View source for Testosterone

{{Drugbox|
|IUPAC_name = (8R,9S,10R,13S,14S,17S)-17-hydroxy-10,13-dimethyl-1,2,6,7,8,9,11,12,14,15,1
6,17-dodecahydrocyclopenta[a]phenanthren-3-one
| image=Testosterone structure.png
| width=250
| smiles=C[C@]43CCC(=O)\C=C4\CC[C@@H]1[C@@H]3CC[C@]2(C)[C@@H](O)CC[C@@H]12
| CAS_number=58-22-0
| ATC_prefix=G03
| ATC_suffix=BA03
| ATC_supplemental=
| PubChem=6013
| DrugBank=
| C=19 | H=28 | O=2
| molecular_weight = 288.43
| bioavailability= low (due to extensive [[First pass effect|first pass metabolism]])
| metabolism = [[Liver]], [[Testis]] and [[Prostate]]
| elimination_half-life= 2-4 hours
| excretion =  [[Urine]] (90%), feces (6%)
| pregnancy_category = X ([[United States|USA]]), [[Teratogen]]ic effects
| legal_status = Schedule III ([[Controlled Substances Act|USA]])<br />Schedule IV ([[Controlled Drugs and Substances Act|Canada]])
| routes_of_administration=Intramuscular injection, transdermal (cream, gel, or patch), sub-'Q' pellet
| melting_point=155-156
| specific_rotation=+110,2°
| sec_combustion=−11080 kJ/mol
}}
'''Testosterone''' is a [[steroid hormone]] from the [[androgen]] group. Testosterone is primarily secreted in the [[testis|testes]] of males and the [[ovaries]] of females, although small amounts are also secreted by the [[adrenal gland]]s.  It is the principal [[male]] sex [[hormone]] and an [[anabolic steroid]]. In both males and females, it plays key roles in health and well-being.  Examples include enhanced [[libido]], energy, [[immune function]], and protection against [[osteoporosis]]. On average, an adult [[human]] male body produces about eight to ten times more testosterone than an adult female body.<ref>James McBride Dabbs, 2000</ref> Testosterone is found in numerous animals. 



==History==
Testicular action was linked to circulating blood fractions &mdash; now understood to be a family of androgenic hormones &mdash; in the early work on castration and testicular transplantation in fowl by Arnold Bethold (1803&ndash;1861).  Research on the action of testosterone received a brief boost in 1889, when the Harvard professor Charles-Edouard Brown-Séquard (1817&ndash;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 wellbeing were markedly restored but, predictably, the effects were transient (and likely based on placebo), and Brown-Séquard’s hopes for the compound were dashed.  Suffering the ridicule of his colleagues, his work on the mechanisms and effects of androgens in human beings was abandoned by Brown-Séquard and succeeding generations of biochemists for nearly 40 years.

The trail remained cold until the University of Chicago’s Professor of Physiologic Chemistry, Fred C. Koch, established easy access to a large source of bovine testicles &mdash; the Chicago stockyards &mdash; and to students willing to endure the ceaseless toil of extracting their isolates. In 1927, Koch and his student, Lemuel McGee, derived 20mg of a substance from a supply of 40 pounds of bull testicles that, when administered to castrated roosters, pigs and rats, remasculinized them.<ref>Gallagher and Koch, 1929.</ref>  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 clearly not feasible until three European pharmaceutical giants &mdash; [[Schering]] (Berlin, Germany), [[Organon]] (Oss, Netherlands) and [[Ciba]] (Basel, Switzerland) &mdash; began full-scale steroid research and development programs in the 1930’s.

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)" by Karoly Gyula David, E. Dingemanse, J. Freud and Ernst Laqueur. They named the hormone ''testosterone'', from the [[stem (linguistics)|stems]] of ''testicle'' and ''[[sterol]]'', and the [[suffix]] of ''[[ketone]]''. The structure was worked out by Schering’s [[Adolf Butenandt]] (1903&ndash;1995).

The [[chemical synthesis]] of testosterone was achieved in August that year, when Butenandt and G. Hanisch published a paper describing "A Method for Preparing Testosterone from Cholesterol." Only a week later, the Ciba group in Zurich, [[Leopold Ruzicka]] (1887&ndash;1976) and A. Wettstein, announced a patent application in a paper "On the Artificial Preparation of the Testicular Hormone Testosterone (Androsten-3-one-17-ol)." These independent partial syntheses of testosterone from a cholesterol base earned both Butenandt and Ruzicka the joint 1939 [[Nobel Prize in Chemistry]].<ref>Hoberman and Yesalis 1995, Freeman ''et al.'' 2001.</ref> Testosterone was identified as 17β-hydroxandrost-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 1930’s 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 Charles Kenyon’s group<ref>Kenyon ''et al.'' 1940.</ref> was able to demonstrate both anabolic and androgenic effects of testosterone propionate in eunuchoidal men, boys, and women. The period of the early 1930’s to the 1950’s has been called “The Golden Age of Steroid Chemistry”,<ref>Schwarz ''et al.'' 1999.</ref> and work during this period progressed quickly. Research in this golden age proved that this newly synthesized compound &mdash; testosterone &mdash; or rather family of compounds (for many derivatives were developed in the 1940’s, 50’s and 60’s), was a potent multiplier of muscle, strength, and wellbeing.<ref>deKruif, 1945.</ref>

==Production==
===Natural===
Like other [[steroid]] hormones, testosterone is derived from [[cholesterol]]. The largest amounts of testosterone are produced by the [[testis|testes]] in men. It is also synthesized in far smaller quantities in women by the [[thecal cells]] of the [[ovary|ovaries]], by the [[placenta]], as well as by the [[zona reticularis]] of the [[adrenal gland|adrenal cortex]] in both sexes.   

In the [[testes]], testosterone is produced by the [[Leydig cell]]s. The male [[gonads|generative glands]] also contain [[Sertoli cell]]s 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).

===Artificial===
Testosterone is synthesizable in almost unlimited quantities. Furthermore, there are two possible modifications on it, giving it further abilities. First, it can be esterified, permitting a long-lasting effect when injected into the body. Second, it can be alkylated, permitting oral intake instead of injection.

==== Esterification ====
The C-17 hydroxyl group testosterone can be esterified, or altered by the substitution of an acid group for the hydroxyl group at the C17 position. Esterification lowers the water solubility of the molecule and increases its lipid solubility, permitting a sterile oil-based injectible with testosterone to form a “depot” in the muscle, from which it is gradually released. Esterification temporarily deactivates the steroid molecule, because the presence of the large acid chain prevents the steroid from binding to androgen receptor (AR) molecules within muscle cells that promote protein synthesis. But, as the esterified steroid is gradually leached from the oily depot into the blood, esterases (acid-cleaving molecules) replace the acid chain with a hydroxyl group as in the virgin molecule, permitting the steroid to bind to AR. The overall effect of esterification is to extend the steroid’s half-life, ease its administration, and alter its anabolic/androgenic ratio (A/AR), or the degree to which it affects striated muscle vs. sexual organ tissues such as the testes or prostate.

====Alkylation====
The second importance of the hydroxyl side chain at the C-17 position is that it can not only be esterified, but it can also be alkylated (by substitution of an ethyl or methyl group for the hydroxyl group). Alkylation permits oral steroids, the so-called “17-aa” or alkylated family of androgens such as methyltestosterone, which can be taken up by the digestive tract, and so be easily administered in pill form.

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

* ''Anabolic effects'' include growth of [[muscle mass]] and strength, increased [[bone density]] and strength, and stimulation of linear growth and [[bone maturation]]. 
* ''Virilizing effects'' include [[maturation]] of the [[sex organs]], particularly the [[penis]] and the formation of the [[scrotum]] in unborn children, 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 characteristic]]s.

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.

===Prenatal androgen effects===
Most of the ''prenatal androgen effects'' occur between 7 and 12 weeks of gestation.
*Genital virilization (midline fusion, [[phallus|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 vesicle]]s

===Early infancy androgen effects===
''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. 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.

===Early postnatal effects===
''Early postnatal effects'' are the first visible effects of rising androgen levels in childhood, and occur in both boys and girls in puberty.
*Adult-type body odour
*Increased oiliness of skin and hair, [[Acne vulgaris|acne]]
*[[Pubarche]] (appearance of [[pubic hair]])
*[[Axillary hair]]
*[[Growth spurt]], accelerated [[epiphysis|bone maturation]]
*Fine upper lip and sideburn hair

===Advanced postnatal effects===
''Advanced postnatal 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.
*[[Phallic]] enlargement (including [[clitoromegaly]])
*Increased [[libido]] and frequency of [[erection]] or clitoral engorgement
*Pubic hair extends to thighs and up toward [[Navel|umbilicus]]
*[[Facial hair]] ([[sideburns]], [[beard]], [[moustache]])
*[[Chest hair]], [[periareolar]] hair, [[perianal]] hair
*Subcutaneous fat in face decreases
*Increased muscle strength and mass
*Deepening of voice
*Growth of the [[adam's apple]]
*Growth of [[spermatogenic]] tissue in testes, male [[fertility]]
*Growth of jaw, brow, chin, nose, and remodeling of facial bone contours
*Shoulders widen 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.

===Adult testosterone effects===
''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 decline in the later decades of adult life.
*Maintenance of muscle mass and strength
*Maintenance of bone density and strength
*Libido and clitoral engorgement/penile erection frequency.
*Mental and physical energy
*The most recent and reliable studies have shown that testosterone does not cause prostate cancer, but that it can increase the rate of spead of any existing prostate cancer.  Recent studies have also shown its importance in maintaining cardio vascular health.
*Increase [[eumelanin]] and reduce [[pheomelanin]] {{Fact|date=August 2007}}
*A lack of testosterone can lead to a statistically significant increase in the liklihood of cardio vascular disease (CVD), type 2 diabetes (a third of all me with type 2 diabetes have low testosterone), low testosterone can cause osteoporosis in males.  A lack of testosterone has been shown to be associated with increased adipose fat, obesity and a difficulty in losing excess weight and has been strongly associated with depression.  Most alarming is the recent evidence/studies that have shown that a lack of testosterone greatly increase mortality rates in men over 50.

==Effects on the brain==
As testosterone affects the entire body (often by enlarging; men have bigger hearts, lungs, liver, etc.), the brain is also affected by this "sexual" advancement; the [[enzyme]] [[aromatase]] converts testosterone into [[estradiol]] that is responsible for [[masculinization]] of the brain in a male fetus.

There are some differences in a male and female brain (the result of different testosterone levels); a clear difference is the size, the male human brain is on average larger, however in females (who do not use testosterone as much) the [[corpus callosum]] is proportionally larger. This means that the effect of testosterone is a greater overall brain volume, but a decreased connection between the [[Cerebral hemisphere|hemispheres]].<ref name="Mark Solms & Oliver Turnbull"> Solms and Turnbull 2002.</ref>

The literature suggests that attention, memory, and spatial ability are key cognitive functions affected by testosterone in humans, though the literature is rather sparse. 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>e.g., Moffat et al, 2005; Hogervorst et al 2005.</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>e.g., Moffat and Hampson, 1996.</ref> where both hypo- and hypersecretion of circulating androgens have negative effects on cognition and cognitively-modulated aggressivity, as detailed above.

A lack of testosterone is strongly linked to depression and anxiety syndromes, when a lack of testosterone and a hypogondal state are the cause of such problems restortion of eugondal status by appropriate testosterone replacement often helps reduce or resolve such conditions.

Contrary to what has been postulated in outdated studies and by certain sections of the media, agressive behaviour is not typically seen in hypogondal men who have their testosterone replaced adequately to the eugonadal/normal range.  In fact aggressive behaviour has 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, with eugondal/normal testosterone levels being important for mental well-being.

==Mechanism==

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 receptor]]s.

Free testosterone (T) is transported into the [[cytoplasm]] of target [[tissue]] [[Cell (biology)|cells]], where it can bind to the androgen [[Receptor (biochemistry)|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 T, so that its androgenic potency is about 2.5 times that of T.{{Fact|date=February 2007}} 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 [[chromosome|chromosomal]] DNA. The areas of binding are called [[hormone response element]]s (HREs), and influence transcriptional activity of certain [[gene]]s, producing the androgen effects. It is important to note that if there is a 5-alpha reductase deficiency,<!-- in the womb? during childhood? --> the body (of a human) will ''continue'' growing into a female with testicles.

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 [[sexual differentiation|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 [[epiphysis|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 [[luteinizing hormone|LH]] secretion). In many [[mammal]]s, prenatal or perinatal "masculinization" of the [[sexual dimorphism|sexually dimorphic]] areas of the brain by estradiol derived from testosterone programs later male sexual behavior.

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, estrogens simply lower testosterone, decrease muscle mass, stunt growth in teenagers, introduce [[gynecomastia]], increase feminine characteristics, and decrease susceptibility to prostate cancer.

==Therapeutic use==
===Routes of administration===
There are many [[routes of administration]] for testosterone. Forms of testosterone for human administration currently available in North America include injectable (such as testosterone cypionate or testosterone enanthate in oil), oral,<ref>{{cite web
|url = http://google2.fda.gov/search?client=FDA&site=FDA&oe=&lr=&proxystylesheet=FDA&output=xml_no_dtd&getfields=*&q=Andriol&as=GO
|title=Andriol|publisher=Food and Drug Administration}}</ref> buccal,<ref>{{cite web
|url = http://google2.fda.gov/search?client=FDA&site=FDA&oe=&lr=&proxystylesheet=FDA&output=xml_no_dtd&getfields=*&q=Striant&as=GO
|title=Striant|publisher=Food and Drug Administration}}</ref> transdermal skin patches, and transdermal creams or gels.<ref>{{cite web
|url = http://www.fda.gov/medwatch/SAFETY/2003/03SEP_PI/AndroGel_PI.pdf
|title=Androgel|publisher=Food and Drug Administration}} and {{cite web
|url = http://google2.fda.gov/search?client=FDA&site=FDA&oe=&lr=&proxystylesheet=FDA&output=xml_no_dtd&getfields=*&q=Testim.&as=GO
|title=Testim|publisher=Food and Drug Administration}}</ref> In the pipeline are "roll on" methods and nasal sprays.

===Indications===
The original and primary use of testosterone is for the treatment of males who have too little or no natural endogenous testosterone production—males with [[hypogonadism]]. Appropriate use for this purpose is legitimate hormone replacement therapy, 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 variable success but higher rates of side effects or problems. Examples include [[infertility]], lack of libido or erectile dysfunction, [[osteoporosis]], [[penis enlargement|penile enlargement]], height growth, [[bone marrow]] stimulation and reversal 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''). Decline of testosterone production with age has led to a demand for [[Androgen Replacement Therapy]].

To take advantage of its [[virilizing]] effects, testosterone is often administered to [[female-to-male]] [[transsexual]] men as part of the [[Hormone replacement therapy (trans)|hormone replacement therapy]], with a "target level" of the normal male testosterone level. Like-wise, [[male-to-female]] [[transsexual]] women are sometimes prescribed drugs ([[antiandrogen|anti-androgens]]) to decrease the level of testosterone in the body and allow for the effects of estrogen to develop.

Women use testosterones to treat low libido, often 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 non-transgendered women (the majority) may be controlled by hair-reduction strategies, acne prevention, etc.  

There is a myth that [[exogenous]] testosterone can more or less definitively be used for male birth control.  However, the vast majority of physicians will agree that to prescribe exogenous testosterone for this purpose is inappropriate. But, perhaps more important, many men found this, in first-hand experience, to be untrue or at least, unreliable.

Some drugs specifically target testosterone as a way of treating certain conditions. For example, [[finasteride]] inhibits the conversion of testosterone into [[dihydrotestosterone]] (DHT), a metabolite which is more potent than testosterone.  By lowering the levels of dihydrotestosterone, finasteride may be used for various conditions associated with androgens, such as [[benign prostatic hyperplasia]] (BPH) and [[androgenetic alopecia]] ([[male-pattern baldness]]).

===Adverse effects===
Exogenous testosterone supplementation comes with a number of health risks.  [[Fluoxymesterone]] and [[methyltestosterone]] are synthetic derivatives of testosterone. In 2006 it was reported that women taking [[Estratest]], a combination pill including estrogen and methyltestosterone, were at considerably heightened risk of [[breast cancer]].{{Fact|date=February 2007}}

===Athletic use===
Testosterone may be administered to an [[sportsperson|athlete]] in order to improve performance, and is considered to be a form of [[Doping (sport)|doping]] in most sports.  There are several application methods for testosterone, including [[intramuscular injection]]s, [[transdermal|transdermal gels and patches]], and implantable pellets.

[[Anabolic steroids]] (of which testosterone is one) have also been taken to enhance muscle development, strength, or endurance. They do so directly by increasing the muscles' protein synthesis.  In 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 (sprinter)|Ben Johnson's]] improved performance at the [[1988 Summer Olympics]]), [[prohibition]]s 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]].<ref>{{cite web
|url = http://www.ussc.gov/USSCsteroidsreport-0306.pdf#search=%22Anabolic%20Steroid%20Control%20Act%20of%201990%22
|title = Anabolic Steroid Control Act| publisher = United States Sentencing Commission|year = 1990}}</ref>

==Changes during aging==

Testosterone levels decline gradually with age in human beings. The clinical significance of this decrease is debated (see [[andropause]]). There is disagreement about if and when to treat aging men with testosterone replacement therapy. The [[American Society of Andrology]]'s position is that testosterone therapy "is indicated when both clinical symptoms and signs suggestive of [[androgen deficiency]] and decreased testosterone levels are present". 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."<ref>{{cite web
|url = http://www.aace.com/pub/pdf/guidelines/sexdysguid.pdf
|title = Medical guildelines for clinical practice for the evaluation and treatment of male sexual dysfunction
|publisher = American association of clinical endocrinologists}}</ref> 

There isn't 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 200 to 300 ng/dl from a morning sample are generally considered low. However these numbers are typically not age-adjusted, but based on an average of a test group which includes elderly males with low testosterone levels. Therefore a value of 300 ng/dl might be normal for a 65 year old male, but not normal for a 30 year old. Identification of inadequate testosterone in an aging male by symptoms alone can be difficult. The signs and symptoms are non-specific, and might be confused with normal aging characteristics, such as loss of muscle mass and bone density, decreased physical endurance, decreased memory ability and loss of libido. 

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]], exacerbation of [[sleep apnea]] and acceleration of pre-existing [[prostate cancer]] growth. Exogenous testosterone also causes suppression of [[spermatogenesis]] and can lead to infertility.<ref name="Lancet">World Health Organisation (1990), The Lancet.</ref>
It is recommended that physicians screen for prostate cancer with a digital rectal exam and PSA ([[prostate specific antigen]]) level prior to initiating therapy, and monitor hematocrit and PSA  levels closely during therapy.

Large scale trials to assess the efficiency and long-term safety of testosterone are still lacking. Many caution against embracing testosterone replacement therapy because of lessons from the female [[hormone replacement therapy]] trials, where initially promising results were later refuted by larger studies.  Still, testosterone replacement therapies in women to treat/prevent osteoporosis have yet to show the risks now shown with estrogen replacement therapies.

==Additional images==
<gallery>
 Image:Steroidogenesis.gif|[[Steroidogenesis]]
</gallery>

==See also==
*[[Male]]
*[[Testosterone spray]]

==Notes==
{{Reflist|2}}

==References==

* {{cite journal
|author=E.R. Freeman, D.A. Bloom, and E.J. McGuire
|title=A brief history of testosterone
|journal=Journal of Urology
|volume=165
|issue=
|pages=371&ndash;373
|year=2001
|pmid= 11176375}}
* {{cite journal
|author=J.M. Hoberman and C.E. Yesalis 
|title=The history of synthetic testosterone
|journal=Scientific American
|volume=272
|issue=
|pages=76&ndash;81
|year=1995
|pmid=7817189}}
* {{cite book| author = P.R. Larsen ''et al.'' |title = Williams textbook of endocrinology| edition = 10th edition|publisher = Saunders| year = 2003| isbn =978-0-7216-9184-8}} (Seventh edition by J.D. Wilson and R.H. Williams, 1985, ISBN 072161082X.)
* {{cite journal|author = S.D. Moffat and E. Hampson| title =  A curvilinear relationship between testosterone and spatial cognition in humans: Possible influence of hand preference| journal = Psychoneuroendocrinology|volume = 21|issue = 3| pages = 323&ndash;337|year = 1996}}
* {{cite journal|author = S.D. Moffat, A.B. Zonderman, E.J. Metter ''et al.''| year = 2004| title = Free testosterone and risk for Alzheimer's disease in older men|journal = Neurology|volume = 62| pages = 188&ndash;193}}
* {{cite journal|author = M. Parssinen, U. Kujala, E. Vartiainen, ''et al.''| year= 2000|title = Increased premature mortality of competitive powerlifters suspected to have used anabolic agents| journal = International Journal of Sports Medicine|volume = 21|pages= 225&ndash;227}}
* {{cite journal|author = S. Schwarz, D. Onken, and A. Schubert|title = The steroid story of Jenapharm: From the late 1940s to the early 1970s
|journal = Steroids|volume = 64|year = 1999|pages = 439&ndash;445|url = http://www.ingentaconnect.com/content/els/0039128x/1999/00000064/00000007/art00003|doi = 10.1016/S0039-128X(99)00003-3}}
* {{cite book| author= M. Solms and O. Turnbull| title = The brain and the inner world| publisher = Other Press, New York| year = 2002|isbn = 978-1590510179}}
* {{cite journal | author = World Health Organization Task Force on methods for the regulation of male fertility
|title = Contraceptive efficacy of testosterone-induced azoospermia in normal men| journal = Lancet
|year = 1990 | volume = 336 |pages =955&ndash;959| pmid = 1977002}}

==External links==
* [http://webbook.nist.gov/cgi/cbook.cgi?ID=C58220&Units=SI NIST entry for Testosterone]
* [http://webbook.nist.gov/cgi/cbook.cgi?Name=testosterone&Units=SI NIST results of search for Testosterone (Shows androstenone.)]

{{Hormones}}
{{Sex hormones}}
{{Anabolic steroids}}

[[Category:Androgens]]
[[Category:Erectile dysfunction drugs]]
[[Category:Neuroendocrinology]]
[[Category:Anabolic steroids]]

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