Sex hormones seem to play a central role in depression. In a recent study by the Vienna Clinic for Psychiatry and Psychotherapy, the effect of testosterone and estrogen on the density of serotonin transporters in the brain was examined using the model of hormone therapy for transsexuals. The researchers were able to show that the serotonin transporter is significantly increased after four weeks of testosterone therapy and continues to increase with ongoing therapy.

Frontal section of the distribution of the serotonin transporter in female-to-male transsexuals before (PET 1, left) and one (PET 2, middle) or four months (PET 3, right) after the start of the opposite sex hormone therapy. The increase in the binding potential over time is evident from the increase in the green-yellow-red color in subcortical structures.

Epidemiological studies show that women are almost twice as likely to experience depression and anxiety disorders as men. Women are usually younger at first onset and show a greater number of symptoms and depressive episodes. Above all, the fact that many women have depressive symptoms in times of strong hormonal fluctuations (cycle, change, post-partum) suggests that sex hormones influence the biological mechanism underlying mood. Furthermore, the suicide rate is higher in depressed men, and they tend to aggression and increased risk behavior.

When the sex hormone testosterone decreases in older age, men often suffer from depression, and some studies have shown a positive effect of testosterone on mood in those affected. Therefore, mood swings in both sexes appear to be closely associated with sex hormones, a result that is not surprising given the strong modulation of the serotonin system by sex hormones. A number of animal studies have previously demonstrated this close connection between the neurotransmitter system serotonin, which is central to depression, and the sex hormones estrogen and testosterone.

The first human studies also exist which use positron emission tomography to suggest that receptor and transporter availability in the synaptic cleft is dependent on sex hormones. Most of these studies are based on cross-sectional studies and therefore do not allow any conclusions to be drawn about the causality of the observed dependency. In a recent study published in the journal “Biological Psychiatry” ( http://dx.doi.org/10.1016/j.biopsych.2014.09.010 ), hormone therapy for transsexuals was the first to establish a causal mechanism for the effect of testosterone on the Binding potential of serotonin transporters (5-HTT) in the brain are shown.

The study

Transsexual subjects of both sexes were examined, who were measured three times in a longitudinal study design using PET and the radioligand [11C] DASB to quantify the 5-HTT concentration in the synaptic cleft. The first measurement was made before the start of the opposite sex hormone therapy, a second measurement was made four weeks after the start of the therapy and a third measurement four months after the start of the therapy. Female-to-male transsexuals (FzMT) received testosterone, while male-to-female transsexuals (MzFT) were given anti-androgens to suppress testosterone and estrogen. This corresponds to standard therapy,

Blood was taken at each PET appointment to determine the plasma levels of estrogen and testosterone. Furthermore, female and male control subjects were measured once and a subset of the male control subjects was measured twice with PET and [11C] DASB. As expected by the researchers, after four weeks of testosterone therapy with FzMT, there was a significant increase in plasma testosterone in the male reference range, which was even more pronounced after four months of therapy. In contrast, the testosterone concentration in plasma from MzFT after four weeks of anti-androgen therapy in the female reference range, where they remained after four months of therapy.

Analysis of the PET data showed that the 5-HTT binding potential after four weeks – and even more so after four months – of testosterone therapy with FzMT was significantly increased in contrast to the first measurement in several subcortical regions (see figure). This increase was particularly evident in the almond kernel and in the striatum. Furthermore, a significant positive correlation between the increase in testosterone concentration in plasma and the increase in 5-HTT binding in these regions was found, a finding that underpins the postulated causal relationship between testosterone and transporter density. In contrast, there was no significant difference in MFT after four weeks of antiandrogen and estrogen therapy; however, there was a significant reduction in 5-HTT binding in the striatum as well as in the cingular cortex and the island after four months of therapy. Interestingly, however, there was a significantly negative relationship between the decrease in 5-HTT binding in these regions and the increase in estrogen levels.

Implications

The results of this study suggest that testosterone increases the density of serotonin transporters on the cell surface in subcortical brain structures. These findings are in line with rat studies, which found increased 5-HTT density and 5-HTT messenger RNA after testosterone administration. Since testosterone is largely converted to estrogen in the brain via the aromatase enzyme and many functions of testosterone affect the function and structure of the brain in this way, it can be assumed that the testosterone effect observed here can also be explained by this mechanism.

This is also supported by the result that the increase in estrogen in MFT had an apparently “protective” effect on the decline in serotonin transporters. Furthermore, it can be assumed that testosterone (and the estrogen that arises from it in the brain) not only act directly on the expression of the serotonin transporter through the binding of nuclear receptors but also indirectly increases the expression of the serotonin transporter through the increased release of serotonin. This may explain why testosterone therapy has a positive effect on mood in hypogonadal men.

The serotonin transporter, in turn, is responsible for the uptake of extracellular serotonin, and an increased 5-HTT density suggests an increased serotonin uptake; the expression of the serotonin transporter itself is strongly regulated by the serotonin content in the synaptic cleft. A low 5-HTT density can thus be interpreted as an expression of reduced serotonergic neurotransmission, while an increased 5-HTT binding potential reflects higher serotonin concentrations in the synaptic cleft.