Estradiol and Tamoxifen Reverse Ovariectomy-Induced Physical Inactivity in Mice (try number 2)

Gorzek JF, Hendrickson KC, Forstner JP, Rixen JL, Moran AL, Lowe DA.

Medicine and Science in Sports and Exercise 2007

                Physical activity is crucial to maintaining good health and it has been shown that there are many positive adaptations in multiple different body systems that can come from regular physical activity. These systems can include the cardiovascular system, immune system, musculoskeletal system and the nervous system as well. Many studies have shown that female rats consistently run more than their male counterparts. Furthermore, it has been shown that this difference in running is most likely due to the presence of female hormones produced in the ovaries. Something interesting to me is why are the females running more than the males. If it is the ovarian hormones, what are they doing to cause the female to run more? Is it affecting their motivation to run or their physical ability to run? If it is the physical ability to run are the changes produced by the ovarian hormones in the musculoskeletal system or in the nervous system. The current study tried to shed some light on the previous questions by using tamoxifen, a compound that works at estrogen receptors, as well as estrogen in their replacement therapy post-ovariectomy. Tamoxifen has been shown to have agonist and antagonist properties at estrogen receptors depending on the tissue that it has its action in. The purpose of this study was to evaluate the effect that estrogen or tamoxifen has on running behaviors of female rats after ovariectomy.

                There were two studies conducted in this paper. In the first study mice were assigned to either sham group, ovariectomy with estrogen group, or ovariectomy with placebo group. Mice were obtained at 10 weeks of age and then given 3 weeks to acclimate to their environment at which point exercise wheels were placed in all cages and mice were allowed one week to acclimate to the running wheel. At week 4 of the experiment (mice were 14 weeks old) sham and ovariectomy surgeries were performed. During the one-week recovery period mice had not access to wheels, and then were given access to their wheels again at week 5 of the experiment. Mice were then allowed to freely run on their wheels for four weeks (weeks 5-9 of experiment). At week 9 placebo and estradiol replacement was initiated using subcutaneous placement of pellets that contained those compounds. Mice were then allowed to run on their wheels for another 4 weeks at which point mice were anesthetized and subsequently weighed, and the soleus and extensor digitorum longus and heart muscles were removed and weighed.

In the second study, all mice were given approximately 3 weeks to acclimate to the environment without a wheel at which point a wheel was placed in the cages for 10 days prior to the surgeries. After these 10 days all mice were ovariectomized and then placed in one of three groups: estradiol replacement, tamoxifen replacement or placebo replacement. In this study surgeries were performed at the same time as the pellet placement and then mice were given 3 days to recover and then put in their cages with wheels. After recovery mice were allowed to run voluntarily on their wheels for 6 weeks. At the end of this period mice were anesthetized and soleus, extensor digitorum longus, and heart muscles were taken out and weighed. In both studies the amount of wheel running was measured using a digital magnetic counter attached to the wheel that stored the amount of revolutions of the running wheel per 24 hours.

                Data from the first study show that mice in the sham surgery group ran at a consistent level throughout the study and was significantly higher than the ovariectomy + placebo group. The ovariectomy + placebo group also ran a consistent amount across the study but this significantly lower than the sham group as stated above. The ovariectomy + estrogen group ran lower amounts that were closer to the ovariectomy + placebo group prior to replacement. After estradiol replacement the mice started to run significantly more and ended up not being statistically different than the sham surgery group. All groups increased body mass over time, however, the ovariectomy + placebo group increased body mass the most. The ovariectomy + estradiol group increased body mass similar to the placebo group until the replacement therapy was initiated at which point the estradiol group stopped increasing body mass and plateaued.

In the second study the data shows that all three groups increased their running as they acclimated to the wheel in the pre-surgery time frame. Once the ovariectomy surgeries were performed the running of the placebo group declined significantly from before the surgery. The groups that were immediately treated with tamoxifen or estradiol maintained their running behavior more steadily, although there was some decline over time. The replacement groups with tamoxifen and estradiol ran significantly more than the placebo group, but the two treatment groups were not significantly different from one another.
                This study indicates that the decrease seen in physical activity in females after loss of ovarian hormones is indeed due to the loss of those ovarian hormones. Due to the use of tamoxifen in this study, it was also indicated that this hormone dependent change in running behavior is mediated by the estrogen receptor and not the antioxidant effects of estrogen as tamoxifen is not known to have any antioxidant effects. The authors of this paper also suggest that the changes caused by action at estrogen receptor are in the nervous system and not in the musculoskeletal system. They think that estrogen may cause an increase in the motivation to run. This is based on the findings that running quickly increases after replacement therapy and that if it was changes in the musculoskeletal system the increase in running behavior would take longer manifest. However, the authors assume that it is an increase in motivation and not another change that could arise from the central nervous system. The current study did not have any measures of motivation and their claims are, at this point, just speculation. The estrogenic compounds could have caused changes in the RVLM which could have caused a greater ability of the RVLM to regulate cardiovascular parameters such as blood pressure, heart rate and contractility. Changes in this area and these parameters could cause a greater ability of the mice to run without necessarily changing their musculoskeletal system.

Ben R