Androstenedione   中文名称: 4-雄烯二酮

Endogenous hormone

睾酮、雄烯二酮和黄体酮衍生物的生物转化研究最为深入的一项研究是在培养的蓝鲍属真菌菌株中进行的。所有检查的底物都经过转化或羟基化，这使研究人员能够分离出生物转化的代谢物。同一作者和他的同事研究了睾酮、雄烯二酮和具有额外C1-C2双键和/或17α-甲基的黄体酮衍生物在培养的蓝鲍属真菌菌株中的转化，作为评估类固醇（包括4A）的真核生物转化的模型。尽管底物包括4-烯-3-氧代体系，但它们在C-17的取代基和/或额外的C1-C2双键的存在方面显示出一些差异。

雄激素或类固醇应在广泛的医疗监督下进行监管，特别是雄烯二酮或4-雄烯3-17-二酮（4A）及其衍生物。它们的代谢产物影响人类和非人类，即真菌、动物和啮齿动物。此外，运动员只考虑睾酮水平的增加和骨骼成熟，而忽略了服用此类补充剂的其他已知和未知后果。此外，其中一些积极影响尚未得到充分的科学证明。据报道，雄烯二酮对雄性和雌性小鼠具有致癌作用，现有的雄烯二酮类致癌数据有限，因此有必要进行更多的研究，以提供更广泛的剂量限制，从而减少或预防此类毒性作用。显然，与雄烯二酮的益处相比，在男性、女性和儿童中补充雄烯二酮类会产生许多毒性作用。这篇综述旨在对雄烯二酮的消费、代谢、健康影响和毒性提供详细的见解。预计随着更多关于雄烯二酮药物补充的研究数据的提供，对人类健康有用剂量的更大控制将成为可能。

Hormone replacement therapy is a potential strategy for the protection of bones from postmenopausal osteoporosis. However, there are multiple disadvantages due to their potential harmful side effects in other organs. It is unclear whether androstenedione could impact the levels of physiological hormones by changing the liver enzyme activities that metabolize steroid hormones or not. Hence, Flynn conducted a study on mature female rats, where they were gavaged with androstenedione (0, 5, 30, or 60 mg/kg/day) two weeks before mating and continued through gestation day 19. In addition, non-pregnant female rats were gavaged for the same timeframe with androstenedione (0 or 60 mg/kg/day) and the liver was further dissected from pregnant rats on gestation day 20, as well as from non-pregnant rats after five weeks of treatment. Liver microsomes were incubated with testosterone, leading to the production of 6-hydroxytestosterone, 15-hydroxytestosterone, 7- hydroxytestosterone, 16- hydroxytestosterone, and 2-hydroxytestosterone at high levels compared to controls. The formation of 6-hydroxytestosterone was observed at both 30 and 60 mg/kg/day dose levels. On the other hand, in non-pregnant rats, androstenedione (60 mg/kg/day) markedly increased the formation of 15-, 6-, 16 -, and 2 -hydroxytestosterone. The results highlighted that high oral doses of androstenedione could enhance some female rat liver cytochrome P450 activities that metabolize steroid hormones. It is worth noting that there were no response differences among androstenedione doses between pregnant and non-pregnant female rats.

Absorption, Distribution and Excretion
The absorption of orally administered androstenedione appears to vary among individuals, but some absorption does occur. Androstenedione is distributed throughout various tissues of the body… /Breast Milk/ It is unclear whether anabolic steroids are distributed into breast milk. There are no records of human cases. Women taking anabolic steroids should not breastfeed. /Anabolic Steroids/

---

Metabolism/Metabolites This study compared the metabolism of the androgen precursor androstenedione (AD) in two species of gastropod snails: Bolinus brandaris and Hexaplex trunculus. Microsomal fractions isolated from Bolinus brandaris primarily converted AD to 5α-dihydrotestosterone, while Hexaplex trunculus primarily metabolized it to testosterone. Sexual differences in AD metabolism were detected only in Bolinus brandaris, attributed to higher 5α-reductase activity in males. Subsequently, researchers investigated the effects of the organotin compounds tributyltin (TBT) and triphenyltin (TPT) on AD metabolism. The results showed that significant interference was observed only in females, and the mechanisms of action of the two compounds differed: TPT potently inhibited 5α-reductase activity in Hypophthalmichthys trunculus at concentrations as low as 100 nM, while TBT (10 μM) altered AD metabolism in H. trunculus by increasing the activity of 17β-hydroxysteroid dehydrogenase (17β-HSD). Therefore, this study demonstrates significant differences in the activity and metabolic profile of the androgen precursor AD in gastropods, further confirming that TBT and TPT can interfere with key enzymatic pathways in androgen synthesis. Skeletal tissue is a target organ for androgens. The mechanisms by which these steroids exert their effects within bone cells remain poorly understood. Therefore, this study evaluated the metabolism of androstenedione (a major circulating androgen in women) in osteoblast-like osteocytes cultured from the bones of 16 postmenopausal women (mean age 69 years, range 56–80 years) and 3 older men who underwent total hip arthroplasty (mean age 71 years, range 69–73 years). Each cell line was incubated under standardized conditions with different concentrations of [1,2,6,7-(3)H]androstenedione (0.05–5 μM). 5α-reducing metabolites and 17β-hydroxysteroids were generated in all cases. There was no correlation between the volumetric density of the excised bone and the androstenedione metabolism of the corresponding cultured osteoblast cell lines. The apparent Km values for 5α-reductase activity (sum of androstenedione and dihydrotestosterone) in all 19 cell lines were 0.7 ± 0.1 μM (mean ± standard error), and the apparent Km value for 17β-hydroxysteroid dehydrogenase (sum of testosterone and dihydrotestosterone) was 2.3 ± 0.8 μM (mean ± standard error), similar to reported values for other androgen target organs. Our results indicate that human osteoblast-like cells are capable of converting androstenedione into the more potent biological androgens testosterone and dihydrotestosterone. Since the Km values for both 5α-reductase and 17β-hydroxysteroid dehydrogenase were higher than serum androstenedione concentrations, testosterone and dihydrotestosterone production appears to be primarily dependent on substrate availability. Upregulation of aromatase expression in endometrial cells that have diffused into the peritoneal cavity may enhance their survival through local estrogen synthesis, potentially contributing to endometriosis. The factors mediating aromatase induction in the endometrium remain unclear, but increased expression of steroidogenic factor (SF)-1 may play a role. This study aimed to determine whether androstenedione (A4), a major sex steroid in peritoneal fluid, regulates aromatase expression in the endometrium. This was a cell/tissue culture study conducted at an academic center. Quantitative real-time PCR, high-performance liquid chromatography (HPLC), and chromatin immunoprecipitation were employed. Treatment of cultured human endometrial tissue blocks and stromal cells with A4 (10 nM) significantly upregulated the expression of aromatase mRNA transcripts containing exon IIa at the 5' end. In endometrial stromal cells and the human endometrial surface epithelium (HES) cell line, A4-induced aromatase mRNA expression was associated with increased SF-1 expression. In HES cells, tritium-labeled A4 is metabolized to estradiol, testosterone (T), dihydrotestosterone, and androstenedione. Both estradiol and T (but not non-aromatized androgens) upregulate the expression of aromatase and SF-1 mRNA in HES cells. Chromatin immunoprecipitation experiments showed that A4 enhanced SF-1 recruitment to its response element (-136 bp) located upstream of exon IIa of CYP19. The finding that both the estrogen receptor antagonist ICI 182,780 and the aromatase inhibitor fazodazole inhibited A4 and T-induced aromatase and SF-1 mRNA expression suggests that the induction of A4 and T is mediated by their conversion to estrogen. Endometrial cell exposure to A4 may enhance CYP19 gene expression through its aromatization into estrogen. Androstenedione is synthesized in the adrenal glands and gonads from dehydroepiandrosterone. It is metabolized to testosterone by 17β-hydroxysteroid dehydrogenase and to estrone by aromatase complex. Estrone is metabolized to estradiol. Androstenedione is distributed throughout the body and metabolized into testosterone and estrone. The amount of testosterone produced per dose of androstenedione appears to vary from person to person. Generally, women experience a greater increase in serum testosterone levels after oral administration of androstenedione than men. Androstenedione is a known metabolite of human testosterone. Androstenedione originates from the conversion of dehydroepiandrosterone (DHEA) or 17-hydroxyprogesterone. It can be further converted into testosterone or estrone. Adrenal androstenedione production is regulated by adrenocorticotropic hormone (ACTH), while gonadal androstenedione production is regulated by gonadotropins. In men, the conversion of androstenedione to testosterone requires the catalysis of 17β-hydroxysteroid dehydrogenase. In women, the conversion of androstenedione to estrogens (such as estrone and estradiol) requires the catalysis of aromatase.

Toxicity Summary
Identification and Uses: Androstenedione is a synthetic androgen analogue that has been used as a dietary supplement. Human Studies: There are case reports of androstenedione-induced erectile dysfunction and severe oligospermia. One study investigated the effects of androstenedione supplementation on hormone levels in 10 men and its interaction with resistance exercise. Exercise increased testosterone levels, with no significant difference under different conditions. After androstenedione supplementation, exercise significantly increased plasma estradiol levels by approximately 83% within 90 minutes. Therefore, androstenedione supplementation is unlikely to provide any anabolic benefits to male athletes and will increase estrogen levels during high-intensity resistance exercise. Another study showed that daily oral administration of 300 mg of androstenedione increased serum testosterone and estradiol concentrations in some healthy men. However, androstenedione supplementation led to a significant increase in estrogen-related compounds and dehydroepiandrosterone sulfate concentrations, downregulation of testosterone synthesis, and adverse effects on blood lipids and coronary heart disease risk in men aged 35 to 65. Animal studies: In the maximum sensitization test in guinea pigs, androstenedione showed no skin sensitization at an intradermal induction concentration of 5% and a transdermal induction and challenge concentration of 25%. Rabbits reported eye irritation symptoms. A single oral dose of 1000 mg/kg androstenedione in male rats resulted in death, while animals survived at a dose of 500 mg/kg. Clinical symptoms associated with the compound included lethargy, gait disturbance, and crouching posture. At lethal doses, other symptoms included prone position, loss of consciousness, respiratory disturbances, and increased diuresis. Oral administration of androstenedione at doses of 0, 15, 50, and 150 mg/kg once daily for 4 weeks to male and female rats resulted in dose-dependent effects in female rats, such as weight gain, uterine, cervical, pituitary, and adrenal atrophy, and increased red blood cell and hemoglobin counts. Thymic changes were observed in male rats. These effects are considered typical endocrine effects of steroid hormones. Infusion of androstenedione into pregnant monkeys induced premature parturition-like myometrial activity and elevated maternal plasma estrogen, oxytocin, and amniotic fibronectin concentrations, similar to levels observed during normal full-term delivery. In rats, androstenedione had no specific effect on the development of individual bones or soft tissues. According to OECD TG 471 (Ames test in Salmonella Typhimurium TA98, TA1537, TA100, TA102, and TA1535), androstenedione did not show mutagenicity at the highest recommended dose of 5.0 mg/plate (regardless of metabolic activation) in bacterial reverse mutation assays. Ecotoxicity studies: Aquatic exposure to androstenedione induced masculinization in adult female mosquitofish within a relatively short timeframe. Environmentally relevant concentrations of exogenous androstenedione significantly modulated the reproductive physiology of the gudgeon, and this modulation was sex-specific. Androstenedione can be converted into testosterone and estrogen. When ingested in sufficient doses, androstenedione can cause undesirable masculinizing and feminizing effects. Androstenedione is considered a precursor to androgenic steroids because testosterone is an androgen or male hormone. In men, the conversion of androstenedione to testosterone requires the catalysis of 17β-hydroxysteroid dehydrogenase. In women, the conversion of androstenedione to estrogens (such as estrone and estradiol) requires the catalysis of aromatase.

---

Interactions
It is known that the concentration of intratesticular testosterone (IT) is 100–200 times that of serum testosterone; however, the concentration of intratesticular testosterone precursors, their concentration gradient from the testes to serum, their dependence on gonadotropins, and their response to human chorionic gonadotropin (hCG) stimulation have not been studied in detail. We hypothesized that the use of gonadotropin-releasing hormone (GnRH) antagonists would significantly reduce serum and testicular levels of androstenedione (ADD) and dehydroepiandrosterone (DHEA), while stimulation with human chorionic gonadotropin (hCG) would increase ADD and DHEA levels, but serum DHEA levels would not be similarly suppressed. We used the GnRH antagonist acillin to suppress gonadotropin levels in 23 healthy men and randomly assigned them to four hCG dose groups: 0, 15, 60, or 125 IU, administered subcutaneously every other day for 10 days. Blood and testicular fluid samples were collected at baseline and 10 days after treatment to determine serum and testicular hormone levels. Baseline intratesticular androstenedione (IT ADD) [median (25th percentile, 75th percentile)] was 629 (308, 860) nmol/L, and intratesticular dehydroepiandrosterone (IT DHEA) was 564 (411, 879) nmol/L, representing 175-fold and 27-fold higher concentrations than their serum levels, respectively. Acillin inhibited intratesticular ADD and DHEA by 98% and 82%, respectively, while human chorionic gonadotropin (hCG) administration significantly increased both levels. Similarly, serum ADD was inhibited by 50%, but serum DHEA levels remained unchanged. Compared to serum, the concentrations of ADD and DHEA were higher in human testes. Serum and intratesticular ADD and DHEA were significantly inhibited after GnRH administration, while hCG stimulated their increase, but serum DHEA was unaffected, suggesting that most circulating DHEA does not originate from the testes.
Coumarins or indanedione derivatives or anti-inflammatory analgesics (nonsteroidal or salicylates) may have enhanced anticoagulant effects when used in combination with anabolic steroids (especially 17α-alkylated compounds). This is due to changes in the synthesis or catabolism of procoagulant factors leading to decreased concentrations of these factors, as well as increased receptor affinity for the anticoagulant. During and after use with anabolic steroids, the dosage of the anticoagulant may need to be adjusted based on prothrombin time measurements. /Anabolic Steroids/
The use of antidiabetic drugs, sulfonylureas, or insulin in combination with anabolic steroids may lower blood glucose levels; diabetic patients should be closely monitored for hypoglycemia…/Anabolic Steroids/
Concomitant use of corticosteroids, glucocorticoids (especially those with significant mineralocorticoid activity), long-term therapeutic corticotropin, or sodium-containing drugs or foods in combination with anabolic steroids may increase the likelihood of edema; in addition, concomitant use of glucocorticoids or corticotropin in combination with anabolic steroids may promote the development of severe acne. /Anabolic Steroids/
For more complete data on interactions of androstenediones (7 in total), please visit the HSDB record page.

---

Non-human Toxicity Values
Oral LD50 in male rats: 500 to 1000 mg/kg body weight
Oral LD50 in female rats: >500 mg/kg body weight
Dermal LD50 in male and female rats: >2000 mg/kg body weight

[1]. Molecules. 2021 Oct; 26(20): 6210.

According to data from the National Toxicology Program (NTP), androstenedione may be carcinogenic. Androstenedione-4-ene-3,17-dione is a 3-oxoΔ(4) steroid with the structure androstenedione-4-ene, substituted with oxo groups at positions 3 and 17. It is a steroid hormone synthesized in the adrenal glands and gonads. It is an androgen and a metabolite in humans, large fleas (Daphnia magna), and mice. It is a 17-oxosteroid, an androstane compound, and a 3-oxoΔ(4) steroid. It is a Δ-4 C19 steroid produced not only in the testes but also in the ovaries and adrenal cortex. Depending on the tissue type, androstenedione can serve as a precursor to testosterone, estrone, and estradiol. Androstenedione has been reported in locusts, Homo sapiens, and other organisms with relevant data. Therapeutic androstenedione is a potent androgen precursor, a direct precursor to testosterone, and can be used as a supplement to increase plasma testosterone levels and promote muscle anabolism. (NCI) Androstenedione is a steroid hormone synthesized by the adrenal glands and gonads using 17α-hydroxyprogesterone or dehydroepiandrosterone as substrates, and is a precursor to testosterone. Androstenedione is a δ-4, 19-carbon steroid produced not only in the testes but also in the ovaries and adrenal cortex. Depending on tissue type, androstenedione can serve as a precursor to testosterone, estrone, and estradiol. It is a common precursor to both male and female sex hormones. A portion of androstenedione is also secreted into the plasma and can be converted to testosterone and estrogen in peripheral tissues. Androstenedione originates from the conversion of dehydroepiandrosterone or 17-hydroxyprogesterone. It can be further converted to testosterone or estrone. The production of adrenal androstenedione is regulated by adrenocorticotropic hormone (ACTH), while the production of gonadal androstenedione is regulated by gonadotropins. Androstenedione is a delta-4 C19 steroid produced not only in the testes but also in the ovaries and adrenal cortex. Depending on the tissue type, androstenedione can serve as a precursor to testosterone, estrone, and estradiol. Mechanism of Action: 4-Androstenedione is a 19-carbon steroid hormone produced by the adrenal glands and gonads, and is an intermediate step in the biochemical pathways that synthesize the androgens testosterone and estrogens estrone and estradiol. If adequate calories and protein are consumed simultaneously, anabolic steroids can reverse catabolic processes and negative nitrogen balance by promoting protein anabolism and stimulating appetite. /Anabolic Steroids/

---

Therapeutic Uses/Clinical Trials/ ClinicalTrials.gov is a registry and results database that includes publicly and privately funded human clinical studies worldwide. This website is maintained by the National Library of Medicine (NLM) and the National Institutes of Health (NIH). Each record on ClinicalTrials.gov provides summary information about the research protocol, including: the disease or condition; the intervention (e.g., the medical product, behavior, or procedure being investigated); the title, description, and design of the study; participation requirements (eligibility criteria); the location where the study is conducted; contact information for the study location; and links to relevant information from other health websites, such as the NLM's MedlinePlus (which provides patient health information) and PubMed (which provides citations and abstracts of academic articles in the medical field). The database contains androstenedione.

---

Drug Warning
If given in adequate doses and for an adequate period of time, androstenedione and its associated molecules may produce androgenic (and thus anabolic) or estrogenic effects in the human body. …Children and adolescents are particularly vulnerable to the irreversible effects of androstenedione because it is converted into an active hormone.
These effects include disrupting normal sexual development, particularly masculinizing symptoms in girls, manifested as severe acne, excessive body and facial hair, a deepening voice, permanent clitoral enlargement, menstrual cycle disorders, and infertility. Conversion to estrogen can lead to feminization in boys, manifested as breast enlargement and testicular atrophy. Long-term exposure to excessive estrogen in girls may increase the risk of breast and uterine cancer. Finally, the combined effects of excessive androgens and estrogens in both boys and girls can lead to precocious puberty and premature closure of the epiphyses in long bones, significantly affecting adult height. Currently, there is no data on the safety of long-term use of androstenedione supplementation. Adverse effects of exogenous testosterone in men include acne, testicular atrophy, gynecomastia, behavioral changes, and a possible increased risk of prostate cancer. Adverse effects of exogenous testosterone use in women include hirsutism, a deepening voice, acne, clitoral hypertrophy, amenorrhea, male pattern baldness, and rough skin. Adolescent use of exogenous testosterone can lead to premature epiphyseal closure and reduced adult height. Other adverse effects of testosterone include liver failure and increased platelet aggregation. /Testosterone/
Androstenedione is contraindicated in patients with prostate cancer, breast cancer, and uterine cancer.
Studies have found that oral androstenedione can lower high-density lipoprotein cholesterol (HDL-C) levels, which may increase the risk of cardiovascular disease.
For more complete data on androstenedione (21 in total), please visit the HSDB records page.

C19H26O2

286.41

286.193

63-05-8

6128

Crystals from hexane

1.1±0.1 g/cm3

431.4±45.0 °C at 760 mmHg

170-173ºC

161.1±25.7 °C

0.0±1.0 mmHg at 25°C

1.552

2.9

34.14

0

2

0

21

546

5

O=C1C([H])([H])C([H])([H])[C@]2([H])[C@]1(C([H])([H])[H])C([H])([H])C([H])([H])[C@]1([H])[C@@]3(C([H])([H])[H])C([H])([H])C([H])([H])C(C([H])=C3C([H])([H])C([H])([H])[C@]12[H])=O

AEMFNILZOJDQLW-QAGGRKNESA-N

InChI=1S/C19H26O2/c1-18-9-7-13(20)11-12(18)3-4-14-15-5-6-17(21)19(15,2)10-8-16(14)18/h11,14-16H,3-10H2,1-2H3/t14-,15-,16-,18-,19-/m0/s1

(8R,9S,10R,13S,14S)-10,13-dimethyl-2,6,7,8,9,11,12,14,15,16-decahydro-1H-cyclopenta[a]phenanthrene-3,17-dione

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO: > 10 mM