Pregnenolone: What It Is and How It Works

Pregnenolone is called the "mother of all steroid hormones": it is precisely from it that the body begins the synthesis of progesterone, cortisol, aldosterone, DHEA, testosterone, and estrogens. In addition, pregnenolone and its sulfate act directly in the brain as neurosteroids. The editorial team explains how this molecule is formed, which mechanisms of its action have been established, and why biochemical "centrality" does not yet mean that a supplement with pregnenolone is capable of controlling the hormonal background.

What pregnenolone is

Pregnenolone (3β-hydroxypregn-5-en-20-one) is a steroid with 21 carbon atoms, formed directly from cholesterol. It occupies the first place in the chain of steroidogenesis: all classes of human steroid hormones — progestagens, glucocorticoids, mineralocorticoids, androgens, and estrogens — are derived from it.

Pregnenolone itself has weak classical hormonal activity: it practically does not bind to progesterone, androgen, or estrogen receptors in a physiologically significant way. Its main role in peripheral organs is to be a substrate for subsequent enzymes.

At the same time, in the nervous system pregnenolone and especially its sulfated derivative, pregnenolone sulfate, have their own effects. Nerve and glial cells are able to synthesize pregnenolone locally, so it is classified as a neurosteroid — a substance that is formed and acts in the brain independently of the endocrine glands.

Interest in pregnenolone arose as early as the 1940s, when it was studied as a possible remedy for the treatment of fatigue and rheumatoid arthritis. Later, attention was taken over by corticosteroids with a more pronounced action, and pregnenolone returned to science already as an object of neurobiology and psychiatry.

How the body synthesizes pregnenolone

The synthesis of pregnenolone takes place in the mitochondria of cells of the adrenal glands, gonads, placenta, and nervous system. The key enzyme is CYP11A1, also known as the cholesterol side-chain cleavage enzyme (P450scc). It cuts off a six-carbon fragment from cholesterol and converts it into pregnenolone.

The slowest, that is, rate-limiting step is not the enzyme reaction itself but the delivery of cholesterol from the outer membrane of the mitochondrion to the inner one. This role is performed by the StAR protein (steroidogenic acute regulatory protein). Its activity is regulated by pituitary hormones — ACTH in the adrenal glands and LH in the gonads.

This has practical significance: the body controls the rate of steroidogenesis at the level of cholesterol entry into the mitochondria, and not through the amount of ready pregnenolone. Therefore, adding pregnenolone from outside does not "switch" the central regulation of hormone synthesis.

Genetic defects of CYP11A1 or StAR lead to a severe congenital insufficiency of all steroid hormones — lipoid adrenal hyperplasia. This rare condition illustrates how fundamental the reaction of pregnenolone formation is for life.

Conversion pathways: from progesterone to DHEA

Two main pathways branch off from pregnenolone. The enzyme 3β-hydroxysteroid dehydrogenase (3β-HSD) converts it into progesterone, from which mineralocorticoids (aldosterone) and, through 17-hydroxylation, glucocorticoids (cortisol) are then formed.

The second pathway goes through the enzyme CYP17A1, which first hydroxylates pregnenolone into 17-hydroxypregnenolone and then cleaves off the side chain to form DHEA. In humans it is precisely this so-called Δ5 pathway that is the main source of adrenal androgens.

Which pathway predominates is determined by the set of enzymes in a particular tissue. The glomerulosa zone of the adrenal glands directs pregnenolone toward aldosterone, the fasciculata — toward cortisol, the reticularis — toward DHEA. In the gonads the synthesis of testosterone or estrogens predominates.

The idea popular on the internet of "pregnenolone steal," supposedly that stress "takes" pregnenolone for cortisol at the expense of sex hormones, is a simplification: synthesis takes place in different cells and is regulated by different signals, not from a single common "reservoir."

Pregnenolone as a neurosteroid

Pregnenolone sulfate modulates the operation of a number of receptors in the brain. It acts as a positive allosteric modulator of NMDA glutamate receptors and as a negative modulator of GABA-A receptors. In animal models this was linked to an effect on memory and learning.

On the other hand, pregnenolone through progesterone can be converted into allopregnanolone — a potent positive modulator of GABA-A receptors with a calming action. That is, depending on the direction of metabolism, the effects may be opposite in sign, which complicates predicting the result of taking the supplement.

Notable was the work of Vallée and colleagues in the journal Science (2014): in animals pregnenolone acted as an endogenous inhibitor of CB1 receptor signaling and weakened the effects of high doses of THC. This opened a new direction of research on cannabis dependence, but in humans such results are so far only being verified.

• NMDA receptors — enhancement of excitatory transmission (pregnenolone sulfate);
• GABA-A receptors — suppression (pregnenolone sulfate) or enhancement (allopregnanolone);
• CB1 receptors — negative modulation of the signal (data in animals);
• neuronal microtubule proteins — possible effect on the structure of nerve processes.

Pregnenolone as a supplement: what is known

In the USA pregnenolone is sold as a dietary supplement; in many other countries its status depends on national regulation. Clinical studies with humans mostly concern psychiatry: schizophrenia, bipolar depression, cognitive impairments. Their results are heterogeneous and require confirmation.

There is virtually no data that would show an effect of pregnenolone on the athletic performance, strength, or body composition of healthy people. This is important to consider, because marketing often presents it as a "natural hormonal booster."

Since pregnenolone can be converted into progesterone, DHEA, and further into sex hormones, it potentially carries the same risks for hormone-dependent tissues as other precursors. There is no reliable long-term safety data.

Pregnenolone is not directly named on the WADA Prohibited List, but the list contains general wording regarding substances with a similar chemical structure or biological action, and supplements may be contaminated. Athletes should consult their anti-doping organization.

Editorial conclusions

Pregnenolone is the first steroid formed from cholesterol and the starting point for the synthesis of all steroid hormones. The rate of this process is regulated at the level of cholesterol transport and pituitary hormones.

In the brain pregnenolone and its sulfate act as neurosteroids, affecting NMDA, GABA-A and, according to animal studies, CB1 receptors.

As a supplement, pregnenolone has been studied mainly in psychiatry; there is no convincing data on benefit for athletes, and long-term safety has not been established.

Our articles "The Benefits of Pregnenolone for Athletes: The Evidence Base," "Side Effects of Pregnenolone," and "Myths About DHEA" will help continue the topic.

References

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2. Vallée M, Vitiello S, Bellocchio L, et al. Pregnenolone can protect the brain from cannabis intoxication. Science. 2014;343(6166):94–98.
3. 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.
4. 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.
5. Baulieu EE, Robel P. Neurosteroids: a new brain function? J Steroid Biochem Mol Biol. 1990;37(3):395–403.
6. World Anti-Doping Agency. Prohibited List. Montreal: WADA; чинна редакція.