Epistane

Epistane (Methylepitiostanol): A Comprehensive Reference

1. Identity and Chemical Characterization

Names and Synonyms

Methylepitiostanol — commonly known by the trade names Epistane, Hemapolin, Havoc, and Epi Plex — is a synthetic and orally active anabolic–androgenic steroid (AAS) of the dihydrotestosterone (DHT) group, first described in the literature in 1974 but never marketed for medical use. Its systematic IUPAC-derived chemical name is 2α,3α-epithio-17α-methyl-5α-androstan-17β-ol. Additional synonyms documented in chemical databases include 2,3-Thioepoxy Madol; pistone; (2α,3α,5α,17β)-2,3-Epithio-17-methylandrostan-17-ol; and Methepitiostane. The compound carries the CAS registry number 4267-80-5. Trade names used in the supplement market included Epistane, RPN Havoc, Hemaguno, Epi Plex, and Hemapolin.

Chemical Classification and Structure

Methylepitiostanol is a synthetic androstane steroid and a 17α-alkylated derivative of DHT. More specifically, it is the 17α-methylated derivative of epitiostanol, an AAS and antiestrogen which was formerly used in the treatment of breast cancer in Japan. Epistane is a methylated derivative of the steroid epitiostanol and is a readily orally active compound that lacks the 3-ketone common to most anabolic steroids. The defining structural feature of the molecule is the 2α-3α epithio ring (a sulfur-containing epoxide bridge) fused to the A-ring of the androstane skeleton, combined with the 17α-methyl group that confers oral bioavailability. Due to its C17α methyl group, the drug is considered to have a high potential for hepatotoxicity.

Epistane is a synthetic derivative of dihydrotestosterone (DHT) that has been used as an ingredient in various nutritional and bodybuilding supplements. The molecular formula is C₂₀H₃₂OS, with the sulfur atom incorporated into the epithio ring distinguishing it from most other synthetic androgens.

Natural Source and Origin

Epistane is an entirely synthetic compound with no plant, botanical, or naturally occurring source. It was originally developed as a designer anabolic steroid. It has no existence in nature. Its chemical lineage traces back to the natural androgen DHT, but the epithio modification and the 17α-methylation are both fully synthetic.

Common Forms and Preparations

Epistane is not an injectable; it is taken orally. In the supplement market prior to its controlled-substance classification, it was sold primarily as oral capsules or tablets, generally in doses of 10 mg per unit. Methylepitiostanol surfaced on the internet as a novel designer steroid in dietary supplements around 2009, and was identified in 2015 in over 30 products sold online that listed it as an ingredient on their product label. Because of the 17α-methyl group, Epistane is a methylated compound; this structural modification helps prevent the molecule from breaking down in the liver, allowing it to be effective when taken orally.

An important product integrity concern was identified through chemical analysis: although the labelling of Epistane products indicated that they contained 17alpha-methyl-2alpha,3alpha-epithio-5alpha-androstane-17beta-ol only, 17alpha-methyl-2beta,3beta-epithio-5alpha-androstane-17beta-ol and desoxymethyltestosterone were identified in the supplement. This confirmed that marketed products could contain undisclosed substances in addition to, or instead of, the stated ingredient.

2. Historical Development and Context

Synthetic Origins

Methylepitiostanol was first described in the literature in 1974 but was never marketed for medical use. It is the 17α-methylated derivative of epitiostanol, an AAS and antiestrogen which was formerly used in the treatment of breast cancer in Japan. Similarly to mepitiostane, methylepitiostanol is an orally active variant of epitiostanol.

The parent compound, epitiostanol, has a documented medicinal history: the mechanism of action of epitiostanol in breast cancer is multimodal; it directly suppresses tumor growth through activation of the AR and inhibition of the ER, and, in premenopausal women, it additionally acts as an antigonadotropin, reducing systemic estrogen levels via AR activation and consequent suppression of the hypothalamic-pituitary-gonadal axis. Epitiostanol is unique among AAS in acting as an antagonist of the ER. Similarly to the case of testosterone, epitiostanol shows poor bioavailability and weak therapeutic efficacy when taken orally due to extensive first-pass metabolism. It was in seeking a more bioavailable oral variant of epitiostanol that methylepitiostanol was synthesized. The chemical structure of Epistane (Methylepitiostanol) was created and formulated by Japanese researchers. It was originally developed to produce a methylated version of mepitiostane that could be used in conjunction with Nolvadex (tamoxifen) to fight breast cancer, suppressing excessive levels of estrogen in the body. After testing, results revealed that not only did the drug have anti-estrogen properties, epistane also produced significant anabolic and androgenic properties.

A published Japanese clinical case from the late 1980s documented the use of the parent compound epitiostanol: a patient with stage IV advanced breast cancer with multiple metastases was treated by ovariectomy, administration of a non-steroidal antiestrogen (tamoxifen) and mild chemotherapeutic drugs, with favorable results. After four years, the patient had a relapse of the cancer. A steroidal antiestrogen (epitiostanol) was then administered with satisfactory results. There is a possibility that the mechanism of action of Epitiostanol, which is regarded as a steroidal antiestrogen, is different from that of tamoxifen in which an estrogen receptor (ER) system is included. Mepitiostane, a closely related prodrug of epitiostanol, was patented and described in 1968 and is used as an antiestrogen and antineoplastic agent in the treatment of breast cancer, and also as an AAS in the treatment of anemia of renal failure.

Entry into the Supplement Market

First introduced in the 1970s, Epistane didn't gain much traction as a medical drug. However, it carved out a niche as a designer steroid, often marketed as a dietary supplement. Epistane appeared in the bodybuilding scene since the mid-1960s (in terms of its research origins), but did not spearhead the prohormone market until 2006. It was sold as a dietary supplement under the Recomp Performance Nutrition brand, with trademarked names RPN Havoc and Hemaguno. Its popularity surged with products like Havoc, which brought Epistane to the forefront of the bodybuilding community.

Epistane belongs to the category colloquially referred to as a "designer steroid" or "prohormone." These compounds were colloquially referred to by various misleading monikers such as 'pro-hormones', 'natural steroids', and 'testosterone boosters'. Epistane is the 17-alpha-alkylated version of the known AAS epitiostanol.

3. Key Constituents and Active Compounds

Epistane is itself the sole pharmacologically active entity. It is not a botanical or herbal preparation and does not contain multiple plant-derived constituents. Its pharmacological activity derives directly from the methylepitiostanol molecule and its structural features.

Structural Features Conferring Activity

• 17α-Methyl group: Epistane is a methylated compound. This structural modification helps prevent the molecule from breaking down in the liver, allowing it to be effective when taken orally.
• 2α,3α-Epithio (sulfur-containing) ring: The sulfur atom in the epithio bridge is the structural basis of epitiostanol's and methylepitiostanol's anti-estrogenic properties. Epistane is a sulfur-containing steroid which is known to have strong and long-lasting anti-estrogenic activity as well as weak androgenic and myotrophic activities.
• DHT backbone: As a synthetic derivative of dihydrotestosterone (DHT), it cannot be aromatized (converted to estrogen). Epistane is a derivative of DHT but is not aromatizing and non-progestanic.
• Absence of 3-ketone: Epistane is a readily orally active compound that lacks the 3-ketone common to most anabolic steroids.

4. Mechanisms of Action

Androgen Receptor Agonism

Epistane binds strongly to the androgen receptor in muscle tissue, which is the primary driver of its anabolic effects, leading to increased protein synthesis and nitrogen retention. It works by binding to androgen receptors across all skeletal and muscle stem cells. This sends messages from the androgen receptors to cells across the body, inducing protein synthesis and nitrogen retention.

Anti-Estrogenic Activity

As a DHT derivative, Epistane cannot be converted into estrogen by the aromatase enzyme. Its most unique trait is that the molecule itself is believed to have Selective Estrogen Receptor Modulator (SERM) properties, particularly in breast tissue. It can bind to the estrogen receptor without activating it, effectively blocking estrogen from causing gynecomastia. This is a direct inheritance from its parent compound, Epitiostanol.

The broader anti-estrogenic mechanism of the parent compound was documented in the peer-reviewed literature: epitiostanol directly suppresses tumor growth through activation of the AR and inhibition of the ER, and, in premenopausal women, it additionally acts as an antigonadotropin, reducing systemic estrogen levels via AR activation and consequent suppression of the hypothalamic-pituitary-gonadal axis.

Hepatocellular Nuclear Receptor Interactions

A 2020 peer-reviewed study published in Archives of Toxicology (Petrov et al.) specifically investigated the molecular mechanisms of epistane in human hepatocytes. Epistane (EPI) is an orally administered 17α-alkylated testosterone derivative with a 2α-3α epithio ring. The investigators identified four individuals who, after EPI consumption, developed long-lasting cholestasis. The bile acid (BA) profile of three patients was characterized, as well as the molecular mechanisms involved in this pathology.

In the in vitro component of that same study, as low as 0.01 μM EPI upregulated the expression of key BA synthesis genes (CYP7A1, by 65% and CYP8B1, by 67%) and BA transporters (NTCP, OSTA and BSEP), and downregulated FGF19. EPI increased the uptake/accumulation of a fluorescent BA analogue in hepatocytes by 50–70%. Results also evidenced that 40 μM EPI trans-activated the nuclear receptors LXR and PXR. More importantly, 0.01 μM EPI activated AR in hepatocytes, leading to an increase in the expression of CYP8B1. In samples from a human liver bank, expression of AR was positively correlated with that of CYP8B1 in men. The investigators concluded that EPI could cause cholestasis by inducing BA synthesis and favouring BA accumulation in hepatocytes, at least in part by AR activation, and that the large phenotypic variability of BA synthesis enzymes and transport genes in man provides a putative explanation for the idiosyncratic nature of EPI-induced cholestasis.

5. Scientific Evidence by Area of Use

5.1 Muscle Mass and Athletic Performance

Epistane's purported use for muscle building and athletic enhancement represents its primary market rationale. Scientific validation for the use of Epistane in nutritional products is limited. Few clinical studies have been conducted specifically on Epistane in humans. Most available evidence comes from anecdotal reports and extrapolation from animal studies or research on structurally similar compounds. These suggest that Epistane may promote muscle hypertrophy and strength gains, likely due to its anabolic and anti-estrogenic properties.

From a scientific perspective, the clinical validation of Epistane's efficacy and safety remains limited. Most of the evidence supporting its use is anecdotal or derived from user reports rather than large-scale, peer-reviewed clinical trials. Some studies in related compounds support the notion that DHT derivatives can promote muscle growth and inhibit estrogenic activity, but direct research on 2α,3α-epithio-17α-methyl-5α-androstan-17β-ol is sparse.

Evidence strength summary: There are no published randomized controlled trials (RCTs), controlled human clinical studies, or peer-reviewed dose-response studies that specifically test the efficacy of methylepitiostanol for muscle mass, strength, or body composition in humans. The mechanistic plausibility (androgen receptor activation → protein synthesis) is extrapolated from studies on other AAS and on the parent compound epitiostanol. No data from systematic reviews or meta-analyses exist for this compound specifically.

5.2 Anti-Estrogenic Effects and Breast Tissue Protection

The anti-estrogenic properties of epistane's parent compound, epitiostanol, were established in the Japanese oncology literature for breast cancer treatment. Mepitiostane, which is a prodrug of epitiostanol, is an epitiosteroid having anti-estrogenic and weak androgenic anabolic activities. The mechanism documented for epitiostanol — estrogen receptor antagonism and suppression of the hypothalamic-pituitary-gonadal axis — is the scientific basis for claims that methylepitiostanol would exhibit similar anti-estrogenic effects.

Epistane's mechanism of action — binding to androgen receptors and inhibiting aromatase — offers a plausible basis for its anti-estrogenic effects. However, no published clinical trials have tested methylepitiostanol specifically for anti-estrogenic endpoints in humans.

Evidence strength summary: Evidence is mechanistically derived from the parent compound; no clinical data specific to methylepitiostanol exist for this application.

5.3 Hepatic (Liver) Effects — Clinical Evidence

This is the area with the most direct clinical evidence for epistane. The 2020 study by Petrov et al. in Archives of Toxicology (PMID 31894354) reported both clinical cases and in vitro mechanistic findings. Four individuals who had consumed EPI developed long-lasting cholestasis. The bile acid profile of three patients was characterized, as well as the molecular mechanisms involved in this pathology. The serum BA pool was increased from 14- to 61-fold, basically on account of primary conjugated BA (cholic acid conjugates), whereas secondary BA were very low.

The clinical-laboratory pattern and the evolution of these four cases suggested AAS-induced cholestasis, with significant weight loss, a high increase in direct bilirubin, and a slow curve of normalization after discontinuing the drug.

Hepatotoxicity occurs particularly with testosterone derivatives that have undergone 17α-alkylation at the C-17 residue, a group that includes epistane. Biochemically, this typically manifests as a mild increase in serum transaminases (AST, ALT), lactate dehydrogenase (LDH), and gamma-glutamyl transpeptidase (GGT); jaundice and pruritus are uncommon. Other reports suggest a correlation between prolonged use of these compounds and hepatic peliosis, and in the most severe cases, hepatic adenoma or hepatocellular carcinoma.

Evidence strength summary: There are documented clinical cases of epistane-induced cholestasis supported by a peer-reviewed mechanistic study (Petrov et al., 2020). The hepatotoxicity signal, while based on a small number of identified cases, is mechanistically well-characterized and consistent with the known toxicological profile of all C17α-alkylated oral AAS.

5.4 Cardiovascular Effects

No clinical studies have specifically evaluated the cardiovascular effects of methylepitiostanol in isolation. However, anabolic–androgenic steroids are synthetic derivatives of testosterone used therapeutically but frequently abused by athletes and individuals seeking to increase muscle mass; their anabolic and androgenic effects result from androgen receptor activation in target tissues, and chronic supraphysiological AAS exposure is associated with serious cardiovascular consequences, ranging from hypertension and lipid disorders to cardiomyopathy, atherosclerosis, and sudden cardiac death. Supraphysiologic and long-term use of AASs affects all organs, leading to cardiovascular, neurological, endocrine, gastrointestinal, renal, and hematologic disorders.

Evidence strength summary: No cardiovascular clinical data exist specifically for methylepitiostanol. The cardiovascular risk profile is inferred from the broader AAS literature, which documents consistent findings across multiple C17α-alkylated oral steroids.

5.5 Endocrine Effects — Testosterone Suppression

From a suppression standpoint, both Epistane and structurally related compounds suppress endogenous testosterone production. This is consistent with the documented mechanism of epitiostanol, where in premenopausal women, epitiostanol acts as an antigonadotropin, reducing systemic estrogen levels via AR activation and consequent suppression of the hypothalamic-pituitary-gonadal axis. Suppression of endogenous gonadotropins and testosterone is expected from any exogenous androgen receptor agonist through negative feedback on the hypothalamic-pituitary-gonadal axis.

Evidence strength summary: Gonadal suppression is a mechanistically predicted and class-wide effect of exogenous AAS, including methylepitiostanol. No controlled clinical studies quantifying the degree of suppression specific to methylepitiostanol have been published.

6. Body Systems and Health Areas Associated with Epistane

• Musculoskeletal system: Claimed anabolic effect on skeletal muscle via androgen receptor activation and stimulation of protein synthesis. No controlled clinical evidence exists specific to methylepitiostanol.
• Hepatic system: Hepatotoxicity is one of the major concerns regarding AAS treatment and abuse. Documented clinical cases of drug-induced cholestasis following epistane consumption have been published in peer-reviewed literature.
• Endocrine system: Suppression of the hypothalamic-pituitary-gonadal axis and reduction in endogenous testosterone production, consistent with all exogenous AAS.
• Cardiovascular system: Chronic supraphysiological AAS exposure is associated with serious cardiovascular consequences, ranging from hypertension and lipid disorders to cardiomyopathy, atherosclerosis, and sudden cardiac death.
• Reproductive system: Side effects reported include infertility and behavioral changes.
• Dermatological and androgenic effects: Some users report androgenic side effects like acne, oily skin, and accelerated male pattern baldness in those predisposed. Virilization in women is a high risk, making it generally unsuitable for female use.

7. Regulatory and Legal Status

United States

The Designer Anabolic Steroid Control Act of 2014 (H.R. 4771) is a bill that expanded the list of anabolic steroids regulated by the Drug Enforcement Administration (DEA) to include about two dozen new substances and established new crimes relating to false labeling of steroids. Barack Obama signed the bill into law on December 18, 2014. Methylepitiostanol became a controlled substance in the United States in 2014 with the passage of the Designer Anabolic Steroid Control Act, which explicitly listed it among 27 newly scheduled substances. In the US, epistane is a Schedule III controlled substance that is not legal for use in supplements, but it is still found in some supplement products.

International Anti-Doping Status

Epistane is also banned by the World Anti-Doping Agency (WADA). The current WADA Prohibited List explicitly names 17α-Methylepithiostanol (epistane) as a prohibited anabolic androgenic steroid under the S1.1 category, applicable at all times both in- and out-of-competition. The World Anti-Doping Agency prohibits the misuse of mepitiostane by athletes — the closest clinically used analogue — as well.

Detection of epistane in anti-doping testing is possible using standard analytical methods. Urine samples can be screened after EPISTANE administration using the normal screening procedure for anabolic steroids with GC/MS.

8. Dosage Forms and Reported Dosages

There isn't enough reliable information from controlled studies to know what an appropriate dose of epistane might be. The following dosage information was reported in supplement-market documentation prior to the compound's scheduling:

• Typical doses reported in the supplement community were 20–40 mg per day, with beginners advised to start at the lower end.
• Epistane was taken for cycles of 4–6 weeks. Beginners were directed to start with 4 weeks; novice/advanced users might go up to 6 weeks.
• It was typically split into 2–3 doses per day, taken 4–6 hours apart.
• Pulse cycle doses reported were 40 mg every other day.

None of these dosing regimens were validated in peer-reviewed clinical trials. The only pharmacologically characterized doses come from the in vitro component of Petrov et al. (2020), where as low as 0.01 μM EPI upregulated the expression of key bile acid synthesis genes in cultured human hepatocytes, demonstrating hepatocellular activity at very low concentrations.

9. Safety Considerations

Hepatotoxicity

Due to its C17α methyl group, the drug is considered to have a high potential for hepatotoxicity. This is not theoretical: four individuals who consumed EPI developed long-lasting cholestasis. The clinical-laboratory pattern in these cases suggested AAS-induced cholestasis, with significant weight loss, a high increase in direct bilirubin, and a slow curve of normalization after discontinuing the drug. The large phenotypic variability of BA synthesis enzymes and transport genes in man provides a putative explanation for the idiosyncratic nature of EPI-induced cholestasis, suggesting that susceptibility may differ between individuals and cannot be predicted in advance.

Hepatotoxicity from 17α-alkylated compounds including epistane typically manifests as a mild increase in serum transaminases (AST, ALT), lactate dehydrogenase (LDH), and gamma-glutamyl transpeptidase (GGT); jaundice and pruritus are uncommon. Other reports suggest a correlation between prolonged use of these compounds and hepatic peliosis, and in the most severe cases, hepatic adenoma or hepatocellular carcinoma.

Endocrine Suppression

Side effects reported include infertility and behavioral changes. Suppression of the hypothalamic-pituitary-gonadal axis, resulting in reduced endogenous testosterone production, is an expected pharmacological consequence of any exogenous androgen.

Androgenic Side Effects

Possible side effects with Epistane include back pumps, cramps, dry skin and joints, and increased blood pressure. Hair loss is also reported. Virilization in women is a high risk, making it generally unsuitable for female use.

Product Adulteration and Contamination

A published chemical analysis found that although labelling of EPISTANE products indicated that they contained 17alpha-methyl-2alpha,3alpha-epithio-5alpha-androstane-17beta-ol only, 17alpha-methyl-2beta,3beta-epithio-5alpha-androstane-17beta-ol and desoxymethyltestosterone were identified in the supplement. This finding indicates that consumers using products labeled as epistane could be unknowingly exposed to additional undeclared anabolic steroids, including desoxymethyltestosterone, which is itself a controlled substance.

Drug Interactions and Nuclear Receptor Cross-Talk

The Petrov et al. (2020) study documented that 40 μM EPI trans-activated the nuclear receptors LXR and PXR in human hepatocytes. PXR activation is of particular clinical relevance because this nuclear receptor regulates the expression of multiple cytochrome P450 enzymes responsible for drug metabolism, which implies a theoretical potential for epistane to alter the metabolism of co-administered medications through CYP enzyme induction. However, no specific drug interaction studies have been conducted in humans.

Legal and Sports Eligibility Risks

In the US, epistane is a Schedule III controlled substance that is not legal for use in supplements. WADA explicitly lists 17α-Methylepithiostanol (epistane) as a prohibited anabolic androgenic steroid. Athletes competing under any anti-doping framework that adopts the WADA code face disqualification and sanctions for its use. Urine samples can be screened after EPISTANE administration using the normal screening procedure for anabolic steroids with GC/MS.

Overall Evidence Assessment

Epistane 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. Scarce data from scientific studies suggest that designer steroids including methylepitiostanol may have severe side effects, which include hepatotoxicity, cholestasis, renal failure, hypogonadism, gynecomastia, and infertility. The totality of the current scientific literature provides no peer-reviewed evidence of efficacy for any indication in humans, while documenting clinically verified hepatic harm.

References

• Petrov PD, Fernández-Murga L, Conde I, et al. Epistane, an anabolic steroid used for recreational purposes, causes cholestasis with elevated levels of cholic acid conjugates, by upregulating bile acid synthesis (CYP8B1) and cross-talking with nuclear receptors in human hepatocytes. Archives of Toxicology. 2020. PubMed PMID: 31894354.
• Wikipedia: Methylepitiostanol (Epistane)
• Wikipedia: Epitiostanol
• Wikipedia: Mepitiostane
• World Anti-Doping Agency (WADA): The Prohibited List
• Wikipedia: Designer Anabolic Steroid Control Act of 2014
• U.S. Congress: H.R.4771 — Designer Anabolic Steroid Control Act of 2014
• Council for Responsible Nutrition: The Designer Anabolic Steroid Control Act of 2014
• WebMD/Natural Medicines: Epistane — Overview, Uses, Side Effects
• Rahnema CD, Crosnoe LE, Kim ED. Designer steroids – over-the-counter supplements and their androgenic component: review of an increasing problem. Andrology. 2015;3(2):150–5. Wiley Online Library.
• ResearchGate: Petrov et al. (2020) — Epistane cholestasis study (full reference)
• Frontiers in Cardiovascular Medicine: Forensic approach in cases of anabolic-androgenic steroid abuse and cardiovascular mortality. 2025.
• PMC: Impact of Anabolic–Androgenic Steroid Abuse on the Cardiovascular System: Molecular Mechanisms and Clinical Implications.
• PubMed: A case of advanced breast cancer successfully treated with combined tamoxifen and epitiostanol. PMID: 3395140.
• Suppversity: Designer Steroids Exposed — Epistane, Methylstenbolone, DMZ, and Others. 2015.