Medical Research: What is the background for this study? What are the main findings?
Dr. Kabbaj: While anxiety and depressive disorders a major public health concern worldwide, so too are the pervasive sex differences that exist within these pathologies. Fluctuations in the predominant female reproductive hormones, estradiol and progesterone, are thought to be a major contributor to the higher prevalence of anxiety and depression in women compared to men. However, many studies in humans and rodents alike have demonstrated that testosterone, the primary male sex hormone, also influences affective status and may yield protective benefits against the development of mood-related disturbances. Indeed, hypogonadal males with low testosterone levels experience increased rates of anxiety and depressive symptoms. In many of these cases, testosterone replacement alone or in addition to antidepressant medication have been shown to effectively improve mood. How this hormone acts in the brain to exert its beneficial effects, however, is much less clear. Interestingly, it is well-known that many of testosterone’s effects in the brain occur via its conversion to estrogen by the enzyme aromatase. What remained unclear was whether or not this conversion to estrogen was critical for testosterone’s protective anxiolytic and antidepressant effects—so Nicole Carrier and Samantha Saland from Dr. Kabbaj’s lab aimed to figure out just that.
To do this, Carrier and Saland targeted an area of the hippocampus in the brain involved in mood regulation where testosterone is known to act to carry out some of its anxiolytic and antidepressant effects in male rats. Here, they inhibited the enzyme responsible for the conversion of testosterone into estrogen and investigated performance in mood-related behaviors. In doing so, they discovered that testosterone’s anxiolytic- and antidepressant-like effects were lost unless this hormone was first converted into estrogen. Importantly, they also found that continuous testosterone and estrogen treatments had very similar effects on the expression of genes within this brain region that are highly implicated in the regulation of mood as well as antidepressant treatments.
Medical Research: What should clinicians and patients take away from your report?
Dr. Kabbaj: While there are several anti-anxiety and antidepressant medications currently available, many patients show little or no response to these drugs. When they do, the beneficial effects can take weeks or months to occur—this is a significant public health concern. Given the pervasiveness of sex differences in the prevalence of anxiety and depression, understanding how hormones modulate these mood disorders will likely by essential to uncovering not only their pathophysiology, but also provide important clues to develop more efficacious individualized treatments. The findings of this study provide important insights into some the mechanisms by which testosterone exerts its anti-anxiety and –depression effects. It is possible that targeting some of these mechanisms may be useful in developing safer and more effective treatments for males with low testosterone levels suffering with depression that is resistant to currently available treatment
Medical Research: What recommendations do you have for future research as a result of this study?
Dr. Kabbaj: The findings from this study not only support previous evidence regarding the important role that testosterone plays in protecting against mood-related disturbances, but also provide novel mechanistic avenues worth exploring in greater detail in future studies. Importantly, it will be critical to identify how testosterone and estrogen act within the brain in both males and females to modulate affective behavior in order to improve our understanding not only of sex differences in mood disorders, but also of new ways to approach the development of treatments that are more effective in both men and women. Some of the key hormonally-regulated pathways identified in this work by Carrier, Saland and Dr. Kabbaj may provide a good place to begin.
MedicalResearch.com Interview with: Mohamed Kabbaj, PHD (2015). Testosterone May Protect Against Mood-Related Disorders