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Testosterone is the primary
sex hormone 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 ar ...
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 ...
in
males Male (symbol: ♂) is the sex of an organism that produces the gamete (sex cell) known as sperm, which fuses with the larger female gamete, or ovum, in the process of fertilization. A male organism cannot reproduce sexually without access to ...
. In humans, testosterone plays a key role in the development of male reproductive tissues such as
testes A testicle or testis (plural testes) is the male reproductive gland or gonad in all bilaterians, including humans. It is homologous to the female ovary. The functions of the testes are to produce both sperm and androgens, primarily testoster ...
and
prostate The prostate is both an Male accessory gland, accessory gland of the male reproductive system and a muscle-driven mechanical switch between urination and ejaculation. It is found only in some mammals. It differs between species anatomically, ...
, as well as promoting
secondary sexual characteristic Secondary sex characteristics are features that appear during puberty in humans, and at sexual maturity in other animals. These characteristics are particularly evident in the sexual dimorphism, sexually dimorphic phenotypic traits that distinguis ...
s such as increased
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 ...
and
bone A bone is a Stiffness, rigid Organ (biology), organ that constitutes part of the skeleton in most vertebrate animals. Bones protect the various other organs of the body, produce red blood cell, red and white blood cells, store minerals, provid ...
mass, and the growth of
body hair Body hair, or androgenic hair, is the terminal hair that develops on the human body during and after puberty. It is differentiated from the head hair and less visible vellus hair, which is much finer and lighter in color. The growth of androge ...
. In addition, testosterone in both sexes is involved in health and well-being, including moods, behaviour, and in the prevention of
osteoporosis Osteoporosis is a systemic skeletal disorder characterized by low bone mass, micro-architectural deterioration of bone tissue leading to bone fragility, and consequent increase in fracture risk. It is the most common reason for a broken bone ...
. Insufficient levels of testosterone in men may lead to abnormalities including frailty and bone loss. Testosterone is a
steroid A steroid is a biologically active organic compound with four rings arranged in a specific molecular configuration. Steroids have two principal biological functions: as important components of cell membranes that alter membrane fluidity; and a ...
from the
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 ...
class containing a
ketone In organic chemistry, a ketone is a functional group with the structure R–C(=O)–R', where R and R' can be a variety of carbon-containing substituents. Ketones contain a carbonyl group –C(=O)– (which contains a carbon-oxygen double bo ...
and a
hydroxyl In chemistry, a hydroxy or hydroxyl group is a functional group with the chemical formula and composed of one oxygen atom covalently bonded to one hydrogen atom. In organic chemistry, alcohols and carboxylic acids contain one or more hydroxy ...
group at positions three and seventeen respectively. It is
biosynthesized Biosynthesis is a multi-step, enzyme-catalyzed process where substrates are converted into more complex products in living organisms. In biosynthesis, simple compounds are modified, converted into other compounds, or joined to form macromolecules. ...
in several steps from cholesterol and is converted in the liver to inactive metabolites. It exerts its action through binding to and activation of 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 humans and most other
vertebrate Vertebrates () comprise all animal taxa within the subphylum Vertebrata () ( chordates with backbones), including all mammals, birds, reptiles, amphibians, and fish. Vertebrates represent the overwhelming majority of the phylum Chordata, ...
s, testosterone is secreted primarily by the
testicles A testicle or testis (plural testes) is the male reproductive gland or gonad in all bilaterians, including humans. It is homologous to the female ovary. The functions of the testes are to produce both sperm and androgens, primarily testostero ...
of males (see
Biosynthesis Biosynthesis is a multi-step, enzyme-catalyzed process where substrates are converted into more complex products in living organisms. In biosynthesis, simple compounds are modified, converted into other compounds, or joined to form macromolecules. ...
) and, to a lesser extent, the
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 ...
of
female Female (Venus symbol, symbol: ♀) is the sex of an organism that produces the large non-motile ovum, ova (egg cells), the type of gamete (sex cell) that fuses with the Sperm, male gamete during sexual reproduction. A female has larger gamet ...
s. On average, in adult males, levels of testosterone are about seven to eight times as great as in adult females. As the metabolism of testosterone in males is more pronounced, the daily production is about 20 times greater in men. Females are also more sensitive to the hormone. In addition to its role as a natural hormone, testosterone is used as a
medication A medication (also called medicament, medicine, pharmaceutical drug, medicinal drug or simply drug) is a drug used to diagnose, cure, treat, or prevent disease. Drug therapy (pharmacotherapy) is an important part of the medical field and re ...
in the treatment of
hypogonadism Hypogonadism means diminished functional activity of the gonads—the testes or the ovaries—that may result in diminished production of sex hormones. Low androgen (e.g., testosterone) levels are referred to as hypoandrogenism and low estrogen ...
in men and
breast cancer Breast cancer is cancer that develops from breast tissue. Signs of breast cancer may include a lump in the breast, a change in breast shape, dimpling of the skin, milk rejection, fluid coming from the nipple, a newly inverted nipple, or a re ...
in women. Since testosterone levels decrease as men age, testosterone is sometimes used in older men to counteract this deficiency. It is also used illicitly to enhance physique and performance, for instance in
athlete An athlete (also sportsman or sportswoman) is a person who competes in one or more sports that involve physical strength, speed, or endurance. Athletes may be professionals or amateurs. Most professional athletes have particularly well-devel ...
s. 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 ...
is listing it as S1 Anabolic agent substance "prohibited at all times".


Biological effects

In general,
androgens 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 inc ...
such as testosterone promote
protein synthesis Protein biosynthesis (or protein synthesis) is a core biological process, occurring inside Cell (biology), cells, homeostasis, balancing the loss of cellular proteins (via Proteolysis, degradation or Protein targeting, export) through the product ...
and thus growth of tissues with
androgen receptors 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 the ...
. Testosterone can be described as having virilising and
anabolic Anabolism () is the set of metabolic pathways that construct molecules from smaller units. These reactions require energy, known also as an endergonic process. Anabolism is the building-up aspect of metabolism, whereas catabolism is the breaking ...
effects (though these categorical descriptions are somewhat arbitrary, as there is a great deal of mutual overlap between them). * ''Anabolic effects'' include growth of
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 strength, increased
bone density Bone density, or bone mineral density, is the amount of bone mineral in bone tissue. The concept is of mass of mineral per volume of bone (relating to density in the physics sense), although clinically it is measured by proxy according to optica ...
and strength, and stimulation of linear growth and
bone maturation Bone age is the degree of a person's skeletal development. In children, bone age serves as a measure of physiological maturity and aids in the diagnosis of growth abnormalities, endocrine disorders, and other medical conditions. As a person grows f ...
. * ''Androgenic effects'' include maturation of the
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, a ...
, particularly the
penis A penis (plural ''penises'' or ''penes'' () is the primary sexual organ that male animals use to inseminate females (or hermaphrodites) during copulation. Such organs occur in many animals, both vertebrate and invertebrate, but males do n ...
, and the formation of the
scrotum The scrotum or scrotal sac is an anatomical male reproductive structure located at the base of the penis that consists of a suspended dual-chambered sac of skin and smooth muscle. It is present in most terrestrial male mammals. The scrotum cont ...
in the fetus, and after birth (usually at
puberty Puberty is the process of physical changes through which a child's body matures into an adult body capable of sexual reproduction. It is initiated by hormonal signals from the brain to the gonads: the ovaries in a girl, the testes in a boy. ...
) a deepening of the
voice The human voice consists of sound made by a human being using the vocal tract, including talking, singing, laughing, crying, screaming, shouting, humming or yelling. The human voice frequency is specifically a part of human sound production in ...
, growth of
facial hair Facial hair is hair grown on the face, usually on the chin, cheeks, and upper lip region. It is typically a secondary sex characteristic of human males. Men typically start developing facial hair in the later stages of puberty or adolescence, ...
(such as the
beard A beard is the hair that grows on the jaw, chin, upper lip, lower lip, cheeks, and neck of humans and some non-human animals. In humans, usually pubescent or adult males are able to grow beards. Throughout the course of history, societal at ...
) and axillary (underarm) hair. Many of these fall into the category of male
secondary sex characteristics Secondary sex characteristics are features that appear during puberty in humans, and at sexual maturity in other animals. These characteristics are particularly evident in the sexually dimorphic phenotypic traits that distinguish the sexes of a sp ...
. Testosterone effects can also be classified by the age of usual occurrence. For
postnatal The postpartum (or postnatal) period begins after childbirth and is typically considered to end within 6 weeks as the mother's body, including hormone levels and uterus size, returns to a non-pregnant state. The terms puerperium, puerperal perio ...
effects in both males and females, these are mostly dependent on the levels and duration of circulating free testosterone.


Before birth

Effects before birth are divided into two categories, classified in relation to the stages of development. The first period occurs between 4 and 6 weeks of the gestation. Examples include genital virilisation such as midline fusion,
phallic A phallus is a penis (especially when erect), an object that resembles a penis, or a mimetic image of an erect penis. In art history a figure with an erect penis is described as ithyphallic. Any object that symbolically—or, more precisely ...
urethra The urethra (from Greek οὐρήθρα – ''ourḗthrā'') is a tube that connects the urinary bladder to the urinary meatus for the removal of urine from the body of both females and males. In human females and other primates, the urethra con ...
,
scrotal The scrotum or scrotal sac is an anatomical male reproductive structure located at the base of the penis that consists of a suspended dual-chambered sac of skin and smooth muscle. It is present in most terrestrial male mammals. The scrotum co ...
thinning and rugation, and
phallic A phallus is a penis (especially when erect), an object that resembles a penis, or a mimetic image of an erect penis. In art history a figure with an erect penis is described as ithyphallic. Any object that symbolically—or, more precisely ...
enlargement; although the role of testosterone is far smaller than that of
dihydrotestosterone Dihydrotestosterone (DHT, 5α-dihydrotestosterone, 5α-DHT, androstanolone or stanolone) is an endogenous androgen sex steroid and hormone. The enzyme 5α-reductase catalyzes the formation of DHT from testosterone in certain tissues includi ...
. There is also development of the
prostate The prostate is both an Male accessory gland, accessory gland of the male reproductive system and a muscle-driven mechanical switch between urination and ejaculation. It is found only in some mammals. It differs between species anatomically, ...
gland and
seminal vesicle The seminal vesicles (also called vesicular glands, or seminal glands) are a pair of two convoluted tubular glands that lie behind the urinary bladder of some male mammals. They secrete fluid that partly composes the semen. The vesicles are 5 ...
s. During the second trimester, androgen level is associated with
sex Sex is the trait that determines whether a sexually reproducing animal or plant produces male or female gametes. Male plants and animals produce smaller mobile gametes (spermatozoa, sperm, pollen), while females produce larger ones ( ova, of ...
formation. Specifically, testosterone, along with anti-Müllerian hormone (AMH) promote growth of the Wolffian duct and degeneration of the Müllerian duct respectively. This period affects the femininization or masculinization of the fetus and can be a better predictor of feminine or masculine behaviours such as sex typed behaviour than an adult's own levels. Prenatal androgens apparently influence interests and engagement in gendered activities and have moderate effects on spatial abilities. Among women with CAH, a male-typical play in childhood correlated with reduced satisfaction with the female gender and reduced heterosexual interest in adulthood.


Early infancy

Early infancy androgen effects are the least understood. In the first weeks of life for male infants, testosterone levels rise. The levels remain in a pubertal range for a few months, but usually reach the barely detectable levels of childhood by 4–7 months of age. The function of this rise in humans is unknown. It has been theorized that brain
masculinization Virilization or masculinization is the biological development of adult male characteristics in young males or females. Most of the changes of virilization are produced by androgens. Virilization is most commonly used in three medical and biology ...
is occurring since no significant changes have been identified in other parts of the body. The male brain is masculinized by the aromatization of testosterone into
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 acti ...
, which crosses the
blood–brain barrier The blood–brain barrier (BBB) is a highly selective semipermeable membrane, semipermeable border of endothelium, endothelial cells that prevents solutes in the circulating blood from ''non-selectively'' crossing into the extracellular fluid of ...
and enters the male brain, whereas female fetuses have
α-fetoprotein Alpha-fetoprotein (AFP, α-fetoprotein; also sometimes called alpha-1-fetoprotein, alpha-fetoglobulin, or alpha fetal protein) is a protein that in humans is encoded by the ''AFP'' gene. The ''AFP'' gene is located on the ''q'' arm of chromosome 4 ...
, which binds the estrogen so that female brains are not affected.


Before puberty

Before puberty, effects of rising androgen levels occur in both boys and girls. These include adult-type
body odor Body odor or body odour (BO) is present in all animals and its intensity can be influenced by many factors (behavioral patterns, survival strategies). Body odor has a strong genetic basis, but can also be strongly influenced by various diseases ...
, increased oiliness of skin and hair,
acne Acne, also known as ''acne vulgaris'', is a long-term Cutaneous condition, skin condition that occurs when Keratinocyte, dead skin cells and Sebum, oil from the skin clog hair follicles. Typical features of the condition include comedo, black ...
,
pubarche Pubarche refers to the first appearance of pubic hair at puberty. Pubarche is one of the physical changes of puberty and can occur independently of complete puberty. Pubarche usually results from rising levels of androgen and not estrogens in femal ...
(appearance of
pubic hair Pubic hair is terminal body hair that is found in the genital area of adolescent and adult humans. The hair is located on and around the sex organs and sometimes at the top of the inside of the thighs. In the pubic region around the pubis bon ...
),
axillary hair Underarm hair, also known as axillary hair, is the hair in the underarm area (''axilla''). Development Underarm or axillary hair goes through four stages of development, driven by weak androgens produced by the adrenal in males and females du ...
(armpit hair),
growth spurt Human height or stature is the distance from the bottom of the feet to the top of the head in a human body, standing erect. It is measured using a stadiometer, in centimetres when using the metric system or SI system, or feet and inches when u ...
, accelerated
bone maturation Bone age is the degree of a person's skeletal development. In children, bone age serves as a measure of physiological maturity and aids in the diagnosis of growth abnormalities, endocrine disorders, and other medical conditions. As a person grows f ...
, and
facial hair Facial hair is hair grown on the face, usually on the chin, cheeks, and upper lip region. It is typically a secondary sex characteristic of human males. Men typically start developing facial hair in the later stages of puberty or adolescence, ...
.


Pubertal

Pubertal Puberty is the process of physical changes through which a child's body matures into an adult body capable of sexual reproduction. It is initiated by hormonal signals from the brain to the gonads: the ovaries in a girl, the testes in a boy. ...
effects begin to occur when androgen has been higher than normal adult female levels for months or years. In males, these are usual late pubertal effects, and occur in women after prolonged periods of heightened levels of free testosterone in the
blood Blood is a body fluid in the circulatory system of humans and other vertebrates that delivers necessary substances such as nutrients and oxygen to the cells, and transports metabolic waste products away from those same cells. Blood in the c ...
. The effects include: * Growth of
spermatogenic 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 ...
tissue in testicles, male
fertility Fertility is the capability to produce offspring through reproduction following the onset of sexual maturity. The fertility rate is the average number of children born by a female during her lifetime and is quantified demographically. Fertili ...
,
penis A penis (plural ''penises'' or ''penes'' () is the primary sexual organ that male animals use to inseminate females (or hermaphrodites) during copulation. Such organs occur in many animals, both vertebrate and invertebrate, but males do n ...
or
clitoris The clitoris ( or ) is a female sex organ present in mammals, ostriches and a limited number of other animals. In humans, the visible portion – the glans – is at the front junction of the labia minora (inner lips), above the ope ...
enlargement, increased
libido Libido (; colloquial: sex drive) is a person's overall sexual drive or desire for sexual activity. Libido is influenced by biological, psychological, and social factors. Biologically, the sex hormones and associated neurotransmitters that act up ...
and frequency of
erection An erection (clinically: penile erection or penile tumescence) is a physiological phenomenon in which the penis becomes firm, engorged, and enlarged. Penile erection is the result of a complex interaction of psychological, neural, vascular, ...
or clitoral engorgement occurs. * Growth of
jaw The jaw is any opposable articulated structure at the entrance of the mouth, typically used for grasping and manipulating food. The term ''jaws'' is also broadly applied to the whole of the structures constituting the vault of the mouth and serv ...
, brow, chin, and nose and remodeling of facial bone contours, in conjunction with
human growth hormone Growth hormone (GH) or somatotropin, also known as human growth hormone (hGH or HGH) in its human form, is a peptide hormone that stimulates growth, cell reproduction, and cell regeneration in humans and other animals. It is thus important in h ...
occurs. * Completion of bone maturation and termination of growth. This occurs indirectly via
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 of f ...
metabolites 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 ...
and hence more gradually in men than women. * Increased muscle strength and mass, shoulders become broader and rib cage expands, deepening of voice, growth of the Adam's apple. * Enlargement of
sebaceous glands A sebaceous gland is a microscopic exocrine gland in the skin that opens into a hair follicle to secrete an oily or waxy matter, called sebum, which lubricates the hair and skin of mammals. In humans, sebaceous glands occur in the greatest num ...
. This might cause acne, subcutaneous
fat In nutrition science, nutrition, biology, and chemistry, fat usually means any ester of fatty acids, or a mixture of such chemical compound, compounds, most commonly those that occur in living beings or in food. The term often refers spec ...
in face decreases. * Pubic hair extends to thighs and up toward umbilicus, development of
facial hair Facial hair is hair grown on the face, usually on the chin, cheeks, and upper lip region. It is typically a secondary sex characteristic of human males. Men typically start developing facial hair in the later stages of puberty or adolescence, ...
(
sideburns Sideburns, sideboards, or side whiskers are facial hair grown on the sides of the face, extending from the hairline to run parallel to or beyond the ears. The term ''sideburns'' is a 19th-century corruption of the original ''burnsides'', named ...
,
beard A beard is the hair that grows on the jaw, chin, upper lip, lower lip, cheeks, and neck of humans and some non-human animals. In humans, usually pubescent or adult males are able to grow beards. Throughout the course of history, societal at ...
,
moustache A moustache (; en-US, mustache, ) is a strip of facial hair grown above the upper lip. Moustaches have been worn in various styles throughout history. Etymology The word "moustache" is French, and is derived from the Italian ''mustaccio'' ...
), loss of scalp hair (androgenetic alopecia), increase in
chest hair Chest hair is hair that grows on the chest in the region between the neck and the abdomen. Chest hair develops during and after puberty along with other types of androgenic hair. Development and growth Although vellus hair is already presen ...
, periareolar hair,
perianal The anus (Latin, 'ring' or 'circle') is an opening at the opposite end of an animal's digestive tract from the mouth. Its function is to control the expulsion of feces, the residual semi-solid waste that remains after food digestion, which, d ...
hair,
leg hair Leg hair is hair that grows on the legs of humans, generally appearing after the onset of puberty. For aesthetic reasons and for some sports, people shave, wax, epilate, or use hair removal creams to remove the hair from their legs: see leg sha ...
,
armpit hair Underarm hair, also known as axillary hair, is the hair in the underarm area (''axilla''). Development Underarm or axillary hair goes through four stages of development, driven by weak androgens produced by the adrenal in males and females du ...
.


Adult

Testosterone is necessary for normal
sperm Sperm is the male reproductive cell, or gamete, in anisogamous forms of sexual reproduction (forms in which there is a larger, female reproductive cell and a smaller, male one). Animals produce motile sperm with a tail known as a flagellum, whi ...
development. It activates genes in
Sertoli cell Sertoli cells are a type of sustentacular "nurse" cell found in human testes which contribute to the process of spermatogenesis (the production of sperm) as a structural component of the seminiferous tubules. They are activated by follicle-stimul ...
s, which promote differentiation of
spermatogonia A spermatogonium (plural: ''spermatogonia'') is an undifferentiated male germ cell. Spermatogonia undergo spermatogenesis to form mature spermatozoa in the seminiferous tubules of the testis. There are three subtypes of spermatogonia in humans: ...
. It regulates acute HPA (
hypothalamic–pituitary–adrenal axis The hypothalamic–pituitary–adrenal axis (HPA axis or HTPA axis) is a complex set of direct influences and feedback interactions among three components: the hypothalamus (a part of the brain located below the thalamus), the pituitary gland (a ...
) response under dominance challenge. Androgens including testosterone enhance muscle growth. Testosterone also regulates the population of thromboxane A2 receptors on
megakaryocytes A megakaryocyte (''mega-'' + '' karyo-'' + '' -cyte'', "large-nucleus cell") is a large bone marrow cell with a lobated nucleus responsible for the production of blood thrombocytes (platelets), which are necessary for normal blood clotting. In hum ...
and
platelets Platelets, also called thrombocytes (from Greek θρόμβος, "clot" and κύτος, "cell"), are a component of blood whose function (along with the coagulation factors) is to react to bleeding from blood vessel injury by clumping, thereby ini ...
and hence platelet aggregation in humans. Adult testosterone effects are more clearly demonstrable in males than in females, but are likely important to both sexes. Some of these effects may decline as testosterone levels might decrease in the later decades of adult life.


Health risks

Testosterone does not appear to increase the risk of developing
prostate cancer Prostate cancer is cancer of the prostate. Prostate cancer is the second most common cancerous tumor worldwide and is the fifth leading cause of cancer-related mortality among men. The prostate is a gland in the male reproductive system that sur ...
. In people who have undergone testosterone deprivation therapy, testosterone increases beyond the castrate level have been shown to increase the rate of spread of an existing prostate cancer. Conflicting results have been obtained concerning the importance of testosterone in maintaining cardiovascular health. Nevertheless, maintaining normal testosterone levels in elderly men has been shown to improve many parameters that are thought to reduce cardiovascular disease risk, such as increased lean body mass, decreased visceral fat mass, decreased total cholesterol, and glycemic control. High androgen levels are associated with
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 ...
irregularities in both clinical populations and healthy women.


Sexual arousal

Testosterone levels follow a nycthemeral rhythm that peaks early each day, regardless of sexual activity. There are positive correlations between positive orgasm experience in women and testosterone levels where relaxation was a key perception of the experience. There is no correlation between testosterone and men's perceptions of their orgasm experience, and also no correlation between higher testosterone levels and greater sexual assertiveness in either sex. Sexual arousal and
masturbation Masturbation is the sexual stimulation of one's own genitals for sexual arousal or other sexual pleasure, usually to the point of orgasm. The stimulation may involve hands, fingers, everyday objects, sex toys such as vibrators, or combinatio ...
in women produce small increases in testosterone concentrations. 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 ...
levels of various
steroids A steroid is a biologically active organic compound with four rings arranged in a specific molecular configuration. Steroids have two principal biological functions: as important components of cell membranes that alter membrane fluidity; and a ...
significantly increase after masturbation in men and the testosterone levels correlate to those levels.


Mammalian studies

Studies conducted in rats have indicated that their degree of sexual arousal is sensitive to reductions in testosterone. When testosterone-deprived rats were given medium levels of testosterone, their sexual behaviours (copulation, partner preference, etc.) resumed, but not when given low amounts of the same hormone. Therefore, these mammals may provide a model for studying clinical populations among humans with sexual arousal deficits such as hypoactive sexual desire disorder. Every mammalian species examined demonstrated a marked increase in a male's testosterone level upon encountering a ''novel'' female. The reflexive testosterone increases in male mice is related to the male's initial level of sexual arousal. In non-human primates, it may be that testosterone in puberty stimulates sexual arousal, which allows the primate to increasingly seek out sexual experiences with females and thus creates a sexual preference for females. Some research has also indicated that if testosterone is eliminated in an adult male human or other adult male primate's system, its sexual motivation decreases, but there is no corresponding decrease in ability to engage in sexual activity (mounting, ejaculating, etc.). In accordance with
sperm competition Sperm competition is the competitive process between spermatozoa of two or more different males to fertilize the same egg during sexual reproduction. Competition can occur when females have multiple potential mating partners. Greater choice and ...
theory, testosterone levels are shown to increase as a response to previously neutral stimuli when conditioned to become sexual in male rats. This reaction engages penile reflexes (such as erection and ejaculation) that aid in sperm competition when more than one male is present in mating encounters, allowing for more production of successful sperm and a higher chance of reproduction.


Males

In men, higher levels of testosterone are associated with periods of sexual activity. Men who watch a sexually explicit movie have an average increase of 35% in testosterone, peaking at 60–90 minutes after the end of the film, but no increase is seen in men who watch sexually neutral films. Men who watch sexually explicit films also report increased motivation, competitiveness, and decreased exhaustion. A link has also been found between relaxation following sexual arousal and testosterone levels. Men's levels of testosterone change depending on whether they are exposed to an ovulating or nonovulating woman's body odour. Men who are exposed to scents of ovulating women maintained a stable testosterone level that was higher than the testosterone level of men exposed to nonovulation cues. Men are heavily aware of hormone cycles in females. This may be linked to the ''ovulatory shift hypothesis'', where males are adapted to respond to the ovulation cycles of females by sensing when they are most fertile and whereby females look for preferred male mates when they are the most fertile; both actions may be driven by hormones.


Females

Androgens may modulate the physiology of vaginal tissue and contribute to female genital sexual arousal. Women's level of testosterone is higher when measured pre-intercourse vs pre-cuddling, as well as post-intercourse vs post-cuddling. There is a time lag effect when testosterone is administered, on genital arousal in women. In addition, a continuous increase in vaginal sexual arousal may result in higher genital sensations and sexual appetitive behaviors. When females have a higher baseline level of testosterone, they have higher increases in sexual arousal levels but smaller increases in testosterone, indicating a ceiling effect on testosterone levels in females. Sexual thoughts also change the level of testosterone but not the level of cortisol in the female body, and hormonal contraceptives may affect the variation in testosterone response to sexual thoughts. Testosterone may prove to be an effective treatment in
female sexual arousal disorder Female sexual arousal disorder (FSAD) is a disorder characterized by a persistent or recurrent inability to attain sexual arousal or to maintain arousal until the completion of a sexual activity. The diagnosis can also refer to an inadequate lu ...
s, and is available as a
dermal patch A dermal patch or skin patch is a medicated adhesive patch that is placed on the skin to deliver a medication into the skin. This is in contrast to a transdermal patch, which delivers the medication through the skin and into the bloodstream. ...
. There is no FDA-approved androgen preparation for the treatment of androgen insufficiency; however, it has been used as an
off-label use Off-label use is the use of pharmaceutical drugs for an unapproved indication (medicine), indication or in an unapproved age group, dose (biochemistry), dosage, or route of administration. Both prescription drugs and over-the-counter drugs (OTCs) ...
to treat low
libido Libido (; colloquial: sex drive) is a person's overall sexual drive or desire for sexual activity. Libido is influenced by biological, psychological, and social factors. Biologically, the sex hormones and associated neurotransmitters that act up ...
and
sexual dysfunction Sexual dysfunction is difficulty experienced by an individual or partners during any stage of normal sexual activity, including physical pleasure, desire, preference, arousal, or orgasm. The World Health Organization defines sexual dysfunction as ...
in older women. Testosterone may be a treatment for postmenopausal women as long as they are effectively estrogenized.


Romantic relationships

Falling in love Falling in love is the development of strong feelings of attachment and love, usually towards another person. The term is metaphorical, emphasizing that the process, like the physical act of falling, is sudden, uncontrollable and leaves the ...
has been linked with decreases in men's testosterone levels while mixed changes are reported for women's testosterone levels. There has been speculation that these changes in testosterone result in the temporary reduction of differences in behavior between the sexes. However, the testosterone changes observed do not seem to be maintained as relationships develop over time. Men who produce less testosterone are more likely to be in a relationship or married, and men who produce more testosterone are more likely to divorce. Marriage or commitment could cause a decrease in testosterone levels. Single men who have not had relationship experience have lower testosterone levels than single men with experience. It is suggested that these single men with prior experience are in a more competitive state than their non-experienced counterparts. Married men who engage in bond-maintenance activities such as spending the day with their spouse and/or child have no different testosterone levels compared to times when they do not engage in such activities. Collectively, these results suggest that the presence of competitive activities rather than bond-maintenance activities are more relevant to changes in testosterone levels. Men who produce more testosterone are more likely to engage in extramarital sex. Testosterone levels do not rely on physical presence of a partner; testosterone levels of men engaging in same-city and long-distance relationships are similar. Physical presence may be required for women who are in relationships for the testosterone–partner interaction, where same-city partnered women have lower testosterone levels than long-distance partnered women.


Fatherhood

Fatherhood decreases testosterone levels in men, suggesting that the emotions and behaviour tied to decreased testosterone promote paternal care. In humans and other species that utilize allomaternal care, paternal investment in offspring is beneficial to said offspring's survival because it allows the two parents to raise multiple children simultaneously. This increases the reproductive fitness of the parents because their offspring are more likely to survive and reproduce. Paternal care increases offspring survival due to increased access to higher quality food and reduced physical and immunological threats. This is particularly beneficial for humans since offspring are dependent on parents for extended periods of time and mothers have relatively short inter-birth intervals. While the extent of paternal care varies between cultures, higher investment in direct child care has been seen to be correlated with lower average testosterone levels as well as temporary fluctuations. For instance, fluctuation in testosterone levels when a child is in distress has been found to be indicative of fathering styles. If a father's testosterone levels decrease in response to hearing their baby cry, it is an indication of empathizing with the baby. This is associated with increased nurturing behavior and better outcomes for the infant.


Motivation

Testosterone levels play a major role in risk-taking during financial decisions.


Aggression and criminality

Most studies support a link between adult criminality and testosterone. Nearly all studies of juvenile delinquency and testosterone are not significant. Most studies have also found testosterone to be associated with behaviors or personality traits linked with criminality such as
antisocial behavior Antisocial may refer to: Sociology, psychiatry and psychology *Anti-social behaviour * Antisocial personality disorder *Psychopathy *Conduct disorder Law *Anti-social Behaviour Act 2003 *Anti-Social Behaviour Order *Crime and Disorder Act 1998 * ...
and
alcoholism Alcoholism is, broadly, any drinking of alcohol (drug), alcohol that results in significant Mental health, mental or physical health problems. Because there is disagreement on the definition of the word ''alcoholism'', it is not a recognize ...
. Many studies have also been done on the relationship between more general aggressive behavior and feelings and testosterone. About half the studies have found a relationship and about half no relationship. Studies have also found that testosterone facilitates aggression by modulating
vasopressin Human vasopressin, also called antidiuretic hormone (ADH), arginine vasopressin (AVP) or argipressin, is a hormone synthesized from the AVP gene as a peptide prohormone in neurons in the hypothalamus, and is converted to AVP. It then travel ...
receptors in the
hypothalamus The hypothalamus () is a part of the brain that contains a number of small nuclei with a variety of functions. One of the most important functions is to link the nervous system to the endocrine system via the pituitary gland. The hypothalamu ...
. There are two theories on the role of testosterone in aggression and competition. The first one is the
challenge hypothesis The challenge hypothesis outlines the dynamic relationship between Aggression#Testosterone, testosterone and aggression in mating contexts. It proposes that testosterone promotes aggression when it would be beneficial for reproduction, such as mate ...
which states that testosterone would increase during puberty, thus facilitating reproductive and competitive behavior which would include aggression. It is therefore the challenge of competition among males of the species that facilitates aggression and violence. Studies conducted have found direct correlation between testosterone and dominance, especially among the most violent criminals in prison who had the highest testosterone levels. The same research also found fathers (those outside competitive environments) had the lowest testosterone levels compared to other males. The second theory is similar and is known as " evolutionary neuroandrogenic (ENA) theory of male aggression". Testosterone and other androgens have evolved to masculinize a brain in order to be competitive even to the point of risking harm to the person and others. By doing so, individuals with masculinized brains as a result of pre-natal and adult life testosterone and androgens enhance their resource acquiring abilities in order to survive, attract and copulate with mates as much as possible. The masculinization of the brain is not just mediated by testosterone levels at the adult stage, but also testosterone exposure in the womb as a fetus. Higher pre-natal testosterone indicated by a low
digit ratio The digit ratio is the ratio of the lengths of different digits or fingers on a hand, the study of which has been considered pseudoscience. The 2D:4D ratio is the most studied digit ratio and is calculated by dividing the length of the index f ...
as well as adult testosterone levels increased risk of fouls or aggression among male players in a soccer game. Studies have also found higher pre-natal testosterone or lower digit ratio to be correlated with higher aggression in males.
Lay summary:
The rise in testosterone levels during competition predicted aggression in males but not in females. Subjects who interacted with hand guns and an experimental game showed rise in testosterone and aggression. Natural selection might have evolved males to be more sensitive to competitive and status challenge situations and that the interacting roles of testosterone are the essential ingredient for aggressive behaviour in these situations. Testosterone mediates attraction to cruel and violent cues in men by promoting extended viewing of violent stimuli. Testosterone-specific structural brain characteristic can predict aggressive behaviour in individuals. Testosterone might encourage fair behavior. For one study, subjects took part in a behavioral experiment where the distribution of a real amount of money was decided. The rules allowed both fair and unfair offers. The negotiating partner could subsequently accept or decline the offer. The fairer the offer, the less probable a refusal by the negotiating partner. If no agreement was reached, neither party earned anything. Test subjects with an artificially enhanced testosterone level generally made better, fairer offers than those who received placebos, thus reducing the risk of a rejection of their offer to a minimum. Two later studies have empirically confirmed these results. However men with high testosterone were significantly 27% less generous in an ultimatum game. The Annual NY Academy of Sciences has also found anabolic steroid use (which increases testosterone) to be higher in teenagers, and this was associated with increased violence. Studies have also found administered testosterone to increase verbal aggression and anger in some participants. A few studies indicate that the testosterone derivative
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 of f ...
(one form of
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 acti ...
) might play an important role in male aggression. Estradiol is known to correlate with aggression in male mice. Moreover, the conversion of testosterone to estradiol regulates male aggression in
sparrows Sparrow may refer to: Birds * Old World sparrows, family Passeridae * New World sparrows, family Passerellidae * two species in the Passerine family Estrildidae: ** Java sparrow ** Timor sparrow * Hedge sparrow, also known as the dunnock or hed ...
during breeding season. Rats who were given anabolic steroids that increase testosterone were also more physically aggressive to provocation as a result of "threat sensitivity". The relationship between testosterone and aggression may also function indirectly, as it has been proposed that testosterone does not amplify tendencies towards aggression but rather amplifies whatever tendencies will allow an individual to maintain social status when challenged. In most animals, aggression is the means of maintaining social status. However, humans have multiple ways of obtaining social status. This could explain why some studies find a link between testosterone and pro-social behaviour if pro-social behaviour is rewarded with social status. Thus the link between testosterone and aggression and violence is due to these being rewarded with social status. The relationship may also be one of a "permissive effect" whereby testosterone does elevate aggression levels but only in the sense of allowing average aggression levels to be maintained; chemically or physically castrating the individual will reduce aggression levels (though it will not eliminate them) but the individual only needs a small-level of pre-castration testosterone to have aggression levels to return to normal, which they will remain at even if additional testosterone is added. Testosterone may also simply exaggerate or amplify existing aggression; for example, chimpanzees who receive testosterone increases become more aggressive to chimps lower than them in the social hierarchy but will still be submissive to chimps higher than them. Testosterone thus does not make the chimpanzee indiscriminately aggressive but instead amplifies his pre-existing aggression towards lower-ranked chimps. In humans, testosterone appears more to promote status-seeking and social dominance than simply increasing physical aggression. When controlling for the effects of belief in having received testosterone, women who have received testosterone make fairer offers than women who have not received testosterone.


Brain

The brain is also affected by this sexual differentiation; the
enzyme Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrates, and the enzyme converts the substrates into different molecules known as products. A ...
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 ...
converts testosterone into
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 of f ...
that is responsible for
masculinization Virilization or masculinization is the biological development of adult male characteristics in young males or females. Most of the changes of virilization are produced by androgens. Virilization is most commonly used in three medical and biology ...
of the brain in male mice. In humans, masculinization of the fetal brain appears, by observation of gender preference in patients with
congenital disease A birth defect, also known as a congenital disorder, is an abnormal condition that is present at birth regardless of its cause. Birth defects may result in disabilities that may be physical, intellectual, or developmental. The disabilities can r ...
s of androgen formation or androgen receptor function, to be associated with functional androgen receptors. There are some differences between a male and female brain (possibly the result of different testosterone levels), one of them being size: the male human brain is, on average, larger. Men were found to have a total myelinated fiber length of 176 000 km at the age of 20, whereas in women the total length was 149 000 km (approx. 15% less). No immediate short term effects on mood or behavior were found from the administration of supraphysiologic doses of testosterone for 10 weeks on 43 healthy men. A correlation between testosterone and risk tolerance in career choice exists among women. Attention, memory, and spatial ability are key cognitive functions affected by testosterone in humans. Preliminary evidence suggests that low testosterone levels may be a risk factor for cognitive decline and possibly for
dementia Dementia is a disorder which manifests as a set of related symptoms, which usually surfaces when the brain is damaged by injury or disease. The symptoms involve progressive impairments in memory, thinking, and behavior, which negatively affe ...
of the Alzheimer's type, a key argument in
life extension Life extension is the concept of extending the human life expectancy, lifespan, either modestly through improvements in medicine or dramatically by increasing the maximum lifespan beyond its generally-settled oldest people, limit of 125 years. S ...
medicine for the use of testosterone in anti-aging therapies. Much of the literature, however, suggests a curvilinear or even quadratic relationship between spatial performance and circulating testosterone, where both hypo- and hypersecretion (deficient- and excessive-secretion) of circulating androgens have negative effects on cognition.


Immune system and inflammation

Testosterone deficiency is associated with an increased risk of
metabolic syndrome Metabolic syndrome is a clustering of at least three of the following five medical conditions: abdominal obesity, high blood pressure, high blood sugar, high serum triglycerides, and low serum high-density lipoprotein (HDL). Metabolic syndrome ...
,
cardiovascular disease Cardiovascular disease (CVD) is a class of diseases that involve the heart or blood vessels. CVD includes coronary artery diseases (CAD) such as angina and myocardial infarction (commonly known as a heart attack). Other CVDs include stroke, h ...
and
mortality Mortality is the state of being mortal, or susceptible to death; the opposite of immortality. Mortality may also refer to: * Fish mortality, a parameter used in fisheries population dynamics to account for the loss of fish in a fish stock throug ...
, which are also sequelae of chronic
inflammation Inflammation (from la, wikt:en:inflammatio#Latin, inflammatio) is part of the complex biological response of body tissues to harmful stimuli, such as pathogens, damaged cells, or Irritation, irritants, and is a protective response involving im ...
. Testosterone plasma concentration inversely correlates to multiple
biomarker In biomedical contexts, a biomarker, or biological marker, is a measurable indicator of some biological state or condition. Biomarkers are often measured and evaluated using blood, urine, or soft tissues to examine normal biological processes, ...
s of inflammation including CRP,
interleukin 1 beta Interleukin-1 beta (IL-1β) also known as leukocytic pyrogen, leukocytic endogenous mediator, mononuclear cell factor, lymphocyte activating factor and other names, is a cytokine protein that in humans is encoded by the ''IL1B'' gene."Catabolin" ...
,
interleukin 6 Interleukin 6 (IL-6) is an interleukin that acts as both a pro-inflammatory cytokine and an anti-inflammatory myokine. In humans, it is encoded by the ''IL6'' gene. In addition, osteoblasts secrete IL-6 to stimulate osteoclast formation. Smooth ...
,
TNF alpha Tumor necrosis factor (TNF, cachexin, or cachectin; formerly known as tumor necrosis factor alpha or TNF-α) is an adipokine and a cytokine. TNF is a member of the TNF superfamily, which consists of various transmembrane proteins with a homolog ...
and
endotoxin Lipopolysaccharides (LPS) are large molecules consisting of a lipid and a polysaccharide that are bacterial toxins. They are composed of an O-antigen, an outer core, and an inner core all joined by a covalent bond, and are found in the outer ...
concentration, as well as
leukocyte White blood cells, also called leukocytes or leucocytes, are the cells of the immune system that are involved in protecting the body against both infectious disease and foreign invaders. All white blood cells are produced and derived from mult ...
count. As demonstrated by a
meta-analysis A meta-analysis is a statistical analysis that combines the results of multiple scientific studies. Meta-analyses can be performed when there are multiple scientific studies addressing the same question, with each individual study reporting me ...
, substitution therapy with testosterone results in a significant reduction of inflammatory markers. These effects are mediated by different mechanisms with synergistic action. In androgen-deficient men with concomitant
autoimmune thyroiditis Autoimmune thyroiditis, is a chronic disease in which the body interprets the thyroid glands and its hormone products T3, T4 and TSH as threats, therefore producing special antibodies that target the thyroid's cells, thereby destroying it. It may ...
, substitution therapy with testosterone leads to a decrease in thyroid autoantibody titres and an increase in
thyroid's secretory capacity Thyroid's secretory capacity (''GT'', also referred to as thyroid's incretory capacity, maximum thyroid hormone output, T4 output or, if calculated from serum levels of thyrotropin and thyroxine, as SPINA-GT) is the maximum stimulated amount of thy ...
(SPINA-GT).


Medical use

Testosterone is used as a medication for the treatment of male hypogonadism,
gender dysphoria Gender dysphoria (GD) is the distress a person experiences due to a mismatch between their gender identitytheir personal sense of their own genderand their sex assigned at birth. The diagnostic label gender identity disorder (GID) was used until ...
, and certain types of
breast cancer Breast cancer is cancer that develops from breast tissue. Signs of breast cancer may include a lump in the breast, a change in breast shape, dimpling of the skin, milk rejection, fluid coming from the nipple, a newly inverted nipple, or a re ...
. This is known as
hormone replacement therapy Hormone replacement therapy (HRT), also known as menopausal hormone therapy or postmenopausal hormone therapy, is a form of hormone therapy used to treat symptoms associated with female menopause. These symptoms can include hot flashes, vaginal ...
(HRT) or testosterone replacement therapy (TRT), which maintains serum testosterone levels in the normal range. Decline of testosterone production with age has led to interest in
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 ...
. It is unclear if the use of testosterone for low levels due to aging is beneficial or harmful. Testosterone is included in the
World Health Organization's list of essential medicines The WHO Model List of Essential Medicines (aka Essential Medicines List or EML), published by the World Health Organization (WHO), contains the medications considered to be most effective and safe to meet the most important needs in a health ...
, which are the most important medications needed in a basic
health system Health, according to the World Health Organization, is "a state of complete physical, mental and social well-being and not merely the absence of disease and infirmity".World Health Organization. (2006)''Constitution of the World Health Organiza ...
. It is available as a
generic medication A generic drug is a pharmaceutical drug that contains the same chemical substance as a drug that was originally protected by chemical patents. Generic drugs are allowed for sale after the patents on the original drugs expire. Because the active ch ...
. It can be administered as a cream or
transdermal patch A transdermal patch is a medicated adhesive patch that is placed on the skin to deliver a specific dose of medication through the skin and into the bloodstream. An advantage of a transdermal drug delivery route over other types of medicat ...
that is applied to the skin, by
injection into a muscle Intramuscular injection, often abbreviated IM, is the injection of a substance into a muscle. In medicine, it is one of several methods for parenteral administration of medications. Intramuscular injection may be preferred because muscles ha ...
, as a tablet that is placed in the cheek, or by ingestion. Common
side effect In medicine, a side effect is an effect, whether therapeutic or adverse, that is secondary to the one intended; although the term is predominantly employed to describe adverse effects, it can also apply to beneficial, but unintended, consequence ...
s from testosterone medication include
acne Acne, also known as ''acne vulgaris'', is a long-term Cutaneous condition, skin condition that occurs when Keratinocyte, dead skin cells and Sebum, oil from the skin clog hair follicles. Typical features of the condition include comedo, black ...
, swelling, and breast enlargement in males. Serious side effects may include liver toxicity,
heart disease Cardiovascular disease (CVD) is a class of diseases that involve the heart or blood vessels. CVD includes coronary artery diseases (CAD) such as angina and myocardial infarction (commonly known as a heart attack). Other CVDs include stroke, hea ...
, and behavioral changes. Women and children who are exposed may develop
virilization Virilization or masculinization is the biological development of adult male characteristics in young males or females. Most of the changes of virilization are produced by androgens. Virilization is most commonly used in three medical and biology ...
. It is recommended that individuals with
prostate cancer Prostate cancer is cancer of the prostate. Prostate cancer is the second most common cancerous tumor worldwide and is the fifth leading cause of cancer-related mortality among men. The prostate is a gland in the male reproductive system that sur ...
not use the medication. It can cause harm if used during
pregnancy Pregnancy is the time during which one or more offspring develops ( gestates) inside a woman's uterus (womb). A multiple pregnancy involves more than one offspring, such as with twins. Pregnancy usually occurs by sexual intercourse, but ca ...
or
breastfeeding Breastfeeding, or nursing, is the process by which human breast milk is fed to a child. Breast milk may be from the breast, or may be expressed by hand or pumped and fed to the infant. The World Health Organization (WHO) recommends that br ...
. 2020 guidelines from the
American College of Physicians The American College of Physicians (ACP) is a national organization of internists, who specialize in the diagnosis, treatment, and care of adults.Sokanu "What is an Internist?" Retrieved October 20, 2014 With 161,000 members, ACP is the largest ...
support the discussion 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 system, male reproductive tissues such as testes and prostate, as well as promoting secondar ...
treatment in adult men with age-related low levels of testosterone who have
sexual dysfunction Sexual dysfunction is difficulty experienced by an individual or partners during any stage of normal sexual activity, including physical pleasure, desire, preference, arousal, or orgasm. The World Health Organization defines sexual dysfunction as ...
. They recommend yearly evaluation regarding possible improvement and, if none, to discontinue testosterone; physicians should consider intramuscular treatments, rather than transdermal treatments, due to costs and since the effectiveness and harm of either method is similar. Testosterone treatment for reasons other than possible improvement of sexual dysfunction may not be recommended.


Biological activity


Free testosterone

Lipophilic Lipophilicity (from Greek λίπος "fat" and φίλος "friendly"), refers to the ability of a chemical compound to dissolve in fats, oils, lipids, and non-polar solvents such as hexane or toluene. Such non-polar solvents are themselves lipop ...
hormones A hormone (from the Ancient Greek, Greek participle , "setting in motion") is a class of cell signaling, signaling molecules in multicellular organisms that are sent to distant organs by complex biological processes to regulate physiology and beh ...
(soluble in
lipids Lipids are a broad group of naturally-occurring molecules which includes fats, waxes, sterols, fat-soluble vitamins (such as vitamins A, D, E and K), monoglycerides, diglycerides, phospholipids, and others. The functions of lipids include ...
but not in
water Water (chemical formula ) is an inorganic, transparent, tasteless, odorless, and nearly colorless chemical substance, which is the main constituent of Earth's hydrosphere and the fluids of all known living organisms (in which it acts as a ...
), such as
steroid A steroid is a biologically active organic compound with four rings arranged in a specific molecular configuration. Steroids have two principal biological functions: as important components of cell membranes that alter membrane fluidity; and a ...
hormones, including testosterone, are transported in water-based
blood plasma Blood plasma is a light amber-colored liquid component of blood in which blood cells are absent, but contains proteins and other constituents of whole blood in suspension. It makes up about 55% of the body's total blood volume. It is the intra ...
through specific and non-specific
proteins Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, respo ...
. Specific proteins include
sex hormone-binding globulin Sex hormone-binding globulin (SHBG) or sex steroid-binding globulin (SSBG) is a glycoprotein that binds to androgens and estrogens. When produced by the Sertoli cells in the seminiferous tubules of the testis, it has also been called androgen ...
(SHBG), which binds testosterone,
dihydrotestosterone Dihydrotestosterone (DHT, 5α-dihydrotestosterone, 5α-DHT, androstanolone or stanolone) is an endogenous androgen sex steroid and hormone. The enzyme 5α-reductase catalyzes the formation of DHT from testosterone in certain tissues includi ...
,
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 of f ...
, and other
sex steroids 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 are ...
. Non-specific binding proteins include
albumin Albumin is a family of globular proteins, the most common of which are the serum albumins. All the proteins of the albumin family are water-soluble, moderately soluble in concentrated salt solutions, and experience heat denaturation. Albumins ...
and
lipoprotein A lipoprotein is a biochemical assembly whose primary function is to transport hydrophobic lipid (also known as fat) molecules in water, as in blood plasma or other extracellular fluids. They consist of a triglyceride and cholesterol center, sur ...
. The part of the total hormone concentration that is not bound to its respective specific carrier protein is the free part. As a result, testosterone which is not bound to SHBG is called ''free testosterone''. It seems that only the free amount of testosterone can bind to an androgenic receptor, which means they have biological activity.


Steroid hormone activity

The effects of testosterone in humans and other
vertebrates Vertebrates () comprise all animal taxa within the subphylum Vertebrata () ( chordates with backbones), including all mammals, birds, reptiles, amphibians, and fish. Vertebrates represent the overwhelming majority of the phylum Chordata, ...
occur by way of multiple mechanisms: by activation of 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 ...
(directly or as dihydrotestosterone), and by conversion to
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 of f ...
and activation of certain
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. Androgens such as testosterone have also been found to bind to and activate
membrane androgen receptor Membrane androgen receptors (mARs) are a group of G protein-coupled receptors (GPCRs) which bind and are activated by testosterone and/or other androgens. Unlike the androgen receptor (AR), a nuclear receptor which mediates its effects via genomi ...
s. Free testosterone (T) is transported into the
cytoplasm In cell biology, the cytoplasm is all of the material within a eukaryotic cell, enclosed by the cell membrane, except for the cell nucleus. The material inside the nucleus and contained within the nuclear membrane is termed the nucleoplasm. The ...
of target tissue cells, where it can bind to 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 ...
, or can be reduced to 5α-dihydrotestosterone (DHT) by the cytoplasmic enzyme
5α-reductase 5α-Reductases, also known as 3-oxo-5α-steroid 4-dehydrogenases, are enzymes involved in steroid metabolism. They participate in three metabolic pathways: bile acid biosynthesis, androgen and estrogen metabolism. There are three isozymes of ...
. DHT binds to the same androgen receptor even more strongly than testosterone, so that its androgenic potency is about 5 times that of T. The T-receptor or DHT-receptor complex undergoes a structural change that allows it to move into the
cell nucleus The cell nucleus (pl. nuclei; from Latin or , meaning ''kernel'' or ''seed'') is a membrane-bound organelle found in eukaryotic cells. Eukaryotic cells usually have a single nucleus, but a few cell types, such as mammalian red blood cells, h ...
and bind directly to specific
nucleotide Nucleotides are organic molecules consisting of a nucleoside and a phosphate. They serve as monomeric units of the nucleic acid polymers – deoxyribonucleic acid (DNA) and ribonucleic acid (RNA), both of which are essential biomolecules wi ...
sequences of the
chromosomal A chromosome is a long DNA molecule with part or all of the genetic material of an organism. In most chromosomes the very long thin DNA fibers are coated with packaging proteins; in eukaryotic cells the most important of these proteins are ...
DNA. The areas of binding are called
hormone response element Response elements are short sequences of DNA within a gene promoter or enhancer region that are able to bind specific transcription factors and regulate transcription of genes. Under conditions of stress, a transcription activator protein binds ...
s (HREs), and influence transcriptional activity of certain
gene In biology, the word gene (from , ; "...Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a ba ...
s, producing the androgen effects. Androgen receptors occur in many different vertebrate body system tissues, and both males and females respond similarly to similar levels. Greatly differing amounts of testosterone prenatally, at puberty, and throughout life account for a share of biological differences between males and females. The bones and the brain are two important tissues in humans where the primary effect of testosterone is by way of
aromatization Aromatization is a chemical reaction in which an aromatic system is formed from a single nonaromatic precursor. Typically aromatization is achieved by dehydrogenation of existing cyclic compounds, illustrated by the conversion of cyclohexane int ...
to
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 of f ...
. In the bones, estradiol accelerates ossification of cartilage into bone, leading to closure of the
epiphyses The epiphysis () is the rounded end of a long bone, at its joint with adjacent bone(s). Between the epiphysis and diaphysis (the long midsection of the long bone) lies the metaphysis, including the epiphyseal plate (growth plate). At the join ...
and conclusion of growth. In the central nervous system, testosterone is aromatized to estradiol. Estradiol rather than testosterone serves as the most important feedback signal to the hypothalamus (especially affecting LH secretion). In many
mammal Mammals () are a group of vertebrate animals constituting the class Mammalia (), characterized by the presence of mammary glands which in females produce milk for feeding (nursing) their young, a neocortex (a region of the brain), fur or ...
s, prenatal or perinatal "masculinization" of the
sexually dimorphic 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 ...
areas of the brain by estradiol derived from testosterone programs later male sexual behavior.


Neurosteroid activity

Testosterone, via its
active metabolite An active metabolite is an active form of a drug after it has been processed by the body. Metabolites of drugs An active metabolite results when a drug is metabolized by the body into a modified form which continues to produce effects in the body ...
3α-androstanediol, is a potent
positive allosteric modulator In pharmacology and biochemistry, allosteric modulators are a group of substances that bind to a receptor to change that receptor's response to stimulus. Some of them, like benzodiazepines, are drugs. The site that an allosteric modulator binds to ...
of the GABAA receptor. Testosterone has been found to act as an
antagonist An antagonist is a character in a story who is presented as the chief foe of the protagonist. Etymology The English word antagonist comes from the Greek ἀνταγωνιστής – ''antagonistēs'', "opponent, competitor, villain, enemy, riv ...
of the
TrkA Tropomyosin receptor kinase A (TrkA), also known as high affinity nerve growth factor receptor, neurotrophic tyrosine kinase receptor type 1, or TRK1-transforming tyrosine kinase protein is a protein that in humans is encoded by the ''NTRK1'' gen ...
and p75NTR,
receptor Receptor may refer to: * Sensory receptor, in physiology, any structure which, on receiving environmental stimuli, produces an informative nerve impulse *Receptor (biochemistry), in biochemistry, a protein molecule that receives and responds to a ...
s for the neurotrophin
nerve growth factor Nerve growth factor (NGF) is a neurotrophic factor and neuropeptide primarily involved in the regulation of growth, maintenance, proliferation, and survival of certain target neurons. It is perhaps the prototypical growth factor, in that it was on ...
(NGF), with high
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 ...
(around 5 nM). In contrast to testosterone, DHEA and
DHEA sulfate Dehydroepiandrosterone sulfate, abbreviated as DHEA sulfate or DHEA-S, also known as androstenolone sulfate, is an endogenous androstane steroid that is produced by the adrenal cortex. It is the 3β-sulfate ester and a metabolite of dehydroep ...
have been found to act as high-affinity
agonist An agonist is a chemical that activates a receptor to produce a biological response. Receptors are cellular proteins whose activation causes the cell to modify what it is currently doing. In contrast, an antagonist blocks the action of the ago ...
s of these receptors. Testosterone is an antagonist of the
sigma-1 receptor The sigma-1 receptor (σ1R), one of two sigma receptor subtypes, is a chaperone protein at the endoplasmic reticulum (ER) that modulates calcium signaling through the IP3 receptor. In humans, the σ1 receptor is encoded by the ''SIGMAR1'' gene. ...
(Ki = 1,014 or 201 nM). However, the concentrations of testosterone required for binding the receptor are far above even total circulating concentrations of testosterone in adult males (which range between 10 and 35 nM).


Biochemistry


Biosynthesis

Like other
steroid A steroid is a biologically active organic compound with four rings arranged in a specific molecular configuration. Steroids have two principal biological functions: as important components of cell membranes that alter membrane fluidity; and a ...
hormones, testosterone is derived from
cholesterol Cholesterol is any of a class of certain organic molecules called lipids. It is a sterol (or modified steroid), a type of lipid. Cholesterol is biosynthesized by all animal cells and is an essential structural component of animal cell mem ...
(see figure). The first step in the
biosynthesis Biosynthesis is a multi-step, enzyme-catalyzed process where substrates are converted into more complex products in living organisms. In biosynthesis, simple compounds are modified, converted into other compounds, or joined to form macromolecules. ...
involves the oxidative cleavage of the side-chain of cholesterol by
cholesterol side-chain cleavage enzyme Cholesterol side-chain cleavage enzyme is commonly referred to as P450scc, where "scc" is an acronym for side-chain cleavage. P450scc is a mitochondrial enzyme that catalyzes conversion of cholesterol to pregnenolone. This is the first reactio ...
(P450scc, CYP11A1), a
mitochondrial A mitochondrion (; ) is an organelle found in the cells of most Eukaryotes, such as animals, plants and fungi. Mitochondria have a double membrane structure and use aerobic respiration to generate adenosine triphosphate (ATP), which is use ...
cytochrome P450 Cytochromes P450 (CYPs) are a Protein superfamily, superfamily of enzymes containing heme as a cofactor (biochemistry), cofactor that functions as monooxygenases. In mammals, these proteins oxidize steroids, fatty acids, and xenobiotics, and are ...
oxidase with the loss of six carbon atoms to give
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 ...
. In the next step, two additional carbon atoms are removed by the
CYP17A1 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 ...
(17α-hydroxylase/17,20-lyase) enzyme in the
endoplasmic reticulum The endoplasmic reticulum (ER) is, in essence, the transportation system of the eukaryotic cell, and has many other important functions such as protein folding. It is a type of organelle made up of two subunits – rough endoplasmic reticulum ( ...
to yield a variety of C19 steroids. In addition, the 3β-hydroxyl group is oxidized by 3β-hydroxysteroid dehydrogenase to produce
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 ...
. In the final and rate limiting step, the C17 keto group androstenedione is reduced by 17β-hydroxysteroid dehydrogenase to yield testosterone. The largest amounts of testosterone (>95%) are produced by the
testes A testicle or testis (plural testes) is the male reproductive gland or gonad in all bilaterians, including humans. It is homologous to the female ovary. The functions of the testes are to produce both sperm and androgens, primarily testoster ...
in men, while 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 which ...
s account for most of the remainder. Testosterone is also synthesized in far smaller total quantities in women by the adrenal glands, thecal cells of the
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 ...
, and, during
pregnancy Pregnancy is the time during which one or more offspring develops ( gestates) inside a woman's uterus (womb). A multiple pregnancy involves more than one offspring, such as with twins. Pregnancy usually occurs by sexual intercourse, but ca ...
, by the
placenta The placenta is a temporary embryonic and later fetal organ that begins developing from the blastocyst shortly after implantation. It plays critical roles in facilitating nutrient, gas and waste exchange between the physically separate mater ...
. In the testes, testosterone is produced by the
Leydig cell Leydig cells, also known as interstitial cells of the testes and interstitial cells of Leydig, are found adjacent to the seminiferous tubules in the testicle and produce testosterone in the presence of luteinizing hormone (LH). They are polyhedral ...
s. The male generative glands also contain
Sertoli cell Sertoli cells are a type of sustentacular "nurse" cell found in human testes which contribute to the process of spermatogenesis (the production of sperm) as a structural component of the seminiferous tubules. They are activated by follicle-stimul ...
s, which require testosterone for
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 ...
. Like most hormones, testosterone is supplied to target tissues in the blood where much of it is transported bound to a specific
plasma protein Blood-proteins, also termed plasma proteins, are proteins present in blood plasma. They serve many different functions, including transport of lipids, hormones, vitamins and minerals in activity and functioning of the immune system. Other blood pr ...
,
sex hormone-binding globulin Sex hormone-binding globulin (SHBG) or sex steroid-binding globulin (SSBG) is a glycoprotein that binds to androgens and estrogens. When produced by the Sertoli cells in the seminiferous tubules of the testis, it has also been called androgen ...
(SHBG).


Regulation

In males, testosterone is synthesized primarily in
Leydig cells Leydig cells, also known as interstitial cells of the testes and interstitial cells of Leydig, are found adjacent to the seminiferous tubules in the testicle and produce testosterone in the presence of luteinizing hormone (LH). They are polyhedra ...
. The number of Leydig cells in turn is regulated by
luteinizing hormone Luteinizing hormone (LH, also known as luteinising hormone, lutropin and sometimes lutrophin) is a hormone produced by gonadotropic cells in the anterior pituitary gland. The production of LH is regulated by gonadotropin-releasing hormone (GnRH) ...
(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). In addition, the amount of testosterone produced by existing Leydig cells is under the control of LH, which regulates the expression of 17β-hydroxysteroid dehydrogenase. The amount of testosterone synthesized is regulated by the hypothalamic–pituitary–testicular axis (see figure to the right). When testosterone levels are low, gonadotropin-releasing hormone (
GnRH Gonadotropin-releasing hormone (GnRH) is a releasing hormone responsible for the release of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) from the anterior pituitary. GnRH is a tropic peptide hormone synthesized and released f ...
) is released by the
hypothalamus The hypothalamus () is a part of the brain that contains a number of small nuclei with a variety of functions. One of the most important functions is to link the nervous system to the endocrine system via the pituitary gland. The hypothalamu ...
, which in turn stimulates the
pituitary gland In vertebrate anatomy, the pituitary gland, or hypophysis, is an endocrine gland, about the size of a chickpea and weighing, on average, in humans. It is a protrusion off the bottom of the hypothalamus at the base of the brain. The ...
to release FSH and LH. These latter two hormones stimulate the testis to synthesize testosterone. Finally, increasing levels of testosterone through a negative
feedback Feedback occurs when outputs of a system are routed back as inputs as part of a chain of cause-and-effect that forms a circuit or loop. The system can then be said to ''feed back'' into itself. The notion of cause-and-effect has to be handled ...
loop act on the hypothalamus and pituitary to inhibit the release of GnRH and FSH/LH, respectively. Factors affecting testosterone levels may include: * Age: Testosterone levels gradually reduce as men age. This effect is sometimes referred to as andropause or
late-onset hypogonadism Late-onset hypogonadism (LOH) or testosterone deficiency syndrome (TDS) is a condition in older men characterized by measurably low testosterone levels and clinical symptoms mostly of a sexual nature, including decreased desire for sex, fewer spon ...
. * Exercise:
Resistance 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 ...
increases testosterone levels acutely, however, in older men, that increase can be avoided by protein ingestion.
Endurance training Endurance training is the act of exercising to increase endurance. The term endurance training generally refers to training the aerobic system as opposed to the anaerobic system. The need for endurance in sports is often predicated as the need o ...
in men may lead to lower testosterone levels. * Nutrients:
Vitamin A deficiency Vitamin A deficiency (VAD) or hypovitaminosis A is a lack of vitamin A in blood and tissues. It is common in poorer countries, especially among children and women of reproductive age, but is rarely seen in more developed countries. Nyctalopia (ni ...
may lead to sub-optimal plasma testosterone levels. The secosteroid
vitamin D Vitamin D is a group of fat-soluble secosteroids responsible for increasing intestinal absorption of calcium, magnesium, and phosphate, and many other biological effects. In humans, the most important compounds in this group are vitamin D3 (c ...
in levels of 400–1000  IU/d (10–25 µg/d) raises testosterone levels.
Zinc deficiency Zinc deficiency is defined either as insufficient zinc to meet the needs of the body, or as a serum zinc level below the normal range. However, since a decrease in the serum concentration is only detectable after long-term or severe depletion, s ...
lowers testosterone levels but over-supplementation has no effect on serum testosterone. There is limited evidence that
low-fat diet A low-fat diet is one that restricts fat, and often saturated fat and cholesterol as well. Low-fat diets are intended to reduce the occurrence of conditions such as heart disease and obesity. For weight loss, they perform similarly to a low-carb ...
s may reduce total and free testosterone levels in men, and moderate evidence that short-term, very high protein diets (≥35% protein) decrease total testosterone levels in men. * Weight loss: Reduction in weight may result in an increase in testosterone levels. Fat cells synthesize the enzyme aromatase, which converts testosterone, the male sex hormone, into estradiol, the female sex hormone. However no clear association between
body mass index Body mass index (BMI) is a value derived from the mass (weight) and height of a person. The BMI is defined as the body mass divided by the square of the body height, and is expressed in units of kg/m2, resulting from mass in kilograms and he ...
and testosterone levels has been found. * Miscellaneous: ''Sleep'': (
REM sleep Rapid eye movement sleep (REM sleep or REMS) is a unique phase of sleep in mammals and birds, characterized by random rapid movement of the eyes, accompanied by low muscle tone throughout the body, and the propensity of the sleeper to dream viv ...
) increases nocturnal testosterone levels. ''Behavior'': Dominance challenges can, in some cases, stimulate increased testosterone release in men. ''Drugs'': Natural or man-made
antiandrogens Antiandrogens, also known as androgen antagonists or testosterone blockers, are a class of drugs that prevent androgens like testosterone and dihydrotestosterone (DHT) from mediating their biological effects in the body. They act by blocking the ...
including
spearmint Spearmint, also known as garden mint, common mint, lamb mint and mackerel mint, is a species of mint, ''Mentha spicata'' (, native to Europe and southern temperate Asia, extending from Ireland in the west to southern China in the east. It is nat ...
tea reduce testosterone levels.
Licorice Liquorice (British English) or licorice (American English) ( ; also ) is the common name of ''Glycyrrhiza glabra'', a flowering plant of the bean family Fabaceae, from the root of which a sweet, aromatic flavouring can be extracted. The liq ...
can decrease the production of testosterone and this effect is greater in females.


Distribution

The
plasma protein binding Plasma protein binding refers to the degree to which medications attach to proteins within the blood. A drug's efficiency may be affected by the degree to which it binds. The less bound a drug is, the more efficiently it can traverse or diffuse th ...
of testosterone is 98.0 to 98.5%, with 1.5 to 2.0% free or unbound. It is bound 65% to
sex hormone-binding globulin Sex hormone-binding globulin (SHBG) or sex steroid-binding globulin (SSBG) is a glycoprotein that binds to androgens and estrogens. When produced by the Sertoli cells in the seminiferous tubules of the testis, it has also been called androgen ...
(SHBG) and 33% bound weakly to
albumin Albumin is a family of globular proteins, the most common of which are the serum albumins. All the proteins of the albumin family are water-soluble, moderately soluble in concentrated salt solutions, and experience heat denaturation. Albumins ...
.


Metabolism

Both testosterone and 5α-DHT 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 The liver is a major Organ (anatomy), organ only found in vertebrates which performs many essential biological functions such as detoxification of the organism, and the Protein biosynthesis, synthesis of proteins and biochemicals necessary for ...
. Approximately 50% of testosterone is metabolized via
conjugation Conjugation or conjugate may refer to: Linguistics * Grammatical conjugation, the modification of a verb from its basic form * Emotive conjugation or Russell's conjugation, the use of loaded language Mathematics * Complex conjugation, the chang ...
into testosterone glucuronide and to a lesser extent testosterone sulfate by
glucuronosyltransferase Uridine 5'-diphospho-glucuronosyltransferase ( UDP-glucuronosyltransferase, UGT) is a microsomal glycosyltransferase () that catalyzes the transfer of the glucuronic acid component of UDP-glucuronic acid to a small hydrophobic molecule. This is ...
s and
sulfotransferase Sulfotransferases (SULTs) are transferase enzymes that catalyze the transfer of a sulfo group from a donor molecule to an acceptor alcohol or amine. The most common sulfo group donor is 3'-phosphoadenosine-5'-phosphosulfate (PAPS). In the case o ...
s, respectively. An additional 40% of testosterone is metabolized in equal proportions into the 17-ketosteroids
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 ...
and
etiocholanolone Etiocholanolone, also known as 5β-androsterone, as well as 3α-hydroxy-5β-androstan-17-one or etiocholan-3α-ol-17-one, is an etiocholane (5β-androstane) steroid as well as an endogenous 17-ketosteroid that is produced from the metabolism of ...
via the combined actions of 5α- and 5β-reductases, 3α-hydroxysteroid dehydrogenase, and 17β-HSD, in that order. Androsterone and etiocholanolone are then
glucuronidated Glucuronidation is often involved in drug metabolism of substances such as drugs, pollutants, bilirubin, androgens, estrogens, mineralocorticoids, glucocorticoids, fatty acid derivatives, retinoids, and bile acids. These linkages involve glycosid ...
and to a lesser extent sulfated similarly to testosterone. The conjugates of testosterone and its hepatic metabolites are released from the liver into circulation and
excreted Excretion is a process in which metabolic waste is eliminated from an organism. In vertebrates this is primarily carried out by the lungs, kidneys, and skin. This is in contrast with secretion, where the substance may have specific tasks after lea ...
in the
urine Urine is a liquid by-product of metabolism in humans and in many other animals. Urine flows from the kidneys through the ureters to the urinary bladder. Urination results in urine being excretion, excreted from the body through the urethra. Cel ...
and
bile Bile (from Latin ''bilis''), or gall, is a dark-green-to-yellowish-brown fluid produced by the liver of most vertebrates that aids the digestion of lipids in the small intestine. In humans, bile is produced continuously by the liver (liver bile ...
. Only a small fraction (2%) of testosterone is excreted unchanged in the urine. In the hepatic 17-ketosteroid pathway of testosterone metabolism, testosterone is converted in the liver by 5α-reductase and 5β-reductase into 5α-DHT and the inactive 5β-DHT, respectively. Then, 5α-DHT and 5β-DHT are converted by 3α-HSD into 3α-androstanediol and 3α-etiocholanediol, respectively. Subsequently, 3α-androstanediol and 3α-etiocholanediol are converted by 17β-HSD into androsterone and etiocholanolone, which is followed by their conjugation and excretion.
3β-Androstanediol 3β-Androstanediol, also known as 5α-androstane-3β,17β-diol, and sometimes shortened in the literature to 3β-diol, is an endogenous steroid hormone and a metabolite of androgens like dehydroepiandrosterone (DHEA) and dihydrotestosterone (DHT). ...
and 3β-etiocholanediol can also be formed in this pathway when 5α-DHT and 5β-DHT are acted upon by 3β-HSD instead of 3α-HSD, respectively, and they can then be transformed into
epiandrosterone Epiandrosterone, or isoandrosterone, also known as 3β-androsterone, 3β-hydroxy-5α-androstan-17-one, or 5α-androstan-3β-ol-17-one, is a steroid hormone with weak androgenic activity. It is a metabolite of testosterone and dihydrotestosterone ...
and
epietiocholanolone Epietiocholanolone, also known as 3β-hydroxy-5β-androstan-17-one or as etiocholan-3β-ol-17-one, is an etiocholane (5β-androstane) steroid as well as an inactive metabolite of testosterone that is formed in the liver. The metabolic pathway i ...
, respectively. A small portion of approximately 3% of testosterone is reversibly converted in the liver into
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 ...
by 17β-HSD. In addition to conjugation and the 17-ketosteroid pathway, testosterone can also be
hydroxylated In chemistry, hydroxylation can refer to: *(i) most commonly, hydroxylation describes a chemistry, chemical process that introduces a hydroxyl group () into an organic compound. *(ii) the ''degree of hydroxylation'' refers to the number of OH gr ...
and
oxidized Redox (reduction–oxidation, , ) is a type of chemical reaction in which the oxidation states of substrate change. Oxidation is the loss of electrons or an increase in the oxidation state, while reduction is the gain of electrons or a ...
in the liver by
cytochrome P450 Cytochromes P450 (CYPs) are a Protein superfamily, superfamily of enzymes containing heme as a cofactor (biochemistry), cofactor that functions as monooxygenases. In mammals, these proteins oxidize steroids, fatty acids, and xenobiotics, and are ...
enzyme Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrates, and the enzyme converts the substrates into different molecules known as products. A ...
s, including
CYP3A4 Cytochrome P450 3A4 (abbreviated CYP3A4) () is an important enzyme in the body, mainly found in the liver and in the intestine. It oxidizes small foreign organic molecules (xenobiotics), such as toxins or drugs, so that they can be removed from t ...
,
CYP3A5 Cytochrome P450 3A5 is a protein that in humans is encoded by the ''CYP3A5'' gene. Tissue distribution ''CYP3A5'' encodes a member of the cytochrome P450 superfamily of enzymes. Like most of the cytochrome P450, the CYP3A5 is expressed in the ...
,
CYP2C9 Cytochrome P450 family 2 subfamily C member 9 (abbreviated CYP2C9) is an enzyme protein. The enzyme is involved in metabolism, by oxidation, of both xenobiotics, including drugs, and endogenous compounds, including fatty acids. In humans, the prote ...
,
CYP2C19 Cytochrome P450 2C19 (abbreviated CYP2C19) is an enzyme protein. It is a member of the CYP2C subfamily of the cytochrome P450 mixed-function oxidase system. This subfamily includes enzymes that catalyze metabolism of xenobiotics, including some pr ...
, and
CYP2D6 Cytochrome P450 2D6 (CYP2D6) is an enzyme that in humans is encoded by the ''CYP2D6'' gene. ''CYP2D6'' is primarily expressed in the liver. It is also highly expressed in areas of the central nervous system, including the substantia nigra. CYP2D ...
. 6β-Hydroxylation and to a lesser extent 16β-hydroxylation are the major transformations. The 6β-hydroxylation of testosterone is catalyzed mainly by CYP3A4 and to a lesser extent CYP3A5 and is responsible for 75 to 80% of cytochrome P450-mediated testosterone metabolism. In addition to 6β- and 16β-hydroxytestosterone, 1β-, 2α/β-, 11β-, and 15β-hydroxytestosterone are also formed as minor metabolites. Certain cytochrome P450 enzymes such as CYP2C9 and CYP2C19 can also oxidize testosterone at the C17 position to form androstenedione. Two of the immediate metabolites of testosterone, 5α-DHT and
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 of f ...
, are biologically important and can be formed both in the liver and in extrahepatic tissues. Approximately 5 to 7% of testosterone is converted by 5α-reductase into 5α-DHT, with circulating levels of 5α-DHT about 10% of those of testosterone, and approximately 0.3% of testosterone is converted into estradiol by
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 ...
. 5α-Reductase is highly expressed in the male reproductive organs (including the
prostate gland The prostate is both an accessory gland of the male reproductive system and a muscle-driven mechanical switch between urination and ejaculation. It is found only in some mammals. It differs between species anatomically, chemically, and physio ...
,
seminal vesicle The seminal vesicles (also called vesicular glands, or seminal glands) are a pair of two convoluted tubular glands that lie behind the urinary bladder of some male mammals. They secrete fluid that partly composes the semen. The vesicles are 5 ...
s, and epididymides),
skin Skin is the layer of usually soft, flexible outer tissue covering the body of a vertebrate animal, with three main functions: protection, regulation, and sensation. Other cuticle, animal coverings, such as the arthropod exoskeleton, have diffe ...
,
hair follicle The hair follicle is an organ found in mammalian skin. It resides in the dermal layer of the skin and is made up of 20 different cell types, each with distinct functions. The hair follicle regulates hair growth via a complex interaction between h ...
s, and
brain A brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. It is located in the head, usually close to the sensory organs for senses such as vision. It is the most complex organ in a v ...
and aromatase is highly expressed in adipose tissue,
bone A bone is a Stiffness, rigid Organ (biology), organ that constitutes part of the skeleton in most vertebrate animals. Bones protect the various other organs of the body, produce red blood cell, red and white blood cells, store minerals, provid ...
, and the brain. As much as 90% of testosterone is converted into 5α-DHT in so-called androgenic tissues with high 5α-reductase expression, and due to the several-fold greater potency of 5α-DHT as an AR agonist relative to testosterone, it has been estimated that the effects of testosterone are potentiated 2- to 3-fold in such tissues.


Levels

Total levels of testosterone in the body have been reported as 264 to 916 ng/dL (nanograms per deciliter) in non-obese European and American men age 19 to 39 years, while mean testosterone levels in adult men have been reported as 630 ng/dL. Although commonly used as a
reference range In medicine and health-related fields, a reference range or reference interval is the range or the interval of values that is deemed normal for a physiological measurement in healthy persons (for example, the amount of creatinine in the blood, o ...
, some physicians have disputed the use of this range to determine
hypogonadism Hypogonadism means diminished functional activity of the gonads—the testes or the ovaries—that may result in diminished production of sex hormones. Low androgen (e.g., testosterone) levels are referred to as hypoandrogenism and low estrogen ...
. Several professional medical groups have recommended that 350 ng/dl generally be considered the minimum normal level, which is consistent with previous findings. Levels of testosterone in men decline with age. In women, mean levels of total testosterone have been reported to be 32.6 ng/dL. In women with
hyperandrogenism Hyperandrogenism is a medical condition characterized by high levels of androgens. It is more common in women than men. Symptoms of hyperandrogenism may include acne, seborrhea (inflamed skin), hair loss on the scalp, increased body or facia ...
, mean levels of total testosterone have been reported to be 62.1 ng/dL.


Measurement

Testosterone's bioavailable concentration is commonly determined using the Vermeulen calculation or more precisely using the modified Vermeulen method, which considers the dimeric form of sex-hormone-binding-globulin. Both methods use chemical equilibrium to derive the concentration of bioavailable testosterone: in circulation, testosterone has two major binding partners, albumin (weakly bound) and sex-hormone-binding-globulin (strongly bound). These methods are described in detail in the accompanying figure. File:Dimeric SHBG.png, Dimeric sex-hormone-binding-globulin with its testosterone ligands File:Method for determining testosterone.png, Two methods for determining the concentration of bioavailable testosterone.


History

A
testicular A testicle or testis (plural testes) is the male reproductive gland or gonad in all bilaterians, including humans. It is homologous to the female ovary. The functions of the testes are to produce both sperm and androgens, primarily testosteron ...
action was linked to circulating blood fractions – now understood to be a family of androgenic hormones – in the early work on castration and testicular transplantation in fowl by
Arnold Adolph Berthold Arnold Adolph Berthold (also Arnold Adolf Berthold) (26 February 1803, in Soest – 3 January 1861, in Göttingen) was a German scientist, most notably a physiologist and zoologist . He is best known in modern science for his pioneering experim ...
(1803–1861). Research on the action of testosterone received a brief boost in 1889, when the Harvard professor
Charles-Édouard Brown-Séquard Charles-Édouard Brown-Séquard FRS (8 April 1817 – 2 April 1894) was a Mauritian physiologist and neurologist who, in 1850, became the first to describe what is now called Brown-Séquard syndrome. Early life Brown-Séquard was born at Port ...
(1817–1894), then in Paris, self-injected subcutaneously a "rejuvenating elixir" consisting of an extract of dog and guinea pig testicle. He reported in ''
The Lancet ''The Lancet'' is a weekly peer-reviewed general medical journal and one of the oldest of its kind. It is also the world's highest-impact academic journal. It was founded in England in 1823. The journal publishes original research articles, ...
'' that his vigor and feeling of well-being were markedly restored but the effects were transient, and Brown-Séquard's hopes for the compound were dashed. Suffering the ridicule of his colleagues, he abandoned his work on the mechanisms and effects of androgens in human beings. In 1927, the University of Chicago's Professor of Physiologic Chemistry, Fred C. Koch, established easy access to a large source of bovine testicles — the Chicago stockyards — and recruited students willing to endure the tedious work of extracting their isolates. In that year, Koch and his student, Lemuel McGee, derived 20 mg of a substance from a supply of 40 pounds of bovine testicles that, when administered to castrated roosters, pigs and rats, re-masculinized them. The group of Ernst Laqueur at the University of Amsterdam purified testosterone from bovine testicles in a similar manner in 1934, but the isolation of the hormone from animal tissues in amounts permitting serious study in humans was not feasible until three European pharmaceutical giants— Schering (Berlin, Germany),
Organon The ''Organon'' ( grc, Ὄργανον, meaning "instrument, tool, organ") is the standard collection of Aristotle's six works on logical analysis and dialectic. The name ''Organon'' was given by Aristotle's followers, the Peripatetics. The si ...
(Oss, Netherlands) and Ciba (Basel, Switzerland)—began full-scale steroid research and development programs in the 1930s. The Organon group in the Netherlands were the first to isolate the hormone, identified in a May 1935 paper "On Crystalline Male Hormone from Testicles (Testosterone)". They named the hormone ''testosterone'', from the stems of ''testicle'' and ''
sterol Sterol is an organic compound with formula , whose molecule is derived from that of gonane by replacement of a hydrogen atom in position 3 by a hydroxyl group. It is therefore an alcohol of gonane. More generally, any compounds that contain the go ...
'', and the
suffix In linguistics, a suffix is an affix which is placed after the stem of a word. Common examples are case endings, which indicate the grammatical case of nouns, adjectives, and verb endings, which form the conjugation of verbs. Suffixes can carry ...
of ''
ketone In organic chemistry, a ketone is a functional group with the structure R–C(=O)–R', where R and R' can be a variety of carbon-containing substituents. Ketones contain a carbonyl group –C(=O)– (which contains a carbon-oxygen double bo ...
''. The structure was worked out by Schering's
Adolf Butenandt Adolf Friedrich Johann Butenandt (; 24 March 1903 – 18 January 1995) was a German biochemist. He was awarded the Nobel Prize in Chemistry in 1939 for his "work on sex hormones." He initially rejected the award in accordance with government po ...
, at the ''Chemisches Institut'' of
Technical University An institute of technology (also referred to as: technological university, technical university, university of technology, technological educational institute, technical college, polytechnic university or just polytechnic) is an institution of te ...
in
Gdańsk Gdańsk ( , also ; ; csb, Gduńsk;Stefan Ramułt, ''Słownik języka pomorskiego, czyli kaszubskiego'', Kraków 1893, Gdańsk 2003, ISBN 83-87408-64-6. , Johann Georg Theodor Grässe, ''Orbis latinus oder Verzeichniss der lateinischen Benen ...
. The
chemical synthesis As a topic of chemistry, chemical synthesis (or combination) is the artificial execution of chemical reactions to obtain one or several products. This occurs by physical and chemical manipulations usually involving one or more reactions. In moder ...
of testosterone from cholesterol was achieved in August that year by Butenandt and Hanisch. Only a week later, the Ciba group in Zurich,
Leopold Ruzicka Leopold may refer to: People * Leopold (given name) * Leopold (surname) Arts, entertainment, and media Fictional characters * Leopold (''The Simpsons''), Superintendent Chalmers' assistant on ''The Simpsons'' * Leopold Bloom, the protagonist o ...
(1887–1976) and A. Wettstein, published their synthesis of testosterone. These independent partial syntheses of testosterone from a cholesterol base earned both Butenandt and Ruzicka the joint 1939
Nobel Prize in Chemistry ) , image = Nobel Prize.png , alt = A golden medallion with an embossed image of a bearded man facing left in profile. To the left of the man is the text "ALFR•" then "NOBEL", and on the right, the text (smaller) "NAT•" then "M ...
. Testosterone was identified as 17β-hydroxyandrost-4-en-3-one (C19H28O2), a solid polycyclic alcohol with a hydroxyl group at the 17th carbon atom. This also made it obvious that additional modifications on the synthesized testosterone could be made, i.e., esterification and alkylation. The partial synthesis in the 1930s of abundant, potent
testosterone ester This is a list of androgen esters, including esters (as well as ethers) of natural androgens like testosterone and dihydrotestosterone (DHT) and synthetic anabolic–androgenic steroids (AAS) like nandrolone (19-nortestosterone). Esters of nat ...
s permitted the characterization of the hormone's effects, so that Kochakian and Murlin (1936) were able to show that testosterone raised nitrogen retention (a mechanism central to anabolism) in the dog, after which Allan Kenyon's group was able to demonstrate both anabolic and androgenic effects of testosterone propionate in eunuchoidal men, boys, and women. The period of the early 1930s to the 1950s has been called "The Golden Age of Steroid Chemistry", and work during this period progressed quickly.


Other species

Testosterone is observed in most vertebrates. Testosterone and the classical nuclear
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 ...
first appeared in
gnathostome Gnathostomata (; from Greek: (') "jaw" + (') "mouth") are the jawed vertebrates. Gnathostome diversity comprises roughly 60,000 species, which accounts for 99% of all living vertebrates, including humans. In addition to opposing jaws, living ...
s (jawed vertebrates). Agnathans (jawless vertebrates) such as
lamprey Lampreys (sometimes inaccurately called lamprey eels) are an ancient extant lineage of jawless fish of the order Petromyzontiformes , placed in the superclass Cyclostomata. The adult lamprey may be characterized by a toothed, funnel-like s ...
s do not produce testosterone but instead use
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 ...
as a male sex hormone.
Fish Fish are aquatic, craniate, gill-bearing animals that lack limbs with digits. Included in this definition are the living hagfish, lampreys, and cartilaginous and bony fish as well as various extinct related groups. Approximately 95% of li ...
make a slightly different form called 11-ketotestosterone. Its counterpart in insects is
ecdysone Ecdysone is a prohormone of the major insect molting hormone 20-hydroxyecdysone, which is secreted from the prothoracic glands. It is of steroidal structure. Insect molting hormones (ecdysone and its homologues) are generally called ecdysteroids. ...
. The presence of these ubiquitous steroids in a wide range of animals suggest that
sex hormone 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 ar ...
s have an ancient evolutionary history.


See also

*
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 human hormones


References


Further reading

* * * {{Authority control Cyclopentanols Alkene derivatives Androgens and anabolic steroids Androstanes Estrogens GABAA receptor positive allosteric modulators Hormones of the testis Hormones of the ovary Hormones of the hypothalamus-pituitary-gonad axis Hormones of the suprarenal cortex Enones Neuroendocrinology Human hormones Sex hormones