Understanding the Divergent Data on Postmenopausal Hormone Therapy

Grodstein, Francine; Clarkson, Thomas B.; Manson, JoAnn E.

doi:10.1056/nejmsb022365

Cited by 304 publications

(182 citation statements)

References 39 publications

(13 reference statements)

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“…However, the potent activity of exogenous estrogens in experimental models is paralleled by controversial results in humans ( [210,209]). Secondary analyses of recent randomized clinical trials, that originally raised controversies among the scientific community as to the risk/benefit ratio of HT ( [85,159,237]), helped to consolidate a novel hypothesis on the efficacy of hormone therapy [200]; it is now hypothesized that HT should be started in early menopause, as a preventative treatment of relatively healthy women, in order to avoid the negative consequences of hypoestrogenicity per se [92]. In fact, observational and randomized clinical trials show that HT does not improve memory or intellectual functions in women already affected by mild to moderate AD ( [70,172,199]), whereas it delays disease onset when administered in healthy perimenopausal women ( [100,117,200,228]).…”

Section: The Timing Hypothesismentioning

confidence: 99%

Estrogen anti-inflammatory activity in brain: A therapeutic opportunity for menopause and neurodegenerative diseases

Vegeto

Benedusi

Maggi

2008

Frontiers in Neuroendocrinology

273

206

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a b s t r a c tRecent studies highlight the prominent role played by estrogens in protecting the central nervous system (CNS) against the noxious consequences of a chronic inflammatory reaction. The neurodegenerative process of several CNS diseases, including Multiple Sclerosis, Alzheimer's and Parkinson's Diseases, is associated with the activation of microglia cells, which drive the resident inflammatory response. Chronically stimulated during neurodegeneration, microglia cells are thought to provide detrimental effects on surrounding neurons. The inhibitory activity of estrogens on neuroinflammation and specifically on microglia might thus be considered as a beneficial therapeutic opportunity for delaying the onset or progression of neurodegenerative diseases; in addition, understanding the peculiar activity of this female hormone on inflammatory signalling pathways will possibly lead to the development of selected anti-inflammatory molecules. This review summarises the evidence for the involvement of microglia in neuroinflammation and the anti-inflammatory activity played by estrogens specifically in microglia.

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Section: The Timing Hypothesismentioning

confidence: 99%

Estrogen anti-inflammatory activity in brain: A therapeutic opportunity for menopause and neurodegenerative diseases

Vegeto

Benedusi

Maggi

2008

Frontiers in Neuroendocrinology

273

206

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“…In examining outcomes among women who received hormone replacement therapy (HRT), although observational studies did not yield similar results in the area of coronary heart disease, the two types of studies yielded almost identical point estimates in the areas of risk for breast and colorectal cancer, hip fracture, stroke, and pulmonary embolism (6). Grodstein et al (6) systematically reviewed these studies and suggested that methodologic differences may have explained why discrepancies were noted for certain outcomes and not for others. For example, observational data supporting the use of HRT primarily examined women who initiated therapy at the time of menopause, whereas approximately 70% of women in the Women's Health Initiative (RCT examining HRT and outcomes) were enrolled at the 60 yr or older.…”

Section: Selection Biasmentioning

confidence: 99%

Cohort Studies

Thadhani

Tonelli

2006

Clinical Journal of the American Society of Nephrology

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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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Understanding the Divergent Data on Postmenopausal Hormone Therapy

Cited by 304 publications

References 39 publications

Estrogen anti-inflammatory activity in brain: A therapeutic opportunity for menopause and neurodegenerative diseases

Estrogen anti-inflammatory activity in brain: A therapeutic opportunity for menopause and neurodegenerative diseases

Cohort Studies

Association of Achieved Dialysis Dose with Mortality in the Hemodialysis Study

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