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Different methods for administering 17 beta-estradiol to ovariectomized rats result in opposite effects on ischemic brain damage
Linköping University, Department of Clinical and Experimental Medicine, Clinical Chemistry. Linköping University, Faculty of Health Sciences.
Linköping University, Department of Clinical and Experimental Medicine, Clinical Chemistry. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Chemistry.
Linköping University, Department of Clinical and Experimental Medicine, Clinical Chemistry. Linköping University, Faculty of Health Sciences.
Linköping University, Department of Clinical and Experimental Medicine, Clinical Chemistry. Linköping University, Department of Clinical and Experimental Medicine, Neurosurgery. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Reconstruction Centre, Department of Neurosurgery UHL.
2010 (English)In: BMC neuroscience (Online), ISSN 1471-2202, E-ISSN 1471-2202, Vol. 11, 39- p.Article in journal (Refereed) Published
Abstract [en]

Background: Numerous stroke studies have controversially shown estrogens to be either neuroprotective or neurodamaging. The discordant results observed in rat brain ischemia models may be a consequence of discrepancies in estrogen administration modes resulting in plasma concentration profiles far from those intended. To test this hypothesis we reproduced in detail and extended an earlier study from our lab using a different mode of 17 beta-estradiol administration; home-made silastic capsules instead of commercial slow-release 17 beta-estradiol pellets. Four groups of female rats (n = 12) were ovariectomized and administered 17 beta-estradiol or placebo via silastic capsules. All animals underwent MCAo fourteen days after ovariectomy and were sacrificed three days later.

Results: In contrast to our earlier results using the commercial pellets, the group receiving 17 beta-estradiol during the entire experiment had significantly smaller lesions than the group receiving placebo (mean +/- SEM: 3.85 +/- 0.70% versus 7.15 +/- 0.27% of total slice area, respectively; p = 0.015). No significant neuroprotection was found when the 17 beta-estradiol was administered only during the two weeks before or the three days immediately after MCAo.

Conclusions: The results indicate that different estrogen treatment regimens result in diametrically different effects on cerebral ischemia. Thus the effects of estrogens on ischemic damage seem to be concentration-related, with a biphasic, or even more complex, dose-response relation. These findings have implications for the design of animal experiments and also have a bearing on the estrogen doses used for peri-menopausal hormone replacement therapy.

Place, publisher, year, edition, pages
BioMed Central, 2010. Vol. 11, 39- p.
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:liu:diva-55058DOI: 10.1186/1471-2202-11-39ISI: 000276444500001PubMedID: 20236508OAI: oai:DiVA.org:liu-55058DiVA: diva2:315258
Note

Original Publication: Jakob O Ström, Elvar Theodorsson, Lovisa Holm and Annette Theodorsson, Different methods for administering 17 beta-estradiol to ovariectomized rats result in opposite effects on ischemic brain damage, 2010, BMC NEUROSCIENCE, (11), 39. http://dx.doi.org/10.1186/1471-2202-11-39 Licensee: BioMed Central http://www.biomedcentral.com/

Available from: 2010-04-28 Created: 2010-04-28 Last updated: 2017-12-12Bibliographically approved
In thesis
1. The dose-dependent effects of estrogens on ischemic stroke
Open this publication in new window or tab >>The dose-dependent effects of estrogens on ischemic stroke
2012 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Estrogens are a group of female sex hormones that in addition to central roles in reproductive functions also have profound impact on for example brain development, blood vessels, bone tissue, metabolism and the immune system. The dominant endogenous production sites for estrogens in females are the ovaries and adipose tissue, while exogenous sources include combined contraceptive hormone treatments and menopausal hormone therapy. A few decades ago, the observation that females in comparison to men seemed to be protected against cerebral ischemia, and that this benefit was partially lost during menopause, sparked the hypothesis that estrogens protect against stroke. This was later confirmed by epidemiological studies and a large number of experimental animal studies, which motivated extensive clinical trials in which estrogens and/or progestagens were administered with the intent to prevent degenerative conditions rather than to ameliorate menopausal symptoms. However, the results were generally disappointing. The largest study, the Women’s Health Initiative (WHI), was discontinued due to the observation of an increased risk of breast cancer, cardiovascular disease and stroke. In parallel, a small number of animal studies in which estrogens were shown to increase damage from cerebral ischemia were published, one of these originating from our laboratory. This was, despite the WHI outcome, a surprising result, since the vast majority of previous animal studies had demonstrated protective effects.

Therefore, in an attempt to explain the discordant results, Paper 1, and later Paper 4, of the current thesis were planned, in which four 17β-estradiol administration methods were tested. Substantial differences in serum hormone concentrations resulted from the different methods. Most importantly, the commercially available slow-release pellets used in our earlier experiments resulted in extremely high serum concentrations of 17β-estradiol. In Paper 2, 66 published studies that had investigated the effects of estrogens on stroke were meta-analyzed to pin-point the methodological reasons for the result dichotomy. Strikingly, in all six studies in which estrogens had produced damaging effects, the same type of slow-release pellets had been used, although these were used in a minority of the total number of studies. Paper 3 substantially strengthened the hypothesis that administration methods were crucial by showing that repeating the earlier experiment from our laboratory in which pellets had been used, but using a low-dose regimen instead, switched the estrogen effects from neurodamaging to neuroprotective. In Paper 5, an effort was made to challenge the assumption that the dose, and not the administration method per se, was the key factor, however this failed due to large intra-group infarct size variability.

The current thesis adds evidence to the notion that differences in administration methods and their resulting serum concentrations of 17β-estradiol constitute a major factor responsible for the dichotomous results in studies investigating estrogens’ effects on cerebral ischemia. Even though results from animal studies are difficult to extrapolate to humans, this has a bearing on the menopausal hormone therapy debate, indicating that the risk of stroke could be reduced if serum concentrations of estrogens are minimized.

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press, 2012. 92 p.
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1301
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-77193 (URN)978-91-7519-937-5 (ISBN)
Public defence
2012-06-05, Berzeliussalen, Ingång 65,, Campus US, Linköpings universitet, Linköping, 09:00 (Swedish)
Opponent
Supervisors
Available from: 2012-05-08 Created: 2012-05-08 Last updated: 2016-02-29Bibliographically approved

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Ström, Jakob OTheodorsson, ElvarHolm, LovisaTheodorsson, Annette

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