Androstenedione
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| Other names | A4; Δ4-dione; Androstenedione; Androst-4-ene-3,17-dione; 4-Androstene-3,17-dione; 17-Ketotestosterone; 17-Oxotestosterone; 3,17-Dioxoandrost-4-ene; Fecundin |
| Routes of administration | By mouth |
| Drug class | Androgen;Anabolic steroid |
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| Pharmacokineticdata | |
| Metabolism | Liver |
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| ECHA InfoCard | 100.000.504 |
| Chemical and physical data | |
| Formula | C19H26O2 |
| Molar mass | 286.415g·mol−1 |
| 3D model (JSmol) | |
| Density | 1.11±0.1[1]g/cm3(predicted) at 20°C and 760 Torr. Calculated using Advanced Chemistry Development (ACD/Labs) Software V11.02 (© 1994-2023 ACD/Labs). |
| Melting point | 173–174[2]°C (343–345 °F) |
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Androstenedione,or4-androstenedione(abbreviated asA4orΔ4-dione), also known asandrost-4-ene-3,17-dione,is anendogenousweakandrogensteroid hormoneandintermediatein thebiosynthesisofestroneand oftestosteronefromdehydroepiandrosterone(DHEA). It is closely related toandrostenediol(androst-5-ene-3β,17β-diol).
Function
[edit]Androstenedione is a precursor of testosterone and other androgens, as well as of estrogens like estrone, in the body. In addition to functioning as an endogenousprohormone,androstenedione also has weak androgenic activity in its own right.
Androstenedione has been found to possess someestrogenicactivity, similarly to other DHEA metabolites.[3]However, in contrast toandrostenediol,itsaffinityfor theestrogen receptorsis very low, with less than 0.01% of the affinity ofestradiolfor both theERαandERβ.[4]
Adrenarche
[edit]In children aged 6 to 8 years old, there is a rise in androstenedione secretion along with DHEA duringadrenarche.This rise in androstenedione and DHEA is hypothesized to play a crucial role for learning social, cultural and ecological skills, such as the development and understanding of sexual attraction. Furthermore, it is thought that androstenedione plays a role in levels of aggression and competition in boys, as a positive correlation between the two were observed, while testosterone levels were below detection.[5]
Biochemistry
[edit]Biosynthesis
[edit]
Androstenedione is the commonprecursorof the androgen and estrogensex hormones.[7]
Androstenedione can be biosynthesized in one of two ways. The primary pathway involves conversion of17α-hydroxypregnenoloneto DHEA by way of17,20-lyase,with subsequent conversion of DHEA to androstenedione via the enzyme3β-hydroxysteroid dehydrogenase.The secondary pathway involves conversion of17α-hydroxyprogesterone,most often a precursor tocortisol,to androstenedione directly by way of17,20-lyase.Thus, 17,20-lyase is required for the synthesis of androstenedione, whether immediately or one step removed.
Androstenedione is produced in theadrenal glandsand thegonads.The production of adrenal androstenedione is governed byadrenocorticotrophic hormone(ACTH), whereas production of gonadal androstenedione is under control by thegonadotropins.Inpremenopausalwomen, the adrenal glands andovarieseach produce about half of the total androstenedione (about 3 mg/day). Aftermenopause,androstenedione production is about halved, due primarily to the reduction of the steroid secreted by the ovary. Nevertheless, androstenedione is the principal steroid produced by thepostmenopausalovary.
Some androstenedione is also secreted into theplasma,and may be converted in peripheral tissues to testosterone and estrogens.
| Sex | Sex hormone | Reproductive phase |
Blood production rate |
Gonadal secretion rate |
Metabolic clearance rate |
Reference range (serum levels) | |
|---|---|---|---|---|---|---|---|
| SIunits | Non-SIunits | ||||||
| Men | Androstenedione | –
|
2.8 mg/day | 1.6 mg/day | 2200 L/day | 2.8–7.3 nmol/L | 80–210 ng/dL |
| Testosterone | –
|
6.5 mg/day | 6.2 mg/day | 950 L/day | 6.9–34.7 nmol/L | 200–1000 ng/dL | |
| Estrone | –
|
150 μg/day | 110 μg/day | 2050 L/day | 37–250 pmol/L | 10–70 pg/mL | |
| Estradiol | –
|
60 μg/day | 50 μg/day | 1600 L/day | <37–210 pmol/L | 10–57 pg/mL | |
| Estrone sulfate | –
|
80 μg/day | Insignificant | 167 L/day | 600–2500 pmol/L | 200–900 pg/mL | |
| Women | Androstenedione | –
|
3.2 mg/day | 2.8 mg/day | 2000 L/day | 3.1–12.2 nmol/L | 89–350 ng/dL |
| Testosterone | –
|
190 μg/day | 60 μg/day | 500 L/day | 0.7–2.8 nmol/L | 20–81 ng/dL | |
| Estrone | Follicular phase | 110 μg/day | 80 μg/day | 2200 L/day | 110–400 pmol/L | 30–110 pg/mL | |
| Luteal phase | 260 μg/day | 150 μg/day | 2200 L/day | 310–660 pmol/L | 80–180 pg/mL | ||
| Postmenopause | 40 μg/day | Insignificant | 1610 L/day | 22–230 pmol/L | 6–60 pg/mL | ||
| Estradiol | Follicular phase | 90 μg/day | 80 μg/day | 1200 L/day | <37–360 pmol/L | 10–98 pg/mL | |
| Luteal phase | 250 μg/day | 240 μg/day | 1200 L/day | 699–1250 pmol/L | 190–341 pg/mL | ||
| Postmenopause | 6 μg/day | Insignificant | 910 L/day | <37–140 pmol/L | 10–38 pg/mL | ||
| Estrone sulfate | Follicular phase | 100 μg/day | Insignificant | 146 L/day | 700–3600 pmol/L | 250–1300 pg/mL | |
| Luteal phase | 180 μg/day | Insignificant | 146 L/day | 1100–7300 pmol/L | 400–2600 pg/mL | ||
| Progesterone | Follicular phase | 2 mg/day | 1.7 mg/day | 2100 L/day | 0.3–3 nmol/L | 0.1–0.9 ng/mL | |
| Luteal phase | 25 mg/day | 24 mg/day | 2100 L/day | 19–45 nmol/L | 6–14 ng/mL | ||
Notes and sources
Notes:"Theconcentrationof a steroid in the circulation is determined by the rate at which it is secreted from glands, the rate of metabolism of precursor or prehormones into the steroid, and the rate at which it is extracted by tissues and metabolized. Thesecretion rateof a steroid refers to the total secretion of the compound from a gland per unit time. Secretion rates have been assessed by sampling the venous effluent from a gland over time and subtracting out the arterial and peripheral venous hormone concentration. Themetabolic clearance rateof a steroid is defined as the volume of blood that has been completely cleared of the hormone per unit time. Theproduction rateof a steroid hormone refers to entry into the blood of the compound from all possible sources, including secretion from glands and conversion of prohormones into the steroid of interest. At steady state, the amount of hormone entering the blood from all sources will be equal to the rate at which it is being cleared (metabolic clearance rate) multiplied by blood concentration (production rate = metabolic clearance rate × concentration). If there is little contribution of prohormone metabolism to the circulating pool of steroid, then the production rate will approximate the secretion rate. "Sources:See template. | |||||||
Metabolism
[edit]Androstenedione is converted to eithertestosteroneorestrone.Conversion of androstenedione to testosterone requires the enzyme17β-hydroxysteroid dehydrogenase.Androstenedione is released into the blood bytheca cells.Conversion of androstenedione to estrone requires the enzymearomatase.Androstenedione is a substrate forestrogenproduction ingranulosa cellswhich produce aromatase. Thus, theca cells and granulosa cells work together to form estrogens.[8]
Androstanedioneis a5α-reducedmetaboliteof 4-androstenedione which serves as an intermediate in the biosynthesis of the androgen andneurosteroidandrosterone.[9]
Androstenedione also has a variety of metabolites in different species. In cattle, androstenedione is converted into oestradiol-17 and epitestosterone.[10]In sheep, the molecule is transformed into the 17-epimer.[11]Androstenedione is converted into different metabolites in invertebrates. As is the case forMarisa cornuarietis,freshwater ramshorn snail, where androstenedione is converted into 5α-dihydrotestosterone (DHT) and testosterone (T) in male and into 5α-dihydroandrostenedione (DHA) in females.[12]
Levels
[edit]Levels are normally 30–200 ng/dL (1.0–7.0 nmol/L) in females and 40–150 ng/dL (1.4–5.2 nmol/L) in males.
In premature infants, serum androstenedione levels hover between 80 and 446 ng/dL. In full-term newborns, levels range from 20 to 290 ng/dL, and between 1 month and 1 year old, serum levels typically stay at less than 69 ng/dL.
Serum levels of androstenedione greater than or equal to 500 ng/dL may indicate the presence of an adrenal or gonadal tumor.[13]
Pharmacology
[edit]Androstenedione has been shown to increase serum testosterone levels over an eight-hour period in men when taken as a single oral dose of 300 mg per day, but a dose of 100 mg had no significant effect on serum testosterone.[14]However, serum levels of estradiol increased following both the 100 mg and 300 mg doses.[14]The study also reported that the serum level of estrogens and testosterone produced varied widely between individuals.[14]
A 2006 review paper summarized several studies that examined the effect of androstenedione onstrength training.[15]At dosages of 50 mg or 100 mg per day, androstenedione had no effect on muscle strength or size, or on body fat levels.[15]One study used a daily dosage of 300 mg of androstenedione combined with several other supplements, and also found no increase in strength when compared to a control group that did not take the supplements.[15]
The review authors speculate that sufficiently high doses may indeed lead to increased muscle size and strength.[15]However, due to the federal ban on androstenedione supplements, it is difficult to carry out new research on its effects.[15]The review authors conclude that individuals should not use androstenedione supplements due to the lack of evidence of beneficial effects, the wide variation in individual responses to the supplement, and the risk of unknown side effects.[15]Side effects for women may include the development of male characteristics,clitoromegaly,voice deepening, hirsutism, abnormal menstrual cycles and abnormal bleeding, blood clots, and metabolic disruption based on a study following 10 healthy females administering 100 mg androstenedione.[16]
Medical use
[edit]Under the brand name Metharmon-F and in combination withsex steroids(pregnenolone,testosterone,estrone,androstenediol) andthyroid hormone(desiccated thyroid), androstenedione is or has been marketed for medical use inThailand.[17]
Chemistry
[edit]Androstenedione, also known as androst-4-ene-3,17-dione, is anaturally occurringandrostanesteroidand a17-ketosteroid.It is closely related structurally toandrostenediol(A5; androst-5-ene-3β,17β-diol),dehydroepiandrosterone(DHEA; androst-5-en-3β-ol-17-one), andtestosterone(androst-4-en-17β-ol-3-one), as well as to5α-androstanedione(5α-androstane-3,17-dione) andestrone(estra-1,3,5(10)-triene-3-ol-17-one or 19-norandrost-1,3,5(10)-triene-3-ol-17-one).
History
[edit]Use as a supplement
[edit]Androstenedione was manufactured as adietary supplement,often calledandroorandrosfor short.Sports IllustratedcreditsPatrick Arnoldwith introducing androstenedione to the North American market.[18]Androstenedione supplements are credited with increasing testosterone levels, enhancing athletic performance, building body muscles, reducing fats, increasing energy, maintaining healthy RBCs, and increasing sexual performance.[16]Although, all of these effects have not been proven through scientific study. Androstenedione was legal and able to be purchasedover the counter,and, as a consequence, it was in common use inMajor League Baseballthroughout the 1990s by record-breaking sluggers likeMark McGwire.[19]
Barry R. McCaffrey,in his capacity as director of theWhite HouseOffice of National Drug Control Policyfrom 1996 to 2001, determined that androstenedione could not be classified as an anabolic steroid because there is no proof that it promotes muscle growth.[20]
Society and culture
[edit]Regulation
[edit]Androstenedione is banned by theWorld Anti-Doping Agency,and from theOlympic Games.The International Olympic Committee in 1997 banned androstenedione and placed it under the category of androgenic-anabolic steroids.[20]Androstenedione is banned by MLB, the NFL, USOC, NCAA, and by the NBA.[20]
On March 12, 2004, the Anabolic Steroid Control Act of 2004 was introduced into the United States Senate. It amended theControlled Substance Actto place bothanabolic steroidsandprohormoneson a list ofcontrolled substances,making possession of the banned substances a federal crime. The law took effect on January 20, 2005. However, androstenedione was legally defined as an anabolic steroid, even though there is scant evidence that androstenedione itself is anabolic in nature. On April 11, 2004, the United StatesFood and Drug Administrationbanned the sale of androstenedione, citing that the drug poses significant health risks commonly associated with steroids. Androstenedione is currently banned by theU.S. military.[21]
References
[edit]- Citations
- ^"Androstenedione".SciFinder.American Chemical Society.
- ^"Androstenedione Compound Summary".PubChem.National Center for Biotechnology Information. U.S. National Library of Medicine.
- ^Miller KK, Al-Rayyan N, Ivanova MM, Mattingly KA, Ripp SL, Klinge CM, Prough RA (January 2013)."DHEA metabolites activate estrogen receptors alpha and beta".Steroids.78(1): 15–25.doi:10.1016/j.steroids.2012.10.002.PMC3529809.PMID23123738.
- ^Kuiper GG, Carlsson B, Grandien K, Enmark E, Häggblad J, Nilsson S, Gustafsson JA (March 1997)."Comparison of the ligand binding specificity and transcript tissue distribution of estrogen receptors alpha and beta".Endocrinology.138(3): 863–70.doi:10.1210/endo.138.3.4979.PMID9048584.
- ^Gray PB, McHale TS, Carré JM (May 2017). "A review of human male field studies of hormones and behavioral reproductive effort".Hormones and Behavior.91:52–67.doi:10.1016/j.yhbeh.2016.07.004.PMID27449532.S2CID4243812.
- ^Häggström M, Richfield D (2014)."Diagram of the pathways of human steroidogenesis".WikiJournal of Medicine.1(1).doi:10.15347/wjm/2014.005.ISSN2002-4436.
- ^Devlin TM (2010).Textbook of Biochemistry: with Clinical Correlations(7th ed.). Hoboken, NJ: John Wiley & Sons. p. 432.ISBN978-0-470-28173-4.
- ^Boulpaep EL, Boron WF (2005).Medical Physiology: A Cellular and Molecular Approach(Updated ed.). Philadelphia, Pa.: Elsevier Saunders. p. 1155.ISBN978-1-4160-2328-9.
- ^Paba S, Frau R, Godar SC, Devoto P, Marrosu F, Bortolato M (2011). [s://www.ingentaconnect.com/content/ben/cpd/2011/00000017/00000002/art00008 "Steroid 5α-reductase as a novel therapeutic target for schizophrenia and other neuropsychiatric disorders" ].Current Pharmaceutical Design.17(2): 151–67.doi:10.2174/138161211795049589.PMID21361868.
- ^Möstl E, Choi HS, Bamberg E (1980). "Rapid conversion of androstenedione into epitestosterone in bovine blood invitro".IRCS Medical Science: Biochemistry.8:440.
- ^Tsan CP (July 1976). "Metabolism of (4-14C)estrone by sheep erythrocytes around the time of parturition".Canadian Journal of Biochemistry.54(7): 666–669.doi:10.1139/o76-096.PMID8195.
- ^Janer G, LeBlanc GA, Porte C (September 2005). "A comparative study on androgen metabolism in three invertebrate species".General and Comparative Endocrinology.143(3): 211–221.doi:10.1016/j.ygcen.2005.03.016.PMID15922341.
- ^"Androstenedione, Serum".Test Catalog.Mayo Clinic.Retrieved1 March2014.
- ^abcLeder BZ, Longcope C, Catlin DH, Ahrens B, Schoenfeld DA, Finkelstein JS (February 2000)."Oral androstenedione administration and serum testosterone concentrations in young men".JAMA.283(6): 779–82.doi:10.1001/jama.283.6.779.PMID10683057.
- ^abcdefBrown GA, Vukovich M, King DS (August 2006)."Testosterone prohormone supplements".Medicine and Science in Sports and Exercise.38(8): 1451–61.doi:10.1249/01.mss.0000228928.69512.2e.PMID16888459.
- ^abBadawy MT, Sobeh M, Xiao J, Farag MA (October 2021)."Androstenedione (a Natural Steroid and a Drug Supplement): A Comprehensive Review of Its Consumption, Metabolism, Health Effects, and Toxicity with Sex Differences".Molecules.26(20): 6210.doi:10.3390/molecules26206210.PMC8539210.PMID34684800.
- ^Sweetman SC, ed. (2009).Martindale: the complete drug reference(36th ed.). London: Pharmaceutical Press.ISBN978-0-85369-840-1.
- ^Dohrmann G (9 October 2006)."Is This Dr. Evil?".CNN.Archived fromthe originalon 8 December 2012.
- ^Rovell D (12 January 2010)."McGwire's Andro Cover Was Very Profitable".CNBC.
- ^abcReents S (2000).Sport and Exercise Pharmacology.Champaign, Ill.: Human Kinetics.ISBN978-0-87322-937-1.
- ^Lopez CT (January 2005)."'Andro' supplement off limits in new year ".U.S. Air Force Medical Service.Archived fromthe originalon 10 February 2012.