Gender differences in stress response

The study has implications for the manner in which clinical trials must be carried out

Sumana Chakravarty; Arvind Kumar (centre) and Bhanu Chandra Karisetty. wanted to show howsexes differed in lab tests.

That male and female mice respond differently to stress has once again been highlighted by a study carried out by scientists from Hyderabad’s Indian Institute of Chemical Technology (CSIR-IICT) and Centre for Cellular and Molecular Biology (CSIR-CCMB).

While female mice were more vulnerable to chronic mild stress compared with male mice, those females with ovaries removed exhibited similar vulnerability as the males. This study was recently published in Neuroscience.

Eight to ten-week-old mice were separated into eight sets of which four were control groups and four were given stress and studied. Fourteen types of stressors were used for the study. Two different stressors were given each day for 21 days. Each of the stressed mice was kept in a separate cage thus socially isolated for the entire chronic mild stress period. After 21 days, various behavioural assays were conducted to assess the anxiety and depression levels of the mice.

The animals were sacrificed on the third day after completion of the stress conditions, and their brain proteins were studied for the expression of stress-related proteins. The females showed a significant increase in the stress protein when compared to males and ovary-removed mice.

Variation between sexes

“Most clinical trials are carried out on male mice and the effect on females is neglected. We wanted to show that both sexes respond differently to stress conditions and drugs,” explains Dr. Sumana Chakravarty, Principal Scientist, CSIR-IICT, and corresponding author of the paper.

Females with ovaries removed resembled males in their behaviour — they exhibited less ability to feel pleasure. The results also showed that there was an increase in body weight in the control groups but not in the stress groups. The stress condition also impaired the locomotive ability of the mice.

“Antidepressant drugs show various side-effects in females and children. Some antidepressants that had been tried and tested in adults were found to cause suicidal tendency when used by children. So it is essential to also study the dosage before administration,” says Dr. Arvind Kumar, Principal Scientist, CSIR-CCMB and co-author of the paper.

In order to evaluate the effect of ovarian hormones on stress, the female mice without ovaries were injected ovarian hormones for 21 days along with stress conditions. One group was injected with 17Beta-Estradiol and another was given progesterone every four days, beginning on day three till the end of experiment. Interestingly, estradiol administration was able to significantly reduce total immobility and also increase the sucrose solution consumption showing inclination to sense pleasure. It also significantly increased the anti-stress protein levels. Noteworthy effect was not seen in mice that received progesterone.

The findings strengthen the evidence that estradiol administration reduces stress-induced, depression-like behaviours. “Future studies are required to investigate the effect of stress during the various stages of the reproductive cycle to get a better understanding of ovarian hormones in stress. A study of the effect of different doses of estradiol is also essential for better conclusions,” said Dr. Bhanu Chandra Karisetty, from CSIR-IICT,the first author.

According to Pranav Joshi, CSIR-IICT, a co-author of the paper, specific estrogen targets need to be identified for better drug development to treat females.