Issues to debate on the Women's Health Initiative (WHI) study. Hormone replacement therapy: an epidemiological dilemma?

Machens, K.; Schmidt-Gollwitzer, K.

doi:10.1093/humrep/deg406

Cited by 37 publications

(21 citation statements)

References 18 publications

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“…This is consistent with critical reviews of the WHI 6 and survey findings of obstetriciangynecologists suggesting that physicians were skeptical of the WHI findings. 12 The themes "discontinuation strategies" and "was not applicable" reflect a similar set of contrasting beliefs.…”

Section: Discussionsupporting

confidence: 83%

“…4,5 Recent publications have criticized the release and interpretation of the WHI findings and questioned the generalizability of findings, given the population studied and medications selected. [6][7][8] Variability in physicians' attitudes and beliefs about HT after WHI has been reported in numerous studies. For example, physicians were less favorable toward using HT for prevention 9,10 and gynecologists indicated they would continue to prescribe HT despite the WHI results 11,12 and that they were more likely to hold positive views of HT than were general internists.…”

Section: Resultsmentioning

confidence: 99%

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How the Women’s Health Initiative (WHI) Influenced Physicians’ Practice and Attitudes

et al. 2007

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BACKGROUND:The landmark Women's Health Initiative (WHI) Postmenopausal Hormone Therapy Trial published in 2002 showed that the health risks of combination hormone therapy (HT) with estrogen and progestin outweighed the benefits in healthy postmenopausal women. Dissemination of results had a major impact on prescriptions for, and physician beliefs about HT. No study has fully examined the influence of the widely publicized WHI on physicians' practice and attitudes or their opinions of the scientific evidence regarding HT; in addition, little is known about how physicians assist women in their decisions regarding HT. DESIGN AND PARTICIPANTS:We conducted in-depth telephone interviews with family practitioners, internists, and gynecologists from integrated health care delivery systems in Washington State (n=10 physicians) and Massachusetts (n=12 physicians). Our objectives were to obtain qualitative information from these physicians to understand their perspectives on use of HT, the scientific evidence regarding its risks and benefits, and counseling strategies around HT use and discontinuation.APPROACH: We used Template Analysis to code transcribed telephone interviews and identify themes. RESULTS:Physicians were conflicted about the WHI results and its implications. Seven themes identified from in-depth interviews suggested that the WHI (1) was a ground-breaking study that changed clinical practice, including counseling; (2) was not applicable to the full range of patients seen in clinical practice; (3) raised concerns over the impact of publicized health information on women; (4) created uncertainty about the risks and benefits of HT; (5) called for the use of decision aids; (6) influenced discontinuation strategies; and (7) provided an opportunity to discuss healthy lifestyle options with patients. As a result of the WHI, physicians reported they no longer prescribe HT for prevention and were more likely to suggest discontinuation, although many felt women should be in charge of the HT decision.CONCLUSIONS: Physicians varied in their opinions of HT and the scientific evidence (positive and negative). Whereas the WHI delineated the risks and benefits of HT, physicians reported that decision aids are needed to guide discussions with women about menopause and HT. Better guidance at the time of WHI study publication might have been valuable to ensure best practices.

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Section: Discussionsupporting

confidence: 83%

Section: Resultsmentioning

confidence: 99%

How the Women’s Health Initiative (WHI) Influenced Physicians’ Practice and Attitudes

et al. 2007

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“…extracellular matrix remodeling; ovariectomy; gender; hypertrophy; hormone; collagen; MT1-MMP; ventricle THE RISKS AND BENEFITS ASSOCIATED with estrogen replacement therapy remain uncertain. Conflicting results regarding the effect of estrogen replacement on the outcome of cardiovascular disease have been obtained from population studies, animal models, and clinical trials (2,16,20,21,32,33,61). The inconsistency of these findings demonstrates the lack of understanding of the mechanisms by which estrogen exerts its beneficial effects on the cardiovascular system.…”

mentioning

confidence: 99%

Estrogen improves TIMP-MMP balance and collagen distribution in volume-overloaded hearts of ovariectomized females

Voloshenyuk

Gardner

2010

American Journal of Physiology-Regulatory, Integrative and Comp

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Our previous studies demonstrate that 17␤-estradiol limits chronic volume overload-induced hypertrophy and improves heart function in ovariectomized rats. One possible cardioprotective mechanism involves the interaction between estrogen, estrogen receptors, and proteins of the extracellular matrix (ECM). The impact of estrogen deficiency and replacement on left ventricular (LV) hypertrophy and ECM protein expression was studied using five female rat groups: intact sham-operated, ovariectomized sham-operated, intact with volume overload, ovariectomized with volume overload, and ovariectomized with volume overload treated with estrogen. After 8 wk, LV protein extracts were evaluated by Western blot analysis for matrix metalloproteinase-2 (MMP-2) and MMP-9, MT1-MMP, tissue inhibitors of MMPs (TIMP)-1, TIMP-2, TIMP-3 and TIMP-4, collagens type I and III, and estrogen receptor ␣ and ␤ expression. MMP proteolytic activity was assessed by zymography. All volume-overloaded groups exhibited LV hypertrophy, which was associated with a loss of interstitial collagen and perivascular fibrosis. After 8 wk of volume overload, 70% of ovariectomized rats developed heart failure, in contrast to only one intact rat. A downregulation of MMP-2, estrogen receptor-␣ (ER␣), and ER␤, and upregulation of MMP-9 and MT1-MMP were found in the volume-overloaded hearts of ovariectomized rats. Estrogen treatment improved TIMP-2/MMP-2 and TIMP-1/MMP-9 protein balance, restored ER␣ expression, and prevented MMP-9 activation, perivascular collagen accumulation and development of heart failure. However, estrogen did not fully restore ER␤ expression and did not prevent the increase of MMP-9 expression or loss of interstitial collagen. These results support that estrogen limits undesirable ECM remodeling and LV dilation, in part, through modulation of ECM protein expression in volume-overloaded hearts of ovariectomized rats. extracellular matrix remodeling; ovariectomy; gender; hypertrophy; hormone; collagen; MT1-MMP; ventricle THE RISKS AND BENEFITS ASSOCIATED with estrogen replacement therapy remain uncertain. Conflicting results regarding the effect of estrogen replacement on the outcome of cardiovascular disease have been obtained from population studies, animal models, and clinical trials (2,16,20,21,32,33,61). The inconsistency of these findings demonstrates the lack of understanding of the mechanisms by which estrogen exerts its beneficial effects on the cardiovascular system. Using a rodent model, we demonstrated that hearts of intact female rats are resistant to chronic volume overload-induced adverse cardiac remodeling and dysfunction (12). This apparent cardioprotection is lost following ovariectomy (6). Estrogen replacement delays the development of left ventricular (LV) hypertrophy and dilation, and it prevents the onset of congestive heart failure (CHF) in ovariectomized rats with volume overload (13). However, the mechanisms of estrogen's protective effects in prevention of adverse myocardial remodeling remain unclear.Changes in extra...

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“…T here has been recent interest in reconciling findings from observational studies and randomized clinical trials (1)(2)(3)(4)(5)(6)(7)(8). The field of nephrology relies heavily on observational studies, most notably from the United States Renal Data System (USRDS) and large providers of treatment for patients with ESRD (9,10).…”

mentioning

confidence: 99%

Association of Achieved Dialysis Dose with Mortality in the Hemodialysis Study

Greene¹,

Daugirdas²,

Depner³

et al. 2005

Journal of the American Society of Nephrology

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In the intention-to-treat analysis of the Hemodialysis Study, all-cause mortality did not differ significantly between the high versus standard hemodialysis dose groups. The association of mortality with delivered dose within each of the two randomized treatment groups was examined, and implications for observational studies were considered. Time-dependent Cox regression was used to relate the relative risk (RR) for mortality to the running mean of the achieved equilibrated Kt/V (eKt/V) over the preceding 4 mo. eKt/V was categorized by quintiles within each dose group. Analyses were controlled for case-mix factors and baseline anthropometric volume. Within each randomized dose group, mortality was elevated markedly when achieved eKt/V was in the lowest quintile (RR, 1.93; 95% confidence interval [CI], 1.40 to 2.66; P < 0.0001 in the standard-dose group; RR, 2.04; 95% CI, 1.50 to 2.76; P < 0.0001 in the high-dose group; RR relative to the middle quintiles). The mortality rate in the lowest eKt/V quintile of the high-dose group was higher than in the full standard-dose group (RR, 1.59; 95% CI, 1.29 to 1.96; P < 0.0001). Each 0.1 eKt/V unit below the group median was associated with a 58% higher mortality in the standard-dose group (P < 0.001) and a 37% higher mortality in the high-dose group (P < 0.001). The magnitude of these dose-mortality effects was seven-to 12-fold higher than the upper limit of the 95% CI from the intention-to-treat analysis. The effects were attenuated in lagged analyses but did not disappear. When dialysis dose is targeted closely, as under the controlled conditions of the Hemodialysis Study, patients with the lowest achieved dose relative to their target dose experience markedly increased mortality, to a degree that is not compatible with a biologic effect of dose. The possibility of similar (albeit smaller) biases should be considered when analyzing observational data sets relating mortality to achieved dose of dialysis.

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Issues to debate on the Women's Health Initiative (WHI) study. Hormone replacement therapy: an epidemiological dilemma?

Cited by 37 publications

References 18 publications

How the Women’s Health Initiative (WHI) Influenced Physicians’ Practice and Attitudes

How the Women’s Health Initiative (WHI) Influenced Physicians’ Practice and Attitudes

Estrogen improves TIMP-MMP balance and collagen distribution in volume-overloaded hearts of ovariectomized females

Association of Achieved Dialysis Dose with Mortality in the Hemodialysis Study

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