Adrenosterone (11-OXO): A Comprehensive Reference
1. Identity, Nomenclature, and Chemical Characterization
Adrenosterone, also known as Reichstein's substance G, as well as 11-ketoandrostenedione (11-KA4), 11-oxoandrostenedione (11-OXO), and androst-4-ene-3,11,17-trione, is a steroid hormone with an extremely weak androgenic effect, and an intermediate/prohormone of 11-ketotestosterone. The compound is further described chemically as a 3-oxo Δ4-steroid that is androst-4-ene carrying three oxo-substituents at positions 3, 11 and 17.
Adrenosterone carries the molecular formula C₁₉H₂₄O₃ and is registered under PubChem CID 223997. Its molecular weight is 300.39 g/mol. The CAS Registry Number for adrenosterone is 382-45-6. It is registered by the European Bioinformatics Institute under ChEBI accession CHEBI:2495, and is listed in the NCATS Inxight Drugs database of the U.S. National Institutes of Health.
The compound belongs to the class of C19 (19-carbon) steroids, also called androgens, and is specifically categorized among the 11-oxygenated C19 steroids — a structurally distinct subgroup characterized by the presence of an oxygen-containing substituent at the 11-position of the steroid nucleus. Its IUPAC name is (8S,9S,10R,13S,14S)-10,13-dimethyl-6,7,8,9,10,12,13,14,15,16-decahydro-1H-cyclopenta[a]phenanthrene-3,11,17(2H)-trione.
Common Synonyms and Trade Names
- Reichstein's substance G (historical)
- 11-Ketoandrostenedione (11-KA4)
- 11-Oxoandrostenedione (11-OXO)
- Androst-4-ene-3,11,17-trione
- 4-Androstene-3,11,17-trione
- 11-OXO (common supplement trade name)
2. Natural Sources and Occurrence
Adrenosterone is a steroid hormone isolated from the adrenal cortex. More specifically, 19-carbon (C19) steroids are synthesized in the adrenal cortex, including androgen precursors, predominantly dehydroepiandrosterone (DHEA), its sulfate (DHEAS), androstenedione, and 11β-hydroxyandrostenedione (11OHA4), and smaller quantities of bioactive androgens such as testosterone and 11β-hydroxytestosterone (11OHT). The kidney expresses 11β-hydroxysteroid dehydrogenase type 2 (HSD11B2), which converts the adrenal-derived 11OHA4 and 11OHT into 11-ketoandrostenedione (11KA4) and 11-ketotestosterone (11KT), respectively.
Adrenosterone occurs in trace amounts in humans as well as most mammals and in larger amounts in fish, where it is a precursor to the primary androgen, 11-ketotestosterone. In a study measuring circulating steroid hormones in healthy young men, the 11-oxy androgens were present in most participants, with 11-ketoandrostenedione detected at a mean level of 0.764 nmol/L in 77% of participants.
11-oxygenated C19 steroids originate almost exclusively from the adrenal cortex. The adrenal gland is thus both the primary biosynthetic source of adrenosterone and the primary driver of its downstream metabolites in the human body.
3. Historical Discovery
Adrenosterone was first isolated in 1936 from the adrenal cortex by Tadeus Reichstein at the Pharmaceutical Institute at the University of Basel. The Polish-Swiss biochemist Tadeus Reichstein shared the 1950 Nobel Prize for Physiology or Medicine with two American medical scientists, Philip S. Hench (1896–1965) and Edward C. Kendall (1886–1972), for discoveries concerning the structure and effects of hormones of the adrenal cortex.
In 1931, Reichstein completed his research on coffee and around 1934 began to work on the adrenal glands. By 1936, he had isolated and identified adrenosterone, and by 1937, he and his colleagues in Zurich had isolated and purified 9 crystalline substances, one of which he named corticosterone, which later proved effective in alleviating Addison disease, a result of failure of the adrenal glands. By 1942, Reichstein and colleagues had isolated 27 different adrenal corticosteroids in crystalline form.
Studies in the 1950s and 1960s revealed that both 11β-hydroxyandrostenedione (11OHA4) and 11-ketoandrostenedione (11KA4, often referred to as adrenosterone in older literature), which were known to be products of the human adrenal, had negligible androgenic activity. For several decades, this finding consigned adrenosterone to the status of an endocrine curiosity with no appreciable physiological role in humans.
Adrenosterone had no documented traditional or ethnobotanical use. It was not identified in herbal medicine or any pre-modern healing system because it is an endogenous mammalian steroid hormone rather than a plant-derived compound. Its emergence as a dietary supplement ingredient therefore has no traditional context — it is entirely a product of modern endocrinology and the sports supplement industry.
4. Emergence as a Dietary Supplement
Adrenosterone has been sold as a dietary supplement since 2007 as a fat loss and muscle gaining supplement. Adrenosterone has been promoted as a dietary supplement capable of reducing body fat and increasing muscle mass. Despite the seeming lack of interest in the role of 11-oxogenated C19 steroids, 11KA4 is widely promoted as a prohormone in dietary supplements (usually referred to as 11-oxoandrostenedione or 11-OXO), capable of reducing body fat and increasing muscle mass.
5. Key Constituents and Active Compounds
As a single steroidal molecule, adrenosterone is itself the active constituent when consumed as a supplement. No additional botanical matrix or cofactor compounds are naturally present in commercial preparations because adrenosterone is synthesized chemically rather than extracted from a plant source. The compound's proposed biological effects depend on its direct enzymatic activity and its metabolic conversion to downstream steroids.
Primary Compound
- Adrenosterone (androst-4-ene-3,11,17-trione) — the parent molecule, a steroid trione with keto groups at C-3, C-11, and C-17 positions.
Key Metabolites Relevant to Activity
- 11-Ketotestosterone (11-KT) — the primary downstream androgen generated from adrenosterone via AKR1C3.
- 11β-hydroxy-androsterone (OHA) and 11β-hydroxy-etiocholanolone (OHE) — the principal urinary metabolites detected after oral administration.
- 11-oxo-androsterone (KA) and 11-oxo-etiocholanolone (KE) — additional urinary metabolites.
The human metabolism of adrenosterone had already been addressed in the 1950s and 1960s, and the main urinary metabolites were identified as 11β-hydroxy-androsterone (OHA), 11β-hydroxy-etiocholanolone (OHE), 11-oxo-androsterone (KA), and 11-oxo-etiocholanolone (KE).
6. Mechanisms of Action
6.1 Inhibition of 11β-Hydroxysteroid Dehydrogenase Type 1 (11β-HSD1)
It is proposed that adrenosterone may function as an inhibitor of the 11β-hydroxysteroid dehydrogenase type 1 enzyme (11β-HSD1), which is primarily responsible for reactivation of cortisol from cortisone. Adrenosterone is thought to be a competitive selective 11β-HSD1 inhibitor, which is responsible for activation of cortisol from cortisone.
Understanding the significance of this proposed mechanism requires understanding the enzyme itself. 11β-HSD1 catalyses intracellular regeneration of active glucocorticoids (cortisol, corticosterone) from inert 11-keto forms in liver, adipose, and brain, amplifying local action. Chronically elevated glucocorticoid levels cause obesity, diabetes, heart disease, mood disorders, and memory impairments. Obese humans and rodents show increased 11β-HSD1 in adipose tissue.
11β-HSD1 interconverts inactive cortisone and active cortisol. Although bidirectional, in vivo it is believed to function as a reductase generating active glucocorticoid at a prereceptor level. 11β-HSD1, which is highly expressed in liver and adipose tissue, converts cortisone to cortisol, leading to higher local concentration of cortisol. Inhibition of 11β-HSD1 prevents or decreases the tissue-specific amplification of glucocorticoid action, thus imparting potential beneficial effects on blood pressure and glucose- and lipid-metabolism.
Adrenosterone has mild androgenic activity and moderate inhibition of 11β-HSD1 (IC₅₀ ~1–2 μM), reducing cortisol levels by blocking its regeneration from cortisone. This in vitro IC₅₀ value indicates the concentration at which adrenosterone inhibits 50% of 11β-HSD1 activity in cell-based assays.
6.2 Prohormone Conversion to 11-Ketotestosterone
Adrenosterone has been shown to be converted into 11-ketotestosterone in humans, which contributes to adrenosterone's androgenic effects. This conversion is mediated by the enzyme AKR1C3. 11-OHA4 is converted to 11-ketoandrostenedione (11-KA4) by HSD11B2 in peripheral tissues, and aldo-keto reductase family 1 member C3 (AKR1C3), present in various tissues including the adrenal gland, catalyzes the conversion of 11-KA4 to 11-KT.
The enzymatic efficiency of AKR1C3 is 8- and 24-fold greater for 11-ketoandrostenedione than for the classic substrates androstenedione and 5α-androstanedione, respectively. This preferential enzymatic efficiency has important implications for the potency of adrenosterone as a prohormone compared with classic androgens.
AKR1C3 has an approximately 8-fold higher catalytic efficiency for the generation of 11-ketotestosterone (11KT) from its precursor 11-ketoandrostenedione (11KA4) than for the generation of testosterone from androstenedione. 11KT activates the androgen receptor with potency and efficacy similar to testosterone and is the predominant circulating androgen in androgen excess conditions including congenital adrenal hyperplasia, polycystic ovary syndrome, and premature adrenarche.
6.3 Direct Androgenic Activity
Adrenosterone is a steroid hormone with an extremely weak androgenic effect. It serves as a prohormone to 11-ketotestosterone, exhibiting weak androgen receptor binding while influencing metabolic and endocrine pathways. The primary androgenic action attributed to adrenosterone therefore derives mainly from its peripheral conversion to 11-KT, not from direct androgen receptor binding by the parent compound.
6.4 Interplay with 11β-HSD1 and AKR1C3 in Adipose Tissue
Aldo-keto reductase 1C3 (AKR1C3) is a key enzyme in the activation of both classic and 11-oxygenated androgens. In adipose tissue, AKR1C3 is co-expressed with 11β-hydroxysteroid dehydrogenase type 1 (HSD11B1), which catalyzes not only the local activation of glucocorticoids but also the inactivation of 11-oxygenated androgens, and thus has the potential to counteract AKR1C3. Using a combination of in vitro assays and in silico modeling, HSD11B1 has been shown to attenuate the biosynthesis of the potent 11-oxygenated androgen 11-ketotestosterone by AKR1C3. Employing ex vivo incubations of human female adipose tissue samples, inhibition of HSD11B1 results in increased peripheral biosynthesis of 11KT.
This bidirectional relationship means that when adrenosterone inhibits 11β-HSD1, it may simultaneously enhance the AKR1C3-driven conversion toward 11-KT, creating a dual mechanism: reduced local cortisol regeneration and increased local androgenic steroid production.
7. Scientific Evidence by Area of Use
7.1 Body Composition (Fat Loss and Muscle Mass)
The claim that adrenosterone can reduce body fat and increase muscle mass is the primary rationale for its use as a dietary supplement. The scientific evidence underpinning this claim is, however, extremely weak.
To the knowledge of researchers reviewing this field, evidence for the effect of 11KA4 on muscle mass is taken from studies conducted in fish (Lone and Matty, 1982). No controlled human clinical trials establishing a direct effect of oral adrenosterone supplementation on body composition have been identified in the peer-reviewed literature.
The proposed mechanism linking adrenosterone to fat loss — reduction in local cortisol through 11β-HSD1 inhibition — is biologically plausible. Transgenic mice overexpressing 11β-HSD1 selectively in adipose tissue faithfully recapitulate metabolic syndrome, and conversely, 11β-HSD1 knockout mice have a 'cardioprotective' phenotype whose effects are also seen with 11β-HSD1 inhibitors in rodents. However, any major metabolic effects of 11β-HSD1 inhibition in humans are, as yet, unreported.
In summary, evidence for body composition effects of adrenosterone in humans is based on: (1) in vitro enzyme inhibition data; (2) animal studies; and (3) extrapolations from the broader 11β-HSD1 inhibition literature. No dedicated human randomized controlled trials for adrenosterone as a fat loss or muscle-gaining supplement have been published in peer-reviewed journals as of the current literature.
7.2 Cortisol Modulation
The role of 11β-HSD1 inhibitors in modulating local tissue cortisol concentrations is an active area of pharmaceutical research. Therapeutic inhibition of 11β-HSD1 reductase activity in patients with obesity and the metabolic syndrome, as well as in glaucoma and osteoporosis, remains an exciting prospect. Several pharmaceutical 11β-HSD1 inhibitors have entered clinical trials for metabolic syndrome, though none have yet achieved regulatory approval.
Reducing glucocorticoid exposure through 11β-HSD1 inhibition showed therapeutic promise across several cardiometabolic outcomes, including lowering weight, blood glucose, blood pressure, and cholesterol; however, variable efficacy and inconsistent effect sizes have delayed clinical progress.
Whether adrenosterone, at typical supplement doses and with its reported limited oral bioavailability, can achieve sufficient plasma concentrations to meaningfully inhibit 11β-HSD1 in vivo in humans has not been established in published clinical studies. The in vitro IC₅₀ of ~1–2 μM represents a pharmacological benchmark, but translation to meaningful in vivo cortisol modulation from oral supplementation remains unverified in peer-reviewed human data.
7.3 11-Oxygenated Androgens in Disease States (Research Context)
While not directly constituting evidence for adrenosterone supplementation, peer-reviewed research into the 11-oxygenated androgen class — of which adrenosterone is a member — has produced substantial insights of clinical importance in endocrinology. These findings contextualize adrenosterone's endogenous role.
Concentrations of 11-oxyandrogens are elevated in several disorders of androgen excess, including premature adrenarche, congenital adrenal hyperplasia, and polycystic ovary syndrome, and they can contribute to the progression of castration-resistant prostate cancer.
For many decades, the prevailing paradigm in endocrinology was that testosterone and 5α-dihydrotestosterone are the only potent androgens in the context of human physiology. The more recent identification of adrenal-derived 11-oxygenated androgens and particularly 11-ketotestosterone have challenged these established norms, prompting a reevaluation of the androgen pool, particularly in women.
Since being recognized as bone fide androgens in humans, numerous studies have focused their attention on understanding the role of 11-oxygenated androgens in human health and disease and have implicated them as role players in conditions such as castration-resistant prostate cancer, congenital adrenal hyperplasia, polycystic ovary syndrome, Cushing's syndrome, and premature adrenarche.
Recent studies have suggested that 11-oxygenated C19 steroids, specifically 11-ketotestosterone, may be a good marker for hyperandrogenism in PCOS. Research in this area involves adrenosterone's downstream metabolite (11-KT) as a biomarker; adrenosterone itself is not being investigated as a therapeutic in PCOS or CAH.
11-oxygenated androgens are currently being discussed as biomarkers to improve diagnosis and therapy of diseases that are associated with disturbed androgen production, including CAH, PCOS, premature adrenarche, metabolic syndrome, or obesity.
7.4 Castration-Resistant Prostate Cancer (CRPC) Research
The progression of castration-resistant prostate cancer is driven by the intratumoral conversion of adrenal androgen precursors to potent androgens. The expression of aldo-keto reductase 1C3 (AKR1C3), which catalyses the reduction of weak androgens to more potent androgens, is significantly increased in CRPC tumours. 11-oxygenated androgen precursors of adrenal origin are the preferred substrate for AKR1C3.
This body of research — largely in vitro and animal-based — highlights that adrenosterone's conversion to 11-KT via AKR1C3 could theoretically be relevant to prostate cancer progression. However, adrenosterone supplementation in the context of CRPC has not been a therapeutic focus; rather, this pathway is being studied to identify targets for inhibition in cancer treatment.
7.5 Doping Control Research (Administration Studies)
The most systematic human pharmacokinetic data available for adrenosterone come from anti-doping research rather than clinical efficacy studies.
The urinary metabolism of adrenosterone was investigated after a single oral administration in two male subjects, by gas chromatography-mass spectrometry (GC-MS) and gas chromatography-combustion-isotope ratio mass spectrometry (GC-C-IRMS). Excretion studies of the dietary supplement adrenosterone (75 mg oral) were conducted with six male individuals.
The administration of 11OXO may be detected by monitoring the urinary concentrations of its main human metabolites 11β-hydroxy-androsterone and 11β-hydroxy-etiocholanolone. As 11-KT is also a metabolite of 11OXO, protocols for KT detection have been tested to elucidate their potential to detect the administration of 11OXO after a single oral dose of 100 mg.
These human administration studies, performed with doses of 75–100 mg, provide the most directly verified human pharmacokinetic evidence for adrenosterone — but they were designed for doping detection purposes and assessed urinary metabolites rather than efficacy outcomes.
8. Body Systems and Health Areas Associated with Adrenosterone
8.1 Endocrine System — Adrenal Cortex
Adrenosterone is an endogenous product of the adrenal cortex and participates in the broader cascade of adrenal androgen synthesis. Target tissues such as adipose tissue, prostate, hair follicles, and genital skin are able to convert the adrenal androgen precursors androstenedione, 11OHA4, and 11KA4 into bioactive androgens via 17β-hydroxysteroid dehydrogenase (HSD17B) enzymes and steroid 5α-reductases (SRD5A).
8.2 Glucocorticoid System — Cortisol Regulation
Through its proposed inhibition of 11β-HSD1, adrenosterone is linked to tissue-level cortisol regulation. 11β-HSD-1 is widely expressed and particularly high expression levels are found in liver, brain, lung, adipose tissue, and vascular smooth muscle cells. Inhibition of this enzyme in these tissues is the proposed mechanism by which adrenosterone may affect cortisol-mediated processes in the metabolic and cardiovascular systems.
8.3 Metabolic System
The connection between 11β-HSD1 and metabolic health is well-established. Obese humans and rodents show increased 11β-HSD1 in adipose tissue, and therapeutic inhibition of 11β-HSD1 reductase activity in patients with obesity and the metabolic syndrome remains a prospect of interest. Adrenosterone's proposed anti-glucocorticoid activity in adipose tissue has been cited as the rationale for its use as a body composition supplement, though human clinical data confirming these metabolic effects remain absent.
8.4 Immune System
Human peripheral blood mononuclear cells (PBMCs) preferentially activate 11-ketotestosterone rather than testosterone when incubated with precursors of both the classic and the adrenal-derived 11-oxygenated androgen biosynthesis pathways. This activity is catalyzed by the enzyme AKR1C3, which primarily resides in natural killer cells, major contributors to the anti-viral immune defense. This potentially links intracrine 11-oxygenated androgen generation to the previously observed decreased NK cell cytotoxicity and increased infection risk in primary adrenal insufficiency.
8.5 Reproductive System and Androgen-Dependent Tissues
Adrenal 19-carbon steroids, including adrenosterone and its metabolites, become relevant starting with adrenarche in children of both sexes and remain so throughout life in females. Pathologically, adrenal androgen production is particularly important in several disorders of androgen excess, such as congenital adrenal hyperplasia (CAH) and polycystic ovary syndrome (PCOS); in androgen-dependent tumors, primarily castration-resistant prostate cancer; and rarely, in androgen-producing adrenal tumors.
9. Dosage Forms and Reported Dosages
Adrenosterone has been sold as a dietary supplement since 2007. Preparations have included oral capsules and tablets, as well as sublingual formulations.
Common dosages cited for adrenosterone as an anabolic supplement are 300 mg to 900 mg daily.
In the context of human doping research and anti-doping studies, the doses used for urinary metabolism characterization were:
- 75 mg administered orally in excretion studies conducted with six male individuals.
- 100 mg administered as a single oral dose in metabolite detection studies.
With a short half-life (~1–2 hours) and limited oral bioavailability, adrenosterone has been explored for its potential in cortisol modulation and body composition management. The limited oral bioavailability has led some commercial preparations to explore sublingual or buccal delivery routes, though no peer-reviewed studies on the pharmacokinetics of these alternative delivery forms have been identified.
10. Safety Considerations and Regulatory Status
10.1 WADA Prohibition and Anti-Doping Status
In the context of doping controls, 11OXO belongs to the compounds forbidden for athletes at all times by the World Anti-Doping Agency (WADA), and it is explicitly mentioned on WADA's Prohibited List. Adrenosterone is prohibited at all times for competing athletes and is listed on WADA's Prohibited List as an anabolic androgenic steroid.
10.2 Detection in Doping Controls
Within research projects, the approach to detecting its misuse was reinvestigated using a retrospective data analysis of more than 100,000 routine doping control samples analyzed in the Cologne doping control laboratory in the years 2014 to 2018. While samples showing elevated urinary concentrations of OHA beyond the established threshold of 10,000 ng/mL were rare, the number of samples showing an elevated OHA/OHE ratio was surprisingly high.
In parallel to the approach for the detection of testosterone misuse, carbon isotope ratios (CIRs) can be employed to identify the source of urinary steroids, i.e., endogenous production or illicit administration. This method assumes that exogenous steroids usually show depleted CIRs compared to endogenous steroids.
10.3 Androgenic Side Effects
As a compound that is converted in vivo to 11-ketotestosterone — an androgen with potency comparable to testosterone — adrenosterone carries the general class risks associated with exogenous androgens, including potential for androgenic side effects. 11-KT and 11-KDHT are as potent as testosterone and DHT in binding and activating the androgen receptor. No dedicated long-term human safety studies for oral adrenosterone supplementation have been published in the peer-reviewed literature. The androgenic potency of its primary metabolite means that androgenic adverse effects (including virilization in women, effects on the hypothalamic-pituitary-gonadal axis, acne, and changes in lipid profiles) cannot be excluded, though these have not been quantified in controlled human trials.
10.4 Absence of Clinical Safety Data
No randomized controlled trials, phase I clinical safety studies, or systematic reviews of adverse events specifically for oral adrenosterone supplementation have been identified in the peer-reviewed literature. The human data available are limited to small-sample (n = 2–6) urinary excretion studies conducted for anti-doping purposes, which did not include formal safety monitoring.
10.5 Regulatory Status in the United States
Adrenosterone is an anabolic steroid and falls under the class of substances covered by the Anabolic Steroid Control Act in the United States. The inclusion of anabolic steroids — including prohormones such as adrenosterone — in dietary supplement products is not permitted under U.S. federal law. The compound is not approved by the U.S. Food and Drug Administration (FDA) as a drug or as a generally recognized as safe (GRAS) substance.
10.6 Potential for Elevated Androgenic States
An increased abundance of 11-oxygenated C19 steroids including 11-ketotestosterone, 11-ketoandrostenedione, 11β-hydroxytestosterone, and 11β-hydroxyandrostenedione have been noted in several disorders of androgen excess, including premature adrenarche and congenital adrenal hyperplasia, as well as in states of high lipodystrophy and insulin resistance. This underscores that pharmacological elevation of 11-oxygenated androgens via exogenous adrenosterone supplementation could, in principle, contribute to androgenic excess in susceptible individuals.
10.7 Considerations for CRPC Risk
The expression of AKR1C3, which catalyses the reduction of weak androgens to more potent androgens, is significantly increased in CRPC tumours. Given that adrenosterone is a preferred substrate for AKR1C3, its supplementation in men with undiagnosed prostate cancer or genetic predisposition to CRPC represents a theoretical concern. This risk has not been quantified in human studies.
11. Summary of Evidence Quality
The table below summarizes the overall strength of evidence for adrenosterone's proposed uses and mechanisms:
- Endogenous production and metabolism in humans: Well-established — human studies document its adrenal origin, peripheral metabolism, and urinary metabolite profile.
- Conversion to 11-ketotestosterone via AKR1C3: Established in vitro and confirmed in human urine after oral dosing.
- Inhibition of 11β-HSD1 in vitro: Demonstrated with IC₅₀ values in the low micromolar range; mechanism is biochemically plausible.
- Cortisol reduction in vivo in humans following supplementation: Not established — no peer-reviewed human clinical trials.
- Body fat reduction in humans: Not established — no controlled human clinical trials; animal/fish data only.
- Muscle mass increase in humans: Not established — no controlled human clinical trials.
- Clinical utility as a biomarker in CAH/PCOS/CRPC: Actively researched for its metabolite 11-KT as a diagnostic marker; adrenosterone itself is not a therapeutic target in these diseases.
In conclusion, adrenosterone is a well-characterized endogenous steroid with established biochemical properties and plausible mechanisms of action. However, there is a profound gap between the proposed supplement claims and the existing human clinical evidence. The peer-reviewed literature robustly characterizes adrenosterone's endocrinology but does not include controlled clinical trials demonstrating meaningful body composition, metabolic, or performance-enhancing effects in healthy humans from oral supplementation. Its prohibition by WADA and its classification as an anabolic androgenic steroid reflect the regulatory consensus on its pharmacological profile.
References
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