Pregnenolone Testing 101: When To Test And How To Understand Results

Pregnenolone, often hailed as the "mother of all hormones," is a pivotal steroid hormone in the human body. It is a precursor to other steroid hormones, including cortisol, estrogen, progesterone, and testosterone. As hormone optimization evolves, healthcare providers and individuals seeking to enhance their well-being are increasingly interested in understanding pregnenolone's role, the circumstances under which testing is necessary, and how to interpret the results effectively.

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What Is Pregnenolone?

Pregnenolone is a steroid hormone precursor synthesized from cholesterol. It is primarily produced in the gonads (ovaries and testes), adrenal glands, and brain. (43) 

Steroidogenesis is the biochemical process of making steroid hormones. Steroidogenesis begins with the transport of cholesterol into a cell's mitochondria. Cholesterol is then converted to pregnenolone by an enzyme called cytochrome P450 side-chain cleavage enzyme (P450scc). (39) 

Depending on the location of steroidogenesis and the enzymes present, pregnenolone can follow various biochemical pathways to ultimately form five classes of steroid hormones:

• Progesterone
• Glucocorticoids (e.g., cortisol)
• Mineralocorticoids (e.g., aldosterone)
• Androgens (e.g., DHEA, testosterone)
• Estrogens (e.g., estradiol)

In addition to being a precursor to other steroid hormones, pregnenolone also has its own biological activities as a neurosteroid. Neurosteroids are synthesized in the brain and directly affect neuronal function without altering genetic expression. 

Pregnenolone has anti-inflammatory and neuroprotective properties that can enhance cognitive functioning (e.g., learning and memory), regulate mood, and influence the immune system to create a healthy balance between pro- and anti-inflammatory immune responses (28).  

When to Test for Pregnenolone

Pregnenolone testing assists in:

• Identifying hormonal deficiencies or excesses
• Guiding treatment plans for hormone-related conditions
• Monitoring the efficacy of hormone replacement therapies

Specific indications and clinical signs/symptoms that could warrant measuring pregnenolone levels during a diagnostic workup include: 

• Chronic fatigue
• Neuroinflammatory diseases, such as multiple sclerosis or Alzheimer's disease
• Cognitive issues, such as reduced capacity to make decisions, memory lapses, or trouble with word recall
• Mood disorders, including anxiety and depression
• Neuropsychiatric conditions, including autism, schizophrenia, and bipolar disorder
• Chronic stress
• Chronic pain
• Traumatic brain injury (TBI)
• Symptoms related to menopause or andropause, such as irregular menstrual cycles, hot flashes, irritability, insomnia, and low libido
• Congenital adrenal hyperplasia (CAH)

How to Test for Pregnenolone Levels

Blood tests are the most common method for measuring pregnenolone levels. They offer a direct measurement of pregnenolone levels at the time of the test, and no special preparation is required for the blood draw.

Pregnenolone is typically measured and interpreted alongside other hormone levels to provide a better understanding of the patient's hormonal profile. Depending upon the reason for ordering pregnenolone, this could include measuring: 

• 17 alpha-hydroxyprogesterone (17-OHP) 
• Cortisol
• DHEA-S
• Testosterone
• Progesterone
• Estrogens

Order one of the following serum pregnenolone tests through Rupa Health:

• Pregnenolone by Empire City Labs
• Pregnenolone by Access Med Labs
• Pregnenolone by Access Labcorp Draw

Understanding Pregnenolone Test Results

Pregnenolone levels are categorized as normal, low, or high based on established reference ranges. Generally, serum pregnenolone's normal value range is 22-237 ng/dL. However, these ranges can differ depending on the laboratory and the testing method used. 

Some suggest that the optimal serum pregnenolone level should be between 125-175 ng/dL for optimal health.

Low Pregnenolone

Low pregnenolone levels can be indicative of:

• Aging: Natural declines in pregnenolone occur with age.
• Adrenal Fatigue: Chronic stress may deplete pregnenolone. This concept is called the "pregnenolone steal."
• Congenital Lipoid Adrenal Hyperplasia (Lipoid CAH): A fatal subtype of CAH that results from genetic mutations that impair cholesterol transport into mitochondria and cause a P450scc deficiency (19).

High Pregnenolone

Elevated pregnenolone levels are less common but may result from:

• Congenital Adrenal Hyperplasia: Most types of CAH are caused by genetic mutations that result in 21-hydroxylase deficiency, which disrupts the conversion of 17-hydroxyprogesterone to 11-deoxycortisol in the steroidogenesis pathway, leading to a buildup of cortisol precursors, including pregnenolone (25).  
• Adrenal Tumors: Some adrenal tumors may produce excess pregnenolone (26).
• Hormone Supplementation: The overuse of pregnenolone supplements can artificially raise levels.

Benefits of Pregnenolone Supplementation

As previously discussed, low pregnenolone levels can create downstream imbalances in other steroid hormones, impair cognitive functions, and dysregulate mood. People with low pregnenolone may benefit from pregnenolone supplementation in the following ways: 

Improve Cognitive Functioning

Pregnenolone and its metabolites enhance synaptic plasticity and memory processes by modulating neurotransmitter systems, particularly the N-methyl-D-aspartate receptor (NMDAR) and gamma-aminobutyric acid (GABA) receptor.

Many animal studies have indicated that pregnenolone and its sulfate derivative enhance cognitive functions (1, 13, 31). 

While more human clinical trials are needed to fully understand pregnenolone's impact on memory and cognition in general populations, studies do show promise that supplementation can improve certain aspects of cognitive functioning and negative symptoms in patients with schizophrenia (22, 23).

Boost Mood

Low levels of pregnenolone and its derivative neurosteroid allopregnanolone have been linked to depression and anxiety.

Allopregnanolone has been shown to potentiate GABA's calming effects on the nervous system and reduce activity in the amygdala, a brain region that largely controls feelings of fear.

In one clinical trial, patients with bipolar depression were randomized to receive pregnenolone or a placebo for 12 weeks. At the end of the study, patients who received pregnenolone had higher remission rates than those who received the placebo. 

Reduce Chronic Pain

A study conducted in 2020 highlighted that pregnenolone can reduce low back pain. United States military veterans who reported low back pain were randomized to receive pregnenolone or a placebo for four weeks. Compared to the placebo group, patients who received pregnenolone reported significant reductions in low back pain and interference with daily activities at the end of the trial.

Prevent Insomnia

Pregnenolone has shown potential in treating insomnia, primarily through its metabolite allopregnanolone's modulation of the GABA_A receptor.

Animal studies provide some evidence for the sedative-hypnotic effects of pregnenolone and its analogs. For instance, one rat study showed that an oral bioavailable analog of pregnenolone promoted sleep while maintaining sleep architecture.

Human studies on pregnenolone's effects on sleep are limited; however, one study showed its potential in attenuating benzodiazepine-induced sedation. 

Given that mood and cognitive function are closely linked to sleep quality, pregnenolone may also contribute to better sleep by reducing anxiety and improving overall mental health.

Treatment and Management of Abnormal Pregnenolone Levels

Managing abnormal pregnenolone levels often involves a multifaceted approach:

• Medical interventions may include hormone replacement therapy (HRT) to supplement pregnenolone or other downstream hormones to restore hormonal balance and alleviate associated symptoms. 
• Stress management techniques like mindfulness, meditation, and cognitive-behavioral therapy can reduce chronic stress and support adrenal health.
• A balanced diet rich in healthy fats, proteins, and essential vitamins supports hormone synthesis.
• Regular physical activity promotes overall hormonal balance and reduces stress levels.

Supplemental pregnenolone is available over the counter and may be used to address deficiencies. If you're considering taking pregnenolone for health purposes, always consult with a healthcare provider to discuss safety and appropriate dosing. 

• Research has shown that doses of up to 500 mg daily are safe and well tolerated, although optimal levels can usually be achieved with daily pregnenolone doses ranging between 10-100 mg. 
• Side effects of supplementation may include diarrhea, cold intolerance, muscle pain, restlessness, and fatigue.

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Key Takeaways

• Pregnenolone is a neurosteroid that influences cognitive function, mood, the stress response, and hormonal balance. 
• Testing pregnenolone levels can provide valuable insights into hormonal health, guiding effective treatment and management strategies. 
• Understanding when to test, how to interpret results, and the implications of abnormal levels empowers healthcare providers and individuals to take proactive steps toward achieving optimal hormonal balance.
• Technological advancements have improved the accuracy and reliability of pregnenolone measurements, with enhanced assay techniques allowing for more precise assessments of hormone levels. 
• Future research is likely to focus on pregnenolone's role in various physiological processes and its potential therapeutic uses, personalizing hormone therapy and leveraging pregnenolone levels to tailor treatments for individual hormonal profiles.