Sex Hormones May Play a Role in the Higher Rate of Depression Among Women

Oral contraceptives could play a role in the higher incidence of major depressive disorder (MDD) in women than in men, according to a recent study.

Conducted by Timothy B. Meier, PhD, of the Department of Neurosurgery at Medical College of Wisconsin and colleagues, the study examined whether or not concentrations of c-reactive protein (CRP) and kynurenine pathway metabolites were different in men and women with depression. Although it is well-documented that the rate of depressive disorders among women is higher than it is among men, the reasons are not clearly understood.

The researchers noted that “most research has focused on hormonal differences, yet it is clear that there are significant differences in immune function between the sexes.” Previous studies have shown that immune dysregulation plays a role in some depressive disorders, leading to researchers to think it could be at least partly responsible for the higher rate of depressive disorders among women compared to men.

The researchers hypothesized that “compared with males, females will have higher levels of inflammation (indexed by C-reactive protein) and will show a greater metabolic shunt towards the neurotoxic branch of the kynurenine pathway.” Furthermore, because there was a recent study showing an epidemiological association between depression and oral contraceptive (OC) use, they expected that serum concentrations of CRP, along with neurotoxic metabolites, could be elevated in females on OCs.

The study enrolled 480 participants, with 130 men and 350 women, using an over-representation of women as an effort to remain consistent with the literature that shows women have higher rates of mood disorders and childhood trauma. The study measured tryptophan (TRP), and kynurenine metabolites including kynurenic acid (KynA), 3-hydroxykynurenine (3HK), and quinolinic acid (QA).

“Our 2 main findings are firstly, a diagnosis-independent reduction in KynA, KynA/3HK, and KynA/QA in females versus males, and secondly, an increase in CRP along with a greater reduction in KynA, KynA/3HK, and KynA/QA in females on OC versus females not on any form of hormonal birth control,” the authors reported.

They noted that the biological mechanisms underlying these interactions are not clear, but it is possible that it could be due to significant interactions between sex hormones and the immune system.

However, the ways the immune system interacts with sex hormones are complex and also not completely understood, and the current study was not designed specifically to investigate sex differences and the impact that sex hormones may have on kynurenine metabolites.

Prior studies that have examined sex differences, OC and inflammation in humans have been done in the context of cardiovascular disease and nutritional research, making this the first study to examine these factors in light of mood disorders such as MDD.

“Here we show that females, irrespective of diagnosis, show a metabolic shunt towards the neurotoxic branch of the kynurenine pathway that is driven by a decrease in levels of the neuroprotective metabolite, KynA,” the researchers said.

Further, the same pattern occurs at a lesser magnitude in healthy women as does in those with mood disorders, a finding that leads the researchers to say “raises the possibility that a reduction in the neuroprotective arm of the kynurenine pathway in females may constitute a vulnerability factor that partly explains the higher incidence of depression in females.”

Although this research is preliminary and raises numerous questions, it offers important clues. The authors suggest future studies should be longitudinal in design and larger-scale. The full study can be found in the journal Brain, Behavior, and Immunity.