Testosterone

Testosterone is a steroid hormone from the androgen 1.1 Before birth

group and is found in mammals, reptiles,[1] birds,[2] and
other vertebrates. In mammals, testosterone is secreted The prenatal androgen eects occur during two dierent
primarily by the testicles of males and the ovaries of stages. Between 4 and 6 weeks of the gestation.
females, although small amounts are also secreted by the
adrenal glands. It is the principal male sex hormone and
Genital virilization (midline fusion, phallic urethra,
an anabolic steroid.
scrotal thinning and rugation, phallic enlargement);
although the role of testosterone is far smaller than
In men, testosterone plays a key role in the developthat of dihydrotestosterone.
ment of male reproductive tissues such as the testis and
prostate as well as promoting secondary sexual charac Development of prostate and seminal vesicles.
teristics such as increased muscle, bone mass, and the
growth of body hair.[3] In addition, testosterone is essen- During the second trimester, androgen level is associated
tial for health and well-being[4] as well as the prevention with gender formation.[13] This period aects the femof osteoporosis.[5]
ininization or masculinization of the fetus and can be
On average, in adult males, levels of testosterone a better predictor of feminine or masculine behaviours
are about 78 times as great as in adult females,[6] such as sex typed behaviour than an adults own levels. A
but, as the metabolic consumption of testosterone in mothers testosterone level during pregnancy is correlated
males is greater, the daily production is about 20 with her daughters sex-typical behavior as an adult, and
times greater in men.[7][8] Females are also more sen- the correlation is even stronger than with the daughters
sitive to the hormone.[9] Testosterone is observed in own adult testosterone level.[14]
most vertebrates. Fish make a slightly dierent form
called 11-ketotestosterone.[10] Its counterpart in insects
is ecdysone.[11] These ubiquitous steroids suggest that sex 1.2 Early infancy
hormones have an ancient evolutionary history.[12]
Early infancy androgen eects are the least understood.
In the rst weeks of life for male infants, testosterone
levels rise. The levels remain in a pubertal range for a
1 Health eects
few months, but usually reach the barely detectable levels
of childhood by 46 months of age.[15][16] The function
In general, androgens promote protein synthesis and of this rise in humans is unknown. It has been specugrowth of those tissues with androgen receptors. Testos- lated that brain masculinization" is occurring since no
terone eects can be classied as virilizing and anabolic, signicant changes have been identied in other parts
though the distinction is somewhat articial, as many of of the body.[17] It is interesting to note that the male
the eects can be considered both.
brain is masculinized by the aromatization of testosterone into estrogen, which crosses the bloodbrain bar Anabolic eects include growth of muscle mass and rier and enters the male brain, whereas female fetuses
strength, increased bone density and strength, and have alpha-fetoprotein, which binds the estrogen so that
female brains are not aected.[18]
stimulation of linear growth and bone maturation.
Androgenic eects include maturation of the sex organs, particularly the penis and the formation of
the scrotum in the fetus, and after birth (usually at
puberty) a deepening of the voice, growth of the
beard and axillary hair. Many of these fall into the
category of male secondary sex characteristics.

1.3 Pre-peripubertal
Pre- Peripubertal eects are the rst observable eects of
rising androgen levels at the end of childhood, occurring
in both boys and girls.
Adult-type body odor

Testosterone eects can also be classied by the age of

usual occurrence. For postnatal eects in both males and
females, these are mostly dependent on the levels and duration of circulating free testosterone.

Increased oiliness of skin and hair, acne

Pubarche (appearance of pubic hair)
1

HEALTH EFFECTS

Axillary hair
Growth spurt, accelerated bone maturation
Hair on upper lip,on chin, and growth of sideburns.

1.4

Pubertal

Pubertal eects begin to occur when androgen has been

higher than normal adult female levels for months or
years. In males, these are usual late pubertal eects, and
occur in women after prolonged periods of heightened
levels of free testosterone in the blood.
Enlargement of sebaceous glands. This might cause
acne.

Reference ranges for blood tests, showing adult male testosterone

levels in light blue at center-left.

1.5.1 Biological uses

Testosterone is necessary for normal sperm development. It activates genes in Sertoli cells, which promote dierentiation of spermatogonia.
Regulates acute HPA (Hypothalamicpituitary
adrenal axis) response under dominance
challenge[20]
Regulator of cognitive and physical energy

Phallic enlargement or clitoromegaly

Maintenance of muscle trophism

Increased libido and frequency of erection or clitoral

engorgement

Testosterone regulates the population of

thromboxane A2 receptors on megakaryocytes
and platelets and hence platelet aggregation in
humans[21][22]

Pubic hair extends to thighs and up toward umbilicus

Facial hair (sideburns, beard, moustache)
Loss of scalp hair (Androgenetic alopecia)

High androgen levels are associated with menstrual

cycle irregularities in both clinical populations and
healthy women.[23] See libido.

Chest hair, periareolar hair, perianal hair

Leg hair
Axillary hair
Subcutaneous fat in face decreases
Increased muscle strength and mass[19]
Deepening of voice
Growth of the Adams apple
Growth of spermatogenic tissue in testicles, male
fertility
Growth of jaw, brow, chin, nose, and remodeling of
facial bone contours
Shoulders become broader and rib cage expands
Completion of bone maturation and termination
of growth. This occurs indirectly via estradiol
metabolites and hence more gradually in men than
women.

1.5

Adult

Adult testosterone eects are more clearly demonstrable

in males than in females, but are likely important to both
sexes. Some of these eects may decline as testosterone
levels decrease in the later decades of adult life.

1.5.2 Cancer prevention and health risks

Testosterone does not cause deleterious eects in
prostate cancer. 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.[24][25][26]
Recent studies have shown conicting results concerning the importance of testosterone in maintaining cardiovascular health.[27][28] 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.[29]
Under dominance challenge, may play a role in the
regulation of the ght-or-ight response[30]
Men whose testosterone levels are slightly above average are less likely to have high blood pressure, less
likely to experience a heart attack, less likely to be
obese, and less likely to rate their own health as fair
or poor. However, high testosterone men are more
likely to report one or more injuries, more likely to
consume ve or more alcoholic drinks in a day, more
likely to have had a sexually transmitted infection,
and more likely to smoke.[31]

1.5
1.5.3

Adult
Romantic relationships and fatherhood

Falling in love decreases mens testosterone levels while

increasing womens testosterone levels. There has been
speculation that these changes in testosterone result in
the temporary reduction of dierences in behavior between the sexes.[32] However, it is suggested that after
the honeymoon phase endsabout one to three years
into a relationshipthis change in testosterone levels is
no longer apparent.[32] Fatherhood also decreases testosterone levels in men, suggesting that the resulting emotional and behavioral changes promote paternal care.[33]
Men who produce less testosterone are more likely to
be in a relationship[34] and/or married,[35] and men who
produce more testosterone are more likely to divorce;[35]
however, causality cannot be determined in this relationship. Marriage or commitment could cause a decrease in
testosterone levels.[36] 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.[37] Married men who engage in bond-maintenance activities such
as spending the day with their spouse/and or child have
no dierent 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.[38]
Men who produce more testosterone are more likely to
engage in extramarital sex.[35] Testosterone levels do not
rely on physical presence of a partner for men engaging
in relationships (same-city vs. long-distance), men have
similar testosterone levels across the board.[34] Physical
presence may be required for women who are in relationships for the testosteronepartner interaction, where
same-city partnered women have lower testosterone levels than long-distance partnered women.[39]

1.5.4

3
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 mens perceptions of their orgasm experience, and also no correlation
between higher testosterone levels and greater sexual assertiveness in either sex.[41]
An increase in testosterone levels has also been found to
occur in both men and women who have masturbationinduced orgasms.[42][43]
Mammalian studies Studies conducted on 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 behaviors (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 suering from sexual arousal decits such as hypoactive sexual
desire disorder.[44]
In one study, almost every mammalian species examined
demonstrated a marked increase in a males testosterone
level upon encountering a novel female. P.J. James et
al. investigated the role of genotype on such so-called
reexive testosterone increases in male mice. They also
concluded that this response is related to the males initial
level of sexual arousal.[45]
In non-human primates it has been suggested that testosterone in puberty stimulates sexual motivation, which allows the primate to increasingly seek out sexual experiences with females and thus creates a sexual preference for females.[46] Some research has also indicated
that if testosterone is eliminated in an adult male human
or other adult male primates system, its sexual motivation decreases, but there is no corresponding decrease in
ability to engage in sexual activity (mounting, ejaculating,
etc.).[46]

Testosterone and sexual arousal

See also: Hormones and sexual arousal

It has been found that when testosterone and endorphins
in ejaculated semen meet the cervical wall after sexual
intercourse, females receive a spike in testosterone, endorphin, and oxytocin levels, and males after orgasm during copulation experience an increase in endorphins and a
marked increase in oxytocin levels. This adds to the hospitable physiological environment in the female internal
reproductive tract for conceiving, and later for nurturing
the conceptus in the pre-embryonic stages, and stimulates
feelings of love, desire, and paternal care in the male (this
is the only time male oxytocin levels rival a females).[32]

Male sexual arousal Higher levels of testosterone

were associated with periods of sexual activity within
subjects, but between subjects testosterone levels were
higher for less sexually active individuals.[47] Men who
have sexual encounters with unfamiliar or multiple partners experience large increases of testosterone the morning after.[48]

Men who watch a sexually explicit movie have an average increase of 35% in testosterone, peaking at 6090
minutes after the end of the lm, but no increase is seen
in men who watch sexually neutral lms.[49] Men who
watch sexually explicit lms also report increased optimism and decreased exhaustion.[50] Previous research has
found a link between relaxation following sexual arousal
[51]
Testosterone levels follow a nyctohemeral rhythm that and testosterone levels.
peaks early each day, regardless of sexual activity.[40]
A 2002 study found that testosterone increased in het-

4
erosexual men after having had a brief conversation with
a woman. The increase in testosterone levels was associated with the degree that the women thought the men
were trying to impress them.[52]
Mens levels of testosterone, a hormone known to aect
mens mating behaviour, changes depending on whether
they are exposed to an ovulating or nonovulating womans
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. Testosterone levels and sexual arousal
in men are heavily aware of hormone cycles in females.[53]
This may be linked to the ovulatory shift hypothesis,[54]
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.

HEALTH EFFECTS

androgen insuciency, however it has been used o-label

to treat low libido and sexual dysfunction in older women.
Testosterone may be a treatment for postmenopausal
women as long as they are eectively estrogenized.[61]

1.5.5 Behavior and personality

Testosterone levels play a major role in risk-taking during
nancial decisions.[62][63]

1.6 Brain
As testosterone aects the entire body (often by enlarging; males have bigger hearts, lungs, liver, etc.), the
brain is also aected by this sexual dierentiation;[13]
the enzyme aromatase converts testosterone into estradiol
that is responsible for masculinization of the brain in male
mice. In humans, masculinization of the fetal brain appears, by observation of gender preference in patients
with congenital diseases of androgen formation or androgen receptor function, to be associated with functional
androgen receptors.[64]

In a 1991 study, males were exposed to either visual or

auditory erotic stimuli and asked to complete a cognitive
task, where the number of errors on the task indicated
how distracted the participant was by the stimuli. It concluded that men with lower thresholds for sexual arousal
have a greater likelihood to attend to sexual information
and that testosterone may have an impact by enhancing There are some dierences between a male and female
brain (possibly the result of dierent testosterone levels),
their attention to the relevant stimuli.[55]
one of them being size: the male human brain is, on avSperm competition theory: Testosterone levels are shown erage, larger.[65] In a Danish study from 2003, men were
to increase as a response to previously neutral stimuli found to have a total myelinated ber length of 176,000
when conditioned to become sexual in male rats.[56] This km at the age of 20, whereas in women the total length
reaction engages penile reexes (such as erection and was 149,000 km (approx. 15% less).[66]
ejaculation) that aid in sperm competition when more
than one male is present in mating encounters, allow- A study conducted in 1996 found no immediate short
ing for more production of successful sperm and a higher term eects on mood or behavior from the administration
of supraphysiologic doses of testosterone for 10 weeks
chance of reproduction.
on 43 healthy men.[19] Another study found a correlation
between testosterone and risk tolerance in career choice
among women.[67][68]
Female sexual arousal Androgens may modulate the
physiology of vaginal tissue and contribute to female gen- The literature suggests that attention, memory, and
ital sexual arousal.[57] Womens level of testosterone is spatial ability are key cognitive functions aected by
higher when measured pre-intercourse vs pre-cuddling, testosterone in humans. Preliminary evidence sugas well as post-intercourse vs post-cuddling.[58] There is a gests that low testosterone levels may be a risk factor
and possibly for dementia of the
time lag eect when testosterone is administered, on gen- for cognitive decline
[69][70][71][72]
Alzheimers
type,
a key argument in life exital arousal in women. In addition, a continuous increase
medicine
for
the
use
of
testosterone in anti-aging
tension
in vaginal sexual arousal may result in higher genital sentherapies.
Much
of
the
literature,
however, suggests a
[59]
sations and sexual appetitive behaviors.
curvilinear or even quadratic relationship between spaWhen females have a higher baseline level of testos- tial performance and circulating testosterone,[73] where
terone, they have higher increases in sexual arousal levels both hypo- and hypersecretion (decient- and excessivebut smaller increases in testosterone, indicating a ceiling secretion) of circulating androgens have negative eects
eect on testosterone levels in females. Sexual thoughts on cognition.
also change the level of testosterone but not level of cortisol in the female body, and hormonal contraceptives may
have an impact on the variation in testosterone response 1.7 Aggression and criminality
to sexual thoughts.[60]
Testosterone may prove to be an eective treatment in See also: Aggression Testosterone and biosocial
female sexual arousal disorders.[61] Currently there is no criminology
FDA approved androgen preparation for the treatment of

5
The evolutionary neuroandrogenic theory focuses on
the hormone testosterone as a factor inuencing aggression and criminality and being evolutionarily benecial
during certain forms of competition. In most species,
males are more aggressive than females. Castration of
males usually has a pacifying eect on their aggressive
behavior. In humans, males engage in crime and especially violent crime more than females. Their involvement in crime usually rises in the early teens to mid teens,
at the same time as testosterone levels rise. Research
on the relationship between testosterone and aggression
is dicult, since the only reliable measurement of brain
testosterone is by a lumbar puncture that is not done for
research purposes. Studies therefore have often instead
used more unreliable measurements from blood or saliva.

these results.[79][80][81]

Testosterone is only one of a myriad of factors that

inuence aggression and the eects of previous experience and environmental stimuli have been found
to correlate more strongly. A few studies indicate
that the testosterone derivative estradiol (one form of
estrogen) might play an even more important role in male
aggression.[74][75][76][77]

replacement therapy.[85]

Estradiol is known to correlate with aggression in male

mice.[82] Moreover, the conversion of testosterone to
estradiol regulates male aggression in sparrows during
breeding season.[83]

2 Medical uses

The primary use of testosterone is the treatment of males

with too little or no natural endogenous testosterone
productionmales with hypogonadism. This is known
as hormone replacement therapy or testosterone replacement therapy (TRT), which maintains serum testosterone
Most studies support a link between adult criminality and levels in the normal range.
testosterone, although the relationship is modest if exam- Testosterone has also been given for many other purined separately for each sex. Nearly all studies of ju- poses besides replacement. Examples include reducing
venile delinquency and testosterone are not signicant. infertility, correcting lack of libido or erectile dysfuncMost studies have also found testosterone to be asso- tion, correcting osteoporosis, encouraging penile enlargeciated with behaviors or personality traits linked with ment, encouraging height growth, encouraging bone marcriminality such as antisocial behavior and alcoholism. row stimulation and reversing the eects of anemia, and
Many studies have also been done on the relationship appetite stimulation. By the late 1940s, testosterone was
between more general aggressive behavior/feelings and being touted as an anti-aging wonder drug (e.g., see Paul
testosterone. About half the studies have found a rela- de Kruif's The Male Hormone).[84] Decline of testostionship and about half no relationship.[74]
terone production with age has led to interest in androgen
Testosterone may be used as a monotherapy in dysthymia
and minor depression or as an augmentation therapy in
major depression in middle-aged men with low testosterone. However, review of the current literature does
not show a statistically signicant impact on the mood of
the men with normal levels of testosterone or on the mood
[86]
It has been empirically shown that boys who had a his- of the older men with low testosterone.
tory of high physical aggression, from age 6 to 12, were To take advantage of its virilizing eects, testosterone
found to have lower testosterone levels at age 13 com- is often administered to transsexual men as part of the
pared with boys with no history of high physical aggres- hormone replacement therapy,[87] with a target level of
sion. The former were also failing in school and were the normal male testosterone level. Likewise, transsexual
unpopular with their peers. Both concurrent and lon- women are sometimes prescribed anti-androgens to degitudinal analyses indicate that testosterone levels were crease the level of testosterone in the body and allow for
positively associated with social success rather than with the eects of estrogen to develop.
physical aggression.[78]
Testosterone therapy may improve the management of
A study at the Universities of Zurich and Royal Holloway type 2 diabetes.[88] Low testosterone has been associated
London with more than 120 experimental subjects has with the development of Alzheimers disease.[71][72] A
shown that the sexual hormone can encourage fair behav- small trial in 2005 showed mixed results in using testosior. For the study subjects took part in a behavioral exper- terone to combat the eects of aging.[89]
iment 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 2.1 Hormone replacement therapy
or decline the oer. The fairer the oer, the less probable a refusal by the negotiating partner. If no agreement
Further information: Testosterone Adverse eects,
was reached, neither party earned anything. Test subjects
Andropause Hormone replacement therapy and
with an articially enhanced testosterone level generally
Androgen replacement therapy Adverse eects
made better, fairer oers than those who received placebos, thus reducing the risk of a rejection of their oer to a
minimum. Two later studies have empirically conrmed Testosterone levels decline gradually with age in human
beings.(see andropause) The clinical signicance of this

6
decrease is debated (see andropause). There is disagreement about when to treat aging men with testosterone replacement therapy. The American Society of
Andrology's position is that testosterone replacement
therapy in aging men is indicated when both clinical
symptoms and signs suggestive of androgen deciency
and decreased testosterone levels are present.[90] The
American Association of Clinical Endocrinologists says
"Hypogonadism is dened as a free testosterone level that
is below the lower limit of normal for young adult control
subjects. Previously, age-related decreases in free testosterone were once accepted as normal. Currently, they are
not considered normal.[91] Males with borderline testosterone levels may benet from a trial of testosterone.[92]
Large-scale trials to assess the eectiveness and longterm safety of testosterone are still lacking.[93]

NON-MEDICAL USE

ommended for improving cognition, the risk of heart disease, bone strength or for generalized well being.[98]

3 Non-medical use
3.1 Athletics

Testosterone can be used by an athlete in order to improve

performance, but it is considered to be a form of doping
in most sports. There are several application methods for testosterone, including intramuscular injections,
transdermal gels and patches, and implantable pellets.
Supplement of the hormone results in lower metabolic
production via the Farquharson phenomenon, creating
There is not total agreement on the threshold of testos- long-term dependence for improved performance level.
terone value below which a man would be considered Anabolic steroids (including testosterone) have also been
hypogonadal. (Currently, there are no standards as to taken to enhance muscle development, strength, or enwhen to treat women.) Testosterone can be measured as durance. They do so directly by increasing the musfree (that is, bioavailable and unbound) or, more com- cles protein synthesis. As a result, muscle bers become
monly, total (including the percentage that is chemi- larger and repair faster than the average persons. After
cally bound and unavailable). In the United States, male a series of scandals and publicity in the 1980s (such as
total testosterone levels below 300 ng/dL (10.4 nmol/L) Ben Johnsons improved performance at the 1988 Sumfrom a morning serum sample are generally considered mer Olympics), prohibitions of anabolic steroid use were
low.[94] Identication of inadequate testosterone in an ag- renewed or strengthened by many sports organizations.
ing male by symptoms alone can be dicult.
Testosterone and other anabolic steroids were designated
a "controlled substance" by the United States Congress in
1990, with the Anabolic Steroid Control Act.[99] Their use
2.2 Insuciency
is seen as a seriously problematic issue in modern sport,
particularly given the lengths to which athletes and proFurther information: Hypogonadism and Androgen fessional laboratories go to in trying to conceal such use
deciency
from sports regulators. Steroid use once again came into
the spotlight recently as a result of the Chris Benoit douTestosterone insuciency (also termed hypotestos- ble murder-suicide in 2007, however, there has been no
teronism or hypotestosteronemia) is an abnormally evidence indicating steroid use as a contributing factor.
low testosterone production. It may occur because Some female athletes may have naturally higher levels of
of testicular dysfunction (primary hypogonadism) or testosterone than others, and may be asked to consent to
hypothalamic-pituitary dysfunction (secondary hypogo- a therapeutic proposal, either surgery or drugs, to denadism) and may be congenital or acquired.[95] An ac- crease testosteone levels to a level thought acceptable to
quired form of hypotestosteronism is the decline in testos- compete fairly with others.[100]
terone levels that occurs by aging, sometimes called
"andropause" in men, as a comparison to the decline in
estrogen that comes with menopause in women. In West3.2 Detection of abuse
ern countries, average testosterone levels are receding in
men of all ages.[96][97]
A number of methods for detecting testosterone use by
athletes have been employed, most based on a urine test.
These include the testosterone/epitestosterone ratio (nor2.3 Women
mally less than 6), the testosterone/luteinizing hormone
ratio and the carbon-13 / carbon-12 ratio (pharmaceuTestosterone supplementation is eective in the short tical testosterone contains less carbon-13 than endogeterm for hypoactive sexual desire disorder.[98] Its long nous testosterone). In some testing programs, an inditerm safety, however, is unclear.[98]
viduals own historical results may serve as a reference
Treating low androgen levels with testosterone is not interval for interpretation of a suspicious nding. Angenerally recommended in women when it is due to other approach being investigated is the detection of the
hypopituitarism, adrenal insuciency, or following sur- administered form of testosterone, usually an ester, in
gical removal of the ovaries.[98] It is also not usually rec- hair.[101][102][103][104]

4.2

Cancer

Adverse eects

4.2 Cancer

Testosterone in the presence of a slow-growing cancer is

assumed to increase its growth rate. However, the association between testosterone supplementation and the
development of prostate cancer is unproven.[118] NeverWhether or not testosterone therapy in men causes importheless, physicians are cautioned about the cancer risk astant adverse eects was unclear as of 2010;[105] however,
sociated with testosterone supplementation.[119]
as of September 2014, such therapy has been under review for appropriateness and safety by the Food and Drug Ethnic groups have dierent rates of prostate canAdministration due to the potential for adverse cardio- cer.[120] Dierences in sex hormones, including testosterone, have been suggested as an explanation for these
vascular outcomes.[106][107][108]
dierences.[120] This apparent paradox can be resolved by
noting that prostate cancer is very common. In autopsies,
80% of 80-year-old men have prostate cancer.[121]
See also: Testosterone Hormone replacement therapy

4.1

Cardiovascular disease

On January 31, 2014, reports of strokes, heart attacks,

and deaths in men taking FDA-approved testosteronereplacement led the Food and Drug Administration to announce that it would be investigating this issue.[109] The
FDA is requiring warnings in the drug labeling of all approved testosterone products regarding deep vein thrombosis and pulmonary embolism.[110]
Adverse eects of testosterone supplementation may include increased cardiovascular events (including strokes
and heart attacks) and deaths based on three peerreviewed studies involving men taking testosteronereplacement.[111] In addition, an increase of 30%
in deaths and heart attacks in older men has been
reported.[112] Due to an increased incidence of adverse
cardiovascular events compared to a placebo group, a
Testosterone in Older Men with Mobility Limitations
(TOM) trial (a National Institute of Aging randomized
trial) was halted early by the Data Safety and Monitoring
Committee.[113] On January 31, 2014, reports of strokes,
heart attacks, and deaths in men taking FDA-approved
testosterone-replacement led the Food and Drug Administration (FDA) to announce that it would be investigating the issue.[114] Later, in September 2014, the
FDA announced, as a result of the potential for adverse
cardiovascular outcomes, a review of the appropriateness and safety of Testosterone Replacement Therapy
(TRT).[106][107][108]
Up to the year 2010, studies had not shown any eect
on the risk of death, prostate cancer or cardiovascular
disease;[105][115] more recent studies, however, do raise
concerns.[116] A 2013 study, published in the Journal of
the American Medical Association, reported the use of
testosterone therapy was signicantly associated with increased risk of adverse outcomes. The study began after a previous, randomized, clinical trial of testosterone
therapy in men was stopped prematurely due to adverse
cardiovascular events raising concerns about testosterone
therapy safety.[117]

4.3 Other
Other adverse eects of testosterone supplementation
may include increased hematocrit (which may require
venipuncture in order to treat), exacerbation of sleep
apnea and acceleration of pre-existing prostate cancer
growth in individuals having undergone androgen deprivation. Other adverse eects may include minor sideeects such as acne and oily skin as well as signicant
hair loss and/or thinning of the hair which may be prevented with 5-alpha reductase inhibitors ordinarily used
for the treatment of benign prostatic hyperplasia such as
nasteride or dutasteride. Exogenous testosterone may
also cause suppression of spermatogenesis, leading to
infertility.[122] It does increase hemoglobin levels and decrease HDL cholesterol levels but it is not clear if these
changes are meaningful.[105]

4.4 Pregnancy and breast feeding

Testosterone is contraindicated in pregnancy and not recommended during breastfeeding.[123]

5 Biochemistry
5.1 Biosynthesis
Like other steroid hormones, testosterone is derived from
cholesterol (see gure to the left).[124] The rst step in
the biosynthesis involves the oxidative cleavage of the
sidechain of cholesterol by CYP11A, a mitochondrial
cytochrome P450 oxidase with the loss of six carbon
atoms to give pregnenolone. In the next step, two additional carbon atoms are removed by the CYP17A enzyme
in the endoplasmic reticulum to yield a variety of C19
steroids.[125] In addition, the 3-hydroxyl group is oxidized
by 3--HSD to produce androstenedione. In the nal and
rate limiting step, the C-17 keto group androstenedione is
reduced by 17- hydroxysteroid dehydrogenase to yield
testosterone.

21
12
19
2
3

HO

1
4

11

24

22

17

15

26

Mineralocorticoids

25

23

16

14

10

20

18

13

OH

17,20 lyase

OH

OH

OH

11-deoxycortisol

O
OH

Corticosterone

OH
O
OH

HO

Cortisol
O

Androstenedione

17-HSD
OH

(21 carbons)

Estrone
HO

OH

OH

OH

Estriol
HO

Estradiol
HO

s
on
arb

5-reductase
OH

s
en

g
tro
Es
O

Glucocorticoids

Testosterone

Androstenediol
HO

OH
O

HO

(liver and placenta)

Dehydroepiandrosterone

17-hydroxy
progesterone

Aromatase

Androgens (19 carbons)

Aldosterone
synthase

OH

11-hydroxylase

HO

HO

DeoxyO
corticosterone
21-hydroxylase

17-hydroxy
pregnenolone

3-beta-hydroxysteroid dehydrogenase (3-HSD)

Progestagens (21 carbons)

Pregnenolone
17-hydroxylase

Aldosterone

Progesterone O

OH

HO

Cholesterol

Cholesterol side-chain
cleavage enzyme

HO

O O

(21 carbons)

27

BIOCHEMISTRY

c
(18

Cellular location
of enzymes

Dihydrotestosterone
H

Mitochondria
Smooth endoplasmic
reticulum

Human steroidogenesis, showing testosterone near bottom.

The largest amounts of testosterone (>95%) are produced

by the testes in men.[3] It is also synthesized in far smaller
quantities in women by the thecal cells of the ovaries,
by the placenta, as well as by the zona reticularis of the
adrenal cortex and even skin[126] in both sexes. In the
testes, testosterone is produced by the Leydig cells.[127]
The male generative glands also contain Sertoli cells,
which require testosterone for spermatogenesis. Like
most hormones, testosterone is supplied to target tissues
in the blood where much of it is transported bound to
a specic plasma protein, sex hormone-binding globulin
(SHBG).

5.2

Regulation

In males, testosterone is synthesized primarily in Leydig

cells. The number of Leydig cells in turn is regulated
by luteinizing hormone (LH) and follicle-stimulating hormone (FSH). In addition, the amount of testosterone produced by existing Leydig cells is under the control of LH,
which regulates the expression of 17- hydroxysteroid
dehydrogenase.[128]
The amount of testosterone synthesized is regulated
by the hypothalamicpituitarytesticular axis (see gure to the right).[129] When testosterone levels are low,
gonadotropin-releasing hormone (GnRH) is released by
the hypothalamus, which in turn stimulates the pituitary
gland to release FSH and LH. These latter two hormones stimulate the testis to synthesize testosterone. Finally, increasing levels of testosterone through a negative
feedback loop act on the hypothalamus and pituitary to
inhibit the release of GnRH and FSH/LH, respectively.
Factors aecting testosterone levels include:
Weight loss 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.[130]

Hypothalamicpituitarytesticular axis

The secosteroid vitamin D in levels of 4001000

IU/d (1025 g/d) raises testosterone levels.[131]
Zinc deciency lowers testosterone levels[132] but
over supplementation has no eect on serum
testosterone.[133]
Dominance challenges can, in some cases, stimulate
increased testosterone release in men.[134]
Aging reduces testosterone release.[135]
Hypogonadism
Sleep (REM dream) increases nocturnal testosterone levels.[136]
Resistance training increases testosterone levels,[137]
however, in older men, that increase can be avoided
by protein ingestion.[138]
Licorice. The active ingredient in licorice root,
glycyrrhizinic acid has been linked to small,
clinically non-signicant decreases in testosterone
levels.[139] In contrast, a more recent study found
that licorice administration produced a substantial testosterone decrease in a small, female-only
sample.[140]

9
Natural or man-made antiandrogens including the most important feedback signal to the hypothalamus
spearmint tea reduce testosterone levels.[141][142][143] (especially aecting LH secretion). In many mammals,
prenatal or perinatal masculinization of the sexually
Posing in high-power nonverbal displays through dimorphic areas of the brain by estradiol derived from
open, expansive postures can increase testosterone testosterone programs later male sexual behavior.
levels.[144]

5.3

Metabolism

7 Synthetic analogs

Approximately 7% of testosterone is reduced to 5dihydrotestosterone (DHT) by the cytochrome P450 enzyme 5-reductase,[145] an enzyme highly expressed in
male sex organs and hair follicles.[3] Approximately 0.3%
of testosterone is converted into estradiol by aromatase
(CYP19A1)[146] an enzyme expressed in the brain, liver,
and adipose tissues.[3]

A number of synthetic analogs of testosterone have been

developed with improved bioavailability and metabolic
half life relative to testosterone. Many of these analogs
have an alkyl group introduced at the C-17 position in
order to prevent conjugation and hence improve oral
bioavailability. These are the so-called 17-aa (17-alkyl
androgen) family of androgens such as uoxymesterone
DHT is a more potent form of testosterone while estradiol and methyltestosterone.
has completely dierent activities (feminization) compared to testosterone (masculinization). Also, testosterone and DHT may be deactivated or cleared by enzymes that hydroxylate at the 6, 7, 15 or 16 positions.[147] 8 Related drugs

Mechanism of action

The eects of testosterone in humans and other

vertebrates occur by way of two main mechanisms: by
activation of the androgen receptor (directly or as DHT),
and by conversion to estradiol and activation of certain
estrogen receptors.[148][149]

Some drugs indirectly target testosterone as a way of

treating certain conditions. For example, 5-alphareductase inhibitors such as nasteride inhibit the conversion of testosterone into dihydrotestosterone (DHT),
a metabolite more potent than testosterone.[151] These
5-alpha-reductase inhibitors have been used to treat
various conditions associated with androgens, such as
androgenetic alopecia (male-pattern baldness), hirsutism,
benign prostatic hyperplasia (BPH), and prostate cancer.[151] In contrast, GnRH antagonists bind to GnRH
receptors in the pituitary gland, blocking the release of
luteinising hormone (LH) and follicle-stimulating hormone (FSH) from the pituitary.[152] In men, the reduction
in LH subsequently leads to rapid suppression of testosterone release from the testes. GnRH antagonists have
been used for the treatment of prostate cancer.

Free testosterone (T) is transported into the cytoplasm

of target tissue cells, where it can bind to the androgen
receptor, or can be reduced to 5-dihydrotestosterone
(DHT) by the cytoplasmic enzyme 5-alpha reductase.
DHT binds to the same androgen receptor even more
strongly than testosterone, so that its androgenic potency
is about 5 times that of T.[150] The T-receptor or DHTreceptor complex undergoes a structural change that allows it to move into the cell nucleus and bind directly to
specic nucleotide sequences of the chromosomal DNA.
The areas of binding are called hormone response ele- 9 Routes of administration
ments (HREs), and inuence transcriptional activity of
There are many routes of administration for testoscertain genes, producing the androgen eects.
terone. Forms of testosterone for human administraAndrogen receptors occur in many dierent vertebrate
tion currently available include injectable (such as testosbody system tissues, and both males and females respond
terone cypionate or testosterone enanthate in oil),[153]
similarly to similar levels. Greatly diering amounts of
oral, buccal,[154] transdermal skin patches, transdermal
testosterone prenatally, at puberty, and throughout life accreams, gels,[155][156] and implantable pellets.[157] Rollcount for a share of biological dierences between males
on methods and nasal sprays are currently under developand females.
ment.
The bones and the brain are two important tissues in
humans where the primary eect of testosterone is by
way of aromatization to estradiol. In the bones, estradiol accelerates ossication of cartilage into bone, lead- 10 History
ing to closure of the epiphyses and conclusion of growth.
In the central nervous system, testosterone is aromatized A testicular action was linked to circulating blood fracto estradiol. Estradiol rather than testosterone serves as tions now understood to be a family of androgenic

10

Vial of testosterone for intramuscular injection

hormones in the early work on castration and testicular transplantation in fowl by Arnold Adolph Berthold
(18031861).[158] Research on the action of testosterone
received a brief boost in 1889, when the Harvard professor Charles-douard Brown-Squard (18171894), then
in Paris, self-injected subcutaneously a rejuvenating
elixir consisting of an extract of dog and guinea pig testicle. He reported in The Lancet that his vigor and feeling of well-being were markedly restored but the eects
were transient,[159] and Brown-Squards hopes for the
compound were dashed. Suering the ridicule of his colleagues, he abandoned his work on the mechanisms and
eects of androgens in human beings.
In 1927, the University of Chicagos 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, remasculinized them.[160] The group of Ernst Laqueur at
the University of Amsterdam puried testosterone from
bovine testicles in a similar manner in 1934, but isolation
of the hormone from animal tissues in amounts permitting serious study in humans was not feasible until three
European pharmaceutical giantsSchering (Berlin, Germany), Organon (Oss, Netherlands) and Ciba (Basel,
Switzerland)began full-scale steroid research and development programs in the 1930s.

10 HISTORY

Leopold Ruzicka

The Organon group in the Netherlands were the rst

to isolate the hormone, identied in a May 1935
paper On Crystalline Male Hormone from Testicles
(Testosterone)".[161] They named the hormone testosterone, from the stems of testicle and sterol, and the sux
of ketone. The structure was worked out by Scherings
Adolf Butenandt.[162][163]
The chemical synthesis of testosterone from cholesterol
was achieved in August that year by Butenandt and
Hanisch.[164] Only a week later, the Ciba group in Zurich,
Leopold Ruzicka (18871976) and A. Wettstein, published their synthesis of testosterone.[165] These independent partial syntheses of testosterone from a cholesterol
base earned both Butenandt and Ruzicka the joint 1939
Nobel Prize in Chemistry.[163][166] Testosterone was identied as 17-hydroxyandrost-4-en-3-one (C19 H28 O2 ), a
solid polycyclic alcohol with a hydroxyl group at the 17th
carbon atom. This also made it obvious that additional
modications on the synthesized testosterone could be
made, i.e., esterication and alkylation.
The partial synthesis in the 1930s of abundant, potent testosterone esters permitted the characterization of
the hormones eects, 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 Kenyons group[167] was able
to demonstrate both anabolic and androgenic eects of
testosterone propionate in eunuchoidal men, boys, and
women. The period of the early 1930s to the 1950s has

11
been called The Golden Age of Steroid Chemistry,[168]
and work during this period progressed quickly. Research in this golden age proved that this newly synthesized compoundtestosteroneor rather family of compounds (for many derivatives were developed from 1940
to 1960), was a potent multiplier of muscle, strength, and
well-being.[84]

11

Society and culture

[8] Southren AL, Tochimoto S, Carmody NC, Isurugi K

(November 1965). Plasma production rates of testosterone in normal adult men and women and in patients
with the syndrome of feminizing testes. J. Clin. Endocrinol. Metab. 25 (11): 144150. doi:10.1210/jcem25-11-1441. PMID 5843701.
[9] Dabbs M, Dabbs JM (2000). Heroes, rogues, and lovers:
testosterone and behavior. New York: McGraw-Hill.
ISBN 0-07-135739-4.
[10] Nelson, Randy F. (2005). An introduction to behavioral
endocrinology. Sunderland, Mass: Sinauer Associates. p.
143. ISBN 0-87893-617-3.

A number of lawsuits are currently underway against

testosterone manufacturers, alleging a signicantly in- [11] De Loof A (October 2006). Ecdysteroids: the overlooked sex steroids of insects? Males: the black box.
creased rate of stroke and heart attack in elderly men who
Insect Science 13 (5): 325338. doi:10.1111/j.1744use testosterone supplements.[169]
7917.2006.00101.x.

12

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External links

Testosterone MS Spectrum
Testosterone bound to proteins in the PDB
Testosterone replacement therapy - Overview
(2014).

EXTERNAL LINKS

19

14
14.1

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Mr.tits505, Kajisav, AdmiralBiscuitz, Pool1440, Njgator88, Twotonbill, Dramanatkar and Anonymous: 764

14.2

Images

File:Blood_values_sorted_by_mass_and_molar_concentration.png Source: http://upload.wikimedia.org/wikipedia/commons/c/cb/

Blood_values_sorted_by_mass_and_molar_concentration.png License: CC0 Contributors: Own work - see also References section above
Original artist: Mikael Hggstrm
File:Depo-testosterone_200_mg_ml_crop.jpg Source: http://upload.wikimedia.org/wikipedia/commons/7/79/Depo-testosterone_200_
mg_ml_crop.jpg License: Public domain Contributors: Cropped version of Image:Depo-testosterone 200 mg ml.jpg. Cropped losslessly
with Better JPEG. Original artist: U.S. Drug Enforcement Administration

20

14

TEXT AND IMAGE SOURCES, CONTRIBUTORS, AND LICENSES

File:Hypothalamus_pituitary_testicles_axis.png Source:
http://upload.wikimedia.org/wikipedia/commons/2/2a/Hypothalamus_
pituitary_testicles_axis.png License: CC-BY-SA-3.0 Contributors:
Testosterona-ciclo.png Original artist: Testosterona-ciclo.png: Acracia
File:Lavoslav_Ruika_1939.jpg Source: http://upload.wikimedia.org/wikipedia/commons/c/c7/Lavoslav_Ru%C5%BEi%C4%87ka_
1939.jpg License: Public domain Contributors: http://nobelprize.org/ Original artist: Nobel Foundation
File:Steroidogenesis.svg Source: http://upload.wikimedia.org/wikipedia/commons/1/13/Steroidogenesis.svg License: CC-BY-SA-3.0
Contributors: Self-made using bkchem and inkscape Original artist: David Richeld (User:Slashme) and Mikael Hggstrm. Derived
from previous version by Homeier and Settersr.
File:Testosteron.svg Source: http://upload.wikimedia.org/wikipedia/commons/c/ce/Testosteron.svg License: Public domain Contributors:
Own work Original artist: NEUROtiker
File:Testosterone-from-xtal-3D-balls.png
Source:
http://upload.wikimedia.org/wikipedia/commons/5/5d/
Testosterone-from-xtal-3D-balls.png License: Public domain Contributors: Own work Original artist: Ben Mills
File:X_mark.svg Source: http://upload.wikimedia.org/wikipedia/commons/a/a2/X_mark.svg License: Public domain Contributors: Own
work Original artist: User:Gmaxwell
File:Yes_check.svg Source: http://upload.wikimedia.org/wikipedia/en/f/fb/Yes_check.svg License: ? Contributors: ? Original artist: ?

14.3

Content license

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