Androstenetrione: Benefits, Side Effects and Dosage

Androstenetrione (often known as 4-androstenetrione or “6-OXO”) is a compound related to androstenedione and androstenedione metabolites. It’s most commonly marketed as a dietary supplement with claims of boosting testosterone, enhancing athletic performance, and aiding muscle growth. However, scientific research paints a complex and sometimes contradictory picture of its true effects, benefits, and risks. This article provides an in-depth, evidence-based exploration of androstenetrione, synthesizing current research findings on its potential benefits, side effects, and optimal dosages.

Benefits of Androstenetrione

Androstenetrione, as a testosterone precursor and aromatase inhibitor, is promoted for its supposed ability to increase testosterone, improve muscle mass, and support athletic performance. But what does clinical research really show about its effectiveness and benefits?

Benefit	Evidence Level	Population Studied	Source(s)
Testosterone Increase	Moderate (dose-dependent)	Healthy men, hypogonadal men	4 8 10
Muscle Mass Gains	Weak (only in hypogonadal men, high doses)	Hypogonadal men	10
Strength Increase	Weak (only in hypogonadal men, high doses)	Hypogonadal men	10
Estrogen Reduction	High (with 4-hydroxyandrostenedione, not all derivatives)	Postmenopausal women (cancer patients)	9

Table 1: Key Reported Benefits of Androstenetrione and Related Compounds

Overview of Proposed Benefits

Testosterone Boosting Effects

One of the main advertised benefits of androstenetrione and related androgens is the ability to increase testosterone levels. Research shows this effect is highly dose-dependent and varies by individual and baseline hormonal status:

• At high daily doses (e.g., 300 mg or more), androstenedione can raise serum testosterone in some healthy men, but the effect is inconsistent and often accompanied by significant increases in estrogen levels as well 8.
• In hypogonadal men (those with low baseline testosterone), very high doses (1,500 mg/day) of androstenedione did produce significant increases in both free and total testosterone 10.
• For most healthy men, typical supplement doses (100–200 mg/day) are not effective at meaningfully increasing testosterone 4 7 8.

Muscle Mass and Strength

While some supplement marketers claim androstenetrione improves muscle size and strength, research in healthy, resistance-trained men does not support this:

• Several randomized controlled trials show that, compared to placebo, androstenedione and similar compounds do not significantly increase muscle mass or strength gains during resistance training 1 3 7.
• Only in hypogonadal men, and only at very high doses, have studies observed modest muscle mass and strength gains 10.
• Increases in lean body mass and muscle strength in healthy men are no greater than with placebo 3 7.

Estrogen Reduction (Aromatase Inhibition)

Some forms of androstenetrione (notably 4-hydroxyandrostenedione, also called formestane) act as aromatase inhibitors, reducing estrogen synthesis:

• In postmenopausal breast cancer patients, oral and intramuscular 4-hydroxyandrostenedione significantly reduces circulating estradiol and estrone, and is used clinically as a treatment 9.
• However, for most over-the-counter androstenetrione supplements, estrogen suppression is not reliably observed; in fact, many increase estrogen due to aromatization 1 4 7 8.

Who Might Benefit

• Hypogonadal men (with clinically low testosterone) may see increases in testosterone, muscle mass, and strength, but only with high doses and under medical supervision 10.
• Healthy, athletic men do not benefit in terms of muscle or performance enhancement, regardless of dose 1 3 7 8.
• Postmenopausal women with breast cancer benefit from specific prescription aromatase inhibitors derived from androstenetrione, but this is a medical use, not a supplement scenario 9.

Limitations of the Evidence

• Most studies are short-term (less than 12 weeks), so long-term benefits (if any) are unknown.
• Individual response varies greatly; some men have strong hormonal responses, others none 8.
• Many “benefits” reported in marketing are not supported by clinical research 6.

Side Effects of Androstenetrione

Like many hormone-affecting compounds, androstenetrione and related supplements are not without risks. Understanding the side effect profile is crucial for anyone considering its use.

Side Effect	Frequency/Severity	Population Observed	Source(s)
Increased estrogen	Common, dose-dependent	Healthy men, athletes	1 2 4 7 8
Lowered HDL ("good cholesterol")	Common, mild to moderate	Healthy men	1 4 7 10
Adverse lipid profile (CHD risk)	Common	Healthy men	1 4 7 10
No significant liver toxicity	Rare	Healthy men, athletes	3 7

Table 2: Key Side Effects and Health Risks of Androstenetrione

Hormonal Side Effects

Estrogen Elevation

• Contrary to popular belief, many androstenetrione and similar supplements actually increase estrogen levels (estradiol, estrone) in men, especially at higher doses 1 2 4 7 8 10.
• This can result in side effects such as gynecomastia (breast tissue growth), water retention, and mood changes.

Suppression of Endogenous Testosterone

• Supplementation can suppress the body’s own testosterone production, especially with prolonged use, as seen by decreased luteinizing hormone levels 1.
• This suppression can persist even after stopping the supplement, potentially leading to low testosterone symptoms.

Cardiometabolic Effects

Adverse Lipid Profile

• Multiple studies have shown that androstenedione and related compounds lower HDL cholesterol (the “good” cholesterol) by 6–10% and can worsen overall lipid ratios, increasing cardiovascular risk 1 4 7 10.
• These changes occur even in healthy, athletic men, and are not offset by exercise or diet 1.

Coronary Heart Disease Risk

• The observed lipid changes translate to a measurable increase in coronary heart disease risk, even over relatively short supplementation periods 1.

Liver and Other Organ Effects

• Clinical studies show little to no evidence of liver toxicity or significant changes in liver enzymes in healthy men during short-term use 3 7.
• No significant adverse effects on prostate-specific antigen (PSA) or liver function observed in most trials 3 4 7.

Other Potential Risks

• Because these compounds affect steroid hormone balance, theoretically, there could be risks related to mood, sexual function, and reproductive health, but human evidence is limited.
• The risk of unwanted side effects is higher in individuals with pre-existing health conditions or those taking other hormone-modulating drugs 6.

Dosage of Androstenetrione

Determining an effective and safe dosage for androstenetrione is challenging due to variability in individual response and lack of long-term studies. Here’s what research reveals about dosing.

Dosage (mg/day)	Effectiveness	Side Effect Risk Level	Source(s)
100	Minimal effect	Low to moderate	3 4 7 8
200	Inconsistent effect	Moderate	1 2 8
300	Testosterone ↑ (some), Estrogen ↑↑	High	8 10
1,500	Testosterone ↑↑, Muscle ↑ (hypogonadal men only)	Very high	10
250 (4-hydroxyandrostenedione)	Estrogen ↓ (clinical cancer use)	High	9

Table 3: Dosage and Observed Effects for Androstenetrione and Related Compounds

Typical Supplement Dosages

• Most commercial androstenetrione supplements recommend 100–300 mg per day, divided into one or more doses.
• Research shows that at 100 mg/day, there is little to no effect on testosterone in healthy men 3 4 7 8.
• At 200–300 mg/day, some men experience increased testosterone, but most see a more prominent rise in estrogen, with potential side effects 1 8.

High-Dose Use

• In clinical research, extremely high doses (up to 1,500 mg/day) have been used in hypogonadal men, producing significant increases in testosterone, muscle mass, and strength—but also marked side effects 10.
• Such dosages are far above what is recommended for over-the-counter use and should only be considered under medical supervision.

Dosing for Aromatase Inhibition (Cancer Use)

• The aromatase inhibitor 4-hydroxyandrostenedione (formestane) is used clinically at 250 mg/day (oral) or 250–500 mg every two weeks (intramuscular) in breast cancer patients to suppress estrogen 9.
• This is a prescription use and not applicable for general supplementation.

Safety Considerations

• Even at lower supplement doses, reductions in HDL cholesterol and adverse lipid changes are common 1 4 7 10.
• Because of the risk of hormonal imbalance and cardiovascular side effects, long-term use is not recommended without medical supervision.

Conclusion

Androstenetrione and its related compounds are often promoted as natural boosters for testosterone, muscle growth, and athletic performance. However, the evidence from clinical research tells a more nuanced—and cautionary—story.

Key takeaways:

• Testosterone-boosting effects are inconsistent: Only at high (sometimes clinically excessive) doses, and primarily in hypogonadal men, does androstenetrione significantly raise testosterone. In healthy men, effects are minimal or absent 4 8 10.
• Muscle and strength benefits are weak: Research does not support muscle mass or strength gains in healthy, resistance-trained adults 1 3 7.
• Estrogen levels often rise: Most users experience a significant increase in estrogen, not a reduction, leading to potential side effects 1 2 4 7 8.
• Cardiovascular risks are real: Adverse changes in lipid profiles and increased heart disease risk are well-documented, even at moderate doses 1 4 7 10.
• No significant liver toxicity: Short-term use does not appear to harm the liver in most healthy adults 3 7.
• Optimal dosage is unclear: Effective and safe dosages vary by individual, and high doses carry substantial risks 10.
• Medical supervision is advised: Use in special populations (e.g., hypogonadal men, breast cancer patients) should be under physician care only.

In summary:
While androstenetrione has some biological activity and limited clinical utility, the risks often outweigh the benefits for most users. Anyone considering its use should weigh the evidence carefully and consult a healthcare provider before starting supplementation.