4-Androstenedione

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Not to be confused with 1-androstenedione, androstanedione, or androstenediol.
4-Androstenedione
Androstendion.svg
Androstediona3D.png
Clinical data
ATC code
  • none
Legal status
Legal status
Pharmacokinetic data
Metabolism Liver
Identifiers
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
ChEBI
ChEMBL
ECHA InfoCard 100.000.504
Chemical and physical data
Formula C19H26O2
Molar mass 286.4 g/mol
3D model (Jmol)
Melting point 173–174[1] °C (343–345 °F)
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Δ4-Androstenedione (abbreviated as Δ4-dione), commonly referred to simply as androstenedione, and also known as androst-4-ene-3,17-dione, 4-androstene-3,17-dione or 17-ketotestosterone, is an endogenous androgen steroid hormone and intermediate in the biosynthesis of testosterone from dehydroepiandrosterone (DHEA). In turn, Δ4-dione is also a precursor of dihydrotestosterone (DHT), estrogens such as estradiol and estrone, and the neurosteroid 3α-androstanediol.

Biosynthesis[edit]

Steroidogenesis. Δ4-Dione is at center.[2]

Δ4-Dione is the common precursor of the androgen and estrogen sex hormones.[3]

Δ4-Dione can be biosynthesized in one of two ways. The primary pathway involves conversion of 17α-hydroxypregnenolone to DHEA by way of 17,20-lyase, with subsequent conversion of DHEA to Δ4-dione via the enzyme 3β-hydroxysteroid dehydrogenase. The secondary pathway involves conversion of 17α-hydroxyprogesterone, most often a precursor to cortisol, to Δ4-dione directly by way of 17,20-lyase. Thus, 17,20-lyase is required for the synthesis of Δ4-dione, whether immediately or one step removed.

Δ4-Dione is produced in the adrenal glands and the gonads. The production of adrenal Δ4-dione is governed by adrenocorticotrophic hormone (ACTH), whereas production of gonadal Δ4-dione is under control by the gonadotropins. In premenopausal women, the adrenal glands and ovaries each produce about half of the total Δ4-dione (about 3 mg/day). After menopause, Δ4-dione production is about halved, due primarily to the reduction of the steroid secreted by the ovary. Nevertheless, Δ4-dione is the principal steroid produced by the postmenopausal ovary.

Some Δ4-dione is also secreted into the plasma, and may be converted in peripheral tissues to testosterone and estrogens.

Biological role[edit]

Precursor/metabolic intermediate[edit]

Δ4-Dione is converted to either testosterone or estrogen.

In males, conversion of Δ4-dione to testosterone requires the enzyme 17β-hydroxysteroid dehydrogenase.

In females, Δ4-dione is released into the blood by theca cells. Conversion of Δ4-dione to estrogen (e.g., estrone and estradiol) requires the enzyme aromatase. Δ4-Dione is a substrate for estrogen production in granulosa cells which produce aromatase. Thus, theca cells and granulosa cells work together to form estrogens.[4]

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.[5]

Androstanedione is a 5α-reduced metabolite of 4-androstenedione which serves as an intermediate in the biosynthesis of the androgen and neurosteroid androsterone.[6]

Estrogen[edit]

Δ4-Dione has been found to possess estrogenic actions, similarly to other DHEA metabolites.[7] However, in contrast to 5-androstenediol, its affinity for the estrogen receptors is very low, with less than 0.01% of the affinity of estradiol for both the ERα and ERβ.[8]

Function in juveniles[edit]

In juveniles aged 6-8 years old, there is a rise in androstenedione secretion along with DHEA called adrenarche. 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.[9]

Use as a supplement[edit]

History[edit]

Δ4-Dione was manufactured as a dietary supplement, often called andro (or andros) for short. Sports Illustrated credits Patrick Arnold for introducing Δ4-dione to the North American market.[10] Andro was legal and able to be purchased over the counter, and, as a consequence, it was in common use in Major League Baseball throughout the 1990s by record-breaking sluggers like Mark McGwire. The supplement is banned by the World Anti-Doping Agency, and from the Olympic Games.

The International Olympic Committee in 1997 banned Δ4-dione and placed it under the category of androgenic-anabolic steroids.[11]

Δ4-Dione is banned by MLB, the NFL, USOC, NCA, and by the NBA.[11]

Barry R. McCaffrey, the director of the White House's Office of National Drug Control Policy, attempted to determine whether Δ4-dione could be classified as an anabolic steroid in July 1999. However, he could not because there is no proof of it promoting muscle growth.[11] Now it is known that human bodies require an equal amount of testosterone and Δ4-dione. The supplement of Δ4-dione works by increasing the amount of Δ4-dione which in turn increases the amount of testosterone in the body and then the effects are similar to those of anabolic steroids.[12]

On March 12, 2004, the Anabolic Steroid Control Act of 2004 was introduced into the United States Senate. It amended the Controlled Substance Act to place both anabolic steroids and prohormones on a list of controlled substances, making possession of the banned substances a federal crime. The law took effect on January 20, 2005. However, Δ4-dione was legally defined as an anabolic steroid, even though there is scant evidence that Δ4-dione itself is anabolic in nature.

On April 11, 2004, the United States Food and Drug Administration banned the sale of Δ4-dione, citing that the drug poses significant health risks commonly associated with steroids. The side effects for men include breast development, behavioral changes, heart disease, and more. Additionally, a study done on an individual links androstenedione intake with priapism in men.[13] Side effects for women are similar to the side effects from anabolic steroids in that their voices will deepen and they may grow facial hair since both occur from an increase level of testosterone. Another side effect of Δ4-dione is male-pattern baldness. The main psychological side effect of Δ4-dione is depression. Mood swings are also common of any user.[14] A 2007 study showed that androstenedione has detrimental effects on endothelial cells in vitro, as a 400 μM concentration was able to kill half of the cells.[15]

Δ4-Dione is currently banned by the U.S. military.[16]

Biological effects[edit]

Δ4-Dione 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. However, serum levels of estradiol increased following both the 100 mg and 300 mg doses. The study also reported that the serum level of estrogens and testosterone produced varied widely between individuals.[17] A 2006 review paper summarized several studies that examined the effect of Δ4-dione on strength training. At dosages of 50 mg or 100 mg per day, andro had no effect on muscle strength or size, or on body fat levels. One study used a daily dosage of 300 mg of Δ4-dione combined with several other supplements, and also found no increase in strength when compared to a control group that did not take the supplements. The review authors speculate that sufficiently high doses may indeed lead to increased muscle size and strength. However, due to the federal ban on Δ4-dione supplements, it is difficult to carry out new research on its positive and negative effects. The review authors conclude that individuals should not use Δ4-dione 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.[18]

Because Δ4-dione can be converted to estrogens, people taking this supplement may have estrogenic side effects.[citation needed] In child development, higher levels of Δ4-dione in boys has been associated with higher levels of acting out behaviours.[19][page needed] -[non-primary source needed] -[better source needed]

In addition to its role as a precursor to testosterone in the body, Δ4-dione has slight androgenic properties in its own right, acting as a weak partial agonist of the androgen receptor.[20][non-primary source needed][better source needed] However, in the presence of full agonists like testosterone or dihydrotestosterone (DHT), due to its lower intrinsic activity in comparison, it has antagonistic effects, and can behave more like an antiandrogen.[20][non-primary source needed][better source needed] One study has shown that the supplement "Andro" (a mixture of Δ4-dione and Δ5-androstenediol) does not significantly increase muscle mass or strength.[21][22][non-primary source needed][better source needed] [23][better source needed]

Additional images[edit]

References[edit]

  1. ^ https://pubchem.ncbi.nlm.nih.gov/compound/androstenedione#section=Top
  2. ^ Häggström, Mikael; Richfield, David (2014). "Diagram of the pathways of human steroidogenesis". WikiJournal of Medicine. 1 (1). doi:10.15347/wjm/2014.005. ISSN 2002-4436. 
  3. ^ Devlin, edited by Thomas M. (2010). Textbook of biochemistry : with clinical correlations (7th ed.). Hoboken, NJ: John Wiley & Sons. p. 432. ISBN 0470281731. 
  4. ^ Medical Physiology, Boron & Boulpaep, ISBN 1-4160-2328-3, Elsevier Saunders 2005. Updated edition. Page 1155
  5. ^ Androstenedione, Serum from Mayo Clinic. Retrieved March 2014
  6. ^ Paba S, Frau R, Godar SC, Devoto P, Marrosu F, Bortolato M (2011). "Steroid 5α-reductase as a novel therapeutic target for schizophrenia and other neuropsychiatric disorders". Curr. Pharm. Des. 17 (2): 151–67. PMID 21361868. 
  7. ^ Miller KK, Al-Rayyan N, Ivanova MM, Mattingly KA, Ripp SL, Klinge CM, Prough RA (2013). "DHEA metabolites activate estrogen receptors alpha and beta". Steroids. 78 (1): 15–25. doi:10.1016/j.steroids.2012.10.002. PMC 3529809Freely accessible. PMID 23123738. 
  8. ^ Kuiper GG, Carlsson B, Grandien K, Enmark E, Häggblad J, Nilsson S, Gustafsson JA (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. PMID 9048584. 
  9. ^ Gray, P. B.; McHale, T. S.; Carre, J. M. "A review of human male field studies of hormones and behavioral reproductive effort." Horm. Behav. July 2016.
  10. ^ "Is This Dr. Evil?". CNN. October 9, 2006. 
  11. ^ a b c Reents, S. Sport and Exercise Pharmacology; Human Kinetics: Champaign, IL, 2000
  12. ^ Cole, Adam. "How Does Androstenedione Work?". livestrong.com. Retrieved 14 March 2013. 
  13. ^ Kachhi, P.; Henderson, S. Priapism after androstenedione intake for athletic performance enhancement. Ann Emerg Med. 2000, 35, 391-393.
  14. ^ "Find a Vitamin or Supplement". WebMD. Retrieved 14 March 2013. 
  15. ^ D'Ascenzo, S.; Millimaggi, D.; Di Massimo, C.; Saccani-Jotti, G.; Botre, F.; Carta, G.; Tozzi-Ciancarelli, M. G.; Pavan, A.; Dolo, V. Detrimental effects of anabolic steroids on human endothelial cells. Toxicol. Lett. 2007, 169, 129-136.
  16. ^ USAF Medical Service Home Page
  17. ^ Leder, B.; Longcope, C.; Catlin, D.; Ahrens, B. Shoenfeld; Finkelstein, J. "Oral Androstenedione Administration and Serum Testosterone Concentrations in Young Men". JAMA. 283 (6): 779–782. doi:10.1001/jama.283.6.779. 
  18. ^ Brown, G., Vukovich, M., and King, D.:"Testosterone Prohormone Supplements", Medicine and Science in Sports and Exercise, 38(8):1451-1461.
  19. ^ Susman, E.J., et al. "Hormones, Emotional Dispositions, and Aggressive Attributes in Young Adolescents", Child Development, Vol. 58, No. 4, Aug 1987.[page needed]
  20. ^ a b Chen F, Knecht K, Leu C, et al. (August 2004). "Partial agonist/antagonist properties of androstenedione and 4-androsten-3beta,17beta-diol". The Journal of Steroid Biochemistry and Molecular Biology. 91 (4-5): 247–57. doi:10.1016/j.jsbmb.2004.04.009. PMID 15336702. [non-primary source needed]
  21. ^ Broeder, CE; Quindry, J; Brittingham, K; Panton, L; Thomson, J; Appakondu, S; Breuel, K; Byrd, R; et al. (2000). "The Andro Project: Physiological and hormonal influences of androstenedione supplementation in men 35 to 65 years old participating in a high-intensity resistance training program". Archives of Internal Medicine. 160 (20): 3093–3104. doi:10.1001/archinte.160.20.3093. PMID 11074738. 
  22. ^ http://archinte.highwire.org/cgi/content/full/160/20/3093
  23. ^ Anderson, Owen. "androstenedione". Guildford, UK: Green Star Media. Archived from the original on 10 August 2007. Retrieved 10 August 2014.