Chances are you know a bit about the DHEA (dehydroepiandrosterone) family of hormones. But you might not know that there are two powerful isomers of 5-DHEA, known as 1-DHEA and 4-DHEA, that can help you build muscle and increase strength in the gym without the harsh side effects of typical prohormones and anabolic androgenic steroids that gym-goers often resort to. This article will get you up to speed on what exactly 1-DHEA and 4-DHEA are, how they work, their benefits, and how to use them appropriately for optimal results.
About DHEA Supplements
5-dehydroepiandrosterone often referred to as simply “DHEA,” is a prohormone that your body naturally produces, primarily in the adrenal glands. While DHEA is a prohormone, it’s not a controlled substance like other harsh compounds of similar nature, such as methyltestosterone and methyltrienolone. In fact, oral DHEA can be quite beneficial without causing stress to the liver since it’s not methylated like many synthetic prohormones and anabolic androgenic steroids (AAS).
The human body mainly produces DHEA in the adrenal cortex, and this serves as a secondary pathway for testosterone – and consequently estrogens – to be synthesized. DHEA supplements are often used by aging individuals who want a safe, natural route to increase their endogenous testosterone levels. Moreover, DHEA has been shown to inhibits the actions of cortisol, which is the primary stress hormone in humans and it’s highly catabolic (breaks down tissues).
In active individuals who have low testosterone, the putative benefits of using a DHEA supplement may include:
- Increased androgen production in males and females
- Reduced cortisol levels
- Enhanced strength, power, and endurance
- Elevated metabolic rate
- Anti-inflammatory actions
- Improved recovery from training
- Boost in libido, erectile function, and sex drive
Unfortunately, oral DHEA isn’t well-absorbed since the gastrointestinal tract isn’t ideal for steroidogenesis. This has led to some companies offering transdermal DHEA supplements since the skin is a steroidogenic tissue that allows for DHEA to be absorbed and converted without the requisite first-pass metabolism that oral DHEA supplements go through.
It’s important not to confuse DHEA with 7-keto-DHEA and DHEA sulfate (DHEA-S) as they are not the same chemicals. 7-Keto DHEA is a metabolite of DHEA that does not convert into androgens or estrogens, but it may help support thyroid production and energy levels due to its unique metabolic fate.
DHEA-S is a 3β-sulfate ester of DHEA that has no hormonal activity in the body but serves a role as a neurotrophin and neurosteroid in the brain. Some physicians and supplement companies claim that DHEA-S can be converted back into DHEA in the liver, but this has been disproved by a recent meta-analysis.
What is a Prohormone? How do they differ from Prehormones?
We’ve used the term “prohormone” quite a bit to describe DHEA, but what exactly is a prohormone?
A prohormone is a hormone, generally with less biological activity, that serves as a precursor to another hormone with more biological activity. Prohormones are a distinct class of biological molecules that are essential for many lifeforms. In fact, cholesterol serves as the principal prohormone for every progestin, androgen, estrogen, glucocorticoid and mineralocorticoid in humans (and many other mammals). So yes, when you consume cholesterol, you’re technically eating sterols (modified steroids).
Prohormones are distinct from prehormones, which are substances that are biologically inert and need to be converted in peripheral tissues to an active hormone. Calcifediol, a metabolite of cholecalciferol (vitamin D3), is an example of a prehormone since it gets converted in the kidneys to calcitriol – the active form of vitamin D.
Why is DHEA a Prohormone?
As part of the steroidogenesis in humans – the pathway by which your body produces steroid hormones – DHEA acts as a precursor hormone (i.e., prohormone) for key androgenic hormones, notably androstenedione, androstenediol, and testosterone.
Both testosterone and androstenedione, play numerous roles in skeletal muscle tissue due to their anabolic nature, such as increasing muscle size, strength and enhancing muscle energy metabolism. The enzymes required for the conversion of DHEA to androstenedione or androstenediol and subsequently testosterone are 3ß-hydroxysteroid dehydrogenase (HSD) and 17ß-HSD. Small amounts of androstenedione are converted to estrone (estrogen) via the aromatase enzyme, whereas testosterone can then be converted to estradiol (the primary estrogen in humans) by the same enzyme, or to dihydrotestosterone (DHT) via the 5ɑ-reductase enzyme.
Importance of DHEA in Males and Females
DHEA is an androgenic anabolic steroid (AAS). For enhancing athletic performance and improving body composition, most research is focused on androgenic and/or anabolic steroids, as they are the most potent. Be careful to note that “androgenic” and “anabolic” are not synonymous terms though.
Androgenic steroids are hormones that promote the development of masculine characteristics (such as deepening of the voice and body hair growth), whereas anabolic steroids are simply hormones that stimulate the growth of certain tissues (such as skeletal muscle) in the body. DHEA, androstenediol, androstenedione, testosterone, and DHT are often referred to as anabolic androgenic steroids (AAS) since they have both anabolic and androgenic properties.
As you may have guessed, estrogenic hormones, like estradiol, are hormones that encourage the development of feminine qualities. Naturally, most males feel that having any estrogen in their system is inherently ruining their muscle gains, but that’s simply not the case.
In fact, having low estrogen can cause a myriad of debilitating health consequences regardless of which sex you are. Like with most hormones, it’s all about maintaining a proper balance and avoiding the extreme ends of the spectrum.
Testosterone is the second most anabolic steroid that the human body naturally produces, while DHT is about twice as strong (in terms of affinity for androgen receptors). However, DHT has strong virilizing effects and is well-known to cause side effects in high amounts, such as baldness, acne, and enlargement of the clitoris (in females). This is why testosterone tends to be the steroid of choice for performance enhancement.
In males, testosterone was once thought to be secreted only from the testis, but it has been demonstrated that testosterone is also synthesized in modest amounts from DHEA through steroidogenesis.
In females, production of androstenedione (the primary female androgen) and testosterone is mainly dependent upon conversion from DHEA secreted from the adrenal cortex. Hence, steroidogenesis plays important roles in maintaining muscular regulation and adaptation in both males and females.
What are 1-DHEA and 4-DHEA?
Now that you have a better understanding of what makes DHEA/5-DHEA so important from a biological standpoint, let’s dive into two related prohormones – 1-DHEA and 4-DHEA.
1-DHEA and 4-DHEA sometimes referred to as 1-androsterone and 4-androsterone, are positional isomers of DHEA – meaning they have identical chemical formulas as 5-DHEA but distinct molecular structures. The DHEA our bodies naturally produces has a dehydrogenated carbon at the fifth carbon in the steroid ring structure. Thus it’s technically called 5-DHEA.
In 1-DHEA and 4-DHEA the dehydrogenated carbon position (and thus, carbon-carbon double bond) in the steroid ring structure simply moves to carbon number one or carbon number four, respectively.
While 1-DHEA and 4-DHEA are not naturally occurring prohormones like 5-DHEA, they have been synthesized in laboratory settings to investigate their potential benefits.
Benefits of 1-DHEA
1-DHEA is a synthetic non-methylated prohormone that’s metabolized to 1-testosterone (dihydroboldenone) and 1-androstenedione, which are positional isomers of testosterone and androstenedione. 1-androstenedione is a prohormone of 1-testosterone, so most of the muscle building benefits of 1-DHEA derive from the conversion to dihydroboldenone, which is a powerful anabolic steroid that doesn’t aromatize to estrogen nor does it convert it to DHT. This means 1-DHEA can help pack on lean body mass with minimal risk of estrogenic side effects (gynecomastia, bloating, etc.) or androgenic side effects (hair loss, acne, etc.).
The problem with taking dihydroboldenone directly is that it’s not orally bioavailable and needs to be injected, making it impractical for many gym-goers. This is why 1-DHEA tends to be the better option since it’s readily converted to 1-testosterone/dihydroboldenone without stressing the liver or requiring injection.
Overall, the benefits of 1-DHEA may include:
- Enhanced muscle building and nitrogen retention
- Increased strength, power, and stamina in the gym
- Minimal risk of estrogenic and androgenic side effects
- Improved immune function
- Reduced recovery time from exercise
In addition, 1-DHEA is a legal prohormone supplement and not a controlled substance in the United States like most anabolic androgenic steroids, including 1-testosterone.
Benefits of 4-DHEA
4-DHEA is another synthetic non-methylated prohormone but with a distinct metabolic fate that makes it complementary to 1-DHEA. Recall that 1-DHEA does not convert to estrogen or DHT. While that is certainly a benefit, it also means you need to take something else to help balance the ratio of steroid hormones in the body.
This is precisely why 4-DHEA is a perfect adjunct to 1-DHEA. 4-DHEA is initially converted to 4-androstenediol and then testosterone, in a somewhat similar fashion as 5-DHEA. However, 4-DHEA is suggested to be better for muscle gains, and strength building than 5-DHEA since the conversion from 4-androstenediol to testosterone happens at a greater rate.
As such, 4-DHEA can be converted into small amounts of estrogen and DHT, thereby helping balance the effects of 1-DHEA.
In other words, the anabolic properties of 4-DHEA kick in quicker than they do from normal DHEA supplements.
Increasing testosterone levels is well-known to provide a myriad of benefits, including:
- Increased libido/sex drive
- Greater muscle gains and intensified pumps during training
- Enhanced erectile quality
- Improvement in energy levels and concentration
- A better sense of vitality, motivation, and confidence
- Having a more regular appetite
- Improved sleep quality
Using a prohormone like 4-DHEA and/or 1-DHEA is generally most beneficial for males over the age of 21 (if not 25 or even 30). Most males produce a normal/adequate amount of testosterone until their mid-late 20s, at which point levels typically start to decline.
Naturally, this has led to sharp increases in diagnoses of males over the age of 30 with low testosterone (clinically known as hypogonadism, andropause, and androgen deficiency).
Common signs and symptoms of low T include:
- Erectile dysfunction (impotence) and infertility
- Low libido
- Loss of muscle mass and strength
- Feeling lethargic and fatigued despite sleeping a lot
- Depression and anxiety
- Poor concentration (brain fog)
- Small or shrinking testes
- Loss of body and pubic hair
- Low red blood cell count (anemia)
- Brittle bones and malaise
- Unexpected body fat gain
- Sleep apnea (or other sleep disorders)
- Development of breast tissue (gynecomastia)
It’s imperative that you get appropriate blood work done rather than just assuming you have low T based on your symptoms, especially if you’re considering using 1-DHEA and 4-DHEA.
How to Cycle 1-DHEA and 4-DHEA
1-DHEA and 4-DHEA orally active prohormones that need to be used in a cyclical (i.e., on-off manner) to reduce the risk of side effects from hormonal imbalance. While these prohormones have undisputed benefits for lean mass building and increasing athletic performance, taking them for more extended periods can cause them to have significant side effects and reduce your quality of life.
In general, you should use 1-DHEA and 4-DHEA for 6-8 weeks at a time, followed by an equal amount of time off cycle (and proper post-cycle therapy).
During a prohormone cycle, the recommended dose of 1-DHEA is 100-150 mg per day, typically split into two doses – one in the morning and one in the afternoon/early evening.
If you’re a first-timer, start with 100 mg of 1-DHEA per day during your cycle. Experienced users can take 150 mg per day during a 1-DHEA cycle, but it’s not recommended to go above this mark.
The recommended 4-DHEA dose during a prohormone cycle is 200-400 mg per day, split into two equal doses; again, take one dose in the morning and another in the afternoon/evening.
If you’re taking both 1-DHEA and 4-DHEA during the same cycle, it’s recommended to cut the dose of each in half and assess your response before working up to higher doses since they have synergistic effects.
Is 1-DHEA Safe?
When used in a proper fashion, both 1-DHEA and 4-DHEA are safe prohormones. Nevertheless, you should listen to your body and be observant of any unusual changes or side effects that may be coming on.
Since 1-DHEA and 4-DHEA are non-methylated prohormones, they tend to be easier on the liver. However, you should use a liver support supplement while using these prohormones to make sure you keep your vital organs in-check throughout the cycle.
It’s also essential to follow up your 1-DHEA and 4-DHEA cycle with a post-cycle therapy supplement protocol to ensure your body bounces back to its intrinsic equilibrium. After all, there’s not much use in doing a 4-DHEA and/or 1-DHEA cycle if you can’t maintain your progress and muscle gains once it’s over.
All in all, start on the lower end of the dosing spectrum if you’re new to the world of prohormone supplements. You can always increase the dose after assessing your response to 1-DHEA/4-DHEA.
1. Ceresini, G., Morganti, S., Rebecchi, I., Freddi, M., Ceda, G. P., Banchini, A., … & Valenti, G. (2000). Evaluation of the circadian profiles of serum dehydroepiandrosterone (DHEA), cortisol, and cortisol/DHEA molar ratio after a single oral administration of DHEA in elderly subjects. Metabolism, 49(4), 548-551.
2. Thiboutot, D., Gilliland, K., Cong, Z., Jabara, S., McAllister, J. M., Sivarajah, A., & Clawson, G. (2003). Human skin is a steroidogenic tissue: steroidogenic enzymes and cofactors are expressed in epidermis, normal sebocytes, and an immortalized sebocyte cell line (SEB-1). Journal of Investigative Dermatology, 120(6), 905-914.
3. Arsenou, E. S., Fousteris, M. A., Koutsourea, A. I., & Nikolaropoulos, S. S. (2003). 7-keto-Δ5-steroids: Key-molecules owning particular biological and chemical interest. Mini reviews in medicinal chemistry, 3(6), 557-567.
4. Prough RA, Clark BJ, Klinge CM (2016). Novel mechanisms for DHEA action. J. Mol. Endocrinol. 56(3): R139–55.
5. Hammer F, Subtil S, Lux P, Maser-Gluth C, Stewart PM, Allolio B, Arlt W (2005). No evidence for hepatic conversion of dehydroepiandrosterone (DHEA) sulfate to DHEA: in vivo and in vitro studies. J. Clin. Endocrinol. Metab. 90(6): 3600–5.
6. Bhasin, S., Storer, T. W., Berman, N., Callegari, C., Clevenger, B., Phillips, J., … & Casaburi, R. (1996). The effects of supraphysiologic doses of testosterone on muscle size and strength in normal men. New England Journal of Medicine, 335(1), 1-7.
7. Young, Nick. R, et al. “Body composition and muscle strength in healthy men receiving testosterone enanthate for contraception.” The Journal of Clinical Endocrinology & Metabolism 77.4 (1993): 1028-1032
8. Miller, W. L., & Auchus, R. J. (2010). The molecular biology, biochemistry, and physiology of human steroidogenesis and its disorders. Endocrine reviews, 32(1), 81-151.
9. Bagatell, C. J., & Bremner, W. J. (1996). Androgens in men—uses and abuses. New England Journal of Medicine, 334(11), 707-715.
10. Askew, E. B., Gampe, R. T., Stanley, T. B., Faggart, J. L., & Wilson, E. M. (2007). Modulation of androgen receptor activation function 2 by testosterone and dihydrotestosterone. Journal of Biological Chemistry, 282(35), 25801-25816.
11. Ward, Margaret G.; Orr, James C.; Engel, Lewis L. (1965). A convenient synthesis of 3β-hydroxyandrost-4-en-17-one. Journal of Organic Chemistry, 30(5), 1421-3.
12. Friedel A, Geyer H, Kamber M, Laudenbach-Leschowsky U, Schänzer W, Thevis M, Vollmer G, Zierau O, Diel P (August 2006). 17beta-hydroxy-5alpha-androst-1-en-3-one (1-testosterone) is a potent androgen with anabolic properties. Toxicol. Lett. 165(2): 149–55.
13. Morley, J. E., Haren, M. T., Kim, M. J., & Kevorkian, R. (2005). Testosterone, aging and quality of life. Journal of endocrinological investigation, 28(3 Suppl), 76-80.
14. Harman, S. M., Metter, E. J., Tobin, J. D., Pearson, J., & Blackman, M. R. (2001). Longitudinal effects of aging on serum total and free testosterone levels in healthy men. The Journal of Clinical Endocrinology & Metabolism, 86(2), 724-731.