZ , Tavri C . What are the real risks for breast cancer? Climacteric . 2012 ; 15 : 133 – 138 .

Gompel A , Santen RJ . Hormone therapy and breast cancer risk 10 years after the WHI . Climacteric . 2012 ; 15 : 241 – 249 .

Yaffe K , Sawaya G , Lieberburg I , Grady D . Estrogen therapy in postmenopausal women: effects on cognitive function and dementia . JAMA . 1998 ; 279 : 688 – 695 .

LeBlanc ES , Janowsky J , Chan BK , Nelson HD . Hormone replacement therapy and cognition: systematic review and meta-analysis . JAMA . 2001 ; 285 : 1489 – 1499 .

Shumaker SA , Legault C , Rapp SR , et al.  . Estrogen plus progestin and the incidence of dementia and mild cognitive impairment in postmenopausal women: the Women's Health Initiative Memory Study: a randomized controlled trial . JAMA . 2003 ; 289 : 2651 – 2662 .

Shumaker SA , Legault C , Kuller L , et al.  . Conjugated equine estrogens and incidence of probable dementia and mild cognitive impairment in postmenopausal women: Women's Health Initiative Memory Study . JAMA . 2004 ; 291 : 2947 – 2958 .

Bagger YZ , Tanko LB , Alexandersen P , et al.  . Early postmenopausal hormone therapy may prevent cognitive impairment later in life . Menopause . 2005 ; 12 : 12 – 17 .

Whitmer RA , Quesenberry CP , Zhou J , Yaffe K . Timing of hormone therapy and dementia: the critical window theory revisited . Ann Neurol . 2011 ; 69 : 163 – 169 .

Shaott H , Breitner JC , Whitmer RA , et al.  . Hormone therapy and Alzheimer disease dementia: new findings from the Cache County Study . Neurology . 2012 ; 79 : 1846 – 1852 .

Pines A , Sturdee DW , MacLennan AH . Quality of life and the role of menopausal hormone therapy . Climacteric . 2012 ; 15 : 213 – 216 .

Ditkoff EC , Crary WG , Cristo M , Lobo RA . Estrogen improves psychological function in asymptomatic postmenopausal women . Obstet Gynecol . 1991 ; 78 : 991 – 995 .

Lekander I , Borgstrom F , Strom O , Zethraeus N , Kanis JA . Cost-effectiveness of hormone therapy in the United States . J Womens Health (Larchmt) . 2009 ; 18 : 1669 – 1677 .

Salpeter SR , Buckley NS , Liu H , Salpeter EE . The cost-effectiveness of hormone therapy in younger and older postmenopausal women . Am J Med . 2009 ; 122 : 42 – 52.e2 .

Santen RJ , Allred DC , Ardoin SP , et al.  . Postmenopausal hormone therapy: an Endocrine Society scientific statement . J Clin Endocrinol Metab . 2010 ; 95 ( 7 suppl 1 ): s1 – s66 .

de Villiers TJ , Stevenson JC . The WHI: the effect of hormonal replacement therapy on fracture prevention . Climacteric . 2012 ; 15 : 263 – 266 .

The 2012 hormone therapy position statement of The North American Menopause Society . Menopause . 2012 ; 19 : 257 – 271 .

Margolis KL , Bonds DE , Rodabough RJ , et al.  .; Women's Health Initiative Investigators . Effect of oestrogen plus progestin on the incidence of diabetes in postmenopausal women: results from the Women's Health Initiative Hormone Trial . Diabetologia . 2004 ; 47 : 1175 – 1187 .

Bonds DE , Lasser N , Qi L , et al.  . The effect of conjugated equine oestrogen on diabetes incidence: the Women's Health Initiative randomized trial . Diabetologia . 2006 ; 49 : 459 – 468 .

Sattar N , Preiss D , Murray HM , et al.  . Statins and risk of incident diabetes: a collaborative meta-analysis of randomized statin trials . Lancet . 2010 ; 375 : 735 – 742 .

Mora S , Glynn RJ , Hsia J , MacFadyen JG , Genest J , Ridker PM . Statins for the primary prevention of cardiovascular events in women with elevated high-sensitivity C-reactive protein or dyslipidemia: results from the Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER) and meta-analysis of women from primary prevention trials . Circulation . 2010 ; 121 : 1069 – 1077 .

Petretta M , Costanzo P , Perrone-Filardi P , Chiariello M . Impact of gender in primary prevention of coronary heart disease with statin therapy: a meta-analysis . Int J Cardiol . 2010 ; 138 : 25 – 31 .

Mitka M . Some question use of statins to reduce cardiovascular risks in healthy women . JAMA . 2012 ; 307 : 893 – 894 .

Berger JS , Roncaglioni MC , Avanzini F , Pangrazzi I , Tognoni G , Brown DL . Aspirin for the primary prevention of cardiovascular events in women and men: a sex-specific meta-analysis of randomized controlled trials . JAMA . 2006 ; 295 : 306 – 313 .

Bolland MJ , Barber PA , Doughty RN , et al.  . Vascular events in healthy older women receiving calcium supplementation: randomized controlled trial . BMJ . 2008 ; 336 : 262 – 266 .

Email alerts

More on this topic, related articles in pubmed, citing articles via.

• About The Journal of Clinical Endocrinology & Metabolism
• About the Endocrine Society
• Recommend to Your Librarian
• Advertising and Corporate Services

Affiliations

• Online ISSN 1945-7197
• Print ISSN 0021-972X
• Copyright © 2023 Oxford University Press
• About Oxford Academic
• Publish journals with us
• University press partners
• What we publish
• New features  
• Open access
• Institutional account management
• Rights and permissions
• Get help with access
• Accessibility
• Advertising
• Media enquiries
• Oxford University Press
• Oxford Languages
• University of Oxford

Oxford University Press is a department of the University of Oxford. It furthers the University's objective of excellence in research, scholarship, and education by publishing worldwide

• Copyright © 2023 Oxford University Press
• Cookie settings
• Cookie policy
• Privacy policy
• Legal notice

This Feature Is Available To Subscribers Only

Sign In or Create an Account

This PDF is available to Subscribers Only

For full access to this pdf, sign in to an existing account, or purchase an annual subscription.

• Published: May 2005

The Women’s Health Initiative Study: Perspectives and Implications for Clinical Practice

• Charles B. Hammond 1 , 2  

Reviews in Endocrine and Metabolic Disorders volume  6 ,  pages 93–99 ( 2005 ) Cite this article

120 Accesses

6 Citations

Metrics details

This is a preview of subscription content, access via your institution .

Access options

Buy single article.

Instant access to the full article PDF.

Price excludes VAT (USA) Tax calculation will be finalised during checkout.

Rent this article via DeepDyve.

Writing Group for the Women’s Health Initiative Investigators. Risks and benefits of estrogen plus progestin in healthy postmenopausal women. JAMA 2002;288:321–333.

Google Scholar  

Women’s Health Initiative Steering Committee. The effects of conjugated equine estrogen in postmenopausal women with hysterectomy (The Women’s Health Initiative randomized, controlled, trial). JAMA 2004;291:1701–1712.

Shumaker SA, Legault C, Rapp SR, Thail, Wallace RB, Ockene JK, Hendrix SL, Jones BN 3rd, Assaf AR, Jackson RD, Kotchen JM, Wassertheil-Smoller S, Wactawski-Wende J;WHIMS Investigators. Estrogen plus progestin and the incidence of dementia and mild cognitive impairment in postmenopausal women: the Women’s Health Initiative Study: A randomized controlled trial. JAMA 2003;289:2651–2662.

Blake JM, Collins JA, Reid RL, Fedorkow DM, Lalonde AB, Christilaw J, Fortier M, Fortin C, Jolly EE, Lemay A, O’Grady T, Smith TE, Cooper J, Maxted JM, O’Grady K, Turek MA;SOGC (Society of Obstetricians and Gynaecologists of Canada). The SOGC statement on the WHI report on estrogen and progestin use in postmenopausal women. J Obstet Gynecol Can 2002;24(10):783–787.

Response to the Women’s Health Initiative Study results by the American College of Obstetricians and Gynecologists. ACOG.net 2002; August 2002.

Schneider, Herman PG. The view of the International Menopause Society on the Women’s Health Initiative, 2002.

Amended report from NAMS Advisory Panel on Postmenopausal Hormone Therapy. Advisory Panel Report. Menopause 2003;10:6–12.

ACOG Statement on the NIH announcement to halt the estrogen-only arm of the WHI study. ACOG.net 2004; March 2004.

ASRM Statement on Suspension of the WHI Trial. Infertility Resources, Internet Health Resources 2004; March 2004.

Grodstein F, Stampfer M. The epidemiology of coronary heart disease and estrogen replacement in postmenopausal women. Prog Cardiovasc Dis 1995;38:199–210.

LHodis HN, Mack WJ, Lobo RA, Shoupe D, Sevanian A, Mahrer PR, Selzer RH, Liu Cr CR, Liu Ch CH, Azen SP. Estrogen in the Prevention of Atherosclerosis Trial Research Group. Estrogen in the prevention of atherosclerosis: A randomized, double-blind, placebo-controlled trial. Ann Intern Med 2001;35:939–953.

Hanke H, Kamenz J, Hanke S, Spiess J, Lenz C, Brehme U, Bruck B, Finking G, Hombach V. Effect of 17-β estradiol on pre-existing atherosclerotic lesions: Role of the endothelium. Atherosclerosis 1999;147:123–132.

Holm P, Andersen HL, Andersen MR, Erhardtsen E, Stender S. The direct atherogenic effect of estrogen is present, absent or reversed, depending on the state of the arterial endothelium. Circulation 1999;100:1727–1733.

The Writing Group for the PEPI Trial. Effects of estrogen or estrogen/progestin regimens on heart disease risk factor in post-menopausal women: The PEPI Trial. JAMA 1995;273:199–208.

Mendelsohn ME, Karas RH. The protective effects of estrogen on the cardiovascular system. N Engl J Med 1999;340:1801–1811.

Adams MR,Washburn SA,Wagner JA,Williams JK, Clarkson TB. Aterial changes: Estrogen deficiency and the effects of hormone replacement. In Lobo RA, ed. Treatment of the Postmenopausal Woman: Basic and Clinical Aspects , 2nd ed. Philadelphia: Lippincott Williams & Wilkins, 1999:377–384.

Karas RH, Clarkson TB. Menopausal Medicine 2003;10:9–12.

Manson JE, Hsai J, Johnson KC, Rossouw JE, Assaf AR, Lasser NL, Trevisan M, Black HR, Heckbert SR, Detrano R, Strickland OL, Wong ND, Crouse JR, Stein E, Cushman M for the Women’s Health Initiative Investigators. Estrogen plus progestin and the risk of coronary heart disease. N Engl J Med 2003;349:523–534.

Mosca L, Collins P, Herrington DM, Mendelsohn ME, Pasternak RC, Robertson RM, Schenck-Gustafsson K, Smith SC Jr, Taubert KA, Wenger NK;American Heart Association. Hormone replacement therapy and cardiovascular disease: A Statement for health care professionals from the American Heart Association. Circulation 2001;104:499–503.

Mendelsohn ME, Karas RH. The time has come to stop letting the HERS tale wag the dogma. Circulation 2001;104(19):2256–2259.

Leblanc ES, Janowsky J, Chan BK, Nelson HD. Hormone replacement therapy and cognition: Systematic review and data analysis. JAMA 2001;295:1489–1499.

Phillips SM, Sherwin BB. Effects of estrogen on memory function in surgically menopausal women. Psychoneuroendocrinology 1992;17:485–495.

Sherwin BB, Tulandi T. “Add-Back“ estrogen reverses cognitive defects induced by GnRH agonists in women with leiomyomata uteri. J Clin Endocrinol Metab 1996;81:2545–2549.

Shaywitz SE, Naftolin F, Zelterman D, Marchione KE, Holahan JM, Palter SF, Shaywitz BA. Better oral reading and short-term memory in midlife, postmenopausal women taking estrogen. Menopause 2003;10:420–426.

Grady D, Yaffe K, Kristof M, Lin F, Richards C, Barrett-Connor E. Effect of postmenopausal hormone therapy on cognitive function: The Heart and Estrogen/Progestin Study. Am J Med 2002;113:543–548.

Download references

Author information

Authors and affiliations.

EC Hamblen Professor of Obstetrics and Gynecology, Department of Obstetrics and Gynecology, Duke University Medical Center, Durham, North Carolina

Charles B. Hammond

Department of Obstetrics and Gynecology, Duke University Medical Center, Durham, North Carolina

You can also search for this author in PubMed   Google Scholar

Corresponding author

Correspondence to Charles B. Hammond .

Rights and permissions

Reprints and Permissions

About this article

Cite this article.

Hammond, C.B. The Women’s Health Initiative Study: Perspectives and Implications for Clinical Practice. Rev Endocr Metab Disord 6 , 93–99 (2005). https://doi.org/10.1007/s11154-005-6721-x

Download citation

Issue Date : May 2005

DOI : https://doi.org/10.1007/s11154-005-6721-x

Share this article

Anyone you share the following link with will be able to read this content:

Sorry, a shareable link is not currently available for this article.

Provided by the Springer Nature SharedIt content-sharing initiative

• postmenopausal hormone therapy
• women’s health initiative

Advertisement

• Find a journal
• Publish with us

An official website of the United States government

The .gov means it’s official. Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

The site is secure. The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

• Publications
• Account settings
• Advanced Search
• Journal List
• v.167(9); 2002 Oct 29

Risks: Absolute or relative?

I think you have done your readers and their patients a disservice by publishing the results of the Women's Health Initiative study in terms of relative rather than absolute risk. 1 Not including the denominator makes it difficult for anyone to assess the meaning of these results. Instead of discussing a 41% increase in strokes, a 26% increase in breast cancer, a 37% reduction in colorectal cancer and a 33% reduction in hip fractures, as was done in the CMAJ piece, 1 why not present the results in terms of absolute excess risk or absolute risk reduction? The abstract of the JAMA article summarizing the results of the original study 2 does just that, stating that there is an absolute risk of 8 more strokes, 8 more invasive breast cancers, 6 fewer colorectal cancers and 5 fewer hip fractures per 10 000 person-years.