Pregnenolone Sulfate

Pregnenolone sulfate is a significant steroid metabolite and neurosteroid synthesized from cholesterol in various tissues, including the brain, adrenal glands, and liver. 

As a neurosteroid, it modulates ion channels, transporters, and enzymes in the nervous system, impacting functions such as memory, learning, and synaptic plasticity. 

Unlike its precursor pregnenolone, which diffuses easily through cell membranes due to its lipophilic nature, pregnenolone sulfate, being hydrophilic, relies on specific transporters to enter cells and cross the blood-brain barrier. 

This sulfate ester form is involved in both neurological and immunoregulatory functions, exhibiting strong immunosuppressive properties by inducing T cell death and reducing proliferation. 

Its levels vary throughout life, with high concentrations at birth, a slight increase during adolescence, and significant rises during pregnancy. Altered levels of pregnenolone sulfate are also observed in conditions like hypothyroidism, hyperthyroidism, and rheumatoid arthritis. 

It serves as a crucial precursor in steroid synthesis, can be converted back into pregnenolone, and has therapeutic potential in treating cognitive, mood, and inflammatory disorders due to its unique interaction with ion channels and receptors.

What is Pregnenolone Sulfate? [12.] 

Pregnenolone sulfate is a significant steroid metabolite and a neurosteroid, synthesized from cholesterol and produced from pregnenolone in various tissues including the brain, adrenal glands, and liver.

As a neurosteroid it modulates a variety of ion channels, transporters, and enzymes in the nervous system, impacting functions like memory, learning, and synaptic plasticity.

Pregnenolone sulfate has been upgraded from a modulator to an activator of ion channels, specifically targeting TRP channels, NMDA, and GABAA receptors.

TRP channels are a diverse family of “transient receptor potential” channels that affect ion flow through and between neurons and therefore have a wide range of physiological functions and effects.

Synthesis and Metabolism [12.] 

Pregnenolone sulfate is formed from pregnenolone by the cytosolic sulfotransferase enzymes SULT2A1, SULT2B1a, SULT2B1b in the adrenal gland, liver, brain, placenta, and other tissues. 

Pregnenolone sulfate is not merely a final metabolite for excretion but acts as a precursor for further steroid synthesis.

For example, pregnenolone sulfate can be converted back into pregnenolone, serving as a precursor for further steroid synthesis. When converted back to pregnenolone, it can re-enter the steroid synthesis pathways.

Serum and Tissue Levels [12.] 

Its concentrations vary throughout life, with high levels at birth that decline to stable levels in adulthood. It plays crucial roles during pregnancy and has altered levels in various diseases.

Transport Mechanisms 

Due to its hydrophilic nature, pregnenolone sulfate relies on specific transporters to enter cells, facilitating its function as a steroid precursor. [11., 12.] 

Pregnenolone, being lipophilic, can diffuse through cell membranes easily. PregS, due to its hydrophilic sulfate moiety, cannot diffuse across membranes as easily and requires transport proteins to cross the blood-brain barrier (BBB) and cell membranes. [11.] 

Lifespan Variation [12.] 

Pregnenolone sulfate levels are high at birth (µM concentrations) and decline to nM levels in adults. During adolescence, these levels increase slightly.

Levels of pregnenolone sulfate rise significantly during pregnancy, peaking at birth.

Altered levels are observed in conditions like hypothyroidism (reduced levels), hyperthyroidism (increased levels), and rheumatoid arthritis (reduced levels).

What Are the Differences Between Pregnenolone and Pregnenolone Sulfate?

Physiological Role and Action [11.] 

Pregnenolone acts as a precursor for various steroid hormones like progesterone, estrogens, and androgens. 

Pregnenolone sulfate seems to have more neurological affinity, modulating ion channels and neurotransmitter receptors, including NMDA and GABAA receptors, and activating TRP channels (TRPM1 and TRPM3) to influence neuronal excitability and potentially offer therapeutic benefits in neurological conditions. [11.] 

Both have immunosuppressive properties via similar pathways, but pregnenolone sulfate also exhibits effects in different pathways including enhanced T cell death and reduced proliferation. [8.]

Localization and Concentration [11.] 

Pregnenolone sulfate concentrations vary across different brain regions, being highest in the striatum and hypothalamus, while pregnenolone levels are generally measured in serum.

Additionally, while the lipophilic pregnenolone molecule can diffuse through cell membranes easily, the hydrophilic pregnenolone sulfate molecule, cannot diffuse across membranes as easily and requires transport proteins to cross the blood-brain barrier (BBB) and cell membranes.

Therapeutic Potential [11.] 

Pregnenolone sulfate has specific roles in brain function modulation and has been proposed for therapeutic use in treating cognitive and mood disorders due to its interaction with ion channels and receptors, unlike pregnenolone, which is more involved in hormone synthesis pathways.

Pregnenolone sulfate produced in the adrenal glands can be acutely regulated by adrenocorticotropic hormone (ACTH). [28.]

Elevated pregnenolone sulfate levels have been observed in conditions like congenital adrenal hyperplasia, reflecting chronic ACTH stimulation. This makes pregnenolone sulfate a potential marker for poor disease control in such conditions. [28.] 

Pregnenolone Sulfate’s Role in the Brain

Neuroprotective Effects

Pregnenolone sulfate plays a significant role in neurological health by modulating inflammation and neuroprotection. [21.] 

Specifically, pregnenolone sulfate is involved in neuroprotection and neuroregeneration, particularly in conditions like Alzheimer's disease (AD) and multiple sclerosis (MS).

Pregnenolone and its derivatives, such as pregnenolone sulfate and allopregnanolone, enhance memory, learning, and cognitive functions, while reversing depressive disorders. [21.]

Neurogenesis and Cognitive Function

Pregnenolone sulfate enhances neurogenesis and hippocampal plasticity, crucial for cognitive function. [17., 18.] 

Pregnenolone sulfate affects acetylcholine release, improving cognitive performance in older animals. [17., 18.] It also increases REM sleep and the growth of new brain cells. [17., 18.] 

Receptor Modulation

Pregnenolone and its metabolites such as pregnenolone sulfate act on NMDA, GABA, and cannabinoid receptors in the central nervous system.

NMDA Receptors

Pregnenolone sulfate modulates NMDA receptor activity based on subunit composition, suggesting a role in cognitive enhancement, neuroprotection, mood modulation, and potential addiction therapies. [15., 33.] 

GABA Receptors

Pregnenolone sulfate inhibits GABAA receptor function, contrasting with other neurosteroids like allopregnanolone, which enhance it. [32.] This inhibition could promote memory and learning but may worsen symptoms in anxiety-based disorders [2., 32.], particularly in PMDD. [32.] 

Cannabinoid Receptors

Pregnenolone acts as an inhibitor of the CB1 receptor, countering THC's effects and protecting against cannabis intoxication. [3., 31.] 

Benefits of Pregnenolone Sulfate: What Does Pregnenolone Sulfate Do? 

Maintains Precursor Pool for Steroid Hormones

Pregnenolone is essential for synthesizing various steroid hormones, including progesterone, estrogen, testosterone, and cortisol.

Because pregnenolone sulfate can be re-converted back to pregnenolone, it can be considered a “precursor pool” in case cholesterol or pregnenolone levels get low. [HARTENECK>>>>>>>>>>

Anti-Inflammatory Effects

Pregnenolone sulfate, a metabolic derivative of pregnenolone, has been studied for its role in modulating inflammation. In various experiments, pregnenolone sulfate, along with other pregnenolone derivatives, was shown to suppress the secretion of pro-inflammatory cytokines such as TNFα and IL-6 in macrophages and microglial cells. [21.] 

Pregnenolone sulfate exhibits stronger immunosuppressive properties compared to pregnenolone. It induces T cell death in a dose-dependent manner, reduces T cell proliferation, and downregulates pro-inflammatory genes. [8.] 

Sleep Improvement

Pregnenolone sulfate enhances deep and REM sleep in animal models, showing potential in sleep regulation. [6.]

Cognitive Enhancement and Neuroprotection

Pregnenolone supports memory, learning, and cognitive function, providing neuroprotection against neuronal damage. [15., 21., 30., 31., 32.] 

Mood Regulation

Pregnenolone and pregnenolone sulfate reduce bipolar depression and show modest benefits in depressive and manic symptoms in individuals with mood disorders and substance abuse history. [2., 4., 7., 23.]  

Lithium, a common therapy used in bipolar disorder, elevates levels of the neurosteroids allopregnanolone and pregnenolone in animals. [4.] 

Another small study demonstrated some improvement in irritability in patients with autism spectrum disorder. [9.] 

Additional research shows that individuals with HIV on antiretroviral therapy who experience depression have lower levels of neurosteroids including pregnenolone sulfate and DHEA-S compared to those without depressive symptoms. [20.] 

These steroids modulate the hypothalamic-pituitary-adrenal (HPA) axis, influencing stress responses and mood regulation. The imbalance of neuroactive steroids, marked by a high cortisol/DHEA-S ratio, is linked to depressive symptoms in this population, suggesting that altered neuroactive steroid metabolism may contribute to depression in ART-treated HIV-infected adults. [20.] 

Despite current research available, further studies are recommended to confirm these benefits. 

Schizophrenia [16.] 

A pilot study investigated pregnenolone as an adjunctive treatment for cognitive and negative symptoms in schizophrenia or schizoaffective disorder. 

Pregnenolone and its metabolites, including pregnenolone sulfate, significantly reduced negative symptoms, particularly in affective flattening and alogia, and patients showed greater overall improvement compared to placebo. 

While cognitive score improvements were not significant, increases in serum pregnenolone and its metabolite allopregnanolone correlated with better cognitive performance, suggesting potential cognitive benefits. 

Pregnenolone was well-tolerated with minimal side effects and did not significantly impact weight, blood pressure, glucose, or other lab parameters. 

Its mechanisms may involve neuroprotection, NMDA receptor modulation, and enhancement of GABAergic transmission. Further large-scale studies are needed to confirm these findings. 

Stress Reduction

As a neuroactive steroid, pregnenolone plays a crucial role in mental health, particularly in response to stress. [10.] 

Research indicates that pregnenolone and its metabolites including pregnenolone sulfate and  allopregnanolone modulate GABAergic activity and the hypothalamic-pituitary-adrenal (HPA) axis, helping restore normal function after stress. [10.] 

While these neurosteroids increase during acute stress to aid adaptation, chronic stress and depressive disorders often show reduced levels of these steroids, leading to dysregulated stress responses and altered HPA function. [10.] 

Pregnenolone was shown to reduce stress- and cocaine cue-induced craving and anxiety, particularly at the 500 mg dose, and decreases stress-induced autonomic responses (heart rate, systolic, and diastolic blood pressure). [19.] 

Lab Testing for Pregnenolone Sulfate

Test Information, Sample Collection and Preparation

Pregnenolone sulfate levels are commonly tested in the blood and saliva. Blood samples are collected via venipuncture, while saliva samples may be collected from the comfort of home. 

It is important to consult with the ordering provider prior to sample collection, as certain supplements or hormones may affect test results. 

Interpreting Pregnenolone Sulfate Test Results

Optimal Pregnenolone Sulfate Test Results

Test results should be interpreted within the context of an individual’s medical history, current symptoms, and complete hormone test results.  

One laboratory reports the following optimal pregnenolone sulfate levels in saliva: [29.] 

Pregnenolone sulfate: 1-23 pg/mL

Another lab reports the following optimal range for pregnenolone in adults in serum: [26.] 

Pregnenolone, Adult: 22-237 ng/dL

Clinical Significance of Elevated Pregnenolone Sulfate Levels

Clinically, it is uncommon to find elevated pregnenolone sulfate levels outside of excessive pregnenolone supplementation. 

Causes of elevated pregnenolone outside of excessive supplementation may include:

Short Term High Stress

Levels of certain neurosteroids can increase short term to accommodate for the effects of high stress.  However, long term stress typically causes a decrease in these levels. [10.] 

Adrenal Hyperplasia and Adrenal Tumors

Some adrenal tumors become very efficient at producing pregnenolone from cholesterol, which can cause higher levels of pregnenolone sulfate. [22.] 

Pregnancy

Pregnenolone and pregnenolone sulfate levels rise in pregnancy. [12., 25.]

Hyperthyroidism 

Elevated levels of pregnenolone sulfate levels can be seen in hyperthyroidism. [12.]

Clinical Significance of Low Pregnenolone Levels

Low pregnenolone levels have been associated with conditions such as chronic stress, depression, and may be associated with hormone deficiency, increased inflammation, or neurodegenerative processes [10., 15., 17., 21., 32.]

It can also be seen in hypothyroidism and rheumatoid arthritis. [12.] 

Aging may also be a factor in low pregnenolone levels. DHEA, DHEA-S, and pregnenolone levels all decrease with age. [5.] 

The decline in pregnenolone is more pronounced in men compared to women. [5.] 

Related Biomarkers to Test

When investigating pregnenolone sulfate levels, it's often beneficial to examine other related hormone levels as well. Hormones such as estrogens, progesterone, testosterone, DHEA and DHEAS, may all be considered along with cortisol. 

Additionally, practitioners may consider ordering downstream hormone metabolites to see how pregnenolone’s steroid hormone metabolites are further metabolized in the body. 

Increasingly, laboratory companies are offering specialized hormone panels for a more comprehensive assessment of steroid hormone production and metabolism.

Key Takeaways about Pregnenolone Sulfate

• Steroid Metabolite and Neurosteroid: pregnenolone sulfate is a sulfated metabolite of pregnenolone, which is synthesized from cholesterol in tissues such as the brain, adrenal glands, and liver. Pregnenolone is sulfated in various tissues in the body, especially the liver, adrenal glands, and brain. 

• Neurological Function: well known for its effects in the nervous system, pregnenolone sulfate modulates ion channels, transporters, and enzymes, impacting memory, learning, and synaptic plasticity.

• Transport Mechanisms: unlike lipophilic pregnenolone, hydrophilic pregnenolone sulfate requires specific transporters to enter cells and cross the blood-brain barrier.

• Immunoregulatory Properties: pregnenolone sulfate exhibits strong immunosuppressive effects by inducing T cell death and reducing proliferation.

• Lifespan Variation: levels are high at birth, slightly increase during adolescence, rise significantly during pregnancy, and vary in conditions like hypothyroidism, hyperthyroidism, and rheumatoid arthritis.

• Precursor for Steroid Synthesis: pregnenolone sulfate acts as a reservoir for steroid hormones; it can be converted back into pregnenolone, re-entering steroid synthesis pathways.

• Therapeutic Potential: pregnenolone sulfate is a neurosteroid proposed for treating cognitive, mood, and inflammatory disorders due to its interaction with ion channels and receptors.

Order Pregnenolone Sulfate Testing

Click here to compare testing options and order testing for steroid hormones.