Androstenedione: Biological Roles and Supplement Risks

Androstenedione is a steroid hormone that sits at a metabolic crossroads in the body, serving as the immediate precursor to both testosterone and estrone. Produced mainly in the adrenal glands and the gonads, it gained widespread public attention in the late 1990s as an over-the-counter supplement marketed to athletes, only to be pulled from shelves after research showed it failed to boost testosterone and carried real health risks. Understanding what androstenedione actually does, where it comes from, and why it matters clinically is more nuanced than the supplement headlines ever suggested.

Where Androstenedione Comes From

Your body makes androstenedione through a chain of chemical conversions that starts with cholesterol. The adrenal cortex and the gonads (ovaries or testes) are the primary production sites, and the hormone functions as a key intermediate in the pathway that ultimately yields the sex steroids your body relies on for development and reproduction.¹ In practical terms, androstenedione is made from dehydroepiandrosterone (DHEA) and then gets shuttled in one of two directions depending on which enzyme acts on it. The enzyme 17β-hydroxysteroid dehydrogenase converts it into testosterone, while the aromatase enzyme complex converts it into estrone, a form of estrogen.²

What makes this branching point so important is that both of those converting enzymes are expressed in many tissues throughout the body, including skeletal muscle and fat tissue.³ So even though the adrenals and gonads are the main factories, the final conversion of androstenedione into testosterone or estrogen can happen locally in tissues far from where it was originally produced. This decentralized conversion is a recurring theme in androstenedione biology and helps explain some of its less intuitive effects.

Daily Rhythms and Normal Fluctuation

Androstenedione levels in the blood are not static throughout the day. Like cortisol, androstenedione follows a diurnal rhythm, peaking around 8 a.m. just after waking and declining as the day progresses.⁴ This morning spike is significant enough that the mean concentration at the early morning peak is statistically higher than at all other time points measured during the day.⁵

This matters for anyone getting blood work done. A sample drawn at 7:30 in the morning will give a meaningfully different reading than one drawn at 3 in the afternoon. Clinicians who measure androstenedione for diagnostic purposes generally try to standardize timing, but patients are not always told this. If you have been asked to get your androgen levels checked, morning draws give the most reliable and comparable results.

Why Androstenedione Matters After Menopause

After the ovaries stop producing estrogen in meaningful quantities, the body does not become estrogen-free. Instead, it relies more heavily on a backup route: the conversion of androstenedione into estrone in peripheral tissues, especially fat. In postmenopausal women, the main factor determining how much estrone circulates in the blood is how much androstenedione is available in the first place.⁶

Body weight plays a significant role here. Research has found a strong correlation between body weight and the rate at which androstenedione gets converted to estrone, with heavier postmenopausal women converting at higher rates. Obesity and aging appear to work together to increase this conversion in tissues outside the ovaries, so the conversion rate is considerably greater in obese postmenopausal women than in comparably obese younger women.⁷ This has implications for endometrial health: excess estrone production through this pathway is considered one mechanism by which obesity increases the risk of endometrial cancer in postmenopausal women.

Androstenedione in Polycystic Ovary Syndrome

Polycystic ovary syndrome (PCOS) is one of the most common endocrine conditions in women of reproductive age, and androstenedione is one of the androgens that tends to run high in affected individuals. Women with PCOS have been found to excrete roughly twice the amount of testosterone and androstenedione metabolites in urine compared with women without the condition, even after adjusting for body weight.⁸

This excess production makes androstenedione a useful diagnostic marker. Research has shown that combining androstenedione measurements with testosterone and a free testosterone index improves diagnostic accuracy for PCOS, and that serum androstenedione is a meaningful biomarker for the hyperandrogenism that characterizes the condition.⁹ In clinical practice, androstenedione does not always get checked alongside testosterone, but there is a growing case that it should be, especially when testosterone levels are borderline and the clinical picture is ambiguous.

Monitoring Congenital Adrenal Hyperplasia

Congenital adrenal hyperplasia (CAH) is a group of inherited conditions where the adrenal glands overproduce certain hormones while underproducing others, typically cortisol. The most common form involves an enzyme deficiency that causes a buildup of 17-hydroxyprogesterone (17OHP), which then gets shunted into androstenedione production. Tracking androstenedione levels is one way clinicians gauge how well treatment is controlling the condition.

Recent modeling work has clarified the relationship between 17OHP and androstenedione in CAH patients. In healthy people, the two hormones stay at roughly similar absolute levels, but in CAH patients, 17OHP runs disproportionately high. When 17OHP stays below about 1,250 ng/dL, androstenedione falls into the normal range in the vast majority of patients. A high androstenedione level signals poor disease control, though the reverse is not necessarily true: a low androstenedione does not confirm that someone is being overtreated.¹⁰ Newer modified-release formulations of hydrocortisone that flatten the daily hormone profile allow clinicians to use a single morning blood sample of either 17OHP or androstenedione to assess control, which simplifies monitoring significantly.

Extremely High Levels and Androgen-Producing Tumors

While mildly elevated androstenedione points toward conditions like PCOS or poorly controlled CAH, dramatically elevated levels can signal something more serious. Certain ovarian and adrenal tumors produce androgens in very large quantities. In one reported case, a young woman with an androgen-producing ovarian tumor had an androstenedione level of 1,738 ng/dL, more than ten times the upper end of the normal female range, alongside a testosterone level of 485 ng/dL.¹¹ Adrenal tumors can similarly produce androstenedione and other steroid precursors, sometimes leading to estrogen overproduction and effects like breast tissue growth in men.¹²

Tumor-driven androstenedione elevation tends to be rapid in onset and dramatic in magnitude, which distinguishes it clinically from the more gradual and moderate elevations seen in PCOS or CAH. A sudden onset of severe acne, rapid body hair growth, deepening voice, or menstrual irregularity in a previously healthy person warrants urgent investigation.

The Supplement That Did Not Work

Androstenedione became a household name in 1998 when a bottle of it was spotted in a baseball player’s locker during a record-breaking home run season. The reasoning behind the supplement was straightforward: since androstenedione is one step away from testosterone in the body’s production chain, taking it orally should raise testosterone levels and therefore build muscle. The reasoning was wrong.

A systematic review and meta-analysis of randomized controlled trials found that androstenedione supplementation had no significant effect on serum testosterone levels. The pooled data showed an average change of less than 0.1 ng/mL, which is essentially zero.¹³ Individual trials confirmed the picture. One study in men aged 35 to 65 who were already doing high-intensity resistance training found that neither androstenedione nor a related compound, androstenediol, improved body composition or muscular strength compared with placebo.¹⁴ Another study in young healthy men found that androstenedione supplementation was unlikely to provide any anabolic benefit and, when combined with heavy resistance exercise, actually elevated estrogen.¹⁵

The body appears to shunt supplemental androstenedione preferentially toward estrogen rather than testosterone. This makes biochemical sense given that aromatase, the enzyme that converts androstenedione to estrone, is widely distributed in fat and other tissues. When you flood the system with extra substrate, aromatase gets fed first.

Real Risks of Supplementation

The failure to raise testosterone would have been merely disappointing if supplements had been harmless. They were not. The same meta-analysis that showed no testosterone increase found a significant rise in estradiol (a potent estrogen) and a significant drop in HDL cholesterol, the type associated with cardiovascular protection.¹⁶ One trial found that HDL dropped by about 12% within just two weeks of supplementation and stayed suppressed for the entire eight-week study period.¹⁷

There was also an odd diminishing-returns effect. In middle-aged men, the acute spike in blood androstenedione levels after a single dose was much larger at the start of supplementation than after four weeks of daily use. The integrated exposure dropped from roughly 108 nmol/L on day 0 to about 43 nmol/L after 28 days of supplementation, suggesting the body adapts by ramping up clearance or dialing down absorption.¹⁸ So not only did the supplement fail to do what people wanted, its own blood-level effect weakened with continued use, while the side effects persisted.

Regulation and the Ban

Based on the accumulating evidence that androstenedione did not deliver the promised benefits and carried measurable health risks, the FDA took action in the early 2000s, warning manufacturers and eventually classifying androstenedione as an anabolic steroid under federal law through the Anabolic Steroid Control Act of 2004. This moved it from the gray zone of dietary supplements into Schedule III controlled substance territory, making it illegal to sell without a prescription. The International Olympic Committee, the World Anti-Doping Agency (WADA), and major professional sports leagues had already banned it before the legislative action caught up.

The official method used to confirm androstenedione abuse in athletes is isotope ratio mass spectrometry (IRMS), which can distinguish synthetic androstenedione from the version the body makes naturally. One of its urinary metabolites, etiocholanolone, clears more slowly than the parent compound and may provide a more reliable detection window for confirming doping.¹⁹

Effects on Skin and Hair

The skin is not just a passive barrier. It is an active endocrine organ with the full set of enzymes needed to convert androstenedione and other precursors into potent androgens locally.²⁰ This means that even when blood levels of testosterone are within normal range, local androgen production in skin cells from circulating androstenedione can contribute to conditions like acne, oily skin, excess facial or body hair, and pattern hair loss. This local conversion pathway helps explain why some women with PCOS develop acne or hirsutism even when their serum testosterone is not dramatically elevated: androstenedione and DHEA may be doing the work at the tissue level.

For people dealing with androgen-sensitive skin conditions, understanding this pathway matters because treatments that target only circulating testosterone may miss part of the picture. Some dermatological approaches aim to block the local conversion enzymes in skin or block the androgen receptor itself, which addresses the problem closer to where it occurs.

Androstenedione and Fetal Development

Maternal androgen levels during pregnancy appear to have some influence on early fetal anatomy. A study of first-trimester pregnancies found that in female fetuses at 12 weeks, higher maternal androstenedione was associated with longer anogenital distance, a measurement used as a marker of prenatal androgen exposure. In male fetuses at the same gestational age, the relationship was reversed: higher maternal androstenedione was associated with shorter anogenital distance.²¹ The fact that the correlations ran in opposite directions for male and female fetuses suggests a more complex interaction with fetal sex hormones than a simple dose-response relationship. This area of research is still early, and the practical implications for prenatal care remain unclear, but it underscores the reach of androgens like androstenedione into developmental biology.

Androstenedione in the Plant Kingdom

One of the more surprising corners of androstenedione research is its detection in plants. Though most people associate steroid hormones exclusively with animal biology, androstenedione and related compounds have been identified in species including wheat, tobacco, and Tribulus terrestris, a plant long marketed as a testosterone booster in herbal supplement form.²² In wheat, cold temperatures appear to reduce androstenedione content, and concentrations vary widely across plant species. The foxglove plant (Digitalis purpurea), for instance, does not seem to contain it at all.

What these plant steroids actually do for the plants themselves remains an open question. There is no evidence that eating androstenedione-containing plants has any hormonal effect in humans; the concentrations are orders of magnitude below anything pharmacologically relevant. But the presence of these compounds across kingdoms of life suggests that the biochemical machinery for steroid synthesis is very ancient, predating the evolutionary split between plants and animals by hundreds of millions of years. It is one of those findings that quietly reframes how we think about hormones as a biological phenomenon rather than a human-specific concern.