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Methods for 17 beta-oestradiol administration to rats
Östergötlands Läns Landsting, Center for Diagnostics, Department of 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, Anaesthetics, Operations and Specialty Surgery Center, Department of Neurosurgery.
Linköping University, Department of Clinical and Experimental Medicine, Clinical Chemistry. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Diagnostics, Department of Clinical Chemistry.
Linköping University, Department of Clinical and Experimental Medicine, Clinical Chemistry. Linköping University, Faculty of Health Sciences.
2011 (English)In: Scandinavian Journal of Clinical and Laboratory Investigation, ISSN 0036-5513, E-ISSN 1502-7686, Vol. 71, no 7, 583-592 p.Article in journal (Refereed) Published
Abstract [en]

Several studies indicate that the beneficial or harmful effects of oestrogens in stroke are dose-dependent. Rats are amongst the most frequently used animals in these studies, which calls for thoroughly validated methods for administering 17 beta-oestradiol to rats. In an earlier study we characterised three different administration methods for 17 beta-oestradiol over 42 days. The present study assesses the concentrations in a short time perspective, with the addition of a novel peroral method. Female Sprague-Dawley rats were ovariectomised and administered 17 beta-oestradiol by subcutaneous injections, silastic capsules, pellets and orally (in the nut-cream Nutella (R)), respectively. One group received 17 beta-oestradiol by silastic capsules without previous washout time. Blood samples were obtained after 30 minutes, 1, 2, 4, 8, 12, 24, 48 and 168 hours and serum 17 beta-oestradiol (and oestrone sulphate in some samples) was subsequently analysed. For long-term characterisation, one group treated perorally was blood sampled after 2, 7, 14, 21, 28, 35 and 42 days. At sacrifice, uterine horns were weighed and subcutaneous tissue samples were taken for histological assessment. The pellets, silastic capsule and injection groups produced serum 17 beta-oestradiol concentrations that were initially several orders of magnitude higher than physiological levels, while the peroral groups had 17 beta-oestradiol levels that were within the physiological range during the entire experiment. The peroral method is a promising option for administering 17 beta-oestradiol if physiological levels or similarity to womens oral hormone therapy are desired. Uterine weights were found to be a very crude measure of oestrogen exposure.

Place, publisher, year, edition, pages
Informa Healthcare , 2011. Vol. 71, no 7, 583-592 p.
Keyword [en]
Dosage, drug administration routes, injection, oestradiol, per os, rat, silastic capsule, slow-release pellet, uterine weight, washout
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:liu:diva-71772DOI: 10.3109/00365513.2011.596944ISI: 000295799300009OAI: oai:DiVA.org:liu-71772DiVA: diva2:453962
Available from: 2011-11-04 Created: 2011-11-04 Last updated: 2017-12-08Bibliographically 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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Theodorsson, AnnetteTheodorsson, ElvarStröm, Jakob

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