Androgens and antiandrogens
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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 receptor The androgen receptor (AR), also known as NR3C4 (nuclear receptor subfamily 3, group C, member 4), is a type of nuclear receptor that is activated by binding any of the androgenic hormones, including testosterone and dihydrotestosterone in th ...
s. This includes the embryological development of the primary
male sex organs A sex organ (or reproductive organ) is any part of an animal or plant that is involved in sexual reproduction. The reproductive organs together constitute the reproductive system. In animals, the testis in the male, and the ovary in the female, ...
, 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 males and females during puberty. The major androgen in males is testosterone. Dihydrotestosterone (DHT) and
androstenedione Androstenedione, or 4-androstenedione (abbreviated as A4 or Δ4-dione), also known as androst-4-ene-3,17-dione, is an endogenous weak androgen steroid hormone and intermediate in the biosynthesis of estrone and of testosterone from dehydroepia ...
are of equal importance in male development. DHT ''in utero'' causes differentiation of the penis, scrotum and prostate. In adulthood, DHT contributes to balding, prostate growth, and sebaceous gland activity. Although androgens are commonly thought of only as male sex hormones, females also have them, but at lower levels: they function in libido and
sexual arousal Sexual arousal (also known as sexual excitement) describes the physiological and psychological responses in preparation for sexual intercourse or when exposed to sexual stimuli. A number of physiological responses occur in the body and mind as ...
. Also, androgens are the precursors to estrogens in both men and women. In addition to their role as natural hormones, androgens are used as medications; for information on androgens as medications, see the
androgen replacement therapy Androgen replacement therapy (ART), often referred to as testosterone replacement therapy (TRT) or hormone replacement therapy (HRT), is a form of hormone therapy in which androgens, often testosterone, are supplemented or replaced exogenously ...
and
anabolic steroid Anabolic steroids, also known more properly as anabolic–androgenic steroids (AAS), are steroidal androgens that include natural androgens like testosterone (medication), testosterone as well as synthetic androgens that are structurally related ...
articles.


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 The adrenal cortex is the outer region and also the largest part of an adrenal gland. It is divided into three separate zones: zona glomerulosa, zona fasciculata and zona reticularis. Each zone is responsible for producing specific hormones. It is ...
. Adrenal androgens function as weak steroids (though some are precursors), and the subset includes dehydroepiandrosterone (DHEA), dehydroepiandrosterone sulfate (DHEA-S),
androstenedione Androstenedione, or 4-androstenedione (abbreviated as A4 or Δ4-dione), also known as androst-4-ene-3,17-dione, is an endogenous weak androgen steroid hormone and intermediate in the biosynthesis of estrone and of testosterone from dehydroepia ...
(A4), and androstenediol (A5). Besides testosterone, other androgens include: * Dehydroepiandrosterone (DHEA) is a steroid hormone produced in the adrenal cortex from cholesterol. It is the primary precursor of both the androgen and estrogen sex hormones. DHEA is also called dehydroisoandrosterone or dehydroandrosterone. * Androstenedione (A4) is an androgenic steroid produced by the testes, adrenal cortex, and ovaries. While androstenedione is converted metabolically to testosterone and other androgens, it is 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 a steroid
metabolite In biochemistry, a metabolite is an intermediate or end product of metabolism. The term is usually used for small molecules. Metabolites have various functions, including fuel, structure, signaling, stimulatory and inhibitory effects on enzymes, c ...
of DHEA and the precursor to sex hormones testosterone and estradiol. * Androsterone is a chemical byproduct created during the breakdown of androgens, or derived from
progesterone Progesterone (P4) is an endogenous steroid and progestogen sex hormone involved in the menstrual cycle, pregnancy, and embryogenesis of humans and other species. It belongs to a group of steroid hormones called the progestogens and is the m ...
, that also exerts minor masculinising effects, but with one-seventh the intensity of testosterone. It is found in approximately equal amounts in the
plasma Plasma or plasm may refer to: Science * Plasma (physics), one of the four fundamental states of matter * Plasma (mineral), a green translucent silica mineral * Quark–gluon plasma, a state of matter in quantum chromodynamics Biology * Blood pla ...
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 ():''Steroid Biochemistry and Pharmacology'' by Briggs and Brotherton, Academic Press.


Female ovarian and adrenal androgens

The ovaries and adrenal glands also produce androgens, but at much lower levels than the testes. Regarding the relative contributions of ovaries and adrenal glands to female androgen levels, in a study with six menstruating women the following observations have been made: * Adrenal contribution to peripheral T, DHT, A, DHEA and DHEA-S is relatively constant throughout the
menstrual cycle The menstrual cycle is a series of natural changes in hormone production and the structures of the uterus and ovaries of the female reproductive system that make pregnancy possible. The ovarian cycle controls the production and release of eggs a ...
. * Ovarian contribution of peripheral T, A and DHEA-S reaches maximum levels at mid-cycle, 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 mid-cycle 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.


Biological function


Male prenatal development


Testes formation

During mammalian development, the gonads are at first capable of becoming either ovaries or testes. 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 In embryogenesis, the sex cords (primitive sex cords, primitive seminiferous cords, or gonadal cords) are structures that develop from the genital ridges that further differentiate based on an embryo's sex. After sexual differentiation, at day 49, ...
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 The mesonephric duct (also known as the Wolffian duct, archinephric duct, Leydig's duct or nephric duct) is a paired organ that forms during the embryonic development of humans and other mammals and gives rise to male reproductive organs. Struct ...
, develop into the
epididymis The epididymis (; plural: epididymides or ) is a tube that connects a testicle to a vas deferens in the male reproductive system. It is a single, narrow, tightly-coiled tube in adult humans, in length. It serves as an interconnection between the ...
, 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 Human chorionic gonadotropin (hCG) is a hormone for the maternal recognition of pregnancy produced by trophoblast cells that are surrounding a growing embryo (syncytiotrophoblast initially), which eventually forms the placenta after implantation ...
(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).


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 Spermatogenesis is the process by which haploid spermatozoa develop from germ cells in the seminiferous tubules of the testis. This process starts with the mitotic division of the stem cells located close to the basement membrane of the tubule ...
and fertility and masculine behavioral changes such as increased sex drive. Masculine secondary sexual characteristics include androgenic hair, voice deepening, emergence of the
Adam's apple The Adam's apple or laryngeal prominence is the protrusion in the human neck formed by the angle of the thyroid cartilage surrounding the larynx, typically visible in men, less frequently in women. Structure The topographic structure which is e ...
, broadening of the shoulders, increased
muscle mass Skeletal muscles (commonly referred to as muscles) are organs of the vertebrate muscular system and typically are attached by tendons to bones of a skeleton. The muscle cells of skeletal muscles are much longer than in the other types of muscle ...
, and
penile growth The human penis is an external male intromittent organ that additionally serves as the urinary duct. The main parts are the root (radix); the body (corpus); and the epithelium of the penis including the shaft skin and the foreskin (prepuce) co ...
.


Spermatogenesis

During puberty, androgen, LH and
follicle stimulating hormone Follicle-stimulating hormone (FSH) is a gonadotropin, a glycoprotein polypeptide hormone. FSH is synthesized and secreted by the gonadotropic cells of the anterior pituitary gland and regulates the development, growth, pubertal maturation, an ...
(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. 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. Also, androgens, but not estrogens, increase beta
adrenergic receptor The adrenergic receptors or adrenoceptors are a class of G protein-coupled receptors that are targets of many catecholamines like norepinephrine (noradrenaline) and epinephrine (adrenaline) produced by the body, but also many medications like beta ...
s 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 Skeletal muscles (commonly referred to as muscles) are organs of the vertebrate muscular system and typically are attached by tendons to bones of a skeleton. The muscle cells of skeletal muscles are much longer than in the other types of muscl ...
mass than females. Androgens promote the enlargement of skeletal muscle cells in a coordinated manner by acting on several cell types in skeletal muscle tissue. One cell type, called the myoblast, conveys androgen receptors for generating muscle. Fusion of myoblasts generates
myotube Myogenesis is the formation of skeletal muscular tissue, particularly during embryonic development. Muscle fibers generally form through the fusion of precursor myoblasts into multinucleated fibers called ''myotubes''. In the early development ...
s, in a process linked to androgen receptor levels. Higher androgen levels lead to increased expression of
androgen receptor The androgen receptor (AR), also known as NR3C4 (nuclear receptor subfamily 3, group C, member 4), is a type of nuclear receptor that is activated by binding any of the androgenic hormones, including testosterone and dihydrotestosterone in th ...
.


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 Aggression is overt or covert, often harmful, social interaction with the intention of inflicting damage or other harm upon another individual; although it can be channeled into creative and practical outlets for some. It may occur either reacti ...
and libido. Indeed, androgens are capable of altering the structure of the brain in several species, including mice, rats, and primates, producing
sex differences Sexual dimorphism is the condition where the sexes of the same animal and/or plant species exhibit different morphological characteristics, particularly characteristics not directly involved in reproduction. The condition occurs in most ani ...
. Numerous reports have shown androgens alone are capable of altering the structure of the brain, but identification of which alterations in neuroanatomy stem from androgens or estrogens is difficult, because of their potential for conversion. Evidence from
neurogenesis Neurogenesis is the process by which nervous system cells, the neurons, are produced by neural stem cells (NSCs). It occurs in all species of animals except the porifera (sponges) and placozoans. Types of NSCs include neuroepithelial cells (NECs) ...
(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 Neurogenesis is the process by which nervous system cells, the neurons, are produced by neural stem cells (NSCs). It occurs in all species of animals except the porifera (sponges) and placozoans. Types of NSCs include neuroepithelial cells (NECs) ...
, 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 Neurogenesis is the process by which nervous system cells, the neurons, are produced by neural stem cells (NSCs). It occurs in all species of animals except the porifera (sponges) and placozoans. Types of NSCs include neuroepithelial cells (NECs) ...
. Analysis showed that testosterone and dihydrotestosterone regulated adult hippocampal
neurogenesis Neurogenesis is the process by which nervous system cells, the neurons, are produced by neural stem cells (NSCs). It occurs in all species of animals except the porifera (sponges) and placozoans. Types of NSCs include neuroepithelial cells (NECs) ...
(AHN). Adult hippocampal
neurogenesis Neurogenesis is the process by which nervous system cells, the neurons, are produced by neural stem cells (NSCs). It occurs in all species of animals except the porifera (sponges) and placozoans. Types of NSCs include neuroepithelial cells (NECs) ...
was regulated through the
androgen receptor The androgen receptor (AR), also known as NR3C4 (nuclear receptor subfamily 3, group C, member 4), is a type of nuclear receptor that is activated by binding any of the androgenic hormones, including testosterone and dihydrotestosterone in th ...
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 Bromodeoxyuridine (5-bromo-2'-deoxyuridine, BrdU, BUdR, BrdUrd, broxuridine) is a synthetic nucleoside analogue with a chemical structure similar to thymidine. BrdU is commonly used to study cell proliferation in living tissues and has been stu ...
cells, while flutamide inhibited these cells. Moreover, estrogens had no effect. This research demonstrates how androgens can increase AHN. 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 Bromodeoxyuridine (5-bromo-2'-deoxyuridine, BrdU, BUdR, BrdUrd, broxuridine) is a synthetic nucleoside analogue with a chemical structure similar to thymidine. BrdU is commonly used to study cell proliferation in living tissues and has been stu ...
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. Androgen regulation decreases the likelihood of depression in males. In preadolescent male rats,
neonatal An infant or baby is the very young offspring of human beings. ''Infant'' (from the Latin word ''infans'', meaning 'unable to speak' or 'speechless') is a formal or specialised synonym for the common term ''baby''. The terms may also be used to ...
rats treated with flutamide developed more depression-like symptoms compared to control rats. Again
BrdU Bromodeoxyuridine (5-bromo-2'-deoxyuridine, BrdU, BUdR, BrdUrd, broxuridine) is a synthetic nucleoside analogue with a chemical structure similar to thymidine. BrdU is commonly used to study cell proliferation in living tissues and has been stu ...
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 Neurogenesis is the process by which nervous system cells, the neurons, are produced by neural stem cells (NSCs). It occurs in all species of animals except the porifera (sponges) and placozoans. Types of NSCs include neuroepithelial cells (NECs) ...
that may be linked with lower depression-like symptoms. 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 Neurogenesis is the process by which nervous system cells, the neurons, are produced by neural stem cells (NSCs). It occurs in all species of animals except the porifera (sponges) and placozoans. Types of NSCs include neuroepithelial cells (NECs) ...
reaching homeostasis—regulation that keeps internal conditions stable. A
Brdu Bromodeoxyuridine (5-bromo-2'-deoxyuridine, BrdU, BUdR, BrdUrd, broxuridine) is a synthetic nucleoside analogue with a chemical structure similar to thymidine. BrdU is commonly used to study cell proliferation in living tissues and has been stu ...
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.


Female-specific effects

Androgens have potential roles in relaxation of the myometrium via non-genomic,
androgen receptor The androgen receptor (AR), also known as NR3C4 (nuclear receptor subfamily 3, group C, member 4), is a type of nuclear receptor that is activated by binding any of the androgenic hormones, including testosterone and dihydrotestosterone in th ...
-independent pathways, preventing premature uterine contractions in pregnancy.


Androgen insensitivity

Reduced ability of an XY-
karyotype A karyotype is the general appearance of the complete set of metaphase chromosomes in the cells of a species or in an individual organism, mainly including their sizes, numbers, and shapes. Karyotyping is the process by which a karyotype is disce ...
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.


Biological activity

Androgens bind to and activate
androgen receptor The androgen receptor (AR), also known as NR3C4 (nuclear receptor subfamily 3, group C, member 4), is a type of nuclear receptor that is activated by binding any of the androgenic hormones, including testosterone and dihydrotestosterone in th ...
s (ARs) to mediate most of their
biological effect In evolutionary biology, function is the reason some object or process occurred in a system that evolved through natural selection. That reason is typically that it achieves some result, such as that chlorophyll helps to capture the energy of sunl ...
s.


Relative potency

Determined by consideration of all biological assay methods (): 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.


Non-genomic actions

Androgens have also been found to signal through membrane androgen receptors, which are distinct from the classical nuclear androgen receptor.


Biochemistry


Biosynthesis

Androgens are synthesized from cholesterol and are produced primarily in the
gonad A gonad, sex gland, or reproductive gland is a mixed gland that produces the gametes and sex hormones of an organism. Female reproductive cells are egg cells, and male reproductive cells are sperm. The male gonad, the testicle, produces sper ...
s (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 in prostate gland, liver, brain and skin.


Metabolism

Androgens are
metabolized Metabolism (, from el, μεταβολή ''metabolē'', "change") is the set of life-sustaining chemical reactions in organisms. The three main functions of metabolism are: the conversion of the energy in food to energy available to run cell ...
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 Orchiectomy (also named orchidectomy, and sometimes shortened as orchi or orchie) is a surgical procedure in which one or both testicles are removed. The surgery is performed as treatment for testicular cancer, as part of surgery for transgend ...
); or agents which block androgens from accessing their receptor: antiandrogens.


See also

* Andrology * Endocrine system *
Exercise and androgen levels Physical exercise has been found to be associated with changes in androgen levels. In cross-sectional analyses, aerobic exercisers have lower basal total and free testosterone compared to the sedentary. Anaerobic exercisers also have lower testost ...
* Androgen insensitivity syndrome * Androgen insufficiency syndrome *
Testosterone and the cardiovascular system The predominant androgen in men, testosterone, has shown to substantially decline throughout the aging process. The decline in both serum and total testosterone with age have been linked to several disease states in men. In particular, cardiac failu ...
*
List of steroid abbreviations The steroid hormone A hormone (from the Greek participle , "setting in motion") is a class of signaling molecules in multicellular organisms that are sent to distant organs by complex biological processes to regulate physiology and behavior. ...
*
List of androgens/anabolic steroids This is a list of androgens/ anabolic steroids (AAS) or testosterone derivatives. Esters are mostly not included in this list; for esters, see here instead. The major classes of testosterone derivatives include the following (as well as combinat ...
*
List of androgens/anabolic steroids available in the United States This is a complete list of androgens/anabolic steroids (AAS) and formulations that are approved by the and available in the United States. AAS like testosterone are used in androgen replacement therapy (ART), a form of hormone replacement therap ...


References

{{Authority control Hepatotoxins Hormones of the hypothalamus-pituitary-gonad axis Sex hormones