Trials Of Hormone Replacement Therapy Research Articles

Critique of the evidence from large trials of hormone replacement therapy

During several decades, hormone replacement therapy (HRT) was the only long-term treatment used by millions of women without any trial. A huge amount of observational studies performed on surrogate markers, animals or women has suggested that HRT reduces cardiovascular morbidity and mortality in postmenopausal women. Numerous observational studies have also suggested a slight increase of breast cancer risk. Other results from observational studies include prevention of osteoporosis, diminished colorectal cancer risk and increased venous thromboembolism risk. During the past decade, several trials have been set up, mostly to compare cancer and cardiovascular disease endpoints in HRT users and nonusers. With the early termination of part of the Women's Health Initiative (WHI) trial, the most important trial ever done on HRT, it is timely to review the evidence from such studies. Results from the main randomised trials broadly agree with findings from the majority of observational studies on the following points: reduction in incidence of osteoporotic fractures and colorectal cancer, increased incidence of venous thromboembolism and breast cancer risk and no significant change in endometrial cancer. However, the trials reported opposite results on the effect of HRT on cardiovascular risk, with a significantly increased incidence of coronary events and stroke. Furthermore, these trials tested only one drug regimen, and they do not necessarily apply to lower dosages of these drugs, to other formulations or methods of administering estrogen and progestins, or to estrogens alone.

Hormone replacement therapy: Review, update, and remaining questions after the women’s health initiative study

Hormone replacement therapy (HRT) is a collective term to include a variety of sex steroids, estrogens, and progestogens, given to postmenopausal women at various doses and administered through various routes. HRT is used for the relief of menopausal symptoms, with many women experiencing considerable improvement in their quality of life. It is also used for the prevention and treatment of osteoporosis, which is as effective as other available therapies. Other potential benefits of HRT are the prevention of cardiovascular disease and dementia. The main risks of HRT are an increased incidence of breast cancer and a transient increase in venous thromboembolism. The Women's Health Initiative is the largest randomized clinical trial of HRT to date, and has demonstrated benefits and risks of one specific HRT regimen. Skeletal benefits have been confirmed in terms of fracture reduction, as has a small risk of breast cancer development. Further studies of other HRT regimens are urgently required to clarify the cardiovascular effects.

Patient and clinician collaboration in the design of a national randomized breast cancer trial.

To show breast cancer patient involvement in the design of a national randomized trial of hormone replacement therapy (HRT) in symptomatic patients will increase accrual. Three stakeholder groups [(1) researchers from the Lynda Jackson Macmillan Centre, (2) the Consumers' Advisory Group for Clinical Trials (CAG-CT), (3) clinicians responsible for a pilot randomized HRT study in breast cancer patients] developed this collaborative study. (1) Nine focus group discussions were conducted to identify issues relevant to breast cancer patients about HRT and a national trial: six involved women from breast cancer support groups nationwide and three patients who had previously participated in the pilot randomized HRT study. (2) Recommendations from the focus groups (analysed by Grounded Theory) were debated by the research stakeholders and focus group representatives at a 1-day meeting and consensus reached (using a voting system) on mutual priorities for incorporation into the design of a national HRT trial. (3) Representatives from the CAG-CT and focus groups participated in subsequent national HRT steering committee meetings to ensure that these priorities were accounted for and the resulting trial design summary was circulated to the CAG-CT and all focus group representatives for comment. Focus groups demonstrated that the complexity of factors relating to trial participation was not just restricted to the research topic in question. Patient-clinician interaction provided a platform for negotiating potential conflicts over trial design and outcomes. Patient feedback suggested that mutually agreed priorities were accounted for in the trial design. Clinical research planning should involve all research stakeholders at the outset. Quantifying the impact of patient involvement in terms of trial accrual may be too simple given the complexity of their motivations for participating in trials.

Two to three years of hormone replacement treatment in healthy women have long-term preventive effects on bone mass and osteoporotic fractures: the PERF study

Hormone replacement therapy (HRT) is often prescribed for a few years to suppress menopausal symptoms. Although its long-term use of HRT for the primary prevention of osteoporosis is not currently recommended, the long-term skeletal benefits of the limited therapy are of great interest. To determine whether administration of HRT for 2–3 years in the early postmenopausal years provides long-term benefits, such as prevention of bone loss and osteoporotic fractures, we studied a group of 347 healthy postmenopausal women with normal bone mass who had earlier completed one of four placebo-controlled HRT trials and who were reexamined 5, 11, or 15 years after stopping HRT. Of these women, 263 received either HRT or placebo for 2–3 years with no further bone-sparing treatment until follow-up, and the remaining 84 women reported either prolonged or current use of HRT at reexamination. Bone mineral density (BMD) at the spine (L1–L4) and bone mineral content (BMC) in the forearm were measured at baseline, the end of the trials, and follow-up. At follow-up, we assessed the radiological presence of vertebral fracture and collected information on the new incidence of nonvertebral fractures. Compared with that of the placebo-treated women, the BMD and BMC of HRT-treated women continued to show significantly higher values (>5%) even many years after stopping HRT. After stopping treatment, the rate of bone loss returned to normal postmenopausal rates. The preservation of bone mass in the HRT group was accompanied by a significantly reduced risk of all osteoporotic fractures as compared with the placebo group [OR = 0.48 (95% CI, 0.26–0.88)]. ‘Fast losers’ on placebo had more than a 4-fold higher risk of fractures than had the women on limited HRT with a normal rate of bone loss after withdrawal. In conclusion, limited HRT administered in the early postmenopausal years offers long-lasting benefits for the prevention of postmenopausal bone loss and osteoporotic fracture.

Danger of Hormone Replacement Therapy on Cardiovascular Disease

A myriad of the retrospective studies have shown the benefit of hormone replacement therapy (HRT) on cardiovascular disease. It has been consistently shown that estrogen decreases total and LDL cholesterol, but increases the HDL cholesterol, resulting in a favorable cardiovascular outcome. In addition, it has been reported that estrogen has a beneficial role toward vascular function. The benefit of HRT on cardiovascular disease did not become a matter for suspicion or skepticism until the arrival of primary and secondary prevention clinical trial data. A large body of evidence from secondary prevention trials, such as HERS, EVA and WAVE, revealed that HRT has no beneficial effect at all toward cardiovascular disease protection; conversely, it was revealed to even be harmful. HRT increased the risk of CHD, DVT and strokes, as well as of cancers in postmenopausal women with CHD, with the worst evidence coming from a primary prevention trial. The Women’ s Health Initiative (WHI) study, the largest of the HRT trials, revealed the same findings as those of secondary prevention trials. In this trial, HRT significantly increased the risks of CHD, DVT, strokes and cancers, further confirming the previous findings. The lack of benefit of HRT in those trials can not be explained by the beneficial influence of HRT on the lipid profile and vascular function. Many researchers that still regard HRT as cardioprotective argue that the route, combination of drugs or even the dose of the drug administered would make differences. However, it is the increased VLDL synthesis and risk of thrombosis that make HRT harmful. HRT increase, VLDL synthesis that results in the generation of atherogenic small dense LDL and thrombus formation. In addition, HRT increases the risk of thrombosis by activating the coagulation pathway independently of VLDL synthesis. It has been reported that transdermal estrogen therapy does not increase VLDL synthesis or thrombus formation, being allegedly beneficial. However, it should not be forgotten that even the present data is not decisive and not confirmative for performing another new clinical trial of HRT being potentially harmful. (Korean Circulation J 2004; 34(11):1015-1021)

Hormone replacement therapy update: who should we be prescribing this to now?

To summarize results from the Women's Health Initiative trial and other recent randomized placebo-controlled trials of hormone replacement therapy, which fundamentally changed our understanding of its risks and benefits. The Women's Health Initiative study for the first time provided evidence of harmful effects of hormone replacement therapy on the cardiovascular system and also confirmed significantly increased risk of breast cancer which was previously documented in a metaanalysis. Most recent studies indicate a particularly harmful effect of combined estrogen/progestin regimens in terms of increased breast cancer risk. The effects of hormone replacement therapy on coronary heart disease, stroke, venous thromboembolism, breast cancer, gallbladder, diabetes, cognitive function, health-related quality of life, colorectal cancer, osteoporosis and menopausal symptoms are discussed briefly. The emphasis is on providing concise clinical guidelines for hormone replacement therapy use in new circumstances. We also discuss some alternative therapeutic modalities for women who have menopausal symptoms, but contraindications for hormone replacement therapy.

Hormone replacement therapy is associated with improved survival in women with advanced heart failure

ObjectivesWe sought to determine whether hormone replacement therapy (HRT) is associated with an improved prognosis in women with advanced heart failure (HF) and systolic dysfunction. BackgroundThere are about two million postmenopausal women in the U.S. with HF. However, limited data are available to assess the effects of HRT on survival in this large group of patients. MethodsA retrospective analysis of women age 50 years and over entered into the Beta-Blocker Evaluation of Survival Trial (BEST) was conducted using Cox regression analysis comparing survival in HRT users and non-users after correcting for baseline variables known to predict survival in women with HF and systolic dysfunction. ResultsIn 493 women age 50 years and older, HRT was associated with a significant reduction in mortality—21% mortality in HRT users and 34% in non-users (p = 0.025). Multivariate analysis demonstrated a hazard ratio for mortality of 0.6 (95% confidence interval = 0.36 to 0.97) (p = 0.039) for HRT users. The benefits of HRT were noted only in women with a nonischemic etiology of HF (n = 237). ConclusionsHormone replacement therapy is associated with a marked improvement in survival in postmenopausal women with advanced HF. A prospective, randomized trial of HRT should be performed in this large group of patients.

An evaluation of the benefits of taking hormone replacement therapy with other prescription drugs

Objectives: Clinical trials of hormone replacement therapy (HRT) exclude women who have other health problems. The aim of our community survey was to investigate the impact of HRT on women with a variety of other health problems. Method: Questionnaire sample of 935 women aged 45–58 years. The questionnaire assessed menopausal quality of life (QOL); self reported health status, prescription drug use and history of hormone supplement use. Results: Thirty five percent of the total sample had taken a variety of prescription drugs in the last 2 months. Prescription drug use was significantly higher in current and former users of HRT/ERT than in non-HRT/ERT users. Current and former HRT users who also took prescription drugs had a significantly lower mean length of HRT/ERT use when compared to women who took HRT/ERT with no prescription drugs. Peri and postmenopausal women currently taking HRT/ERT reported significantly higher MQOL than both former and non-HRT users, which suggest that the benefits of taking hormone supplements during the menopausal transition for some women. There was a significant interaction between hormone use, level of prescription drug use and QOL. Among women who have high levels of prescription drug use, those who take hormone supplements report significantly fewer deficits in QOL when compared to non or former users of HRT/ERT. Additionally, women taking selective serotonin re-uptake inhibitors (SSRI) plus HRT report significantly higher levels of QOL compared to women taking SSRI alone. Conclusions: The advantages of taking HRT among who take prescription drugs could be attributed to the mood enhancing effects of estrogens. HRT should be considered for some peri and postmenopausal women who are taking SSRIs or who are taking at least three different types of prescription drugs.

Hormone Replacement Therapy and Menopause: A Review of Randomized, Double-Blind, Placebo-Controlled Trials

Hormone replacement therapy (HRT) is frequently prescribed to healthy women to ameliorate menopausal symptoms. HRT is used long term (> or = 1 year) to prevent chronic disease in older women. The objective of this study was to review the benefits and risks of HRT and studies of menopause or HRT in Taiwan via a MEDLINE search. Recommendations are provided for future HRT research in Taiwan. Randomized, double-blind, placebo-controlled clinical trials are considered the gold standard of scientific evidence. A MEDLINE literature search (January 1966-July 2002) identified 23 papers on trials (> or = 1 year) that met the inclusion criteria. The results showed that various HRT regimens used for more than 1 year caused more harm than good in healthy menopausal women and that there was no benefit for women with coronary artery disease, Alzheimer's disease, hysterectomy, hysterosalpingo-oophorectomy, and ischemic stroke. None of this research was conducted in Taiwan. A MEDLINE search using the key words "estrogen replacement therapy and menopause in Taiwan" identified 16 studies. There was only one, short-term, HRT trial. No evidence suggested benefits from long-term HRT in menopausal women in Taiwan.

Perspectives on the Womenʼs Health Initiative Trial of Hormone Replacement Therapy

Perspectives on the Womenʼs Health Initiative Trial of Hormone Replacement Therapy

Role of estrogen receptor-alpha in pharmacogenetics of estrogen action.

To summarize recent data regarding the role of estrogen receptor-alpha polymorphisms in determining the response to estrogen therapy or the risk of clinical cardiovascular events. Recent clinical trials of hormone replacement therapy for cardiovascular disease have yielded surprisingly negative results, shifting clinical opinions from a position of presumed cardiovascular benefit to one of confirmed harm. Understanding why hormone replacement therapy has beneficial effects on intermediate risk markers for cardiovascular disease, but produces an increase in cardiovascular events, is an important public health question with the potential to elucidate fundamentally important aspects on atherogenesis, cardiovascular disease, and the biology of estrogen action. One question concerning the cardiovascular effects of hormone replacement therapy is whether genetic factors can substantially modify individual responses to estrogen treatment. New clinical trial evidence is emerging that links the presence of particular variants in the estrogen receptor to the response of HDL and other intermediate endpoints to hormone replacement therapy. One or more common variants in estrogen receptor-alpha are associated with a differential response to hormone replacement therapy in several domains of estrogen action. However, the effect of these variants on the risk of clinical cardiovascular events in the setting of hormone replacement therapy is not yet known. Additional research focusing on the clinical impact of common variants in estrogen receptor-alpha, estrogen receptor-beta and the progesterone receptor promise to improve clinical decision-making concerning the use of hormone replacement therapy and other novel estrogen agonists.

Perspectives on the Womenʼs Health Initiative Trial of Hormone Replacement Therapy

Department of Obstetrics and Gynecology, Women's and Children's Hospital, Keck School of Medicine, University of Southern California, Los Angeles, California

Perspectives on the Womenʼs Health Initiative Trial of Hormone Replacement Therapy

Perspectives on the Womenʼs Health Initiative Trial of Hormone Replacement Therapy

Perspectives on the Womenʼs Health Initiative Trial of Hormone Replacement Therapy

© 2003 by The American College of Obstetricians and Gynecologists. Published by Wolters Kluwer Health, Inc. All rights reserved.

Perspectives on the Womenʼs Health Initiative Trial of Hormone Replacement Therapy

Perspectives on the Womenʼs Health Initiative Trial of Hormone Replacement Therapy

The Effects of Hormone Replacement Therapy on Sleep-Disordered Breathing in Postmenopausal Women: A Pilot Study

To evaluate the impact of estrogen and estrogen plus progesterone hormone-replacement therapy (HRT) on mild-to-moderate sleep-disordered breathing (SDB) in postmenopausal women. Within-subjects, progesterone placebo-controlled prospective HRT trial in a clinical laboratory. Six postmenopausal women, diagnosed with mild-moderate SDB. Transdermal estradiol and oral micronized progesterone. Subjects underwent polysomnography (PSG) on four occasions: a screening/adaptation night; a baseline night on no HRT; and two nights on HRT: one night after 7 to 12 days on estrogen plus placebo followed by a second night after 7-13 days on estrogen plus progesterone. The PSG was performed with a Sandman computerized PSG system using a standard clinical montage. Modified sleep diaries were used in the baseline week and throughout the study period. Mood was measured with the 20-item version of the Positive and Negalive Affect Schedule (PANAS). Estrogen monotherapy was associated with a significant reduction in the overall apnea-hypopnea index (AHI) (from a mean of 22.7 events per hour at baseline to a mean of 12.2 events per hour), but the AHI reduction on estradiol plus progesterone relative to baseline was not statistically significant (AHI=16.2 events per hour). Similar results were found for the percentages of total sleep time and of total non-rapid eye movement sleep time with oxygen saturation less than 90%. Estrogen, neither alone nor in combination with progesterone, significantly altered PSG- or diary-based measures of total sleep time, time to sleep onset, or time awake after sleep onset. While the data are preliminary and based on a small number of subjects, estrogen appeared to have a substantial beneficial effect on measures of SDB in postmenopausal women. Overall, no additional benefit was seen with the addition of progesterone. In fact, progesterone attenuated the beneficial effects of estrogen in 4 out of the 6 participants.

Hormone replacement therapy for primary and secondary prevention of heart disease

Cardiovascular disease is the leading cause of death in women. In pooled analysis, observational studies have shown a 50% reduction in death and myocardial infarction among users of hormone replacement therapy (HRT) for the primary and secondary prevention of cardiovascular disease. The first randomized trial of HRT for secondary prevention of heart disease found no benefit to therapy (Heart and Estrogen/progestin Replacement Study ). Even after 6.8 years of follow-up, there was still no cardiovascular benefit from the use of HRT (HERS II). HRT was associated with a 50% increased risk of heart attacks within the first year as well as an increased risk of deep venous thrombosis (DVT) and pulmonary embolism (PE) (relative risk 2.89) and gallbladder disease (RR 1.38). The Estrogen Replacement and Atherosclerosis trial found no evidence that HRT slowed the progression of subclinical angiographic disease either. This was despite a favorable effect on high-density lipoprotein and low-density lipoprotein. The first randomized trial of HRT for the primary prevention of heart disease found no overall benefit (Women's Health Initiative). The combination of estrogen and progestin resulted in a 29% increase in heart attacks, 41% increase in stroke, a doubling of thrombotic events (DVT and PE), as well as a 26% increase in breast cancer. The risk for thrombotic events was greatest in the first year whereas the risk of breast cancer increased progressively with duration of therapy. HRT is no longer recommended for the primary or secondary prevention of cardiovascular disease or stroke. It may still be considered for short-term relief of menopausal symptoms in women without high-risk conditions, but alternatives exist.

Are menstruating women protected from heart disease because of, or in spite of, estrogen? Relevance to the iron hypothesis

Am Heart J 2003;145:190-4.

Observational studies and randomized trials of hormone replacement therapy: what can we learn from them?

In Brief “…We give the observational studies a grade of B on their performance in charting the short- to moderate-term effects of [HRT]…”

Perspectives on the Womenʼs Health Initiative Trial of Hormone Replacement Therapy

Perspectives on the Womenʼs Health Initiative Trial of Hormone Replacement Therapy