Testosterone

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Testosterone

Systematic (IUPAC) name

R,9S,10R,13S,14S,17S)- 17-hydroxy-10,13-dimethyl1,2,6,7,8,9,11,12,14,15,16,17- dodecahydrocyclopenta[a]phenanthren-3one

Clinical data
Trade names

Androderm, Delatestryl, Intrinsa

AHFS/Drugs.com

monograph

MedlinePlus

a614041

License data
EU EMA:

US FDA:

Intrinsa

Testosterone

Pregnancy
category

US: X

(Contraindicated)

Contraindicated due
toteratogenic effects
Routes of
administration

Intramuscular injection, transdermal (cream, gel,

or patch), sub-'Q' pellet
Legal status

Legal status
CA: Schedule

IV

US: Schedule

III

(Prescription only)
Pharmacokinetic data
Bioavailability

Low (due to extensive first pass metabolism)

Metabolism

Liver, testis and prostate

Biological half-life 24 hours

Excretion

Urine (90%), feces (6%)

Identifiers

CAS Number

58-22-0
57-85-2 (propionate ester)

ATC code

G03BA03 (WHO)

PubChem

CID 6013

IUPHAR/BPS

2858

DrugBank

DB00624

ChemSpider

5791

UNII

3XMK78S47O

KEGG

D00075

ChEBI

CHEBI:17347

ChEMBL

CHEMBL386630
Chemical data

Formula

C19H28O2

Molar mass

288.42

Specific rotation

+110.2

SMILES[show]
InChI[show]
Physical data
Melting point

155 C (311 F)

SEC combustion

11080 kJ/mol
(verify)

Testosterone is a steroid hormone from the androgen group and is found in humans and
other vertebrates. In humans and other mammals, testosterone is secreted primarily by
thetesticles of males and, to a lesser extent, the ovaries of females. Small amounts are also secreted by
the adrenal glands. It is the principal male sex hormone and an anabolic steroid.
In men, testosterone plays a key role in the development of male reproductive tissues such as
the testis and prostate as well as promoting secondary sexual characteristics such as
increased muscle and bone mass, and the growth of body hair.[1] In addition, testosterone is essential for
health and well-being[2] as well as the prevention of osteoporosis.[3]
On average, in adult males, levels of testosterone are about 78 times as great as in adult females. [4] As
the metabolic consumption of testosterone in males is greater, the daily production is about 20 times
greater in men.[5][6] Females are also more sensitive to the hormone.[7] Testosterone is observed in most
vertebrates. Fish make a slightly different form called 11-ketotestosterone.[8] Its counterpart in insects
is ecdysone.[9] These ubiquitous steroids suggest that sex hormones have an ancient evolutionary
history.[10]
It is on the WHO Model List of Essential Medicines, the most important medications needed in a
basic health system.[11]
Contents
[hide]

1Health effects
o

1.1Before birth

1.2Early infancy

1.3Pre-peripubertal

1.4Pubertal

1.5Adult

1.6Brain

1.7Aggression and criminality

2Medical uses

2.1Low levels due to aging

2.2Insufficiency

2.3Women

2.4Other

3Non-medical use
o

3.1Athletics

3.2Detection of abuse

4Adverse effects
o

4.1Cardiovascular disease

4.2Cancer

4.3Other

4.4Pregnancy and breast feeding

5Biochemistry
o

5.1Biosynthesis

5.2Regulation

5.3Metabolism

6Mechanism of action

7Synthetic analogs

8Related drugs

9Routes of administration

10History

11Society and culture

12References

13External links

Health effects[edit]

In general, androgens promote protein synthesis and growth of those tissues with androgen receptors.
Testosterone effects can be classified as virilizing and anabolic, though the distinction is somewhat
artificial, as many of the effects can be considered both.

Anabolic effects include growth of muscle mass and strength, increased bone density and
strength, and stimulation of linear growth and bone maturation.

Androgenic effects 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 thevoice, growth of
the beard and axillary hair. Many of these fall into the category of male secondary sex
characteristics.

Testosterone effects can also be classified by the age of usual occurrence. For postnatal effects in both
males and females, these are mostly dependent on the levels and duration of circulating free
testosterone.

Before birth[edit]
The prenatal androgen effects occur during two different stages. Between 4 and 6 weeks of the
gestation.

Genital virilization (midline fusion, phallic urethra, scrotal thinning and

rugation, phallic enlargement); although the role of testosterone is far smaller than that
ofdihydrotestosterone.
Development of prostate and seminal vesicles.

During the second trimester, androgen level is associated with gender formation.[12] 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. A mother's testosterone level during
pregnancy is correlated with her daughter's sex-typical behavior as an adult, and the correlation is even
stronger than with the daughter's own adult testosterone level. [13]

Early infancy[edit]
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 46 months of age. [14][15] The function of this rise in humans is
unknown. It has been speculated that "brain masculinization" is occurring since no significant changes
have been identified in other parts of the body.[16]The male brain is masculinized by the aromatization of
testosterone into estrogen, which crosses the bloodbrain barrier and enters the male brain, whereas
female fetuses have alpha-fetoprotein, which binds the estrogen so that female brains are not affected.
[17]

Pre-peripubertal[edit]
Pre- Peripubertal effects are the first observable effects of rising androgen levels at the end of
childhood, occurring in both boys and girls.

Adult-type body odor

Increased oiliness of skin and hair, acne

Pubarche (appearance of pubic hair)

Axillary hair

Growth spurt, accelerated bone maturation

Hair on upper lip,on chin, and growth of sideburns.

Pubertal[edit]
Pubertal 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.

Enlargement of sebaceous glands. This might cause acne.

Penis or clitoris enlargement

Increased libido and frequency of erection or clitoral engorgement

Pubic hair extends to thighs and up toward umbilicus

Facial hair (sideburns, beard, moustache)

Loss of scalp hair (Androgenetic alopecia)

Chest hair, periareolar hair, perianal hair

Leg hair, armpit hair

Subcutaneous fat in face decreases

Increased muscle strength and mass[18]

Deepening of voice

Growth of the Adam's apple

Growth of spermatogenic tissue in testicles, male fertility

Growth of jaw, brow, chin, nose, and remodeling of facial bone contours, in conjunction
with human growth hormone[citation needed]
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.

Mental: More aggressive, active attitude. Interest in sex develops.

Skin: Sebaceous gland secretion thickens and increases (predisposing to acne) [19]

Adult[edit]

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 decrease in the later
decades of adult life.

Reference ranges for blood tests, showing adult male testosterone levels in light blue at center-left.

Biological uses[edit]

Testosterone is necessary for normal sperm development. It activates genes in Sertoli cells,
which promote differentiation of spermatogonia.

Regulates acute HPA (Hypothalamicpituitaryadrenal axis) response under dominance

challenge[20]

Regulator of cognitive and physical energy

Maintenance of muscle trophism

Testosterone regulates the population of thromboxane A2 receptors

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

High androgen levels are associated with menstrual cycle irregularities in both clinical
populations and healthy women.[23] See libido.

Cancer prevention and health risks[edit]

Testosterone does not cause deleterious effects 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 conflicting 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]

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 five or more alcoholic drinks in a day, more likely to have had a
sexually transmitted infection, and more likely to smoke. [30]

Romantic relationships[edit]
Falling in love decreases men's testosterone levels while increasing 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.[31] However, it is suggested that after the "honeymoon phase" ends
about one to three years into a relationshipthis change in testosterone levels is no longer apparent.
[31]
Men who produce less testosterone are more likely to be in a relationship[32] and/or married,[33] and
men who produce more testosterone are more likely to divorce; [33] however, causality cannot be

determined in this correlation. Marriage or commitment could cause a decrease in testosterone levels.
[34]
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.[35] 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.[36]
Men who produce more testosterone are more likely to engage in extramarital sex. [33] Testosterone levels
do not rely on physical presence of a partner for men engaging in relationships (same-city vs. longdistance), men have similar testosterone levels across the board. [32] 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. [37]
Fatherhood[edit]
Fatherhood also decreases testosterone levels in men, suggesting that the resulting emotional and
behavioral changes promote paternal care.[38] The way testosterone levels change when a child keys is
indicative of fathering styles. If the levels reduce then there is more empathy by the father than in
fathers whose levels go up.[39]
Testosterone and sexual arousal[edit]
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
female's).[31]
Testosterone levels follow a nyctohemeral rhythm that peaks early each day, regardless of sexual
activity.[40]
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.[41]
An increase in testosterone levels has also been found to occur in both men and women who have
masturbation-induced orgasms.[42][43]
Mammalian studies[edit]
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 suffering from sexual arousal deficits such as hypoactive sexual desire disorder.[44]
In one study, almost every mammalian species examined demonstrated a marked increase in a male's
testosterone level upon encountering a novel female. P.J. James et al. investigated the role of genotype
on such so-called reflexive testosterone increases in male mice. They also concluded that this response
is related to the male's 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 primate's system, its sexual motivation decreases, but there is
no corresponding decrease in ability to engage in sexual activity (mounting, ejaculating, etc.).[46]
Male sexual arousal[edit]
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 watch a sexually explicit movie have an average increase of 35% in testosterone, peaking at
6090 minutes after the end of the film, but no increase is seen in men who watch sexually neutral films.
[48]
Men who watch sexually explicit films also report increased motivation, competitiveness, and
decreased exhaustion.[49] Previous research has found a link between relaxation following sexual arousal
and testosterone levels.[50]
A 2002 study found that testosterone increased in heterosexual 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.[51]
Men's levels of testosterone, a hormone known to affect men's mating behaviour, changes 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. Testosterone levels and sexual arousal in men
are heavily aware of hormone cycles in females.[52] This may be linked to the ovulatory shift hypothesis,
[53]
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.
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 their attention to
the relevant stimuli.[54]
Sperm competition theory: Testosterone levels are shown to increase as a response to previously
neutral stimuli when conditioned to become sexual in male rats.[55] 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.
Female sexual arousal[edit]
Androgens may modulate the physiology of vaginal tissue and contribute to female genital sexual
arousal.[56] Women's level of testosterone is higher when measured pre-intercourse vs pre-cuddling, as
well as post-intercourse vs post-cuddling.[57] 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.[58]
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 level of cortisol in the female
body, and hormonal contraceptives may have an impact on the variation in testosterone response to
sexual thoughts.[59]
Testosterone may prove to be an effective treatment in female sexual arousal disorders. [60] Currently
there is no FDA approved androgen preparation for the treatment of androgen insufficiency, however it
has been used off-label to treat low libido and sexual dysfunction in older women. Testosterone may be
a treatment for postmenopausal women as long as they are effectively estrogenized. [60]
Behavior and personality[edit]
Testosterone levels play a major role in risk-taking during financial decisions. [61][62]

Brain[edit]
As testosterone affects the entire body (often by enlarging; males have bigger hearts, lungs, liver, etc.),
the brain is also affected by this sexual differentiation;[12] 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.[63]
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.[64] In a Danish
study from 2003, 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).[65]
A study conducted in 1996 found no immediate short term effects on mood or behavior from the
administration of supraphysiologic doses of testosterone for 10 weeks on 43 healthy men.[18] Another
study found a correlation between testosterone and risk tolerance in career choice among women. [61][66]
The literature suggests that 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 of the Alzheimer's type,[67][68][69][70] a key argument in life
extension 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,[71] where both hypo- and hypersecretion (deficient- and excessive-secretion) of circulating
androgens have negative effects on cognition.

Aggression and criminality [edit]

See also: Aggression Testosterone, and Biosocial criminology
Most studies support a link between adult criminality and testosterone, although the relationship is
modest if examined separately for each sex. 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 and alcoholism. Many studies have
also been done on the relationship between more general aggressive behavior/feelings and
testosterone. About half the studies have found a relationship and about half no relationship. [72]
Testosterone is only one of many factors that influence aggression and the effects 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 important role in male
aggression.[72][73][74][75] Studies have also found that testosterone facilitates aggression by
modulating vasopressin receptors in the hypothalamus.[76]
A study at the Universities of Zurich and Royal Holloway London with more than 120 experimental
subjects has shown that the sexual hormone can encourage fair behavior. For the 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. [77][78]
[79]
However men with high testosterone was significantly 27% less generous in an ultimatum game while
men with the lowest testosterone were 560% more generous.[80] The Annual NY Academy of Sciences
has also found anabolic steroid use which increase testosterone to be higher in teenagers and this was
associated with increased violence.[81] Studies have also found administered testosterone to increase
verbal aggression and anger in some participants. [82]
Estradiol is known to correlate with aggression in male mice. [83] Moreover, the conversion of testosterone
to estradiol regulates male aggression in sparrows during breeding season.[84] Rats who were given
anabolic steroids that increase testosterone were also more physical aggressive to provocation as a
result of "threat sensitivity".[85]

Testosterone is significantly correlated with aggression and competitive behaviour and is directly
facilitated by the latter. There are two theories on the role of testosterone in aggression and competition.
[86]
The first one is theChallenge hypothesis which states that testosterone would increase during puberty
thus facilitating reproductive and competitive behaviour which would include aggression. [86] Thus it is the
challenge of competition among males of the species that facilitates aggression and violence. [86] Studies
conducted have found direct correlation between testosterone and dominance especially among the
most violent criminals in prison who had the highest testosterone levels. [86] The same research also
found fathers (those outside competitive environments) had the lowest testosterone levels compared to
other males.[86]
The second theory is similar and is known as Evolutionary neuroandrogenic (ENA) theory of male
aggression[87][88] 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.
[89]
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 as well as adult testosterone levels increased risk of fouls or aggression among male players in a
soccer game.[90] Studies have also found higher pre-natal testosterone or lower digit ratio to be
correlated with higher aggression in males[91][92][93][94][95]
The rise in testosterone levels during competition predicted aggression in males but not in females.
[96]
Subjects who interacted with hand guns and an experimental game showed rise in testosterone and
aggression.[97] 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.[98]Testosterone produces aggression by activating subcortical
areas in the brain, which may also be inhibited or suppressed by social norms or familial situations while
still manifesting in diverse intensities and ways through thoughts, anger, verbal aggression, competition,
dominance and to physical violence.[99] Testosterone mediates attraction to cruel and violent cues in men
by promoting extended viewing of violent stimuli.[100] Testosterone specific structural brain characteristic
can predict aggressive behaviour in individuals.[101]

Medical uses[edit]
The primary use of testosterone is the treatment of males with too little or no natural testosterone
productionmales with hypogonadism.[citation needed] This is known as hormone replacement therapy 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.
[102]

Low levels due to aging[edit]

Testosterone levels decline gradually with age (see andropause). The Food and Drug
Administration (FDA) stated in 2015 that neither the benefits nor the safety of testosterone have been
established for low testosterone levels due to aging.[103] The FDA has required that labels on testosterone
include warning information about the possibility of an increased risk of heart attacks and stroke. [103]

Insufficiency[edit]
Further information: Hypogonadism and Androgen deficiency
Testosterone insufficiency (also termed hypotestosteronism or hypotestosteronemia) is an abnormally
low testosterone production. It may occur because of testicular dysfunction (primary hypogonadism) or
hypothalamic-pituitary dysfunction (secondary hypogonadism) and may be congenital or acquired.[104] An
acquired form of hypotestosteronism is the decline in testosterone 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 Western countries, average testosterone levels are receding in men of all
ages.[105][106]

Women[edit]

Testosterone supplementation is effective in the short term for hypoactive sexual desire disorder.[107] Its
long term safety, however, is unclear.[107]
Treating low androgen levels with testosterone is not generally recommended in women when it is due
to hypopituitarism, adrenal insufficiency, or following surgical removal of the ovaries.[107] It is also not
usually recommended for improving cognition, the risk of heart disease, bone strength or for generalized
well being.[107]

Other[edit]
Testosterone may be used for depression in men who are of middle age with low testosterone. However,
a review did not show a benefit on the mood of the men with normal levels of testosterone or on the
mood of the older men with low testosterone.[108]
To take advantage of its virilizing effects, testosterone is often administered to transgender men as part
of the hormone replacement therapy,[109] with a "target level" of the average male's testosterone level.
Likewise,transgender women are sometimes prescribed anti-androgens to decrease the level of
testosterone in the body and allow for the effects of estrogen to develop.
Testosterone therapy may improve the management of type 2 diabetes.[110] Low testosterone has been
associated with the development of Alzheimer's disease.[69][70] A small trial in 2005 showed mixed results
in using testosterone to combat the effects of aging.[111]
Males with borderline testosterone levels and sexual dysfunction may benefit from a trial of
testosterone.[112]

Non-medical use[edit]
Athletics[edit]
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. Hormone
supplements cause the endocrine system to adjust its production and lower the natural production of the
hormone, so when supplements are discontinued, natural hormone production is lower than it was
originally. This is known as the Farquharson phenomenon.[citation needed]
Anabolic steroids (including testosterone) have also been taken to enhance muscle development,
strength, or endurance. They do so directly by increasing the muscles' protein synthesis. As a result,
muscle fibers become larger and repair faster than the average person's.
After a series of scandals and publicity in the 1980s (such as Ben Johnson's improved performance at
the 1988 Summer Olympics), prohibitions of anabolic steroid use were renewed or strengthened by
many sports organizations. Testosterone and other anabolic steroids were designated a "controlled
substance" by the United States Congress in 1990, with the Anabolic Steroid Control Act.[113] Their use is
seen as a seriously problematic[citation needed] issue in modern sport, particularly given the lengths to which
athletes and professional laboratories go to in trying to conceal such use from sports regulators. Steroid
use once again came into the spotlight recently as a result of the Chris Benoit double murder-suicide in
2007; however, there has been no evidence indicating steroid use as a contributing factor.[citation needed]
Some female athletes may have naturally higher levels of testosterone than others, and may be asked
to consent to a therapeutic proposal, either surgery or drugs, to decrease testosterone levels to a level
thought acceptable to compete fairly with others.[114]

Detection of abuse[edit]
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 (normally less than 6), the
testosterone/luteinizing hormone ratio and the carbon-13/carbon-12 ratio (pharmaceutical testosterone
contains less carbon-13 than endogenous testosterone). In some testing programs, an individual's own
historical results may serve as a reference interval for interpretation of a suspicious finding. Another

approach being investigated is the detection of the administered form of testosterone, usually an ester,
in hair.[115][116][117][118]

Adverse effects[edit]
See also: Androgen replacement therapy Adverse effects
The Food and Drug Administration (FDA) stated in 2015 that neither the benefits nor the safety of
testosterone have been established for low testosterone levels due to aging.[103] The FDA has required
that testosterone pharmaceutical labels include warning information about the possibility of an increased
risk of heart attacks and stroke.[103]

Cardiovascular disease[edit]
Adverse effects of testosterone supplementation may include increased cardiovascular events
(including strokes and heart attacks) and deaths based on three peer-reviewed studies involving men
taking testosterone-replacement.[119] In addition, an increase of 30% in deaths and heart attacks in older
men has been reported.[120] 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.[121] On January
31, 2014, reports of strokes, heart attacks, anddeaths in men taking FDA-approved testosteronereplacement led the Food and Drug Administration (FDA) to announce that it would be investigating the
issue.[122] 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).[123][124][125] The FDA now requires warnings in the drug labeling of all approved testosterone
products regarding deep vein thrombosis and pulmonary embolism.[126]
Up to the year 2010, studies had not shown any effect on the risk of death, prostate
cancer or cardiovascular disease;[27][127] more recent studies, however, do raise concerns.[128] A 2013 study,
published in the Journal of the American Medical Association, reported "the use of testosterone therapy
was significantly 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." [120]

Cancer[edit]
Testosterone in the presence of a slow-growing prostate cancer is assumed to increase its growth rate.
However, the association between testosterone supplementation and the development of prostate
cancer is unproven.[129]Nevertheless, physicians are cautioned about the cancer risk associated with
testosterone supplementation.[130]
Ethnic groups have different rates of prostate cancer.[131] Differences in sex hormones, including
testosterone, have been suggested as an explanation for these differences. [131] 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.[132]

Other[edit]
Other significant adverse effects of testosterone supplementation include acceleration of preexisting prostate cancer growth in individuals who have undergone androgen deprivation;
increased hematocrit, which can requirevenipuncture in order to treat; and, exacerbation of sleep apnea.
[133]
Adverse effects may also include minor side-effects such as acne and oily skin, as well as, significant
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 finasteride or dutasteride.[134] Exogenous
testosterone may also cause suppression of spermatogenesis, leading to, in some cases, infertility.[135] It
is recommended that physicians screen for prostate cancer with a digital rectal exam and prostatespecific antigen (PSA) level before starting therapy, and monitor PSA and hematocrit levels closely
during therapy.[136]

Pregnancy and breast feeding[edit]

Testosterone is contraindicated in pregnancy and not recommended during breastfeeding. [137]

Biochemistry[edit]
Biosynthesis[edit]

Human steroidogenesis, showing testosterone near bottom.

Like other steroid hormones, testosterone is derived from cholesterol (see figure to the left).[138] The first
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.[139] In addition, the 3-hydroxyl group is oxidized by 3--HSD to
produce androstenedione. In the final and rate limiting step, the C-17 keto group androstenedione is
reduced by 17- hydroxysteroid dehydrogenase to yield testosterone.
The largest amounts of testosterone (>95%) are produced by the testes in men.[1] 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[140] in both sexes. In thetestes, testosterone is
produced by the Leydig cells.[141] The male generative glands also contain Sertoli cells, which require
testosterone forspermatogenesis. Like most hormones, testosterone is supplied to target tissues in the
blood where much of it is transported bound to a specific plasma protein, sex hormone-binding
globulin (SHBG).

Regulation[edit]

Hypothalamicpituitarytesticular axis

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.[142]
The amount of testosterone synthesized is regulated by the hypothalamicpituitarytesticular axis (see
figure to the right).[143] 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 affecting 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.[144]
The secosteroid vitamin D in levels of 4001000 IU/d (1025 g/d) raises testosterone levels.[145]
Zinc deficiency lowers testosterone levels[146] but over supplementation has no effect on serum
testosterone.[147]

Vitamin A deficiency may lead to sub-optimal plasma Testosterone levels.[148]

Dominance challenges can, in some cases, stimulate increased testosterone release in men. [149]

Aging reduces testosterone release.[150]

Hypogonadism

Sleep (REM dream) increases nocturnal testosterone levels.[151]

Resistance training increases testosterone levels,[152] however, in older men, that increase can be
avoided by protein ingestion.[153]

Licorice can decrease the production of testosterone and this effect is greater in females. [154]

Natural or man-made antiandrogens including spearmint tea reduce testosterone levels.[155][156][157]

Posing in high-power nonverbal displays through open, expansive postures can increase
testosterone levels.[158]

Metabolism[edit]
98% of testosterone in plasma is bound to protein. 65% is bound to beta-globulin called Gonadal
steroid-binding globulin ( GBG) or Sex steroid-binding globulin and 33% to albumin. Plasma
testosterone level in the body( free or bound):10.4-2.43 nmol/L) in adult men. In women:30-70 ng/dL A
small amount of circulating testosterone is converted to estradiol, but most of the testosterone is
converted to 17-ketosteroids, principally androsterone and its isomer etio-cholanolone, and excreted in
urine.[19]
Approximately 7% of testosterone is reduced to 5-dihydrotestosterone (DHT) by the cytochrome
P450 enzyme 5-reductase,[159] an enzyme highly expressed in male sex organs and hair follicles.
[1]
Approximately 0.3% of testosterone is converted into estradiol by aromatase (CYP19A1)[160] an enzyme
expressed in the brain, liver, and adipose tissues.[1]
DHT is a more potent form of testosterone while estradiol has completely different 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. [161]

Mechanism of action[edit]
The effects of testosterone in humans and other vertebrates occur by way of multiple mechanisms: by
activation of the androgen receptor (directly or as DHT), and by conversion to estradiol and activation of
certain estrogen receptors.[162][163] Androgens such as testosterone have also been found to bind to and
activate membrane androgen receptors.[164][165][166]
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.[167] The T-receptor or DHT-receptor
complex undergoes a structural change that allows it to move into the cell nucleus and bind directly to
specific nucleotide sequences of the chromosomal DNA. The areas of binding are called hormone
response elements (HREs), and influence transcriptional activity of certain genes, 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 to estradiol. In the bones, estradiol accelerates ossification of cartilage into
bone, leading to closure of the epiphyses 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).[citation needed] In many mammals,

prenatal or perinatal "masculinization" of the sexually dimorphic areas of the brain by estradiol derived
from testosterone programs later male sexual behavior.[citation needed]

Synthetic analogs[edit]
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 fluoxymesterone and methyltestosterone.

Related drugs[edit]
Some drugs indirectly target testosterone as a way of treating certain conditions. For example, 5-alphareductase inhibitors such as finasteride inhibit the conversion of testosterone
into dihydrotestosterone (DHT), a metabolite more potent than testosterone.[168] 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.
[168]
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.[169] 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.

Routes of administration[edit]

Vial of testosterone cypionate for intramuscular injection

There are many routes of administration for testosterone. Forms of testosterone for human
administration currently available include injectable (such as testosterone cypionate or
testosterone enanthate in oil),[170] oral, buccal,[171] transdermal skin patches, transdermal creams, gels,[172]
[173]
and implantable pellets.[174] Roll-on methods and nasal sprays are currently under development.

History[edit]

Leopold Ruzicka

A testicular 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 (18031861).[175] 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 effects
were transient,[176] and Brown-Squard'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, remasculinized them. [177] The group of Ernst Laqueur at
the University of Amsterdam purified 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.
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)". [178] They named the
hormone testosterone, from the stems of testicle and sterol, and the suffix of ketone. The structure was
worked out by Schering's Adolf Butenandt.[179][180]
The chemical synthesis of testosterone from cholesterol was achieved in August that year by Butenandt
and Hanisch.[181] Only a week later, the Ciba group in Zurich, Leopold Ruzicka(18871976) and A.
Wettstein, published their synthesis of testosterone.[182] These independent partial syntheses of
testosterone from a cholesterol base earned both Butenandt and Ruzicka the joint 1939 Nobel Prize in
Chemistry.[180][183] Testosterone was identified as 17-hydroxyandrost-4-en-3-one (C 19H28O2), 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 esters 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[184] 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",[185] 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.[186]

Society and culture[edit]

A number of lawsuits are currently (2014) underway against testosterone manufacturers, alleging a
significantly increased rate of stroke and heart attack in elderly men who use testosterone supplements.
[187]

Glucocorticoid
From Wikipedia, the free encyclopedia

Chemical structure of cortisol, a glucocorticoid

Dexamethasone binds more powerfully to the glucocorticoid receptor than cortisol does. Dexamethasone is based
on the cortisol structure but differs in three positions (extra double bond in the A-ring between carbons 1 and 2 and
addition of a 9--fluoro group and a 16--methyl substituent).

Glucocorticoids (GCs) are a class of corticosteroids, which are a class of steroid hormones.
Glucocorticoids are corticosteroids that bind to the glucocorticoid receptor (GR),[1] that is present in
almost every vertebrate animal cell. The name glucocorticoid (glucose + cortex + steroid) is composed

from its role in regulation of glucose metabolism, synthesis in theadrenal cortex, and
its steroidal structure (see structure to the right). A less common synonym is glucocorticosteroid.
GCs are part of the feedback mechanism in the immune system which reduces certain aspects of
immune function, such as reduction of inflammation. They are therefore used in medicine to treat
diseases caused by an overactive immune system, such as allergies, asthma, autoimmune diseases,
and sepsis. GCs have many diverse (pleiotropic) effects, including potentially harmful side effects, and
as a result are rarely sold over the counter.[2] They also interfere with some of the abnormal mechanisms
in cancer cells, so they are used in high doses to treat cancer. This includes: inhibitory effects on
lymphocyte proliferation as in the treatment of lymphomas and leukemias; and the mitigation of side
effects of anticancer drugs.
GCs affect cells by binding to the glucocorticoid receptor (GR). The activated GR complex, in turn, upregulates the expression of anti-inflammatory proteins in the nucleus (a process known
as transactivation) and represses the expression of proinflammatory proteins in the cytosol by
preventing the translocation of other transcription factors from the cytosol into the nucleus
(transrepression).[2]
Glucocorticoids are distinguished from mineralocorticoids and sex steroids by their specific receptors,
target cells, and effects. In technical terms, "corticosteroid" refers to both glucocorticoids and
mineralocorticoids (as both are mimics of hormones produced by the adrenal cortex), but is often used
as a synonym for "glucocorticoid." Glucocorticoids are chiefly produced in the zona fasciculata of the
adrenal cortex, whereas mineralocorticoids are synthesized in the zona glomerulosa.
Cortisol (or hydrocortisone) is the most important human glucocorticoid. It is essential for life, and it
regulates or supports a variety of important cardiovascular, metabolic,immunologic,
and homeostatic functions. Various synthetic glucocorticoids are available; these are used either as
replacement therapy in glucocorticoid deficiency or to suppress the immune system.
Contents
[hide]

1Effects
o

1.1Immune

1.2Metabolic

1.3Developmental

1.4Arousal and cognition

1.5Body fluid homeostasis

1.6Cannabinoid CB1 receptor decrease

2Mechanism of action
o

2.1Transactivation

2.2Transrepression

2.3Nongenomic effects
3Pharmacology

4Therapeutic use
o

4.1Physiological replacement

4.2Therapeutic immunosuppression

4.3Anti-inflammatory

4.4Hyperaldosteronism

4.5Resistance

4.6Heart failure

5Side effects
o

5.1Immunodeficiency

5.2Withdrawal

6See also

7References

8External links

Effects[edit]

Steroidogenesis showing glucocorticoids in green ellipse at right - it is not a strictly bounded group, but a
continuum of structures with increasing glucocorticoid effect, with the primary example being cortisol.

Glucocorticoid effects may be broadly classified into two major

categories: immunological and metabolic. In addition, glucocorticoids play important roles in
fetaldevelopment and body fluid homeostasis.

Immune[edit]
As discussed in more detail below, glucocorticoids function through interaction with the glucocorticoid
receptor:

up-regulate the expression of anti-inflammatory proteins.

down-regulate the expression of proinflammatory proteins.

Glucocorticoids are also shown to play a role in the development and homeostasis of T lymphocytes.
This has been shown in transgenic mice with either increased or decreased sensitivity of T cell lineage
to glucocorticoids.[3]

Metabolic[edit]
The name "glucocorticoid" derives from early observations that these hormones were involved
in glucose metabolism. In the fasted state, cortisol stimulates several processes that collectively serve
to increase and maintain normal concentrations of glucose in blood.
Metabolic effects:

Stimulation of gluconeogenesis, in particular, in the liver: This pathway results in the synthesis of
glucose from nonhexose substrates, such as amino acidsand glycerol from triglyceride breakdown,
and is particularly important in carnivores and certain herbivores. Enhancing the expression
of enzymes involved in gluconeogenesis is probably the best-known metabolic function of
glucocorticoids.

Mobilization of amino acids from extrahepatic tissues: These serve as substrates for
gluconeogenesis.

Inhibition of glucose uptake in muscle and adipose tissue: A mechanism to conserve glucose

Stimulation of fat breakdown in adipose tissue: The fatty acids released by lipolysis are used for
production of energy in tissues like muscle, and the released glycerol provide another substrate for
gluconeogenesis.

Excessive glucocorticoid levels resulting from administration as a drug or hyperadrenocorticism have

effects on many systems. Some examples include inhibition of bone formation, suppression of calcium
absorption (both of which can lead to osteoporosis), delayed wound healing, muscle weakness, and
increased risk of infection. These observations suggest a multitude of less-dramatic physiologic roles for
glucocorticoids.[3]

Developmental[edit]
Glucocorticoids have multiple effects on fetal development. An important example is their role in
promoting maturation of the lung and production of the surfactant necessary for extrauterine lung
function. Mice with homozygousdisruptions in the corticotropin-releasing hormone gene (see below) die
at birth due to pulmonary immaturity. In addition, glucocorticoids are necessary for normal brain
development, by initiating terminal maturation, remodeling axons and dendrites, and affecting cell
survival[4] and may also play a role in hippocampal development.

Arousal and cognition[edit]

A graphical representation of theYerkes-Dodson curve

Glucocorticoids act on the hippocampus, amygdala, and frontal lobes. Along with adrenaline, these
enhance the formation of flashbulb memories of events associated with strong emotions, both positive
and negative.[5] This has been confirmed in studies, whereby blockade of either glucocorticoids or
noradrenaline activity impaired the recall of emotionally relevant information. Additional sources have
shown subjects whose fear learning was accompanied by high cortisol levels had better consolidation of
this memory (this effect was more important in men). The effect that glucocorticoids have on memory
may be due to damage specifically to the CA1 area of the hippocampal formation. In multiple animal
studies, prolonged stress (causing prolonged increases in glucocorticoid levels) have shown destruction
of the neurons in this area of the brain, which has been connected to memory performance. [6][7][8]
Glucocorticoids have also been shown to have a significant impact on vigilance (attention deficit
disorder) and cognition (memory). This appears to follow the Yerkes-Dodson curve, as studies have
shown circulating levels of glucocorticoids vs. memory performance follow an upside-down U pattern,
much like the Yerkes-Dodson curve. For example, long-term potentiation(LTP; the process of forming
long-term memories) is optimal when glucocorticoid levels are mildly elevated, whereas significant
decreases of LTP are observed after adrenalectomy (low-GC state) or after exogenous glucocorticoid
administration (high-GC state). Elevated levels of glucocorticoids enhance memory for emotionally
arousing events, but lead more often than not to poor memory for material unrelated to the source of
stress/emotional arousal.[9] In contrast to the dose-dependent enhancing effects of glucocorticoids on
memory consolidation, these stress hormones have been shown to inhibit the retrieval of already stored
information.[10] Long-term exposure to glucocorticoid medications, such as asthma and anti-inflammatory
medication, has been shown to create deficits in memory and attention both during and, to a lesser
extent, after treatment,[11][12] a condition known as "steroid dementia."[13]

Body fluid homeostasis[edit]

Glucocorticoids could act centrally, as well as peripherally, to assist in the normalization of extracellular
fluid volume by regulating bodys action to atrial natriuretic peptide (ANP). Centrally, glucocorticoids
could inhibit dehydration induced water intake;[14] peripherally, glucocorticoids could induce a potent
diuresis.[15]

Cannabinoid CB1 receptor decrease[edit]

Prolonged glucocorticoid treatment decreases cannabinoid CB1 receptor density in the hippocampus. [16]

Mechanism of action[edit]
Transactivation[edit]
Glucocorticoids bind to the cytosolic glucocorticoid receptor (GR), a type of nuclear receptor that is
activated by ligand binding. After a hormone binds to the corresponding receptor, the newly formed
complex translocates itself into the cell nucleus, where it binds to glucocorticoid response
elements (GRE) in the promoter region of the target genes resulting in the regulation of gene
expression. This process is commonly referred to as transcriptional activation, or transactivation.[17][18]

The proteins encoded by these up-regulated genes have a wide range of effects, including, for example:
[18]

anti-inflammatory lipocortin I, p11/calpactin binding protein, secretory leukoprotease inhibitor 1

(SLPI), and Mitogen-activated protein kinase phosphatase (MAPK phosphatase)
increased gluconeogenesis glucose-6-phosphatase and tyrosine aminotransferase

Transrepression[edit]
The opposite mechanism is called transcriptional repression, or transrepression. The classical
understanding of this mechanism is that activated GR binds to DNA in the same site where
another transcription factor would bind, which prevents the transcription of genes that are transcribed
via the activity of that factor.[17][18] While this does occur, the results are not consistent for all cell types and
conditions; there is no generally accepted, general mechanism for transrepression. [18]
New mechanisms are being discovered where transcription is repressed, but the activated GR is not
interacting with DNA, but rather with another transcription factor directly, thus interfering with it, or with
other proteins that interfere with the function of other transcription factors. This latter mechanism
appears to be the most likely way that activated GR interferes with NF-B - namely by recruiting histone
deacetylase, which deacetylate the DNA in the promoter region leading to closing of the chromatin
structure where NF-B needs to bind.[17][18]

Nongenomic effects[edit]
Activated GR has effects that have been experimentally shown to be independent of any effects on
transcription and can only be due to direct binding of activated GR with other proteins or with mRNA. [17][18]
For example, Src kinase which binds to inactive GR, is released when a glucocorticoid binds to GR, and
phosphorylates a protein that in turn displaces an adaptor protein from a receptor important in
inflammation, epidermal growth factor (EGF), reducing its activity, which in turn results in reduced
creation of arachidonic acid - a key proinflammatory molecule. This is one mechanism by which
glucocorticoids have an anti-inflammatory effect.[17]

Pharmacology[edit]
A variety of synthetic glucocorticoids, some far more potent than cortisol, have been created for
therapeutic use. They differ in both pharmacokinetics (absorption factor, half-life, volume of distribution,
clearance) andpharmacodynamics (for example the capacity of mineralocorticoid activity: retention
of sodium (Na+) and water; renal physiology). Because they permeate the intestines easily, they are
administered primarily per os (by mouth), but also by other methods, such as topically on skin. More
than 90% of them bind different plasma proteins, though with a different binding specificity. Endogenous
glucocorticoids and some synthetic corticoids have high affinity to the protein transcortin (also called
corticosteroid-binding globulin), whereas all of them bind albumin. In the liver, they quickly metabolize by
conjugation with a sulfate or glucuronic acid, and are secreted in the urine.
Glucocorticoid potency, duration of effect, and the overlapping mineralocorticoid potency
vary. Cortisol (hydrocortisone) is the standard of comparison for glucocorticoid
potency. Hydrocortisone is the name used for pharmaceutical preparations of cortisol.
The data below refer to oral dosing, except where mentioned. Oral potency may be less than parenteral
potency because significant amounts (up to 50% in some cases) may not be absorbed from the
intestine. Fludrocortisone, DOCA (Deoxycorticosterone acetate), and aldosterone are, by definition, not
considered glucocorticoids, although they may have minor glucocorticoid potency, and are included in
this table to provide perspective on mineralocorticoid potency.
Comparative steroid potencies [19] [20]

Name

Mineralocorticoid
potency

Glucocorticoid potency

Duration of action
(t1/2 in hours)

Cortisol (hydrocortisone)

Cortisone

0.8

0.8

oral 8, intramuscular
18+

Prednisone

3.5-5

0.8

16-36

Prednisolone

0.8

16-36

Methylprednisolone

5-7.5

0.5

18-40

Dexamethasone

25-80

36-54

Betamethasone

25-30

36-54

Triamcinolone

12-36

Beclometasone

8 puffs 4 times a day

equals 14 mg oral
prednisone once a
day[clarification needed]

Fludrocortisone acetate

15

200

24

Deoxycorticosterone acetate
(DOCA)

20

Aldosterone

0.3

200-1000

Therapeutic use[edit]
Glucocorticoids may be used in low doses in adrenal insufficiency. In much higher doses, oral or inhaled
glucocorticoids are used to suppress various allergic, inflammatory, and autoimmune disorders. Inhaled

glucocorticoids are the second-line treatment for asthma. They are also administered as posttransplantory immunosuppressants to prevent the acute transplant rejection and the graft-versus-host
disease. Nevertheless, they do not prevent an infection and also inhibit later reparative processes.
Newly emerging evidence showed that glucocorticoids could be used in the treatment of heart failure to
increase the renal responsiveness to diuretics and natriuretic peptides.

Physiological replacement[edit]
Any glucocorticoid can be given in a dose that provides approximately the same glucocorticoid effects
as normal cortisol production; this is referred to as physiologic, replacement, or maintenance dosing.
This is approximately 612 mg/m/day of hydrocortisone (m refers to body surface area (BSA), and is a
measure of body size; an average man's BSA is 1.9 m).

Therapeutic immunosuppression[edit]
See section on "Immunodeficiency" below for adverse effects
Glucocorticoids cause immunosuppression, and the therapeutic component of this effect is mainly the
decreases in the function and numbers of lymphocytes, including both B cells and T cells.
The major mechanism for this immunosuppression through inhibition of nuclear factor kappa-light-chainenhancer of activated B cells(NF-B). NF-B is a critical transcription factor involved in the synthesis of
many mediators (i.e., cytokines) and proteins (i.e., adhesion proteins) that promote the immune
response. Inhibition of this transcription factor, therefore, blunts the capacity of the immune system to
mount a response.[2]
Glucocorticoids suppress cell-mediated immunity by inhibiting genes that code for the cytokines IL-1, IL2, IL-3, IL-4, IL-5, IL-6, IL-8 and IFN-, the most important of which is IL-2. Smaller cytokine production
reduces the T cellproliferation.[21]
Glucocorticoids, however, not only reduce T cell proliferation, but also lead to another well known effect
- glucocorticoid-induced apoptosis. The effect is more prominent in immature T cells still inside in the
thymus, but peripheral T cells are also affected. The exact mechanism regulating this glucocorticoid
sensitivity lies in the Bcl-2 gene.[22]
Glucocorticoids also suppress the humoral immunity, thereby causing a humoral immune deficiency.
Glucocorticoids cause B cells to express smaller amounts of IL-2 and of IL-2 receptors. This diminishes
both B cell clone expansion and antibody synthesis. The diminished amounts of IL-2 also cause fewer T
lymphocyte cells to be activated.
The effect of glucocorticoids on Fc receptor expression in immune cells is complicated. Dexamethasone
decreases IFN-gamma simulated Fc gamma RI expression in neutrophils while conversely causing an
increase inmonocytes.[23] Glucocorticoids may also decrease the expression of Fc receptors in
macrophages,[24] but the evidence supporting this regulation in earlier studies has been questioned.
[25]
The effect of Fc receptor expression inmacrophages is important since it is necessary for
the phagocytosis of opsonised cells. This is because Fc receptors bind antibodies attached to cells
targeted for destruction by macrophages.

Anti-inflammatory[edit]
Glucocorticoids are potent anti-inflammatories, regardless of the inflammation's cause; their primary
anti-inflammatory mechanism is lipocortin-1 (annexin-1) synthesis. Lipocortin-1 both
suppresses phospholipase A2, thereby blocking eicosanoid production, and inhibits
various leukocyte inflammatory events
(epithelial adhesion, emigration, chemotaxis, phagocytosis, respiratory burst, etc.). In other words,
glucocorticoids not only suppress immune response, but also inhibit the two main products of
inflammation, prostaglandins and leukotrienes. They inhibit prostaglandin synthesis at the level
of phospholipase A2 as well as at the level of cyclooxygenase/PGE isomerase (COX-1 and COX-2),
[26]
the latter effect being much like that of NSAIDs, potentiating the anti-inflammatory effect.
In addition, glucocorticoids also suppress cyclooxygenase expression.[27]

Glucocorticoids marketed as anti-inflammatories are often topical formulations, such as nasal sprays
for rhinitis or inhalers for asthma. These preparations have the advantage of only affecting the targeted
area, thereby reducing side effects or potential interactions. In this case, the main compounds used
are beclometasone, budesonide, fluticasone, mometasone and ciclesonide. In rhinitis, sprays are used.
For asthma, glucocorticoids are administered as inhalants with a metered-dose or dry powder inhaler.[28]

Hyperaldosteronism[edit]
Glucocorticoids can be used in the management of familial hyperaldosteronism type 1. They are not
effective, however, for use in the type 2 condition.

Resistance[edit]

Corticosteroid resistance mechanisms

Resistance to the therapeutic uses of glucocorticoids can present difficulty; for instance, 25% of cases of
severe asthma may be unresponsive to steroids. This may be the result of genetic predisposition,
ongoing exposure to the cause of the inflammation (such as allergens), immunological phenomena that
bypass glucocorticoids, and pharmacokinetic disturbances (incomplete absorption or accelerated
excretion or metabolism).[21]

Heart failure[edit]
Glucocorticoids could be used in the treatment of decompensated heart failure to potentiate renal
responsiveness to diuretics, especially in heart failure patients with refractory diuretic resistance with
large dose of loop diuretics.[29][30][31][32][33][34][35]

Side effects[edit]
Glucocorticoid drugs currently being used act nonselectively, so in the long run they may impair many
healthy anabolic processes. To prevent this, much research has been focused recently on the
elaboration of selectively acting glucocorticoid drugs. Side effects include:

Immunodeficiency (see section below)

Hyperglycemia due to increased gluconeogenesis, insulin resistance, and impaired glucose
tolerance ("steroid diabetes"); caution in those with diabetes mellitus

Increased skin fragility, easy bruising

Negative calcium balance due to reduced intestinal calcium absorption[36]

Steroid-induced osteoporosis: reduced bone density (osteoporosis, osteonecrosis, higher

fracture risk, slower fracture repair)

Weight gain due to increased visceral and truncal fat deposition (central obesity)
and appetite stimulation

Hypercortisolemia with prolonged or excessive use (also known as, exogenous Cushing's
syndrome)

Impaired memory and attention deficits[37]

Adrenal insufficiency (if used for long time and stopped suddenly without a taper)

Muscle breakdown (proteolysis), weakness, reduced muscle mass and repair

Expansion of malar fat pads and dilation of small blood vessels in skin

Lipomatosis within the epidural space[38]

Excitatory effect on central nervous system (euphoria, psychosis)

Anovulation, irregularity of menstrual periods

Growth failure, delayed puberty

Increased plasma amino acids, increased urea formation, negative nitrogen balance

Glaucoma due to increased ocular pressure

Cataracts

Topical steroid addiction

In high doses, hydrocortisone (cortisol) and those glucocorticoids with appreciable mineralocorticoid
potency can exert a mineralocorticoid effect as well, although in physiologic doses this is prevented by
rapid degradation of cortisol by 11-hydroxysteroid dehydrogenase isoenzyme 2 (11-HSD2) in
mineralocorticoid target tissues. Mineralocorticoid effects can include salt and water
retention, extracellular fluid volume expansion, hypertension,potassium depletion, and metabolic
alkalosis.

Immunodeficiency[edit]
Glucocorticoids cause immunosuppression, decreasing the function and/or numbers of neutrophils,
lymphocytes (including both B cells and T cells), monocytes, macrophages, and the anatomical
barrier function of the skin.[39]This suppression, if large enough, can cause manifestations
of immunodeficiency, including T cell deficiency, humoral immune deficiency and neutropenia.
Main pathogens of concern in glucocorticoid-induced immunodeficiency:[39]

Bacteria

Enterobacteriaceae

Fungi

Legionella micdadei

Listeria monocytogenes

Mycobacterium tuberculosis

Nontuberculous mycobacteria

Nocardia asteroides

Rhodococcus equi

Salmonella species

Staphylococcus aureus

Streptococci

Aspergillus

Blastomyces

Candida albicans and nonalbicans species

Coccidioides immitis

Cryptococcus neoformans

Fusarium species

Histoplasma capsulatum

Penicillium marneffei

Pseudallescheria boydii

Zygomycosis

Adenovirus

Cytomegalovirus

Herpes simplex virus

Human papillomavirus

Viruses

Other

Influenza/parainfluenza

Respiratory syncytial virus

Varicella zoster

Cryptosporidiosis/Isospora belli

Pneumocystis carinii

Strongyloides stercoralis

Toxoplasma gondii

Withdrawal[edit]
In addition to the effects listed above, use of high-dose steroids for more than a week begins to produce
suppression of the patient's adrenal glands because the exogenous glucocorticoids suppress
hypothalamic corticotropin-releasing hormone and pituitary adrenocorticotropic hormone. With
prolonged suppression, the adrenal glands atrophy (physically shrink), and can take months to recover
full function after discontinuation of the exogenous glucocorticoid.
During this recovery time, the patient is vulnerable to adrenal insufficiency during times of stress, such
as illness. While suppressive dose and time for adrenal recovery vary widely, clinical guidelines have
been devised to estimate potential adrenal suppression and recovery, to reduce risk to the patient. The
following is one example:

If patients have been receiving daily high doses for five days or less, they can be abruptly
stopped (or reduced to physiologic replacement if patients are adrenal-deficient). Full adrenal
recovery can be assumed to occur by a week afterward.

If high doses were used for six to 10 days, reduce to replacement dose immediately and taper
over four more days. Adrenal recovery can be assumed to occur within two to four weeks of
completion of steroids.

If high doses were used for 1130 days, cut immediately to twice replacement, and then by 25%
every four days. Stop entirely when dose is less than half of replacement. Full adrenal recovery
should occur within one to three months of completion of withdrawal.

If high doses were used more than 30 days, cut dose immediately to twice replacement, and
reduce by 25% each week until replacement is reached. Then change to oral hydrocortisone or
cortisone as a single morning dose, and gradually decrease by 2.5 mg each week. When the
morning dose is less than replacement, the return of normal basal adrenal function may be
documented by checking 0800 cortisol levels prior to the morning dose; stop drugs when 0800
cortisol is 10 g/dl. Predicting the time to full adrenal recovery after prolonged suppressive
exogenous steroids is difficult; some people may take nearly a year.

Flare-up of the underlying condition for which steroids are given may require a more gradual
taper than outlined above.

See also[edit]

Aminoglutethimide blocks GC secretion

GITR (glucocorticoid-induced TNF receptor)

Glucocorticoid receptor

Immunosuppressive drug

Membrane glucocorticoid receptor

Metyrapone blocks GC secretion

Selective glucocorticoid receptor agonist (SEGRA)

Topical steroid

Steroid atrophy

Topical steroid withdrawal

Non-steroidal anti-inflammatory drug (NSAID)

YerkesDodson law
From Wikipedia, the free encyclopedia
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Original data from which the YerkesDodson law was derived

Original YerkesDodson law

Hebbian version of the YerkesDodson law (this version leaves out that hyperarousal does not adversely impact
simple tasks). This version is the most common version and often incorrectly cited in text books.

The YerkesDodson law is an empirical relationship between arousal and performance, originally
developed by psychologists Robert M. Yerkes and John Dillingham Dodson in 1908.[1]The law dictates
that performance increases with physiological or mental arousal, but only up to a point. When levels of
arousal become too high, performance decreases. The process is often illustrated graphically as a bellshaped curve which increases and then decreases with higher levels of arousal.
Contents
[hide]

1Levels of arousal

2Relationship to glucocorticoids

3See also

4References

Levels of arousal[edit]
Research has found that different tasks require different levels of arousal for optimal performance. For
example, difficult or intellectually demanding tasks may require a lower level of arousal (to facilitate
concentration), whereas tasks demanding stamina or persistence may be performed better with higher
levels of arousal (to increase motivation).
Because of task differences, the shape of the curve can be highly variable. [2] For simple or well-learned
tasks, the relationship can be considered linear with improvements in performance as arousal
increases. For complex, unfamiliar, or difficult tasks, the relationship between arousal and performance
becomes inverse, with declines in performance as arousal increases.
The effect of task difficulty led to the hypothesis that the YerkesDodson Law can be decomposed into
two distinct factors as in a bathtub curve. The upward part of the inverted U can be thought of as the
energizing effect of arousal. The downward part is caused by negative effects of arousal (or stress) on
cognitive processes like attention (e.g., "tunnel vision"), memory, and problem-solving.

There has been research indicating that the correlation suggested by Yerkes and Dodson exists (such
as that of Broadhurst, 1959; Duffy, 1962; Anderson, 1988), but a cause of the correlation has not yet
successfully been established (Anderson, Revelle, & Lynch, 1989). [3]

Relationship to glucocorticoids[edit]
A 2007 review of the effects of stress hormones (glucocorticoids, GC) and human cognition revealed
that memory performance vs. circulating levels of glucocorticoids does manifest an upside down U
shaped curve and the authors noted the resemblance to the YerkesDodson curve. For example, longterm potentiation (the process of forming long-term memories) is optimal when glucocorticoid levels are
mildly elevated whereas significant decreases of LTP are observed after adrenalectomy (low GC state)
or after exogenous glucocorticoid administration (high GC state).
This review also revealed that in order for a situation to induce a stress response, it has to be
interpreted as:

novel, and/or

unpredictable, and/or

not controllable by the individual, and/or

a social evaluative threat (negative social evaluation possibly leading to social rejection).

It has also been shown that elevated levels of glucocorticoids enhance memory for emotionally arousing
events but lead more often than not to poor memory for material unrelated to the source of
stress/emotional arousal.[4]

See also[edit]

Drive theory

Emotion

Emotion and memory

Flashbulb memory

Low arousal theory

Arousal
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the article. (discuss). (October 2015)

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Arousal is the physiological and psychological state of being awake. It involves activation of
the reticular activating system in the brainstem, the autonomic nervous system and theendocrine
system, leading to increased heart rate and blood pressure and a condition of sensory alertness,
mobility and readiness to respond.

The arousal system involves many different neural systems. Five major systems originating in the
brainstem, with connections extending throughout the cortex, are based on the brain's
neurotransmitters, acetylcholine, norepinephrine, dopamine, histamine, and serotonin. When these
systems are in action, the receiving neural areas become sensitive and responsive to incoming signals,
producing alertness and cortical activity.
Arousal is important in regulating consciousness, attention, and information processing. It is a crucial
for motivating certain behaviours, such as mobility, the pursuit of nutrition, thefight-or-flight
response and sexual activity (known as the arousal phase of Masters and Johnson's human sexual
response cycle). It is also important in emotion and has been included as a part of theories such as
the James-Lange theory of emotion. According to Hans Eysenck, differences in baseline arousal level
lead people to be extraverts or introverts.
The Yerkes-Dodson law states that an optimal level of arousal for performance exists, and too little or
too much arousal can adversely affect task performance. One interpretation of the Yerkes-Dodson Law
is the Easterbrook Cue-Utilisation hypothesis. Easterbrook states that an increase of arousal decreases
the number of cues that can be used.
Contents
[hide]

1Neurophysiology

2Importance

3Personality
o

3.1Introversion and extraversion

3.2Emotional stability vs. introversion-extraversion

3.3Four personality types

4Emotion
o

4.1CannonBard theory

4.2JamesLange theory

4.3SchachterSinger two-factor theory

5Memory

6Preference

7Associated problems

8Abnormally increased behavioral arousal

9See also

10References

Neurophysiology[edit]

Structures of the brainstem, the origin of the arousal system, viewed along the sagittal plane

The arousal system involves many different neural systems. Five major systems originating in the
brainstem, with connections extending throughout the cortex, are based on the brain's
neurotransmitters, acetylcholine, norepinephrine,dopamine, histamine, and serotonin.[1] When
stimulated, these systems produce cortical activity and alertness.
The noradrenergic system is a bundle of axons that originate in the locus coeruleus and ascends up into
the neocortex, limbic system, and basal forebrain. Most of the neurons are projected to the posterior
cortex which is important with sensory information, and alertness. The activation of the locus coeruleus
and release of norepinephrine causes wakefulness and increases vigilance. The neurons that project
into the basal forebrain impact cholinergic neurons that results in a flood of acetylcholine into the
cerebral cortex.
The acetylcholinergic system has its neurons located in the pons and in the basal forebrain. Stimulation
of these neurons result in cortical activity, shown from EEG records, and alertness. All of the other four
neurotransmitters play a role in activating the acetylcholine neurons.
Another arousal system is the dopaminergic system, which releases dopamine that is produced by
the substantia nigra. The neurons arise in the ventral tegmental area in the midbrain, and projects to the
nucleus accumbens, the striatum forebrain, limbic system, and prefrontal cortex. The limbic system is
important for control of mood and the nucleus accumbens signal excitement and arousal. The path
terminating in the prefrontal cortex is important in regulating motor movements, especially reward
oriented movements.
The serotonergic system which has almost all of its serotonergic neurons originating in the raphe nuclei.
This system projects to the limbic system as well as the prefrontal cortex. Stimulation of these axons
and release of serotonin causes cortical arousal and impacts locomotion as well as mood.
The last is the histamergenic system. The neurons are located in the tuberomammillary nucleus of the
hypothalamus. These neurons send pathways to the cerebral cortex, thalamus, and the basal forebrain,
where is stimulate the release of acetylcholine into the cerebral cortex. All of these systems are very
much linked and show similar redundancy. The pathways described are all ascending pathways, but
there also arousal pathways that descend. One example is the Ventrolateral Preoptic area which

release GABA inhibitors, which interrupt wakefulness and arousal. Neurotransmitters of the Arousal
system such as Acetylcholine and norepinephrine work to inhibit the Ventrolateral preoptic area.

Importance[edit]

Mental state in terms of challenge level and skill level, according to Csikszentmihalyi's flow model.[2](Click on a
fragment of the image to go to the appropriate article)

Arousal is important in regulating consciousness, attention, and information processing. It is crucial

for motivating certain behaviors, such as mobility, the pursuit of nutrition, thefight-or-flight
response and sexual activity (see Masters and Johnson's human sexual response cycle, where it is
known as the arousal phase). Arousal is also an essential element in many influential theories
of emotion, such as the James-Lange theory of emotion or the Circumplex Model. According to Hans
Eysenck, differences in baseline arousal level lead people to be either extroverts or introverts. Later
research suggest it is most likely that extroverts and introverts have different arousability. Their baseline
arousal level is the same, but the response to stimulation is different.[3]
The YerkesDodson law states that there is a relationship between arousal and task performance,
essentially arguing that there is an optimal level of arousal for performance, and too little or too much
arousal can adversely affect task performance. One interpretation of the YerkesDodson law is the
Easterbrook cue-utilisation hypothesis. Easterbrook states that an increase of emotion leads to a
decrease in number of cues that can be utilised.[4]
In positive psychology, arousal is described as a response to a difficult challenge for which the subject
has moderate skills.[2]

Personality[edit]
Introversion and extraversion[edit]
Hans Eysenck's theory of arousal describes the different natural frequency or arousal states of the
brains of people who are introverted versus people who are extroverted. The theory states that the
brains of extroverts are naturally less stimulated, so these types have a predisposition to seek out
situations and partake in behaviors that will stimulate arousal. [5] Whereas extroverts are naturally understimulated and therefore actively engage in arousing situations, introverts are naturally over-stimulated
and therefore avoid intense arousal. Campbell and Hawley (1982) studied the differences in introverts
versus extroverts responses to particular work environments in the library.[5]The study found that
introverts were more likely to choose quiet areas with minimal to no noise or people. Extroverts were
more likely to choose areas with much activity with more noise and people. [5] Daoussiss and McKelvie's

(1986) research showed that introverts performed worse on memory tasks when they were in the
presence of music compared to silence. Extroverts were less affected by the presence of music.
[5]
Similarly, Belojevic, Slepcevic and Jokovljevic (2001) found that introverts had more concentration
problems and fatigue in their mental processing when work was coupled with external noise or
distracting factors.[5] The level of arousal surrounding the individuals greatly affected their ability to
perform tasks and behaviors, with the introverts being more affected than the extroverts, because of
each's naturally high and low levels of stimulation, respectively.

Emotional stability vs. introversion-extraversion[edit]

Neuroticism or emotional instability and extroversion are two factors of the Big Five Personality Index.
These two dimensions of personality describe how a person deals with anxiety-provoking or emotional
stimuli as well as how a person behaves and responds to relevant and irrelevant external stimuli in their
environment. Neurotics experience tense arousal which is characterized by tension and nervousness.
Extroverts experience high energetic arousal which is characterized by vigor and energy.[6] Gray (1981)
claimed that extroverts have a higher sensitivity to reward signals than to punishment in comparison to
introverts. Reward signals aim to raise the energy levels.[6] Therefore extroverts typically have a higher
energetic arousal because of their greater response to rewards.

Four personality types[edit]

Hippocrates theorized that there are four personality types: choleric, melancholic, sanguine,
and phlegmatic.
Put in terms of the 5 factor level of personality, choleric people are high in neuroticism and high in
extraversion. The choleric react immediately, and the arousal is strong, lasting, and can easily create
new excitement about similar situations, ideas, or impressions.[7] Melancholic people are high in
neuroticism and low in extraversion (or more introverted). The melancholic are slow to react and it takes
time for an impression to be made upon them if any is made at all. However, when aroused by
something, melancholics have a deeper and longer lasting reaction, especially when exposed to similar
experiences.[7] Sanguine people are low in neuroticism (or more emotionally stable) and high in
extraversion. The sanguine are quickly aroused and excited, like the cholerics, but unlike the cholerics,
their arousal is shallow, superficial, and shortly leaves them as quickly as it developed. [7] Phlegmatic
people are low in neuroticism and low in extraversion. The phlegmatic are slower to react and the
arousal is fleeting.[7]
The contrasts in the different temperaments come from individuals variations in a person's brain stem,
limbic system, and thalamocortical arousal system. These changes are
observed Electroencephalogram or EEG recordings which monitor brain activity.[8] Limbic
system activation is typically linked to neuroticism, which high activation showing high neuroticism.
[9]
Cortical arousal is associated with introversion-extraversion differences, with high arousal associated
with introversion.[9] Both the limbic system and the thalamocortical arousal system are influenced by the
brain stem activation.[9] Robinson's study (1982) concluded that melancholic types had the
greatest natural frequencies, or a "predominance of excitation," meaning that melancholics (who are
characterized by introversion) have a higher internal level of arousal. [8] Sanguine people (or those with
high extraversion and low neuroticism) had the lowest overall levels of internal arousal, or a
"predominance of inhibition.[8]" Melancholics also had the highest overall thalamocortical excitation,
whereas cholerics (those with high extraversion and high neuroticism) had the lowest intrinsic
thalamocortical excitation.[8] The differences in the internal system levels is the evidence that Eysenck
used to explain the differences between the introverted and the extroverted. Ivan Pavlov, the founder of
classical conditioning, also partook in temperament studies with animals. Pavlov's findings with animals
are consistent with Eysenck's conclusions. In his studies, melancholics produced an inhibitory response
to all external stimuli, which holds true that melancholics shut out outside arousal, because they are
deeply internally aroused.[8] Pavlov found that cholerics responded to stimuli with aggression and
excitement whereas melancholics became depressed and unresponsive.[8] The high neuroticism,
characterized by both melancholics and cholerics both manifested themselves differently because of the
different levels of internal arousal both types had.

Emotion[edit]
CannonBard theory[edit]
The CannonBard theory is a theory of undifferentiated arousal, where the physical and emotional
states occur at the same time in response to an event. This theory states that an emotionally provoking
event results in both the physiological arousal and the emotion occurring concurrently.[10] For example, a
dear family member dies. A potential physiological response would be tears falling down your face and
your throat feeling dry. You are "sad." The CannonBard theory states that the tears and the sadness
both happen at the same time. The process goes: event (family member dies) physiological arousal
(tears) AND emotion (sadness) simultaneously.[10] The fact that people can experience different emotions
when they have the same pattern of physiological arousal is one argument in favor of the Cannon-Bard
theory. For example, a person may have a heart racing and rapid breathing when they are angry or
afraid. Even though not completely in accordance with the theory, it is taken as one piece of evidence in
favor of the Cannon-Bard theory that physiological reactions sometimes happen more slowly than
experiences of emotion. For example, if you are in the forest or woods, a sudden sound can create an
immediate response of fear, while the physical symptoms of fear follow that feeling, and do not precede
it.[11]

JamesLange theory[edit]
The JamesLange theory describes how emotion is caused by the bodily changes which come from the
perception of the emotionally arousing experience or environment. [12] This theory states that events
cause the autonomic nervous system to induce physiological arousal, characterized by muscular
tension, heart rate increases, perspiration, dryness of mouth, tears, etc. [13] According to James and
Lange, the emotion comes as a result of the physiological arousal. [14] The bodily feeling as a reaction to
the situation IS the emotion.[12] For example, someone just deeply insulted you and your family. Your fists
ball up, you begin to perspire, and you are tense all around. You feel that your fists are balled and that
you are tense. You then realize that you are angry. The process here is: event (insult) --> physiological
arousal (balled fists, sweat, tension) --> interpretation (I have balled fists, and tension) --> emotion
(anger: I am angry).[14] This type of theory emphasizes the physiological arousal as the key, in that the
cognitive processes alone would not be sufficient evidence of an emotion.

SchachterSinger two-factor theory[edit]

The SchachterSinger two-factor theory or the cognitive labeling theory takes into account both the
physiological arousal and the cognitive processes that respond to an emotion provoking situation.
Schachter and Singer's theory states that an emotional state is the product of the physiological arousal
and the cognition appropriate state of arousal. Meaning, that cognition determines how the physical
response is labeled, either as "anger," "joy," "fear," etc.[12] Emotion is a product of the interaction between
the state of arousal as well as how one's thought processes appraise the current situation. [15] The
physiological arousal, however, does not label the emotion, but the cognitive label does. For example,
let's say you are being pursued by a serial killer. You will be sweating and your heart will be racing,
which is your physiological state. Your cognitive label will come from accessing your quickly beating
heart and sweat as "fear." Then you will feel the emotion of "fear," but only after it has been established
through cognition. The process is: the event (serial killer chasing you) --> physiological arousal (sweat,
heart racing) --> cognitive label (reasoning; this is fear) --> emotion (fear). [14]

Memory[edit]
Arousal is involved in the detection, retention, and retrieval of information in the memory process.
Emotionally arousing information can lead to better memory encoding, therefore influencing better
retention and retrieval of information. Arousal is related to selective attention during the encoding
process by showing that people are more subject to encode arousing information than neutral
information.[16] The selectivity of encoding arousing stimuli produces better long-term memory results
than the encoding of neutral stimuli.[17] In other words, the retention and accumulation of information is
strengthened when exposed to arousing events or information. Arousing information is also retrieved or
remembered more vividly and accurately.[18]

Although arousal improves memory under most circumstances, there are some considerations. Arousal
at learning is associated more with long-term recall and retrieval of information than short-term recall of
information. For example, one study found that people could remember arousing words better after one
week of learning them than merely two minutes after learning them.[19] Another study found that arousal
affects the memory of people in different ways. Hans Eysenck found an association between memory
and the arousal of introverts versus extroverts. Higher levels of arousal increased the amount of words
retrieved by extroverts and decreased the amount of words retrieved by introverts. [19]

Preference[edit]
A person's level of arousal when introduced to stimuli can be indicative of his or her preferences. One
study found that familiar stimuli are often preferred to unfamiliar stimuli. The findings suggested that the
exposure to unfamiliar stimuli was correlated to avoidance behaviors. The unfamiliar stimuli may lead to
increased arousal and increased avoidance behaviors.[20]
On the contrary, increased arousal can increase approach behaviors as well. People are said to make
decisions based on their emotional states. They choose specific options that lead to more favorable
emotional states.[21]When a person is aroused, he or she may find a wider range of events
appealing[22] and view decisions as more salient, specifically influencing approach-avoidance conflict.
[21]
The state of arousal might lead a person to view a decision more positively than he or she would have
in a less aroused state.
The reversal theory accounts for the preference of either high or low arousal in different situations. Both
forms of arousal can be pleasant or unpleasant, depending on a person's moods and goals at a specific
time.[23] Wundt's and Berlyne's hedonic curve differ from this theory. Both theorists explain a person's
arousal potential in terms of his or her hedonic tone. These individual differences in arousal
demonstrate Eysenck's theory that extroverts prefer increased stimulation and arousal, whereas
introverts prefer lower stimulation and arousal.[24]

Associated problems[edit]
Altered experiences of arousal are associated with both anxiety and depression.
Depression can influence a person's level of arousal by interfering with the right hemisphere's
functioning. Arousal in women has been shown to be slowed in the left visual field due to depression,
indicating the influence of the right hemisphere.[25]
Arousal and anxiety have a different relationship than arousal and depression. People who suffer from
anxiety disorders tend to have abnormal and amplified perceptions of arousal. The distorted perceptions
of arousal then create fear and distorted perceptions of the self. For example, a person may believe that
he or she will get sick from being so nervous about taking an exam. The fear of the arousal of
nervousness and how people will perceive this arousal will then contribute to levels of anxiety.[26]

Abnormally increased behavioral arousal[edit]

This is caused by withdrawal from alcohol or barbiturates, acute encephalitis, head trauma resulting
in coma, partial seizures in epilepsy, metabolic disorders of electrolyte imbalance, Intra-cranial spaceoccupying lesions, Alzheimer's disease, rabies, hemispheric lesions in stroke and multiple sclerosis. [27]
Anatomically this is a disorder of the limbic system, hypothalamus, temporal lobes, amygdala and frontal
lobes.[27] It is not to be confused with mania.

See also[edit]
Look up arousal in
Wiktionary, the free

dictionary.

Low arousal approach

Low arousal theory

Sexual arousal

Drive theory
From Wikipedia, the free encyclopedia
(Redirected from Drive theory (social psychology))

For other uses, see Drive reduction theory (learning theory).

In psychology, a drive theory or drive doctrine[1] is a theory that attempts to define, analyze or classify
the psychological drives. A drive is an excitatory state produced by a homeostatic disturbance, [2] an
instinctual need that has the power of driving the behaviour of an individual. [3]
Drive theory is based on the principle that organisms are born with certain psychological needs and that
a negative state of tension is created when these needs are not satisfied. When a need is satisfied,
drive is reduced and the organism returns to a state of homeostasis and relaxation. According to the
theory, drive tends to increase over time and operates on a feedback control system, much like a
thermostat.
Contents
[hide]

1Psychoanalysis

2Early attachment theory

3Social psychology

3.1Corroborative evidence

3.2Evaluation apprehension
4References

Psychoanalysis[edit]
Part of a series of articles on

Psychoanalysis

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Important figures[show]
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Psychology portal

In psychoanalysis, drive theory (German: Triebtheorie or Trieblehre)[1] refers to the theory of drives,
motivations, or instincts, that have clear objects.[citation needed] When an internal imbalance is detected by
homeostatic mechanisms, a drive to restore balance is produced. [4] In 1927 Sigmund Freud said that a
drive theory was what was lacking most in psychoanalysis. He was opposed to systematics in
psychology, rejecting it as a form of paranoia, and instead classified drives with dichotomies
like Eros/Thanatos drives, the drives toward Life and Death, respectively, and sexual/ego drives. [1]
Freud's Civilization and Its Discontents was published in Germany in 1930 when the rise of fascism in
that country was well under way, and the warnings of a second European war were leading to opposing
calls for rearmament and pacifism. Against this background, Freud wrote "In face of the destructive
forces unleashed, now it may be expected that the other of the two 'heavenly forces,' eternal Eros, will
put forth his strength so as to maintain himself alongside of his equally immortal adversary." [5]
In 1947, Hungarian psychiatrist and psychologist Leopold Szondi, aimed instead at a systematic drive
theory.[1][6] Szondi Drive Diagram has been described as a revolutionary addition to psychology, and as
paving the way for a theoretical psychiatry and a psychoanalytical anthropology.[1][7]

Early attachment theory[edit]

In early attachment theory, behavioural drive reduction was proposed by Dollard and Miller (1950) as an
explanation of the mechanisms behind early attachment in infants. Behavioural drive reduction theory
suggests that infants are born with innate drives, such as hunger and thirst, which only the caregiver,
usually the mother, can reduce. Through a process of classical conditioning, the infant learns to
associate the mother with the satisfaction of reduced drive and is thus able to form a key attachment
bond. However, this theory is challenged by the work done by Harlow, particularly the experiments
involving the maternal separation of rhesus monkeys, which indicate that comfort possesses greater
motivational value than hunger.[8]

Social psychology[edit]
In social psychology, drive theory was used by Robert Zajonc in 1965 as an explanation of the
phenomenon of social facilitation.[9] The audience effect notes that in some cases the presence of a
passive audience will facilitate the better performance of a task, while in other cases the presence of an
audience will inhibit the performance of a task. Zajonc's drive theory suggests that the variable
determining direction of performance is whether the task is composed of a correct dominant response
(that is, the task is perceived as being subjectively easy to the individual) or an incorrect dominant
response (perceived as being subjectively difficult).
In the presence of a passive audience, an individual is in a heightened state of arousal. Increased
arousal, or stress, causes the individual to enact behaviours that form dominant responses, since an
individual's dominant response is the most likely response, given the skills which are available. If the
dominant response is correct, then social presence enhances performance of the task. However, if the
dominant response is incorrect, social presence produces an impaired performance.

Corroborative evidence[edit]
Such behaviour was first noticed by Triplett (1898) while observing the cyclists who were racing together
versus cyclists who were racing alone.[citation needed] It was found that the mere presence of other cyclists
produced greater performance. A similar effect was observed by Chen (1937) in ants building colonies.
[citation needed]
However, it was not until Zajonc investigated this behaviour in the 1960s that any empirical
explanation for the audience effect was pursued.[citation needed]
Zajonc's drive theory is based on an experiment[10] involving the investigation of the effect of social
facilitation in cockroaches. Zajonc devised a study in which individual cockroaches were released into a
tube, at the end of which there was a light. In the presence of other cockroaches as spectators,
cockroaches were observed to achieve a significantly faster time in reaching the light than those in the
control, no-spectator group. However, when cockroaches in the same conditions were given a maze to
negotiate, performance was impaired in the spectator condition, demonstrating that incorrect dominant
responses in the presence of an audience impair performance.[citation needed]

Evaluation apprehension[edit]
Cottrell's evaluation apprehension model later refined this theory to include yet another variable in the
mechanisms of social facilitation. He suggested that the correctness of dominant responses only plays a
role in social facilitation when there is an expectation of social reward or punishment based on
performance. His study differs in design from Zajonc's as he introduced a separate condition in which
participants were given tasks to perform in the presence of an audience that was blindfolded, and thus
unable to evaluate the participant's performance. It was found that no social facilitation effect occurred,
and hence the anticipation of performance evaluation must play a role in social facilitation. [citation
needed]
Evaluation apprehension, however, is only key in human social facilitation and not observed in
animals.[citation needed]

Steroid hormone
From Wikipedia, the free encyclopedia

A steroid hormone is a steroid that acts as a hormone. Steroid hormones can be grouped into 2
classes, corticosteroids (typically made in the adrenal cortex, hence cortico-) and sex steroids (typically
made in the gonads orplacenta). Within those 2 classes are 5 types according to the receptors to which
they bind: glucocorticoids and mineralocorticoids (corticosteroids) and androgens, estrogens,
and progestogens (sex steroids). Vitamin Dderivatives are a sixth closely related hormone system with
homologous receptors. They have some of the characteristics of true steroids as receptor ligands.
Steroid hormones help control metabolism, inflammation, immune functions, salt and water balance,
development of sexual characteristics, and the ability to withstand illness and injury. The
term steroid describes both hormones produced by the body and artificially produced medications that
duplicate the action for the naturally occurring steroids.[1][2][3]
Contents
[hide]

1Synthesis
1.1Synthetic steroids and sterols

2Effects

3See also

4References

5Further reading

6External links

Synthesis[edit]
Further information: Steroidogenesis

Steroidogenesis with enzymes and intermediates

The natural steroid hormones are generally synthesized from cholesterol in the gonads and adrenal
glands. These forms of hormones are lipids. They can pass through the cell membrane as they are fatsoluble,[4] and then bind to steroid hormone receptors (which may be nuclear or cytosolic depending on
the steroid hormone) to bring about changes within the cell. Steroid hormones are generally carried in
the blood, bound to specific carrier proteins such as sex hormone-binding globulin or corticosteroidbinding globulin. Further conversions and catabolism occurs in the liver, in other "peripheral" tissues,
and in the target tissues.

Synthetic steroids and sterols[edit]

A variety of synthetic steroids and sterols have also been contrived. Most are steroids, but some nonsteroidal molecules can interact with the steroid receptors because of a similarity of shape. Some
synthetic steroids are weaker or stronger than the natural steroids whose receptors they activate. [5]
Some examples of synthetic steroid hormones:

Glucocorticoids: alclometasone, prednisone, dexamethasone, triamcinolone, cortisone

Mineralocorticoid: fludrocortisone

Vitamin D: dihydrotachysterol

Androgens: apoptone, oxandrolone, oxabolone, testosterone, nandrolone (also known

as anabolic steroids)
Oestrogens: diethylstilbestrol (DES) and beta estradiol
Progestins: danazol, norethisterone, medroxyprogesterone acetate, 17-hydroxyprogesterone
caproate.

Some steroid antagonists:

Androgen: cyproterone acetate

Progestins: mifepristone, gestrinone

Effects[edit]
Steroids exert a wide variety of effects, mediated by slow genomic as well as by rapid nongenomic
mechanisms. They bind to nuclear receptors in the cell nucleus for genomic actions. Membraneassociated steroid receptors activate intracellular signaling cascades involved in nongenomic actions.
Because steroids and sterols are lipid-soluble, they can diffuse fairly freely from the blood through
the cell membrane and into the cytoplasm of target cells. This is in contrast to the actions of non-steroid
hormones, which are water-soluble typically peptide hormones, acting through membrane bound
receptors and intracellular second messenger systems to exert their effects. In the cytoplasm, the
steroid may or may not undergo an enzyme-mediated alteration such as reduction, hydroxylation, or
aromatization. In the cytoplasm, the steroid binds to the specific receptor, a large metalloprotein. Upon
steroid binding, many kinds of steroid receptor dimerize: Two receptor subunits join together to form one
functional DNA-binding unit that can enter the cell nucleus. In some of the hormone systems known, the
receptor is associated with a heat shock protein, which is released on the binding of the ligand, the
hormone. Once in the nucleus, the steroid-receptor ligand complex binds to specific DNA sequences
and induces transcription of its target genes.[2][6][7][8]

Membrane steroid receptor

From Wikipedia, the free encyclopedia

Membrane steroid receptors (mSRs), also called extranuclear steroid receptors, are a class
of receptors that bind and are activated by endogenous steroids and mediate rapid, nongenomic signaling via modulation ofintracellular signaling cascades.[1][2][3][4] They are another means
besides classical nuclear steroid hormone receptors by which steroids mediate their biological effects.[1][2]
[3][4]

Known groups of mSRs include:

Membrane sex steroid receptors

Membrane estrogen receptors (mERs) e.g., GPER, ER-X, Gq-mER

Membrane progesterone receptors (mPRs) mPR, mPR, mPR

Membrane androgen receptors (mARs) GPRC6A, ZIP9

Membrane corticosteroid receptors

Membrane glucocorticoid receptors (mGRs)

Membrane mineralocorticoid receptors (mMRs)

Ligand-gated ion channels such as the GABAA receptor and the NMDA receptor bind and are modulated
by neurosteroids such as dehydroepiandrosterone (DHEA), allopregnanolone, and 3androstanediol. Vomeronasal receptors bind and are activated by pheromones such
as androstenone and androstenol.

Membrane steroid receptor

From Wikipedia, the free encyclopedia

Membrane steroid receptors (mSRs), also called extranuclear steroid receptors, are a class
of receptors that bind and are activated by endogenous steroids and mediate rapid, nongenomic signaling via modulation ofintracellular signaling cascades.[1][2][3][4] They are another means
besides classical nuclear steroid hormone receptors by which steroids mediate their biological effects.[1][2]
[3][4]

Known groups of mSRs include:

Membrane sex steroid receptors

Membrane estrogen receptors (mERs) e.g., GPER, ER-X, Gq-mER

Membrane progesterone receptors (mPRs) mPR, mPR, mPR

Membrane androgen receptors (mARs) GPRC6A, ZIP9

Membrane corticosteroid receptors

Membrane glucocorticoid receptors (mGRs)

Membrane mineralocorticoid receptors (mMRs)

Ligand-gated ion channels such as the GABAA receptor and the NMDA receptor bind and are modulated
by neurosteroids such as dehydroepiandrosterone (DHEA), allopregnanolone, and 3androstanediol. Vomeronasal receptors bind and are activated by pheromones such
as androstenone and androstenol.

References[edit]
1.

^ Jump up to:a b Levin ER (2014). "Translating extranuclear steroid receptor signaling to clinical
medicine". Horm Cancer 5 (3): 1405. doi:10.1007/s12672-014-0179-9. PMC 4040225. PMID 24752388.

2.

^ Jump up to:a b Hammes SR, Levin ER (2011). "Minireview: Recent advances in extranuclear
steroid receptor actions".Endocrinology 152 (12): 448995. doi:10.1210/en.20111470. PMC 3858720. PMID 22028449.

3.

^ Jump up to:a b Sen A, Prizant H, Hammes SR (2011). "Understanding extranuclear

(nongenomic) androgen signaling: what a frog oocyte can tell us about human biology". Steroids 76 (9):
8228. doi:10.1016/j.steroids.2011.02.016.PMID 21354434.