The Timing Hypothesis remains a valid explanation of differential cardioprotective effects of menopausal hormone treatment

Choi, Seung Do; Steinberg, Emma M.; Lee, Hae‐Hyeog; Naftolin, Frederick

doi:10.1097/gme.0b013e3181e97344

Cited by 26 publications

(11 citation statements)

References 76 publications

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“…The current dilemma, therefore, is reconciling the overwhelming beneficial effects conferred by estrogen in animal models of stroke with the findings of clinical trials. One of the main hypotheses to emerge from these efforts is the timing hypothesis, which proposes that hormone therapy is more benign for stroke when taken by younger women or during the peri-menopausal or early post-menopausal period, but deleterious when taken by women significantly past the menopause (Barrett-Conner, 2007; Choi et al, 2011). …”

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confidence: 99%

Revisiting the timing hypothesis: Biomarkers that define the therapeutic window of estrogen for stroke

Sohrabji

Selvamani

Balden

2013

Hormones and Behavior

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Significantly extended life expectancy coupled with contemporary sedentary lifestyles and poor nutrition have created a global epidemic of cardiovascular disease and stroke. For women, this issue is complicated by the discrepant outcomes of hormone therapy (HT) for stroke incidence and severity as well as the therapeutic complications for stroke associated with advancing age. Here we propose that the impact of estrogen therapy cannot be considered in isolation, but should include age-related changes in endocrine, immune, and nucleic acid mediators that collaborate with estrogen to produce neuroprotective effects commonly seen in younger, healthier demographics. Due to their role as modulators of ischemic cell death, the post-stroke inflammatory response, and neuronal survival and regeneration, this review proposes that Insulin-like Growth Factor (IGF)-1, Vitamin D, and discrete members of the family of non-coding RNA peptides called microRNAs (miRNAs) may be crucial biochemical markers that help determine the neuroprotective “window” of HT. Specifically, IGF-1 confers neuroprotection in concert with, and independently of, estrogen and failure of the insulin/IGF-1 axis is associated with metabolic disturbances that increase the risk for stroke. Vitamin D and miRNAs regulate and complement IGF-1 mediated function and neuroprotective efficacy via modulation of IGF-1 availability and neural stem cell and immune cell proliferation, differentiaton and secretions. Together, age-related decline of these factors differentially affects stroke risk, severity, and outcome, and may provide a novel therapeutic adjunct to traditional HT practices.

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confidence: 99%

Revisiting the timing hypothesis: Biomarkers that define the therapeutic window of estrogen for stroke

Sohrabji

Selvamani

Balden

2013

Hormones and Behavior

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“…We proved that pretreatment of human coronary artery endothelial cells (HCAECs) from both sexes with E2, testosterone (T), or DHT strongly inhibits monocyte binding (see below). However, since prevention against atherogenesis must be started before there is significant intravascular plaque, 5 estimated at age 35 to 45, we sought a possible alternative that could furnish the effects of E2, T, or DHT without side effects that would compromise compliance by reproductively active men and women. Dehydroepiandrosterone (DHEA) is a widely used, clinically safe prohormone for estrogens and androgens.…”

Section: Introductionmentioning

confidence: 99%

Dehydroepiandrosterone (DHEA) Inhibition of Monocyte Binding by Vascular Endothelium Is Associated With Sialylation of Neural Cell Adhesion Molecule

2012

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Rationale: Adhesion of monocytes to vascular endothelium is necessary for atheroma formation. This adhesion requires binding of endothelial neural cell adhesion molecule (NCAM) to monocyte NCAM. NCAM:NCAM binding is blocked by sialylation of NCAM (polysialylated NCAM; PSA-NCAM). Since estradiol (E2) and dihydrotestosterone (DHT) induced PSA-NCAM and decreased monocyte adhesion, in consideration of possible clinical applications we tested whether their prohormone dehydroepiandrosterone (DHEA) has similar effects. Experimental: (1) DHEA was administered to cultured human coronary artery endothelial cells (HCAECs) from men and women. Monocyte binding was assessed using fluorescence-labeled monocytes. (2) HCEACs were incubated with E2, DHT, DHEA alone, or with trilostane, fulvestrant or flutamide. Expression of PSA-NCAM was assessed by immunohistochemistry and Western blotting. Results: Dehydroepiandrosterone inhibited monocyte adhesion to HCAECs by !50% (P < .01). Fulvestrant or flutamide blockade of DHEA's inhibition of monocyte binding appeared to be gender dependent. The DHEA-induced expression of PSA-NCAM was completely blocked by trilostane. Conclusions: In these preliminary in vitro studies, DHEA increased PSA-NCAM expression and inhibited monocyte binding in an estrogen-and androgen receptor-dependent manner. Dehydroepiandrosteroneappears to act via its end metabolites, E2 and DHT. Dehydroepiandrosterone could furnish clinical prevention against atherogenesis and arteriosclerosis.

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“…The beneficial effects of estrogen replacement were lost after the hypoestrogenic hiatus. 4 Choi et al 5 have reviewed the literature for the timing hypothesis and conclude that it remains Ba valid explanation of differential cardioprotective effects of menopausal hormone treatment. [ The Early and Late Intervention Trials of Estradiol and the Kronos Early Estrogen Prevention Study randomized controlled trials should further elucidate the timing hypothesis in postmenopausal women and substantiate our clinical experience.…”

Section: Discussionmentioning

confidence: 99%

Renal stones, timing hypothesis, and eu-estrogenemia

Turner

Kerber²

2012

Menopause

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The timing hypothesis of Clarkson (Menopause 14:373-384; 2007) seems to explain the hazard ratio and CI of renal stones in the Women's Health Initiative. A closer analysis of the subgroups of women who had a higher incidence of renal stones suggests that the timing hypothesis may explain the results from the Women's Health Initiative versus previous studies such as the Nurses' Health Study. The CIs of the hazard ratios of the subgroups that did not overlap 1.0 included women 6 to 10 years beyond menopause, those who were aged from 60 to 64 years, and "never users" of hormone therapy. The hazard ratio for renal stones among "current users" in the Women's Health Initiative was 0.99. This analysis suggests that the timing hypothesis may affect estrogen receptor-α-mediated processes in the kidney. Furthermore, Clarkson's work may support the vascular etiology of renal stones.

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The Timing Hypothesis remains a valid explanation of differential cardioprotective effects of menopausal hormone treatment

Cited by 26 publications

References 76 publications

Revisiting the timing hypothesis: Biomarkers that define the therapeutic window of estrogen for stroke

Revisiting the timing hypothesis: Biomarkers that define the therapeutic window of estrogen for stroke

Dehydroepiandrosterone (DHEA) Inhibition of Monocyte Binding by Vascular Endothelium Is Associated With Sialylation of Neural Cell Adhesion Molecule

Renal stones, timing hypothesis, and eu-estrogenemia

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