Myths about Pregnenolone

A whole mythology has grown up around pregnenolone: it is called the “mother hormone,” an “anti-aging remedy” and a “natural testosterone booster.” Part of these notions grew out of real biochemistry, part out of oversimplifications and marketing. The editorial team checked the most common claims against scientific data.

Myth 1: The “mother hormone” restores all hormones

Pregnenolone does indeed stand at the start of steroidogenesis: progesterone, corticosteroids, DHEA, and further androgens and estrogens are synthesized from it. Hence the popular metaphor of the “mother hormone.” The problem arises when this metaphor leads to the conclusion: take the precursor and all the “descendants” will automatically level out.

In reality, the synthesis of each hormone is controlled not by the amount of pregnenolone in the blood but by the activity of specific enzymes in particular tissues, which are regulated by pituitary hormones — ACTH, LH, FSH. If the pituitary signal has not changed, the additional substrate will not necessarily be converted into the desired hormone.

Moreover, the main part of pregnenolone is formed inside the mitochondria of the producing cells and is immediately used on the spot. Pregnenolone that arrives from the blood enters these cells differently and is also metabolized in the liver and other tissues. As a result, it is difficult to predict the hormone profile after taking it.

So pregnenolone is not a “switch” that restores hormonal balance. It is only one of many links in a system with numerous feedback loops, and repairing it by adding raw material at the input is too simplistic an approach.

Myth 2: “Pregnenolone steal” due to stress

In alternative medicine the concept of “pregnenolone steal” is popular: supposedly, under chronic stress the body “diverts” all pregnenolone into the synthesis of cortisol, so that there is not enough raw material for sex hormones. Hence the advice — add pregnenolone to “replenish the supply.”

This scheme does not correspond to modern ideas about steroidogenesis. Cortisol synthesis occurs mainly in the zona fasciculata of the adrenal cortex, while sex hormones in men are produced in the testes and in women in the ovaries. These are different organs with their own cholesterol stores and their own regulation. There is no common “reservoir” of pregnenolone in the blood that they compete for.

The real reasons for a decline in sex hormones under chronic stress are different: suppression of the hypothalamic-pituitary-gonadal axis, insufficient energy availability, sleep disturbances. Pregnenolone eliminates none of these causes.

Endocrinologists criticize the “steal” concept as an oversimplification not supported by cellular biochemistry. The editorial team advises treating tests and protocols built on it with caution.

Myth 3: Pregnenolone raises testosterone and muscle

On sports forums pregnenolone is often counted among “testosterone boosters.” The logic is simple: if testosterone is synthesized from pregnenolone, then more pregnenolone means more testosterone. However, in men with normal pituitary and testicular function the rate of testosterone synthesis is limited by the LH signal, not by a lack of precursor.

The editorial team did not find controlled studies that would show an increase in muscle mass, strength or endurance in athletes taking pregnenolone. Clinical work on pregnenolone has focused on psychiatry and neurology, not on athletic performance.

Even for its “descendant” DHEA, which has been studied much better, the data on the effect on testosterone and muscle in young men are mostly negative. Part of DHEA in men is aromatized into estrogens rather than converted into testosterone. There is no reason to expect that a precursor one step higher will give a better result.

Instead, for athletes there is a real risk: a change in the steroid profile of the urine and problems with anti-doping control, since DHEA is on the WADA Prohibited List.

Myth 4: A proven remedy for memory and mood

This myth has the most serious scientific basis. Pregnenolone and its sulfate affect GABA-A and NMDA receptors, and in animals in some experiments they improved learning and memory. The work of Eugene Roberts back in the 1990s popularized the idea of pregnenolone as a “memory neurosteroid.”

However, transferring the results to humans has not succeeded unequivocally. In a pilot study by Marx et al. (2009) in schizophrenia, pregnenolone as an add-on to antipsychotics improved certain measures, and in a study by Brown et al. (2014) in bipolar depression a reduction in depressive symptoms was observed. These are small studies in specific groups of patients.

For healthy people there is no convincing evidence of improved memory or mood. A study by Sripada et al. (2013) showed that a single dose of pregnenolone raises the level of allopregnanolone and changes the activity of the brain's emotion-regulation networks, but this is a neuroimaging, not a clinical, result.

Conclusion: the hypothesis is promising, but for now pregnenolone cannot be considered a proven “nootropic” or antidepressant. For people with mental disorders, self-administration is all the more not recommended.

Myth 5: Natural means safe

Pregnenolone is indeed a molecule natural to the body. But testosterone, cortisol and insulin are also natural — and each of them, in the wrong dose or situation, can do harm. The origin of a molecule does not determine its safety.

Commercial pregnenolone is usually obtained semi-synthetically from plant steroids, for example diosgenin from yam. The claim that yam itself or its extract “contains pregnenolone” or is converted into it in the human body is another myth: humans do not have the enzymes for such a conversion.

There are no long-term safety studies in healthy people. Short-term clinical work generally reported acceptable tolerability, but it was carried out under medical supervision and with selection of participants.

So “naturalness” is a marketing argument, not a medical one. The decision to take it should rest on indications, contraindications and monitoring, as with any hormonally active substance.

• Natural origin does not guarantee safety.
• Yam is not converted into pregnenolone in the human body.
• There are no long-term safety data in healthy people.

Editorial conclusions

Most popular claims about pregnenolone rest on a simplistic reading of biochemistry: the precursor does not automatically “restore” hormones, and the concept of “pregnenolone steal” does not correspond to modern knowledge about steroidogenesis.

For athletic purposes pregnenolone has no evidence base, but it carries anti-doping risks. Its neuroactive properties, on the other hand, are a real direction of scientific research, but so far in clinical groups rather than in healthy people.

A critical attitude toward marketing and consultation with a doctor remain the best protection against disappointment and unwanted effects.

We also recommend our materials “Who should not take Pregnenolone,” “Pregnenolone: dosage forms and which to choose” and a review of DHEA in sports nutrition.

References

1. Miller WL, Auchus RJ. The molecular biology, biochemistry, and physiology of human steroidogenesis and its disorders. Endocr Rev. 2011;32(1):81–151.
2. Roberts E. Pregnenolone — from Selye to Alzheimer and a model of the pregnenolone sulfate binding site on the GABA_A receptor. Biochem Pharmacol. 1995;49(1):1–16.
3. Marx CE, Keefe RS, Buchanan RW, et al. Proof-of-concept trial with the neurosteroid pregnenolone targeting cognitive and negative symptoms in schizophrenia. Neuropsychopharmacology. 2009;34(8):1885–1903.
4. Brown ES, Park J, Marx CE, et al. A randomized, double-blind, placebo-controlled trial of pregnenolone for bipolar depression. Neuropsychopharmacology. 2014;39(12):2867–2873.
5. Sripada RK, Marx CE, King AP, et al. Allopregnanolone elevations following pregnenolone administration are associated with enhanced activation of emotion regulation neurocircuits. Biol Psychiatry. 2013;73(11):1045–1053.
6. World Anti-Doping Agency. Prohibited List. Montreal: WADA; current edition.