In utero development has been intimately linked with placental functioning. As an endocrine organ, the placenta not only supports the physical and metabolic needs of the growing fetus but also plays a central role in neurosteroid biosynthesis (Kratimenos and Penn, 2019). These neurosteroids, synthesized and secreted by the placenta, are essential for maintaining pregnancy and regulating the development of the fetal nervous system [for review, see (Kratimenos and Penn, 2019)]. During gestation, neurosteroids such as allopregnanolone exert neuroprotective effects, aiding in the suppression of excess neuronal excitation that could otherwise compromise neural circuit formation (Hirst et al., 2014). Throughout gestation, allopregnanolone levels steadily increase, peaking in the fetal circulation during late pregnancy before declining sharply at birth. This trajectory mirrors maternal neurosteroid levels, which also precipitously decline during parturition. Impaired synthesis of allopregnanolone has been linked to dysregulated central nervous system (CNS) activity in the fetus, increasing the risk of excitotoxicity and long-term neurological deficits (Nicol et al., 2001; Yawno et al., 2007). Impaired neurosteroid signaling in the mother has also been implicated in postpartum depression, which is discussed in more detail below (see Pregnancy and the postpartum period).

Progesterone, another key placental steroid, plays a significant role in promoting brain growth and supporting the proliferation of both neuronal and glial cells in the developing fetal brain (Melcangi et al., 2008; Schumacher et al., 2000, 2012). Additionally, progesterone influences fetal behavior states, including breathing and arousal. Elevated progesterone levels are associated with reduced arousal and diminished electro-ocular activity, while suppression of progesterone results in heightened arousal and increased electro-ocular activity (Crossley et al., 1997; Nicol et al., 1997; Nicol et al., 2001). The third trimester represents a critical window for neurodevelopment, marked by peak levels of pregnenolone, progesterone, and allopregnanolone (Schumacher et al., 2020). This stage is characterized by rapid brain maturation, active myelination, and synaptogenesis, all of which are influenced by the neurosteroid milieu (Clouchoux et al., 2012). Disruption in neurosteroid levels during this period may therefore have profound and lasting effects on neurodevelopmental outcomes.

Postnatal development represents a critical phase in the maturation of synaptic networks, during which changes to neurotransmitter signaling play a fundamental role in shaping neuronal circuitry. Among these, GABAergic signaling undergoes a key developmental transition that is essential for the establishment of functional neuronal networks. In the first postnatal week, GABA acts predominantly as a depolarizing neurotransmitter, exerting profound effects on the developing brain (Ganguly et al., 2001). This excitatory action of GABA facilitates processes such as neuronal migration and maturation (Bortone and Polleux, 2009; Owens and Kriegstein, 2002).

A hallmark of early postnatal development is the shift in GABAergic polarity from depolarizing to hyperpolarizing, occurring within the first two postnatal weeks (Peerboom and Wierenga, 2021). This transformation supports the synchronization and functional integration of emerging neuronal networks (Owens and Kriegstein, 2002). Importantly, this polarity shift coincides with a transient increase in the neurosteroid allopregnanolone, which, along with related neurosteroid, modulates synaptic and extrasynaptic GABA_A-receptor function (Darbra and Pallarès, 2022; Dehorter et al., 2012). By enhancing the actions of GABA, neurosteroids help orchestrate the transition from excitatory to inhibitory GABAergic signaling (Darbra and Pallarès, 2022; Dehorter et al., 2012; Mellon, 2007; Mellon and Griffin, 2002). Likewise, disruptions in neurosteroidogenesis during this critical period can alter the expression of GABA_A-receptor subtypes, potentially affecting neuronal excitability and circuit formation (Mennerick et al., 2004; Mòdol et al., 2014). As development progresses, neurosteroid levels begin to decline by the third postnatal week, which in turn influences the expression of K+/Cl- cotransporter KCC2, a key mediator of the GABA polarity shift (Mòdol et al., 2014).

Exogenous neurosteroid exposure during the early postnatal development has been shown to influence the layer-specific distribution of GABAergic interneurons in the cortex, suggesting a regulatory role in the spatial organization of cortical connectivity (Grobin et al., 2003). Aberrant neurosteroid levels during this period can have lasting effects, influencing behavior during adolescence and adulthood (Gore and Gould, 2024; Gunn et al., 2013). Further, early adversity has been linked to disruptions in neurosteroid signaling, potentially altering the trajectory of neurodevelopment and increasing vulnerability to psychiatric disorders (Gore and Gould, 2024; Gunn et al., 2013; Paris and Frye, 2011). Under basal conditions, the brains response to stress originates in the paraventricular nucleus (PVN) of the hypothalamus, where corticotropin releasing hormone (CRH) is secreted from neuroendocrine cells. CRH is then shuttled to the anterior pituitary gland where along with adrenocorticotropic hormone (ACTH) is secreted by corticotrope cells in the posterior pituitary gland. ACTH stimulates the synthesis and release of glucocorticoids such as cortisol from the adrenal gland that functions as a negative feedback mechanism to terminate the stress response by inhibiting the release of CRH from the PVN. Neurosteroids also have been demonstrated to be released during stress and exert negative feedback much like glucocorticoids. Early life adversity appears to dysregulate stress-responsive circuits, impairing the ability of neurosteroids to modulate the activity of the PVN to suppress excessive stress responses in animal models (Sze and Brunton, 2020). Notably, exogenous administration of neurosteroids, such as 5α-THDOC, has shown promise in mitigating behavioral and neuroendocrine disturbances associated with early life adversity in rats, highlighting their therapeutic potential in neurodevelopmental and mood disorders (Sze and Brunton, 2020).

Emerging research highlights the complex interplay between neurosteroids and developmental, psychological, and physiological processes during crucial periods of development such as the transition from childhood through adolescence. Serum allopregnanolone levels appear to be comparable between male and female infants during the first years of life (Fadalti et al., 1999). However, children diagnosed with ADHD exhibit lower levels of allopregnanolone relative to healthy peers (Sahin et al., 2022), an effect with both potential diagnostic and therapeutic relevance.

Puberty is a period marked by dramatic shifts in the levels of steroid hormones and neurosteroids. In both sexes throughout puberty there is a progressive increase in DHEA, progesterone, and allopregnanolone levels (Fadalti et al., 1999). These hormonal shifts may have critical implications for mental health; for example recent findings reveal that there is a negative correlation between DHEA levels and self-esteem (del Río et al., 2024), alongside a positive correlation between depression scores and DHEA-sulfate (del Río et al., 2024). Progesterone levels in females, meanwhile, follow a predictable trajectory during the menstrual cycle- remaining steady through the follicular phase and gradually increasing during the early to mid-luteal phases before precipitously declining in the late luteal phase (Reed and Carr, 2018).

Rodent studies have demonstrated that stress to the immune system may not only delay puberty but expedite the depletion of ovarian follicles. These effects were linked to diminished expression of the gene Srd5a1, which encodes for the enzyme 5α-reductase type 1, in the hypothalamus and ovaries (Bar-Sadeh et al., 2022). These findings reinforce the sensitive interaction between immune, endocrine, and neurodevelopmental systems.

Neurosteroid levels are dynamically regulated across the lifespan and reproductive cycle, particularly in women. Fluctuations in the expression of δ-subunit-containing GABA_ARs have been reported across the estrous cycle and in affective disorders such as postpartum depression, major depressive disorder, and anxiety disorders (Gilfarb and Leuner, 2022; Lüscher and Möhler, 2019; Maguire et al., 2005). These alterations are frequently concurrent with changes in endogenous neurosteroid levels, suggesting that dysregulation of neurosteroid-GABAergic interactions may contribute to the pathophysiology of mood disorders (Walton et al., 2023; Walton and Maguire, 2019; Zorumski et al., 2025). Notably, women with Premenstrual Dysphoric Disorder (PMDD), demonstrate significantly higher plasma and serum levels of allopregnanolone during the luteal phase (Girdler et al., 2001), implicating potential neurosteroid dysregulation in the emergence of impaired mood regulation.

One of the most well-characterized age-related changes is the progressive decline in circulating DHEA. DHEA levels peak in early adulthood, typically during the third decade of life, and then decrease steadily with advancing age (Stárka et al., 2015). This decline contributes to the broader hormonal shifts associated with aging that occur in response to age-related depletion of organ reserve (Atamna et al., 2018), which may impact the synthesis of neurosteroid.

Over the menstrual cycle in women, neurosteroid concentrations also exhibit significant cyclical fluctuations (Kimball et al., 2019). During the early follicular phase, progesterone levels remain relatively low. As the cycle progresses into the luteal phase, progesterone concentrations rise substantially, coinciding with increasing estradiol levels as the corpus luteum becomes active. However, in the absence of fertilization, the regression of the corpus luteum leads to a sharp decline in both progesterone and estradiol to trigger menstruation.

These cyclical and age-related changes in neurosteroid levels highlight the complex regulation of the neuroendocrine environment in women. Understanding the patterns is essential for elucidating the full physiological roles of neurosteroids and their potential therapeutic implications in both reproductive and post-reproductive phases of life.

Pregnancy is a state of remarkable neuroendocrine changes, during which the brain (and placenta) undergoes significant and unique adaptations to support pregnancy and ultimately coordinate a successful parturition. The brain undergoes dramatic reorganization to prepare for motherhood (Ballesteros et al., 2025; Pawluski, 2024; Pawluski et al., 2022). A hallmark of this period is the dramatic upregulation of neurosteroidogenesis, with progesterone and its potent metabolite allopregnanolone reaching peak levels as gestation progresses (Concas et al., 1998). These neurosteroids are synthesized in both the central and peripheral nervous system, with the placenta becoming the primary source of progesterone after the first trimester, following initial production by the corpus luteum until about the 9^th week of pregnancy (Cable and Grider, 2023). Subsequently it is produced by trophoblasts (Cable and Grider, 2023).

Neurosteroids are not only byproducts of hormonal flux but are themselves active neuromodulators. During pregnancy, the brain exhibits increased expression of neurosteroidogenic enzymes, a shift that enhances the synthesis of neurosteroids like allopregnanolone (Hirst et al., 2006), known for its anxiolytic and GABAergic potentiating properties. One key role of this neurosteroid surge is the suppression of the maternal hypothalamic-pituitary-adrenal (HPA) axis, effectively dampening stress responsiveness and promoting fetal development in a low-stress intrauterine environment (Brunton et al., 2009).

Importantly, neurosteroids also interface with the oxytocinergic system to finely regulate the timing of labor (Blyth et al., 2000). Oxytocin is a peptide hormone produced by the hypothalamus and released into the bloodstream by the pituitary gland. Secretion of oxytocin is initiated by neural inputs from the birth canal and brainstem to increase uterine contractions resulting in fetal dissent through the birth canal. During pregnancy, increased allopregnanolone levels exert a neuroprotective role by increasing inhibitory tone through positive allosteric modulation of GABA_A receptors upon magnocellular oxytocin neurons (Blyth et al., 2000). In addition to these actions, allopregnanolone also modulates the body’s endogenous opioid system (Brunton et al., 2009), providing another layer of protection against secretion of oxytocin before term. At parturition, the loss of progesterone through placental expulsion initiates the upregulation of oxytocin receptor expression in the myometrium, the smooth muscle of the uterus, facilitating coordinated uterine contractions (Grazzini et al., 1998).

The dynamic and robust changes in steroid hormone and neurosteroid levels throughout the peripartum period introduces a window of vulnerability for the emergence of mood disorders (Maguire et al., 2020; Payne and Maguire, 2019; Vesga-López et al., 2008; Walton and Maguire, 2019). The rapid decline in neurosteroid levels, particularly allopregnanolone, coincides with a sharp increase in the incidence of depressive symptoms, with postpartum women displaying significantly higher rates of depression compared to their non-pregnant counterparts (Vesga-López et al., 2008). This underscores the critical role of neurosteroids not only in maintaining pregnancy but also in safeguarding maternal mental health during and after this profound period of physiological transition. In fact, allopregnanolone analogs which act as positive allosteric modulators of GABA_A receptors have been FDA approved for the treatment of postpartum depression (Kanes et al., 2017; Walton and Maguire, 2019), highlighting the role of neurosteroids in regulating mental health throughout the peripartum period.

Menopause marks the transition during which the menstrual cycle ceases in women, signaling the end of reproductive capacity. This period is characterized by significant hormonal changes, including a decline in the levels of allopregnanolone and progesterone (Kimball et al., 2019; Slopien et al., 2018). As follicles diminish, estradiol and progesterone levels decrease, while levels of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) increase in response to reduced negative feedback (Giannini et al., 2021). Additionally, dehydroepiandrosterone (DHEA) levels progressively decline with age (Giannini et al., 2021), contributing to the broader hormonal shifts observed during and after menopause.

One therapeutic strategy aimed at alleviating the neuroendocrine and psychological consequences of menopause is hormone replacement therapy (HRT) (Andréen et al., 2005). The use of neurosteroids for HRT has gained clinical attention however, outcomes related to its use have been variable. Progestogens, synthetic hormones that mimic the actions of progesterone, are frequently utilized in HRT protocols, particularly for their protective properties against endometrial cancers in women undergoing natural menopause (Weise et al., 2021). The literature pertaining to neurosteroid-based interventions for both naturally occurring and medically induced menopause is limited, with clinical studies having conflicting results (Luine, 2014; Weise et al., 2021), underscoring the need for more comprehensive and targeted research into this area.

Biological aging has been associated with a marked decline in the enzymatic activity required for neurosteroid synthesis. In aged rodents 5α-reductase activity is significantly reduced, impairing neurosteroidogenesis (Livingstone et al., 2014; Munetomo et al., 2015; Rosario et al., 2009; Rossetti et al., 2015). In humans, this decline is paralleled by a significant reduction in circulating neurosteroid levels, which drop substantially with age. By 80 years of age, neurosteroid concentrations are approximately 20% of those measured at 20 years of age (Orentreich et al., 1984), indicating a profound age-related reduction in neurosteroid availability.

Collectively, these findings underscore the potential contribution of impaired neurosteroidogenesis to the neurobiological changes associated with aging. However, the functional consequences of this age-related decline in neurosteroid synthesis are not yet fully understood, however, evidence suggests a potential link to both cognitive decline and mood disorders observed in older adults.

Neurosteroids are synthesized from cholesterol (Mellon and Vaudry, 2001) (For review see Table 2) and are increasingly recognized as being modulated by dietary factors, with growing evidence supporting the role of specific nutrients in maintaining neurosteroid homeostasis. Diets rich in antioxidants (e.g., polyphenols), unsaturated fats, and probiotics have not only been shown to influence multiple cellular pathways but also function to mitigate some of the deleterious effects of environmental and emotional stressors on neurosteroid levels (Iban-Arias et al., 2022; Leri et al., 2020; Marotta et al., 2020; Scuto et al., 2024).

Metabolic dysfunction, particularly obesity (excessive body fat), is associated with altered neurosteroid profiles. Reduced levels of allopregnanolone and its precursor pregnenolone have been observed in obese individuals, with pregnenolone levels in cerebrospinal fluid (CSF), negatively correlating with body max index (BMI) yet positively correlating with cognitive measures (Ramírez et al., 2022). Dietary composition also appears to play a significant role in these outcomes. For instance, consumption of a high-fat and high-sucrose diet significantly decreased pregnenolone levels in the arcuate nucleus of the hypothalamus - a brain region central to governing energy expenditure and metabolic regulation (Ramírez et al., 2022). Moreover, a ketogenic diet, which is high in fat and low in carbohydrate content, has been reported to reduce dihydroprogesterone (DHP), allopregnanolone, dihydrotestosterone (DHT), and 3α-androstanediol (Rhodes et al., 2005).

The impact of diet on neurosteroidogenesis is particularly pronounced during pregnancy. High sugar intake prior to and during gestation alters both maternal and fetal neurosteroid profiles. For example, a high-sugar maternal diet has been shown to increase serum levels of aldosterone, 11-dehydrocorticosterone, and 11-deoxycorticosterone in maternal serum, while simultaneously increasing aldosterone in the labyrinth zone and decreasing testosterone in the junctional zone of the placenta (Seib et al., 2025). In the fetus, this diet led to elevated blood aldosterone and brain region-specific changes in neurosteroid levels, including decreased testosterone in the nucleus accumbens, suppressed corticosterone in the orbital cortex and preoptic area, and increased aldosterone in the nucleus accumbens and medial prefrontal cortex (Seib et al., 2025). Elevated aldosterone and 11-dehydrocorticosterone levels were also detected in amniotic fluid (Seib et al., 2025). Similarly, fructose consumption during pregnancy impaired neurosteroidogenesis in offspring by downregulating expression of mRNAs for StAR, TSPO, and 17β-HSD-3, while upregulating mRNAs for P450(11β)-2, 11β-HSD-2, and 17β-HSD-1 (Ohashi et al., 2015).

Nutraceutical interventions have been proposed to offer potential to restore neurosteroidogenic balance. Palmitoylethanolamide (PEA), a saturated fatty acid naturally found in peanuts, soy lecithin, and egg yolks (Lambert et al., 2012), has been shown to exert neuroprotective effects in rodent models of post-traumatic stress disorder (PTSD) (Locci and Pinna, 2019). Administration of PEA increased brain levels of allopregnanolone, pregnenolone, progesterone, and 5α-DHP (Locci and Pinna, 2019). This was accompanied by normalization of neurosteroidogenic enzyme expression, including StAR, CYP11A1, and 5α-reductase type 1, which are typically downregulated in PTSD models (Locci and Pinna, 2019).

Collectively, these findings underscore the influence of dietary composition on neurosteroid biosynthesis and highlight the potential of dietary interventions to modulate neurosteroid profiles in both physiological and pathological states.

Physical activity has been recognized as a potent modulator of neurosteroidogenesis, with specific impacts shown during pain regulation, mood, and cognitive function (Scioli-Salter et al., 2016). One of the most notable neurosteroids influenced by exercise is allopregnanolone. Exercise-induced elevations in allopregnanolone have been shown to be correlated with increased pain tolerance (Scioli-Salter et al., 2016), suggesting a neuromodulatory role in stress resilience and sensory perception. Interestingly, in this study it was also demonstrated that cortisol and dehydroepiandrosterone (DHEA) levels rose from baseline following exercise; however, these increases were inversely correlated with pain tolerance, ultimately highlighting the complex and potentially divergent roles of individual neurosteroids in pain modulation (Scioli-Salter et al., 2016).

Exercise has also demonstrated benefits in aging populations, where hormonal and neurochemical shifts contribute to mood dysregulation and cognitive decline. In older adults, regular cycling was found to elevate circulating DHEA levels, an effect associated with improved mood and reduced symptoms of fatigue, tension, depression, and anger (Sonnenblick et al., 2018). Similarly, in aged rodents, a low-aerobic exercise routine led to, increased brain levels of allopregnanolone, suggesting that even mild physical activity can promote neurosteroidogenesis in the aging brain (Aoyama et al., 2019).

Further supporting the role of exercise in neurosteroidogenic balance, mild physical activity has been shown to upregulate 5α-reductase expression and levels of dihydrotestosterone (DHT) in the hippocampus - a brain region essential for learning, memory, and stress regulation (Okamoto et al., 2012). These changes may contribute to the neuroprotective and mood-stabilizing effects often observed with consistent exercise.

Together, these findings highlight the multifaceted role of exercise in regulating neurosteroid levels and support its potential as a non-pharmacological intervention for enhancing pain tolerance, mood stability, and neuroendocrine function across the lifespan.

Emerging evidence suggests that mindfulness-based practices can positively influence neurosteroid levels, particularly dehydroepiandrosterone sulfate (DHEAS) and its precursor DHEA, which are associated with stress resilience and mood regulation (Jørgensen et al., 2021; Nagendra et al., 2022). In a study examining the effects of a structured mindfulness-based stress reduction program, participants who engaged in 8 weeks of daily 45 min yoga and mediation session, weekly 90 min mindfulness training, and two 7 h silent retreats exhibited significantly elevated DHEAS levels 12 weeks after completing the intervention (Jørgensen et al., 2021). These findings indicate that consistent engagement in mindfulness practices may promote long-term neuroendocrine adaptations. In addition to structured programs, long-term engagement with meditation independently correlates with elevated DHEA levels. Individuals with an extensive history of regular meditation practice were found to have higher circulating DHEA concentrations compared to non-meditators, suggesting sustained neurosteroidogenic benefits associated with long-term meditation practices (Nagendra et al., 2022).