testosterone Testosterone is a steroid hormone from the androgen group and is found in mammals, reptiles,[1] birds, [2] and

other vertebrates. In mammals, testosterone is primarily secreted in the testes of males and the ovaries of females, although 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.[3] In addition, testosterone is essential for health and well-being[4] as well as the prevention of osteoporosis.[5] On average, an adult human male body produces about ten times more testosterone than an adult human female body, but females are more sensitive to the hormone.[6] Testosterone is observed in most vertebrates. Fish make a slightly different form called 11ketotestosterone.[7] Its counterpart in insects is ecdysone.[8] These ubiquitous steroids suggest that sex hormones have an ancient evolutionary history.

Efek fisiologis
In general, androgens promote protein synthesis and growth of those tissues with androgen receptors. Testosterone effects can be classified as virilizing and anabolic, although the distinction is somewhat artificial, as many of the effects can be considered both. Testosterone is anabolic, meaning it builds up bone and muscle mass. 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 the beard and axillary hair. Many of these fall into the category of male secondary sex characteristics. Testosterone effects can also be classified by the age of usual occurrence. For postnatal effects in both males and females, these are mostly dependent on the levels and duration of circulating free testosterone.

[edit] Prenatal
the prenatal androgen effects occur during two different stages. Between 4 and 6 weeks of the gestation. Genital virilization (midline fusion, phallic urethra, scrotal thinning and rugation, phallic enlargement); although the role of testosterone is far smaller than that of Dihydrotestosterone. Development of prostate and seminal vesicles During the 2nd trimester androgen level is associated with Gender identity[10] This period effects the femininization or masculinization of the fetus and is a better predictor of an adult's femininity or masculinity than an adult's own levels. In other words, an adult's own testosterone level influences behavior less than the mother's during pregnancy.[11]

[edit] 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 46 months of age.[12][13] 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.[14][citation needed] Surprisingly, the male brain is masculinized by testosterone being aromatized into estrogen, which crosses the blood-brain barrier and enters the male brain, whereas female fetuses have alpha-fetoprotein which binds up the estrogen so that female brains are not affected.[15]

[edit] 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. Adult-type body odour Increased oiliness of skin and hair, acne Pubarche (appearance of pubic hair) Axillary hair Growth spurt, accelerated bone maturation Hair on upper lip and sideburns.

[edit] 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. Enlargement of sebaceous glands. This might cause acne. Phallic enlargement or clitoromegaly Increased libido and frequency of erection or clitoral engorgement Pubic hair extends to thighs and up toward umbilicus Facial hair (sideburns, beard, moustache) Loss of scalp hair (Androgenetic alopecia) Chest hair, periareolar hair, perianal hair Leg hair Axillary hair Subcutaneous fat in face decreases Increased muscle strength and mass[16] Deepening of voice Growth of the Adam's apple Growth of spermatogenic tissue in testicles, male fertility Growth of jaw, brow, chin, nose, and remodeling of facial bone contours Shoulders become broader and rib cage expands Completion of bone maturation and termination of growth. This occurs indirectly via estradiol metabolites and hence more gradually in men than women.

[edit] 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. Testosterone is necessary for normal sperm development. It activates genes in Sertoli cells, which promote differentiation of spermatogonia. Regulates acute HPA (Hypothalamicpituitaryadrenal axis) response under dominance challenge[17] Mental and physical energy Maintenance of muscle trophism Testosterone regulates the population of thromboxane A2 receptors on megakaryocytes and platelets and hence platelet aggregation in humans[18][19] Testosterone does not cause or produce deleterious effects on 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.[20][21][22] Recent studies have shown conflicting results concerning the importance of testosterone in maintaining cardiovascular health.[23][24] Nevertheless, maintaining normal testosterone levels in elderly men has been shown to improve many parameters which are thought to reduce cardiovascular disease risk, such as increased lean body mass, decreased visceral fat mass, decreased total cholesterol, and glycemic control.[25] Under dominance challenge, may play a role in the regulation of the fight-or-flight response[26] Falling in love decreases men's testosterone levels while increasing women's testosterone levels. It is speculated that these changes in testosterone result in the temporary reduction of differences in behavior between the sexes.[27] It has been found that when the testosterone and endorphins in the 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).[28] Recent studies suggest that testosterone levels play a major role in risk-taking during financial decisions.[29][30] The administration of testosterone makes men selfish and more likely to punish others for being selfish towards them.[31] Fatherhood also decreases testosterone levels in men, suggesting that the resulting emotional and behavioral changes promote paternal care.[32]

 In animals (grouse and sand lizards), higher testosterone levels have been linked to a reduced immune system activity. Testosterone seems to have become part of the honest signaling system between potential mates in the course of evolution.[33][34]

[edit] 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;[10] 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.[35] 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.[36] 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.[37] 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.[16] Another study found a correlation between testosterone and risk tolerance in career choice among women.[38] 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 Alzheimers type,[39][40] 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,[41] where both hypo- and hypersecretion (deficient- and excessive-secretion) of circulating androgens have negative effects on cognition and cognitively modulated aggressivity, as detailed above.[citation needed] Contrary to what has been postulated in outdated studies and by certain sections of the media, aggressive behaviour is not typically seen in hypogonadal men who have their testosterone replaced adequately to the eugonadal/normal range.[citation needed] In fact, aggressive behaviour has been associated with hypogonadism and low testosterone levels and it would seem as though supraphysiological and low levels of testosterone and hypogonadism cause mood disorders and aggressive behaviour,[citation needed] with eugondal/normal testosterone levels being important for mental well-being. Testosterone depletion is a normal consequence of aging in men. One possible consequence of this could be an increased risk for the development of Alzheimers disease.[42][43]

[edit] Aggression
Main article: Aggression#Testosterone The positive correlation between testosterone levels and aggression in humans has been demonstrated in many studies.[44] While testosterone itself is not shown to be the direct cause of aggression in males, the testosterone derivative estradiol is known to correlate with aggression in male mice.[45]

[edit] Fatherhood
Fatherhood has been demonstrated to lower men's testosterone levels

Penggunaan medis The original and primary use of testosterone is for the treatment of males who have too little or no natural endogenous testosterone productionmales with hypogonadism. Appropriate use for this purpose is legitimate hormone replacement therapy (testosterone replacement therapy [TRT]), which maintains serum testosterone levels in the normal range. However, over the years, as with every hormone, testosterone or other anabolic steroids has also been given for many other conditions and purposes besides replacement, with varying success but higher rates of side effects or problems. Examples include reducing infertility, correcting lack of libido or erectile dysfunction, correcting osteoporosis, encouraging penile enlargement, encouraging height growth, encouraging bone marrow stimulation and reversing the effects of anemia, and even appetite stimulation. By the late 1940s testosterone was being touted as an anti-aging wonder drug (e.g., see Paul de Kruif's The Male Hormone).[50] Decline of testosterone production with age has led to interest in androgen replacement therapy.[51] To take advantage of its virilizing effects, testosterone is often administered to transsexual men as part of the hormone replacement therapy, with a "target level" of the normal male testosterone level. Likewise, transsexual 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 patches are effective at treating low libido in post-menopausal women.[52] Low libido may also occur as a symptom or outcome of hormonal contraceptive use. Women may also use testosterone therapies to treat or prevent loss of bone density, muscle mass and to treat certain kinds of depression and low energy state. Women on testosterone therapies may experience an increase in weight without an increase in body fat due to changes in bone and muscle density. Most undesired effects of testosterone therapy in women may be controlled by hair-reduction strategies, acne prevention, etc. There is a theoretical risk that testosterone therapy may increase the risk of breast or gynaecological cancers, and further research is needed to define any such risks more clearly.[52]

[edit] Hormone replacement therapy

Main article: Androgen replacement therapy Testosterone levels decline gradually with age in human beings. The clinical significance of this decrease is debated (see andropause). There is disagreement about when to treat aging men with testosterone replacement therapy. The American Society of Andrology's position is that "testosterone replacement therapy in aging men is indicated when both clinical symptoms and signs suggestive of androgen deficiency and decreased testosterone levels are present."[53] The American Association of Clinical Endocrinologists says "Hypogonadism is defined as a free testosterone level that is below the lower limit of normal for young adult control subjects. Previously, age-related decreases in free testosterone were once accepted as normal. Currently, they are not considered normal. Patients with low-normal to subnormal range testosterone levels warrant a clinical trial of testosterone."[54] There is not total agreement on the threshold of testosterone value below which a man would be

considered hypogonadal. (Currently there are no standards as to when to treat women.) Testosterone can be measured as "free" (that is, bioavailable and unbound) or more commonly, "total" (including the percentage which is chemically bound and unavailable). In the United States, male total testosterone levels below 300 ng/dL from a morning serum sample are generally considered low.[55] Identification of inadequate testosterone in an aging male by symptoms alone can be difficult. Replacement therapy can take the form of injectable depots, transdermal patches and gels, subcutaneous pellets, and oral therapy. Adverse effects of testosterone supplementation include minor side effects such as acne and oily skin, and more significant complications such as increased hematocrit which can require venipuncture in order to treat, exacerbation of sleep apnea and acceleration of pre-existing prostate cancer growth in individuals who have undergone androgen deprivation. Another adverse effect may be significant hair loss and/or thinning of the hair. This may be prevented with Propecia (Finasteride), which blocks DHT (a byproduct of testosterone in the body), during treatment. Exogenous testosterone also causes suppression of spermatogenesis and can lead to infertility.[56] It is recommended that physicians screen for prostate cancer with a digital rectal exam and PSA (prostate specific antigen) level before starting therapy, and monitor hematocrit and PSA levels closely during therapy.

[edit] Benefits
Appropriate testosterone therapy may improve the management of type 2 diabetes,.[57] Low testosterone also brings with it an increased risk for the development of Alzheimer's disease.[42][43] A small trial in 2005 showed mixed results in using testosterone to combat the effects of aging.[58] Large scale trials to assess the efficiency and long-term safety of testosterone are still lacking.[59]

[edit] Adverse effects

Exogenous testosterone supplementation comes with a number of health risks. Fluoxymesterone and methyltestosterone are synthetic derivatives of testosterone. Methyltestosterone and Fluoxymesterone are no longer prescribed by physicians given their poor safety record, and testosterone replacement in men does have a very good safety record as evidenced by over sixty years of medical use in hypogonadal men. A 2006 article in Official Journal of the American Urological Association - The Journal of Urology pointed out that: Prostate cancer may become clinically apparent within months to a few years after the initiation of testosterone treatment. [...] Physicians prescribing testosterone supplementation and patients receiving it should be cognizant of this risk, and serum PSA testing and digital rectal examination should be performed frequently during treatment.[citation needed]

[edit] Athletic use

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. 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.[60] The use is seen as being a seriously problematic issue in modern sport, particularly given the lengths to which athletes and professional laboratories go to in trying to conceal such abuse from sports regulators. Steroid abuse once again came into the spotlight recently as a result of the Chris Benoit double murder-suicide in 2007, and the media frenzy surrounding it - however, there has been no evidence indicating steroid use as a contributing factor.

[edit] 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.[61][62][63][64]

[edit] Routes of administration

Vial of testosterone 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),[65] oral, buccal,[66] transdermal skin patches, transdermal creams, gels,[67][68] and implantable pellets.[69] Roll-on methods and nasal sprays are currently under development.

Biosintesis
Like other steroid hormones, testosterone is derived from cholesterol (see figure to the right).[70] 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.[71] In addition, the 3-hydroxyl group is oxidized by 3--HSD to produce androstenedione. In the final and rate limiting step, the C-17 keto group androstenedione is reduced by 17- hydroxysteroid dehydrogenase to yield testosterone. The largest amounts of testosterone (>95%) are produced by the testes in men.[3] It is also synthesized in far smaller quantities in women by the thecal cells of the ovaries, by the placenta, as well as by the zona reticularis of the adrenal cortex in both sexes. In the testes, testosterone is produced by the Leydig cells.[72] 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).

[edit] Regulation

Hypothalamic-pituitarytesticular axis In males, testosterone is primarily synthesized in Leydig cells. The number of Leydig cells in turn is regulated by luteinizing hormone (LH) and follicle stimulating hormone (FSH). In addition, the amount of testosterone produced by existing Leydig cells is under the control of LH which regulates the expression of 17- hydroxysteroid dehydrogenase.[73] The amount of testosterone synthesized is regulated by the hypothalamic-pituitarytesticular axis (see figure to the right).[74] 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 later 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. Environmental factors affecting testosterone levels include:

 Implicit power motivation[clarification needed] predicts an increased testosterone release in men.[75] Aging reduces testosterone release.[76] Hypogonadism Sleep (REM dream) increases nocturnal testosterone levels.[77] Resistance training increases testosterone levels,[78] however, in older men, that increase can be avoided by protein ingestion.[79] Zinc deficiency lowers testosterone levels[80] but over supplementation has no effect on serum testosterone.[81] Licorice. The active ingredient in licorice root, glycyrrhizinic acid has been linked to small, clinically non-significant decreases in testosterone levels.[82] In contrast, a more recent study found that licorice administration produced a substantial testosterone decrease in a small, female-only sample.[83] Natural or man-made antiandrogens including spearmint tea reduce testosterone levels.[84][85][86]

[edit] Metabolism
Approximately 7% of testosterone is reduced to 5-dihydrotestosterone (DHT) by the cytochrome P450 enzyme 5-reductase,[87] an enzyme highly expressed in male accessory sex organs and hair follicles.[3] Approximately 0.3% of testosterone is converted into estradiol by aromatase (CYP19A1)[88] an enzyme expressed in the brain, liver, and adipose tissues.[3] DHT is a more potent form of testosterone while estradiol has completely different activities (feminization) compared to testosterone (masculinization). Finally testosterone and DHT may be deactivated or cleared by enzymes that hydroxylate at the 6, 7, 15 or 16 positions.[89]

[edit] Mechanism of action

The effects of testosterone in humans and other vertebrates occur by way of two main mechanisms: by activation of the androgen receptor (directly or as DHT), and by conversion to estradiol and activation of certain estrogen receptors.[90][91] Free testosterone (T) is transported into the cytoplasm of target tissue cells, where it can bind to the androgen receptor, or can be reduced to 5-dihydrotestosterone (DHT) by the cytoplasmic enzyme 5alpha 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.[92] 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 maturation 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]. The human hormone testosterone is produced in greater amounts by males, and less by females. The human hormone estrogen is produced in greater amounts by females, and less by males. Testosterone causes the appearance of masculine traits (i.e., deepening voice, pubic and facial hairs, muscular build, etc.) Like men, women rely on testosterone to maintain libido, bone density and muscle mass throughout their lives. In men, inappropriately high levels of estrogens lower testosterone, decrease muscle mass, stunt growth in teenagers, introduce gynecomastia, increase feminine characteristics, and decrease susceptibility to prostate cancer, reduces libido and causes erectile dysfunction and can cause excessive sweating and hot flushes[citation needed]. However, an appropriate amount of estrogens is required in the male in order to ensure well-being, bone density, libido, erectile function, etc.[citation needed]

[edit] 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.

[edit] Related drugs

Some drugs indirectly target testosterone as a way of treating certain conditions. For example, 5-alphareductase inhibitors such as finasteride inhibits the conversion of testosterone into dihydrotestosterone (DHT), a metabolite which is more potent than testosterone.[93] 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.[93] Alternatively 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.[94] 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.

[edit] Insufficiency
Further information: Hypogonadism 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. [95] An acquired form of hypotestosteronism is a decline in testosterone levels that occurs by aging, sometimes being called "andropause" in men, as a comparison to the decline in estrogen that comes with menopause in women.