Epiandrosterone (Epiandrostenolone)
1. Identity and Chemical Characterization
Names and Chemical Taxonomy
Epiandrosterone, or isoandrosterone, also known as 3β-androsterone, 3β-hydroxy-5α-androstan-17-one, or 5α-androstan-3β-ol-17-one, is a steroid hormone with weak androgenic activity. The term epiandrostenolone is an alternate systematic name for the same compound, reflecting its status as an androstenolone (androsterone-type) compound bearing an "epi" (inverted) hydroxyl configuration at carbon-3. Its molecular formula is C19H30O2 and it carries the CAS registry number 481-29-8.
Epiandrosterone belongs to the androstane class of steroids, characterized by a fully saturated (5α-reduced) tetracyclic ring system. The key structural feature distinguishing it from its close isomer androsterone is the stereochemical orientation of the 3-hydroxyl group: androsterone is a 3-alpha isomer, and epiandrosterone is a 3-beta isomer of the compound. Androsterone's 3β-isomer is epiandrosterone, and its 5β-epimer is etiocholanolone.
Epiandrosterone is a steroid hormone with weak androgenic activity and is a metabolite of testosterone and dihydrotestosterone (DHT). DHT is inactivated in the liver and extrahepatic tissues like the skin into 3α-androstanediol and 3β-androstanediol by the enzymes 3α-hydroxysteroid dehydrogenase and 3β-hydroxysteroid dehydrogenase, respectively. These metabolites are in turn converted, respectively, into androsterone and epiandrosterone, then conjugated (via glucuronidation and/or sulfation), released into circulation, and excreted in urine.
Natural Sources and Occurrence
Epiandrosterone has been shown to naturally occur in most mammals including pigs. In humans, epiandrosterone is naturally produced by the enzyme 5-alpha reductase from the adrenal hormone dehydroepiandrosterone (DHEA). It is a steroid hormone with weak androgenic activity and a natural metabolite of dehydroepiandrosterone via the 5-alpha reductase enzyme. Epiandrosterone can also be produced from the natural steroids androstanediol via 17β-hydroxysteroid dehydrogenase or from androstanedione via 3β-hydroxysteroid dehydrogenase.
Beyond endogenous biosynthesis in mammals, epiandrosterone has also been documented in botanical sources. Research on pine pollen (Pinus spp.) has identified the presence of various androgens in that matrix. Androsterone has been shown to naturally occur in pine pollen, and androsterone and its 3β-isomer (epiandrosterone) are naturally produced by the enzyme 5α-reductase from the adrenal hormone DHEA. A 1979 study published in Phytochemistry described the isolation and quantitative determination of steroid hormones from the pollen of Pinus nigra, documenting sex hormones and corticosteroids in pine pollen.
Commercially Available Forms and Preparations
Epiandrosterone has been marketed as a dietary supplement in oral capsule and tablet forms. In the US, epiandrosterone is classified as a Schedule III controlled substance that is not legal for use in supplements; however, it is still found in some supplement products. Sublingual and transdermal formulations (creams and gels) have also appeared on the consumer market, marketed on the premise that bypassing first-pass hepatic metabolism may increase bioavailability, though no peer-reviewed clinical evidence substantiates this claim for epiandrosterone specifically. There is sparse pharmacokinetics data in humans; there is little to no high-quality information about oral bioavailability, first-pass metabolism, peak concentrations, or dose-response curves for efficacy or adverse events in typical users.
2. Discovery and Historical Context
Scientific Discovery
Epiandrosterone was first isolated in 1931 by Adolf Friedrich Johann Butenandt and Kurt Tscherning. They distilled over 17,000 litres of male urine, from which they got 50 milligrams of crystalline androsterone (most likely mixed isomers), which was sufficient to find that the chemical formula was very similar to estrone. This pioneering work was part of the broader early twentieth-century effort to isolate and characterize steroid hormones from biological fluids, a program for which Butenandt was later awarded the Nobel Prize in Chemistry in 1939. The initial crystalline product from that urine-distillation process was likely a mixture of androsterone and epiandrosterone isomers, which were subsequently separated and individually characterized as the field of steroid chemistry matured.
No Established Traditional Medical Use
Unlike plant-derived botanical supplements with centuries of documented use in Ayurvedic, Traditional Chinese Medicine, or European folk medicine, epiandrosterone has no pre-modern ethnobotanical or ethnopharmacological history of use as an isolated compound. Its existence was entirely unknown prior to laboratory isolation in the early 1930s. Its identification was a product of 20th-century endocrinology research, and its subsequent use as a supplement emerged exclusively from the sports nutrition and prohormone market of the late 1990s and 2000s, following growing public awareness of DHEA-related metabolites after the Anabolic Steroid Control Acts.
3. Biosynthesis and Endogenous Metabolism
Biosynthetic Pathways
Epiandrosterone occupies a specific position in the human steroid metabolic network. Its primary biosynthetic precursor is dehydroepiandrosterone (DHEA), also known as androstenolone, which is an endogenous steroid hormone precursor and one of the most abundant circulating steroids in humans, produced in the adrenal glands, the gonads, and the brain. Epiandrosterone is naturally produced by the enzyme 5α-reductase from the adrenal hormone DHEA. The 5α-reductase enzyme reduces the Δ5 double bond between carbons 5 and 6 of DHEA and simultaneously retains the 3β-hydroxyl orientation, yielding epiandrosterone (5α-androstan-3β-ol-17-one).
Two additional biosynthetic routes have been characterized enzymatically. Epiandrosterone can also be converted from the natural steroids androstanediol via 17β-hydroxysteroid dehydrogenase or from androstanedione via 3β-hydroxysteroid dehydrogenase.
DHEA mediates its action via multiple signaling pathways involving specific membrane G protein-coupled receptors and via transformation into androgen and estrogen derivatives (androgens, estrogens, 7α and 7β DHEA, and 7α and 7β epiandrosterone derivatives) acting through their specific nuclear receptors. Cytochrome P450 7B1 (CYP7B1) 7α-hydroxylates DHEA, epiandrosterone, and 5α-androstane-3β,17β-diol (Adiol). 11β-Hydroxysteroid dehydrogenase type 1 (11β-HSD1) interconverts 7α- and 7β-forms.
Within the broader androgen cascade, epiandrosterone is also documented as an intermediate in what researchers have termed the "backdoor pathway" to dihydrotestosterone (DHT). Although it is well known that 3α-diol and 3β-diol have no direct stimulation to AR, they have theoretically biochemical potential to be converted to the most potent androgen, DHT, via androsterone (AND), or epiandrosterone (EpiAND) and androstanedione (5α-A-dione).
Relationship to DHT Metabolism
Because epiandrosterone is a downstream metabolite of DHT via hepatic and peripheral 3β-hydroxysteroid dehydrogenase activity, urinary epiandrosterone levels — measured as conjugates — are used in clinical and doping-control laboratories as markers of androgen metabolism. DHT is inactivated in the liver and extrahepatic tissues like the skin into 3α-androstanediol and 3β-androstanediol by the enzymes 3α- and 3β-hydroxysteroid dehydrogenase, respectively, which are in turn converted into androsterone and epiandrosterone, then conjugated (via glucuronidation and/or sulfation), released into circulation, and excreted in urine.
4. Key Active Constituents and Mechanisms of Action
4.1 Androgenic Activity and Prohormone Character
Epiandrosterone itself is a weak androgen at the androgen receptor (AR). Its primary androgenic significance in the context of supplementation lies in its role as a prohormone — that is, a compound that can be converted metabolically to more potent androgens. One of the primary physiological functions of epiandrosterone is its role as a precursor to dihydrotestosterone (DHT), a potent androgen hormone. The conversion involves oxidation at C-3 (via 3β-hydroxysteroid dehydrogenase) to yield androstanedione, followed by reduction at C-17 (via 17β-hydroxysteroid dehydrogenase) to yield DHT (stanolone). This two-step enzymatic sequence takes place in peripheral tissues including skeletal muscle, skin, and liver. Unlike testosterone, DHT cannot be aromatized into an estrogen like estradiol, and for this reason, has no propensity for estrogenic effects.
Because epiandrosterone itself possesses only weak AR binding and intrinsic activity, its pharmacological profile is largely determined by the efficiency and tissue distribution of this peripheral conversion to DHT, which varies between individuals based on enzymatic expression.
4.2 Inhibition of Glucose-6-Phosphate Dehydrogenase (G6PD)
A mechanistically well-characterized action of epiandrosterone, documented in cellular and isolated-organ research, is its inhibition of glucose-6-phosphate dehydrogenase (G6PD), the rate-limiting enzyme of the pentose phosphate pathway. Epiandrosterone, as a 17-ketosteroid, attenuates L-type Ca²⁺ currents (ICa-L) in cardiac myocytes and inhibits myocardial contractility. Because 17-ketosteroids are known to inhibit glucose-6-phosphate dehydrogenase (G6PD), the rate-limiting enzyme in the pentose phosphate pathway, and to reduce intracellular NADPH levels, inhibition of G6PD was hypothesized as a novel signaling mechanism which inhibits ICa-L and, therefore, cardiac contractile function.
Inhibition of G6PD by DHEA has been shown to deplete cytosolic glutathione levels, thereby causing contractile dysfunction through dysregulation of Ca²⁺ homeostasis, and inhibition of G6PD by epiandrosterone has been shown to evoke suppression of ICa-L by decreasing the amplitude and shifting steady-state inactivation curve to hyperpolarizing potentials.
Subsequent work extended this mechanism to vascular smooth muscle. G6PD forms a complex with the pore-forming α1C-subunit of the L-type Ca²⁺ channel Cav1.2, as demonstrated by proximity ligation assay. FRET analysis demonstrated strong interaction between the proteins. Epiandrosterone, as a G6PD inhibitor, disrupted the G6PD-Cav1.2 complex, also decreasing the amplitude of L-type Ca²⁺ currents and window currents, thereby reducing the availability of the c1 component. All such findings to date are from in vitro and isolated-organ (animal) experiments; no controlled human trials have been conducted to assess these cardiovascular actions.
4.3 Neurosteroid Activity: Modulation of Glycine and GABA Receptors
Epiandrosterone has been identified as an endogenous neurosteroid — a steroid that is synthesized in the brain and/or exerts direct modulatory effects on ligand-gated ion channels in the central nervous system. Research published in Frontiers in Molecular Neuroscience (2020) investigated nine endogenous androstane and androstene neurosteroids using the patch-clamp technique in isolated rat neurons.
The glycine- and GABA-induced chloride currents (IGly and IGABA) were measured in isolated pyramidal neurons of the rat hippocampus and isolated rat cerebellar Purkinje cells using the patch-clamp technique. The results demonstrate that all nine neurosteroids display similar biological activity, namely they strongly inhibited IGly and weakly inhibited IGABA. The threshold concentration of neurosteroids inducing effects on IGly was 0.1 μM, and for effects on IGABA was 10–50 μM.
The compounds accelerated desensitization of IGly with IC50 values varying from 0.12 to 0.49 μM and decreased the peak amplitude with IC50 values varying from 16 to 22 μM. Notably, only epiandrosterone (compound 4) and dehydroepiandrosterone (compound 8) were able to cause a significant change in IGABA in 10 μM concentration. This selective dual modulation (strong inhibition of glycine receptor currents and weaker inhibition of GABAA receptor currents) distinguishes epiandrosterone from other androstane neurosteroids in this class. All findings are from isolated animal neurons; human neurophysiological studies do not exist.
GABAA receptors and glycine receptors (GlyR) are the major inhibitory ligand-gated ion channels of the central nervous system which mediate both fast synaptic and tonic extrasynaptic inhibition. Disturbance of functional activity of GlyRs and GABAARs underlies many neurological disorders. Dysfunction of GABAARs leads to channelopathies associated with epilepsy, insomnia, anxiety, and chronic pain.
4.4 Antiproliferative Properties — In Vitro Research
Much attention has been paid to DHEA active metabolites (e.g., DHEA-S, androsterone, epiandrosterone, etiocholanolone) that were tested for antiproliferative properties in different human cancer cell lines, including HepG2 (hepatocarcinoma), Caco-2 (colon carcinoma), and HT-29 cells (colon adenocarcinoma). These studies are cell-culture based and do not constitute evidence for anticancer activity in humans.
Additionally, research on microbial biotransformation of epiandrosterone has examined aromatase inhibitory activity in resulting metabolites. A study described the microbial transformation of epiandrosterone by fungi, including Cunninghamella blakesleeana and Aspergillus alliaceus, which yielded multiple metabolites. All compounds were evaluated for their aromatase inhibitory activity, and a new metabolite from metenolone acetate biotransformation exhibited significant human placental aromatase activity with an IC50 = 19.602 ± 0.47 μM. These findings concern biotransformation products rather than epiandrosterone itself.
5. Scientific Evidence by Area of Use
5.1 Athletic Performance and Body Composition
Epiandrosterone has been widely marketed in the sports nutrition industry under the premise that its peripheral conversion to DHT can enhance muscle mass, strength, and reduce body fat. However, the clinical evidence base for these effects is essentially absent.
Epiandrosterone is used for weight loss, to improve athletic performance, to reduce sexual problems, and for many other uses, but there is no good scientific evidence to support its use. In short, epiandrosterone is real biology — but as an endogenous weak androgen and metabolite, not a clinically validated performance enhancer. Understanding it as one node in a complex steroid network helps set expectations: local effects are plausible; strong, consistent whole-body effects in healthy trainees are unproven.
For epiandrosterone, the honest answer is unusually stark: there is no evidence-based oral dosing range for healthy humans that improves performance or physique outcomes while maintaining safety. Commercial labels vary widely, but label copy is not clinical guidance and often cites no peer-reviewed data.
Evidence strength: No published randomized controlled trials (RCTs) in humans specifically investigating epiandrosterone as the sole intervention for athletic performance or body composition were identified in the peer-reviewed literature. Evidence is limited to mechanistic rationale (conversion to DHT) and preclinical or in vitro data.
5.2 Cardiovascular Effects
Preclinical research has documented direct cardiac effects of epiandrosterone that raise questions about both therapeutic potential (e.g., for cardiac protection via G6PD/Ca²⁺ channel modulation) and risk (reduced myocardial contractility). Epiandrosterone, as a 17-ketosteroid, attenuates L-type Ca²⁺ currents (ICa-L) in cardiac myocytes and inhibits myocardial contractility. These findings emerged from isolated rat cardiomyocytes and Langendorff-perfused heart preparations and have not been translated into human studies. The clinical significance — whether cardioprotective or potentially harmful in supplementation settings — cannot be determined from available data.
Evidence strength: Preclinical (in vitro and isolated-organ animal models) only. No human clinical data.
5.3 Neurological and Cognitive Effects
The characterization of epiandrosterone as a neurosteroid is based on in vitro electrophysiology research. All tested neurosteroids in one structural study displayed similar biological activity: they strongly inhibited glycine-induced chloride current (IGly) and weakly inhibited GABA-induced current (IGABA). The threshold concentration of neurosteroids inducing effects on IGly was 0.1 μM, and for effects on IGABA was 10–50 μM. The inhibition of glycine receptor function may have implications for excitability, pain signaling, and motor neuron activity, since glycine receptors are prominent in the spinal cord and brainstem.
Evidence strength: In vitro electrophysiology in isolated rat neurons only. No human neurological or cognitive clinical data.
5.4 Gonadal and Endocrine Function
Epiandrosterone has been studied as a urinary biomarker of gonadal androgenic activity. The biological relevance of the epiandrosterone enzyme immunoassay (EIA) was validated by demonstrating a significant increase in fecal testosterone metabolite (fTM) levels in response to a testosterone injection within 16 hours, and the epiandrosterone EIA is a reliable non-invasive method to monitor gonadal activity in spotted hyenas. This reflects its utility as an endocrine biomarker rather than evidence for therapeutic endocrine effects of supplemental epiandrosterone.
Evidence strength: Epiandrosterone as a biomarker is well-validated; its use as an exogenous supplement to modify endocrine function is unvalidated in human trials.
6. Body Systems Associated with Epiandrosterone
- Endocrine and Reproductive System: Epiandrosterone, a natural steroid hormone and metabolite of DHEA, serves as a precursor to the potent androgen hormone DHT, influencing male sexual characteristics, muscle mass, bone density, and libido.
- Skeletal Muscle: Via conversion to DHT, epiandrosterone is theoretically associated with anabolic androgen receptor-mediated effects in muscle tissue, though human clinical evidence is absent.
- Central Nervous System: GABAA receptors and glycine receptors (GlyR) are the major inhibitory ligand-gated ion channels of the central nervous system which mediate both fast synaptic and tonic extrasynaptic inhibition, and epiandrosterone modulates both at differing concentration thresholds in preclinical models.
- Cardiovascular System: Epiandrosterone attenuates L-type Ca²⁺ currents in cardiac myocytes and inhibits myocardial contractility in preclinical preparations via G6PD inhibition.
- Liver: As a steroid undergoing conjugation (glucuronidation and sulfation) and phase I metabolism in hepatic tissue, the liver is a primary site of epiandrosterone processing. A study by Chalbot and Morfin investigated human liver S9 fractions and the metabolism of dehydroepiandrosterone, epiandrosterone, and related 7-hydroxylated derivatives (Drug Metab Dispos, 2005).
- Pentose Phosphate Pathway / Redox Biology: 17-ketosteroids including epiandrosterone are known to inhibit glucose-6-phosphate dehydrogenase (G6PD), the rate-limiting enzyme in the pentose phosphate pathway, and to reduce intracellular NADPH levels. Inhibition of G6PD by epiandrosterone reduces NADPH levels in the isolated rat heart.
7. Dosage Forms and Dosages Reported
There are no peer-reviewed clinical trials reporting specific tested doses of epiandrosterone for human health or performance outcomes. There is sparse pharmacokinetics data in humans; there is little to no high-quality information about oral bioavailability, first-pass metabolism, peak concentrations, or dose-response curves for efficacy or adverse events in typical users.
In cellular and preclinical mechanistic research, the following concentrations have been used:
- The threshold concentration of neurosteroids (including epiandrosterone) inducing effects on glycine receptor currents (IGly) was 0.1 μM in isolated rat hippocampal neurons.
- Effects on GABA-induced currents (IGABA) required concentrations of 10–50 μM.
- The cardiovascular and G6PD inhibition studies used isolated cardiomyocyte and perfused heart preparations with direct compound application; these in vitro concentrations are not translatable to oral supplement dosing in humans.
Weak androgen with tissue-specific conversion means that intracrine metabolism allows the same oral dose to produce different local androgenic effects between individuals, or even across tissues within the same person. No validated human clinical dosing range exists in the published scientific literature.
8. Regulatory Status
Epiandrosterone is a type of chemical known as an anabolic steroid that is converted in the body to other sex hormones. In the US, epiandrosterone is a Schedule III controlled substance that is not legal for use in supplements, but it is still found in some supplement products.
In sport, epiandrosterone is explicitly banned. The WADA Prohibited List specifically names epiandrosterone (3β-hydroxy-5α-androstan-17-one) as a prohibited anabolic agent. The World Anti-Doping Agency (WADA) explicitly lists epiandrosterone (and its 1-ene analog 1-epiandrosterone) among anabolic agents prohibited at all times. Laboratories can detect characteristic metabolites and altered steroid ratios, and analytical methods continue to improve. The prohibition applies in-competition and out-of-competition under the current WADA Code.
Currently employed strategies for detection include non-targeted and indirect analytical approaches for modified steroids, the athlete's biological passport, and isotope ratio mass spectrometry for the detection of misuse of endogenous anabolic androgenic steroids. Among these parameters, the best elucidated is the ratio of testosterone and epitestosterone (T/E), which was introduced in doping controls to detect the misuse of testosterone. The administration of testosterone and other endogenous steroids leads to abnormal steroid profiles, including abnormally increased T/E ratios.
9. Safety Considerations and Interactions
9.1 General Safety Profile
When taken by mouth, epiandrosterone is possibly unsafe for most people. Side effects include infertility, behavioral changes, and hair loss. Epiandrosterone might also lead to liver damage and heart disease. These safety concerns parallel those documented for anabolic androgenic steroids as a class and reflect the downstream consequences of elevated DHT activity.
9.2 Androgenic and Reproductive Adverse Effects
As a prohormone to DHT — a non-aromatizable, potent androgen — epiandrosterone supplementation at pharmacological doses carries androgenic adverse effect risks. In men, anabolic steroid use can cause shrinkage of the testicles, decreased sperm count, and sterility. Gynecomastia (enlargement of the male breast tissue) can develop with the use of those anabolic steroids with estrogenic actions. Because epiandrosterone converts to DHT (which does not aromatize to estrogen), gynecomastia is considered less likely than with testosterone-precursor prohormones; however, suppression of endogenous testosterone production via hypothalamic-pituitary-gonadal axis feedback remains a concern.
9.3 Cardiovascular Risks
In both men and women, anabolic steroid use can damage the liver and can cause high cholesterol levels, which may increase the risk of strokes and heart attacks. Additionally, the direct cardiosuppressant effect of epiandrosterone demonstrated in preclinical models — via G6PD inhibition and L-type calcium channel blockade — may be relevant at high supplemental doses, though no human data characterize this risk. In both men and women, anabolic steroid use can damage the liver and can cause high cholesterol levels, which may increase the risk of strokes and heart attacks, and use is purported to induce psychological effects such as aggression, increased feelings of hostility, and psychological dependence and addiction.
9.4 Hepatotoxicity
Epiandrosterone might also lead to liver damage. Hepatotoxicity associated with androgenic supplement use is a documented pattern in the literature, particularly with compounds that undergo significant hepatic first-pass metabolism. Epiandrosterone, as a 17-ketosteroid lacking the 17α-alkyl modification typical of the most hepatotoxic synthetic anabolic steroids, may carry a different hepatotoxic profile; however, no controlled human safety studies define this risk quantitatively.
9.5 Withdrawal and Dependence
Upon abrupt termination of long-term anabolic steroid use, a withdrawal syndrome may appear including severe depression. This risk applies to the class of anabolic androgen precursors to which epiandrosterone belongs, particularly if prolonged use has suppressed endogenous testosterone production.
9.6 Drug Interactions
No published controlled studies have specifically characterised drug interactions of epiandrosterone. However, pharmacological inference from its mechanism of action suggests relevant considerations. As a G6PD inhibitor that reduces intracellular NADPH, epiandrosterone may potentially interact with NADPH-dependent enzymatic processes, including those relevant to drug metabolism and antioxidant defense. Its androgenic effects could theoretically interact with anticoagulants (androgenic steroids as a class are known to potentiate warfarin), though this has not been specifically studied for epiandrosterone. El Kihel (Steroids, 2012) reviewed the oxidative metabolism of DHEA and biologically active oxygenated metabolites of DHEA and epiandrosterone, noting the complexity of their downstream metabolic fate.
9.7 Special Populations
Given its androgenic and DHT-prohormone properties, epiandrosterone is contraindicated in pregnancy (risk of fetal virilization), and its use in children, adolescents, and people with hormone-sensitive conditions (e.g., prostate hyperplasia, prostate cancer, polycystic ovary syndrome) is associated with significant androgen-related risks. No clinical safety data for any special population exist.
10. Research Gaps and Status of Evidence
The scientific literature on epiandrosterone as a supplement ingredient is characterized by a marked disparity between the mechanistic richness of its in vitro and preclinical pharmacology and the near-total absence of controlled human studies. Several specific gaps are notable:
- No published randomized controlled trials have examined its effects on muscle mass, body composition, strength, or athletic performance in humans.
- Oral pharmacokinetics (bioavailability, half-life, tissue distribution, dose-response) have not been characterized in human subjects in the peer-reviewed literature.
- Neurological and cognitive effects suggested by glycine/GABA receptor modulation have not been examined in humans.
- Systematic safety data — including hepatic, cardiovascular, and reproductive outcomes from oral supplementation — are absent from the controlled clinical trial literature.
Epiandrosterone is real biology — but as an endogenous weak androgen and metabolite, not a clinically validated performance enhancer. Local effects are plausible; strong, consistent whole-body effects in healthy trainees are unproven.
References
Go back