Androstenedione, or 4-androstenedione (abbreviated as A4 or Δ
4-dione), also known as androst-4-ene-3,17-dione, is an
endogenous weak
androgen
An androgen (from Greek ''andr-'', the stem of the word meaning "man") is any natural or synthetic steroid hormone that regulates the development and maintenance of male characteristics in vertebrates by binding to androgen receptors. This in ...
steroid hormone
A steroid hormone is a steroid that acts as a hormone. Steroid hormones can be grouped into two classes: corticosteroids (typically made in the adrenal cortex, hence ''cortico-'') and sex steroids (typically made in the gonads or placenta). Withi ...
and
intermediate in the
biosynthesis of
estrone
Estrone (E1), also spelled oestrone, is a steroid, a weak estrogen, and a minor female sex hormone. It is one of three major endogenous estrogens, the others being estradiol and estriol. Estrone, as well as the other estrogens, are synthesized ...
and of
testosterone
Testosterone is the primary sex hormone and anabolic steroid in males. In humans, testosterone plays a key role in the development of male reproductive tissues such as testes and prostate, as well as promoting secondary sexual characteristi ...
from
dehydroepiandrosterone
Dehydroepiandrosterone (DHEA), also known as androstenolone, is an endogenous steroid hormone precursor. It is one of the most abundant circulating steroids in humans. DHEA is produced in the adrenal glands, the gonads, and the brain. It fun ...
(DHEA). It is closely related to
androstenediol
Androstenediol, or 5-androstenediol (abbreviated as A5 or Δ5-diol), also known as androst-5-ene-3β,17β-diol, is an endogenous weak androgen and estrogen steroid hormone and intermediate in the biosynthesis of testosterone from dehydroepia ...
(androst-5-ene-3β,17β-diol).
Biological function
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 endogenous
prohormone
A prohormone is a committed precursor of a hormone consisting of peptide hormones synthesized together that has a minimal hormonal effect by itself because of its expression-suppressing structure, often created by protein folding and binding additi ...
, androstenedione also has weak androgenic activity in its own right.
Androstenedione has been found to possess some
estrogen
Estrogen or oestrogen is a category of sex hormone responsible for the development and regulation of the female reproductive system and secondary sex characteristics. There are three major endogenous estrogens that have estrogenic hormonal ac ...
ic activity, similarly to other DHEA metabolites.
However, in contrast to
androstenediol
Androstenediol, or 5-androstenediol (abbreviated as A5 or Δ5-diol), also known as androst-5-ene-3β,17β-diol, is an endogenous weak androgen and estrogen steroid hormone and intermediate in the biosynthesis of testosterone from dehydroepia ...
, its
affinity
Affinity may refer to:
Commerce, finance and law
* Affinity (law), kinship by marriage
* Affinity analysis, a market research and business management technique
* Affinity Credit Union, a Saskatchewan-based credit union
* Affinity Equity Par ...
for the
estrogen receptor
Estrogen receptors (ERs) are a group of proteins found inside cells. They are receptors that are activated by the hormone estrogen (17β-estradiol). Two classes of ER exist: nuclear estrogen receptors ( ERα and ERβ), which are members of the ...
s is very low, with less than 0.01% of the affinity of
estradiol
Estradiol (E2), also spelled oestradiol, is an estrogen steroid hormone and the major female sex hormone. It is involved in the regulation of the estrous and menstrual female reproductive cycles. Estradiol is responsible for the development o ...
for both the
ERα
Estrogen receptor alpha (ERα), also known as NR3A1 (nuclear receptor subfamily 3, group A, member 1), is one of two main types of estrogen receptor, a nuclear receptor (mainly found as a chromatin-binding protein)
that is activated by the sex h ...
and
ERβ
Estrogen receptor beta (ERβ) also known as NR3A2 (nuclear receptor subfamily 3, group A, member 2) is one of two main types of estrogen receptor—a nuclear receptor which is activated by the sex hormone estrogen. In humans ERβ is encoded by ...
.
Adrenarche
In children aged 6 to 8 years old, there is a rise in androstenedione secretion along with DHEA during
adrenarche
Adrenarche is an early stage in sexual maturation that happens in some higher primates and in humans, typically peaks at around 20 years of age, and is involved in the development of pubic hair, body odor, skin oiliness, axillary hair, sexual ...
. 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.
Biochemistry
Biosynthesis
![Steroidogenesis](https://upload.wikimedia.org/wikipedia/commons/1/13/Steroidogenesis.svg)
Androstenedione is the common
precursor
Precursor or Precursors may refer to:
* Precursor (religion), a forerunner, predecessor
** The Precursor, John the Baptist
Science and technology
* Precursor (bird), a hypothesized genus of fossil birds that was composed of fossilized parts of u ...
of the androgen and estrogen
sex hormones
Sex hormones, also known as sex steroids, gonadocorticoids and gonadal steroids, are steroid hormones that interact with vertebrate steroid hormone receptors. The sex hormones include the androgens, estrogens, and progestogens. Their effects a ...
.
Androstenedione can be biosynthesized in one of two ways. The primary pathway involves conversion of
17α-hydroxypregnenolone to DHEA by way of
17,20-lyase
Cytochrome P450 17A1 (steroid 17α-monooxygenase, 17α-hydroxylase, 17-alpha-hydroxylase, 17,20-lyase, 17,20-desmolase) is an enzyme of the hydroxylase type that in humans is encoded by the ''CYP17A1'' gene on chromosome 10. It is ubiquitously exp ...
, with subsequent conversion of DHEA to androstenedione via the enzyme
3β-hydroxysteroid dehydrogenase. The secondary pathway involves conversion of
17α-hydroxyprogesterone
17α-Hydroxyprogesterone (17α-OHP), also known as 17-OH progesterone (17-OHP), or hydroxyprogesterone (OHP), is an endogenous progestogen steroid hormone related to progesterone. It is also a chemical intermediate in the biosynthesis of many o ...
, most often a precursor to
cortisol, to androstenedione directly by way of
17,20-lyase
Cytochrome P450 17A1 (steroid 17α-monooxygenase, 17α-hydroxylase, 17-alpha-hydroxylase, 17,20-lyase, 17,20-desmolase) is an enzyme of the hydroxylase type that in humans is encoded by the ''CYP17A1'' gene on chromosome 10. It is ubiquitously exp ...
. Thus, 17,20-lyase is required for the synthesis of androstenedione, whether immediately or one step removed.
Androstenedione is produced in the
adrenal gland
The adrenal glands (also known as suprarenal glands) are endocrine glands that produce a variety of hormones including adrenaline and the steroids aldosterone and cortisol. They are found above the kidneys. Each gland has an outer cortex whic ...
s and the
gonads. The production of adrenal androstenedione is governed by
adrenocorticotrophic hormone
Adrenocorticotropic hormone (ACTH; also adrenocorticotropin, corticotropin) is a polypeptide tropic hormone produced by and secreted by the anterior pituitary gland. It is also used as a medication and diagnostic agent. ACTH is an important c ...
(ACTH), whereas production of gonadal androstenedione is under control by the
gonadotropin
Gonadotropins are glycoprotein hormones secreted by gonadotropic cells of the anterior pituitary of vertebrates. This family includes the mammalian hormones follicle-stimulating hormone (FSH) and luteinizing hormone (LH), the placental/ chorioni ...
s. In
premenopausal
Menopause, also known as the climacteric, is the time in women's lives when menstrual periods stop permanently, and they are no longer able to bear children. Menopause usually occurs between the age of 47 and 54. Medical professionals often d ...
women, the adrenal glands and
ovaries
The ovary is an organ in the female reproductive system that produces an ovum. When released, this travels down the fallopian tube into the uterus, where it may become fertilized by a sperm. There is an ovary () found on each side of the body. T ...
each produce about half of the total androstenedione (about 3 mg/day). After
menopause
Menopause, also known as the climacteric, is the time in women's lives when menstrual periods stop permanently, and they are no longer able to bear children. Menopause usually occurs between the age of 47 and 54. Medical professionals often ...
, 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 the
postmenopausal
Menopause, also known as the climacteric, is the time in women's lives when menstrual periods stop permanently, and they are no longer able to bear children. Menopause usually occurs between the age of 47 and 54. Medical professionals often d ...
ovary.
Some androstenedione is also secreted into the
plasma, and may be converted in peripheral tissues to testosterone and estrogens.
Metabolism
Androstenedione is converted to either
testosterone
Testosterone is the primary sex hormone and anabolic steroid in males. In humans, testosterone plays a key role in the development of male reproductive tissues such as testes and prostate, as well as promoting secondary sexual characteristi ...
or
estrone
Estrone (E1), also spelled oestrone, is a steroid, a weak estrogen, and a minor female sex hormone. It is one of three major endogenous estrogens, the others being estradiol and estriol. Estrone, as well as the other estrogens, are synthesized ...
. Conversion of androstenedione to testosterone requires the enzyme
17β-hydroxysteroid dehydrogenase
A hydroxysteroid is a molecule derived from a steroid with a hydrogen replaced with a hydroxy group. When the hydroxy group is specifically at the C3 position, hydroxysteroids are referred to as sterols, with an example being cholesterol.
See ...
. Androstenedione is released into the blood by
theca cells. Conversion of androstenedione to estrone requires the enzyme
aromatase
Aromatase (), also called estrogen synthetase or estrogen synthase, is an enzyme responsible for a key step in the biosynthesis of estrogens. It is CYP19A1, a member of the cytochrome P450 superfamily, which are monooxygenases that catalyze many ...
. Androstenedione is a substrate for
estrogen
Estrogen or oestrogen is a category of sex hormone responsible for the development and regulation of the female reproductive system and secondary sex characteristics. There are three major endogenous estrogens that have estrogenic hormonal ac ...
production in
granulosa cells which produce aromatase. Thus, theca cells and granulosa cells work together to form estrogens.
Androstanedione
Androstanedione, also known as 5α-androstanedione or as 5α-androstane-3,17-dione, is a naturally occurring androstane (5α-androstane) steroid and an endogenous metabolite of androgens like testosterone, dihydrotestosterone (DHT), dehydroepian ...
is a
5α-reduced metabolite of 4-androstenedione which serves as an intermediate in the biosynthesis of the androgen and
neurosteroid androsterone
Androsterone, or 3α-hydroxy-5α-androstan-17-one, 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. Androsterone is a metabolite of test ...
.
Levels
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.
Pharmacology
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.
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 androstenedione on
strength training
Strength training or resistance training involves the performance of physical exercises that are designed to improve strength and endurance. It is often associated with the lifting of weights. It can also incorporate a variety of training te ...
.
At dosages of 50 mg or 100 mg per day, androstenedione had no effect on muscle strength or size, or on body fat levels.
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.
The review authors speculate that sufficiently high doses may indeed lead to increased muscle size and strength.
However, due to the federal ban on androstenedione supplements, it is difficult to carry out new research on its effects.
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.
Medical use
Under the brand name Metharmon-F and in combination with
sex steroids (
pregnenolone
Pregnenolone (P5), or pregn-5-en-3β-ol-20-one, is an endogenous steroid and precursor/ metabolic intermediate in the biosynthesis of most of the steroid hormones, including the progestogens, androgens, estrogens, glucocorticoids, and mineraloc ...
,
testosterone
Testosterone is the primary sex hormone and anabolic steroid in males. In humans, testosterone plays a key role in the development of male reproductive tissues such as testes and prostate, as well as promoting secondary sexual characteristi ...
,
estrone
Estrone (E1), also spelled oestrone, is a steroid, a weak estrogen, and a minor female sex hormone. It is one of three major endogenous estrogens, the others being estradiol and estriol. Estrone, as well as the other estrogens, are synthesized ...
,
androstenediol
Androstenediol, or 5-androstenediol (abbreviated as A5 or Δ5-diol), also known as androst-5-ene-3β,17β-diol, is an endogenous weak androgen and estrogen steroid hormone and intermediate in the biosynthesis of testosterone from dehydroepia ...
) and
thyroid hormone (
desiccated thyroid), androstenedione is or has been marketed for medical use in
Thailand
Thailand ( ), historically known as Siam () and officially the Kingdom of Thailand, is a country in Southeast Asia, located at the centre of the Indochinese Peninsula, spanning , with a population of almost 70 million. The country is b ...
.
Chemistry
Androstenedione, also known as androst-4-ene-3,17-dione, is a
naturally occurring
A natural product is a natural compound or substance produced by a living organism—that is, found in nature. In the broadest sense, natural products include any substance produced by life. Natural products can also be prepared by chemical sy ...
androstane
Androstane is a C19 steroidal hydrocarbon with a gonane core. Androstane can exist as either of two isomers, known as 5α-androstane and 5β-androstane.
File:androstane.png, 5α-Androstane
File:androstane 5beta.png, 5β-Androstane
Pharmacology ...
steroid and a
17-ketosteroid
150px, Androstenedione
150px, Androsterone
150px, Estrone
A ketosteroid, or an oxosteroid, is a steroid in which a hydrogen atom has been replaced with a ketone (C=O) group.
A 17-ketosteroid is a ketosteroid in which the ketone is located s ...
. It is closely related structurally to
androstenediol
Androstenediol, or 5-androstenediol (abbreviated as A5 or Δ5-diol), also known as androst-5-ene-3β,17β-diol, is an endogenous weak androgen and estrogen steroid hormone and intermediate in the biosynthesis of testosterone from dehydroepia ...
(A5; androst-5-ene-3β,17β-diol),
dehydroepiandrosterone
Dehydroepiandrosterone (DHEA), also known as androstenolone, is an endogenous steroid hormone precursor. It is one of the most abundant circulating steroids in humans. DHEA is produced in the adrenal glands, the gonads, and the brain. It fun ...
(DHEA; androst-5-en-3β-ol-17-one), and
testosterone
Testosterone is the primary sex hormone and anabolic steroid in males. In humans, testosterone plays a key role in the development of male reproductive tissues such as testes and prostate, as well as promoting secondary sexual characteristi ...
(androst-4-en-17β-ol-3-one), as well as to
5α-androstanedione (5α-androstane-3,17-dione) and
estrone
Estrone (E1), also spelled oestrone, is a steroid, a weak estrogen, and a minor female sex hormone. It is one of three major endogenous estrogens, the others being estradiol and estriol. Estrone, as well as the other estrogens, are synthesized ...
(estra-1,3,5(10)-triene-3-ol-17-one or 19-norandrost-1,3,5(10)-triene-3-ol-17-one).
History
Use as a supplement
Androstenedione was manufactured as a
dietary supplement, often called ''andro'' or ''andros'' for short. ''
Sports Illustrated
''Sports Illustrated'' (''SI'') is an American sports magazine first published in August 1954. Founded by Stuart Scheftel, it was the first magazine with circulation over one million to win the National Magazine Award for General Excellence twi ...
'' credits
Patrick Arnold with introducing androstenedione to the North American market.
Androstenedione was legal and able to be purchased
over the counter
Over-the-counter (OTC) drugs are medicines sold directly to a consumer without a requirement for a prescription from a healthcare professional, as opposed to prescription drugs, which may be supplied only to consumers possessing a valid prescr ...
, and, as a consequence, it was in common use in
Major League Baseball
Major League Baseball (MLB) is a professional baseball organization and the oldest major professional sports league in the world. MLB is composed of 30 total teams, divided equally between the National League (NL) and the American League (AL), ...
throughout the 1990s by record-breaking sluggers like
Mark McGwire
Mark David McGwire (born October 1, 1963), nicknamed "Big Mac", is an American former professional baseball first baseman who played 16 seasons in Major League Baseball (MLB) from 1986 to 2001 for the Oakland Athletics and the St. Louis Card ...
.
Barry R. McCaffrey, in his capacity as director of the
White House
The White House is the official residence and workplace of the president of the United States. It is located at 1600 Pennsylvania Avenue NW in Washington, D.C., and has been the residence of every U.S. president since John Adams in ...
Office of National Drug Control Policy from 1996 to 2001, determined that androstenedione could not be classified as an anabolic steroid because there is no proof that it promotes muscle growth.
Society and culture
Regulation
Androstenedione is banned by the
World Anti-Doping Agency
The World Anti-Doping Agency (WADA; french: Agence mondiale antidopage, AMA) is a foundation initiated by the International Olympic Committee based in Canada to promote, coordinate, and monitor the fight against drugs in sports. The agency's key ...
, and from the
Olympic Games
The modern Olympic Games or Olympics (french: link=no, Jeux olympiques) are the leading international sporting events featuring summer and winter sports competitions in which thousands of athletes from around the world participate in a vari ...
. The International Olympic Committee in 1997 banned androstenedione and placed it under the category of androgenic-anabolic steroids.
Androstenedione is banned by MLB, the NFL, USOC, NCAA, and by the NBA.
On March 12, 2004, the Anabolic Steroid Control Act of 2004 was introduced into the United States Senate. It amended the
Controlled Substance Act
The Controlled Substances Act (CSA) is the statute establishing federal U.S. drug policy under which the manufacture, importation, possession, use, and distribution of certain substances is regulated. It was passed by the 91st United States ...
to place both
anabolic steroids and
prohormone
A prohormone is a committed precursor of a hormone consisting of peptide hormones synthesized together that has a minimal hormonal effect by itself because of its expression-suppressing structure, often created by protein folding and binding additi ...
s on a list of
controlled substance
A controlled substance is generally a drug or chemical whose manufacture, possession and use is regulated by a government, such as illicitly used drugs or prescription medications that are designated by law. Some treaties, notably the Single ...
s, 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 States
Food and Drug Administration
The United States Food and Drug Administration (FDA or US FDA) is a List of United States federal agencies, federal agency of the United States Department of Health and Human Services, Department of Health and Human Services. The FDA is respon ...
banned the sale of androstenedione, citing that the drug poses significant health risks commonly associated with steroids. Androstenedione is currently banned by the
U.S. military.
References
Androstenedione
; Citations
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{{Androgen receptor modulators
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Androgens and anabolic steroids
Androstanes
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Pregnane X receptor agonists