Neurosteroid Levels in Pregnancy and Its Implications for Mental Health: A Literature Review

Abstract

Background

Perinatal mood disorders are being increasingly recognised and may have deleterious outcomes for the mother and offspring, underlining the importance of understanding their pathophysiology. Neurosteroids can alter the excitability of neurons through rapid non-genomic actions. Here, we review the changes in neurosteroids across pregnancy and their impact on maternal mental health.

Summary

Among the neurosteroids, the most studied is allopregnanolone, followed by 5-DHP in pregnancy. Predominantly, allopregnanolone is shown to be increased across pregnancy with a drop in the post-partum levels. With respect to the mood changes in pregnancy and the role of neurosteroids, there are conflicting reports about pregnanolone and its isomers. However, a few studies reported that lower allopregnanolone levels during mid-pregnancy seem to be associated with an increased risk for postpartum depression (PPD).

Key Message

Thus, while there are reports that have examined individual neurosteroids across pregnancy, studies with serial measurements that include comprehensively all neurosteroids throughout pregnancy and their temporal relationship to mood are needed. Such studies will pave the way for a better understanding of the neurobiology of mood disorders in pregnancy. Additionally, it will facilitate the development of novel antenatal tests for potential predictive biomarkers, thus improving clinical decision-making, patient management and evolving appropriate preventive lifestyle interventions/therapeutic measures.

Keywords

Neurosteroids pregnancy mood depression gestation

Introduction

Neurosteroids are steroids endogenous to the brain that can alter the excitability of neurons through rapid non-genomic actions.¹ Neurosteroids were first described by Etienne-Emile Baulieu and colleagues in a series of experiments in the 1980s. They showed that brain tissues were rich in steroids such as pregnenolone (Preg) and dehydroepiandrosterone (DHEA), even when peripheral sources such as the gonads and the adrenals are removed. They also demonstrated that the enzyme cytochrome P450 side chain cleavage (scc) was present in oligodendrocytes and can thus point to the existence of steroidogenic machinery in the brain.² Subsequent studies have shown the presence of multiple steroidogenic enzymes such as 3β-hydroxysteroid dehydrogenase 17, 20-lyase, 17-β hydroxysteroid dehydrogenase, 5α-reductase, 3α-hydroxysteroidoxidoreductase, and aromatase in the brain of both rodents and humans.³ These enzymes synthesise various types of neurosteroids such as tetrahydrodeoxycorticosterone (THDOC) and allopregnanolone (pregnane neurosteroids), androstanediol and etiocholanone (androstane neurosteroids), PregS and DHEAS (sulphated neurosteroids).¹

Mental health disorders such as depression and anxiety during pregnancy and postpartum are being increasingly recognised. Prevalence of depression and anxiety in pregnant women is high^4–9 and studies have demonstrated that pregnancy causes major changes in the neuroendocrine and psychosocial status of pregnant women, so it may also increase predisposition to depression.^{5, 7} In Western countries, the prevalence of depression was higher in the second trimester compared to the first trimester and plateaued in the third trimester.^{7, 10, 11} The rates were as high as 17% during the late pregnancy, which either dropped during the post-partum period,¹¹ or remained at the same level.¹² The prevalence rates differ between the developing and developed countries, with a higher prevalence in the developing countries.¹³ During the period of the COVID-19 pandemic, the pooled prevalence of perinatal and postnatal depression was higher (23%).¹⁴ Further, the prevalence of perinatal depression might be higher in individuals with a prior history of major depressive disorder (MDD) and in those with a history of postpartum depression (PPD).^{15, 16} Perinatal depression may have deleterious outcomes for the individual, her children and family.¹⁵ Perinatal depression can also modify the delivery outcomes, resulting in preterm delivery and low birth weight. Further, it could affect the mental health of the mother during the postpartum period.¹⁵ This underlines the importance of understanding the pathophysiology of perinatal and PPD.

The pathophysiology of perinatal depression is not completely understood, and several hypotheses have been put forward. Immune mediators are thought to play a role in the pathophysiology of perinatal depression. Increase in pro-inflammatory and decrease in anti-inflammatory activity, with a failure to adapt to the immune changes in pregnancy, has been shown to be associated with antenatal depression (reviewed in detail elsewhere¹⁷). Mediators such as hsCRP and glycoprotein acetyl levels are shown to be associated with depression during pregnancy.¹⁸ In addition, there is a cross-talk between the immune mediators and the gut microbiota, which in turn might influence the mood in pregnant women.¹⁷ Several other mediators, such as metabolites of the serine/threonine or glycerol lipids pathway¹⁹ have also been implicated in perinatal depression.

It is evident that the pregnancy and the post-partum period are characterised by significant changes in hormones such as oestrogen and progesterone.¹⁵ Further, there is a hypothesis that susceptible individuals show an abnormal response to the normal levels of oestrogen/progesterone.²⁰ The hypothalamo-pituitary-adrenal (HPA) axis has been implicated in the pathogenesis of depression, in general and is known to be hyperactive during pregnancy (partly due to the stimulatory effects of high levels of oestrogen and progesterone). During the post-partum period, the oestrogen and progesterone levels sharply decline, but the cortisol gradually decreases because of the hypertrophic adrenal cortex. Thus, an altered HPA axis might contribute to pregnancy-related depression. The role of the HPA axis has been reviewed in detail elsewhere.^{15, 21} During pregnancy, in addition to changes in oestrogen and progesterone, there is considerable evidence that the levels of neurosteroids change during the course of pregnancy and post-partum, and might contribute to the changes in mood. This topic has been of interest and has received attention through review articles.^{22, 23} However, they are not comprehensive and do not provide an unbiased (with respect to the neurosteroid molecule) description of the changes in neurosteroids during pregnancy.²² For example, highlighted the role of only certain neurosteroids such as allopregnanolone, allotetrahydroDOC, pregnanolone, DHEA, DHEAs and testosterone. Meltzer-Brody, 2020²³ describes PPD but not perinatal depression and focuses only on allopregnanolone. This forms the basis for the current literature review.

Methods

We used the search strategy shown in the Supplementary Table 1 in PubMed and comprehensively reviewed all the selected articles based on the topic of neurosteroids, pregnancy and mood disorders without any time period restrictions.

Table 1.

Summary of Circulating Neurosteroid Levels in Pregnancy.

Study Number and Neurosteroid	Details of the Subjects	Age	Matrix	Method	Findings	Reference
Pregnenolone
1. Pregnenolone	The samples were divided into early preterm (22–29 week gestation; n = 10), late preterm (30–36 week  gestation; n = 18), and term  (37–40 week gestation; n = 20) groups	31.6 ± 3.58 years	Serum	ELISA	No change between early pre-term, late pre-term and term	⁴⁵
2. Pregnenolone	Healthy women with no previous  history of mental illness	21–45 years	Plasma	Fractionation in HPLC followed by RIA	Levels peaked around 15 weeks of gestation and plateaued till delivery  No change between depression and non-depressed women in mid- and late-pregnancy	⁷⁰
3. Pregnenolone	Normal pregnant women	34.6 ± 3.12 years	Plasma	GC-MS	No change across pregnancy, but dropped post-parturition	⁴⁶
4. Pregnenolone	Not specified	Not specified	Plasma	GC-MS	There was a marginal decrease in the second trimester compared to the first, which plateaued, but was not statistically significant. The levels significantly dropped post-partum	⁴⁸
5. Pregnenolone	Healthy perinatal women, at-risk for perinatal depression (AR-PND) and perinatal depression (PND)	29.3 ± 4.9 years  29.9 ± 5 years  28.5 ± 4.6 years	Plasma	LC-MS/MS	The levels did not change between the second and third trimesters but decreased drastically post-partum. The decline in the AR-PND/PND subjects was similar to controls	⁴⁹
6. Pregnenolone	Pregnant women with and without anxiety	32.23 ± 3.64	Plasma	GC-MS	Marginal increase from second to third trimester and significant decrease post-partum; there was no difference between the subjects with or without anxiety	⁵⁰
7. Pregnenolone	Pregnant women with and without PPD	32.8 ± 4 years	Plasma	GC-MS	Marginal increase from second to third trimester	⁵¹
Dehydroepiandrosterone (DHEA)
1. Dehydroepiandrosterone (DHEA)	Groups: early preterm (22–29 week gestation; n = 10), late preterm (30–36 week gestation; n = 18), and term (37–40 week gestation; n = 20) groups	31.6 ± 3.58 years	Serum		There was an increase between early pre-term and late pre-term, which remained elevated at term	⁴⁹
2. DHEA	<16, 22–32 and >34 weeks of gestation and > 4 weeks post-partum	Average of 31 years of normal subjects	Serum	GC-MS	There was a decrease in the second trimester and plateau thereafter, which went back to the first  trimester levels, at postpartum	⁶¹
3. DHEA	Not specified	Not specified	Plasma	GC-MS	There was a modest increase across the three trimesters, which dropped post-partum, but was not statistically significant.	⁴⁸
4. DHEA	gestational weeks 27–39	16–39 years	Serum	chemiluminescent enzyme immunoassay	Levels were lower in the subjects with anxiety in the third trimester of pregnancy	¹⁰⁴
Dehydroepiandrosterone sulphate (DHEAs)
1. Dehydroepiandrosterone sulphate (DHEAs)	Third trimester of pregnancy	33.6 ± 4.7 years (controls) 35.3 ± 5.1 years (Preeclampsia)	Serum	ELISA	DHEA-S levels decreased across pregnancy, while in women with preeclampsia, there was no change between the first and second trimester, while the levels were marginally increased in the third trimester. No significant difference in DHEA levels between the control and preeclampsia However, there was a decrease in the cord blood in preeclampsia	⁶²
2. DHEAs	Subjects with SCL-90 global score  <30 and >50, but <70	31.5 ± 2.7 years	Serum	Extraction followed by RIA	Levels did not change across pregnancy, and there was no difference between the two groups at each measurement	⁶³
5-α-dihydroprogesterone (DHP)
1. 5-α-dihydroprogesterone (DHP)	Normal subjects; weekly blood  collection from 30–42nd week of pregnancy	18–30 years	Plasma	GC-MS	Gradual increase in the levels from the 30th week up to the 34th, which plateaued till delivery	³⁰
2. 5-α-dihydroprogesterone	Healthy women with no previous  history of mental illness	21–45 years	Plasma	Fractionation in HPLC followed by RIA	Levels peaked around 15 weeks of gestation and plateaued till deliveryDepressed women had higher levels at both mid and late stages of pregnancy	⁷⁰
3. 5-α-dihydroprogesterone	<16, 22–32 and >34 weeks of  gestation and > 4 weeks post- partum	Average of  31 years for  normal subjects	Serum	GC-MS	No change across pregnancy and postpartum	⁶¹
4. 5-α-dihydroprogesterone	Normal pregnant women	34.6 ± 3.12 years	Plasma	GC-MS	Gradual increase in the levels from 8–10 up to 38 weeks of pregnancy, which dropped post-parturition	⁴⁶
5. 5-α-dihydroprogesterone	Normal pregnant women	Not specified	Plasma	Chromatography followed by RIA	Gradual increase up to 36 weeks of pregnancy, plateaued thereafter	⁶⁹
6. 5-α-dihydroprogesterone	Not specified	Not specified	Plasma	GC-MS	There was a marginal increase across the three trimesters. The levels significantly dropped post-partum	⁴⁸
7. 5-α-dihydroprogesterone	Healthy perinatal women, at-risk for perinatal depression (AR-PND) and perinatal depression (PND)	29.3 ± 4.9 years 29.9 ± 5 years 28.5 ± 4.6 years	Plasma	LC-MS/MS	The levels marginally increased between the second and third trimesters but decreased drastically post-partum. The levels in the AR-PND/PND subjects were similar to controls	⁴⁹
8. 5-α-dihydroprogesterone	Pregnant women with and without anxiety	32.23 ± 3.64	Plasma	GC-MS	Marginal increase from second to third trimester and significant decrease post-partum; there was no difference between the subjects with or without anxiety	⁵⁰
9. 5-α-dihydroprogesterone	Pregnant women with and without PPD	32.8 ± 4 years	Plasma	GC-MS	Marginal increase from second to third trimester	⁵¹
5-beta-dihydroprogesterone
1. 5-beta-dihydroprogesterone	Normal subjects; weekly blood collection from 30–42nd week of pregnancy	18–30 years	Plasma	GC-MS	No change	³⁰
2. 5-beta-dihydroprogesterone	Healthy women with no previous  history of mental illness	21–45 years	Plasma	Fractionation in HPLC followed by RIA	Levels peaked around 15 weeks of gestation and plateaued till deliveryNo change between depressed and non-depressed women in  mid- and late-pregnancy	⁷⁰
3. 5-beta-dihydroprogesterone	<16, 22–32 and >34 weeks of gestation and > 4 weeks post-partum	Average of 31 years for normal subjects	Serum	GC-MS	No change across pregnancy and postpartum	⁶¹
4. 5-beta-dihydroprogesterone	Normal pregnant women	34.6 ± 3.12 years	Plasma	GC-MS	Marginal increase in the levels from 8–10 up to 30 weeks of pregnancy, which declines in the 38th week and further drops post-parturition	⁴⁶
5. 5-beta-dihydroprogesterone	Healthy perinatal women, at-risk for perinatal depression (AR-PND) and perinatal depression (PND)	29.3 ± 4.9 years 29.9 ± 5 years 28.5 ± 4.6 years	Plasma	LC-MS/MS	The levels did not change between the second and third trimesters but decreased drastically post-partum. The decline in AR-PND/PND groups was similar to the controls.	⁴⁹
6. 5-beta-dihydroprogesterone	Pregnant women with and without anxiety	32.23 ± 3.64	Plasma	GC-MS	Marginal increase from second to third trimester and significant decrease post-partum; there was no difference between the subjects with or without anxiety	⁵⁰
7. 5-beta-dihydroprogesterone	Pregnant women with and without PPD	32.8 ± 4 years	Plasma	GC-MS	Marginal increase from second to third trimester	⁵¹
Allopregnanolone
1. Allopregnanolone	Normal subjects; weekly blood  collection from 30–42nd week of pregnancy	18–30 years	Plasma	GC-MS	Gradual increase in the levels up to the 35th week, which plateaued thereafter till delivery	³⁰
2. Allopregnanolone	Healthy women with no previous  history of mental illness	21–45 years	Plasma	Fractionation in HPLC followed by RIA	Levels peaked around 15 weeks of gestation and plateaued till delivery No change between depressed and non-depressed women in mid- and late-pregnancy	⁷⁰
3. Allopregnanolone	<16, 22–32 and >34 weeks of  gestation and > 4 weeks post- partum	Average of  31 years for  normal subjects	Serum	GC-MS	There was an increase in median levels in third trimester compared to the first trimester, which fell close to the first trimester levels at postpartum	⁶¹
4. Allopregnanolone	Normal Pregnant women	34.6 ± 3.12 years	Plasma	GC-MS	Steep increase in levels across pregnancy up to the 38th week, which precipitously dropped post-partum	⁴⁶
5. Allopregnanolone	Both normal and depressed subjects	30–39 years	Serum	ELISA	Levels in the third trimester were higher compared to the second trimester	⁸¹
6. Allopregnanolone	Not specified	Not specified	Plasma	GC-MS	There was a statistically significant increase in the second trimester compared to the first, with a marginal increase in the third, but this was not statistically significant. The levels significantly dropped post-partum	⁴⁸
7. Allopregnanolone	Subjects with SCL-90 global score <30 and >50, but <70	31.5 ± 2.7 years	Serum	Extraction followed by RIA	Levels steadily increased across pregnancy, but there was no difference between the two groups at all time points	⁶³
8. Allopregnanolone	Normal subjectsThey made monthly measurements	Not specified	Plasma	GC-MS	There was an increase in the mid of the second trimester, which continued into the third trimester	⁸³
9. Allopregnanolone	Normal subjects	23–35 years	Serum	RIA	There was a steady increase from the second trimester onwards	⁸⁴
10. Allopregnanolone	Healthy perinatal women, at-risk for perinatal depression (AR-PND) and perinatal depression (PND)	29.3 ± 4.9 years 29.9 ± 5 years 28.5 ± 4.6 years	Plasma	LC-MS/MS	The levels did not change between the second and third trimesters but decreased drastically post-partum.The decline across pregnancy was similar in the AR-PND and PND groups. However, in the third trimester, subjects with PND had higher levels compared to healthy controls	⁴⁹
11. Allopregnanolone	Pregnant women with and without anxiety	32.23 ± 3.64	Plasma	GC-MS	Significant increase from second to third trimester and significant decrease post-partum; there was no difference between the subjects with or without anxiety	⁵⁰
12. Allopregnanolone	Pregnant women with and without PPD	32.8 ± 4 years	Plasma	GC-MS	Marginal increase from second to third trimester	⁵¹
13. Allopregnanolone	Pregnant women with reduced foetal movement	29 (16–42) years old	Serum	LC-MS	Significant increase in 37–39 weeks, when compared to 31–33 weeks of gestation	⁸⁵
Allopregnanolone (conjugated)
1. Allopregnanolone (conjugated)	Normal subjects; Weekly blood  collection from 30–42nd week of pregnancy	18–30 years	Plasma	GC-MS	A gradual increase in the levels up to the 37th week, which plateaued thereafter till delivery	³⁰
Pregnanolone
1. Pregnanolone	27–34 weeks of gestation Subjects at risk for postpartum  depression (AR-PPD)				AR-PPD women showed higher  levels in second and third trimesters compared to healthy controls	¹⁰⁸
2. Pregnanolone	Normal subjects; Weekly blood  collection from 30–42nd week of pregnancy	18–30 years	Plasma	GC-MS	No change in the levels from 30th week until parturition	³⁰
3. Pregnanolone	Normal pregnant women	34.6 ± 3.12 years	Plasma	GC-MS	No change between 8th and 20th week, but increased till 38th week and dropped post-partum	⁴⁶
4. Pregnanolone	Not specified	Not specified	Plasma	GC-MS	There was a marginal increase across the three trimesters, but it was not statistically significant. The levels significantly dropped post-partum	⁴⁸
5. Pregnanolone	Normal subjects They made monthly measurements	Not specified	Plasma	GC-MS	There was an increase in the mid of the second trimester, which continued into the third trimester	⁸³
6. Pregnanolone	Healthy perinatal women, at-risk for perinatal depression (AR-PND) and perinatal depression (PND)	29.3 ± 4.9 years 29.9 ± 5 years 28.5 ± 4.6 years	Plasma	LC-MS/MS	The levels did not change between the second and third trimesters but decreased drastically post-partum. The decline in the AR-PND and PND groups was similar to the controls	⁴⁹
7. Pregnanolone	Pregnant women with and without anxiety	32.23 ± 3.64	Plasma	GC-MS	Marginal increase from second to third trimester and significant decrease post-partum; there was no difference between the subjects with or without anxiety	⁵⁰
8. Pregnanolone	Pregnant women with and without PPD	32.8 ± 4 years	Plasma	GC-MS	Marginal increase from second to third trimester	⁵¹
9. Pregnanolone	Pregnant women with reduced foetal movement	29 (16–42) years old	Serum	LC-MS	No change across 28–30 weeks to 40–42 weeks of pregnancy	⁸⁵
Pregnanolone (conjugated)
1. Pregnanolone (conjugated)	Normal subjects; Weekly blood  collection from 30–42nd week of pregnancy	18–30 years	Plasma	GC-MS	Gradual increase in the levels from the 30th week up to the 39th week, and plateaued thereafter until delivery	³⁰
Isopregnanolone
1. Isopregnanolone	Weekly blood collection from 30 to 42nd week of pregnancy	18–30 years forNormal subjects	Plasma	GC-MS	Gradual increase in the levels from 30th week up to the 36th week and plateaued thereafter until delivery	³⁰
2. Isopregnanolone	Healthy women with no previous  history of mental illness	21–45 years old	Plasma	Fractionation in HPLC followed by RIA	Levels peaked around 15 weeks of gestation and plateaued till delivery No change between depressed and non-depressed women in mid- and late-pregnancy	⁷⁰
3. Isopregnanolone	Normal pregnant women	34.6 ± 3.12 years	Plasma	GC-MS	Decrease in the 20th week compared to the 8th week, which increased until delivery but dropped post-parturition	⁴⁶
4. Isopregnanolone	Normal subjects (monthly  measurements)	Not specified	Plasma	GC-MS	There was an increase in the mid of the second trimester, which continued into the third trimester	⁸³
5. Isopregnanolone	Pregnant women with and without anxiety	32.23 ± 3.64	Plasma	GC-MS	Marginal increase from second to third trimester and significant decrease post-partum; there was no difference between the subjects with or without anxiety	⁵⁰
6. Isopregnanolone	Pregnant women with and without PPD	32.8 ± 4 years	Plasma	GC-MS	Marginal increase from second to third trimester	⁵¹
7. Isopregnanolone	Pregnant women with reduced foetal movement	29 (16–42) years old	Serum	LC-MS	Significant increase in 37–39 weeks and 40–42 weeks, when compared to 31–33 weeks of gestation	⁸⁵
Isopregnanolone (conjugated)
1. Isopregnanolone (conjugated)	Weekly blood collection from  30–42nd week of pregnancy	18–30 years normal subjects	Plasma	GC-MS	Gradual increase in the levels from 30th week up to the 37th week and plateaued thereafter until delivery	³⁰
Epipregnanolone
1. Epipregnanolone	Normal subjects; weekly blood collection from 30–42nd week of pregnancy	18–30 years	Plasma	GC-MS	No change in the levels from the 30th week till parturition	³⁰
2. Epipregnanolone	Healthy women with no previous  history of mental illness	21–45 years old	Plasma	Fractionation in HPLC followed by RIA	Levels peaked around 15 weeks of gestation and plateaued till delivery No change between depressed and non-depressed women in mid- and late-pregnancy	⁷⁰
3. Epipregnanolone	Normal subjects They made monthly measurements	Not specified	Plasma	GC-MS	There was a marginal increase from the first trimester, which continued into the second trimester and plateaued in the third trimester	⁸³
4. Epipregnanolone	Pregnant women with and without anxiety	32.23 ± 3.64	Plasma	GC-MS	Marginal increase from second to third trimester and significant decrease post-partum; there was no difference between the subjects with or without anxiety	⁵⁰
5. Epipregnanolone	Pregnant women with and without PPD	32.8 ± 4 years	Plasma	GC-MS	Marginal decrease from second to third trimester	⁵¹
6. Epipregnanolone	Pregnant women with reduced foetal movement	29 (16–42) years old	Serum	LC-MS	No change in 37–39 weeks, when compared to 31–33 weeks of  gestation	⁸⁵
Epipregnanolone (conjugated)
1. Epipregnanolone (conjugated)	Normal subjects; Weekly blood  collection from 30–42nd week of pregnancy	18–30 years	Plasma	GC-MS	Increases from the 30th week till the 36th week and plateaus thereafter.	³⁰
Deoxycorticosterone (DOC)
1. Deoxycorticosterone (DOC)	Healthy women	23–32 years	Plasma	Extraction by chromatography followed by RIA	Levels increased from the early  gestation up to the 38th week, which dropped at delivery	⁸⁸
2. Deoxycorticosterone	Healthy women	Around 18 years	Plasma	Chromatographic isolation followed by RIA	Steadily increased from early  gestation upto delivery	⁸⁹
3. Deoxycorticosterone	Healthy women	Not specified	Plasma	Double isotope dilution derivative assay	Increased steadily from 12 weeks of gestation up to delivery and steeply decreased during post-partum	⁹⁰
4. Deoxycorticosterone	Healthy women	Not specified	Urine	Competitive-binding technique/TLC	Increased from mid-gestation until delivery and dropped during postpartum	⁹¹
5. Deoxycorticosterone	Healthy perinatal women, at-risk for perinatal depression (AR-PND) and perinatal depression (PND)	29.3 ± 4.9 years 29.9 ± 5 years 28.5 ± 4.6 years	Plasma	LC-MS/MS	The levels were increased in the third trimester compared to the second and decreased drastically post-partum. The decline in the  AR-PND and PND groups was similar to the controls.	⁴⁹
Tetrahydrodeoxy-corticosterone (THDOC)
1. Tetrahydrodeoxy-corticosterone (THDOC)	Not specified	Not specified	Plasma	GC-MS	There was a marginal increase in the third trimester, compared to the first and second trimesters, which plateaued post-partum, but was not statistically significant.	⁴⁸
2. THDOC	Subjects with SCL-90 global score <30 and >50, but <70	31.5 ± 2.7 years	Serum	Extraction followed by RIA	Levels steadily increased across pregnancy, but there was no difference between the two groups at all time points	⁶³
3. THDOC	Healthy perinatal women, at-risk for perinatal depression (AR-PND) and perinatal depression (PND)	29.3 ± 4.9 years 29.9 ± 5 years 28.5 ± 4.6 years	Plasma	LC-MS/MS	There was no difference in the levels across pregnancy or  postpartum. The decline in the  AR-PND and PND groups was similar to the controls.	⁴⁹
Androstanediol
Androstanediol	Healthy women	Not specified	Plasma	RIA	The levels of androstanediol were higher in pregnancy compared to normally menstruating women. The levels of androstanediol in the  second and at term were significantly higher than in the first.	⁹⁴
Androstanediol glucuronide (AG)
1. Androstanediol glucuronide (AG)	Healthy women	Not specified	Serum	RIA	Compared to the 6th week of  gestation, there was a marginal  decrease in the tenth week, which was sustained 4 days after delivery.	⁹⁵
2. Androstanediol glucuronide (AG)	Healthy women	Not specified	Serum	Extracted with ether, purified by Celite column chromatography, and measured by radioimmunoassay	There was no change in the levels across the three trimesters of pregnancy	⁹⁶
3. Androstanediol glucuronide (AG)	Healthy women	Not specified	Plasma	RIA	Throughout pregnancy, the levels were significantly higher than in normally menstruating women. Concentrations in the second  trimester were significantly lower than in the first trimester and at term.	⁹⁴

Results

Biosynthesis of Neurosteroids

The different neurosteroids and their synonyms are summarised in Supplementary Table 2. De novo biosynthesis of neurosteroids was first demonstrated in mammals, and it is conserved in all vertebrate species.²⁴ In vertebrates, neurosteroids are synthesised mostly by glial cells in discrete brain regions such as the cortex, hippocampus and hypothalamus.² This is also supported by studies that demonstrate the presence of enzymes for neurosteroidogenesis in the brain,²⁵ especially in the hippocampal pyramidal neurons of the CA1 and CA3 regions²⁴ whose expression is influenced by certain neurotransmitters and neuropeptides.²⁶

Biosynthesis of neurosteroids takes place in the mitochondria and smooth endoplasmic reticulum²⁷ and begins with the transport of cholesterol from outer mitochondrial membrane to inner mitochondrial membrane by steroidogenic acute regulatory (StAR) protein, and is the first rate-limiting step in the pathway.²⁸ It is regulated by peripheral/mitochondrial benzodiazepine receptor (PBR) or translocator protein (TSPO)²⁹ and eventually undergo a cascade of enzymatic reactions. An increase in stimulation of this transport results in enhanced biosynthesis of neuroactive steroids.²⁶ The detailed biosynthesis of neurosteroids is presented in Figure 1.

Figure 1.

Biosynthetic Pathway of Neurosteroids. The Neurosteroids in Blue Colour Bold Font Are Presented in the Current Review.^{3, 30}

Cholesterol is one of the major structural components of the membranes, especially in myelin sheath formation.²⁶ Neurosteroidogenesis depends on tissue-specific synthesis of steroidogenic enzymes³¹ present in different regions of the brain. Enzymes for neurosteroid biosynthesis are also localised in glutamatergic neurons; hence, they are synthesised within the same neuron which expresses the target receptor.¹

Once the cholesterol is transported into the mitochondria of neurons, it is converted to pregnanolone in the presence of a mitochondrial cholesterol scc enzyme called cytochrome P450 enzyme 11A1 (CYP11A1).³² This enzyme cleaves the side chain between carbon 20 and 22²⁶ to form pregnenolone. Pregnenolone is called the ‘mother’ of all other neurosteroids²⁷ since it is the key immediate precursor for all other neurosteroids.

Pregnenolone is metabolised in the endoplasmic reticulum into DHEA through the conversion of 17-hydroxy pregnenolone in the presence of a microsomal enzyme 17α hydroxylase (P450c17), or it is converted to progesterone³¹ in the presence of a mitochondrial enzyme 3β-hydroxysteroid dehydrogenase (3β-HSD). Progesterone is further metabolised through three pathways, which is shown in Figure 1. Progesterone is either converted to dihydroprogesterone (DHP) in the presence of a microsomal enzyme 5α-R or it is metabolised to 17-hydroxyprogesterone by P450c17, which is converted to androstenedione by the same enzyme, then to testosterone in the presence of a mitochondrial enzyme 17β-hydroxysteroid dehydrogenase (17βHSD). Alternatively, progesterone is converted to deoxycorticosterone by a microsomal enzyme 21β hydroxylase (P450c21), then to corticosterone in the presence P450_c11. DHP is converted to THP by 3α-HSD, DOC is converted to DihydroDOC by 5a-R and finally to tetrahydro-DOC. Testosterone is converted by 5α-R to dihydrotestosterone and to androstanediol by 3α-HSD. Androstenedione can also be converted to oestradiol through aromatase and 17β-HSD.

Both the peripheral and brain-derived neurosteroids can influence mood and cognition in the perinatal period. However, since data is available only in the periphery (blood), this review focuses on the neurosteroid levels in pregnancy.

Neurobiology of Neurosteroids

Steroid hormones, being lipophilic, bind to intracellular receptors and usually bring about changes in gene expression in a period of minutes to hours.³³ However, the effects of neurosteroids are rapid and non-genomic. The well-known mechanism is the positive allosteric modulation of GABA_A receptors (GABA_ARs) by 3α-hydroxy A-ring reduced metabolites of progesterone and deoxycorticosterone, allopregnanolone and THDOC.³⁴ In contrast, PregS acts as a negative allosteric modulator of GABA_ARs³⁵ but as a potentiator of NMDA (N- methyl-D- Aspartate) receptors that bind glutamate.³⁶ Similarly, DHEAS also acts as a negative allosteric modulator of GABA_ARs and positive allosteric modulator of NMDARs in addition to acting on sigma-1 receptors.³⁷ 17β-oestradiol negatively modulates NMDA and 5-HT₃ (serotonin) receptors while positively modulates kainate receptors. Testosterone has been shown to modulate positively GABA_AR and negatively 5-HT₃ receptor. Progesterone positively modulates kainate receptors and negatively modulates glycine and 5-HT₃ receptors.³¹

The functions of neurosteroids are as wide and varied as they are significant, as shown in rodent and human studies. For example, progesterone was shown to promote the formation of myelin sheath³⁸ while DHEA, DHEAS are essential for the proper axon growth and formation of synaptic connections in the developing brain.³⁹ In rodents, Pregnenolone treatment enhances memory in active avoidance assay after footshock, while in human subjects, it enhances cognition and prevents negative symptoms in schizophrenia and schizoaffective disorders in combination with other antipsychotic drugs.⁴⁰ In the hippocampus, synaptic plasticity is affected by neurosteroids—oestradiol enhances long-term potentiation while dihydrotestosterone (DHT) enhances long-term depression, as well as the latter being involved in exercise-induced neurogenesis in the dentate gyrus.⁴¹ Neurosteroids such as DHEA, progesterone and allopregnanolone enhance neurogenesis, neural stem cell self-renewal and differentiation, neuronal survival and prevent apoptosis.⁴² In the context of the plethora of effects that neurosteroids have on neuronal function, it can be expected that changes in their levels during pregnancy would influence mood. The role of neuroactive steroids in perinatal depression⁴³ and the role of allopregnanolone in PPD²³ has been reviewed earlier. In addition to building on these earlier reviews, we have made an attempt to comprehensively map all the neurosteroids in human pregnancy-related mental health outcomes and neurosteroid changes in non-human animal species.

Changes in Neurosteroids in Pregnancy

The changes in neurosteroids in pregnancy from human and animal studies are summarised in Table 1 and Supplementary Table 4, respectively.

Pregnenolone

In addition to being a precursor to all the other neurosteroids, pregnenolone itself exerts several effects on the brain’s function. There is evidence that pregnenolone modulates cognition, and is beneficial in psychiatric diseases like schizophrenia and addiction, and neurological conditions like spinal cord injury.⁴⁰ The levels of pregnenolone during pregnancy have been studied as early as 1967.⁴⁴ In pregnancy, there are studies which show that there is no change in systemic pregnenolone levels across the three trimesters.^{45, 46} A few others have shown that it peaks around 15 weeks⁴⁷ or decreases in the second trimester,⁴⁸ with significantly lower post-partum levels.^{46, 48} Between the second and third trimesters, there was no change⁴⁹ or a marginal increase^{50, 51} (Supplementary Figure 1A). In non-human animal species, there was an increase in mid or late gestation, which declined post-partum.^52–55 In human subjects, levels of free and conjugated pregnenolone dropped rapidly within 24 hours.⁵⁶

Dehydroepiandrosterone

DHEA is synthesised in the adrenal cortex and has been shown to have profound effects on brain function. DHEA (or DHEAs) has been shown to have presynaptic effects such as influencing the release of glutamate, acetylcholine and norepinephrine in hippocampus and prelimbic cortex. It can also have postsynaptic actions, including antagonising GABA_A receptors, stimulating sigma-1 receptors and blocking voltage-gated calcium channels.⁵⁷ DHEA is shown to be involved in neurodevelopment, neuroprotection, memory and emotional behaviour, addiction and Alzheimer’s disease.⁵⁷ Animal studies show that DHEA has antidepressant-like effects,⁵⁸ while in humans, there are contradictory reports.^{49, 60} DHEA levels have been reported to either decrease in the second trimester and plateau thereafter⁶¹ or marginal increase across the three trimesters, which dropped post-partum, but was not statistically significant.⁴⁸ Interestingly, Hong et al.⁴⁵ reported that there was an increase in serum DHEA between early pre-term and late-pre-term, which remained elevated at term (Supplementary Figure 1B). DHEAs levels were decreased across pregnancy,⁶² while Paoletti et al. reported that there was no change⁶³ (Supplementary Figure 1C). In thoroughbred mares, Legacki et al. reported that DHEA levels increased from the 17th week, which peaked around the 35th week and then declined.⁵³ However, the same authors also showed that there was a marginal increase in the first 4 weeks, which was maintained up to the 8th week, and dropped suddenly thereafter and continued to decrease gradually until the end of pregnancy.⁶⁴ In Sprague Dawley rats, there was a significant increase in DHEA levels in late pregnancy compared to non-pregnant controls, which declined marginally after parturition.⁵⁴ DHEA levels in female killer whales steadily increased from the 5th month of pregnancy up to the 10th month, which was maintained until parturition and dropped precipitously after birth.⁶⁵

Dihydroprogesterone

Dihydroprogesterone has been shown to have anti-seizure effects⁶⁶ and protective effects on myelin.⁶⁷ In addition, its effects might be mediated through tetrahydroprogesterone,⁶⁸ which has been shown to have significant anxiolytic and antidepressant effects (see below). We discuss the changes in both 5-α-dihydroprogesterone and 5-beta-dihydroprogesterone below.

5-α-dihydroprogesterone

There was a gradual or marginal increase in the levels across pregnancy^{46, 48, 69} or between the second and third trimesters,^49–51 which dropped post-partum.^{46, 48–50} Hill et al.³⁰ reported a gradual increase in the levels from the 30th week up to 34th, which plateaued till delivery, while another study demonstrated that 5α-DHP levels were elevated around 15 weeks of gestation, which plateaued till delivery.⁷⁰ No change in 5α-DHP levels across pregnancy and postpartum has also been reported⁶¹ (Supplementary Figure 1D). In thoroughbred mares, 5a-DHP levels started increasing from the 7th week, peaked around 30th week and plateaued thereafter.⁵³

5-beta-dihydroprogesterone

Two studies have reported no change in the 5β-DHP levels across pregnancy.^{30, 61} Between the second and third trimesters, 5β-DHP levels were either increased^{50, 51} or did not change⁴⁹ and declined post-partum.^{59, 50} Further, 5β-DHP levels have been shown to peak at the 15th week or marginally increase from 8 to 10 weeks up to the 30th week, which declined in the 38th week and further dropped post-parturition^{46, 70} (Supplementary Figure 1E).

Tetrahydroprogesterone

In the case of tetrahydroprogesterone—we discuss allopregnanolone (3α,5α-Tetrahydroprogesterone), pregnanolone (3α,5β-Tetrahydroprogesterone), Isopregnanolone (3β,5α-Tetrahydroprogesterone) and Epipregnanolone (3β,5β-Tetrahydroprogesterone). 3α-pregnanolone isomers have been shown to potentiate,³⁰ while the 3β-isomers antagonise the effect of 3α-isomers on GABA_A receptors.⁷¹ The 5β-isomers are known to block T-type calcium channels⁷² and 5α-isomers positively modulate the NMDA receptors.⁷³ Allopregnanolone has been shown to be involved in mood and neurodegenerative disorders⁷⁴ and its analogues, brexanolone and zuranolone, are approved for the treatment of PPD.^{75, 76} Allopregnanolone and its effects have been reviewed in detail elsewhere.^{22,74,77–80}

Allopregnanolone (3α,5α-Tetrahydroprogesterone)

Almost all studies report an increase in allopregnanolone levels across pregnancy, and a few studies show that the levels drop post-partum. While one study documented a steep increase in the allopregnanolone levels in the second trimester,⁷⁰ another study showed no change between the second and third trimesters.⁴⁹ The recent study by Osborne et al.⁵¹ showed a marginal increase in allopregnanolone levels between second and third trimesters. All other studies demonstrate that the levels peak in the third trimester.^{30,46,50,61,63,81–85} Post-partum levels have been shown to drop significantly^{46,48–50,61} (Supplementary Figure 2A). Conjugated allopregnanolone levels also show to have a similar profile³⁰ (Supplementary Figure 3A). In thoroughbred mares, allopregnanolone levels started increasing from the 7th week, which peaked around 30th week and plateaued thereafter.⁵³

Pregnanolone (3α,5β -Tetrahydroprogesterone)

There is a gradual increase in the pregnanolone levels in the second and third trimesters of pregnancy.^{52, 54, 55, 87} There are also studies that show that there was no change in the levels in the first and second trimesters, but an increase in the third trimester⁴⁶ or no change across pregnancy³⁰ or between the second and third trimester.^{49, 85} (Supplementary Figure 2B) Post-partum pregnanolone levels have been consistently shown to decrease.^{46, 48–50} Hill et al.,³⁰ showed that conjugated pregnanolone levels increased from the 30th week up to 39th week and plateaued thereafter until delivery (Supplementary Figure 3B). There are no animal studies reporting pregnanolone levels in pregnancy.

Isopregnanolone (3β,5α-Tetrahydroprogesterone)

There was an increase in isopregnanolone levels in the mid of the second trimester, which continued into the third trimester.^{50, 51, 83, 85} Another study showed that isopregnanolone levels peaked around 15 weeks of gestation and plateaued till delivery⁷⁰ (Supplementary Figure 2C). Hill et al. (2007)³⁰ reported that both conjugated and unconjugated isopregnanolone levels increase from the 30th week up to the 37th week, which plateaued thereafter until delivery. Interestingly, isopregnanolone levels have been shown to dip in the 20th week compared to the 8th week, and increased thereafter, but dropped post-partum^{46, 50} (Supplementary Figure 3C). No animal studies have reported isopregnanolone levels in pregnancy.

Epipregnanolone (3β,5β -Tetrahydroprogesterone)

The epipregnanolone levels have been shown to either peak during the second trimester and plateau till delivery,^{70, 83} marginal increase from second to third trimester^{50, 51} or not change from the 30th week till parturition^{30, 85} (Supplementary Figure 2D). Conjugated epipregnanolone peaked at the 36th week when measured from the 30th week, and plateaus thereafter³⁰ (Supplementary Figure 3D).

Deoxy and Tetrahydrodeoxy-corticosterone

Deoxycorticosterone is a mineralocorticoid, but its metabolite—tetrahydrodeoxycorticosterone (THDOC), is a positive allosteric modulator of GABA_A receptors.^{86, 87} THDOC has been shown to have anti-seizure potency and has also been proposed to have a role in panic disorder, PTSD, depression, alcohol dependence and pain.^{86, 87} Deoxycorticosterone levels are shown to increase either from early gestation^88–90 or mid-gestation^{49, 91} up to delivery and dropped post-partum (Supplementary Figure 4A). Tetrahydrodeoxycorticosterone levels were either marginally increased in the third trimester, compared to the first and second trimesters, which plateaued post-partum, but were not statistically significant,⁴⁸ or no difference across pregnancy and postpartum⁵⁹ or steadily increased throughout the pregnancy⁶³ (Supplementary Figure 4B).

Androstanediol

Androstanediol is shown to be a positive modulator of the GABA_A receptors and has anti-seizure effects.⁹² Although its effects on stress have been studied,⁹³ there is not much literature on the effects of androstanediol on mood. Both conjugated and unconjugated androstanediol levels were higher in pregnancy compared to normally menstruating women.⁹⁴ The levels of androstanediol in the second and at term were significantly higher than in the first. Androstanediol glucuronide (AG) levels in the second trimester were significantly lower than in the first trimester and at term.⁹⁴ Another study reports that compared to the 6th week of gestation, there was a marginal decrease in AG levels in the tenth week, which was sustained 4 days after delivery.⁹⁵ There is also a study that reported no change in the levels of AG across the three trimesters of pregnancy⁹⁶ (Supplementary Figure 4C). In female killer whales, androstenedione levels steadily increased from the 5th month of pregnancy up to the 13th week, and started decreasing until parturition and dropped precipitously after birth.⁶⁵

In summary, allopregnanolone is the most widely studied neurosteroid, and it is shown to increase with the progression of pregnancy and drop post-partum (Supplementary Figure 2A). Although the number of studies is limited, the findings with DOC and THDOC are similar, with a steady increase across pregnancy (Supplementary Figure 4A&B). With the other neurosteroids, either there are limited studies or the results are conflicting. As outlined in Table 1, there might be several factors such as age, assay methodology, sample size and ethnicity that could have contributed to the conflicting results. Further, the entire gamut of neurosteroids has not been studied in the same cohort. Therefore, additional studies are needed with a prospective design, adequate power and different ethnicities with multiple measurements across pregnancy to unequivocally understand the gestational changes in neurosteroids.

Placental Neurosteroids

The placental hormones are known to be released into the maternal circulation and could be used as biomarkers for pregnancy-related outcomes. However, the lack of availability of studies across pregnancy has hindered our understanding about the role of placental-derived neurosteroids. However, the placental might serve as a major source of steroid hormones during pregnancy.⁹⁷ Hong et al.⁴⁵ reported that there was an increase in placental DHEA between early pre-term and late-pre-term, which remained elevated at term. However, there was no change in pregnenolone levels. The P450scc and 3β-HSD mRNA expression increased in the late pre-term and term compared to early pre-term. 17-α-hydroxylase (P450_C17) mRNA expression did not change across three time-points. There was no change in the protein expression of P450scc and 3β-HSD at all time points, while 17-α-hydroxylase increased only in the term compared to early pre-term, but there was no difference between early pre-term and late pre-term.⁴⁵ The changes in the placental neurosteroids across pregnancy are summarised in Supplementary Table 3.

Effect of Sex of the Foetus on the Maternal Circulating Neurosteroid Levels

Interestingly, there are studies which examine the relationship between the sex of the foetus and neurosteroid levels. In maternal blood at the 37th week, there were significant differences between steroids depending on the sex of the foetus. Cortisol was higher in mothers carrying sons, while 17-OH-pregnenolone was higher in mothers carrying daughters. Progesterone was non-significantly higher in women carrying daughters. Although the authors claim that there were certain sex differences in cortisol and 17-OH-pregnenolone, the data do not seem to support this. Overall, it appears that there are no differences in the neurosteroid levels based on the sex of the foetus.^{96, 98} Even in the amniotic fluid, several studies find that there is a sexual difference only in the levels of testosterone,^99–103 and not AG.⁹⁶

Discussion

Neurosteroids and Mood Changes in Pregnancy

As described earlier, several of the neurosteroids have been shown to be involved in the regulation of mood in general. A few studies have examined this in the context of pregnancy, which are reviewed below. Pregnenolone levels did not differ between subjects with and without depression,⁷⁰ at risk for depression versus controls⁴⁹ or subjects with and without anxiety.⁵⁰ Lower DHEA levels were found in pregnant women with anxiety in the third trimester.¹⁰⁴ Depressed women had higher levels of 5α-DHP at both mid and late stages of pregnancy,⁷⁰ or was not changed in subjects at risk for depression⁴⁹ or with anxiety.⁵⁰ However, there was no change in 5β-DHP levels.^{49, 50, 70} There are contradictory reports about the role of pregnanolone and its isomers on mood in pregnancy and postpartum. Pearson Murphy et al., showed that there was no difference in either allopregnanolone, isopregnanolone or epipregnanolone levels between the depressed and non-depressed women in mid and late-pregnancy⁷⁰ or with and without anxiety.⁵⁰ Also, second-trimester allopregnanolone levels did not correlate with the depression scores during the 17th or 32nd week of pregnancy.¹⁰⁵ On the other hand, low serum allopregnanolone levels were associated with depression in women in late (37–40 weeks) pregnancy.¹⁰⁶ Interestingly, Deligiannidis et al. reported that subjects with perinatal depression had higher levels of allopregnanolone, although no differences were observed post-partum.⁴⁹ However, pregnanolone levels were similar to controls.⁴⁹ Standeven et al.¹⁰⁷ observed a negative correlation between allopregnanolone levels in the second trimester with depression but not with anxiety scores. However, they did not observe a clear correlation between allopregnanolone levels with depression or anxiety scores in the third trimester. Subjects at risk for PPD have been shown to have higher levels of pregnanolone in the second and third trimesters compared to healthy controls¹⁰⁸ or an increase in the ratio of isopregnanolone/pregnanolone in the third trimester.⁵¹ The second or third trimester allopregnanolone levels have been shown to negatively correlate with the PPD/anxiety scores at week 6.^{109, 110} However, there is also a report that levels of allopregnanolone, pregnenolone or pregnanolone at 34–36 weeks do not show any significant difference in subjects who were normal or at risk for PPD.¹¹¹ THDOC levels were not different between normal and anxious pregnant women (based on the SCL-90 scale).⁶³

The strength of the present review is that we provide a comprehensive account of the changes in neurosteroid levels in pregnancy, not only from humans but also from other species. In addition, the study focuses on its relationship with mood disorders during pregnancy. However, one of the limitations is that only one search engine was used. Since most medical literature is covered by Medline, we believe that we have covered all the literature in the field.

Conclusion

While there are reports that have examined individual neurosteroids across pregnancy, studies with serial measurements that include comprehensively all neurosteroids throughout pregnancy and their temporal relationship to mood are lacking. Hence, prospective studies with measurements of all neurosteroids and a detailed evaluation of the mental health are needed. Such studies will enable us to get one step closer to understanding the neurobiology of mood disorders in pregnancy. Based upon recent technological developments and studies, it is now becoming a reality that clinically useful antenatal screening test(s) can be developed. The development of such test(s) will provide data that better informs clinical decision-making and patient management. Further, it would help in identifying potential precision biomarkers and also in developing suitable preventive lifestyle interventions/therapeutic measures.

Abbreviations

AG: Androstanediol glucuronide; DOC: Deoxycorticosterone; ELISA: Enzyme Linked Immunosorbent Assay; GC-MS: Gas Chromatography – Mass Spectrometry; HPLC: High performance liquid chromatography; LC-MS: Liquid Chromatography – Mass Spectrometry RIA: Radioimmunoassay; THDOC: Tetrahydrodeoxy-corticosterone

Authors Contribution

KG and BNS performed the literature search, curated the literature, and wrote the draft manuscript. KG, BNS, and VM reviewed and revised it.

Statement of Ethics

Not applicable.

Footnotes

Declaration of Conflicting Interests

The authors declared no potential conflicts of interest with respect to the research, authorship and/or publication of this article.

Funding

The authors disclosed receipt of the following financial support for the research, authorship and/or publication of this article: The research in the lab of BNS is supported by Indian Council for Medical Research grant (ICMR Project ID: Small2234; F.NO.EMDR/SG/13/2023-2234); the research in the laboratory of KG is funded by DBT/Wellcome Trust India Alliance Intermediate Fellowship (IA/CPHI/18/1/503964).

ICMJE Statement

Enclosed.

Patient Consent

Not applicable.

Supplemental Material

ORCID iDs

Kuppan Gokulakrishnan

Viswanathan Mohan

BN Srikumar

References

Reddy

DS.

Neurosteroids: Endogenous role in the human brain and therapeutic potentials. Prog Brain Res 2010; 186: 113–137.

Baulieu

and Robel

Neurosteroids: A new brain function?

J Steroid Biochem Mol Biol 1990; 37: 395–403.

Do Rego

, Seong

, Burel

, . Neurosteroid biosynthesis: Enzymatic pathways and neuroendocrine regulation by neurotransmitters and neuropeptides. Front Neuroendocrinol 2009; 30: 259–301.

Bavle

, Chandahalli

, Phatak

, . Antenatal depression in a tertiary care hospital. Indian J Psychol Med 2016; 38: 31–35.

Fisher

, de Mello

, Patel

, . Prevalence and determinants of common perinatal mental disorders in women in low-and lower-middle-income countries: A systematic review. Bull World Health Organ 2012; 90: 139–149.

Dahiya

, Aggarwal

and Kumar

Prevalence and correlates of antenatal depression among women registered at antenatal clinic in North India. Tzu Chi Med J 2020; 32: 267–271.

Bennett

, Einarson

, Taddio

, . Prevalence of depression during pregnancy: Systematic review. Obstet Gynecol 2004; 103: 698–709.

Dennis

, Falah-Hassani

and Shiri

Prevalence of antenatal and postnatal anxiety: Systematic review and meta-analysis. Br J Psychiatry 2017; 210: 315–323.

Dalke

, Wenzel

and Kim

DR.

Depression and anxiety during pregnancy: Evaluating the literature in support of clinical risk-benefit decision-making. Curr Psychiatry Rep 18. Epub ahead of print 2016. DOI: 10.1007/s11920-016-0698-x

10.

Ryan

, Milis

and Misri

Depression during pregnancy. Can Fam Physician 2005; 51: 1087–1093.

11.

Josefsson

, Berg

, Nordin

, . Prevalence of depressive symptoms in late pregnancy and postpartum. Acta Obstet Gynecol Scand 2001; 80: 251.

12.

Lappin

, Sheehan

, Crotty

, . Depressed mood during pregnancy and after childbirth. BMJ 2001; 323: 1367–1367.

13.

Sheeba

, Nath

, Metgud

, . Prenatal depression and its associated risk factors among pregnant women in Bangalore: A hospital based prevalence study. Front Public Health 2019; 7: 1–9.

14.

Behera

, Bohora

, Tripathy

, . Perinatal depression and its associated risk factors during the COVID-19 pandemic in low- and middle-income countries: A systematic review and meta-analysis. Soc Psychiatry Psychiatr Epidemiol . Epub ahead of print 1 October 2024. DOI: 10.1007/s00127-024-02628-y

15.

Meltzer-Brody

New insights into perinatal depression: Pathogenesis and treatment during pregnancy and postpartum. Dialogues Clin Neurosci 2011; 13: 89–100.

16.

Turner

, Sikander

, Bangash

, . The effectiveness of the peer delivered Thinking Healthy Plus (THPP+) Programme for maternal depression and child socio-emotional development in Pakistan: Study protocol for a three-year cluster randomized controlled trial. Trials 2016; 17: 442.

17.

Fransson

Psychoneuroimmunology in the context of perinatal depression: Tools for improved clinical practice. Brain Behav Immun Health 2021; 17: 100332.

18.

Lahti-Pulkkinen

, Girchenko

, Robinson

, . Maternal depression and inflammation during pregnancy. Psychol Med 2020; 50: 1839–1851.

19.

Bränn

, Malavaki

, Fransson

, . Metabolic profiling indicates diversity in the metabolic physiologies associated with maternal postpartum depressive symptoms. Front Psychiatry 12. Epub ahead of print 2021. DOI: 10.3389/fpsyt.2021.685656

20.

Bloch

Effects of gonadal steroids in women with a history of postpartum depression. Am J Psychiatry 2000; 157: 924–930.

21.

Seth

, Lewis

and Galbally

Perinatal maternal depression and cortisol function in pregnancy and the postpartum period: A systematic literature review. BMC Pregnancy Childbirth 16. Epub ahead of print 2016. DOI: 10.1186/s12884-016-0915-y

22.

McEvoy

and Osborne

LM.

Allopregnanolone and reproductive psychiatry: An overview. Int Rev Psychiatry 2019; 31: 237–244.

23.

Meltzer-Brody

and Kanes

SJ.

Allopregnanolone in postpartum depression: Role in pathophysiology and treatment. Neurobiol Stress 2020; 12: 100212.

24.

Ogino

, Sato

and Iguchi

Chapter 94 - Gonadal steroids. In: Takei

, Ando

, Tsutsui

(eds) Handbook of hormones . San Diego: Academic Press, 2015, pp. 504–506.

25.

Petratos

, Hirst

, Mendis

, . Localization of p450scc and 5alpha-reductase type-2 in the cerebellum of fetal and newborn sheep. Brain Res Dev Brain Res 2000; 123: 81–86.

26.

Schumacher

, Robel

, Baulieu

E-E

. Neurosteroids. In: Encyclopedia of neuroscience . Elsevier, 1991, pp. 1015–1020.

27.

Tvrdeić

and Poljak

Neurosteroids, GABA A receptors and neurosteroid based drugs: Are we witnessing the dawn of the new psychiatric drugs?

Endocr Oncol Metab 2016; 49–60.

28.

Kita

and Furukawa

Involvement of neurosteroids in the anxiolytic-like effects of AC-5216 in mice. Pharmacol Biochem Behav 2008; 89: 171–178.

29.

Reddy

and Estes

WA.

Clinical potential of neurosteroids for CNS disorders. Trends Pharmacol Sci 2016; 37: 543–561.

30.

Hill

, Cibula

, Havlíková

, . Circulating levels of pregnanolone isomers during the third trimester of human pregnancy. J Steroid Biochem Mol Biol 2007; 105: 166–175.

31.

Mellon

and Griffin

LD.

Neurosteroids: Biochemistry and clinical significance. Trends Endocrinol Metab 2002; 13: 35–43.

32.

Chisari

, Eisenman

, Covey

, . The sticky issue of neurosteroids and GABA(A) receptors. Trends Neurosci 2010; 33: 299–306.

33.

Wang

Neurosteroids and GABA-A receptor function. Front Endocrinol (Lausanne) 2011; 2: 1–23.

34.

Majewska

, Harrison

, Schwartz

, . Steroid hormone metabolites are barbiturate-like modulators of the GABA receptor. Science (1979) 1986; 232: 1004–1007.

35.

Majewska

MD.

Steroid regulation of the GABAA receptor: Ligand binding, chloride transport and behaviour. Ciba Found Symp 153. Epub ahead of print 1990. DOI: 10.1002/ 9780470513989.ch5

36.

Mathis

, Paul

and Crawley

JN.

The neurosteroid pregnenolone sulfate blocks NMDA antagonist-induced deficits in a passive avoidance memory task. Psychopharmacology (Berl) 1994; 116: 201–206.

37.

Reddy

and Bakshi

Neurosteroids: Biosynthesis, molecular mechanisms, and neurophysiological functions in the human brain. In: Hormonal signaling in biology and medicine: Comprehensive modern endocrinology . Elsevier, 2019, pp. 69–82.

38.

Baulieu

EE.

Neurosteroids: A novel function of the brain. Psychoneuroendocrinology 1998; 23: 963–987.

39.

Mellon

and Griffin

LD.

Synthesis, regulation, and function of neurosteroids. Endocr Res 2002; 28: 463.

40.

Weng

J-H

and Chung

Nongenomic actions of neurosteroid pregnenolone and its metabolites. Steroids 2016; 111: 54–59.

41.

Hojo

and Kawato

Neurosteroids in adult hippocampus of male and female rodents: Biosynthesis and actions of sex steroids. Front Endocrinol (Lausanne) 2018; 9: 1–8.

42.

Charalampopoulos

, Remboutsika

, Margioris

, . Neurosteroids as modulators of neurogenesis and neuronal survival. Trends Endocrinol Metab 2008; 19: 300–307.

43.

McEvoy

, Payne

and Osborne

LM.

Neuroactive steroids and perinatal depression: A review of recent literature. Curr Psychiatry Rep 20. Epub ahead of print 1 September 2018. DOI: 10.1007/s11920-018-0937-4

44.

Conrad

, Pion

and Kitchin

JD.

Pregnenolone sulfate in human pregnancy plasma. J Clin Endocrinol Metab 1967; 27: 114–119.

45.

Hong

, Kim

, Park

, . Expression of steroidogenic enzymes in human placenta according to the gestational age. Mol Med Rep 2019; 49: 3903–3911.

46.

Evans

SEG

, Ross

, Sellers

, . 3Α-reduced neuroactive steroids and their precursors during pregnancy and the postpartum period. Gynecol Endocrinol 2005; 21: 268–279.

47.

Pearson Murphy

and Allison

CM.

Determination of progesterone and some of its neuroactive ring A-reduced metabolites in human serum. J Steroid Biochem Mol Biol 2000; 74: 137–142.

48.

Pennell

, Woodin

and Pennell

PB.

Quantification of neurosteroids during pregnancy using selective ion monitoring mass spectrometry. Steroids 2015; 95: 24–31.

49.

Deligiannidis

, Kroll-Desrosiers

, Tan

, . Longitudinal proneuroactive and neuroactive steroid profiles in medication-free women with, without and at-risk for perinatal depression: A liquid chromatography-tandem mass spectrometry analysis. Psychoneuroendocrinology 121. Epub ahead of print 1 November 2020. DOI: 10.1016/j.psyneuen.2020.104827

50.

Etyemez

, Miller

, Voegtline

, . Metabolites of progesterone in pregnancy: Associations with perinatal anxiety. Psychoneuroendocrinology 2023; 106327.

51.

Osborne

, Etyemez

, Pinna

, . Neuroactive steroid biosynthesis during pregnancy predicts future postpartum depression? A role for the 3α and/or 3β-HSD neurosteroidogenic enzymes. Neuropsychopharmacology . Epub ahead of print 1 May 2025. DOI: 10.1038/s41386-025-02052-z

52.

Miura

, Yamazaki

, Kikuchi

, . Plasma steroid hormone concentrations and their relationships in Suffolk ewes during gestation and parturition. Anim Sci J 2019; 90: 1426–1431.

53.

Legacki

, Scholtz

, Ball

, . The dynamic steroid landscape of equine pregnancy mapped by mass spectrometry. Reproduction 2016; 151: 421–430.

54.

Maayan

, Abou-Kaud

, Strous

, . The influence of parturition on the level and synthesis of sulfated and free neurosteroids in rats. Neuropsychobiology 2004; 49: 17–23.

55.

Parkening

, Lau

, Saksena

, . Circulating plasma levels of pregnenolone, progesterone, estrogen, luteinizing hormone, and follicle stimulating hormone in young and aged C57BL/6 mice during various stages of pregnancy. J Gerontol 1978; 33: 191–196.

56.

Yamaguchi

, Kimura

, Yanaihara

, . [Sequential changes of serum steroid levels in puerperium]. Nihon Sanka Fujinka Gakkai Zasshi 1983; 35: 1732–1740.

57.

Dong

and Zheng

Dehydroepiandrosterone sulphate: Action and mechanism in the brain. J Neuroendocrinol 2012; 24: 215–224.

58.

Malkesman

, Asaf

, Shbiro

, . Monoamines, BDNF, dehydroepiandrosterone, DHEA-sulfate, and childhood depression—an animal model study. Adv Pharmacol Sci 2009; 2009: 1–11.

59.

Wong

SYS

, Leung

, Kwok

, . Low DHEAS levels are associated with depressive symptoms in elderly Chinese men: Results from a large study. Asian J Androl 2011; 13: 898–902.

60.

Takebayashi

, Kagaya

, Uchitomi

, . Plasma dehydroepiandrosterone sulfate in unipolar major depression. Short communication. J Neural Transm (Vienna) 1998; 105: 537–542.

61.

Pecks

, Rath

, Kleine-Eggebrecht

, . Maternal serum lipid, estradiol, and progesterone levels in pregnancy, and the impact of placental and hepatic pathologies. Geburtshilfe Frauenheilkd 2016; 76: 799–808.

62.

Lan

, Lai

, Cheng

, . Levels of sex steroid hormones and their receptors in women with preeclampsia. Reprod Biol Endocrinol 2020; 18: 1–7.

63.

Paoletti

, Romagnino

, Contu

, . Observational study on the stability of the psychological status during normal pregnancy and increased blood levels of neuroactive steroids with GABA-A receptor agonist activity. Psychoneuroendocrinology 2006; 31: 485–492.

64.

Legacki

, Scholtz

, Ball

, . Concentrations of sulphated estrone, estradiol and dehydroepiandrosterone measured by mass spectrometry in pregnant mares. Equine Vet J 2019; 51: 802–808.

65.

Robeck

, Steinman

and O’Brien

JK.

Characterization and longitudinal monitoring of serum androgens and glucocorticoids during normal pregnancy in the killer whale (Orcinus orca). Gen Comp Endocrinol 2017; 247: 116–129.

66.

and Burnham

WMI.

The anti-seizure effects of IV 5α-dihydroprogesterone on amygdala-kindled seizures in rats. Epilepsy Res 2018; 146: 132–136.

67.

Cermenati

, Giatti

, Audano

, . Diabetes alters myelin lipid profile in rat cerebral cortex: Protective effects of dihydroprogesterone. J Steroid Biochem Mol Biol 2017; 168: 60–70.

68.

Guidotti

, Dong

, Matsumoto

, . The socially-isolated mouse: A model to study the putative role of allopregnanolone and 5alpha-dihydroprogesterone in psychiatric disorders. Brain Res Brain Res Rev 2001; 37: 110–115.

69.

Parker

, Evereti

, Quirk

, . Hormone production during pregnancy in the primigravid patient. I. Plasma levels of progesterone and 5α-pregnane-3,20-dione throughout pregnancy of normal women and women who developed pregnancy-induced hypertension. Am J Obstet Gynecol 1979; 135: 778–782.

70.

Pearson Murphy

, Steinberg

, Hu

, . Neuroactive ring A-reduced metabolites of progesterone in human plasma during pregnancy: Elevated levels of 5 alpha-dihydroprogesterone in depressed patients during the latter half of pregnancy. J Clin Endocrinol Metab 2001; 86: 5981–5987.

71.

Lundgren

, Strömberg

, Bäckström

, . Allopregnanolone-stimulated GABA-mediated chloride ion flux is inhibited by 3β-hydroxy-5α-pregnan-20-one (isoallopregnanolone). Brain Res 2003; 982: 45–53.

72.

Todorovic

, Pathirathna

, Brimelow

, . 5beta-reduced neuroactive steroids are novel voltage-dependent blockers of T-type Ca2+ channels in rat sensory neurons in vitro and potent peripheral analgesics in vivo. Mol Pharmacol 2004; 66: 1223–1235.

73.

Weaver

, Land

, Purdy

, . Geometry and charge determine pharmacological effects of steroids on N-methyl-D-aspartate receptor-induced Ca(2+) accumulation and cell death. J Pharmacol Exp Ther 2000; 293: 747–754.

74.

Diviccaro

, Cioffi

, Falvo

, . Allopregnanolone: An overview on its synthesis and effects. J Neuroendocrinol 2022; 34: 1–17.

75.

Edinoff

, Odisho

, Lewis

, . Brexanolone, a GABAA modulator, in the treatment of postpartum depression in adults: A comprehensive review. Front Psychiatry 2021; 12: 1–9.

76.

Deligiannidis

, Meltzer-Brody

, Maximos

, . Zuranolone for the treatment of postpartum depression. Am J Psychiatry 2023; appiajp20220785.

77.

Chen

, Gao

, Li

, . Allopregnanolone in mood disorders: Mechanism and therapeutic development. Pharmacol Res 2021; 169: 105682.

78.

Irwin

, Solinsky

and Brinton

RD.

Frontiers in therapeutic development of allopregnanolone for Alzheimer’s disease and other neurological disorders. Front Cell Neurosci 2014; 8: 203.

79.

Schiller

, Schmidt

and Rubinow

DR.

Allopregnanolone as a mediator of affective switching in reproductive mood disorders. Psychopharmacology (Berl) 2014; 231: 3557–3567.

80.

Almeida

, Pinna

and Barros

HMT.

The role of HPA axis and allopregnanolone on the neurobiology of major depressive disorders and PTSD. Int J Mol Sci 22. Epub ahead of print 23 May 2021. DOI: 10.3390/ijms22115495

81.

Osborne

, Clive

, Kimmel

, . Replication of epigenetic postpartum depression biomarkers and variation with hormone levels. Neuropsychopharmacology 2016; 41: 1648–1658.

82.

Pennell

, Woodin

and Pennell

PB.

Erratum: Quantification of neurosteroids during pregnancy using selective ion monitoring mass spectrometry (Steroids 95 (2015) 24-31). Steroids 2015; 101: 130.

83.

Pařízek

, Hill

, Kancheva

, . Neuroactive pregnanolone isomers during pregnancy. J Clin Endocrinol Metab 2005; 90: 395–403.

84.

Luisi

, Petraglia

, Benedetto

, . Serum allopregnanolone levels in pregnant women: Changes during pregnancy, at delivery, and in hypertensive patients. J Clin Endocrinol Metab 2000; 85: 2429–2433.

85.

Hinchliffe

and Heazell

Profiling neuroactive steroids in pregnancy. A non-derivatised liquid chromatography tandem mass spectrometry method for the quantitation of allopregnanolone and four related isomers in maternal serum. J Chromatogr B Analyt Technol Biomed Life Sci 1256. Epub ahead of print 15 April 2025. DOI: 10.1016/j.jchromb.2025.124541

86.

Reddy

DS.

Physiological role of adrenal deoxycorticosterone-derived neuroactive steroids in stress-sensitive conditions. Neuroscience 2006; 138: 911–920.

87.

Mediratta

, Gambhir

, Sharma

, . Antinociceptive activity of a neurosteroid tetrahydrodeoxycorticosterone (5alpha-pregnan-3alpha-21-diol-20-one) and its possible mechanism(s) of action. Indian J Exp Biol 2001; 39: 1299–1301.

88.

Dôrr

, Heller

, Versmold

, . Longitudinal study of progestins, mineralocorticoids, and glucocorticoids throughout human pregnancy. J Clin Endocrinol Metab 1989; 68: 863–868.

89.

Parker

, Everett

, Whalley

, . Hormone production during pregnancy in the primigravid patient. II. Plasma levels of deoxycorticosterone throughout pregnancy of normal women and women who developed pregnancy-induced hypertension. Am J Obstet Gynecol 1980; 138: 626–631.

90.

Wintour

, Coghlan

, Oddie

, . A sequential study of adrenocorticosteroid level in human pregnancy. Clin Exp Pharmacol Physiol 1978; 5: 399–403.

91.

Brown

, Strott

and Liddle

GW.

Plasma deoxycorticosterone in normal and abnormal human pregnancy. J Clin Endocrinol Metab 1972; 35: 736–742.

92.

Reddy

and Jian

The testosterone-derived neurosteroid androstanediol is a positive allosteric modulator of GABAA receptors. J Pharmacol Exp Ther 2010; 334: 1031–1041.

93.

Brunton

, Donadio

, Yao

, . 5-reduced neurosteroids sex-dependently reverse central prenatal programming of neuroendocrine stress responses in rats. J Neurosci 2015; 35: 666–677.

94.

Mathur

, Katikaneni

, Garza

, . 3 alpha-Androstanediol and 3 alpha-androstanediol glucuronide. Maternal and umbilical cord plasma concentrations in normal pregnancy. J Reprod Med 1992; 37: 721–724.

95.

Kerlan

, Nahoul

, Le Martelot

, . Longitudinal study of maternal plasma bioavailable testosterone and androstanediol glucuronide levels during pregnancy. Clin Endocrinol (Oxf) 1994; 40: 263–267.

96.

Braunstein

and Horton

Increased maternal serum 3α, 17β-androstanediol glucuronide concentrations during pregnancy. Fertil Steril 1985; 44: 210–213.

97.

Costa

MA.

The endocrine function of human placenta: An overview. Reprod Biomed Online 2016; 32: 14–43.

98.

Adamcová

, Kolátorová

, Škodová

, . Steroid hormone levels in the peripartum period: Differences caused by fetal sex and delivery type. Physiol Res 2018; 67: S489–S497.

99.

Wang

, Tiosano

, Sánchez-Guijo

, . Characterizing the steroidal milieu in amniotic fluid of mid-gestation: A LC–MS/MS study. J Steroid Biochem Mol Biol 2019; 185: 47–56.

100.

Perera

, McGarrigle

, Lawrence

, . Amniotic fluid testosterone and testosterone glucuronide levels in the determination of foetal sex. J Steroid Biochem 1987; 26: 273–277.

101.

Robinson

, Judd

, Young

, . Amniotic fluid androgens and estrogens in midgestation. J Clin Endocrinol Metab 1977; 45: 755–761.

102.

Wudy

, Dörr

, Solleder

, . Profiling steroid hormones in amniotic fluid of midpregnancy by routine stable isotope dilution/gas chromatography-mass spectrometry: Reference values and concentrations in fetuses at risk for 21-hydroxylase deficiency. J Clin Endocrinol Metab 1999; 84: 2724–2728.

103.

Fahlbusch

, Heussner

, Schmid

, . Measurement of amniotic fluid steroids of midgestation via LC-MS/MS. J Steroid Biochem Mol Biol 2015; 152: 155–160.

104.

Leff-Gelman P, Flores-Ramos M, Carrasco AEÁ, et al.

Cortisol and DHEA-S levels in pregnant women with severe anxiety. BMC Psychiatry 2020; 20: 393.

105.

Hellgren

, Comasco

, Skalkidou

, . Allopregnanolone levels and depressive symptoms during pregnancy in relation to single nucleotide polymorphisms in the allopregnanolone synthesis pathway. Horm Behav 2017; 94: 106–113.

106.

Hellgren

, Åkerud

, Skalkidou

, . Low serum allopregnanolone is associated with symptoms of depression in late pregnancy. Neuropsychobiology 2014; 69: 147–153.

107.

Standeven

, Osborne

, Betz

, . Allopregnanolone and depression and anxiety symptoms across the peripartum: An exploratory study. Arch Womens Ment Health 2022; 25: 521–526.

108.

Deligiannidis

, Kroll-Desrosiers

, Mo

, . Peripartum neuroactive steroid and γ-aminobutyric acid profiles in women at-risk for postpartum depression. Psychoneuroendocrinology 2016; 70: 98–107.

109.

Osborne

, Betz

, Yenokyan

, . The role of allopregnanolone in pregnancy in predicting postpartum anxiety symptoms. Front Psychol 2019; 10: 1–6.

110.

Osborne

, Gispen

, Sanyal

, . Lower allopregnanolone during pregnancy predicts postpartum depression: An exploratory study. Psychoneuroendocrinology 2017; 79: 116–121.

111.

Deligiannidis

, Sikoglu

, Shaffer

, . GABAergic neuroactive steroids and resting-state functional connectivity in postpartum depression: A preliminary study. J Psychiatr Res 2013; 47: 816–828.

Supplementary Material

Please find the following supplemental material available below.

For Open Access articles published under a Creative Commons License, all supplemental material carries the same license as the article it is associated with.

For non-Open Access articles published, all supplemental material carries a non-exclusive license, and permission requests for re-use of supplemental material or any part of supplemental material shall be sent directly to the copyright owner as specified in the copyright notice associated with the article.

0.74 MB

0.00 MB

Neurosteroid Levels in Pregnancy and Its Implications for Mental Health: A Literature Review

Abstract

Background

Summary

Key Message

Keywords

Introduction

Methods

Summary of Circulating Neurosteroid Levels in Pregnancy.

Results

Biosynthesis of Neurosteroids

Biosynthetic Pathway of Neurosteroids. The Neurosteroids in Blue Colour Bold Font Are Presented in the Current Review.3, 30

Neurobiology of Neurosteroids

Changes in Neurosteroids in Pregnancy

Pregnenolone

Dehydroepiandrosterone

Dihydroprogesterone

5-α-dihydroprogesterone

5-beta-dihydroprogesterone

Tetrahydroprogesterone

Allopregnanolone (3α,5α-Tetrahydroprogesterone)

Pregnanolone (3α,5β -Tetrahydroprogesterone)

Isopregnanolone (3β,5α-Tetrahydroprogesterone)

Epipregnanolone (3β,5β -Tetrahydroprogesterone)

Deoxy and Tetrahydrodeoxy-corticosterone

Androstanediol

Placental Neurosteroids

Effect of Sex of the Foetus on the Maternal Circulating Neurosteroid Levels

Discussion

Neurosteroids and Mood Changes in Pregnancy

Conclusion

Abbreviations

Authors Contribution

Statement of Ethics

Footnotes

Declaration of Conflicting Interests

Funding

ICMJE Statement

Patient Consent

Supplemental Material

ORCID iDs

References

Supplementary Material

Biosynthetic Pathway of Neurosteroids. The Neurosteroids in Blue Colour Bold Font Are Presented in the Current Review.^{3, 30}