Hormone Biomarkers: Pregnenolone

Optimal Takeaways

Pregnenolone is the precursor to several hormones, including estrogen, testosterone, and cortisol. It is produced from cholesterol and has anti-inflammatory, immune-regulating, and neuroprotective properties. An insufficiency may compromise cognitive and metabolic function.

Low levels may be seen in conditions such as schizophrenia, chronic alcohol intake, type 2 diabetes, and adrenal dysfunction, while high levels may occur with pregnenolone supplementation or enzyme deficiencies. The balance of sulfated pregnenolone in the brain may play a role in mood disorders like anxiety and depression, while impaired production of pregnenolone in the hypothalamus may contribute to cognitive dysfunction in obesity-related metabolic disorders.

Standard Range:

Male: 10 - 200 ng/dL  

Female: 10 - 230 ng/dL

The ODX Range:

Male: 125 - 200 ng/dL  

Female: 130 - 230 ng/dL

Low pregnenolone may be seen in schizophrenia, chronic alcohol intake (Tomaselli 2019), pre-diabetes, type 2 diabetes (Jiang 2019), impaired adrenal function, and below-optimal cholesterol levels. Low levels may also be associated with fatigue (Murugan 2019).

High levels of pregnenolone may be seen in acute alcohol intake (Tomaselli 2019), or with a deficiency of the enzymes that convert pregnenolone to downstream metabolites such as cortisol (Pagana 2021). Higher levels can occur with pregnenolone supplementation, though these higher levels may be considered therapeutic (Marx 2014, Naylor 2020).

Overview

Pregnenolone is a primary steroid hormone produced from cholesterol in the adrenal gland and in lymphocytes, gonads, brain, and central and peripheral nervous systems (Murugan 2019). It serves as a precursor to several other hormones, including cortisol, DHEA, aldosterone, progesterone, estrogen, and testosterone. The initial conversion of cholesterol to pregnenolone is the rate-limiting step for the production of all steroid hormones (Craig 2021).

Pregnenolone itself has significant anti-inflammatory and immune regulatory properties. It is considered neuroprotective and, along with its metabolites such as DHEA, has been found to support cognition, reduce depression, and enhance learning and memory. It may be protective against Alzheimer’s, multiple sclerosis, autism, schizophrenia, and cannabis intoxication. The pregnenolone-progesterone-allopregnanolone pathway may be significant in the pathophysiology of stress-related disorders, substance abuse, and the endocannabinoid system (Murugan 2019).

A randomized trial of adjunctive pregnenolone supplementation in male and female schizophrenic patients found that serum levels increased from a mean of 80 ng/dL to 246 ng/dL, along with significant improvements in functional capacity. Researchers note that females appeared to respond to treatment better than males (Marx 2014).

Research also suggests a role for neurosteroids such as pregnenolone in chronic pain. In one double-blind, placebo-controlled randomized trial of male and female military veterans with chronic back pain, pregnenolone supplementation reduced chronic back pain and pain intensity scores. Serum levels of pregnenolone significantly and progressively increased as dosing increased from a serum low of 58.5 ng/dL at baseline to a high of 278.6 ng/dL over a four-week period (Naylor 2020). Downstream metabolites of pregnenolone should also be monitored throughout supplementation.

Sulfation of pregnenolone in the brain may determine its effects on mood disorders such as anxiety and depression. In one controlled study of male subjects, serum pregnenolone was higher in those with anxiety and depression. However, sulfated pregnenolone levels were significantly lower in these disorders than in controls (Dušková 2015). Contemporary research suggests that impaired production of pregnenolone in the hypothalamus may contribute to cognitive dysfunction in obesity-related metabolic disorders (Bellocchio 2022).

References

Bellocchio, Luigi, and Giovanni Marsicano. “Forgetting in obesity: The pregnenolone link.” Cell metabolism vol. 34,2 (2022): 187-188. doi:10.1016/j.cmet.2022.01.006

Craig, Micah, et al. “Biochemistry, Cholesterol.” StatPearls, StatPearls Publishing, 18 August 2021.

Dušková, M et al. “The steroid metabolome in men with mood and anxiety disorders.” Physiological research vol. 64,Suppl 2 (2015): S275-82. doi:10.33549/physiolres.933067

Jiang, Jingjing et al. “The effect of progesterone and pregnenolone on diabetes status in Chinese rural population: a dose-response analysis from Henan Rural Cohort.” European journal of endocrinology vol. 181,6 (2019): 603-614. doi:10.1530/EJE-19-0352

Marx, Christine E et al. “Proof-of-concept randomized controlled trial of pregnenolone in schizophrenia.” Psychopharmacology vol. 231,17 (2014): 3647-62. doi:10.1007/s00213-014-3673-4

Murugan, Subathra et al. “The neurosteroid pregnenolone promotes degradation of key proteins in the innate immune signaling to suppress inflammation.” The Journal of biological chemistry vol. 294,12 (2019): 4596-4607. doi:10.1074/jbc.RA118.005543

Naylor, Jennifer C et al. “Effect of Pregnenolone vs Placebo on Self-reported Chronic Low Back Pain Among US Military Veterans: A Randomized Clinical Trial.” JAMA network open vol. 3,3 e200287. 2 Mar. 2020, doi:10.1001/jamanetworkopen.2020.0287

Pagana, Kathleen Deska, et al. Mosby's Diagnostic and Laboratory Test Reference. 15th ed., Mosby, 2021.

Tomaselli, Giovanni, and Monique Vallée. “Stress and drug abuse-related disorders: The promising therapeutic value of neurosteroids focus on pregnenolone-progesterone-allopregnanolone pathway.” Frontiers in neuroendocrinology vol. 55 (2019): 100789. doi:10.1016/j.yfrne.2019.100789