Introduction: Anxiety disorders manifest in women more than in men by almost twofold.
This narrative review aims to summarize the sex-related biological factors, which underpin anxiety, focusing
on the interactions of sex and tryptophan/serotonin with anxiety.
Methods: A literature search was conducted using Google Scholar, PubMed/MEDLINE, Scopus, and
EMBASE databases from inception until December 31, 2017.
Results: This review shows that sex may interact with many serotonin functions thereby modulating
anxiety, including 5-HT1A and 5-HT2C receptors, 5-HT transporter and central 5-HT concentrations
and metabolism. Sex-steroids modulate the expression of serotonin transporter genes, creating a difference
in serotonin availability. Sex and estrous cycle phases lead to varying anxiety responses to tryptophan
depletion. Testosterone, progesterone and estrogen are important factors in mediating sex differences
in serotonin responses to anxiety-generating behavioral tests. At prenatal levels, there are sexrelated
differences in the reciprocal relationships between serotonin and the HPA-axis, which modulate
anxiety-like behaviors. Activated immune-inflammatory pathways induce indoleamine-2,3-dioxynease
(IDO) and the tryptophan catabolite (TRYCAT) pathway thereby increasing tryptophan degradation and
increasing the production of TRYCATs including kynurenine and quinolinic acid, which may create an
overall anxiogenic effect. The effects of immune activation on IDO are significantly more pronounced
in women than men, and therefore, females may show increased levels of anxiogenic TRYCAT following
immune challenge. Aberrations in the IDO-activated TRYCAT pathway are found in pregnant females
and parturients and are associated with increased anxiety levels in the postnatal period.
Conclusion: The results of this review underscore the necessity of studying the associations between
serotonin and anxiety in both sexes taking into account the effects of immune activation on IDO and
production of anxiogenic TRYCATs. Future anxiety research should focus on the interactions between
serotonin/tryptophan and sex, sex hormones, the menstrual cycle, pregnancy, the HPA axis and the immune
system through the production of anxiogenic TRYCATs.