Who should not take Pregnenolone

Pregnenolone is often advertised as a “mild” supplement for energy, memory and hormonal balance. But by its nature it is a steroid — the first link in the cascade from which sex hormones and corticosteroids are formed. That is why there are groups of people for whom it must not be taken, or may be taken only under strict medical supervision. The editorial team gathered these situations in a single article.

Why a “supplement” has contraindications

Pregnenolone is formed from cholesterol in the mitochondria of the adrenal glands, gonads and brain under the action of the enzyme CYP11A1. From there it can be converted into progesterone, 17-hydroxypregnenolone, DHEA, cortisol, aldosterone, and, a few steps later, into testosterone and estradiol. Where exactly the molecule goes depends on the tissue and the activity of the enzymes.

When a person takes pregnenolone from outside, they add substrate to this system. It is impossible to predict precisely which hormones it will be converted into in a particular body: in a man and a woman, in a young person and an elderly one, in a healthy person and a patient with an endocrine disorder the result may differ.

In addition, pregnenolone and its sulfate are themselves neurosteroids. They interact with GABA-A and NMDA receptors in the brain, and the metabolite allopregnanolone is a potent modulator of GABA-A. Thus the effect extends not only to hormones but also to the excitability of the nervous system.

It is precisely from these two mechanisms — hormonal and neuroactive — that the main contraindications follow. It is important that there are no large long-term safety studies in healthy people, so the list of restrictions is built on physiology and caution rather than on complete statistics.

Absolute restrictions

The first and most important group is people with hormone-dependent tumors or with a history of such tumors: cancer of the breast, ovaries, endometrium, prostate. Since pregnenolone can be converted into estrogens and androgens, it is theoretically capable of stimulating the growth of such tumors. There are no clinical data that would prove safety.

The second group is pregnant and breastfeeding women. During pregnancy steroid metabolism is radically restructured, and the placenta actively synthesizes progesterone from pregnenolone. Interfering with this system without medical indications is impermissible, and there are no data on fetal safety.

The third group is children and adolescents. During puberty the hormonal system is especially sensitive, and any intake of steroid precursors can affect growth, the closure of bone growth plates and the course of puberty.

The fourth group is people with known hypersensitivity to pregnenolone or the product's components, as well as those already receiving hormonal therapy prescribed by a doctor, without coordination with that doctor. Additional steroid substrate can distort the results of treatment and monitoring tests.

Conditions requiring medical supervision

Endocrine diseases — disorders of the adrenal glands, polycystic ovary syndrome, hypogonadism, thyroid dysfunction — require individual assessment. Pregnenolone can change the levels of DHEA, progesterone and androgens, which will complicate diagnosis and affect the course of the disease.

Neurological conditions, in particular epilepsy. In experimental models pregnenolone sulfate behaves as a negative modulator of GABA-A and a positive modulator of NMDA receptors, meaning it can increase neuronal excitability. At the same time, allopregnanolone acts in the opposite way. The resulting effect in a person with seizure susceptibility is difficult to predict.

Mental disorders. Pregnenolone has been studied as an add-on therapy in schizophrenia and bipolar depression, but under controlled conditions and against the background of the main treatment. Self-administration by people with such diagnoses may affect mood, sleep and anxiety unpredictably.

Liver diseases. The liver metabolizes steroids, so when it is damaged the body's ability to control their level decreases. Caution is also needed in cardiovascular diseases and a history of thrombosis, since steroid hormones affect blood clotting and water-salt balance.

• Diseases of the adrenal, thyroid and sex glands.
• Epilepsy and other conditions with seizure susceptibility.
• Mental disorders, especially bipolar disorder.
• Liver damage, thrombosis, pronounced cardiovascular pathology.

Interactions with medications

The most obvious group is hormonal medications: combined oral contraceptives, hormone replacement therapy, testosterone, progesterone, corticosteroids. An additional precursor can change the hormone balance and affect the efficacy or side effects of these medicines.

The second group is medications that act on the GABA system: benzodiazepines, sleeping pills, some antiepileptic drugs. Pregnenolone metabolites modulate the same receptors, so theoretically an increase in sedation or, conversely, a change in the seizure threshold is possible.

The third group is antipsychotics, antidepressants and mood stabilizers. There are practically no studies of interaction specifically with over-the-counter pregnenolone, so any combination should be discussed with a psychiatrist.

Finally, other supplements with hormonal activity — DHEA, so-called “testosterone boosters” based on plant extracts — create a cumulative effect. The editorial team considers combining several steroid precursors without monitoring tests an unjustified risk.

Athletes and doping control

For athletes subject to anti-doping control, the question is separate. DHEA (prasterone) is included in the anabolic agents section of the WADA Prohibited List, and pregnenolone is its immediate precursor. The list also contains wording about substances with a similar chemical structure or biological effect.

Even if a specific substance is not named directly, the athlete bears strict liability for everything found in their sample. A change in the steroid profile, in particular the ratios of metabolites, may draw the laboratory's attention.

A separate problem is supplement contamination. Products positioned as hormonal boosters more often than others contain undeclared anabolic substances. Therefore athletes should either completely give up pregnenolone or obtain a written consultation from the national anti-doping agency.

It should also be taken into account that the benefits of pregnenolone for athletic performance have not been demonstrated in controlled studies. The risk-benefit ratio for a professional athlete looks unfavorable.

Editorial conclusions

Pregnenolone is not a neutral supplement but a steroid precursor with hormonal and neuroactive action. Hence the real contraindications, which should not be ignored just because the product is sold without a prescription.

It should categorically not be taken in hormone-dependent tumors, during pregnancy and breastfeeding, by children and adolescents. Endocrine, neurological, mental diseases and liver diseases require a doctor's decision.

Any hormonal or psychotropic therapy is a reason to discuss pregnenolone with a doctor in advance. Athletes should remember the anti-doping risks and supplement contamination.

For a deeper understanding of the topic, we recommend our articles “Myths about Pregnenolone,” “Pregnenolone: dosage forms and which to choose” and “What to combine Pregnenolone with.”

References

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