4-Androstenedione

Not to be confused with 1-androstenedione, androstanedione, or androstenediol.

4-Androstenedione

Systematic (IUPAC) name
4-Androstene-3,17-dione
Clinical data
Legal status	Schedule III (US)
Pharmacokinetic data
Metabolism	Liver
Identifiers
CAS Number	63-05-8 Y
ATC code	none
PubChem	CID: 6128
IUPHAR/BPS	2860
DrugBank	DB01536 Y
ChemSpider	5898 Y
UNII	409J2J96VR Y
ChEBI	CHEBI:16422 Y
ChEMBL	CHEMBL274826 Y
Chemical data
Formula	C19H26O2
Molecular mass	286.4 g/mol
SMILES O=C4/C=C3/CC[C@@H]2[C@H](CC[C@@]1(C(=O)CC[C@H]12)C)[C@@]3(C)CC4
InChI 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 Y Key:AEMFNILZOJDQLW-QAGGRKNESA-N Y
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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 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

Steroidogenesis. Δ⁴-Dione is at center.

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

Δ⁴-Dione can be biosynthesized in one of two ways. The primary pathway involves conversion of 17-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 17-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

Precursor/metabolic intermediate

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.

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.

Estrogen

Δ⁴-Dione has been found to possess estrogenic actions, similarly to other DHEA metabolites.

Use as a supplement

History

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. 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.

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

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. 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.

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. 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.

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

Biological effects

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. 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.

Because Δ⁴-dione can be converted to estrogens, people taking this supplement may have estrogenic side effects. In child development, higher levels of Δ⁴-dione in boys has been associated with higher levels of acting out behaviours. - -

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. 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. One study has shown that the supplement "Andro" (a mixture of Δ⁴-dione and Δ⁵-androstenediol) does not significantly increase muscle mass or strength.

Additional images

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  Conversion of Δ⁴-dione to estrone

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  Dehydroepiandrosterone

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  17-Hydroxyprogesterone

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  Testosterone

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  Estrone

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  Boldione