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Androgen
An androgen (from Greek andr-, the stem of the word meaning
Androgen
"man") is any natural or synthetic steroid hormone that regulates the
development and maintenance of male characteristics in vertebrates by Drug class
binding to androgen receptors.[1] This includes the embryological
development of the primary male sex organs, and the development of
male secondary sex characteristics at puberty. Androgens are
synthesized in the testes, the ovaries, and the adrenal glands.

Androgens increase in both boys and girls during puberty.[2] The major
androgen in males is testosterone.[3] Dihydrotestosterone (DHT) and
androstenedione are of equal importance in male development.[3] DHT Testosterone, the major androgen.
in utero causes differentiation of penis, scrotum and prostate. In
Class identifiers
adulthood, DHT contributes to balding, prostate growth, and sebaceous
Synonyms Androgenic hormone;
gland activity.
Testoid
Although androgens are commonly thought of only as male sex Use Hypogonadism,
hormones, females also have them, but at lower levels: they function in transgender men,
libido and sexual arousal. Also, androgens are the precursors to performance
estrogens in both men and women. enhancement,
bodybuilding, others
In addition to their role as natural hormones, androgens are used as
medications; for information on androgens as medications, see the ATC code G03B
androgen replacement therapy and anabolic steroid articles. Biological Androgen receptor,
target mARs (e.g., GPRC6A,
others)

Contents External links


MeSH D000728
Types and examples
Female ovarian and adrenal androgens In Wikidata

Biological function
Male prenatal development
Male pubertal development
Spermatogenesis
Fat deposition
Muscle mass
Brain
Female-specific effects
Androgen insensitivity
Miscellaneous
Biological activity
Relative potency
Non-genomic actions

Biochemistry

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Biosynthesis
Metabolism

Medical uses
See also
References

Types and examples


The main subset of androgens, known as adrenal androgens, is composed of 19-carbon steroids synthesized in the
zona reticularis, the innermost layer of the adrenal cortex. Adrenal androgens function as weak steroids (though
some are precursors), and the subset includes dehydroepiandrosterone (DHEA), dehydroepiandrosterone sulfate
(DHEA-S), androstenedione (A4), and androstenediol (A5).

Besides testosterone, other androgens include:

Dehydroepiandrosterone (DHEA) is a steroid hormone produced in the adrenal cortex from cholesterol.[4] It is
the primary precursor of natural estrogens. DHEA is also called dehydroisoandrosterone or
dehydroandrosterone.
Androstenedione (A4) is an androgenic steroid produced by the testes, adrenal cortex, and ovaries. While
androstenediones are converted metabolically to testosterone and other androgens, they are also the parent
structure of estrone. Use of androstenedione as an athletic or bodybuilding supplement has been banned by
the International Olympic Committee, as well as other sporting organizations.
Androstenediol (A5) is the steroid metabolite thought to act as the main regulator of gonadotropin secretion.
Androsterone is a chemical byproduct created during the breakdown of androgens, or derived from
progesterone, that also exerts minor masculinising effects, but with one-seventh the intensity of testosterone.
It is found in approximately equal amounts in the plasma and urine of both males and females.
Dihydrotestosterone (DHT) is a metabolite of testosterone, and a more potent androgen than testosterone in
that it binds more strongly to androgen receptors. It is produced in the skin and reproductive tissue.
Determined by consideration of all biological assay methods (circa 1970):[5]

Female ovarian and adrenal androgens


Ovaries and adrenal gland produce much lower levels than the testes. Regarding the relative contributions of
ovaries and adrenal gland to female androgen levels, in a study with six menstruating women the following
observations have been made:[6]

Adrenal contribution to peripheral T, DHT, A, DHEA and DHEA-S is relatively constant throughout the
menstrual cycle
Ovarian contribution of peripheral T, A and DHEA-S reaches maximum levels at midcycle, whereas ovarian
contribution to peripheral DHT and DHEA does not seem to be influenced by the menstrual cycle
Ovary and adrenal cortex contribute equally to peripheral T, DHT and A. With the exception that at midcycle
ovarian contribution of peripheral A is twice that of the adrenal.
Peripheral DHEA and DHEA-S are produced mainly in the adrenal cortex which provides 80% of DHEA and
over 90% of DHEA-S.

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Ovarian and adrenal contribution to peripheral androgens


during the menstrual cycle[6]

Androgen Ovarian (%) (F, M, L) Adrenal (%)

DHEA 20 80

DHEA-S 4, 10, 4 90–96

Androstenedione 45, 70, 60 30–55

Testosterone 33, 60, 33 40–66

DHT 50 50

F = early follicular, M = midcycle, L = late luteal phase.

Biological function

Male prenatal development

Testes formation
During mammalian development, the gonads are at first capable of becoming either ovaries or testes.[7] In humans,
starting at about week 4, the gonadal rudiments are present within the intermediate mesoderm adjacent to the
developing kidneys. At about week 6, epithelial sex cords develop within the forming testes and incorporate the
germ cells as they migrate into the gonads. In males, certain Y chromosome genes, particularly SRY, control
development of the male phenotype, including conversion of the early bipotential gonad into testes. In males, the
sex cords fully invade the developing gonads.

Androgen production
The mesoderm-derived epithelial cells of the sex cords in developing testes become the Sertoli cells, which will
function to support sperm cell formation. A minor population of nonepithelial cells appear between the tubules by
week 8 of human fetal development. These are Leydig cells. Soon after they differentiate, Leydig cells begin to
produce androgens.

Androgen effects
The androgens function as paracrine hormones required by the Sertoli cells to support sperm production. They are
also required for masculinization of the developing male fetus (including penis and scrotum formation). Under the
influence of androgens, remnants of the mesonephron, the Wolffian ducts, develop into the epididymis, vas
deferens and seminal vesicles. This action of androgens is supported by a hormone from Sertoli cells, Müllerian
inhibitory hormone (MIH), which prevents the embryonic Müllerian ducts from developing into fallopian tubes
and other female reproductive tract tissues in male embryos. MIH and androgens cooperate to allow for movement
of testes into the scrotum.

Early regulation
Before the production of the pituitary hormone luteinizing hormone (LH) by the embryo starting at about weeks
11–12, human chorionic gonadotrophin (hCG) promotes the differentiation of Leydig cells and their production of
androgens at week 8. Androgen action in target tissues often involves conversion of testosterone to 5α-
dihydrotestosterone (DHT).

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Male pubertal development


At the time of puberty, androgen levels increase dramatically in males, and androgens mediate the development of
masculine secondary sexual characteristics as well as the activation of spermatogenesis and fertility and masculine
behavioral changes such as gynephilia and increased sex drive. Masculine secondary sexual characteristics include
androgenic hair, voice deepening, emergence of the Adam's apple, broadening of the shoulders, increased muscle
mass, and penile growth.

Spermatogenesis
During puberty, androgen, LH and follicle stimulating hormone (FSH) production increase and the sex cords
hollow out, forming the seminiferous tubules, and the germ cells start to differentiate into sperm. Throughout
adulthood, androgens and FSH cooperatively act on Sertoli cells in the testes to support sperm production.[8]
Exogenous androgen supplements can be used as a male contraceptive. Elevated androgen levels caused by use of
androgen supplements can inhibit production of LH and block production of endogenous androgens by Leydig
cells. Without the locally high levels of androgens in testes due to androgen production by Leydig cells, the
seminiferous tubules can degenerate, resulting in infertility. For this reason, many transdermal androgen patches
are applied to the scrotum.

Fat deposition
Males typically have less body fat than females. Recent results indicate androgens inhibit the ability of some fat
cells to store lipids by blocking a signal transduction pathway that normally supports adipocyte function.[9] Also,
androgens, but not estrogens, increase beta adrenergic receptors while decreasing alpha adrenergic receptors-
which results in increased levels of epinephrine/ norepinephrine due to lack of alpha-2 receptor negative feedback
and decreased fat accumulation due to epinephrine/ norepinephrine then acting on lipolysis-inducing beta
receptors.

Muscle mass
Males typically have more skeletal muscle mass than females. Androgens promote the enlargement of skeletal
muscle cells and probably act in a coordinated manner to function by acting on several cell types in skeletal muscle
tissue.[10] One cell type conveys hormone signals to generating muscle, the myoblast. Higher androgen levels lead
to increased expression of androgen receptor. Fusion of myoblasts generates myotubes, in a process linked to
androgen receptor levels.[11]

Brain
Circulating levels of androgens can influence human behavior because some neurons are sensitive to steroid
hormones. Androgen levels have been implicated in the regulation of human aggression and libido. Indeed,
androgens are capable of altering the structure of the brain in several species, including mice, rats, and primates,
producing sex differences.[12]

Numerous reports have shown androgens alone are capable of altering the structure of the brain,[13] but
identification of which alterations in neuroanatomy stem from androgens or estrogens is difficult, because of their
potential for conversion.

Evidence from neurogenesis (formation of new neurons) studies on male rats has shown that the hippocampus is a
useful brain region to examine when determining the effects of androgens on behavior. To examine neurogenesis,

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wild-type male rats were compared with male rats that had testicular feminization mutation (TMF), a genetic
disorder resulting in complete or partial insensitivity to androgens and a lack of external male genitalia.

Neural injections of Bromodeoxyuridine (BrdU) were applied to males of both groups to test for neurogenesis.
Analysis showed that testosterone and dihydrotestosterone regulated adult hippocampal neurogenesis (AHN).
Adult hippocampal neurogenesis was regulated through the androgen receptor in the wild-type male rats, but not
in the TMF male rats. To further test the role of activated androgen receptors on AHN, flutamide, an antiandrogen
drug that competes with testosterone and dihydrotestosterone for androgen receptors, and dihydrotestosterone
were administered to normal male rats. Dihydrotestosterone increased the number of BrdU cells, while flutamide
inhibited these cells.

Moreover, estrogens had no effect. This research demonstrates how androgens can increase AHN.[14]

Researchers also examined how mild exercise affected androgen synthesis which in turn causes AHN activation of
N-methyl-D-aspartate (NMDA) receptors.

NMDA induces a calcium flux that allows for synaptic plasticity which is crucial for AHN.

Researchers injected both orchidectomized (ORX) (castrated) and sham castrated male rats with BrdU to
determine if the number of new cells was increased. They found that AHN in male rats is increased with mild
exercise by boosting synthesis of dihydrotestosterone in the hippocampus.

Again it was noted that AHN was not increase via activation of the estrogen receptors.[15]

Androgen regulation decreases the likelihood of depression in males. In preadolescent male rats, neonatal rats
treated with flutamide developed more depression-like symptoms compared to control rats.

Again BrdU was injected into both groups of rats in order to see if cells were multiplying in the living tissue. These
results demonstrate how the organization of androgens has a positive effect on preadolescent hippocampal
neurogenesis that may be linked with lower depression-like symptoms.[16]

Social isolation has a hindering effect in AHN whereas normal regulation of androgens increases AHN. A study
using male rats showed that testosterone may block social isolation, which results in hippocampal neurogenesis
reaching homeostasis—regulation that keeps internal conditions stable. A Brdu analysis showed that excess
testosterone did not increase this blocking effect against social isolation; that is, the natural circulating levels of
androgens cancel out the negative effects of social isolation on AHN.[17]

Female-specific effects
Androgens have potential roles in relaxation of the myometrium via non-genomic, androgen receptor-independent
pathways, preventing premature uterine contractions in pregnancy.[18]

Androgen insensitivity
Reduced ability of an XY-karyotype fetus to respond to androgens can result in one of several conditions, including
infertility and several forms of intersex conditions.

Miscellaneous
Yolk androgen levels in certain birds have been positively correlated to social dominance later in life. See American
coot.

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Biological activity
Androgens bind to and activate androgen receptors (ARs) to mediate most of their biological effects.

Relative potency
Determined by consideration of all biological assay methods (circa 1970):[5]

Androgen Potency (%)

Testosterone 100

5α-Dihydrotestosterone (DHT) 90

Androstanediol 60

Androstenedione 20

Dehydroepiandrosterone 10

Androsterone 10

5α-Dihydrotestosterone (DHT) was 2.4 times more potent than testosterone at maintaining normal prostate
weight and duct lumen mass (this is a measure of epithelial cell function stimulation). Whereas DHT was equally
potent as testosterone at preventing prostate cell death after castration.[19]

Non-genomic actions
Androgens have also been found to signal through membrane androgen receptors, which are distinct from the
classical nuclear androgen receptor.[20][21][22]

Biochemistry

Biosynthesis
Androgens are synthesized from cholesterol and are produced primarily in the gonads (testicles and ovaries) and
also in the adrenal glands. The testicles produce a much higher quantity than the ovaries. Conversion of
testosterone to the more potent DHT occurs the prostate gland, liver, brain and skin.

Metabolism
Androgens are metabolized mainly in the liver.

Medical uses
A low testosterone level (hypogonadism) in men may be treated with testosterone administration. Prostate cancer
may be treated by removing the major source of testosterone: testicle removal (orchiectomy); or agents which
block androgens from accessing their receptor: antiandrogens.

See also
Andrology

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Endocrine system
Exercise and androgen
levels
Androgen insensitivity
syndrome
Testosterone and the
cardiovascular system
List of steroid abbreviations
List of androgens/anabolic
steroids
List of androgens/anabolic
steroids available in the
United States

References
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Medicinal Chemistry.
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2. "15 Ways To Get Rid Of
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(http://www.fasthealthfitness bottom left. Estrone and estradiol, in contrast, are estrogens.[23]
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Fast Health Fitness.
2016-05-17.
3. Carlson, Neil (January 22,
2012). Physiology of
Behavior. Reproductive
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ISBN 978-0205239399.
4. "Androgens"
(http://www.diasource-
diagnostics.com
/en/Products
/ImmunoAssays/Fertility
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5. Steroid Biochemistry and
Pharmacology by Briggs
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14. Hamson DK, Wainwright SR, Taylor JR, Jones BA, Watson NV, Galea LA (2013). "Androgens increase
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doi:10.1073/pnas.1210023109 (https://doi.org/10.1073%2Fpnas.1210023109). PMC 3420174
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16. Zhang JM, Tonelli L, Regenold WT, McCarthy MM (2010). "Effects of neonatal flutamide treatment on
hippocampal neurogenesis and synaptogenesis correlate with depression-like behaviors in preadolescent
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17. Spritzer MD, Ibler E, Inglis W, Curtis MG (2011). "Testosterone and social isolation influence adult
neurogenesis in the dentate gyrus of male rats" (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3198792).
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18. Makieva S, Saunders PT, Norman JE (2014). "Androgens in pregnancy: roles in parturition"
(https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4063701). Hum. Reprod. Update. 20 (4): 542–59.
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22. Lang F, Alevizopoulos K, Stournaras C (2013). "Targeting membrane androgen receptors in tumors". Expert
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ISSN 2002-4436 (https://www.worldcat.org/issn/2002-4436).

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