Researchers have long searched for biomarkers that could be used to identify women with postpartum depression (PPD) or, even better, biomarkers that could be used to predict which women are at highest risk for postpartum depressive illness. A new study from Osborne and colleagues, focusing on blood levels of neuroactive steroids derived from progesterone, has identified patterns of neuroactive steroid metabolites in women during their third trimester of pregnancy that predict an increased likelihood of developing PPD.
The Role of Neuroactive Steroids in Postpartum Mood Disorders
Neuroactive steroids (NAS) are molecules produced by the body and are derived from the hormone progesterone. Neuroactive steroids play a crucial role in regulating mood and the brain’s response to stress. Through their modulation of GABA-ergic neurons, they can exert potent anxiolytic effects. Recent studies exploring the biological mechanisms underlying postpartum depression suggest that neuroactive steroids may significantly influence vulnerability to PPD. This research has led to the development of two novel antidepressants effective for the treatment of PPD: brexanolone and zuranolone. Both are derivatives of the progesterone metabolite pregnanolone and function as GABA-A receptor-selective positive allosteric modulators. Both have shown effectiveness in treating PPD, offering new hope for women struggling with this condition.
Study Design and Findings
The current study investigated associations between levels of several different progesterone metabolites during pregnancy and the subsequent development of postpartum depressive symptoms. The cohort included 136 women who were not depressed at entry into the study during the first trimester. Blood samples were collected at specific timepoints during the second and third trimesters, and participants were followed up for nine months after giving birth. Of the 136 participants, 33 developed symptoms of depression during the postpartum period.
Slightly over half (56.9%) had a pre-gravid history of a mood disorder (either major depressive disorder or bipolar disorder), and 18.3% used psychiatric medications during pregnancy.
Psychological assessments were completed at each trimester (T1, T2, T3) and during the postpartum period (2 weeks, 6 weeks, 3 months, 6 months, and 9 months).
The study’s key findings include:
- Elevated progesterone levels in late pregnancy were associated with a higher risk of PP
- Women with higher isoallopregnanolone/pregnanolone ratios in the third trimester (T3) were more likely to develop PPD
- Women with lower ratios of pregnanolone/progesterone at T3 were also more likely to develop PPD
These results suggest an imbalance in the metabolism of progesterone may be a contributing factor to PPD development. Considering the normal metabolic pathways of progesterone (see figure), the researchers hypothesize that PPD may be more likely when there is decreased metabolism of progesterone to metabolites acting as positive allosteric modulators of the GABA-A receptor (e.g. allopregnanolone). In addition, PPD may be more likely when there is increased metabolism of progesterone to metabolites acting as negative allosteric modulators of the GABA-A receptor (e.g. isoallopregnanolone).
Clinical Implications
While postpartum depression has long been conceptualized as a hormonally mediated mood disorder, efforts to identify hormonally derived biomarkers have been disappointing. Older studies typically measured absolute levels of hormones, including progesterone and estradiol, and did not identify differences between women with and without postpartum depression. Recent research has taken a more nuanced (and fruitful) approach and has focused on the progesterone metabolic pathway.
The study’s findings shed light on the complex biological mechanisms underlying PPD. The researchers propose that the relative activity of two enzymes, 3?-HSD and 3?-HSD, which help convert progesterone to pregnanolone and isoallopregnanolone, may play a crucial role in determining PPD risk. The findings align with previous research on the role of neuroactive steroids in mood disorders and studies indicating that neuroactive steroids derived from progesterone can modulate the function of GABA receptors, the primary inhibitory neurotransmitter system in the brain.
While this was a relatively small study, including online 33 women with PPD, the sample size was large enough to identify statistically significant differences in the levels of progesterone metabolites that could ultimately be used to screen women during the third trimester. Research studies including larger and more diverse populations are needed
Dr. Lauren Osborne, lead author and associate professor at Weill Cornell Medicine, notes the potential clinical significance of these findings: “If we were able to replicate these results, then this could reasonably become a clinical test that could predict the development of future illness.” Currently, two treatments, brexanolone and zuranolone, are neuroactive steroids that have been approved for the treatment of PPD. However, the new findings open up possibilities for preventive interventions. Dr. Osborne suggests that these drugs might have the potential to prevent PPD in individuals identified as high-risk based on their neuroactive steroid profiles.
The ability to identify women at risk for PPD before symptoms appear could transform perinatal care and mental health interventions. Early identification would allow for the implementation of interventions that could potentially prevent the onset of PPD or mitigate its severity.
Ruta Nonacs, MD PhD
References
Osborne LM, Etyemez S, Pinna G, Alemani R, Standeven LR, Wang XQ, Payne JL. Neuroactive steroid biosynthesis during pregnancy predicts future postpartum depression: a role for the 3alpha and/or 3beta-HSD neurosteroidogenic enzymes? Neuropsychopharmacology. 2025 Jan 30.
