DHEA or Pregnenolone: What's the Difference

DHEA (dehydroepiandrosterone) and pregnenolone are often mentioned together as “hormones of youth” and “the mother of hormones.” Both are steroids synthesized in the body from cholesterol, and in some countries they are sold as supplements. However, in terms of biological role, evidence and regulatory status they differ substantially. The editorial team explains exactly where in the hormonal cascade each substance stands and what follows from this.

Place in the cascade of steroid hormones

All human steroid hormones begin with cholesterol. In the mitochondria of cells of the adrenal glands, the gonads and the brain, the enzyme CYP11A1 (P450scc) cleaves off the side chain of cholesterol, and pregnenolone is formed. This is the first and obligatory step of steroidogenesis, so pregnenolone is rightly called the starting point of the entire cascade.

Then the pathways diverge. Under the action of the enzyme 3β-hydroxysteroid dehydrogenase, pregnenolone is converted into progesterone, from which corticosteroids — cortisol and aldosterone — are formed. Via the enzyme CYP17A1, pregnenolone is converted into 17-hydroxypregnenolone, and then into DHEA.

DHEA stands several steps lower. It is a precursor of androstenedione, and therefore of testosterone and estrogens. Most of the DHEA in the blood circulates in the form of sulfate (DHEA-S), which has a longer half-life and serves as a kind of reserve.

Hence the key difference: pregnenolone can theoretically “go” into any branch — glucocorticoid, mineralocorticoid, androgenic or estrogenic — or turn into neurosteroids. DHEA is already directed mostly toward sex hormones. A detailed description of these pathways is given in the review by Miller and Auchus (2011).

Biological role and age-related changes

DHEA and DHEA-S are the most abundant steroids in human blood. They are produced mostly by the adrenal glands, and their level peaks in young adulthood and gradually declines with the years. It is precisely this age-related decline that became the basis for the hypothesis that replacement intake of DHEA can slow aging.

In women, DHEA is an important source of androgens, since a significant part of their testosterone is formed in peripheral tissues from adrenal precursors. In men the main source of testosterone is the testes, so the contribution of DHEA to the overall androgen background is relatively smaller.

Pregnenolone, besides its role as a precursor, is synthesized directly in the nervous system. The work of Baulieu and his school formed the concept of “neurosteroids” — steroids that form in the brain and affect the receptors of neurotransmitters, in particular GABA-A and NMDA. Pregnenolone and its sulfate were studied in the context of memory, mood and mental disorders.

Importantly, neither pregnenolone nor DHEA has its own “classic” receptors with as well-described an action as those of testosterone or cortisol. A significant part of their effects is realized through conversion into other hormones, and this conversion is highly individual.

What clinical studies have shown

The most serious test of the “DHEA as an anti-aging agent” hypothesis is the randomized study by Nair and colleagues (2006) in the New England Journal of Medicine. Elderly men and women received 50 mg of DHEA per day for two years, but no improvement in body composition, physical performance, insulin sensitivity or quality of life was found.

In the sports context, Brown and colleagues (1999) did not find that oral DHEA in young men raises the level of testosterone or enhances adaptation to strength training. This is consistent with physiology: in men, additional DHEA has little effect on testosterone, but can raise estrogens.

The medical indications for DHEA are narrow. In the study by Arlt and colleagues (1999), in women with adrenal insufficiency, replacement DHEA improved wellbeing and sexual function. The Endocrine Society guidelines on androgen therapy in women (Wierman et al., 2014), however, do not recommend routine use of DHEA due to the limited data. The FDA approved intravaginal prasterone (DHEA) for the treatment of dyspareunia associated with menopause.

For pregnenolone there are even fewer clinical data. The best-known works concern psychiatry, in particular the pilot study by Marx and colleagues (2009) in schizophrenia. There is no convincing evidence of a benefit of pregnenolone for healthy people, athletes or “hormonal balance.”

Risks, tests and status in sport

Since DHEA is converted into androgens and estrogens, its side effects are predictable: acne, oily skin, increased hair growth, in women — signs of hyperandrogenism, in men — a possible increase in estradiol. Theoretically, an effect on hormone-dependent tumors is discussed, so with such diseases in the history DHEA is contraindicated.

Pregnenolone can be converted in different directions, so its effects are even less predictable. Changes in mood, irritability, insomnia, as well as hormonal effects analogous to DHEA or progesterone, have been described. Data on long-term safety are insufficient.

• Any use of steroid precursors should begin with an examination: DHEA-S, sex hormones, cortisol — as prescribed by a doctor.
• Pregnancy, breastfeeding, hormone-dependent tumors, liver diseases — contraindications.
• The quality of supplements on the market is uneven: the actual steroid content may differ from the stated one.

For athletes the situation is unambiguous regarding DHEA: prasterone belongs to class S1 of the WADA Prohibited List and is prohibited at all times. Pregnenolone is not directly named in the List, but class S1 contains a formulation about substances with a similar chemical structure or biological effect, and the metabolism of pregnenolone can affect the steroid profile. The editorial team does not advise athletes who undergo doping control to experiment with either of these substances.

Editorial conclusions

Pregnenolone is the starting point of all steroidogenesis and a neurosteroid, DHEA is an intermediate link on the way to sex hormones. This determines their effects too: pregnenolone is less predictable, DHEA acts mostly through androgens and estrogens.

Large clinical studies did not confirm a “rejuvenating” effect of DHEA in elderly people, and in young men it does not raise testosterone and does not enhance adaptation to training. For pregnenolone there are even fewer quality data.

Both substances are hormones, not harmless supplements, and their use should be justified by tests and a doctor's decision.

Whom and in which situations these substances are considered in medicine we described in the article “DHEA vs Pregnenolone: Which to Choose and for Whom.” We also recommend our materials on the DHEA-S test and on the natural support of hormonal health through sleep and 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. Nair KS, Rizza RA, O'Brien P, et al. DHEA in elderly women and DHEA or testosterone in elderly men. N Engl J Med. 2006;355(16):1647–1659.
3. Brown GA, Vukovich MD, Sharp RL, et al. Effect of oral DHEA on serum testosterone and adaptations to resistance training in young men. J Appl Physiol. 1999;87(6):2274–2283.
4. Arlt W, Callies F, van Vlijmen JC, et al. Dehydroepiandrosterone replacement in women with adrenal insufficiency. N Engl J Med. 1999;341(14):1013–1020.
5. Wierman ME, Arlt W, Basson R, et al. Androgen therapy in women: a reappraisal: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2014;99(10):3489–3510.
6. 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.
7. Baulieu EE. Neurosteroids: a novel function of the brain. Psychoneuroendocrinology. 1998;23(8):963–987.
8. World Anti-Doping Agency. International Standard — Prohibited List. Montreal: WADA (чинна редакція).