Pregnenolone

Pregnenolone is a steroid hormone synthesized from cholesterol in various tissues, including the adrenal gland, gonads, placenta, central and peripheral nervous systems, and lymphocytes.

It serves as a precursor for essential steroid hormones like estrogens, progestogens, glucocorticoids, androgens, and mineralocorticoids, supporting cardiometabolic homeostasis, reproduction, brain function, neuroprotection, and mood regulation. 

Pregnenolone and its derivatives, such as pregnenolone sulfate and allopregnanolone, enhance memory, learning, cognitive functions, and neurogenesis, while modulating NMDA, GABA, and cannabinoid receptors.

In schizophrenia, pregnenolone has shown potential in reducing negative symptoms and improving overall patient outcomes with minimal side effects, suggesting mechanisms involving neuroprotection, NMDA receptor modulation, and enhancement of GABAergic transmission.

However, further large-scale studies are necessary to confirm these benefits. 

Pregnenolone also helps in stress reduction by modulating GABAergic activity and the hypothalamic-pituitary-adrenal (HPA) axis. 

Despite its promising effects, clinical use requires careful monitoring due to potential mild side effects and the fact that additional studies are needed to confirm many of pregnenolone’s purported benefits. 

What Is Pregnenolone?

Pregnenolone Production

Pregnenolone is a steroid hormone synthesized from cholesterol.

Pregnenolone is synthesized in various steroidogenic tissues such as the adrenal gland, gonads, and placenta by the mitochondrial enzyme CYP11A1. [18.] CYP11A catalyzes the conversion of cholesterol to pregnenolone through three sequential oxidation reactions.  [22.] 

Pregnenolone is also produced in the central and peripheral nervous systems, primarily in glial cells and neurons, and in lymphocytes. [18.] 

Pregnenolone is a Precursor for Essential Steroid Hormones

Pregnenolone is a precursor to various steroid hormones and neuroactive steroids including estrogens, progestogens, glucocorticoids, androgens, and mineralocorticoids.

Pregnenolone and its downstream hormones are essential for cardiometabolic homeostasis and reproduction, and they have many other important roles including supporting brain function, neuroprotection, and mood regulation.  [27., 28.] 

Some experts report that pregnenolone may have potential therapeutic applications in neurological diseases. [27., 28.] 

Pregnenolone’s Role in the Brain

Neuroprotective Effects:

Pregnenolone and its derivatives, such as pregnenolone sulfate and allopregnanolone, enhance memory, learning, and cognitive functions, while reversing depressive disorders. [18.]

Lower levels of pregnenolone are observed in neuroinflammatory diseases, indicating its role in neuroprotection and neuroregeneration. [18.] 

Neurogenesis and Cognitive Function:

Pregnenolone sulfate (PREG-S) enhances neurogenesis and hippocampal plasticity, crucial for cognitive function. [15.] 

PREG-S affects acetylcholine release, improving cognitive performance in older animals. [15.] It also increases REM sleep and the growth of new brain cells. [15.] 

Receptor Modulation:

Pregnenolone and its metabolites 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. [12.] 

GABA Receptors

Pregnenolone sulfate (PS) inhibits GABAA receptor function, contrasting with other neurosteroids like allopregnanolone, which enhance it. [29.] This inhibition could promote memory and learning but may worsen symptoms in anxiety-based disorders [2., 29.], particularly in PMDD. [29.] 

Cannabinoid Receptors

Pregnenolone acts as an inhibitor of the CB1 receptor, countering THC's effects and protecting against cannabis intoxication. [28.]

Benefits of Pregnenolone: What Does Pregnenolone Do? 

Precursor to Steroid Hormones

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

Anti-Inflammatory Effects

Pregnenolone reduces inflammation by promoting degradation of key proteins in immune signaling pathways, leading to reduced pro-inflammatory cytokines like TNFα and IL-6. [18.]

Another study showed a significant reduction in pain with regular use of pregnenolone after 4 weeks. [19.]

Sleep Improvement

Pregnenolone enhances deep and REM sleep in animal models, showing potential in sleep regulation. [6., 11.]

Cognitive Enhancement and Neuroprotection

Pregnenolone supports memory, learning, and cognitive function, providing neuroprotection against neuronal damage. [12., 18., 27., 28., 29.] 

Mood Regulation

Pregnenolone reduces bipolar depression and shows modest benefits in depressive and manic symptoms in individuals with mood disorders and substance abuse history. [2., 3., 6., 21.]

Lithium, a common therapy used in bipolar disorder, elevates levels of the neurosteroids allopregnanolone and pregnenolone in animals. [3.] 

Another small study demonstrated some improvement in irritability in patients with autism spectrum disorder. [7.] 

Additional research shows that individuals with HIV on antiretroviral therapy who experience depression have lower levels of pregnenolone and DHEA-S compared to those without depressive symptoms. [17.] 

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. [17.] 

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

Schizophrenia [13.] 

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

Pregnenolone 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. [8.] 

Research indicates that pregnenolone and its metabolites, such as allopregnanolone, modulate GABAergic activity and the hypothalamic-pituitary-adrenal (HPA) axis, helping restore normal function after stress. [8.] 

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. [8.] 

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). [16.] 

Lab Testing for Pregnenolone

Test Information, Sample Collection and Preparation

Pregnenolone 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 Test Results

Optimal Pregnenolone 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: [26.] 

Pregnenolone sulfate: 1-23 pg/mL

Another lab reports the following optimal range for pregnenolone in adults in serum: [24.] 

Pregnenolone, Adult: 22-237 ng/dL

Clinical Significance of Elevated Pregnenolone Levels

Clinically, it is uncommon to find elevated pregnenolone 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. [8.] 

‍Adrenal Hyperplasia and Adrenal Tumors

Some adrenal tumors become very efficient at producing pregnenolone from cholesterol. [20.] 

Pregnancy

Pregnenolone levels rise in pregnancy. [23.]

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 [8., 12., 14. ,15., 18., 29.] 

Aging may also be a factor in low pregnenolone levels. DHEA, DHEA-S, and pregnenolone levels all decrease with age. [4.] 

The decline in pregnenolone is more pronounced in men compared to women. [4.] 

Related Biomarkers to Test

When investigating pregnenolone 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. 

Pregnenolone for Men

Pregnenolone plays a significant role in men's cognitive function, quality of life, and overall health.

Cognitive Function

Higher levels of pregnenolone are linked to better working memory, verbal fluency, and overall cognitive function. [4.] Additionally, pregnenolone has neuroprotective properties, regulating myelin synthesis and modulating synaptic plasticity, which are crucial for memory and cognition. [4.] 

Age-Related Decline

Pregnenolone levels decrease with age, more sharply in men (78%) compared to women (45%). [4.]  Pregnenolone sulfate peaks around age 27, remains stable until 52, and then declines. [9.] 

Quality of Life

Higher levels of pregnenolone correlate with better physical health, social relations, and environmental quality of life in men. [4.] 

Hormonal Balance

There is a correlation between pregnenolone and epitestosterone, indicating a role in balancing androgen levels, which is important for hormonal health. [9.] 

As a precursor to other hormones, such as DHEA and DHEA-S, pregnenolone contributes to mood regulation, energy levels, and sexual health. [9.]

Potential Therapeutic Uses

Pregnenolone's neuroprotective properties suggest potential therapeutic uses in treating cognitive decline, mood disorders, and neurodegenerative conditions. [9.]

In summary, pregnenolone is crucial for maintaining cognitive function, quality of life, and hormonal balance in men. Its significant age-related declines underscore its importance in healthy aging.

Pregnenolone for Women

Gender-Specific Effects

The neuroprotective and cognitive benefits of neurosteroids were more pronounced in men than in women. While neurosteroids like pregnenolone significantly impact cognitive function and quality of life for men, these effects are less evident in women in one study. [4.] 

Age-Related Decline

Both DHEA and DHEA-S levels decrease with age in both genders, with a steeper decline in men. Pregnenolone levels also decline with age, with a 78% decrease in men and a 45% decrease in women. [4.] 

In women, pregnenolone sulfate levels peak around age 32 and then decline. This decline may impact various physiological functions as pregnenolone is a precursor to several important hormones. [9.]

Quality of Life

One study found there were no significant correlations between neurosteroid levels and quality of life measures in women, contrasting with men, where DHEA levels were correlated with physical health, social relations, and environmental dimensions. [4.]

However, the decreases in hormone levels that occur with menopause are known to cause changes in quality of life for many women. 

The decrease in estrogen during menopause leads to vasomotor symptoms, urogenital atrophy, sleep disturbances, and mood changes, all of which significantly impair quality of life. 

These symptoms include hot flashes, vaginal dryness, insomnia, and increased risk of depression, and they often persist or worsen without appropriate treatment. [10.]

Neuroprotection and Neuropsychiatric Disorders

Pregnenolone and pregnenolone sulfate are thought to have neuroprotective effects, regulating myelin synthesis and modulating neurotransmission. These effects might influence the prevalence and severity of neuropsychiatric disorders, although specific impacts in women were not detailed in the study. [9.] 

How Long Does It Take For Pregnenolone to Work?

Research on pregnenolone tends to show some benefit in 4-12 weeks. This will depend on the dosage used, the individual’s biology, and the desired outcome. [7., 19., 21.] 

It is important to work with a licensed healthcare professional before and during any new supplement regimen for appropriate testing, dosage, and monitoring. 

Pregnenolone Side Effects

Side effects that have been noted from pregnenolone use include: [13.] 

• Mild restlessness 

• Mild muscle pain/stiffness 

• Mild cold extremities

• Decreased interest in sex 

• Disorientation (mild) 

• Dry mouth (mild) 

• Hypertension (mild, < 145/90) 

Pregnenolone: Takeaways

• Pregnenolone Production: steroid hormone synthesized from cholesterol in the adrenal gland, gonads, placenta, nervous systems, and lymphocytes.

• Hormone Precursor: essential for synthesizing estrogens, progestogens, glucocorticoids, androgens, and mineralocorticoids.

• Brain Function: enhances memory, learning, and cognitive functions; supports neuroprotection and mood regulation.

• Neurogenesis: promotes hippocampal plasticity and acetylcholine release, improving cognitive performance.

• Receptor Modulation: acts on NMDA, GABA, and cannabinoid receptors, influencing cognitive enhancement and mood.

• Anti-Inflammatory Effects: reduces inflammation by degrading key immune signaling proteins.

• Sleep and Mood: improves REM sleep, may reduce bipolar depression, and may benefit other mood disorders.

• Schizophrenia: may reduce negative symptoms and improve overall outcomes; further studies needed.

• Stress Response: modulates GABAergic activity and the HPA axis, aiding stress adaptation.

• Side Effects: mild restlessness, muscle pain, cold extremities, decreased interest in sex, disorientation, dry mouth, and mild hypertension.

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