The study found that changes in neuroactive steroid (NAS) levels and ratios during pregnancy, especially in the third trimester, are associated with the risk of postpartum depression (PPD). Specifically, an increase in the ratio of isoallopregnanolone to pregnanolone was associated with an increased risk of PPD, while an increase in the ratio of pregnanolone to progesterone had a protective effect. These findings suggest that imbalances in the progesterone metabolic pathway may play an important role in the development of postpartum depression.
Postpartum depression is a serious condition that affects between 10% and 15% of people of childbearing age, with consequences that can impact both parents and children, spanning two generations.
This disorder can compromise the mother's mental health, interfering with her bond with her baby and increasing the risk of emotional and behavioral problems in the child.
Although it is already known that hormonal factors play a fundamental role in the development of postpartum depression, researchers have been delving deeper into the investigation of neuroactive steroids (NAS), which are hormone-derived substances that directly influence the central nervous system and mood regulation.
The aim of this study, conducted by researchers at Weill Cornell Medical College, USA, was to analyze how variations in the levels and proportions of these steroids throughout pregnancy may be associated with the development of postpartum depressive symptoms.
To this end, the researchers monitored participants throughout pregnancy and after delivery, carrying out up to eight assessments to measure the levels of neuroactive steroids in the body and applying psychological scales that assess mood and emotional well-being.
The participants included in the study were pregnant women with no previous history of mood disorders, allowing scientists to analyze hormonal changes that could be directly related to the onset of postpartum depression.
The data collected were analyzed using statistical models that evaluated the relationships between different hormonal biomarkers and the development of postpartum depression.
The results revealed specific patterns in the variation of these hormones in the third trimester of pregnancy, which appeared to influence the risk of postpartum depression.
In particular, an increase in the ratio between two progesterone metabolites, isoallopregnanolone and pregnanolone, was found to be associated with a higher risk of developing postpartum depression.
Specifically, for each one-unit increase in this ratio, the odds of experiencing postpartum depressive symptoms increased by 64%. Isoallopregnanolone and pregnanolone are progesterone metabolites that belong to the group of neuroactive steroids, substances capable of modulating the activity of the central nervous system.
They interact with receptors for the neurotransmitter GABA (gamma-aminobutyric acid), which is responsible for promoting relaxing and anxiolytic effects in the brain.
Pregnanolone and isoallopregnanolone are produced from progesterone through the action of specific enzymes, and their proportion in the body can influence mood regulation and the response to stress.
An increase in the ratio of isoallopregnanolone to pregnanolone may indicate an alteration in the metabolism of these compounds, negatively affecting neurochemical balance and potentially increasing vulnerability to postpartum depression.
On the other hand, another hormonal relationship demonstrated a protective effect. An increase in the ratio of pregnanolone to progesterone in the third trimester was associated with a 36% reduction in the risk of postpartum depression.
This finding suggests that the way the body metabolizes progesterone may play a crucial role in regulating maternal mood after childbirth. In addition, the researchers found that an increase in absolute progesterone levels in the third trimester was associated with a significantly increased risk of postpartum depression.
For each logarithmic unit increase in progesterone levels, the risk of developing postpartum depression quadrupled. This finding reinforces the importance of understanding how hormone levels and their metabolites interact in late pregnancy and how they may predispose some people to postpartum depression.
The analyses also suggested changes in the activity of two enzymes essential for progesterone metabolism: 3α-HSD and 3β-HSD. In the third trimester, the results indicate that there may be a reduction in the activity of 3α-HSD, an enzyme that converts progesterone into compounds with a positive effect on mood, and/or an increase in the activity of 3β-HSD, which generates metabolites with a lower neuroprotective impact.
These changes in hormonal balance may contribute to a neurochemical state that is more vulnerable to the development of postpartum depression.
This study contributes to a deeper understanding of the hormonal factors involved in postpartum depression, paving the way for new preventive and therapeutic approaches.
Monitoring neuroactive steroid levels throughout pregnancy may help identify individuals at higher risk of developing the condition early, enabling more effective and personalized interventions to promote maternal and child mental health.
READ MORE:
Neuroactive steroid biosynthesis during pregnancy predicts future postpartum depression: a role for the 3α and/or 3β-HSD neurosteroidogenic enzymes?
Lauren M. Osborne, Semra Etyemez, Graziano Pinna, Rebecca Alemani, Lindsay R. Standeven, Xin-Qun Wang & Jennifer L. Payne
Neuropsychopharmacology (2025)
Abstract:
Postpartum depression (PPD) affects ~10–15% of childbearing individuals, with deleterious consequences for two generations. Recent research has explored the biological mechanisms of PPD, particularly neuroactive steroids (NAS). We sought here to investigate associations between NAS levels and ratios during pregnancy and the subsequent development of depressive symptoms with postpartum onset. NAS levels and psychological scales were measured in individuals with and without mood disorders at up to eight visits across pregnancy and postpartum. Generalized linear mixed-effects regression models were used to assess relationships in euthymic pregnant individuals between each of the NAS biomarkers and ratios and subsequent PPD. Participants with a one-unit increase in the log isoallopregnanolone/pregnanolone ratio at the third trimester (T3) had higher odds (OR = 1.64, 95% CI: 1.13–2.37, FDR adjusted p = 0.038, C-index = 0.82), and those with a one-unit increase in the log pregnanolone/progesterone ratio at T3 had lower odds (OR = 0.64, 95% CI: 0.47–0.88, FDR adjusted p = 0.036, C-index = 0.82) of developing PPD; those with a one-unit increase in the log progesterone level at T3 had higher odds of developing PPD (OR = 4.00, 95% CI: 1.54–10.37, FDR adjusted p = 0.035, C-index = 0.80). We found key differences in the progesterone metabolic pathway at the third trimester, indicating likely decreased activity/expression of the 3α-HSD enzyme and/or increased activity/expression of 3β-HSD.
Comments