Testosterone

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Testosterone
Testosteron.svg
Testosterone-from-xtal-3D-balls.png
Systematic (IUPAC) name
(8R,9S,10R,13S,14S,17S)- 17-hydroxy-10,13-dimethyl- 1,2,6,7,8,9,11,12,14,15,16,17- dodecahydrocyclopenta[a]phenanthren-3-one
Clinical data
Trade names Androderm, Delatestryl, Intrinsa
AHFS/Drugs.com monograph
MedlinePlus a614041
Licence data EMA:Link, US FDA:link
Pregnancy
category
  • US: X (Contraindicated)
Legal status
Routes of
administration		 Intramuscular injection, transdermal (cream, gel, or patch), sub-'Q' pellet
Pharmacokinetic data
Bioavailability Low (due to extensive first pass metabolism)
Metabolism Liver, testis and prostate
Biological half-life 2–4 hours
Excretion Urine (90%), feces (6%)
Identifiers
CAS Number 58-22-0 YesY
Template:CAS (propionate ester)
ATC code G03BA03 (WHO)
PubChem CID: 6013
IUPHAR/BPS 2858
DrugBank DB00624 YesY
ChemSpider 5791 YesY
UNII 3XMK78S47O YesY
KEGG D00075 YesY
ChEBI CHEBI:17347 YesY
ChEMBL CHEMBL386630 YesY
Chemical data
Formula C19H28O2
Molecular mass 288.42
Physical data
Melting point 155 °C (311 °F)
Specific rotation +110.2°
SEC Combust −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 the testicles 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, 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 7–8 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]

Health effects

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.

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

The prenatal androgen effects occur during two different stages. Between 4 and 6 weeks of the gestation.

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

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 4–6 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] It is interesting to note that the male brain is masculinized by the aromatization of testosterone into estrogen, which crosses the blood–brain 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

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

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.

Adult

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

Cancer prevention and health risks

  • 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

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 relationship—this 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. long-distance), men have similar testosterone levels across the board.[32] 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.[37]

Fatherhood

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

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

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

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 60–90 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

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

Testosterone levels play a major role in risk-taking during financial decisions.[61][62]

Brain

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

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]

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.[76][77][78] However men with high testosterone was significantly 27% less generous in an ultimatum game while men with the lowest testosterone were 560% more generous.[79] 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.[80] Studies have also found administered testosterone to increase verbal aggression and anger in some participants.[81]

Estradiol is known to correlate with aggression in male mice.[82] Moreover, the conversion of testosterone to estradiol regulates male aggression in sparrows during breeding season.[83] Rats who were given anabolic steroids that increase testosterone were also more physical aggressive to provocation as a result of "threat sensitivity".[84]

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 & competition.[85] The first one is the Challenge hypothesis which states that testosterone would increase during puberty thus facilitating reproductive and competitive behaviour which would include aggression.[85] Thus it is the challenge of competition among males of the species that facilitates aggression and violence.[85] Studies conducted have found direct correlation between testosterone and dominance especially among the most violent criminals in prison who had the highest testosterone levels.[85] The same research also found dads (those outside competitive environments) had the lowest testosterone levels compared to other males.[85] The second theory is also similar and is known as Evolutionary neuroandrogenic (ENA) theory of male aggression[86][87] 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.[88] 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.[89] Studies have also found higher pre-natal testosterone or lower digit ratio to be correlated with higher aggression in males[90][91][92][93][94]

The rise in testosterone levels during competition predicted aggression in males but not in female.[95] Subjects who interacted with hand guns and an experimental game showed rise in testosterone and aggression.[96] 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.[97] 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.[98] Testosterone mediates attraction to cruel and violent cues in men by promoting extended viewing of violent stimuli.[99] Testosterone specific structural brain characteristic can predict aggressive behaviour in individuals.[100]

Medical uses

The primary use of testosterone is the treatment of males with too little or no natural testosterone production—males 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.[101]

Low levels due to aging

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.[102] The FDA has required that labels on testosterone include warning information about the possibility of an increased risk of heart attacks and stroke.[102]

Insufficiency

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.[103] 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.[104][105]

Women

Testosterone supplementation is effective in the short term for hypoactive sexual desire disorder.[106] Its long term safety, however, is unclear.[106]

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.[106] It is also not usually recommended for improving cognition, the risk of heart disease, bone strength or for generalized well being.[106]

Other

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.[107]

To take advantage of its virilizing effects, testosterone is often administered to transgender men as part of the hormone replacement therapy,[108] 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.[109] 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.[110]

Males with borderline testosterone levels and sexual dysfunction may benefit from a trial of testosterone.[111]

Non-medical use

Athletics

Testosterone can be used by an athlete in order to improve performance, but it is considered to be a form of doping in most sports. There are several application methods for testosterone, including intramuscular injections, transdermal gels and patches, and implantable pellets. 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.[112] 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.[113]

Detection of abuse

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.[114][115][116][117]

Adverse effects

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.[102] The FDA has required that testosterone pharmaceutical labels include warning information about the possibility of an increased risk of heart attacks and stroke.[102]

Cardiovascular disease

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.[118] In addition, an increase of 30% in deaths and heart attacks in older men has been reported.[119] 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.[120] On January 31, 2014, reports of strokes, heart attacks, and deaths in men taking FDA-approved testosterone-replacement led the Food and Drug Administration (FDA) to announce that it would be investigating the issue.[121] 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).[122][123][124] The FDA now requires warnings in the drug labeling of all approved testosterone products regarding deep vein thrombosis and pulmonary embolism.[125]

Up to the year 2010, studies had not shown any effect on the risk of death, prostate cancer or cardiovascular disease;[27][126] more recent studies, however, do raise concerns.[127] 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."[119]

Cancer

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.[128] Nevertheless, physicians are cautioned about the cancer risk associated with testosterone supplementation.[129]

Ethnic groups have different rates of prostate cancer.[130] Differences in sex hormones, including testosterone, have been suggested as an explanation for these differences.[130] 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.[131]

Other

Other significant adverse effects of testosterone supplementation include acceleration of pre-existing prostate cancer growth in individuals who have undergone androgen deprivation; increased hematocrit, which can require venipuncture in order to treat; and, exacerbation of sleep apnea.[132] 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.[133] Exogenous testosterone may also cause suppression of spermatogenesis, leading to, in some cases, infertility.[134] It is recommended that physicians screen for prostate cancer with a digital rectal exam and prostate-specific antigen (PSA) level before starting therapy, and monitor PSA and hematocrit levels closely during therapy.[135]

Pregnancy and breast feeding

Testosterone is contraindicated in pregnancy and not recommended during breastfeeding.[136]

Biochemistry

Biosynthesis

Human steroidogenesis, showing testosterone near bottom.

Like other steroid hormones, testosterone is derived from cholesterol (see figure to the left).[137] 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.[138] In addition, the 3-hydroxyl group is oxidized by 3-β-HSD to produce androstenedione. In the final and rate limiting step, the C-17 keto group androstenedione is reduced by 17-β 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[139] in both sexes. In the testes, testosterone is produced by the Leydig cells.[140] 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

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 17-β hydroxysteroid dehydrogenase.[141]

The amount of testosterone synthesized is regulated by the hypothalamic–pituitary–testicular axis (see figure to the right).[142] 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.[143]
  • The secosteroid vitamin D in levels of 400–1000 IU/d (10–25 µg/d) raises testosterone levels.[144]
  • Zinc deficiency lowers testosterone levels[145] but over supplementation has no effect on serum testosterone.[146]
  • Vitamin A deficiency may lead to sub-optimal plasma Testosterone levels.[147]
  • Dominance challenges can, in some cases, stimulate increased testosterone release in men.[148]
  • Aging reduces testosterone release.[149]
  • Hypogonadism
  • Sleep (REM dream) increases nocturnal testosterone levels.[150]
  • Resistance training increases testosterone levels,[151] however, in older men, that increase can be avoided by protein ingestion.[152]
  • Licorice can decrease the production of testosterone and this effect is greater in females.[153]
  • Natural or man-made antiandrogens including spearmint tea reduce testosterone levels.[154][155][156]
  • Posing in high-power nonverbal displays through open, expansive postures can increase testosterone levels.[157]

Metabolism

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 5α-dihydrotestosterone (DHT) by the cytochrome P450 enzyme 5α-reductase,[158] an enzyme highly expressed in male sex organs and hair follicles.[1] Approximately 0.3% of testosterone is converted into estradiol by aromatase (CYP19A1)[159] 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.[160]

Mechanism of action

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.[161][162] Androgens such as testosterone have also been found to bind to and activate membrane androgen receptors.[163][164][165]

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 (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.[166] 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

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

Some drugs indirectly target testosterone as a way of treating certain conditions. For example, 5-alpha-reductase inhibitors such as finasteride inhibit the conversion of testosterone into dihydrotestosterone (DHT), a metabolite more potent than testosterone.[167] 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.[167] 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.[168] 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

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),[169] oral, buccal,[170] transdermal skin patches, transdermal creams, gels,[171][172] and implantable pellets.[173] Roll-on methods and nasal sprays are currently under development.

History

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 (1803–1861).[174] 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,[175] 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, remasculinized them.[176] 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 giants—Schering (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)".[177] 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.[178][179]

The chemical synthesis of testosterone from cholesterol was achieved in August that year by Butenandt and Hanisch.[180] Only a week later, the Ciba group in Zurich, Leopold Ruzicka (1887–1976) and A. Wettstein, published their synthesis of testosterone.[181] These independent partial syntheses of testosterone from a cholesterol base earned both Butenandt and Ruzicka the joint 1939 Nobel Prize in Chemistry.[179][182] 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[183] 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",[184] and work during this period progressed quickly. Research in this golden age proved that this newly synthesized compound—testosterone—or rather family of compounds (for many derivatives were developed from 1940 to 1960), was a potent multiplier of muscle, strength, and well-being.[185]

Society and culture

A number of lawsuits are currently underway against testosterone manufacturers, alleging a significantly increased rate of stroke and heart attack in elderly men who use testosterone supplements.[186]

References

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