Pregnenolone : Precursor for steroid hormones ! Part A :

Pregnenolone is the main steroid produced in your body from cholesterol and is produced in the brain, gonads and adrenal glands, it is also the main precursor of other steroid hormones, including allopregnanolone.

It is converted directly into DHEA and/or progesterone. DHEA converts to testosterone and oestrogens; progesterone converts to oestrogens, cortisol, and aldosterone. It is this succession of conversions that makes human life possible. Without pregnenolone, there can be no human steroid hormone production.

Like many health-promoting hormones, levels of pregnenolone drop with age.

Dr Eugene Roberts, a pioneer in hormone research, believes that the age-related drop in pregnenolone is as dramatic as the drop in DHEA. At 75, our bodies typically make 60 percent less pregnenolone than at age 35. This is a point of great concern, considering pregnenolone’s numerous protective, health-promoting properties.

Pregnenolone seems to be a natural antidote to the dark side of cortisol which tend to manifest ever more with ageing and chronic stress.

Natural pregnenolone is present in young people of both sexes at a very high concentration, and one reason for the large amount produced in youth is that it is one of our basic defenses against the harmful side effects that an imbalance of even our natural hormones can produce. In excess, natural cortisone or estrogen can be dangerous, but when there is an abundance of pregnenolone, their side effects are prevented or minimized.

In a healthy young person or animal, taking even a large dose of pregnenolone has no hormone-like or drug-like action at all. It is unique in this way. But if the animal or person is under stress, and producing more cortisone than usual, taking pregnenolone causes the cortisone to come down to the normal level. After the age of 40 or 45, it seems that everyone lives in a state of continuous "stress," just as a normal part of aging. This coincides with the body's decreased ability to produce an abundance of pregnenolone.

Dr Ray Peat

Cortisol neutralizing Power of Pregnenolone: Small amounts of cortisol is essential for life and promote health. Due to chronic stress and ageing our adrenal glands often over produce cortisol.

The production of pregnenolone and its metabolites like DHEA, declines in aging, while the production of stress steroids like cortisol continue to rise.

The ratio of DHEA/Cortisol is one of the best predictors of disease and mortality, and declines with aging.

The HPA axis is a key stress response system. When stressed, the hypothalamus releases CRH, which stimulates the pituitary gland to release ACTH. ACTH then stimulates the adrenal glands to produce cortisol. Chronic stress, early-life stress, and other factors can disrupt the normal functioning of the HPA axis, leading to dysregulation. HPA axis dysfunction, particularly when leading to high cortisol levels, is a significant concern due to its association with a wide range of health problems, including mental health issues, metabolic disorders, and immune system dysfunction. Some of them include :

• Accelerated skin ageing and detoriation

• Impaired wound healing, poor skin quality and excessive scar tissue

• Damage to structure and function of mid brain specially memory

• Depression and lack of empathy for others. It can impair cognitive function, making it difficult to concentrate. It can also contribute to anxiety and irritability.

• Excess fluid retention and puffy flabby skin

• High cortisol can disrupt digestion and lead to digestive problems like indigestion and irritable bowel syndrome (IBS).

• Cortisol can suppress the immune system, increasing the risk of infections.

• Cortisol can contribute to acne by affecting the skin's natural oil production. Cortisol can also break down collagen, the protein that gives skin its strength, leading to thinner skin and easier bruising.

• High cortisol levels can break down muscle tissue, leading to muscle weakness and fatigue. It can lead to weight gain, especially in the abdomen and face, due to increased appetite and the breakdown of muscle tissue.

• Poor quality sleep

Research suggests pregnenolone might act on specific receptors within the hypothalamus, influencing the activity of CRH neurons. It could also affect the sensitivity of CRH neurons to other signals, reducing their overall activity.

Thus Pregnenolone INHIBITS the release of CRH, the hypothalamic precursor of cortisol, targeting stress at the most basic biological root cause.

Pregnenolone may help normalize the hypothalamic-pituitary-adrenal (HPA) axis, which is responsible for regulating cortisol production, potentially leading to a decrease in cortisol release.

"Some of the earliest investigations of pregnenolone’s many benefits showed it to be an energising, anti-stress biochemical."

During 1940 Dr Pincus and Hoagland gave 50 to 100 mg pregnenolone to various types of factory workers', pilots and students trained to use flight simulators . The factory workers noted improved production rates whilst taking pregnenolone. They felt less fatigued, better able to cope with their jobs and experienced an enhanced sense of happiness and well-being. Interestingly, workers in stressful job environments improved more with pregnenolone than those with less demanding tasks.

The flight simulation machine was designed to test hand-eye coordination, learning, memory and stamina. The subjects were to fly the plane correctly, avoiding obstacles and crashes. Half the subjects were airplane pilots; half were not. Tests conducted over several weeks showed that the ability of all subjects to fly the simulated airplane improved significantly after taking 50mg pregnenolone before each test run. The improvement was especially noticeable after the subjects had taken pregnenolone for at least two weeks. This suggests pregnenolone’s anti-stress benefits may be cumulative.

"The professional pilots also reported that they performed better in their real flying jobs and that they suffered less fatigue during their pregnenolone-supplementing period."

Pregnenolone help with addiction:

Supraphysiologic neuroactive steroid PREG doses reduces cocaine craving and may also improve cocaine use outcomes in treatment seeking individuals with CUD.

It decreases stress- and cocaine cue-provoked craving and anxiety and reduces stress-induced autonomic arousal in individuals with CUD.

Pregnenolone Reduces Provoked Craving and Cocaine Use in Men and Women with Cocaine Use Disorder: A Pilot Trial

Elcin Sakmar et al. medRxiv. 2025.

https://www.medrxiv.org/content/10.1101/2025.01.07.25320141v1.full

A study published in 2023 in the journal "Hormones and Behavior" found that pregnenolone decreased stress-induced craving and normalized HPA axis function in individuals with alcohol use disorder.

https://pubmed.ncbi.nlm.nih.gov/36445398/

Pregnenolone : The secret to young brain 🧠

Pregnenolone improves mental performance and memory. Reduced hypothalamic pregnenolone levels have been linked to cognitive deterioration.

It is thought that pregnenolone acts within the hypothalamus and hippocampus to support neuroplasticity.

https://www.sciencedirect.com/science/article/pii/S1550413121006896

Preliminary results of St. Louis School of Medicine researcher, Dr Sih, have shown definite memory enhancement with pregnenolone. Dr Sih gave 500mg pregnenolone or a placebo to men and women three hours before they were asked to perform standard memory tests.

"Pregnenolone resulted in improved memory in both men and women, improved spatial memory and perception in men, and improved verbal recall memory in women."

Women who suffer from menstrual migraines were found to have low levels of pregnenolone, opening up a treatment option with replacement. The researchers state: “Consequently, restoring low endogenous neurosteroid levels could exhibit therapeutic potential in migraine management.”

Pregnenolone anti inflammatory role :

https://www.jbc.org/article/S0021-9258(20)39029-3/fulltext

Pregnenolone has been shown to exhibit anti-inflammatory properties and can play a role in preventing neuroinflammation and enhancing neuroprotection. It can also normalize physiological, endocrine, and subjective alterations associated with alcohol use disorder, including heart rate and blood pressure.

CRH, independent of cortisol production, also contributes to stress, disease and aging, by initiating inflammation. Chronic inflammation can impair the metabolism of macronutrients and can lead to mitochondrial dysfunction, reducing the efficiency of aerobic energy production.

Pregnenolone dampens macrophage secretion of pro-inflammatory cytokines via inhibition of signal activation by promoting the degradation of toll-like receptors, TLR2/415, as well as blocking the binding of TLR4 to myeloid differentiation factor. Pregnenolone promotes the degradation of proteins involved in the TLR signaling pathway, particularly TIRAP and TLR2, in macrophages and microglia. This can suppress the production of pro-inflammatory cytokines like tumor necrosis factor α and interleukin-6.

Studies indicate that pregnenolone and its metabolites may have neuroprotective roles in various neuroinflammatory diseases, including MS and Alzheimer's disease. It may improve remyelination and neuroprotection in MS. Pregnenolone is an endocannabinoid, akin to CBD (cannabidiol) in its action, hence its application for mood and pain. It’s been said to have the potential to improve memory function. It may support myelinization, offering the prospect of slowing multiple sclerosis nerve deterioration.

Pregnenolone as a potential treatment for chronic low back pain :

Pregnenolone is believed to modulate pain signals in the brain and spinal cord, potentially reducing pain intensity and interfering with the perception of pain.

A randomized, double-blind, placebo-controlled trial in 94 veterans with chronic low back pain found that pregnenolone significantly reduced pain intensity ratings compared to placebo. Participants reported a 20% improvement in pain intensity ratings, while the placebo group saw only a 6% improvement.

https://pubmed.ncbi.nlm.nih.gov/32119096/

Dose of pregnenolone matters and is variable from condition to condition. In my subsequent article I will discuss about dosing , adverse effects and my experience with pregnenolone.

Disclaimer : this Article is not intended for medical advice This article is meant for information purposes only.