Androstane derivatives

Other Names

17-Ketosteroids3α,5α-Androstenol3α-Androstanediol3α-Hydroxy-17-androstanone3α-Hydroxy-5α-androstan-17-one3α-Hydroxy-5α-androstane-17-one3α-Hydroxy-5β-androstan-17-one3β,5α-Androstenol3β-Acetoxy-5α-androstan-17-one3β-Androstanediol3β-Hydroxy-5α-androstan-17-one5α-Androst-16-en-3-one5α-Androst-16-en-3α-ol5α-Androst-16-en-3β-ol5α-Androstan-17β-ol-3-one5α-Androstan-3α-ol-17-one5α-Androstan-3β-ol-17-one5α-Androstane5α-Androstane-17β-ol-3-one5α-Androstane-3-one-17β-ol5α-Androstane-3α,17β-diol5α-Androstane-3β,17β-diol5α-Androstanolone5α-Androstenone5α-Dihydrotestosterone5β-Androstan-3β-ol-17-one5β-Androstane5β-AndrosteroneAndrogenic steroidsAndrostaneAndrostane androgensAndrostane neurosteroidsAndrostatrienedioneAndrostenediolAndrostenedioneAndrostenetriolAndrostenetrioneAndrostenolAndrostenoneAndrosteroidsAndrosteroneAndrosterone 3-AcetateC19 steroidsDehydroepiandrosteroneDHEADihydrotestosteroneEpiandrosteroneEpietiocholanoloneEtiocholan-3α-ol-17-oneEtiocholaneEtiocholanoloneStanoloneΔ1-AndrostenediolΔ4-AndrostenediolΔ5-Androsten-3β,17β-diolΔ5-Androstenediol

Synopsis

Androstane Derivatives: A Comprehensive Reference

1. Identity and Chemical Classification

Androstane is a saturated tetracyclic C19 steroid hydrocarbon with the molecular formula C₁₉H₃₂, serving as the fundamental parent structure for androstane-class steroids, including androgens. It features a gonane core with angular methyl groups at positions 10 and 13, distinguishing it from other steroid hydrocarbons like pregnane, which possess an additional side chain at C17. Androstane exists in two principal isomeric forms — 5α-androstane and 5β-androstane — differing in the stereochemistry at the A/B ring junction, with the 5α form being more prevalent in mammalian biochemistry due to its association with 5α-reductase-mediated metabolites.

Androstanes encompass 19 carbons (C19 steroids) and are known for including androgens. Structurally, steroidal hormones are characterized by three cyclohexane rings (labeled A, B, and C) and one cyclopentane ring (D), connected in a specific manner. Androstane derivatives refer to compounds derived from the androstane structure, which include modifications that may enhance anabolic and androgenic activity, such as the incorporation of additional double bonds or alkylation at specific positions.

As the skeletal framework for key endogenous androgens such as testosterone, dihydrotestosterone, and androsterone, androstane derivatives play critical roles in male sexual development, muscle anabolism, and metabolic regulation, underscoring their foundational importance in endocrinology and steroid hormone signaling.

Principal Naturally Occurring Androstane Derivatives

Androsterone (3α-hydroxy-5α-androstan-17-one): Androsterone is an endogenous steroid hormone, neurosteroid, and putative pheromone. It is a weak androgen with a potency that is approximately 1/7 that of testosterone.
Androstenedione (androst-4-ene-3,17-dione): Also known as 4-androstenedione (abbreviated as A4 or Δ4-dione), androstenedione is an endogenous weak androgen steroid hormone and intermediate in the biosynthesis of estrone and of testosterone from dehydroepiandrosterone (DHEA).
Androstenediol (androst-5-ene-3β,17β-diol): Also known as 5-androstenediol (abbreviated as A5 or Δ5-diol), androstenediol is an endogenous weak androgen and estrogen steroid hormone and intermediate in the biosynthesis of testosterone from DHEA.
DHEA (dehydroepiandrosterone; androst-5-en-3β-ol-17-one): Dehydroepiandrosterone (DHEA), also known as androstenolone, is an endogenous steroid hormone precursor and one of the most abundant circulating steroids in humans.
5α-Androstanedione (androstane-3,17-dione): Androstanedione is a 5α-reduced metabolite of 4-androstenedione which serves as an intermediate in the biosynthesis of the androgen and neurosteroid androsterone.
1-Androsterone (3β-hydroxy-5α-androst-1-en-17-one): 1-Androsterone, chemically known as 3β-hydroxy-5α-androst-1-en-17-one, undergoes enzymatic conversion in the body to exert its androgenic and anabolic effects.
Epiandrosterone (3β-hydroxy-5α-androstan-17-one): Epiandrosterone, also known as isoandrosterone or 3β-androsterone, is a steroid hormone with weak androgenic activity and a metabolite of testosterone and dihydrotestosterone (DHT).

Relative Androgenic Potencies

The major naturally occurring steroids with androgenic activity, in decreasing order of relative potency, are: 5α-dihydrotestosterone (150–200%), testosterone (100%), androstanediol (65%), androst-4-ene-3,17-dione (25%), androsterone (10%), and dehydroepiandrosterone (10%).

Natural Sources

Androsterone has been shown to naturally occur in pine pollen, celery, and truffles, and is well known in many animal species. DHEA is produced in the adrenal glands, the gonads, and the brain. The androgens, which possess 19 carbon atoms, are produced in the testes in males, and in the ovaries and placenta in females; under some circumstances the adrenal cortex can also produce physiologically significant androgens such as androsterone, 4-androstene-3,17-dione, and dehydroepiandrosterone.

Androstenedione occurs naturally in Mexican yams and Scotch white pine. A variety of natural compounds, including steroids, are produced by fungi or fungal endophytes or found in extracts of plants, algae, or marine invertebrates.

Common Forms and Preparations

Androstane derivatives have been marketed in several forms. Androstenedione was manufactured as a dietary supplement, often called "andro" or "andros" for short. In the United States, DHEA is sold as an over-the-counter supplement and as a medication called prasterone. The DHEA metabolite 5-AED is not used in clinical practice due to its instability; DHEA in the form of the vaginal gel prasterone belongs to androstane derivatives in the ATC classification, along with such well-known anabolic steroids as norethandrolone, methenolone, androstanolone, and stanozolol.

Androstane derivative supplements have been sold in capsule, tablet, powder, and transdermal forms. Modifications to the androstane core facilitate therapeutic applications by improving solubility and reducing metabolism. Oral prohormone formulations have also included microencapsulated and sublingual delivery systems intended to improve bioavailability.

2. Traditional and Historical Use

Discovery of androsterone dates back to 1931, when Butenandt reported the isolation of a compound from a male policeman's urine and named it androsterone (andro = male, ster = sterol, one = ketone). They distilled over 17,000 litres of male urine, from which they obtained 50 milligrams of crystalline androsterone, which was sufficient to find that the chemical formula was very similar to estrone. This work led to the establishment of the chemical structure of androsterone and its relationship to other sterols; in 1935, both Ruzicka and Wettstein and Butenandt and Kudszus reported the synthesis of androstenedione from cholesterol.

A year later, Charles Kochakian, an expert on steroid hormones, discovered that androstenedione possessed both androgenic and anabolic properties. This breakthrough contributed to early understandings of steroid chemistry and endocrinology, with the structure later confirmed through synthesis efforts, including efficient stereoselective methods by Woodward.

Discovered in the early 20th century, androsterone was initially isolated from male urine and was quickly recognized for its connection to the development and regulation of male characteristics. Its identification helped pave the way for the study of androgens and their therapeutic potential; historically, androsterone and related compounds were investigated for their supposed rejuvenating and restorative effects, as early practitioners believed that these hormones could contribute to increased vitality, improved mood, and enhanced physical performance.

Sports Illustrated credits Patrick Arnold with introducing androstenedione to the North American market. The mass-market supplement era for androstane derivatives began in the late 1990s, particularly following the disclosure that professional baseball player Mark McGwire used androstenedione supplements, a development widely reported in the popular press. The 1990 Anabolic Steroids Control Act classified anabolic-androgenic steroids as Schedule III controlled substances, making them more difficult to obtain; androstenedione's occurrence in Mexican yams and Scotch white pine allowed its unrestricted sale in the United States in accordance with the 1994 Dietary Supplement Health and Education Act (DSHEA).

Androstenedione, 4-androstenediol, 5-androstenediol, 19-norandrostenediol and 19-norandrostenedione are commonly referred to as "Andro" prohormones; over the last few years, supplementation using these prohormones has been aggressively marketed to the general public. Supplement manufacturers often claim that Andro use improves serum testosterone concentrations, increases muscular strength and muscle mass, helps to reduce body fatness, enhances mood, and improves sexual performance.

3. Key Constituents, Biosynthetic Relationships, and Mechanisms of Action

Biosynthetic Cascade

The androstane derivatives are biosynthetically interconnected through an enzymatically controlled cascade. DHEA is converted to androstenedione (4-androstene-3β,17β-dione) by 3β-hydroxysteroid dehydrogenase (3β-HSD) and to androstenediol (5-androstene-3β,17β-diol) by 17β-hydroxysteroid dehydrogenase (17β-HSD). Androstenedione is then converted to testosterone by 17β-hydroxysteroid dehydrogenase. Testosterone is subsequently converted to dihydrotestosterone (DHT), the most potent androgen, via 5-alpha reduction. DHT can be further metabolized to androstane-3α,17β-diol (3-diol).

Androstenedione can be synthesized from dehydroepiandrosterone and further converted into either testosterone through the action of 17β-hydroxysteroid dehydrogenase, or to estrone via the aromatase enzyme complex. DHEA is converted into androstenedione in the adrenal cortex, where it can be either aromatized to estrone or de-hydrogenated in the liver to yield testosterone.

Androgens are circulated through the peripheral tissues in the body, followed by immense metabolism and subsequent excretion in urine. Metabolism of androgen takes place mainly via hydroxysteroid dehydrogenases, reductases, and conjugation enzymes.

Androsterone is sulfated into androsterone sulfate and glucuronidated into androsterone glucuronide, and these conjugates are excreted in urine.

Tissue Distribution of Conversion

Androstenedione and androstenediol are converted to testosterone in the testes and any tissue cells that contain androgen or estrogen receptors. Adipose, bone, muscle, breast, prostate, liver, brain, and skin can be affected. The conversion of androstenedione and androstenediol to testosterone is regulated by the enzymes 17β-hydroxysteroid dehydrogenase and 3β-hydroxysteroid dehydrogenase, respectively.

Androgen Receptor Binding and Prohormone Activity

In addition to functioning as an endogenous prohormone, androstenedione also has weak androgenic activity in its own right. Androstenedione has been found to possess some estrogenic activity, similarly to other DHEA metabolites. In contrast to androstenediol, androstenedione's affinity for the estrogen receptors is very low, with less than 0.01% of the affinity of estradiol for both the ERα and ERβ.

Androstenediol possesses potent estrogenic activity, similarly to DHEA and 3β-androstanediol. It has approximately 6% and 17% of the affinity of estradiol at the ERα and ERβ, respectively.

Neurosteroid Mechanisms

Androsterone is also known to be an inhibitory androstane neurosteroid, acting as a positive allosteric modulator of the GABA_A receptor, and possesses anticonvulsant effects. The naturally occurring neurosteroids — allotetrahydrodeoxycorticosterone (5α,3α-THDOC), androstenediol, and androsterone — which have O=CCH₂OH, alcohol, and keto substituents at the 17-position have GABA receptor modulating activity.

Androstane and pregnane steroid compounds have been investigated for their use as allosteric modulators of the GABA receptor chloride ionophore complex and for their use to alleviate stress, anxiety, mood disorders, seizures, depression, treatment of drug and alcohol abuse, memory, premenstrual disorders, and neural system damage.

Research on androstane and androstene neurosteroids with modifications at C-17, C-5, and C-3 has been conducted to estimate their ability to influence the functional activity of inhibitory glycine and γ-aminobutyric acid (GABA) receptors. Results demonstrate that tested neurosteroids strongly inhibited glycine-induced chloride current and weakly inhibited GABA-induced chloride current. The threshold concentration of neurosteroids inducing effects on glycine receptors was 0.1 μM, and for effects on GABA receptors was 10–50 μM.

Constitutive Androstane Receptor (CAR) and Nuclear Receptor Interactions

DHEA and many of its oxidative metabolites serve as low-affinity ligands for hepatic nuclear receptors, such as the pregnane X receptor, the constitutive androstane receptor, and estrogen receptors α/β (ERα/ERβ), as well as the G protein-coupled estrogen receptor (GPER1).

Immune-Modulating Properties

The natural androstene steroids, consisting of dehydroepiandrosterone (DHEA), androstenediol (Δ5-androstene-3β,17β-diol; β-AED), and androstenetriol (Δ5-androstene-3β,7α/β,17β-triol; α/β-AET), have been shown to have profound effects on host immune regulation and hematopoiesis. The prohormone DHEA and its sulfated derivative are the major circulating steroids in humans, and the source for ovarian and adrenal androgen synthesis; with aging their concentrations decline significantly.

Androstenediol is a direct metabolite of the most abundant steroid produced by the human adrenal cortex, DHEA; it is less androgenic than the related compound Δ4-androstenediol, and has been found to stimulate the immune system.

4. Scientific Evidence by Area of Use

4.1 Athletic Performance and Muscle Anabolism

This has been the most extensively studied application for exogenous androstane derivatives in humans. The overall findings are largely negative for the performance claims.

King et al. (1999), JAMA: The study aimed to determine if short- and long-term oral androstenedione supplementation in men increases serum testosterone levels, skeletal muscle fiber size, and strength, and to examine its effects on blood lipids and markers of liver function. It was an 8-week randomized controlled trial conducted between February and June 1998. Twenty subjects performed 8 weeks of whole-body resistance training; during weeks 1, 2, 4, 5, 7, and 8, the men were randomized to either androstenedione at 300 mg/d or placebo. The effect of a single 100-mg androstenedione dose on serum testosterone and estrogen concentrations was also determined in 10 men. Serum free and total testosterone concentrations were not affected by short- or long-term androstenedione administration. In summary, androstenedione supplementation neither increased serum testosterone concentrations nor enhanced the strength gains of resistance training.

Liederman et al. / The Andro Project (2000–2001): Testosterone precursor supplementation did result in significant increases in estrogen-related compounds, dehydroepiandrosterone sulfate concentrations, down-regulation in testosterone synthesis, and unfavorable alterations in blood lipid and coronary heart disease risk profiles of men aged 35 to 65 years. Fifty men with normal total testosterone levels were randomly assigned to placebo, androstenediol, or androstenedione groups using a double-blind study design; main outcomes included serum sex hormone profile, body composition assessment, muscular strength, and blood lipid profiles. During 12 weeks of androstenedione or androstenediol use, a significant increase in the aromatization by-products estrone and estradiol was observed in both groups (P = 0.03). In the dione group, total testosterone levels significantly increased 16% after 1 month of use, but by the end of 12 weeks returned to pretreatment levels.

Randomized Trial in Middle-Aged Men (100 mg/d, 12 weeks): The purpose of this study was to compare the effects of short-term (12-wk) supplementation with androstenedione versus DHEA on body composition, strength, and related hormones in middle-aged men; a randomized, placebo-controlled, double-blind design was used to study 40 healthy, trained male subjects (mean age 48.1 ± 3.9 yr). Subjects were randomly assigned to placebo (P), DHEA (D), or androstenedione (A); supplements (50 mg capsules) were ingested two times daily for 12 weeks. The results of this study suggest that supplementation with 100 mg/d of either androstenedione or DHEA does not independently elicit a statistically significant increase in lean body mass, strength, or testosterone levels in healthy adult men over a 12-wk period.

Systematic Review and Meta-Analysis (2022): To date, no prior meta-analysis had collected evidence from randomized placebo-controlled trials (RCTs) comprehensively summarizing the effect of androstenedione supplementation; the aim of this research was to perform a systematic review and meta-analysis of all RCTs that explored the effect of androstenedione supplementation on individual hormonal, lipid, and anthropometric indices. These findings indicate that androstenedione supplementation can lower triglycerides and HDL-cholesterol and increase estradiol concentrations. Supplement manufacturers often claim that Andro use improves serum testosterone concentrations, increases muscular strength and muscle mass, helps to reduce body fatness, enhances mood, and improves sexual performance; however, to date, most studies contradict these claims.

1-Androsterone (3β-hydroxy-5α-androst-1-en-17-one), Journal of Applied Physiology (2014): Seventeen resistance-trained men (23 ± 1 yr; 13.1 ± 1.5% body fat) were randomly assigned to receive either 330 mg/day of 3β-hydroxy-5α-androst-1-en-17-one or placebo and complete a 4-week (16-session) structured resistance-training program; body composition, muscular strength, circulating lipids, and markers of liver and kidney dysfunction were assessed at study onset and termination. The prohormone group increased lean body mass by 6.3 ± 1.2%, decreased fat body mass by 24.6 ± 7.1%, and increased their back squat one repetition maximum and competition total by 14.3 ± 1.5 and 12.8%, respectively. The oral prohormone 3β-hydroxy-5α-androst-1-en-17-one improved body composition and muscular strength; however, these changes came at a significant cost, with cardiovascular health and liver function particularly compromised. Multiple adverse effects were noted, including a 38.7 ± 4.0% reduction in HDL (P < 0.01), a 32.8 ± 15.05% elevation in LDL (P < 0.01), elevations in LDL-to-HDL and cholesterol-to-HDL ratios (both P < 0.01), as well as elevations in serum creatinine (19.6 ± 4.3%; P < 0.01) and aspartate transaminase (113.8 ± 61.1%; P = 0.05), and reductions in serum albumin, alkaline phosphatase, and glomerular filtration rate.

Evidence strength summary: Multiple RCTs and at least one meta-analysis consistently show that androstenedione does not increase testosterone or enhance muscle strength in young men. A single small RCT of 1-androsterone found body composition effects but significant adverse metabolic consequences. Overall evidence for anabolic benefit is weak to absent, while evidence for metabolic harms (HDL reduction, estrogenic elevation) is consistent across studies.

4.2 Hormonal and Endocrine Effects

Androstenedione is a precursor of testosterone and other androgens, as well as of estrogens like estrone, in the body. In children aged 6 to 8 years old, there is a rise in androstenedione secretion along with DHEA during adrenarche. DHEA and other adrenal androgens such as androstenedione, although relatively weak androgens, are responsible for the androgenic effects of adrenarche, such as early pubic and axillary hair growth, adult-type body odor, increased oiliness of hair and skin, and mild acne.

Several studies using oral Andro-related prohormones show that Andro use can abnormally elevate estrogen-related hormones as well as alterations in hormonal markers — including abnormal elevations in serum estrogen — thought to increase a person's risk for developing prostate or pancreatic cancers.

Evidence strength summary: The hormonal effects of exogenous androstenedione supplementation (increased estrone/estradiol, suppression of endogenous testosterone synthesis over time) have been demonstrated in multiple well-controlled RCTs. These endocrine changes are robustly documented but are not of the type claimed by manufacturers.

4.3 Bone Mineral Density

DHEA levels decline dramatically with age, concurrent with the onset of osteoporosis, suggesting a role for DHEA supplementation in preventing age-related bone loss. The DAWN trial, a major RCT in this area, specifically examined the androstane-derived precursor DHEA:

A randomized, placebo-controlled trial examined the effect of 50 mg daily oral DHEA supplementation for one year on bone mineral density (BMD), bone metabolism, and body composition in 225 healthy adults aged 55 to 85 years; DHEA treatment increased serum DHEA and DHEA sulfate levels to concentrations seen in young adults. Testosterone, estradiol, and insulin-like growth factor (IGF-1) levels increased in women (all p < 0.001), but not men, receiving DHEA. Serum C-terminal telopeptide of type-1 collagen levels decreased in women (p = 0.03), but not in men, whereas bone-specific alkaline phosphatase levels were not significantly altered in either sex. After 12 months, there was a positive effect of DHEA on lumbar spine BMD in women (p = 0.03), but no effect was observed for hip, femoral neck, or total body BMD, and no significant changes were observed at any site among men. Body composition was not affected by DHEA treatment in either sex.

The androstene steroids, with their ability to up-regulate host immunity and restore bone myeloid cells following whole-body radiation, may have a major role in osteoimmunity.

Evidence strength summary: Evidence for androstane derivative (primarily DHEA)-associated effects on BMD is limited, heterogeneous, and sex-dependent. A modest positive effect at the lumbar spine in older women has been observed in at least one adequately powered RCT; effects in men and at other skeletal sites have not been confirmed. Evidence is preliminary and inconsistent across studies.

4.4 Neurological and Mood Effects

Androsterone is known to be an inhibitory androstane neurosteroid, acting as a positive allosteric modulator of the GABA_A receptor, and possesses anticonvulsant effects. The unnatural enantiomer of androsterone is more potent as a positive allosteric modulator of GABA_A receptors and as an anticonvulsant than the natural form.

Androgenic neurosteroids including androsterone sulfate and androstenedione also enhance long-term potentiation (LTP). While DHEA sulfate enhanced both components of the evoked responses elicited by perforant path stimulation, androstenedione and androsterone sulfate enhanced only the population spike.

Altered DHEA/DHEAS levels have been implicated in neurodegenerative disorders and depression, with emerging evidence supporting their potential therapeutic value. In addition, DHEA plays a multifaceted role in aging-related physiological changes.

DHEA has a variety of potential biological effects in its own right, binding to an array of nuclear and cell surface receptors, and acting as a neurosteroid and modulator of neurotrophic factor receptors.

Evidence strength summary: Neurological and mood effects of androstane derivatives have primarily been characterized in preclinical (in vitro and animal) research. GABA_A receptor modulation by androsterone is well documented mechanistically, but direct clinical evidence from human trials evaluating androstane derivative supplementation on neurological or mood outcomes is sparse and insufficient to draw conclusions.

4.5 Metabolic and Glycemic Effects

Research to establish whether DHEA/DHEAS or its metabolites (such as androstenedione) are responsible for improving hyperglycemia has been conducted. Androstenedione was administered to C57BL6 mice on a high-fat diet; the result showed androstenedione did not increase Akt phosphorylation in the liver, and it only lightly reduced blood glucose levels compared with DHEA, which further supports the idea that the hypoglycemic effects of DHEA are primarily mediated by DHEA or DHEAS per se. Studies on the relationship of DHEA and insulin sensitivity reported mixed results. The possible mechanisms behind the improvement in diabetes mellitus may include increased glucose uptake in adipocytes by promoting the translocation of GLUT4 and GLUT1 through the plasma membrane, antioxidative effects, and preventing production of advanced glycation end-products.

Evidence strength summary: Metabolic effects of androstane derivatives on glucose metabolism are largely derived from animal studies. DHEA itself (not androstenedione) shows the more biologically credible metabolic effects in animal models. Human clinical evidence for androstenedione or other androstane derivative supplementation specifically improving glycemic control is absent.

4.6 Immune and Hematopoietic Effects

The natural androstene steroids — including DHEA, androstenediol, and androstenetriol — have been shown to have profound effects on host immune regulation and hematopoiesis. Research into androstenediol in the context of radioprotection and immune reconstitution has been conducted in animal models. Since it was noted that circulating DHEA-S levels decline as a function of age, experimental pathology experiments in animals were performed to determine how DHEA may protect against cancer, diabetes, aging, obesity, immune function, bone density, depression, adrenal insufficiency, inflammatory bowel disease, diminished sexual function/libido, AIDS/HIV, chronic obstructive pulmonary disease, coronary artery disease, chronic fatigue syndrome, and metabolic syndrome. While the mechanisms by which DHEA ameliorates these conditions in animal models have been elusive to define, even less is known about its role in human disease, other than as a precursor to other sterols, e.g., testosterone and estradiol.

Evidence strength summary: Evidence for immune and hematopoietic effects of androstane derivatives is largely preclinical. Clinical human studies confirming supplementation benefits for immune function from these compounds are not established at the level required for evidence-based therapeutic recommendations.

5. Body Systems and Health Areas Associated with Androstane Derivatives

Endocrine system: Androstane derivatives are central intermediates in sex hormone biosynthesis, connecting adrenal DHEA production to gonadal testosterone and estrogen synthesis in multiple tissues.
Musculoskeletal system: DHEA supports muscle anabolism and bone density maintenance. As prohormones, androstane derivatives can influence muscle protein synthesis indirectly via conversion to more potent androgens, though clinical evidence for meaningful anabolic effects from supplementation is consistently weak.
Cardiovascular system: Testosterone precursor supplementation results in unfavorable alterations in blood lipid and coronary heart disease risk profiles of men. Most studies indicate that significant declines in high-density lipoproteins occur, leading to an increased cardiovascular disease risk.
Central nervous system: Androsterone acts as a positive allosteric modulator of the GABA_A receptor and possesses anticonvulsant effects. DHEA and its metabolites function as neurosteroids influencing long-term potentiation and potentially mood-related pathways.
Reproductive system: Androstane derivatives are biosynthetic precursors to both testosterone and estrogens; their exogenous supplementation has been shown to alter sex hormone ratios, and chronic use has been associated with adverse reproductive effects including testicular atrophy.
Immune system: Androstenediol has been found to stimulate the immune system.
Skin: Androstane derivatives administered locally (topically) display a pronounced sebum-suppressive effect and have been investigated for the topical treatment of diseases such as acne and seborrhea.
Hepatic (liver): DHEA and its oxidative metabolites serve as low-affinity ligands for hepatic nuclear receptors, including the constitutive androstane receptor (CAR) and the pregnane X receptor.

6. Dosage Forms and Dosages Reported in Studies

The following dosages are reported as used in cited studies only and do not represent recommendations.

In the JAMA King et al. (1999) RCT, twenty subjects performed 8 weeks of whole-body resistance training; during intermittent weeks, subjects were randomized to either androstenedione at 300 mg/d or placebo. The effect of a single 100-mg androstenedione dose was also assessed in 10 men.
In the 12-week RCT of 40 trained middle-aged men, subjects were randomly assigned to placebo, DHEA, or androstenedione; supplements (50 mg capsules) were ingested two times daily for 12 weeks (total daily dose: 100 mg).
The DAWN trial used 50 mg daily oral DHEA supplementation for one year in 225 healthy adults aged 55 to 85 years.
In the Journal of Applied Physiology 1-androsterone study, seventeen resistance-trained men received either 330 mg/day of 3β-hydroxy-5α-androst-1-en-17-one or placebo and completed a 4-week structured resistance-training program.
A topical androstane-carbonitrile derivative (WIN 24,540) was studied for clinical efficacy in containing hypercortisolism; clinical efficacy was weak, even at high doses up to 1400 mg daily, and was accompanied by gastrointestinal side effects.
In topical preparations for sebum suppression, the sebum-suppressive androstane agent was preferably present in a concentration of 0.05–5.0% by weight based on the total weight of the preparation.

7. Safety Considerations and Drug Interactions

7.1 Regulatory Status

On March 11, 2004, the Food and Drug Administration (FDA) pronounced that dietary supplement products containing androstenedione were adulterated new dietary ingredients under the Dietary Supplement Health and Education Act of 1994 (DSHEA). The FDA issued a press release, held a news conference, and sent warning letters to 23 companies that had manufactured, marketed, or distributed products containing androstenedione.

In October 2004, President George Bush signed the Anabolic Steroid Control Act, which reclassified androstenedione from a supplement to an anabolic steroid, making it and other steroid-based drugs a controlled substance. Though commonly used as a supplement for body building, androstenedione is listed among performance-enhancing drugs (PEDs) and is banned by the World Anti-Doping Agency, as well as the International Olympic Committee.

Androstenedione is also banned by the National Football League, the National Collegiate Athletic Association, and the International Olympic Committee. The World Anti-Doping Agency (WADA) lists 1-Andro and its metabolites under "anabolic agents" on its Prohibited List.

7.2 Cardiovascular Adverse Effects

Most studies using oral Andro-related prohormones indicate that significant declines in high-density lipoproteins occur, leading to an increased cardiovascular disease risk. The 1-androsterone RCT documented a 38.7 ± 4.0% reduction in HDL (P < 0.01) and a 32.8 ± 15.05% elevation in LDL (P < 0.01), as well as elevations of 120.0 ± 22.6 and 77.4 ± 12.0% in LDL-to-HDL and cholesterol-to-HDL ratios, respectively (both P < 0.01).

7.3 Estrogenic and Reproductive Adverse Effects

Several studies show that Andro use can abnormally elevate estrogen-related hormones as well as alterations in hormonal markers thought to increase a person's risk for developing prostate or pancreatic cancers. Long-term use of androstenedione supplements by men can result in testicular atrophy, impotence, and the development of female characteristics such as breast enlargement. Women who use these products may develop male characteristics such as male pattern baldness, deepening of the voice, increased facial hair, and enlargement of the clitoris. Women can also develop abnormal menstrual cycles, abnormal bleeding, and blood clots.

Androstenedione supplements may also cause positive urine tests for illegal steroid use because they commonly contain a contaminant (19-norandrostenedione).

7.4 Hepatic and Renal Adverse Effects

In the 1-androsterone RCT, the prohormone group exhibited elevations in serum creatinine (19.6 ± 4.3%; P < 0.01) and aspartate transaminase (113.8 ± 61.1%; P = 0.05), as well as reductions in serum albumin (5.1 ± 1.9%; P = 0.04), alkaline phosphatase (16.4 ± 4.7%; P = 0.04), and glomerular filtration rate (18.0 ± 3.3%; P = 0.04).

Cardiovascular health and liver function are particularly compromised by this class of prohormone supplement.

7.5 Effects in Adolescents

Among children and teens, androstenedione can put them at risk for the same hormonal effects as adults, as well as for early onset of puberty and premature cessation of growth.

7.6 Drug Interactions

The ability to metabolize androstenedione can be affected when the drug berotralstat is used. Berotralstat is used to prevent angioedema, a hereditary swelling of the face.

The use of androstenedione in some individuals, including athletes, can cause an increase in the testosterone to epitestosterone ratio (T/E) above the International Olympic Committee (IOC) cut-off of 6, which is likely to occur in men who take testosterone.

7.7 Evidence Gaps and Limitations

Scientific investigations have explored the effects of androgens, including androsterone, on aspects such as stress response, cognitive function, and social behaviors, though most clinical evidence focuses on its role as a biomarker rather than as a supplement. To date, robust clinical studies directly validating the efficacy of androsterone supplementation in humans are limited.

Though supplementation shows potential benefits, especially in conjunction with resistance training, results remain discrepant. Current evidence has revealed that the therapeutic effects of DHEA supplementation are inconsistent in different human systems among different studies. The diversity of results is mainly due to heterogeneous receptor distribution, various action pathways, and distinct tissue responses in different systems. Further research is needed to define efficacy and dosage across various systems.

References

Health Conditions

Health conditions that Androstane derivatives may help support.

No conditions available.

Body Systems

Body systems that Androstane derivatives may help support.

No body systems available.