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Order of magnitude differences between methods for maintaining physiological 17β-estradiol concentrations in ovariectomized rats
Linköping University, Department of Clinical and Experimental Medicine. 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. Östergötlands Läns Landsting, Reconstruction Centre, Department of Neurosurgery UHL.
2008 (English)In: Scandinavian Journal of Clinical and Laboratory Investigation, ISSN 0036-5513, E-ISSN 1502-7686, Vol. 68, no 8, 814-822 p.Article in journal (Refereed) Published
Abstract [en]

The use of animal, especially rat, models, is crucial for elucidating the biological effects and mechanisms of the widely used hormone 17β-estradiol. Unfortunately there is a lack of consensus on optimal means of obtaining and maintaining physiological 17β-estradiol concentrations in plasma. This may be the reason for varying results in several studies including the disagreement on whether 17β-estradiol is neuroprotective or not. Very few studies have been devoted to investigating the characteristics and biological relevance of different methods of 17β-estradiol administration. We therefore ovariectomized 75 Sprague-Dawley rats and, following a 2 weeks wash-out period, administered 17β-estradiol using three different methods; daily injections (10 µg 17β-estradiol/kg), slow-release pellets (0.25 mg 60 day-release pellets, 0.10 mg 90 day-release pellets) and silastic capsules (with/without wash-out periods) (silastic laboratory tubing, inner/outer diameter: 1.575/3.175 mm, filled with 20 mm columns of 180 µg 17β-estradiol/mL sesame oil). Further 45 animals were used as ovariectomized and native controls, studied in different parts of the estrous cycle. Silastic capsules produced concentrations of 17β-estradiol within the physiological range for 4-5 weeks independent of whether a prior wash-out period was included or not. The slow-release pellets, irrespective of dose or release period, resulted in initial concentrations which were an order of magnitude above physiological concentrations during the first two weeks followed by a substantial decrease. Daily injections resulted in increasing 17β-estradiol concentrations, however within physiological levels. Silastic capsules are conveniently manufactured and used, and are superior to pellets and injections in reliably producing long-term 17β-estradiol concentrations within the physiological range.

Place, publisher, year, edition, pages
2008. Vol. 68, no 8, 814-822 p.
Keyword [en]
Estrogens, Injections, Pharmacokinetics, Silastic capsules, Slow-release pellets, Wash-out
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:liu:diva-15389DOI: 10.1080/00365510802409703OAI: oai:DiVA.org:liu-15389DiVA: diva2:114091
Note
Original publication: Jakob O. Ström, Elvar Theodorsson and Annette Theodorsson, Order of magnitude differences between methods for maintaining physiological 17β-estradiol concentrations in ovariectomized rats, 2008, Scandinavian Journal of Clinical and Laboratory Investigation.http://dx.doi.org/10.1080/00365510802409703. Copyright © Taylor & Francis Group, an informa businessAvailable from: 2008-11-05 Created: 2008-11-05 Last updated: 2017-12-14Bibliographically 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)
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Supervisors
Available from: 2012-05-08 Created: 2012-05-08 Last updated: 2016-02-29Bibliographically approved

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Ström, Jakob O.Theodorsson, ElvarTheodorsson, Annette

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