IngredientsThe ingredient listed on supplement labels as 6,17-keto etiocholeva-3-ol (also rendered "6,17-keto-etiocholeve-3-ol tetrahydropyranol") and 3,17-ketoetiochol-triene are non-standard, proprietary trade names for two distinct steroidal compounds that are better recognized by their systematic chemical identities. Understanding this labeling practice is essential before any scientific evaluation can proceed.
The use of non-standard terminology to identify these ingredients in supplement products has been widely criticized as a confusing tactic. These ingredients are actually better known by their systematic names: 3-hydroxy-4-androstene-6,17-dione (commonly abbreviated 3-OHAT, and used in supplement form as a tetrahydropyranyl ether) and 1,4,6-androstatriene-3,17-dione (commonly abbreviated ATD).
ATD has many names in sports supplements, including: 1,4,6-etiollochan-dione, 3,17-keto-etiochol-triene, androst-1,4,6-triene-3,17-dione, and many others. These all refer to CAS# 633-35-2.
3-beta-hydroxyandrost-4-ene-6,17-dione ("3-OHAT") and androst-4-ene-3,6,17-trione (AT) are non-androgenic compounds. 3-OHAT is itself a closely related compound to androst-4-ene-3,6,17-trione (known as 6-OXO), which carries CAS# 2243-06-3. It is important to note that these two proprietary label names — "6,17-keto etiocholeva-3-ol" and "3,17-ketoetiochol-triene" — frequently appear together in the same supplement formulation, as they were in the product Novedex XT (Gaspari Nutrition).
3-OHAT, or 3-beta-hydroxyandrost-4-ene-6,17-dione, is a steroidal compound belonging to the androstane family. It is a naturally occurring 3β-reduced metabolite of 4-androstene-3,6,17-trione (6-OXO), formed rapidly from 6-OXO in the presence of NADPH via an enzyme in human placental microsomes other than aromatase. In supplement products, it was often delivered as a tetrahydropyranyl (THP) ether — a chemical modification of the C-3 hydroxyl group intended to improve oral bioavailability. Studies have demonstrated that ATD is more potent than 3-OHAT or AT.
1,4,6-Androstatriene-3,17-dione (ATD) is a potent irreversible aromatase inhibitor that inhibits estrogen biosynthesis by permanently binding and inactivating aromatase in adipose and peripheral tissue. Its molecular formula is C19H22O2, and its PubChem CID is 104880. ATD acts as a suicide substrate by irreversibly binding to the aromatase enzyme and shutting down its activity.
The trade nomenclature "etiocholeva" and "etiochol" draws on the stem name etiocholanolone, a broader class of endogenous 5β-androstane steroids. Etiocholanolone, also known as 5β-androsterone or 3α-hydroxy-5β-androstan-17-one, is an etiocholane (5β-androstane) steroid as well as an endogenous 17-ketosteroid that is produced from the metabolism of testosterone. ATD and 3-OHAT share a structural androstane backbone with etiocholanolone but are chemically distinct in their degree of unsaturation and ketone positioning. Etiocholanolone is an androgenically inactive metabolite of testosterone and androstenedione.
Etiocholanolone is an endogenous 17-ketosteroid that is produced from the metabolism of testosterone. Etiocholanolone is a DHEA metabolite that is excreted in the urine. It is produced from androstenedione and the 5-beta-reductase metabolic pathway.
6-OXO / androst-4-ene-3,6,17-trione, the parent compound from which 3-OHAT is derived, is described in some scientific literature as naturally occurring. However, ATD (1,4,6-androstatriene-3,17-dione) is a synthetic compound — it does not occur naturally in the human body or in significant quantities in plants. ATD was present in some over-the-counter bodybuilding supplements until 2009, as well as topical ATD solutions that work transdermally. The product was developed and commercialized in the dietary supplement marketplace by Bruce Kneller, who holds a United States Patent (#7,939,517) for use of the compound and related compounds, and Gaspari Nutrition.
6-OXO, commercially available as a nutritional supplement, is sold as an aromatase inhibitor and contains androst-4-ene-3,6,17-trione as its active ingredient. This anabolic steroid is a prohibited substance in sports.
These compounds appeared on the dietary supplement market in the early-to-mid 2000s, primarily in the context of testosterone-boosting and post-cycle therapy (PCT) products. Common delivery forms included:
In many supplement formulations reviewed by researchers, these compounds were included as part of multi-ingredient stacks. For example, one product (Wicked PCT by Anabolic Androgenic Research) listed 6,17 keto etiocholeva-3-ol 3,17-ketoetiochol-triene at 225 mg in an "Estro-PLEXX" anti-aromatase matrix alongside trans-resveratrol and 6-bromoandrostenedione.
It must be stated plainly that ATD (1,4,6-androstatriene-3,17-dione) and 3-OHAT are synthetic steroidal compounds with no documented pre-modern traditional use. Their development is rooted entirely in 20th-century pharmaceutical and biochemical research, not in ethnobotanical or herbal medicine traditions.
The broader etiocholanolone class has been known to biochemistry since the early-to-mid 20th century. Etiocholanolone causes fever, immunostimulation, and leukocytosis, and has been used to evaluate adrenal cortex function, bone marrow performance, and in neoplastic disease to stimulate the immune system. Etiocholanolone is also known to be an inhibitory androstane neurosteroid, acting as a positive allosteric modulator of the GABAA receptor, and possesses anticonvulsant effects. This pharmacological interest preceded and was separate from the later supplement industry's use of structurally related compounds as aromatase inhibitors.
ATD as an aromatase inhibitor was originally described in the scientific literature in the late 1970s and early 1980s, primarily in the context of laboratory and animal research. In early studies, 1,4,6-androstatriene-3,17-dione (ATD) was demonstrated to cause time-dependent loss of aromatase activity in rat ovarian microsomes in vitro. In vivo, an injection of ATD caused inhibition of ovarian aromatase and reduced estrogen secretion in primed rats for at least 24 hours after injection. The compound only entered the consumer dietary supplement marketplace in the early 2000s.
The central mechanism of both ATD and 3-OHAT is inhibition of the enzyme aromatase (CYP19A1). The aromatase enzyme catalyzes the aromatization of endogenous androgens into estrogens. Inhibiting the enzyme's activity usually leads to a decrease in levels of circulating estrogens and an increase in levels of circulating androgens. Chemicals which inhibit the aromatase enzyme present many potential therapeutic applications.
ATD is a potent irreversible aromatase inhibitor that inhibits estrogen biosynthesis by permanently binding and inactivating aromatase in adipose and peripheral tissue. This mechanism classifies it as a suicide substrate or mechanism-based inhibitor. ATD acts as a suicide substrate by irreversibly binding to the aromatase enzyme and shutting down its activity.
Studies have demonstrated that ATD is more potent than 3-OHAT or AT. Specifically, ATD has a Ki of 0.18 micromolar (μM) and AT (androst-4-ene-3,6,17-trione) has a Ki of 0.43 μM.
The metabolism of 4-androstene-3,6,17-trione (AT) and its irreversible binding to aromatase were studied using human placental microsomes. AT was rapidly converted into the 3β-reduced metabolite (3-OHAT) in the presence of NADPH under either aerobic or anaerobic conditions, and this conversion was efficiently prevented by a steroid 5α-reductase inhibitor. 3-OHAT was characterized as a competitive (Ki = 6.5 μM) and irreversible inhibitor of aromatase. Both ¹⁴C-labeled AT and 3-OHAT were demonstrated to be irreversibly bound to aromatase, probably through a sulfur atom of the enzyme, in time-dependent manners in the presence of NADPH, accompanied by time-dependent losses of enzyme activity.
Because ATD is a non-androgenic compound, it has fewer side effects associated with anabolic/androgenic steroid use — at least compared to androgenic aromatase inhibitors such as formestane. However, 3-OHAT and AT may require frequent and high dosing because of their relatively low potency and rapid metabolization.
By suppressing aromatase activity, these compounds were theorized to reduce conversion of testosterone to estradiol, thereby allowing endogenous testosterone and dihydrotestosterone (DHT) levels to rise. Compounds with the same (androst-4-ene-3,6,17-trione) and very similar (androst-5-ene-4,7,17-trione) structure as 6-OXO have been shown to irreversibly bind to the aromatase enzyme, thereby causing a decrease in estradiol production. Use of these aromatase-inhibiting compounds appears to decrease aromatization and subsequent estradiol synthesis, which apparently increases both testosterone and the free testosterone-to-estradiol ratio (T/E).
The body converts some of the male hormone testosterone to the female hormone estrogen. Androstenetrione (6-OXO) blocks this conversion.
The primary claimed application of these compounds in the supplement market was to elevate endogenous testosterone levels by inhibiting aromatase-mediated conversion to estrogen. Two published human studies are most directly relevant.
Study 1: Novedex XT (containing 3-OHAT THP ether + ATD) — Willoughby et al., 2007
This study examined the effects of an aromatase-inhibiting nutritional supplement on serum steroid hormones, body composition, and clinical safety markers, with sixteen eugonadal young men ingesting either Novedex XT™ or a placebo daily for 8 weeks, followed by a 3-week washout period. Novedex XT resulted in average increases of 283%, 625%, 566%, and 438% for total testosterone (P=0.001), free testosterone (P=0.001), dihydrotestosterone (P=0.001), and the testosterone:estrogen ratio (P=0.001), respectively, whereas fat mass decreased 3.5% (P=0.026) during supplementation. No significant differences were observed in blood and urinary clinical safety markers or for any of the other serum hormones (P>0.05).
The Novedex group had average increases of 283%, 625%, and 566% for total testosterone, free testosterone, and DHT (P<0.05), respectively, and all three androgens returned to baseline levels after the 3-week washout period.
The levels of DHT and total testosterone at weeks 4 and 8 were significantly correlated to one another, thereby suggesting a role of Novedex XT in upregulating the 5α-reductase enzyme concomitant with the significant increase in total testosterone. Critically, the dosage of Novedex XT used in this study was 72 mg/day of the proprietary blend.
Limitations: The study was small (n=16), conducted in a specific population (resistance-trained eugonadal men), and involved a multi-ingredient proprietary blend, making it impossible to attribute observed effects to ATD or 3-OHAT individually. The magnitude of the testosterone increases (283–625%) is unusually large and has not been independently replicated with either compound alone.
Study 2: 6-OXO / androst-4-ene-3,6,17-trione — Rohle et al., 2007
While 6-OXO is the parent compound from which 3-OHAT is derived, its human data provides indirect mechanistic context. The purpose of this study was to determine the effects of 6-OXO, a purported nutritional aromatase inhibitor, in a dose-dependent manner on body composition, serum hormone levels, and clinical safety markers in resistance-trained males. Sixteen males were supplemented with either 300 mg or 600 mg of 6-OXO in a double-blind manner for eight weeks.
Compared to baseline, free testosterone underwent overall increases of 90% for 300 mg 6-OXO and 84% for 600 mg, respectively (P<0.05). DHT underwent significant overall increases of 192% and 265% with 300 mg and 600 mg, respectively. The free testosterone-to-estradiol ratio (T/E) increased 53% and 67% for 300 mg and 600 mg 6-OXO, respectively.
For estrone, 300 mg produced an overall increase of 22%, whereas 600 mg caused a 52% increase. Body composition did not change with supplementation (P>0.05) and clinical safety markers were not adversely affected with ingestion of either supplement dose. While neither of the 6-OXO dosages appears to have any negative effects on clinical chemistry markers, supplementation at a daily dosage of 300 mg and 600 mg for eight weeks did not completely inhibit aromatase activity, yet significantly increased free testosterone, DHT, and T/E.
By the end of the three-week washout period, the levels of these hormones (and all others) had returned to normal levels.
Limitations: This study was also small (n=16), unblinded with respect to dose group, and limited to resistance-trained males. The paradoxical increase in estrone (an estrogen) despite supposed aromatase inhibition raised questions about the compounds' actual degree of suppression in vivo. No body composition improvements were observed, which undermines claims of practical athletic benefit.
ATD was found effective in inhibiting mating and ovulation in the rat. Mating did not occur for as long as treatment was continued (up to 13 days) in 68% of the rats. In the remainder, mating and ovulation were delayed for at least 4 days past the expected day of proestrus and for an average of 5.8 days. When treatment was continued after mating, implantation sites were absent when the animals were examined on day 8 of pregnancy, indicating ATD may also be effective postcoitally. These findings have no direct human parallel and were conducted in animal models only.
ATD was demonstrated to cause time-dependent loss of aromatase activity in rat ovarian microsomes in vitro. In vivo, ATD caused inhibition of ovarian aromatase and reduced estrogen secretion in primed rats for at least 24 hours after injection. In rats with 7,12-dimethylbenz[a]anthracene-induced, hormone-dependent mammary tumors, marked regression occurred with ATD treatment. Although estrogen secretion was not reduced below the diestrus level of controls, the rats remained anestrus, indicating that the proestrus surge of estrogen was prevented. LH, FSH, and prolactin levels were also basal, and LH and FSH did not rise after ovariectomy. These are preclinical findings only; no human oncology trials using ATD or 3-OHAT as dietary supplements have been published.
The main objective of one study was to examine effects of the aromatase inhibitor 1,4,6-androstatriene-3,17-dione (ATD) on behavioral disinhibition displayed by adult male rats treated with a high testosterone dose, using intact rats to resemble the clinical situation. Concurrent administration of ATD at 60 mg/kg/day subcutaneously decreased behavioral disinhibition in testosterone-treated rats without affecting accessory sex organ weights, while behavior was not significantly affected in sham-treated animals. This research was conducted in rodent models; no human behavioral studies of ATD used as a supplement have been published.
The patent for ATD claims many potential uses, including cancer treatment, gynecomastia treatment, treatment of growth and development issues, and treatment of abuse or misuse of anabolic steroids. Many breast cancers have estrogen receptors and their growth can be stimulated by estrogen, and ATD may provide a more effective means of aromatase inhibition to fight such cancers. Estrogens have an essential role in the regulation of bone maturation and importantly in the closure of growth plates in both sexes, and the invention could theoretically be used in children of short stature to increase terminal linear height. These are patent claims, not demonstrated clinical outcomes in human subjects.
The primary target of both ATD and 3-OHAT is the endocrine system. The aromatase enzyme catalyzes the aromatization of endogenous androgens into estrogens; inhibiting the enzyme's activity usually leads to a decrease in levels of circulating estrogens and an increase in levels of circulating androgens. Human studies with Novedex XT demonstrated statistically significant changes in testosterone, DHT, and the testosterone:estrogen ratio, though the clinical significance of these shifts in healthy eugonadal men remains unclear.
Many aromatase inhibitors will cause a rise in endogenous androgen levels but also cause a precipitous and possibly unwanted decrease in endogenous estrogen levels when used in men. Aromatase inhibition in men impacts the hypothalamic-pituitary-gonadal (HPG) axis because estradiol provides negative feedback at the hypothalamus and pituitary. Reducing this feedback via aromatase inhibition can increase LH and FSH secretion, driving testicular testosterone production. This mechanism is why these compounds were marketed for post-cycle therapy (PCT) following use of anabolic steroids.
Eight weeks of supplementation with 72 mg/day of the nutritional aromatase inhibitor Novedex XT had no effect on fat-free mass, but was effective at producing a modest, but significant 3.5% decrease in fat mass compared to placebo. The related compound 6-OXO at 300 mg and 600 mg/day also showed no body composition changes after 8 weeks.
Etiocholanolone (a related endogenous 5β-androstane steroid) is known to be an inhibitory androstane neurosteroid, acting as a positive allosteric modulator of the GABAA receptor, and possesses anticonvulsant effects. This property has not been reported for ATD or 3-OHAT in human studies.
Etiocholanolone causes fever, immunostimulation, and leukocytosis, and is used to evaluate adrenal cortex function, bone marrow performance, and in neoplastic disease to stimulate the immune system. These properties relate to etiocholanolone proper, not to ATD or 3-OHAT, for which no immunological data exist in human subjects.
The following dosages are taken directly from peer-reviewed human studies and described formulations — they are not recommendations:
At this time there is not enough scientific information to determine an appropriate range of doses for androstenetrione (6-OXO/ATD class compounds) in humans.
The FDA determined through laboratory testing that some products contained 1,4,6-androstatriene-3,17-dione (ATD) and/or 3,6,17-androstenetrione (6-OXO). Both of these substances are steroids that inhibit the activity of the enzyme aromatase and may be found in dietary supplements promoted to boost testosterone levels. The FDA stated it had no scientific information concerning the safety of the condemned products or their ingredients and therefore could not determine whether they represented a hazard to consumers.
Because androst-4-ene-3,6,17-trione is an anabolic steroid and an aromatase inhibitor, this substance is regarded as a doping agent. A selective and sensitive GC-MS method for the detection of the TMS-enol-TMS-ether derivatives of these substances was developed and validated for doping control purposes.
ATD may cause a positive test for the anabolic steroid boldenone, of which it is a possible metabolite and production contaminant. This is a significant concern for competitive athletes, as boldenone is a prohibited substance under the WADA Prohibited List.
If ATD/6-OXO actually increases testosterone levels in the body, the extra testosterone could cause serious side effects including liver problems, heart problems, and cancer.
Androstenetrione might increase testosterone levels. Men with hormone-sensitive conditions such as prostate cancer should avoid using androstenetrione.
Aromatase inhibitors will cause a rise in endogenous androgen levels but also cause a precipitous and possibly unwanted decrease in endogenous estrogen levels when used in men. Estrogen plays essential physiological roles in males, including regulation of bone mineral density, cardiovascular health, libido, and cognitive function. Excessive suppression carries risk.
Clinical safety markers were not adversely affected with ingestion of either the 300 mg or 600 mg 6-OXO supplement dose (P>0.05) over eight weeks. However, this single small study does not constitute a comprehensive safety assessment. Androstenetrione might increase testosterone levels, and increased testosterone is associated with liver problems. Long-term hepatic safety data for ATD or 3-OHAT in humans are absent from the peer-reviewed literature.
ATD may cause a positive test for the anabolic steroid boldenone, of which it is a possible metabolite and production contaminant. This represents a concrete, documented anti-doping risk for any athlete subject to testing who uses supplements containing ATD or structurally related compounds.
Based on animal research, ATD was found effective in inhibiting mating and ovulation in the rat, and mating did not occur for as long as treatment was continued (up to 13 days) in 68% of the rats. While this was a rodent study, it underscores the compound's powerful reproductive endocrine effects that could theoretically affect human fertility.
Both primary human studies demonstrated normalization of hormone levels after a washout period. All three androgens (total testosterone, free testosterone, and DHT) returned to baseline levels after the 3-week washout period in the Novedex XT study. Similarly, by the end of the three-week washout period following 6-OXO use, the levels of all measured hormones had returned to normal levels.
The overall body of evidence for 6,17-keto etiocholeva-3-ol (3-OHAT) and 3,17-ketoetiochol-triene (ATD) as dietary supplement ingredients is weak and highly preliminary. Key assessments:
Health conditions that 6, 17 keto etiocholeva-3-ol 3, 17 ketoetiochol-triene may help support.
Body systems that 6, 17 keto etiocholeva-3-ol 3, 17 ketoetiochol-triene may help support.
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