The body’s endocrine system is a complex network of glands that produce and secrete hormones that have a broad impact on health. Hormones are known as “chemical messengers” as they regulate or control the activity of cells and organs in the body.
One of these hormones, pregnenolone, is used to synthesize several other hormones and has also been found to have biological effects. This article explores what you need to know about pregnenolone, including pregnenolone health benefits and the pregnenolone steal theory.
What is pregnenolone? The role of pregnenolone in steroid production
Pregnenolone, sometimes referred to as the “mother of hormones”, is a steroid hormone synthesized from cholesterol and used as a precursor for all steroid hormones. (4) Pregnenolone is primarily synthesized in the adrenal glands, brain, and gonads (testes and ovaries). (9)(15)
For this process, cholesterol can be sourced from cholesterol-carrying lipoprotein particles in the blood and obtained or produced from different processes in the cell. In the cell’s mitochondria, cholesterol is converted to pregnenolone with the assistance of an enzyme called cytochrome P450 side-chain cleavage enzyme. (4)
Pregnenolone will follow unique metabolic pathways of hormone synthesis in the adrenal glands, brain, gonads, and even in the placenta during pregnancy. (8) Various factors affect the type of steroid hormone that is eventually produced from pregnenolone, such as the location of steroidogenesis, the enzymes involved, and other hormones present. (2)(4)(15) The two groups of enzymes involved in the biosynthesis of steroids are cytochrome P450 enzymes and hydroxysteroid dehydrogenases. (8)
There are five classes of steroid hormones synthesized from pregnenolone, including:
- Androgens (e.g., testosterone, dihydrotestosterone (DHT)
- Estrogens (e.g., estradiol)
- Glucocorticoids (e.g., cortisol, corticosterone)
- Mineralocorticoids (e.g., aldosterone)
- Progestins (e.g., progesterone) (4)
To learn about nutrients that impact the steroidogenic pathways, view the Fullscript blog.
In addition to being a steroid precursor, pregnenolone exerts different actions in the body. Pregnenolone has anti-inflammatory effects and helps maintain immune balance. It may also protect against neuroinflammatory and psychiatric conditions, such as Alzheimer’s disease, autism, depression, multiple sclerosis, and schizophrenia. (9)
Pregnenolone that is synthesized in the central and peripheral nervous system is considered a neurosteroid, (9) a category of steroid hormones synthesized in the nervous system. (8)(9)(13) Neurosteroids exert effects on cellular functions by binding to receptors and influencing gene transcription, as well as interacting with neurotransmitter receptors and modulating neurotransmission. (13) As a result, neurosteroids have been found to modulate various brain functions. (15)
Pregnenolone and DHEA
One example of the metabolic pathways of pregnenolone is the conversion to dehydroepiandrosterone (DHEA), which occurs in the adrenal cortex, brain, gastrointestinal tract, and gonads. (2)(12) DHEA and its metabolite, dehydroepiandrosterone sulfate (DHEAS), are converted to estradiol and testosterone and involved in functions such as female fertility, metabolism, and nervous system function. (12) Interestingly, supplemental pregnenolone is associated with increased DHEAS levels, which some researchers speculate may be significant to pregnenolone’s therapeutic effects. (6)
Factors influencing pregnenolone levels
Research suggests that factors including certain medications and health conditions may increase or decrease pregnenolone levels. For example, levels of serum pregnenolone sulfate, a metabolite of pregnenolone, were increased following treatments with cosyntropin, used for diagnosis, and decreased following treatments with dexamethasone, used in inflammatory conditions, and carbamazepine, an anticonvulsant. (13)
Certain genetic disorders have been associated with pregnenolone synthesis defects and low pregnenolone. Specifically, mutations in the genes encoding both the cholesterol side-chain cleavage enzyme (P450scc) and the steroidogenic acute regulatory protein (StAR) have been associated with a rare, but serious condition called congenital lipoid adrenal hyperplasia (CLAH). (5) CLAH is characterized by decreased steroid levels including low pregnenolone, elevated adrenocorticotropic hormone (ACTH), and enlarged adrenal glands overloaded with cholesterol. (8)
Onset of CLAH generally occurs in neonates or infants. Low pregnenolone symptoms seen in individuals with CLAH include:
- Failure to thrive
- Salt loss (excessive salt excretion)
- Sudden infant death syndrome (SIDS) (8)
Pregnenolone health benefits have been seen in clinical trials of pregnenolone supplements in individuals with autism, (3) bipolar disorder, (1)(11) chronic pain, (10) and schizophrenia. (6)(7) Pregnenolone supplements may increase levels of other steroid hormones, including allopregnanolone, pregnenolone sulfate, progesterone, and DHEAS. (6)
1. Pregnenolone for autism
In a 12-week open-label study, adults with autism spectrum disorder (ASD) taking a pregnenolone supplement experienced improvements in social withdrawal, irritability, and sensory processing. (3)
2. Pregnenolone for bipolar disorder
A placebo-controlled trial examined the effects of 500 mg of pregnenolone per day for 12 weeks in adults with bipolar disorder. The study found that pregnenolone was associated with improved depressive symptoms and increased levels of neurosteroids compared to baseline. (1) A similar study assessed an eight-week intervention with a pregnenolone supplement or placebo in individuals with bipolar disorder or major depressive disorder and substance abuse history. Pregnenolone supplementation was associated with improvements in manic and depressive symptoms. (11)
3. Pregnenolone for chronic pain
A four-week randomized, double-blind, placebo-controlled trial investigated the effects of pregnenolone supplementation in veterans with chronic low back pain. Individuals who received the pregnenolone supplement reported a reduction in low back pain and improvement in work and activity. (10)
4. Pregnenolone for schizophrenia
Scientific evidence suggests that pregnenolone may help improve symptoms of schizophrenia. For example, one randomized controlled trial found that pregnenolone reduced negative symptoms such as emotional blunting. (6) Another randomized controlled trial in individuals with schizophrenia found that eight-week treatment with a pregnenolone supplement was associated with improved functional capacity scores. The dose was escalated from 100 mg to 500 mg over the eight-week duration. (7)
Pregnenolone side effects
Side effects that may be associated with a pregnenolone supplement include:
- Depressed mood
- Diarrhea (3)
- Feeling cold in the extremities
- Muscle pain or stiffness
- Restlessness (6)
- Tiredness (3)
Due to limited research, there is not enough scientific data to provide a recommended dose of pregnenolone. If you’re considering using pregnenolone for health purposes, avoid self-treating a condition as it may have serious consequences. Always consult an integrative healthcare provider before taking pregnenolone supplements.
The pregnenolone steal is a theory stating that high stress perception leads to an elevated use of pregnenolone for cortisol (stress hormone) production, reducing the total amount of pregnenolone available for the production of other steroid hormones, such as progesterone. (14) However, the pregnenolone steal theory has insufficient evidence and remains to be confirmed.
When considering this theory, keep in mind that the cells that synthesize steroids are only able to store very small quantities of the steroid hormone. A rapid response of steroid hormones, such as the adrenal secretion of cortisol during stress, requires rapidly producing new steroid hormones. (7) As mentioned above, steroid hormone pathways and the hormones produced will vary based on the specific location, steroidogenic cell, and several other factors. (2)(4)(15)
In the case of cortisol, it’s produced from pregnenolone in a layer of the adrenal cortex called the zona fasciculata. (2) The concept of an adrenal pregnenolone steal may be misguided as the different adrenal steroid hormones, such as aldosterone and DHEA, are synthesized in other layers of the adrenal cortex. (2)
The notion that one hormone, cortisol, “steals” pregnenolone from the synthesis of other steroids contradicts the fact that steroids are synthesized from pregnenolone in their respective locations, not from a general pool of available pregnenolone. As the pregnenolone steal is currently a debated topic, we encourage you to speak with an integrative healthcare practitioner if you have individual concerns.
The bottom line
Pregnenolone is the precursor to all steroid hormones in the body and exhibits biological activity, notably brain function modulation and neuroprotection. (9)(15) Although the concept of the pregnenolone steal in times of stress remains to be confirmed, stress management is always considered to be beneficial to overall health and wellness. Lastly, if you’re a patient interested in taking pregnenolone supplements or other dietary supplements, speak with your integrative healthcare provider.
- Brown, E. S., Park, J., Marx, C. E., Hynan, L. S., Gardner, C., Davila, D., Nakamura, A., Sunderajan, P., Lo, A., & Holmes, T. (2014). A randomized, double-blind, placebo-controlled trial of pregnenolone for bipolar depression. Neuropsychopharmacology, 39(12), 2867–2873.
- Dutt, M., Wehrle, C. J., & Jialal, I. (2020). Physiology, adrenal gland. In StatPearls (p. 1). StatPearls Publishing. https://www.ncbi.nlm.nih.gov/books/NBK537260/
- Fung, L. K., Libove, R. A., Phillips, J., Haddad, F., & Hardan, A. Y. (2014). Brief report: An open-label study of the neurosteroid pregnenolone in adults with autism spectrum disorder. Journal of Autism and Developmental Disorders, 44(11), 2971–2977.
- Hu, J., Zhang, Z., Shen, W.-J., & Azhar, S. (2010). Cellular cholesterol delivery, intracellular processing and utilization for biosynthesis of steroid hormones. Nutrition & Metabolism, 7(1), 47.
- Katsumata N. (2012). Genetic defects in pregnenolone synthesis. Pediatric Endocrinology Reviews, 10 Suppl 1, 98–109.
- Marx, C. E., Keefe, R. S., Buchanan, R. W., Hamer, R. M., Kilts, J. D., Bradford, D. W., Strauss, J. L., Naylor, J. C., Payne, V. M., Lieberman, J. A., Savitz, A. J., Leimone, L. A., Dunn, L., Porcu, P., Morrow, A. L., & Shampine, L. J. (2009). Proof-of-concept trial with the neurosteroid pregnenolone targeting cognitive and negative symptoms in schizophrenia. Neuropsychopharmacology, 34(8), 1885–1903.
- Marx, C. E., Lee, J., Subramaniam, M., Rapisarda, A., Bautista, D. C. T., Chan, E., Kilts, J. D., Buchanan, R. W., Wai, E. P., Verma, S., Sim, K., Hariram, J., Jacob, R., Keefe, R. S. E., & Chong, S. A. (2014). Proof-of-concept randomized controlled trial of pregnenolone in schizophrenia. Psychopharmacology, 231(17), 3647–3662.
- Miller, W. L., & Auchus, R. J. (2011). The molecular biology, biochemistry, and physiology of human steroidogenesis and its disorders. Endocrine Reviews, 32(1), 81–151.
- Murugan, S., Jakka, P., Namani, S., Mujumdar, V., & Radhakrishnan, G. (2019). The neurosteroid pregnenolone promotes degradation of key proteins in the innate immune signaling to suppress inflammation. Journal of Biological Chemistry, 294(12), 4596–4607.
- Naylor, J. C., Kilts, J. D., Shampine, L. J., Parke, G. J., Wagner, H. R., Szabo, S. T., Smith, K. D., Allen, T. B., Telford-Marx, E. G., Dunn, C. E., Cuffe, B. T., O’Loughlin, S. H., & Marx, C. E. (2020). Effect of pregnenolone vs placebo on self-reported chronic low back pain among US military veterans. JAMA Network Open, 3(3), e200287.
- Osuji, I. J., Vera-Bolaños, E., Carmody, T. J., & Brown, E. S. (2010). Pregnenolone for cognition and mood in dual diagnosis patients. Psychiatry Research, 178(2), 309–312.
- Prough, R. A., Clark, B. J., & Klinge, C. M. (2016). Novel mechanisms for DHEA action. Journal of Molecular Endocrinology, 56(3), R139–R155.
- Smith, C. C., Gibbs, T. T., & Farb, D. H. (2014). Pregnenolone sulfate as a modulator of synaptic plasticity. Psychopharmacology, 231(17), 3537–3556.
- Solano, M. E., & Arck, P. C. (2020). Steroids, pregnancy and fetal development. Frontiers in Immunology, 10, 3017.
- Vallée, M. (2016). Neurosteroids and potential therapeutics: Focus on pregnenolone. The Journal of Steroid Biochemistry and Molecular Biology, 160, 78–87.