Testosterone

Template:Short description Template:About Template:Use mdy dates Template:Cs1 config Template:Chembox Testosterone is the primary male sex hormone and androgen in males.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> In humans, testosterone plays a key role in the development of male reproductive tissues such as testicles and prostate, as well as promoting secondary sexual characteristics such as increased muscle and bone mass, and the growth of body hair. It is associated with increased aggression, sex drive, dominance, courtship display, and a wide range of behavioral characteristics.<ref name="pmid3549275">Template:Cite journal</ref> In addition, testosterone in both sexes is involved in health and well-being, where it has a significant effect on overall mood, cognition, social and sexual behavior, metabolism and energy output, the cardiovascular system, and in the prevention of osteoporosis.<ref name="pmid19707253">Template:Cite journal</ref><ref name="pmid19011293">Template:Cite book</ref> Insufficient levels of testosterone in men may lead to abnormalities including frailty, accumulation of adipose fat tissue within the body, anxiety and depression, sexual performance issues, and bone loss.

Excessive levels of testosterone in men may be associated with hyperandrogenism, higher risk of heart failure, increased mortality in men with prostate cancer,<ref>Template:Cite journal</ref> and male pattern baldness.

Testosterone is a steroid hormone from the androstane class containing a ketone and a hydroxyl group at positions three and seventeen respectively. It is biosynthesized in several steps from cholesterol and is converted in the liver to inactive metabolites.<ref name = "Luetjens_2012" /> It exerts its action through binding to and activation of the androgen receptor.<ref name = "Luetjens_2012">Template:Cite book</ref> In humans and most other vertebrates, testosterone is secreted primarily by the testicles of males and, to a lesser extent, the ovaries of females. On average, in adult males, levels of testosterone are about seven to eight times as great as in adult females.<ref name="pmid14981046">Template:Cite journal</ref> As the metabolism of testosterone in males is more pronounced, the daily production is about 20 times greater in men.<ref name="pmid6025472">Template:Cite journal</ref><ref name="pmid5843701">Template:Cite journal</ref> Females are also more sensitive to the hormone.<ref name="isbn0-07-135739-4">Template:Cite book</ref>Template:Page needed

In addition to its role as a natural hormone, testosterone is used as a medication to treat hypogonadism and breast cancer.<ref name="AHFS2016">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> Since testosterone levels decrease as men age, testosterone is sometimes used in older men to counteract this deficiency. It is also used illicitly to enhance physique and performance, for instance in athletes.<ref>Template:Cite report</ref> The World Anti-Doping Agency lists it as S1 Anabolic agent substance "prohibited at all times".<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

Biological effects

Effects on physiological development

In general, androgens such as testosterone promote protein synthesis and thus growth of tissues with androgen receptors.<ref name="pmid10821325">Template:Cite journal</ref> Testosterone can be described as having anabolic and androgenic (virilising) effects, though these categorical descriptions are somewhat arbitrary, as there is a great deal of mutual overlap between them.<ref name="pmid25905231">Template:Cite book</ref> The relative potency of these effects can depend on various factors and is a topic of ongoing research.<ref name="Ceponis-2017">Template:Cite book</ref><ref name="pmid12017555">Template:Cite journal</ref> Testosterone can either directly exert effects on target tissues or be metabolized by 5α-reductase into dihydrotestosterone (DHT) or aromatized to estradiol (E2).<ref name="Ceponis-2017"/> Both testosterone and DHT bind to an androgen receptor; however, DHT has a stronger binding affinity than testosterone and may have more androgenic effect in certain tissues at lower levels.<ref name="Ceponis-2017"/>

• 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 the voice, growth of facial hair (such as the beard) and axillary (underarm) 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.<ref>Template:Cite book</ref>

Before birth

Effects before birth are divided into two categories, classified in relation to the stages of development.

The first period occurs between 4 and 6 weeks of the gestation. Examples include genital virilisation such as midline fusion, phallic urethra, scrotal thinning and rugation, and phallic enlargement; although the role of testosterone is far smaller than that of dihydrotestosterone. There is also development of the prostate gland and seminal vesicles.Template:Citation needed

During the second trimester, androgen level is associated with sex formation.<ref name="pmid19403051">Template:Cite journal</ref> Specifically, testosterone, along with anti-Müllerian hormone (AMH) promote growth of the Wolffian duct and degeneration of the Müllerian duct respectively.<ref>Template:Cite journal</ref> This period affects the femininization or masculinization of the fetus and can be a better predictor of feminine or masculine behaviours such as sex typed behaviour than an adult's own levels. Prenatal androgens apparently influence interests and engagement in gendered activities and have moderate effects on spatial abilities.<ref>Template:Cite journal</ref> Among women with congenital adrenal hyperplasia, a male-typical play in childhood correlated with reduced satisfaction with the female gender and reduced heterosexual interest in adulthood.<ref>Template:Cite journal</ref>

Early infancy

Early infancy androgen effects are the least understood. In the first weeks of life for male infants, testosterone levels rise. The levels remain in a pubertal range for a few months, but usually reach the barely detectable levels of childhood by 4–7 months of age.<ref name="pmid4715291">Template:Cite journal</ref><ref name="pmid1379488">Template:Cite journal</ref> The function of this rise in humans is unknown. It has been theorized that brain masculinization is occurring since no significant changes have been identified in other parts of the body.<ref name="pmid18445234">Template:Cite journal</ref> The male brain is masculinized by the aromatization of testosterone into estradiol,<ref name="HäggströmRichfield2014" /> which crosses the blood–brain barrier and enters the male brain, whereas female fetuses have α-fetoprotein, which binds the estrogen so that female brains are not affected.<ref name="isbn0-495-60300-7">Template:Cite book</ref>

Before puberty

Before puberty, effects of rising androgen levels occur in both boys and girls. These include adult-type body odor, increased oiliness of skin and hair, acne, pubarche (appearance of pubic hair), axillary hair (armpit hair), growth spurt, accelerated bone maturation, and facial hair.<ref name="pmid15815567">Template:Cite journal</ref>

Pubertal

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. The effects include:<ref name="pmid15815567" /><ref name= "Ganong_2012">Template:Cite book</ref>

• Growth of spermatogenic tissue in testicles, male fertility, penis or clitoris enlargement, increased libido and frequency of erection or clitoral engorgement occurs.
• Growth of jaw, brow, chin, and nose and remodeling of facial bone contours, in conjunction with human growth hormone occurs.<ref name="pmid20501658">Template:Cite journal</ref>
• Completion of bone maturation and termination of growth. This occurs indirectly via estradiol metabolites and hence more gradually in men than women.
• Increased muscle strength and mass, shoulders become broader and rib cage expands, deepening of voice, growth of the Adam's apple.
• Enlargement of sebaceous glands. This might cause acne, subcutaneous fat in face decreases.
• Pubic hair extends to thighs and up toward umbilicus, development of facial hair (sideburns, beard, moustache), loss of scalp hair (androgenetic alopecia), increase in chest hair, periareolar hair, perianal hair, leg hair, armpit hair.

Adult

Testosterone is necessary for normal sperm development. It activates genes in Sertoli cells, which promote differentiation of spermatogonia. It regulates acute hypothalamic–pituitary–adrenal axis (HPA axis) response under dominance challenge.<ref name="pmid18505319">Template:Cite journal</ref> Androgens including testosterone enhance muscle growth. Testosterone also regulates the population of thromboxane A₂ receptors on megakaryocytes and platelets and hence platelet aggregation in humans.<ref name="pmid15820970">Template:Cite journal</ref><ref name="pmid7758179">Template:Cite journal</ref>

Adult testosterone effects are more clearly demonstrable in males than in females, but are likely important to both sexes. Some of these effects may decline as testosterone levels might decrease in the later decades of adult life.<ref>Template:Cite journal</ref>

The brain is also affected by this sexual differentiation;<ref name="pmid19403051" /> 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 disorders of androgen formation or androgen receptor function, to be associated with functional androgen receptors.<ref name="pmid11534997">Template:Cite journal</ref>

There are some differences between a male and female brain that may be due to different testosterone levels, one of them being size: the male human brain is, on average, larger.<ref name="pmid17544382">Template:Cite journal</ref>

Health effects

Testosterone does not appear to increase the risk of developing 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.<ref name="pmid19011298">Template:Cite book</ref><ref>Template:Cite journal</ref><ref>Template:Cite journal</ref>

Conflicting results have been obtained concerning the importance of testosterone in maintaining cardiovascular health.<ref name="pmid17285783">Template:Cite journal</ref><ref name="pmid19464009">Template:Cite journal</ref> 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 improved glycemic control.<ref name="pmid18488876">Template:Cite journal</ref>

High androgen levels are associated with menstrual cycle irregularities in both clinical populations and healthy women.Template:Better source needed<ref name="pmid17039468">Template:Cite journal</ref> There also can be effects in unusual hair growth, acne, weight gain, infertility, and sometimes even scalp hair loss. These effects are seen largely in women with polycystic ovary syndrome (PCOS). For women with PCOS, hormones like birth control pills can be used to help lessen the effects of this increased level of testosterone.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

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,<ref name="pmid16785599">Template:Cite journal</ref><ref name="pmid15383512">Template:Cite journal</ref><ref name="pmid15582279">Template:Cite journal</ref><ref name="pmid14745052">Template:Cite journal</ref> 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,<ref name="pmid8817730">Template:Cite journal</ref> where both hypo- and hypersecretion (deficient- and excessive-secretion) of circulating androgens have negative effects on cognition.

Immune system and inflammation

Testosterone deficiency is associated with an increased risk of metabolic syndrome, cardiovascular disease and mortality, which are also sequelae of chronic inflammation.<ref name="pmid30582096">Template:Cite journal</ref> Testosterone plasma concentration inversely correlates to multiple biomarkers of inflammation including CRP, interleukin 1 beta, interleukin 6, TNF alpha and endotoxin concentration, as well as leukocyte count.<ref name="pmid30582096" /> As demonstrated by a meta-analysis, substitution therapy with testosterone results in a significant reduction of inflammatory markers.<ref name="pmid30582096" /> These effects are mediated by different mechanisms with synergistic action.<ref name="pmid30582096" /> In androgen-deficient men with concomitant autoimmune thyroiditis, substitution therapy with testosterone leads to a decrease in thyroid autoantibody titres and an increase in thyroid's secretory capacity (SPINA-GT).<ref>Template:Cite journal</ref>

Medical use

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Testosterone is used as a medication for the treatment of male hypogonadism, gender dysphoria, and certain types of breast cancer.<ref name="AHFS2016" /><ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> This is known as hormone replacement therapy (HRT) or testosterone replacement therapy (TRT), which maintains serum testosterone levels in the normal range. Decline of testosterone production with age has led to interest in androgen replacement therapy.<ref name="pmid16985841">Template:Cite journal</ref> It is unclear if the use of testosterone for low levels due to aging is beneficial or harmful.<ref name="FDA2015">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

Testosterone is included in the World Health Organization's list of essential medicines, which are the most important medications needed in a basic health system.<ref name="WHO2015E">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> It is available as a generic medication.<ref name="AHFS2016" /> It can be administered as a cream or transdermal patch that is applied to the skin, by injection into a muscle, as a tablet that is placed in the cheek, or by ingestion.<ref name="AHFS2016" />

Common side effects from testosterone medication include acne, swelling, and breast enlargement in males.<ref name="AHFS2016" /> Serious side effects may include liver toxicity, heart disease (though a randomized trial found no evidence of major adverse cardiac events compared to placebo in men with low testosterone<ref>Template:Cite journal</ref>), and behavioral changes.<ref name="AHFS2016" /> Women and children who are exposed may develop virilization.<ref name="AHFS2016" /> It is recommended that individuals with prostate cancer not use the medication.<ref name="AHFS2016" /> It can cause harm if used during pregnancy or breastfeeding.<ref name="AHFS2016" />

2020 guidelines from the American College of Physicians support the discussion of testosterone treatment in adult men with age-related low levels of testosterone who have sexual dysfunction. They recommend yearly evaluation regarding possible improvement and, if none, to discontinue testosterone; physicians should consider intramuscular treatments, rather than transdermal treatments, due to costs and since the effectiveness and harm of either method is similar. Testosterone treatment for reasons other than possible improvement of sexual dysfunction may not be recommended.<ref name="ANN-20200106">Template:Cite journal</ref><ref name="MSCP-20200107">Template:Cite news</ref>

No immediate short term effects on mood or behavior were found from the administration of supraphysiologic doses of testosterone for 10 weeks on 43 healthy men.<ref name="pmid8637535">Template:Cite journal</ref>

Behavioural correlations

Sexual arousal

Testosterone levels follow a circadian rhythm that peaks early each day, regardless of sexual activity.<ref name="pmid5061159">Template:Cite journal</ref>

In women, correlations may exist between positive orgasm experience and testosterone levels. Studies have shown small or inconsistent correlations between testosterone levels and male orgasm experience, as well as sexual assertiveness in both sexes.<ref name="pmid19409392">Template:Cite journal</ref><ref>Template:Cite journal</ref>

Sexual arousal and masturbation in women produce small increases in testosterone concentrations.<ref name="pmid10367606">Template:Cite journal</ref> The plasma levels of various steroids significantly increase after masturbation in men and the testosterone levels correlate to those levels.<ref name="pmid135817">Template:Cite journal</ref>

Mammalian studies

Studies conducted in rats have indicated that their degree of sexual arousal is sensitive to reductions in testosterone. When testosterone-deprived rats were given medium levels of testosterone, their sexual behaviours (copulation, partner preference, etc.) resumed, but not when given low amounts of the same hormone. Therefore, these mammals may provide a model for studying clinical populations among humans with sexual arousal deficits such as hypoactive sexual desire disorder.<ref name="pmid20920505">Template:Cite journal</ref>

Every mammalian species examined demonstrated a marked increase in a male's testosterone level upon encountering a Template:Em female. The reflexive testosterone increases in male mice is related to the male's initial level of sexual arousal.<ref name="pmid16828762">Template:Cite journal</ref>

In non-human primates, it may be that testosterone in puberty stimulates sexual arousal, which allows the primate to increasingly seek out sexual experiences with females and thus creates a sexual preference for females.<ref name="pmid11534996">Template:Cite journal</ref> 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.).<ref name="pmid11534996"/>

In accordance with sperm competition theory, testosterone levels are shown to increase as a response to previously neutral stimuli when conditioned to become sexual in male rats.<ref name="pmid6665072">Template:Cite journal</ref> This reaction engages penile reflexes (such as erection and ejaculation) that aid in sperm competition when more than one male is present in mating encounters, allowing for more production of successful sperm and a higher chance of reproduction.

Males

In men, higher levels of testosterone are associated with periods of sexual activity.<ref name="pmid1275688">Template:Cite journal</ref><ref name=Roney_2003>Template:Cite journal</ref>

Men who watch a sexually explicit movie have an average increase of 35% in testosterone, peaking at 60–90 minutes after the end of the film, but no increase is seen in men who watch sexually neutral films.<ref>Template:Cite journal</ref> Men who watch sexually explicit films also report increased motivation and competitiveness, and decreased exhaustion.<ref name="pmid4001279">Template:Cite journal</ref> A link has also been found between relaxation following sexual arousal and testosterone levels.<ref name="pmid3602262">Template:Cite journal</ref>

Females

Androgens may modulate the physiology of vaginal tissue and contribute to female genital sexual arousal.<ref name="pmid12007897">Template:Cite journal</ref> Women's level of testosterone is higher when measured pre-intercourse vs. pre-cuddling, as well as post-intercourse vs. post-cuddling.<ref name="pmid17320881">Template:Cite journal</ref> 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.<ref name="pmid10665617">Template:Cite journal</ref>

When females have a higher baseline level of testosterone, they have higher increases in sexual arousal levels but smaller increases in testosterone, indicating a ceiling effect on testosterone levels in females. Sexual thoughts also change the level of testosterone but not the level of cortisol in the female body, and hormonal contraceptives may affect the variation in testosterone response to sexual thoughts.<ref name="pmid21185838">Template:Cite journal</ref>

Testosterone may prove to be an effective treatment in female sexual arousal disorders,<ref name="pmid15889125">Template:Cite journal</ref> and is available as a dermal patch. There is no FDA-approved androgen preparation for the treatment of androgen insufficiency; however, it has been used as an off-label use 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.<ref name="pmid15889125"/>

Romantic relationships

Falling in love has been linked with decreases in men's testosterone levels while mixed changes are reported for women's testosterone levels.<ref name="pmid31683520">Template:Cite journal</ref><ref name="pmid15177709">Template:Cite journal</ref> There has been speculation that these changes in testosterone result in the temporary reduction of differences in behavior between the sexes.<ref name="pmid15177709" /> However, the testosterone changes observed do not seem to be maintained as relationships develop over time.<ref name="pmid31683520" /><ref name="pmid15177709" />

Men who produce less testosterone are more likely to be in a relationship<ref name="pmid16621328">Template:Cite journal</ref> or married,<ref name = "Booth_Dabbs_1993"/> and men who produce more testosterone are more likely to divorce.<ref name = "Booth_Dabbs_1993">Template:Cite journal</ref> Marriage or commitment could cause a decrease in testosterone levels.<ref name=Mazur_Michalek_1998>Template:Cite journal</ref> 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.<ref name="pmid26190409">Template:Cite journal</ref> Married men who engage in bond-maintenance activities such as spending the day with their spouse 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 is more relevant to changes in testosterone levels.<ref name="pmid15219639">Template:Cite journal</ref>

Men who produce more testosterone are more likely to engage in extramarital sex.<ref name=Booth_Dabbs_1993/> Testosterone levels do not rely on physical presence of a partner; testosterone levels of men engaging in same-city and long-distance relationships are similar.<ref name="pmid16621328" /> Physical presence may be required for women who are in relationships for the testosterone–partner interaction, where same-city partnered women have lower testosterone levels than long-distance partnered women.<ref name="pmid17196592">Template:Cite journal</ref>

Fatherhood

Fatherhood decreases testosterone levels in men, suggesting that the emotions and behaviour tied to paternal care decrease testosterone levels. In humans and other species that utilize allomaternal care, paternal investment in offspring is beneficial to said offspring's survival because it allows the two parents to raise multiple children simultaneously. This increases the reproductive fitness of the parents because their offspring are more likely to survive and reproduce. Paternal care increases offspring survival due to increased access to higher quality food and reduced physical and immunological threats.<ref>Template:Cite journal</ref> This is particularly beneficial for humans since offspring are dependent on parents for extended periods of time and mothers have relatively short inter-birth intervals.<ref>Template:Cite journal</ref>

While the extent of paternal care varies between cultures, higher investment in direct child care has been seen to be correlated with lower average testosterone levels as well as temporary fluctuations.<ref>Template:Cite journal</ref> For instance, fluctuation in testosterone levels when a child is in distress has been found to be indicative of fathering styles. If a father's testosterone levels decrease in response to hearing their baby cry, it is an indication of empathizing with the baby. This is associated with increased nurturing behavior and better outcomes for the infant.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

Motivation

Testosterone levels play a major role in risk-taking during financial decisions.<ref name= "pmid19706398">Template:Cite journal</ref><ref name= "Apicella_2008">Template:Cite journal</ref> Higher testosterone levels in men reduce the risk of becoming or staying unemployed.<ref>Template:Cite journal</ref> Research has also found that heightened levels of testosterone and cortisol are associated with an increased risk of impulsive and violent criminal behavior.<ref>Template:Cite news</ref> On the other hand, elevated testosterone in men may increase their generosity, primarily to attract a potential mate.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref><ref>Template:Cite journal</ref>

Aggression and criminality Template:AnchorTemplate:Anchor

Template:See also Most studies support a link between adult criminality and testosterone.<ref name="Armstrong_2022">Template:Cite journal</ref><ref name="pmid1757712">Template:Cite journal</ref><ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref><ref>Template:Cite journal</ref> Nearly all studies of juvenile delinquency and testosterone are not significant. Most studies have found testosterone to be associated with behaviors or personality traits linked with antisocial behavior<ref name="pmid24631306">Template:Cite journal</ref> and alcoholism. Many studiesTemplate:Which have been undertaken on the relationship between more general aggressive behavior, and feelings, and testosterone. About half of studies have found a relationship and about half, no relationship.<ref name="isbn0-12-373612-9">Template:Cite book</ref> Studies have found that testosterone facilitates aggression by modulating vasopressin receptors in the hypothalamus.<ref>Template:Cite journal</ref>

There are two theories on the role of testosterone in aggression and competition.<ref name="Archer_2006">Template:Cite journal</ref> The first is the challenge hypothesis which states that testosterone would increase during puberty, thus facilitating reproductive and competitive behavior which would include aggression.<ref name="Archer_2006" /> It is therefore the challenge of competition among males that facilitates aggression and violence.<ref name="Archer_2006" /> Studies conducted have found direct correlation between testosterone and dominance, especially among the most violent criminals in prison who had the highest testosterone.<ref name="Archer_2006" /> The same research found fathers (outside competitive environments) had the lowest testosterone levels compared to other males.<ref name="Archer_2006" />

The second theory is similar and known as "evolutionary neuroandrogenic (ENA) theory of male aggression".<ref name = "Ellis_2015">Template:Cite journal</ref><ref>Template:Cite journal</ref> Testosterone and other androgens have evolved to masculinize a brain 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 to survive, attract and copulate with mates as much as possible.<ref name="Ellis_2015" /> The masculinization of the brain is not just mediated by testosterone levels at the adult stage, but also testosterone exposure in the womb. 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.<ref>Template:Cite journal</ref> Studies have found higher pre-natal testosterone or lower digit ratio to be correlated with higher aggression.<ref name="Bailey & Hurd 2005">Template:Cite journal
Lay summary: {{#invoke:citation/CS1|citation |CitationClass=web }}</ref><ref>Template:Cite journal</ref><ref>Template:Cite journal</ref><ref>Template:Cite journal</ref><ref>Template:Cite journal</ref>

The rise in testosterone during competition predicted aggression in males, but not in females.<ref>Template:Cite journal</ref> Subjects who interacted with handguns and an experimental game showed rise in testosterone and aggression.<ref>Template:Cite journal</ref> 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.<ref>Template:Cite journal</ref> Testosterone mediates attraction to cruel and violent cues in men by promoting extended viewing of violent stimuli.<ref>Template:Cite journal</ref> Testosterone-specific structural brain characteristic can predict aggressive behaviour in individuals.<ref>Template:Cite journal</ref>

The Annals of the New York Academy of Sciences has found anabolic steroid use (which increases testosterone) to be higher in teenagers, and this was associated with increased violence.<ref>Template:Cite journal</ref> Studies have found administered testosterone to increase verbal aggression and anger in some participants.<ref>Template:Cite journal</ref>

A few studies indicate that the testosterone derivative estradiol might play an important role in male aggression.<ref name="isbn0-12-373612-9"/><ref>Goldman D, Lappalainen J, Ozaki N. Direct analysis of candidate genes in impulsive disorders. In: Bock G, Goode J, eds. Genetics of Criminal and Antisocial Behaviour. Ciba Foundation Symposium 194. Chichester: John Wiley & Sons; 1996.</ref><ref>Template:Cite journal</ref><ref name="pmid9253313">Template:Cite journal</ref> Estradiol is known to correlate with aggression in male mice.<ref name="pmid18280561">Template:Cite journal</ref> Moreover, the conversion of testosterone to estradiol regulates male aggression in sparrows during breeding season.<ref name="pmid11016791">Template:Cite journal</ref> Rats who were given anabolic steroids that increase testosterone were also more physically aggressive to provocation as a result of "threat sensitivity".<ref>Template:Cite journal</ref>

The relationship between testosterone and aggression may also function indirectly, as it has been proposed that testosterone does not amplify tendencies towards aggression, but rather amplifies whatever tendencies will allow an individual to maintain social status when challenged. In most animals, aggression is the means of maintaining social status. However, humans have multiple ways of obtaining status. This could explain why some studies find a link between testosterone and pro-social behaviour, if pro-social behaviour is rewarded with social status. Thus the link between testosterone and aggression and violence is due to these being rewarded with social status.<ref name="pmid30619017">Template:Cite journal</ref> The relationship may also be one of a "permissive effect" whereby testosterone does elevate aggression levels, but only in the sense of allowing average aggression levels to be maintained; chemically or physically castrating the individual will reduce aggression levels (though not eliminate them) but the individual only needs a small-level of pre-castration testosterone to have aggression levels to return to normal, which they will remain at even if additional testosterone is added. Testosterone may also simply exaggerate or amplify existing aggression; for example, chimpanzees who receive testosterone increases become more aggressive to chimps lower than them in the social hierarchy, but will still be submissive to chimps higher than them. Testosterone thus does not make the chimpanzee indiscriminately aggressive, but instead amplifies his pre-existing aggression towards lower-ranked chimps.<ref>Template:Cite book</ref>

In humans, testosterone appears more to promote status-seeking and social dominance than simply increasing physical aggression. When controlling for the effects of belief in having received testosterone, women who have received testosterone make fairer offers than women who have not received testosterone.<ref name="pmid21616702">Template:Cite journal</ref>

Fairness

Testosterone might encourage fair behavior. For one study, subjects took part in a behavioral experiment where the distribution of a real amount of money was decided. The rules allowed both fair and unfair offers. The negotiating partner could subsequently accept or decline the offer. The fairer the offer, the less probable a refusal by the negotiating partner. If no agreement was reached, neither party earned anything. Test subjects with an artificially enhanced testosterone level generally made better, fairer offers than those who received placebos, thus reducing the risk of a rejection of their offer to a minimum. Two later studies have empirically confirmed these results.<ref name="pmid19997098">Template:Cite journal</ref><ref>Template:Cite journal</ref><ref>Template:Cite journal</ref> However men with high testosterone were significantly 27% less generous in an ultimatum game.<ref>Template:Cite journal</ref>

Biological activity

Free testosterone

Lipophilic hormones (soluble in lipids but not in water), such as steroid hormones, including testosterone, are transported in water-based blood plasma through specific and non-specific proteins. Specific proteins include sex hormone-binding globulin (SHBG), which binds testosterone, dihydrotestosterone, estradiol, and other sex steroids. Non-specific binding proteins include albumin. The part of the total hormone concentration that is not bound to its respective specific carrier protein is the free part. As a result, testosterone which is not bound to SHBG is called free testosterone. Only the free amount of testosterone can bind to an androgenic receptor, which means it has biological activity.<ref name="pmid33553985">Template:Cite journal</ref> While a significant portion of testosterone is bound to SHBG, a small fraction of testosterone (1%-2%)<ref name="synevo"/> is bound to albumin and the binding of testosterone to albumin is weak and can be reversed easily;<ref name="pmid30842823"/><ref name="pmid28673039"/> as such, both albumin-bound and unbound testosterone are considered to be bioavailable testosterone.<ref name="pmid30842823"/><ref name="pmid28673039"/> This binding plays an important role in regulating the transport, tissue delivery, bioactivity, and metabolism of testosterone.<ref name="pmid28673039">Template:Cite journal</ref><ref name="pmid30842823">Template:Cite journal</ref> At the tissue level, testosterone dissociates from albumin and quickly diffuses into the tissues. The percentage of testosterone bound to SHBG is lower in men than in women. Both the free fraction and the one bound to albumin are available at the tissue level (their sum constitutes the bioavailable testosterone), while SHBG effectively and irreversibly inhibits the action of testosterone.<ref name="synevo">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> The relationship between sex steroids and SHBG in physiological and pathological conditions is complex, as various factors may influence the levels of plasma SHBG, affecting bioavailability of testosterone.<ref name="pmid4062218">Template:Cite journal</ref><ref name="pmid33139661">Template:Cite journal</ref><ref name="pmid34197576">Template:Cite journal</ref>

Steroid hormone activity

The effects of testosterone in humans and other vertebrates occur by way of multiple mechanisms: by activation of the androgen receptor (directly or as dihydrotestosterone), and by conversion to estradiol and activation of certain estrogen receptors.<ref name="pmid18406296">Template:Cite journal</ref><ref name="pmid11511858">Template:Cite journal</ref> Androgens such as testosterone have also been found to bind to and activate membrane androgen receptors.<ref name="pmid19931639">Template:Cite journal</ref><ref name="pmid25257522">Template:Cite journal</ref><ref name="pmid23746222">Template:Cite journal</ref>

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 5α-dihydrotestosterone (5α-DHT) by the cytoplasmic enzyme 5α-reductase. 5α-DHT binds to the same androgen receptor even more strongly than testosterone, so that its androgenic potency is about 5 times that of T.<ref name="pmid3762019">Template:Cite journal</ref> 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).<ref>Template:Cite book</ref>Template:Failed verification 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.<ref name="pmid18195084">Template:Cite journal</ref>

Neurosteroid activity

Testosterone, via its active metabolite 3α-androstanediol, is a potent positive allosteric modulator of the GABA_A receptor.<ref name="KohtzFrye2012">Template:Cite book</ref>

Testosterone has been found to act as an antagonist of the TrkA and p75^NTR, receptors for the neurotrophin nerve growth factor (NGF), with high affinity (around 5 nM).<ref name="pmid26908835">Template:Cite journal</ref><ref name="pmid21541365">Template:Cite journal</ref><ref name="pmid23074265">Template:Cite journal</ref> In contrast to testosterone, DHEA and DHEA sulfate have been found to act as high-affinity agonists of these receptors.<ref name="pmid26908835" /><ref name="pmid21541365" /><ref name="pmid23074265" />

Testosterone is an antagonist of the sigma-1 receptor (K_i = 1,014 or 201 nM).<ref name="AlbayrakHashimoto2017">Template:Cite book</ref> However, the concentrations of testosterone required for binding the receptor are far above even total circulating concentrations of testosterone in adult males (which range between 10 and 35 nM).<ref name="Regitz-Zagrosek2012">Template:Cite book</ref>

Biochemistry

File:Steroidogenesis.svg

Template:Vanchor: Human steroidogenesis, showing testosterone near bottom<ref name="HäggströmRichfield2014">Template:Cite journal</ref>

Biosynthesis

Like other steroid hormones, testosterone is derived from cholesterol Template:Crossreference.<ref name="pmid1307739">Template:Cite journal</ref> The first step in the biosynthesis involves the oxidative cleavage of the side-chain of cholesterol by cholesterol side-chain cleavage enzyme (P450scc, CYP11A1), 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 CYP17A1 (17α-hydroxylase/17,20-lyase) enzyme in the endoplasmic reticulum to yield a variety of C₁₉ steroids.<ref name="pmid3535074">Template:Cite journal</ref> In addition, the 3β-hydroxyl group is oxidized by 3β-hydroxysteroid dehydrogenase to produce androstenedione. In the final and rate limiting step, the C17 keto group androstenedione is reduced by 17β-hydroxysteroid dehydrogenase to yield testosterone.

The largest amounts of testosterone (>95%) are produced by the testes in men,<ref name="pmid3549275"/> while the adrenal glands account for most of the remainder. Testosterone is also synthesized in far smaller total quantities in women by the adrenal glands, thecal cells of the ovaries, and, during pregnancy, by the placenta.<ref name="pmid15507105">Template:Cite journal</ref> In the testes, testosterone is produced by the Leydig cells.<ref name="pmid58744">Template:Cite journal</ref> The male generative glands also contain Sertoli cells, which require testosterone for spermatogenesis. Like most hormones, testosterone is supplied to target tissues in the blood where much of it is transported bound to a specific plasma protein, sex hormone-binding globulin (SHBG).

Regulation

File:Hypothalamus pituitary testicles axis.png

Template:Vanchor. Hypothalamic–pituitary–testicular 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 17β-hydroxysteroid dehydrogenase.<ref name="isbn0-9627422-7-9">Template:Cite book</ref>

The amount of testosterone synthesized is regulated by the hypothalamic–pituitary–testicular axis Template:Crossreference.<ref name="pmid1377467">Template:Cite journal</ref> 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 may include:

• Age: Testosterone levels gradually reduce as men age.<ref name="pmid25009850">Template:Cite book</ref><ref name="pmid24407185">Template:Cite journal</ref> This effect is sometimes referred to as andropause or late-onset hypogonadism.<ref name="pmid24793989">Template:Cite journal</ref>
• Exercise: Resistance training increases testosterone levels acutely,<ref name="Vingren_2010">Template:Cite journal</ref> however, in older men, that increase can be avoided by protein ingestion.<ref name="pmid18455389">Template:Cite journal</ref> Endurance training in men may lead to lower testosterone levels.<ref name="pmid16268050">Template:Cite journal</ref>
• Nutrients: Vitamin A deficiency may lead to sub-optimal plasma testosterone levels.<ref name="pmid12141930">Template:Cite journal</ref> The secosteroid vitamin D in levels of 400–1000 IU/d (10–25 μg/d) raises testosterone levels.<ref name="pmid21154195">Template:Cite journal</ref> Zinc deficiency lowers testosterone levels<ref name="pmid8875519">Template:Cite journal</ref> but over-supplementation has no effect on serum testosterone.<ref name="pmid17882141">Template:Cite journal</ref> There is limited evidence that low-fat diets may reduce total and free testosterone levels in men.<ref>Template:Cite journal</ref>
• Weight loss: Reduction in weight may result in an increase in testosterone levels. Fat cells synthesize the enzyme aromatase, which converts testosterone, the male sex hormone, into estradiol, the female sex hormone.<ref name="pmid21849026">Template:Cite journal</ref> However no clear association between body mass index and testosterone levels has been found.<ref name="pmid19889752">Template:Cite journal</ref>
• Miscellaneous: Sleep: (REM sleep) increases nocturnal testosterone levels.<ref name="pmid18519168">Template:Cite journal</ref>
• Behavior: Dominance challenges can, in some cases, stimulate increased testosterone release in men.<ref name="pmid10603287">Template:Cite journal</ref>
• Foods: Natural or man-made antiandrogens including spearmint tea reduce testosterone levels.<ref name="pmid17310494">Template:Cite journal</ref><ref name="pmid18804513">Template:Cite journal</ref><ref name="pmid19585478">Template:Cite journal</ref> Licorice can decrease the production of testosterone and this effect is greater in females.<ref>Template:Cite journal</ref>

Distribution

The plasma protein binding of testosterone is 98.0 to 98.5%, with 1.5 to 2.0% free or unbound.<ref name="NieschlagBehre2012">Template:Cite book</ref> It is bound 65% to sex hormone-binding globulin (SHBG) and 33% bound weakly to albumin.<ref name="pmid4044776">Template:Cite journal</ref>

Metabolism

Both testosterone and 5α-DHT are metabolized mainly in the liver.<ref name="MelmedPolonsky2015">Template:Cite book</ref><ref name="Becker2001">Template:Cite book</ref> Approximately 50% of testosterone is metabolized via conjugation into testosterone glucuronide and to a lesser extent testosterone sulfate by glucuronosyltransferases and sulfotransferases, respectively.<ref name="MelmedPolonsky2015" /> An additional 40% of testosterone is metabolized in equal proportions into the 17-ketosteroids androsterone and etiocholanolone via the combined actions of 5α- and 5β-reductases, 3α-hydroxysteroid dehydrogenase, and 17β-HSD, in that order.<ref name="MelmedPolonsky2015" /><ref name="Becker2001" /><ref name="WeckerWatts2009">Template:Cite book</ref> Androsterone and etiocholanolone are then glucuronidated and to a lesser extent sulfated similarly to testosterone.<ref name="MelmedPolonsky2015" /><ref name="Becker2001" /> The conjugates of testosterone and its hepatic metabolites are released from the liver into circulation and excreted in the urine and bile.<ref name="MelmedPolonsky2015" /><ref name="Becker2001" /><ref name="WeckerWatts2009" /> Only a small fraction (2%) of testosterone is excreted unchanged in the urine.<ref name="Becker2001" />

In the hepatic 17-ketosteroid pathway of testosterone metabolism, testosterone is converted in the liver by 5α-reductase and 5β-reductase into 5α-DHT and the inactive 5β-DHT, respectively.<ref name="MelmedPolonsky2015" /><ref name="Becker2001" /> Then, 5α-DHT and 5β-DHT are converted by 3α-HSD into 3α-androstanediol and 3α-etiocholanediol, respectively.<ref name="MelmedPolonsky2015" /><ref name="Becker2001" /> Subsequently, 3α-androstanediol and 3α-etiocholanediol are converted by 17β-HSD into androsterone and etiocholanolone, which is followed by their conjugation and excretion.<ref name="MelmedPolonsky2015" /><ref name="Becker2001" /> 3β-Androstanediol and 3β-etiocholanediol can also be formed in this pathway when 5α-DHT and 5β-DHT are acted upon by 3β-HSD instead of 3α-HSD, respectively, and they can then be transformed into epiandrosterone and epietiocholanolone, respectively.<ref name="pmid20186052">Template:Cite journal</ref><ref name="HorskyPresl2012">Template:Cite book</ref> A small portion of approximately 3% of testosterone is reversibly converted in the liver into androstenedione by 17β-HSD.<ref name="WeckerWatts2009" />

In addition to conjugation and the 17-ketosteroid pathway, testosterone can also be hydroxylated and oxidized in the liver by cytochrome P450 enzymes, including CYP3A4, CYP3A5, CYP2C9, CYP2C19, and CYP2D6.<ref name="Zhou2016">Template:Cite book</ref> 6β-Hydroxylation and to a lesser extent 16β-hydroxylation are the major transformations.<ref name="Zhou2016" /> The 6β-hydroxylation of testosterone is catalyzed mainly by CYP3A4 and to a lesser extent CYP3A5 and is responsible for 75 to 80% of cytochrome P450-mediated testosterone metabolism.<ref name="Zhou2016" /> In addition to 6β- and 16β-hydroxytestosterone, 1β-, 2α/β-, 11β-, and 15β-hydroxytestosterone are also formed as minor metabolites.<ref name="Zhou2016" /><ref name="isbn0-3870-8012-0">Template:Cite book</ref> Certain cytochrome P450 enzymes such as CYP2C9 and CYP2C19 can also oxidize testosterone at the C17 position to form androstenedione.<ref name="Zhou2016" />

Two of the immediate metabolites of testosterone, 5α-DHT and estradiol, are biologically important and can be formed both in the liver and in extrahepatic tissues.<ref name="Becker2001" /> Approximately 5 to 7% of testosterone is converted by 5α-reductase into 5α-DHT, with circulating levels of 5α-DHT about 10% of those of testosterone, and approximately 0.3% of testosterone is converted into estradiol by aromatase.<ref name="pmid3549275"/><ref name="Becker2001" /><ref name="pmid8092979">Template:Cite journal</ref><ref name="pmid12428207">Template:Cite journal</ref> 5α-Reductase is highly expressed in the male reproductive organs (including the prostate gland, seminal vesicles, and epididymides),<ref name="Noakes2009">Template:Cite book</ref> skin, hair follicles, and brain<ref name="NieschlagBehre2004">Template:Cite book</ref> and aromatase is highly expressed in adipose tissue, bone, and the brain.<ref name="Parl2000">Template:Cite book</ref><ref name="NormanHenry2014">Template:Cite book</ref> As much as 90% of testosterone is converted into 5α-DHT in so-called androgenic tissues with high 5α-reductase expression,<ref name="WeckerWatts2009" /> and due to the several-fold greater potency of 5α-DHT as an AR agonist relative to testosterone,<ref name="MozayaniRaymon2011">Template:Cite book</ref> it has been estimated that the effects of testosterone are potentiated 2- to 3-fold in such tissues.<ref name="pmid7626464">Template:Cite journal</ref>

Levels

Total levels of testosterone in the body have been reported as 264 to 916 ng/dL (nanograms per deciliter) in non-obese European and American men age 19 to 39 years,<ref name="pmid28324103">Template:Cite journal</ref> while mean testosterone levels in adult men have been reported as 630 ng/dL.<ref name="Sperling2014" /> Although commonly used as a reference range,<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> some physicians have disputed the use of this range to determine hypogonadism.<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref> Several professional medical groups have recommended that 350 ng/dL generally be considered the minimum normal level,<ref>Template:Cite journal</ref> which is consistent with previous findings.<ref>Template:Cite journal</ref>Template:Primary source inlineTemplate:Medical citation needed Levels of testosterone in men decline with age.<ref name="pmid28324103" /> In women, mean levels of total testosterone have been reported to be 32.6 ng/dL.<ref name="Camacho2012">Template:Cite book</ref><ref name="pmid15251757">Template:Cite journal</ref> In women with hyperandrogenism, mean levels of total testosterone have been reported to be 62.1 ng/dL.<ref name="Camacho2012" /><ref name="pmid15251757" />

Total testosterone levels in males throughout life

Life stage	Tanner stage	Age range	Mean age	Levels range	Mean levels
Child	Stage I	<10 years	–	<30 ng/dL	5.8 ng/dL
Puberty	Stage II	10–14 years	12 years	<167 ng/dL	40 ng/dL
	Stage III	12–16 years	13–14 years	21–719 ng/dL	190 ng/dL
	Stage IV	13–17 years	14–15 years	25–912 ng/dL	370 ng/dL
	Stage V	13–17 years	15 years	110–975 ng/dL	550 ng/dL
Adult	–	≥18 years	–	250–1,100 ng/dL	630 ng/dL
Sources: <ref name="BajajBerman2011">Template:Cite book</ref><ref name="Styne2016">Template:Cite book</ref><ref name="Sperling2014">Template:Cite book</ref><ref name="PaganaPagana2014">Template:Cite book</ref><ref name="HospitalEngorn2014">Template:Cite book</ref>

Measurement

In measurements of testosterone in blood samples, different assay techniques can yield different results.<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref> Immunofluorescence assays exhibit considerable variability in quantifying testosterone concentrations in blood samples due to the cross-reaction of structurally similar steroids, leading to overestimating the results. In contrast, the liquid chromatography/tandem mass spectrometry method is more desirable: it offers superior specificity and precision, making it a more suitable choice for this application.<ref name="pmid38311999">Template:Cite journal</ref>

Testosterone's bioavailable concentration is commonly determined using the Vermeulen calculation or more precisely using the modified Vermeulen method,<ref name="Jong">Template:Cite journal</ref><ref>Template:Cite journal</ref> which considers the dimeric form of sex hormone-binding globulin.<ref name="PDB">Template:Cite journal</ref>

Both methods use chemical equilibrium to derive the concentration of bioavailable testosterone: in circulation, testosterone has two major binding partners, albumin (weakly bound) and sex hormone-binding globulin (strongly bound). These methods are described in detail in the accompanying figure.

• Dimeric SHBG.png

  Dimeric sex hormone-binding globulin with its testosterone ligands

• Method for determining testosterone.png

  Two methods for determining the concentration of bioavailable testosterone

Distribution

Testosterone has been detected at variably higher and lower levels among men of various nations and from various backgrounds, explanations for the causes of this have been relatively diverse.<ref>Template:Cite journal</ref><ref>Template:Cite book</ref>

People from nations of the Eurasian Steppe and Central Asia, such as Mongolia, Kyrgyzstan and Uzbekistan, have consistently been detected to have had significantly elevated levels of testosterone,<ref name="antipufaadmin">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> while people from Central European and Baltic nations such as the Czech Republic, Slovakia, Latvia and Estonia have been found to have had significantly decreased levels of testosterone.<ref name="antipufaadmin"/>

The region with the highest-ever tested levels of testosterone is Chita, Russia, the people group with the highest ever tested levels of testosterone were the Yakuts.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

History and production

File:Lavoslav Ružićka 1939.jpg

Nobel Prize winner, Leopold Ruzicka of Ciba, a pharmaceutical industry giant that synthesized testosterone

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 (1803–1861).<ref name="Berthold_1849">Template:Cite journal</ref> Research on the action of testosterone received a brief boost in 1889, when the Harvard professor Charles-Édouard Brown-Séquard (1817–1894), then in Paris, self-injected subcutaneously a "rejuvenating elixir" consisting of an extract of dog and guinea pig testicle. He reported in The Lancet that his vigor and feeling of well-being were markedly restored but the effects were transient,<ref name="Brown-Sequard_1889">Template:Cite journal</ref> and Brown-Séquard's hopes for the compound were dashed. Suffering the ridicule of his colleagues, he abandoned his work on the mechanisms and effects of androgens in human beings.

In 1927, the University of Chicago's Professor of Physiologic Chemistry, Fred C. Koch, established easy access to a large source of bovine testicles – the Chicago stockyards – and recruited students willing to endure the tedious work of extracting their isolates. In that year, Koch and his student, Lemuel McGee, derived 20 mg of a substance from a supply of 40 pounds of bovine testicles that, when administered to castrated roosters, pigs and rats, re-masculinized them.<ref name="Gallagher_Koch_1929">Template:Cite journal</ref> The group of Ernst Laqueur at the University of Amsterdam purified testosterone from bovine testicles in a similar manner in 1934, but the isolation of the hormone from animal tissues in amounts permitting serious study in humans was not feasible until three European pharmaceutical giants – Schering (Berlin, Germany), Organon (Oss, Netherlands) and Ciba – 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)".<ref name="David_1935">Template:Cite journal</ref> 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, at the Chemisches Institut of Technical University in Gdańsk.<ref name="Butenandt_1935a">Template:Cite journal</ref><ref name="pmid11176375">Template:Cite journal</ref>

The chemical synthesis of testosterone from cholesterol was achieved in August that year by Butenandt and Hanisch.<ref name="Butenandt_1935b">Template:Cite journal</ref> Only a week later, the Ciba group in Zurich, Leopold Ruzicka (1887–1976) and A. Wettstein, published their synthesis of testosterone.<ref name="Ruzicka_1935">Template:Cite journal</ref> These independent partial syntheses of testosterone from a cholesterol base earned both Butenandt and Ruzicka the joint 1939 Nobel Prize in Chemistry.<ref name="pmid11176375"/><ref name="pmid7817189">Template:Cite journal</ref> Testosterone was identified as 17β-hydroxyandrost-4-en-3-one (C₁₉H₂₈O₂), a solid polycyclic alcohol with a hydroxyl group at the 17th carbon atom. This also made it obvious that additional modifications on the synthesized testosterone could be made, i.e., esterification and alkylation.

The partial synthesis in the 1930s of abundant, potent testosterone 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<ref name="Kenyon _1940">Template:Cite journal</ref> 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",<ref name="pmid10443899">Template:Cite journal</ref> and work during this period progressed quickly.<ref name = "de Kruif_1945" >Template:Cite book</ref>

Like other androsteroids, testosterone is manufactured industrially from microbial fermentation of plant cholesterol (e.g., from soybean oil). In the early 2000s, the steroid market weighed around one million tonnes and was worth $10 billion, making it the 2nd largest biopharmaceutical market behind antibiotics.<ref>Template:Cite journal</ref>

Other species

Testosterone is observed in most vertebrates. Testosterone and the classical nuclear androgen receptor first appeared in gnathostomes (jawed vertebrates).<ref name="pmid19456336">Template:Cite journal</ref> Agnathans (jawless vertebrates) such as lampreys do not produce testosterone but instead use androstenedione as a male sex hormone.<ref name="pmid17931674">Template:Cite journal</ref> Fish make a slightly different form called 11-ketotestosterone.<ref name="isbn0-87893-617-3">Template:Cite book</ref> Its counterpart in insects is ecdysone.<ref name="De_Loof_2006">Template:Cite journal</ref> The presence of these ubiquitous steroids in a wide range of animals suggest that sex hormones have an ancient evolutionary history.<ref name="Mechoulam_1984">Template:Cite journal</ref>

See also

• List of androgens/anabolic steroids
• List of human hormones

Further reading

• Template:Cite book
• Template:Cite journal
• Template:Cite journal