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{{Short description|Primary male sex hormone}} {{About|testosterone as a hormone|its use as a medication|Testosterone (medication)|other uses}} {{Use mdy dates|date=February 2015}} {{cs1 config |name-list-style=vanc|display-authors=6}} {{Chembox <!-- Images --> |ImageFile1=Testosteron.svg |ImageSize1=225px |ImageClass1=skin-invert |ImageAlt1=The chemical structure of testosterone. |ImageFile2=Testosterone molecule ball.png |ImageSize2=225px |ImageAlt2=A ball-and-stick model of testosterone. <!-- Names --> |IUPACName=17β-Hydroxyandrost-4-en-3-one |SystematicName=(1''S'',3a''S'',3b''R'',9a''R'',9b''S'',11a''S'')-1-Hydroxy-9a,11a-dimethyl-1,2,3,3a,3b,4,5,8,9,9a,9b,10,11,11a-tetradecahydro-7''H''-cyclopenta[''a'']phenanthren-7-one |OtherNames=Androst-4-en-17β-ol-3-one |Watchedfields=verified |verifiedrevid=649778658 <!-- Sections --> |Section1={{Chembox Identifiers | CASNo_Ref = {{cascite|correct|CAS}} | CASNo = 58-22-0 | ChEBI_Ref = {{ebicite|correct|EBI}} | ChEBI = 17347 | ChEMBL_Ref = {{ebicite|correct|EBI}} | ChEMBL = 386630 | ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}} | ChemSpiderID = 5791 | DrugBank_Ref = {{drugbankcite|correct|drugbank}} | DrugBank = DB00624 | EINECS = 200-370-5 | KEGG_Ref = {{keggcite|correct|kegg}} | KEGG = D00075 | PubChem = 6013 | SMILES = O=C1C=C2[C@](C)(CC1)[C@H]3CC[C@]4(C)[C@H](CC[C@H]4[C@@H]3CC2)O | StdInChI_Ref = {{stdinchicite|correct|chemspider}} | StdInChI = 1S/C19H28O2/c1-18-9-7-13(20)11-12(18)3-4-14-15-5-6-17(21)19(15,2)10-8-16(14)18/h11,14-17,21H,3-10H2,1-2H3/t14-,15-,16-,17-,18-,19-/m0/s1 | StdInChIKey_Ref = {{stdinchicite|correct|chemspider}} | StdInChIKey = MUMGGOZAMZWBJJ-DYKIIFRCSA-N | UNII_Ref = {{fdacite|correct|FDA}} | UNII = 3XMK78S47O }} |Section2={{Chembox Properties | C=19 | H=28 | O=2 | Appearance = | Density = | MeltingPtC = 151.0 | MeltingPt_ref =<ref>{{cite book | veditors = Haynes WM | year = 2011 | title = CRC Handbook of Chemistry and Physics | edition = 92nd | publisher = [[CRC Press]]| isbn = 978-1-4398-5511-9|page=3.304| title-link = CRC Handbook of Chemistry and Physics }}</ref> | BoilingPt = | Solubility = }} |Section5={{Chembox Hazards | MainHazards = | FlashPt = | AutoignitionPt = }} |Section6={{Chembox Pharmacology | ATCvet = | ATCCode_prefix = G03 | ATCCode_suffix = BA03 | ATC_Supplemental = | Licence_EU=yes | AdminRoutes = [[Transdermal]] ([[gel]], [[cream (pharmaceutical)|cream]], [[Topical medication#Topical solution|solution]], [[transdermal patch|patch]]), [[oral administration|by mouth]] (as [[testosterone undecanoate]]), [[buccal administration|in the cheek]], [[intranasal]] (gel), [[intramuscular injection]] (as [[Testosterone esters|ester]]s), [[subdermal implant|subcutaneous pellet]]s | Bioavail = Oral: very low (due to extensive [[first pass effect|first pass metabolism]]) | Excretion = [[Urine]] (90%), [[feces]] (6%) | HalfLife = 30–60 minutes<ref>{{cite journal | url=https://www.goldjournal.net/article/0090-4295(94)90145-7/abstract | doi=10.1016/0090-4295(94)90145-7 | title=The time for serum testosterone to reach castrate level after bilateral orchiectomy or oral estrogen in the management of metastatic prostatic cancer | date=1994 | journal=Urology | volume=43 | issue=6 | pages=834–837 | pmid=8197647 | vauthors = Lin BJ, Chen K, Chen M, Chang LS | url-access=subscription }}</ref> | Metabolism = [[Liver]] (mainly [[redox|reduction]] and [[conjugation (biochemistry)|conjugation]]) | ProteinBound = 97.0–99.5% (to {{abbrlink|SHBG|sex hormone-binding globulin}} and [[human serum albumin|albumin]])<ref name="MelmedPolonsky2015" />}} }} '''Testosterone''' is the primary male [[sex hormone]] and [[androgen]] in [[Male|males]].<ref>{{cite web |title=Understanding the risks of performance-enhancing drugs |url=https://www.mayoclinic.org/healthy-lifestyle/fitness/in-depth/performance-enhancing-drugs/art-20046134 |website=Mayo Clinic |access-date=30 December 2019 |language=en |archive-date=April 21, 2020 |archive-url=https://web.archive.org/web/20200421045948/https://www.mayoclinic.org/healthy-lifestyle/fitness/in-depth/performance-enhancing-drugs/art-20046134 |url-status=live }}</ref> In humans, testosterone plays a key role in the development of [[Male reproductive system|male reproductive]] tissues such as [[testicle]]s and [[prostate]], as well as promoting [[secondary sexual characteristic]]s such as increased [[muscle]] and [[bone]] mass, and the growth of [[androgenic hair|body hair]]. It is associated with increased [[aggression]], [[sex drive]], [[Dominance hierarchy|dominance]], [[courtship display]], and a wide range of behavioral characteristics.<ref name="pmid3549275">{{cite journal | vauthors = Mooradian AD, Morley JE, Korenman SG | title = Biological actions of androgens | journal = Endocrine Reviews| volume = 8 | issue = 1 | pages = 1–28 | date = Feb 1987 | pmid = 3549275 | doi = 10.1210/edrv-8-1-1 }}</ref> In addition, testosterone in both sexes is involved in health and well-being, where it has a significant effect on overall mood, cognition, social and sexual behavior, metabolism and energy output, the cardiovascular system, and in the prevention of [[osteoporosis]].<ref name="pmid19707253">{{cite journal | vauthors = Bassil N, Alkaade S, Morley JE | title = The benefits and risks of testosterone replacement therapy: a review | journal = Therapeutics and Clinical Risk Management | volume = 5 | issue = 3 | pages = 427–48 | date = Jun 2009 | pmid = 19707253 | pmc = 2701485 | doi = 10.2147/tcrm.s3025 | doi-access = free }}</ref><ref name="pmid19011293">{{cite book | vauthors = Tuck SP, Francis RM | chapter = Testosterone, bone and osteoporosis | volume = 37 | pages = 123–32 | year = 2009 | pmid = 19011293 | doi = 10.1159/000176049 | isbn = 978-3-8055-8622-1 | series = Frontiers of Hormone Research | title = Advances in the Management of Testosterone Deficiency }}</ref> Insufficient levels of testosterone in men may lead to abnormalities including frailty, accumulation of adipose fat tissue within the body, anxiety and depression, sexual performance issues, and bone loss. Excessive levels of testosterone in men may be associated with [[hyperandrogenism]], higher risk of [[heart failure]], increased [[Death|mortality]] in men with [[prostate cancer]],<ref>{{cite journal | vauthors = Gann PH, Hennekens CH, Ma J, Longcope C, Stampfer MJ | title = Prospective study of sex hormone levels and risk of prostate cancer | journal = Journal of the National Cancer Institute | volume = 88 | issue = 16 | pages = 1118–1126 | date = August 1996 | pmid = 8757191 | doi = 10.1093/jnci/88.16.1118 | doi-access = free | citeseerx = 10.1.1.524.1837 }}</ref> and [[male pattern baldness]]. Testosterone is a [[steroid hormone]] from the [[androstane]] class containing a [[ketone]] and a [[hydroxyl]] group at positions three and seventeen respectively. It is [[Biosynthesis|biosynthesized]] in several steps from cholesterol and is converted in the liver to inactive metabolites.<ref name = "Luetjens_2012" /> It exerts its action through binding to and activation of the [[androgen receptor]].<ref name = "Luetjens_2012">{{cite book | veditors = Nieschlag E, Behre HM, Nieschlag S | title = Testosterone: Action, Deficiency, Substitution | vauthors = Luetjens CM, Weinbauer GF | pages = 15–32 | chapter = Chapter 2: Testosterone: Biosynthesis, transport, metabolism and (non-genomic) actions | chapter-url = https://books.google.com/books?id=MkrAPaQ4wJkC&pg=PA15 | date = 2012 | publisher = Cambridge University Press | location = Cambridge | isbn = 978-1-107-01290-5 | edition = 4th }}</ref> In humans and most other [[vertebrate]]s, testosterone is secreted primarily by the [[testicles]] of males and, to a lesser extent, the [[ovaries]] of [[female]]s. On average, in adult males, levels of testosterone are about seven to eight times as great as in adult females.<ref name="pmid14981046">{{cite journal | vauthors = Torjesen PA, Sandnes L | title = Serum testosterone in women as measured by an automated immunoassay and a RIA | journal = Clinical Chemistry | volume = 50 | issue = 3 | pages = 678; author reply 678–9 | date = Mar 2004 | pmid = 14981046 | doi = 10.1373/clinchem.2003.027565 | doi-access = free }}</ref> As the metabolism of testosterone in males is more pronounced, the daily production is about 20 times greater in men.<ref name="pmid6025472">{{cite journal | vauthors = Southren AL, Gordon GG, Tochimoto S, Pinzon G, Lane DR, Stypulkowski W | title = Mean plasma concentration, metabolic clearance and basal plasma production rates of testosterone in normal young men and women using a constant infusion procedure: effect of time of day and plasma concentration on the metabolic clearance rate of testosterone | journal = The Journal of Clinical Endocrinology & Metabolism| volume = 27 | issue = 5 | pages = 686–94 | date = May 1967 | pmid = 6025472 | doi = 10.1210/jcem-27-5-686 }}</ref><ref name="pmid5843701">{{cite journal | vauthors = Southren AL, Tochimoto S, Carmody NC, Isurugi K | title = Plasma production rates of testosterone in normal adult men and women and in patients with the syndrome of feminizing testes | journal = The Journal of Clinical Endocrinology & Metabolism| volume = 25 | issue = 11 | pages = 1441–50 | date = Nov 1965 | pmid = 5843701 | doi = 10.1210/jcem-25-11-1441 }}</ref> Females are also more sensitive to the hormone.<ref name="isbn0-07-135739-4">{{cite book | vauthors = Dabbs M, Dabbs JM | title = Heroes, rogues, and lovers: testosterone and behavior | url = https://archive.org/details/heroesrogueslove00jame | url-access = registration | publisher = McGraw-Hill | location = New York | year = 2000 | isbn = 978-0-07-135739-5 }}</ref>{{Page needed|date=June 2023}} In addition to its role as a natural hormone, testosterone is used as a [[medication]] to treat [[hypogonadism]] and [[breast cancer]].<ref name="AHFS2016">{{cite web |date=December 4, 2015 |title=Testosterone |url=https://www.drugs.com/monograph/testosterone.html |url-status=live |archive-url=https://web.archive.org/web/20160820173417/https://www.drugs.com/monograph/testosterone.html |archive-date=August 20, 2016 |access-date=3 September 2016 |website=Drugs.com |publisher=American Society of Health-System Pharmacists}}</ref> Since [[andropause|testosterone levels decrease as men age]], testosterone is sometimes used in older men to counteract this deficiency. It is also used illicitly to [[performance-enhancing substance|enhance physique and performance]], for instance in [[athlete]]s.<ref>{{cite report |collaboration=Institute of Medicine (US) Committee on Assessing the Need for Clinical Trials of Testosterone Replacement Therapy |vauthors=Liverman CT, Blazer DG |chapter=Introduction |title=Testosterone and Aging: Clinical Research Directions |date=2004 |publisher=National Academies Press (US) |chapter-url=https://www.ncbi.nlm.nih.gov/books/NBK216164/ |language=en |access-date=September 26, 2016 |archive-date=January 10, 2016 |archive-url=https://web.archive.org/web/20160110170928/http://www.ncbi.nlm.nih.gov/books/NBK216164/ |url-status=live }}</ref> The [[World Anti-Doping Agency]] lists it as S1 Anabolic agent substance "prohibited at all times".<ref>{{Cite web|title=What is Prohibited|url=https://www.wada-ama.org/en/content/what-is-prohibited/prohibited-at-all-times/anabolic-agents|access-date=2021-07-18|website=World Anti-Doping Agency|language=en|archive-date=November 12, 2020|archive-url=https://web.archive.org/web/20201112011132/https://www.wada-ama.org/en/content/what-is-prohibited/prohibited-at-all-times/anabolic-agents|url-status=dead}}</ref> ==Biological effects== === Effects on physiological development === In general, [[androgens]] such as testosterone promote [[protein synthesis]] and thus growth of tissues with [[androgen receptors]].<ref name="pmid10821325">{{cite journal | vauthors = Sheffield-Moore M | title = Androgens and the control of skeletal muscle protein synthesis | journal = Annals of Medicine | volume = 32 | issue = 3 | pages = 181–186 | date = April 2000 | pmid = 10821325 | doi = 10.3109/07853890008998825 | s2cid = 32366484 }}</ref> Testosterone can be described as having [[anabolism|anabolic]] and androgenic ([[virilization|virilising]]) effects, though these categorical descriptions are somewhat arbitrary, as there is a great deal of mutual overlap between them.<ref name="pmid25905231">{{cite book | chapter = Androgen Physiology, Pharmacology and Abuse | chapter-url = https://www.ncbi.nlm.nih.gov/books/NBK279000/ | vauthors = Handelsman DJ | title = Endotext [Internet] | publisher = MDText.com, Inc | date = January 2013 | pmid = 25905231 | access-date = November 11, 2016 | archive-date = March 9, 2021 | archive-url = https://web.archive.org/web/20210309030923/https://www.ncbi.nlm.nih.gov/books/NBK279000/ | url-status = live }}</ref> The relative potency of these effects can depend on various factors and is a topic of ongoing research.<ref name="Ceponis-2017">{{cite book | chapter-url=https://link.springer.com/referenceworkentry/10.1007/978-3-319-29456-8_11-1 | doi=10.1007/978-3-319-29456-8_11-1 | chapter=Anabolic and Metabolic Effects of Testosterone and Other Androgens: Direct Effects and Role of Testosterone Metabolic Products | title=Thyroid Diseases | series=Endocrinology | date=2017 | last1=Čeponis | first1=Jonas | last2=Wang | first2=Christina | last3=Swerdloff | first3=Ronald S. | last4=Liu | first4=Peter Y. | pages=1–22 | isbn=978-3-319-29195-6 | access-date=April 6, 2024 | archive-date=April 7, 2024 | archive-url=https://web.archive.org/web/20240407084734/https://link.springer.com/referenceworkentry/10.1007/978-3-319-29456-8_11-1 | url-status=live }}</ref><ref name="pmid12017555">{{cite journal |vauthors=Kuhn CM |title=Anabolic steroids |journal=Recent Prog Horm Res |volume=57 |issue= |pages=411–34 |date=2002 |pmid=12017555 |doi=10.1210/rp.57.1.411 |url=|doi-access=free }}</ref> Testosterone can either directly exert effects on target tissues or be metabolized by 5α-reductase into dihydrotestosterone (DHT) or aromatized to estradiol (E2).<ref name="Ceponis-2017"/> Both testosterone and DHT bind to an androgen receptor; however, DHT has a stronger binding affinity than testosterone and may have more androgenic effect in certain tissues at lower levels.<ref name="Ceponis-2017"/> * ''Anabolic effects'' include growth of [[muscle mass]] and strength, increased [[bone density]] and strength, and stimulation of linear growth and [[bone maturation]]. * ''Androgenic effects'' include [[Developmental biology|maturation]] of the [[sex organs]], particularly the [[Human penis|penis]], and the formation of the [[scrotum]] in the fetus, and after birth (usually at [[puberty]]) a deepening of the [[human voice|voice]], growth of [[facial hair]] (such as the [[beard]]) and [[axillary hair|axillary (underarm) hair]]. Many of these fall into the category of male [[secondary sex characteristics]]. Testosterone effects can also be classified by the age of usual occurrence. For [[postnatal]] effects in both males and females, these are mostly dependent on the levels and duration of circulating [[#Free testosterone|free testosterone]].<ref>{{Cite book |vauthors=Sfetcu N |url=https://books.google.com/books?id=8jF-AwAAQBAJ&dq=Testosterone+effects+can+also+be+classified+by+the+age+of+usual+occurrence.+For+postnatal+effects+in+both+males+and+females%2C+these+are+mostly+dependent+on+the+levels+and+duration+of+circulating+free+testosterone&pg=PA1081 |title=Health & Drugs: Disease, Prescription & Medication |date=2014-05-02 |publisher=Nicolae Sfetcu |language=en |access-date=November 21, 2022 |archive-date=November 18, 2023 |archive-url=https://web.archive.org/web/20231118175431/https://books.google.com/books?id=8jF-AwAAQBAJ&dq=Testosterone+effects+can+also+be+classified+by+the+age+of+usual+occurrence.+For+postnatal+effects+in+both+males+and+females%2C+these+are+mostly+dependent+on+the+levels+and+duration+of+circulating+free+testosterone&pg=PA1081 |url-status=live }}</ref> ==== Before birth ==== Effects before birth are divided into two categories, classified in relation to the stages of development. The first period occurs between 4 and 6 weeks of the gestation. Examples include genital virilisation such as midline fusion, [[Primordial phallus|phallic]] [[urethra]], [[scrotum|scrotal]] thinning and [[rugae|rugation]], and [[Primordial phallus|phallic]] enlargement; although the role of testosterone is far smaller than that of [[dihydrotestosterone]]. There is also development of the [[prostate]] gland and [[seminal vesicle]]s.{{citation needed|date=May 2022}} During the second trimester, androgen level is associated with [[sex]] formation.<ref name="pmid19403051">{{cite journal | vauthors = Swaab DF, Garcia-Falgueras A | title = Sexual differentiation of the human brain in relation to gender identity and sexual orientation | journal = Functional Neurology | volume = 24 | issue = 1 | pages = 17–28 | year = 2009 | pmid = 19403051 }}</ref> Specifically, testosterone, along with anti-Müllerian hormone (AMH) promote growth of the Wolffian duct and degeneration of the Müllerian duct respectively.<ref>{{cite journal | vauthors = Xu HY, Zhang HX, Xiao Z, Qiao J, Li R | title = Regulation of anti-Müllerian hormone (AMH) in males and the associations of serum AMH with the disorders of male fertility | journal = Asian Journal of Andrology | volume = 21 | issue = 2 | pages = 109–114 | date = 2019 | pmid = 30381580 | pmc = 6413543 | doi = 10.4103/aja.aja_83_18 | doi-access = free }}</ref> This period affects the femininization or masculinization of the fetus and can be a better predictor of feminine or masculine behaviours such as sex typed behaviour than an adult's own levels. Prenatal androgens apparently influence interests and engagement in gendered activities and have moderate effects on spatial abilities.<ref>{{cite journal | vauthors = Berenbaum SA | title = Beyond Pink and Blue: The Complexity of Early Androgen Effects on Gender Development | journal = Child Development Perspectives | volume = 12 | issue = 1 | pages = 58–64 | date = March 2018 | pmid = 29736184 | pmc = 5935256 | doi = 10.1111/cdep.12261 }}</ref> Among women with [[congenital adrenal hyperplasia]], a male-typical play in childhood correlated with reduced satisfaction with the female gender and reduced heterosexual interest in adulthood.<ref>{{cite journal | vauthors = Hines M, Brook C, Conway GS | s2cid = 33519930 | title = Androgen and psychosexual development: core gender identity, sexual orientation and recalled childhood gender role behavior in women and men with congenital adrenal hyperplasia (CAH) | journal = Journal of Sex Research | volume = 41 | issue = 1 | pages = 75–81 | date = February 2004 | pmid = 15216426 | doi = 10.1080/00224490409552215 }}</ref> ==== Early infancy ==== Early infancy androgen effects are the least understood. In the first weeks of life for male infants, testosterone levels rise. The levels remain in a pubertal range for a few months, but usually reach the barely detectable levels of childhood by 4–7 months of age.<ref name="pmid4715291">{{cite journal | vauthors = Forest MG, Cathiard AM, Bertrand JA | title = Evidence of testicular activity in early infancy | journal = The Journal of Clinical Endocrinology & Metabolism| volume = 37 | issue = 1 | pages = 148–51 | date = July 1973 | pmid = 4715291 | doi = 10.1210/jcem-37-1-148 }}</ref><ref name="pmid1379488">{{cite journal | vauthors = Corbier P, Edwards DA, Roffi J | title = The neonatal testosterone surge: a comparative study | journal = Archives Internationales de Physiologie, de Biochimie et de Biophysique | volume = 100 | issue = 2 | pages = 127–31 | year = 1992 | pmid = 1379488 | doi = 10.3109/13813459209035274 }}</ref> The function of this rise in humans is unknown. It has been theorized that brain [[virilization|masculinization]] is occurring since no significant changes have been identified in other parts of the body.<ref name="pmid18445234">{{cite journal | vauthors = Dakin CL, Wilson CA, Kalló I, Coen CW, Davies DC | title = Neonatal stimulation of 5-HT(2) receptors reduces androgen receptor expression in the rat anteroventral periventricular nucleus and sexually dimorphic preoptic area | journal = The European Journal of Neuroscience | volume = 27 | issue = 9 | pages = 2473–80 | date = May 2008 | pmid = 18445234 | doi = 10.1111/j.1460-9568.2008.06216.x | s2cid = 23978105 }}</ref> The male brain is masculinized by the aromatization of testosterone into [[estradiol]],<ref name="HäggströmRichfield2014" /> which crosses the [[blood–brain barrier]] and enters the male brain, whereas female fetuses have [[α-fetoprotein]], which binds the estrogen so that female brains are not affected.<ref name="isbn0-495-60300-7">{{cite book | vauthors = Kalat JW | title = Biological psychology | publisher = Wadsworth, Cengage Learning | location = Belmont, Calif | year = 2009 | isbn = 978-0-495-60300-9 | chapter = Reproductive behaviors | chapter-url = https://books.google.com/books?id=ZlSbk5rUY60C&pg=PA321 | page = 321 | access-date = October 8, 2020 | archive-date = January 11, 2023 | archive-url = https://web.archive.org/web/20230111143031/https://books.google.com/books?id=ZlSbk5rUY60C&pg=PA321 | url-status = live }}</ref> ==== Before puberty ==== Before puberty, effects of rising androgen levels occur in both boys and girls. These include adult-type [[body odor]], increased oiliness of skin and hair, [[acne vulgaris|acne]], [[pubarche]] (appearance of [[pubic hair]]), [[axillary hair]] (armpit hair), [[growth spurt]], accelerated [[epiphysis|bone maturation]], and [[facial hair]].<ref name="pmid15815567">{{cite journal | vauthors = Pinyerd B, Zipf WB | title = Puberty-timing is everything! | journal = Journal of Pediatric Nursing | volume = 20 | issue = 2 | pages = 75–82 | year = 2005 | pmid = 15815567 | doi = 10.1016/j.pedn.2004.12.011 | s2cid = 28274693 }}</ref> ==== Pubertal ==== [[Puberty|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|free testosterone]] in the [[blood]]. The effects include:<ref name="pmid15815567" /><ref name= "Ganong_2012">{{cite book | vauthors = Barrett KE, Ganong WF | title = Ganong's Review of Medical Physiology | publisher = TATA McGRAW Hill | isbn = 978-1-259-02753-6 | pages = 423–25 | edition = 24 | year = 2012 }}</ref> * Growth of [[spermatogenic]] tissue in testicles, male [[fertility]], [[human penis|penis]] or [[clitoris]] enlargement, increased [[libido]] and frequency of [[erection]] or clitoral engorgement occurs. * Growth of [[jaw]], brow, chin, and nose and remodeling of facial bone contours, in conjunction with [[human growth hormone]] occurs.<ref name="pmid20501658">{{cite journal | vauthors = Raggatt LJ, Partridge NC | title = Cellular and molecular mechanisms of bone remodeling | journal = The Journal of Biological Chemistry | volume = 285 | issue = 33 | pages = 25103–8 | year = 2010 | pmid = 20501658 | pmc = 2919071 | doi = 10.1074/jbc.R109.041087 | doi-access = free }}</ref> * Completion of bone maturation and termination of growth. This occurs indirectly via [[estradiol]] [[metabolites]] and hence more gradually in men than women. * Increased muscle strength and mass, shoulders become broader and rib cage expands, deepening of voice, growth of the [[Adam's apple]]. * Enlargement of [[sebaceous glands]]. This might cause acne, subcutaneous [[body fat|fat]] in face decreases. * Pubic hair extends to thighs and up toward [[Navel|umbilicus]], development of [[facial hair]] ([[sideburns]], [[beard]], [[moustache]]), loss of scalp hair (androgenetic alopecia), increase in [[chest hair]], periareolar hair, [[perianal]] hair, [[leg hair]], [[Axillary hair|armpit hair]]. ==== Adult ==== Testosterone is necessary for normal [[sperm]] development. It activates genes in [[Sertoli cell]]s, which promote differentiation of [[spermatogonia]]. It regulates acute [[hypothalamic–pituitary–adrenal axis]] (HPA axis) response under dominance challenge.<ref name="pmid18505319">{{cite journal |vauthors=Mehta PH, Jones AC, Josephs RA |title=The social endocrinology of dominance: basal testosterone predicts cortisol changes and behavior following victory and defeat |journal=Journal of Personality and Social Psychology |volume=94 |issue=6 |pages=1078–1093 |date=Jun 2008 |pmid=18505319 |doi=10.1037/0022-3514.94.6.1078 |url=http://homepage.psy.utexas.edu/homepage/faculty/josephs/pdf_documents/index.cfm.pdf |archive-url=https://web.archive.org/web/20090419200557/http://homepage.psy.utexas.edu/homepage/faculty/josephs/pdf_documents/index.cfm.pdf |archive-date=April 19, 2009 |url-status=dead |citeseerx=10.1.1.336.2502}}</ref> Androgens including testosterone enhance muscle growth. Testosterone also regulates the population of [[Thromboxane A2|thromboxane A<sub>2</sub>]] receptors on [[megakaryocytes]] and [[platelets]] and hence platelet aggregation in humans.<ref name="pmid15820970">{{cite journal |vauthors=Ajayi AA, Halushka PV | title = Castration reduces platelet thromboxane A2 receptor density and aggregability |journal=QJM |volume=98 |issue=5 |pages=349–356 |date=May 2005 |pmid=15820970 |doi=10.1093/qjmed/hci054 |doi-access=free}}</ref><ref name="pmid7758179">{{cite journal |vauthors=Ajayi AA, Mathur R, Halushka PV |title=Testosterone increases human platelet thromboxane A2 receptor density and aggregation responses |journal=Circulation |volume=91 |issue=11 |pages=2742–2747 |date=Jun 1995 |pmid=7758179 |doi=10.1161/01.CIR.91.11.2742}}</ref> Adult testosterone effects are more clearly demonstrable in males than in females, but are likely important to both sexes. Some of these effects may decline as testosterone levels might decrease in the later decades of adult life.<ref>{{cite journal | vauthors = Kelsey TW, Li LQ, Mitchell RT, Whelan A, Anderson RA, Wallace WH | title = A validated age-related normative model for male total testosterone shows increasing variance but no decline after age 40 years | journal = PLOS ONE | volume = 9 | issue = 10 | pages = e109346 | date = October 8, 2014 | pmid = 25295520 | pmc = 4190174 | doi = 10.1371/journal.pone.0109346 | bibcode = 2014PLoSO...9j9346K | doi-access = free }}</ref> The brain is also affected by this sexual differentiation;<ref name="pmid19403051" /> the [[enzyme]] [[aromatase]] converts testosterone into [[estradiol]] that is responsible for [[masculinization]] of the brain in male mice. In humans, masculinization of the fetal brain appears, by observation of gender preference in patients with [[congenital disease|congenital]] disorders of androgen formation or androgen receptor function, to be associated with functional androgen receptors.<ref name="pmid11534997">{{cite journal |vauthors=Wilson JD |date=Sep 2001 |title=Androgens, androgen receptors, and male gender role behavior |department=Review |journal=Hormones and Behavior |volume=40 |issue=2 |pages=358–66 |doi=10.1006/hbeh.2001.1684 |pmid=11534997 |s2cid=20480423}}</ref> There are some [[Neuroscience of sex differences|differences between a male and female brain]] that may be due to different testosterone levels, one of them being size: the male human brain is, on average, larger.<ref name="pmid17544382">{{cite journal |vauthors=Cosgrove KP, Mazure CM, Staley JK |date=Oct 2007 |title=Evolving knowledge of sex differences in brain structure, function, and chemistry |journal=Biological Psychiatry |volume=62 |issue=8 |pages=847–55 |doi=10.1016/j.biopsych.2007.03.001 |pmc=2711771 |pmid=17544382}}</ref> === Health effects === Testosterone does not appear to increase the risk of developing [[prostate cancer]]. In people who have undergone testosterone deprivation therapy, testosterone increases beyond the castrate level have been shown to increase the rate of spread of an existing prostate cancer.<ref name="pmid19011298">{{cite book | vauthors = Morgentaler A, Schulman C | chapter = Testosterone and prostate safety | volume = 37 | pages = 197–203 | year = 2009 | pmid = 19011298 | doi = 10.1159/000176054 | isbn = 978-3-8055-8622-1 | series = Frontiers of Hormone Research | title = Advances in the Management of Testosterone Deficiency }}</ref><ref>{{cite journal | vauthors = Rhoden EL, Averbeck MA, Teloken PE | title = Androgen replacement in men undergoing treatment for prostate cancer | journal = The Journal of Sexual Medicine | volume = 5 | issue = 9 | pages = 2202–08 | date = Sep 2008 | pmid = 18638000 | doi = 10.1111/j.1743-6109.2008.00925.x }}</ref><ref>{{cite journal | vauthors = Morgentaler A, Traish AM | title = Shifting the paradigm of testosterone and prostate cancer: the saturation model and the limits of androgen-dependent growth | journal = European Urology | volume = 55 | issue = 2 | pages = 310–20 | date = Feb 2009 | pmid = 18838208 | doi = 10.1016/j.eururo.2008.09.024 }}</ref> Conflicting results have been obtained concerning the importance of [[Testosterone and cardiovascular system|testosterone in maintaining cardiovascular health]].<ref name="pmid17285783">{{cite journal | vauthors = Haddad RM, Kennedy CC, Caples SM, Tracz MJ, Boloña ER, Sideras K, Uraga MV, Erwin PJ, Montori VM | title = Testosterone and cardiovascular risk in men: a systematic review and meta-analysis of randomized placebo-controlled trials | journal = Mayo Clinic Proceedings | volume = 82 | issue = 1 | pages = 29–39 | date = Jan 2007 | pmid = 17285783 | doi = 10.4065/82.1.29 }}</ref><ref name="pmid19464009">{{cite journal | vauthors = Jones TH, Saad F | title = The effects of testosterone on risk factors for, and the mediators of, the atherosclerotic process | journal = Atherosclerosis | volume = 207 | issue = 2 | pages = 318–27 | date = Dec 2009 | pmid = 19464009 | doi = 10.1016/j.atherosclerosis.2009.04.016 }}</ref> Nevertheless, maintaining normal testosterone levels in elderly men has been shown to improve many parameters that are thought to reduce cardiovascular disease risk, such as increased lean body mass, decreased visceral fat mass, decreased total cholesterol, and improved glycemic control.<ref name="pmid18488876">{{cite journal | vauthors = Stanworth RD, Jones TH | title = Testosterone for the aging male; current evidence and recommended practice | journal = Clinical Interventions in Aging | volume = 3 | issue = 1 | pages = 25–44 | year = 2008 | pmid = 18488876 | pmc = 2544367 | doi = 10.2147/CIA.S190 | doi-access = free }}</ref> High androgen levels are associated with [[menstrual cycle]] irregularities in both clinical populations and healthy women.{{better source needed|date=July 2021}}<ref name="pmid17039468">{{cite journal | vauthors = Van Anders SM, Watson NV | title = Menstrual cycle irregularities are associated with testosterone levels in healthy premenopausal women | journal = American Journal of Human Biology | volume = 18 | issue = 6 | pages = 841–44 | year = 2006 | pmid = 17039468 | doi = 10.1002/ajhb.20555 | url = https://deepblue.lib.umich.edu/bitstream/2027.42/83925/1/menstrual_cycle_irregularities_are_associated_with_testosterone_levels_in_healthy_premenopausal_women.pdf | hdl = 2027.42/83925 | s2cid = 32023452 | hdl-access = free | access-date = August 29, 2019 | archive-date = February 13, 2021 | archive-url = https://web.archive.org/web/20210213011139/https://deepblue.lib.umich.edu/bitstream/handle/2027.42/83925/menstrual_cycle_irregularities_are_associated_with_testosterone_levels_in_healthy_premenopausal_women.pdf;jsessionid=AC61249B183224834C48B1216A6F6FC6?sequence=1 | url-status = live }}</ref> There also can be effects in unusual hair growth, [[acne]], weight gain, infertility, and sometimes even scalp hair loss. These effects are seen largely in women with polycystic ovary syndrome ([[PCOS]]). For women with PCOS, hormones like [[birth control pills]] can be used to help lessen the effects of this increased level of testosterone.<ref>{{cite web |author= |date=June 6, 2020 |title=Polycystic Ovary Syndrome (PCOS) |url=https://studentaffairs.psu.edu/health-wellness/healthcare-and-medical-services/health-information-resources/polycystic-ovary#:~:text=In%20PCOS%2C%20the%20ovaries%20do,hair%20loss%20from%20the%20scalp. |access-date=May 14, 2024 |website=Penn State Student Affairs |publisher=Penn State University 2022}}</ref> Attention, memory, and spatial ability are key cognitive functions affected by testosterone in humans. Preliminary evidence suggests that low testosterone levels may be a risk factor for cognitive decline and possibly for [[dementia]] of the Alzheimer's type,<ref name="pmid16785599">{{cite journal |vauthors=Pike CJ, Rosario ER, Nguyen TV |date=Apr 2006 |title=Androgens, aging, and Alzheimer's disease |journal=Endocrine |volume=29 |issue=2 |pages=233–41 |doi=10.1385/ENDO:29:2:233 |pmid=16785599 |s2cid=13852805}}</ref><ref name="pmid15383512">{{cite journal |vauthors=Rosario ER, Chang L, Stanczyk FZ, Pike CJ |date=Sep 2004 |title=Age-related testosterone depletion and the development of Alzheimer disease |journal=JAMA |volume=292 |issue=12 |pages=1431–32 |doi=10.1001/jama.292.12.1431-b |pmid=15383512}}</ref><ref name="pmid15582279">{{cite journal |vauthors=Hogervorst E, Bandelow S, Combrinck M, Smith AD |year=2004 |title=Low free testosterone is an independent risk factor for Alzheimer's disease |journal=Experimental Gerontology |volume=39 |issue=11–12 |pages=1633–39 |doi=10.1016/j.exger.2004.06.019 |pmid=15582279 |s2cid=24803152}}</ref><ref name="pmid14745052">{{cite journal |vauthors=Moffat SD, Zonderman AB, Metter EJ, Kawas C, Blackman MR, Harman SM, Resnick SM |date=Jan 2004 |title=Free testosterone and risk for Alzheimer disease in older men |url=https://escholarship.org/uc/item/9kh190b5 |journal=Neurology |volume=62 |issue=2 |pages=188–93 |doi=10.1212/WNL.62.2.188 |pmid=14745052 |s2cid=10302839 |access-date=April 1, 2022 |archive-date=November 19, 2022 |archive-url=https://web.archive.org/web/20221119073953/https://escholarship.org/uc/item/9kh190b5 |url-status=live }}</ref> a key argument in [[life extension]] medicine for the use of testosterone in anti-aging therapies. Much of the literature, however, suggests a curvilinear or even quadratic relationship between spatial performance and circulating testosterone,<ref name="pmid8817730">{{cite journal |vauthors=Moffat SD, Hampson E |date=Apr 1996 |title=A curvilinear relationship between testosterone and spatial cognition in humans: possible influence of hand preference |journal=Psychoneuroendocrinology |volume=21 |issue=3 |pages=323–37 |doi=10.1016/0306-4530(95)00051-8 |pmid=8817730 |s2cid=7135870}}</ref> where both hypo- and hypersecretion (deficient- and excessive-secretion) of circulating androgens have negative effects on cognition. ==== Immune system and inflammation ==== Testosterone deficiency is associated with an increased risk of [[metabolic syndrome]], [[cardiovascular disease]] and [[Mortality rate|mortality]], which are also sequelae of chronic [[inflammation]].<ref name="pmid30582096">{{cite journal |vauthors=Bianchi VE |date=January 2019 |title=The Anti-Inflammatory Effects of Testosterone |journal=Journal of the Endocrine Society |volume=3 |issue=1 |pages=91–107 |doi=10.1210/js.2018-00186 |pmc=6299269 |pmid=30582096}}</ref> Testosterone plasma concentration inversely correlates to multiple [[biomarker]]s of inflammation including [[C-reactive protein|CRP]], [[interleukin 1 beta]], [[interleukin 6]], [[TNF alpha]] and [[endotoxin]] concentration, as well as [[leukocyte]] count.<ref name="pmid30582096" /> As demonstrated by a [[meta-analysis]], substitution therapy with testosterone results in a significant reduction of inflammatory markers.<ref name="pmid30582096" /> These effects are mediated by different mechanisms with synergistic action.<ref name="pmid30582096" /> In androgen-deficient men with concomitant [[autoimmune thyroiditis]], substitution therapy with testosterone leads to a decrease in [[thyroid autoantibody]] titres and an increase in [[thyroid's secretory capacity]] (SPINA-GT).<ref>{{cite journal |vauthors=Krysiak R, Kowalcze K, Okopień B |date=October 2019 |title=The effect of testosterone on thyroid autoimmunity in euthyroid men with Hashimoto's thyroiditis and low testosterone levels |journal=Journal of Clinical Pharmacy and Therapeutics |volume=44 |issue=5 |pages=742–749 |doi=10.1111/jcpt.12987 |pmid=31183891 |s2cid=184487697 |doi-access=free}}</ref> ==== Medical use ==== {{Main|Testosterone (medication)}} Testosterone is used as a medication for the treatment of [[male hypogonadism]], [[gender dysphoria]], and certain types of [[breast cancer]].<ref name="AHFS2016" /><ref>{{cite web |title=List of Gender Dysphoria Medications (6 Compared) |url=https://www.drugs.com/condition/gender-dysphoria.html |access-date=6 May 2020 |website=Drugs.com |language=en |archive-date=April 26, 2020 |archive-url=https://web.archive.org/web/20200426180544/https://www.drugs.com/condition/gender-dysphoria.html |url-status=live }}</ref> This is known as [[hormone replacement therapy]] (HRT) or testosterone replacement therapy (TRT), which maintains serum testosterone levels in the normal range. [[andropause|Decline of testosterone production with age]] has led to interest in [[androgen replacement therapy]].<ref name="pmid16985841">{{cite journal |vauthors=Myers JB, Meacham RB |year=2003 |title=Androgen replacement therapy in the aging male |journal=Reviews in Urology |volume=5 |issue=4 |pages=216–226 |pmc=1508369 |pmid=16985841}}</ref> It is unclear if the use of testosterone for low levels due to aging is beneficial or harmful.<ref name="FDA2015">{{cite web |date=3 March 2015 |title=Testosterone Products: Drug Safety Communication – FDA Cautions About Using Testosterone Products for Low Testosterone Due to Aging; Requires Labeling Change to Inform of Possible Increased Risk of Heart Attack And Stroke |url=https://www.fda.gov/drugs/drug-safety-and-availability/fda-drug-safety-communication-fda-cautions-about-using-testosterone-products-low-testosterone-due |access-date=5 March 2015 |work=[[FDA]] |archive-date=April 22, 2021 |archive-url=https://web.archive.org/web/20210422205532/https://www.fda.gov/drugs/drug-safety-and-availability/fda-drug-safety-communication-fda-cautions-about-using-testosterone-products-low-testosterone-due |url-status=live }}</ref> Testosterone is included in the [[WHO Model List of Essential Medicines|World Health Organization's list of essential medicines]], which are the most important medications needed in a basic [[health system]].<ref name="WHO2015E">{{cite web |date=April 2015 |title=19th WHO Model List of Essential Medicines (April 2015) |url=https://www.who.int/medicines/publications/essentialmedicines/EML2015_8-May-15.pdf |access-date=May 10, 2015 |publisher=WHO |archive-date=May 13, 2015 |archive-url=https://web.archive.org/web/20150513043105/http://www.who.int/medicines/publications/essentialmedicines/EML2015_8-May-15.pdf |url-status=live }}</ref> It is available as a [[generic medication]].<ref name="AHFS2016" /> It can be administered as a cream or [[transdermal patch]] that is applied to the skin, by [[intramuscular injection|injection into a muscle]], as a tablet that is [[Buccal administration|placed in the cheek]], or by ingestion.<ref name="AHFS2016" /> Common [[side effect]]s from testosterone medication include [[acne]], [[swelling (medical)|swelling]], and [[gynecomastia|breast enlargement in males]].<ref name="AHFS2016" /> Serious side effects may include [[liver toxicity]], [[Cardiovascular disease|heart disease]] (though a randomized trial found no evidence of major adverse cardiac events compared to placebo in men with low testosterone<ref>{{cite journal | vauthors = Lincoff AM, Bhasin S, Flevaris P, Mitchell LM, Basaria S, Boden WE, Cunningham GR, Granger CB, Khera M, Thompson IM, Wang Q, Wolski K, Davey D, Kalahasti V, Khan N, Miller MG, Snabes MC, Chan A, Dubcenco E, Li X, Yi T, Huang B, Pencina KM, Travison TG, Nissen SE | title = Cardiovascular Safety of Testosterone-Replacement Therapy | journal = The New England Journal of Medicine | volume = 389 | issue = 2 | pages = 107–117 | date = July 2023 | pmid = 37326322 | doi = 10.1056/NEJMoa2215025 | s2cid = 259176370 }}</ref>), and behavioral changes.<ref name="AHFS2016" /> Women and children who are exposed may develop [[virilization]].<ref name="AHFS2016" /> It is recommended that individuals with [[prostate cancer]] not use the medication.<ref name="AHFS2016" /> It can cause harm if used during [[pregnancy]] or [[breastfeeding]].<ref name="AHFS2016" /> 2020 guidelines from the [[American College of Physicians]] support the discussion of [[testosterone (medication)|testosterone]] treatment in adult men with age-related [[Low T|low levels of testosterone]] who have [[sexual dysfunction]]. They recommend yearly evaluation regarding possible improvement and, if none, to discontinue testosterone; physicians should consider intramuscular treatments, rather than transdermal treatments, due to costs and since the effectiveness and harm of either method is similar. Testosterone treatment for reasons other than possible improvement of sexual dysfunction may not be recommended.<ref name="ANN-20200106">{{cite journal |vauthors=Qaseem A, Horwitch CA, Vijan S, Etxeandia-Ikobaltzeta I, Kansagara D |date=January 2020 |title=Testosterone Treatment in Adult Men With Age-Related Low Testosterone: A Clinical Guideline From the American College of Physicians |journal=Annals of Internal Medicine |volume=172 |issue=2 |pages=126–133 |doi=10.7326/M19-0882 |pmid=31905405 |doi-access=}}</ref><ref name="MSCP-20200107">{{cite news |date=7 January 2020 |title=New Guideline for Testosterone Treatment in Men With 'Low T' |work=Medscape.com |url=https://www.medscape.com/viewarticle/923449 |access-date=7 January 2020 |vauthors=Parry NM |archive-date=January 8, 2020 |archive-url=https://web.archive.org/web/20200108011908/https://www.medscape.com/viewarticle/923449 |url-status=live }}</ref> No immediate short term effects on mood or behavior were found from the administration of [[wikt:supraphysiological|supraphysiologic]] doses of testosterone for 10 weeks on 43 healthy men.<ref name="pmid8637535">{{cite journal |vauthors=Bhasin S, Storer TW, Berman N, Callegari C, Clevenger B, Phillips J, Bunnell TJ, Tricker R, Shirazi A, Casaburi R |date=July 1996 |title=The effects of supraphysiologic doses of testosterone on muscle size and strength in normal men |journal=The New England Journal of Medicine |volume=335 |issue=1 |pages=1–7 |doi=10.1056/NEJM199607043350101 |pmid=8637535 |s2cid=73721690 |doi-access=free}}</ref> === Behavioural correlations === ====Sexual arousal==== {{See also|Hormones and sexual arousal}} Testosterone levels follow a [[circadian rhythm]] that peaks early each day, regardless of sexual activity.<ref name="pmid5061159">{{cite journal | vauthors = Fox CA, Ismail AA, Love DN, Kirkham KE, Loraine JA | title = Studies on the relationship between plasma testosterone levels and human sexual activity | journal = The Journal of Endocrinology | volume = 52 | issue = 1 | pages = 51–8 | date = Jan 1972 | pmid = 5061159 | doi = 10.1677/joe.0.0520051 }}</ref> In women, correlations may exist between positive orgasm experience and testosterone levels. Studies have shown small or inconsistent correlations between testosterone levels and male orgasm experience, as well as sexual assertiveness in both sexes.<ref name="pmid19409392">{{cite journal | vauthors = van Anders SM, Dunn EJ | title = Are gonadal steroids linked with orgasm perceptions and sexual assertiveness in women and men? | journal = Hormones and Behavior | volume = 56 | issue = 2 | pages = 206–213 | date = August 2009 | pmid = 19409392 | doi = 10.1016/j.yhbeh.2009.04.007 | hdl-access = free | s2cid = 14588630 | hdl = 2027.42/83876 }}</ref><ref>{{cite journal | vauthors = Cashdan E | title = Hormones, sex, and status in women | journal = Hormones and Behavior | volume = 29 | issue = 3 | pages = 354–366 | date = September 1995 | pmid = 7490010 | doi = 10.1006/hbeh.1995.1025 | s2cid = 40567580 }}</ref> Sexual arousal and [[masturbation]] in women produce small increases in testosterone concentrations.<ref name="pmid10367606">{{cite journal | vauthors = Exton MS, Bindert A, Krüger T, Scheller F, Hartmann U, Schedlowski M | title = Cardiovascular and endocrine alterations after masturbation-induced orgasm in women | journal = Psychosomatic Medicine | volume = 61 | issue = 3 | pages = 280–89 | year = 1999 | pmid = 10367606 | doi = 10.1097/00006842-199905000-00005 }}</ref> The [[Blood plasma|plasma]] levels of various [[steroids]] significantly increase after masturbation in men and the testosterone levels correlate to those levels.<ref name="pmid135817">{{cite journal | vauthors = Purvis K, Landgren BM, Cekan Z, Diczfalusy E | title = Endocrine effects of masturbation in men | journal = The Journal of Endocrinology | volume = 70 | issue = 3 | pages = 439–44 | date = Sep 1976 | pmid = 135817 | doi = 10.1677/joe.0.0700439 }}</ref> ====Mammalian studies==== Studies conducted in rats have indicated that their degree of sexual arousal is sensitive to reductions in testosterone. When testosterone-deprived rats were given medium levels of testosterone, their sexual behaviours (copulation, partner preference, etc.) resumed, but not when given low amounts of the same hormone. Therefore, these mammals may provide a model for studying clinical populations among humans with sexual arousal deficits such as [[hypoactive sexual desire disorder]].<ref name="pmid20920505">{{cite journal | vauthors = Harding SM, Velotta JP | s2cid = 1577450 | title = Comparing the relative amount of testosterone required to restore sexual arousal, motivation, and performance in male rats | journal = Hormones and Behavior | volume = 59 | issue = 5 | pages = 666–73 | date = May 2011 | pmid = 20920505 | doi = 10.1016/j.yhbeh.2010.09.009 }}</ref> Every mammalian species examined demonstrated a marked increase in a male's testosterone level upon encountering a {{em|novel}} female. The reflexive testosterone increases in male mice is related to the male's initial level of sexual arousal.<ref name="pmid16828762">{{cite journal | vauthors = James PJ, Nyby JG, Saviolakis GA | s2cid = 36436418 | title = Sexually stimulated testosterone release in male mice (Mus musculus): roles of genotype and sexual arousal | journal = Hormones and Behavior | volume = 50 | issue = 3 | pages = 424–31 | date = Sep 2006 | pmid = 16828762 | doi = 10.1016/j.yhbeh.2006.05.004 }}</ref> In non-human primates, it may be that testosterone in puberty stimulates sexual arousal, which allows the primate to increasingly seek out sexual experiences with females and thus creates a sexual preference for females.<ref name="pmid11534996">{{cite journal | vauthors = Wallen K | s2cid = 2214664 | title = Sex and context: hormones and primate sexual motivation | journal = Hormones and Behavior | volume = 40 | issue = 2 | pages = 339–57 | date = Sep 2001 | pmid = 11534996 | doi = 10.1006/hbeh.2001.1696 | citeseerx = 10.1.1.22.5968 }}</ref> Some research has also indicated that if testosterone is eliminated in an adult male human or other adult male primate's system, its sexual motivation decreases, but there is no corresponding decrease in ability to engage in sexual activity (mounting, ejaculating, etc.).<ref name="pmid11534996"/> In accordance with [[sperm competition]] theory, testosterone levels are shown to increase as a response to previously neutral stimuli when conditioned to become sexual in male rats.<ref name="pmid6665072">{{cite journal | vauthors = Hart BL | s2cid = 42155431 | title = Role of testosterone secretion and penile reflexes in sexual behavior and sperm competition in male rats: a theoretical contribution | journal = Physiology & Behavior | volume = 31 | issue = 6 | pages = 823–27 | date = Dec 1983 | pmid = 6665072 | doi = 10.1016/0031-9384(83)90279-2 }}</ref> This reaction engages penile reflexes (such as erection and ejaculation) that aid in sperm competition when more than one male is present in mating encounters, allowing for more production of successful sperm and a higher chance of reproduction. ====Males==== In men, higher levels of testosterone are associated with periods of sexual activity.<ref name="pmid1275688">{{cite journal | vauthors = Kraemer HC, Becker HB, Brodie HK, Doering CH, Moos RH, Hamburg DA | s2cid = 38283107 | title = Orgasmic frequency and plasma testosterone levels in normal human males | journal = Archives of Sexual Behavior | volume = 5 | issue = 2 | pages = 125–32 | date = Mar 1976 | pmid = 1275688 | doi = 10.1007/BF01541869 }}</ref><ref name=Roney_2003>{{cite journal | vauthors = Roney JR, Mahler SV, Maestripieri D | title = Behavioral and hormonal responses of men to brief interactions with women | journal = Evolution and Human Behavior | year = 2003 | volume = 24 | issue = 6 | pages = 365–75 | doi = 10.1016/S1090-5138(03)00053-9 | bibcode = 2003EHumB..24..365R }}</ref> Men who watch a sexually explicit movie have an average increase of 35% in testosterone, peaking at 60–90 minutes after the end of the film, but no increase is seen in men who watch sexually neutral films.<ref>{{cite journal | vauthors = Pirke KM, Kockott G, Dittmar F | s2cid = 43495791 | title = Psychosexual stimulation and plasma testosterone in man | journal = Archives of Sexual Behavior | volume = 3 | issue = 6 | pages = 577–84 | date = Nov 1974 | pmid = 4429441 | doi = 10.1007/BF01541140 }}</ref> Men who watch sexually explicit films also report increased motivation and competitiveness, and decreased exhaustion.<ref name="pmid4001279">{{cite journal | vauthors = Hellhammer DH, Hubert W, Schürmeyer T | s2cid = 41819670 | title = Changes in saliva testosterone after psychological stimulation in men | journal = Psychoneuroendocrinology | volume = 10 | issue = 1 | pages = 77–81 | year = 1985 | pmid = 4001279 | doi = 10.1016/0306-4530(85)90041-1 }}</ref> A link has also been found between relaxation following sexual arousal and testosterone levels.<ref name="pmid3602262">{{cite journal | vauthors = Rowland DL, Heiman JR, Gladue BA, Hatch JP, Doering CH, Weiler SJ | s2cid = 35309934 | title = Endocrine, psychological and genital response to sexual arousal in men | journal = Psychoneuroendocrinology | volume = 12 | issue = 2 | pages = 149–58 | year = 1987 | pmid = 3602262 | doi = 10.1016/0306-4530(87)90045-X }}</ref> ====Females==== Androgens may modulate the physiology of vaginal tissue and contribute to female genital sexual arousal.<ref name="pmid12007897">{{cite journal | vauthors = Traish AM, Kim N, Min K, Munarriz R, Goldstein I | title = Role of androgens in female genital sexual arousal: receptor expression, structure, and function | journal = Fertility and Sterility | volume = 77 | issue = Suppl 4 | pages = S11–8 | date = Apr 2002 | pmid = 12007897 | doi = 10.1016/s0015-0282(02)02978-3 | doi-access = free }}</ref> Women's level of testosterone is higher when measured pre-intercourse vs. pre-cuddling, as well as post-intercourse vs. post-cuddling.<ref name="pmid17320881">{{cite journal | vauthors = van Anders SM, Hamilton LD, Schmidt N, Watson NV | s2cid = 5718960 | title = Associations between testosterone secretion and sexual activity in women | journal = Hormones and Behavior | volume = 51 | issue = 4 | pages = 477–82 | date = Apr 2007 | pmid = 17320881 | doi = 10.1016/j.yhbeh.2007.01.003 | hdl = 2027.42/83880 | hdl-access = free }}</ref> There is a time lag effect when testosterone is administered, on genital arousal in women. In addition, a continuous increase in vaginal sexual arousal may result in higher genital sensations and sexual appetitive behaviors.<ref name="pmid10665617">{{cite journal | vauthors = Tuiten A, Van Honk J, Koppeschaar H, Bernaards C, Thijssen J, Verbaten R | title = Time course of effects of testosterone administration on sexual arousal in women | journal = Archives of General Psychiatry | volume = 57 | issue = 2 | pages = 149–53; discussion 155–6 | date = Feb 2000 | pmid = 10665617 | doi = 10.1001/archpsyc.57.2.149 | doi-access = }}</ref> When females have a higher baseline level of testosterone, they have higher increases in sexual arousal levels but smaller increases in testosterone, indicating a ceiling effect on testosterone levels in females. Sexual thoughts also change the level of testosterone but not the level of cortisol in the female body, and hormonal contraceptives may affect the variation in testosterone response to sexual thoughts.<ref name="pmid21185838">{{cite journal | vauthors = Goldey KL, van Anders SM | s2cid = 18691358 | title = Sexy thoughts: effects of sexual cognitions on testosterone, cortisol, and arousal in women | journal = Hormones and Behavior | volume = 59 | issue = 5 | pages = 754–64 | date = May 2011 | pmid = 21185838 | doi = 10.1016/j.yhbeh.2010.12.005 | hdl = 2027.42/83874 | url = https://deepblue.lib.umich.edu/bitstream/2027.42/83874/1/sexy_thoughts.pdf | hdl-access = free | access-date = September 23, 2019 | archive-date = August 29, 2021 | archive-url = https://web.archive.org/web/20210829082052/https://deepblue.lib.umich.edu/bitstream/handle/2027.42/83874/sexy_thoughts.pdf;jsessionid=AD3535C13DF1611007860B6D237B0C3E?sequence=1 | url-status = live }}</ref> Testosterone may prove to be an effective treatment in [[female sexual arousal disorder]]s,<ref name="pmid15889125">{{cite journal | vauthors = Bolour S, Braunstein G | title = Testosterone therapy in women: a review | journal = International Journal of Impotence Research | volume = 17 | issue = 5 | pages = 399–408 | year = 2005 | pmid = 15889125 | doi = 10.1038/sj.ijir.3901334 | doi-access = }}</ref> and is available as a [[testosterone (patch)|dermal patch]]. There is no FDA-approved androgen preparation for the treatment of androgen insufficiency; however, it has been used as an [[off-label use]] to treat low [[libido]] and [[female sexual arousal disorder|sexual dysfunction]] in older women. Testosterone may be a treatment for postmenopausal women as long as they are effectively estrogenized.<ref name="pmid15889125"/> ====Romantic relationships==== [[Falling in love]] has been linked with decreases in men's testosterone levels while mixed changes are reported for women's testosterone levels.<ref name="pmid31683520">{{cite journal | vauthors = Sorokowski P, et al. | title = Romantic Love and Reproductive Hormones in Women | journal = Int J Environ Res Public Health| volume = 16 | issue = 21 | date = October 2019 | page = 4224 | pmid = 31683520| doi = 10.3390/ijerph16214224 | pmc = 6861983 | doi-access = free }}</ref><ref name="pmid15177709">{{cite journal | vauthors = Marazziti D, Canale D | s2cid = 24651931 | title = Hormonal changes when falling in love | journal = Psychoneuroendocrinology | volume = 29 | issue = 7 | pages = 931–36 | date = August 2004 | pmid = 15177709 | doi = 10.1016/j.psyneuen.2003.08.006 }}</ref> There has been speculation that these changes in testosterone result in the temporary reduction of differences in behavior between the sexes.<ref name="pmid15177709" /> However, the testosterone changes observed do not seem to be maintained as relationships develop over time.<ref name="pmid31683520" /><ref name="pmid15177709" /> Men who produce less testosterone are more likely to be in a relationship<ref name="pmid16621328">{{cite journal | vauthors = van Anders SM, Watson NV | s2cid = 22477678 | title = Relationship status and testosterone in North American heterosexual and non-heterosexual men and women: cross-sectional and longitudinal data | journal = Psychoneuroendocrinology | volume = 31 | issue = 6 | pages = 715–23 | date = July 2006 | pmid = 16621328 | doi = 10.1016/j.psyneuen.2006.01.008 | hdl = 2027.42/83924 | hdl-access = free }}</ref> or married,<ref name = "Booth_Dabbs_1993"/> and men who produce more testosterone are more likely to divorce.<ref name = "Booth_Dabbs_1993">{{cite journal | vauthors = Booth A, Dabbs JM|title=Testosterone and Men's Marriages | journal = Social Forces | year = 1993 | volume = 72 | issue = 2 | pages = 463–77 | doi = 10.1093/sf/72.2.463}}</ref> Marriage or commitment could cause a decrease in testosterone levels.<ref name=Mazur_Michalek_1998>{{cite journal | vauthors = Mazur A, Michalek J | title = Marriage, Divorce, and Male Testosterone | journal = Social Forces | year = 1998 | volume = 77 | issue = 1 | pages = 315–30 | doi = 10.1093/sf/77.1.315 }}</ref> Single men who have not had relationship experience have lower testosterone levels than single men with experience. It is suggested that these single men with prior experience are in a more competitive state than their non-experienced counterparts.<ref name="pmid26190409">{{cite journal | vauthors = Gray PB, Chapman JF, Burnham TC, McIntyre MH, Lipson SF, Ellison PT | s2cid = 33812118 | title = Human male pair bonding and testosterone | journal = Human Nature | volume = 15 | issue = 2 | pages = 119–31 | date = Jun 2004 | pmid = 26190409 | doi = 10.1007/s12110-004-1016-6 }}</ref> Married men who engage in bond-maintenance activities such as spending the day with their spouse or child have no different testosterone levels compared to times when they do not engage in such activities. Collectively, these results suggest that the presence of competitive activities rather than bond-maintenance activities is more relevant to changes in testosterone levels.<ref name="pmid15219639">{{cite journal | vauthors = Gray PB, Campbell BC, Marlowe FW, Lipson SF, Ellison PT | s2cid = 18107730 | title = Social variables predict between-subject but not day-to-day variation in the testosterone of US men | journal = Psychoneuroendocrinology | volume = 29 | issue = 9 | pages = 1153–62 | date = Oct 2004 | pmid = 15219639 | doi = 10.1016/j.psyneuen.2004.01.008 }}</ref> Men who produce more testosterone are more likely to engage in extramarital sex.<ref name=Booth_Dabbs_1993/> Testosterone levels do not rely on physical presence of a partner; testosterone levels of men engaging in same-city and long-distance relationships are similar.<ref name="pmid16621328" /> Physical presence may be required for women who are in relationships for the testosterone–partner interaction, where same-city partnered women have lower testosterone levels than long-distance partnered women.<ref name="pmid17196592">{{cite journal | vauthors = van Anders SM, Watson NV | s2cid = 30710035 | title = Testosterone levels in women and men who are single, in long-distance relationships, or same-city relationships | journal = Hormones and Behavior | volume = 51 | issue = 2 | pages = 286–91 | date = Feb 2007 | pmid = 17196592 | doi = 10.1016/j.yhbeh.2006.11.005 | hdl = 2027.42/83915 | hdl-access = free }}</ref> ====Fatherhood==== Fatherhood decreases testosterone levels in men, suggesting that the emotions and behaviour tied to paternal care decrease testosterone levels. In humans and other species that utilize [[Allomothering|allomaternal care]], paternal investment in offspring is beneficial to said offspring's survival because it allows the two parents to raise multiple children simultaneously. This increases the reproductive fitness of the parents because their offspring are more likely to survive and reproduce. Paternal care increases offspring survival due to increased access to higher quality food and reduced physical and immunological threats.<ref>{{cite journal | vauthors = Bribiescas RG, Ellison PT, Gray PB |date=December 2012|title=Male Life History, Reproductive Effort, and the Evolution of the Genus Homo|journal=Current Anthropology|volume=53|issue=S6|pages=S424–S435|doi=10.1086/667538|s2cid=83046141}}</ref> This is particularly beneficial for humans since offspring are dependent on parents for extended periods of time and mothers have relatively short inter-birth intervals.<ref>{{cite journal | vauthors = Kramer KL, Otárola-Castillo E | title = When mothers need others: The impact of hominin life history evolution on cooperative breeding | journal = Journal of Human Evolution | volume = 84 | pages = 16–24 | date = July 2015 | pmid = 25843884 | doi = 10.1016/j.jhevol.2015.01.009 | doi-access = | bibcode = 2015JHumE..84...16K }}</ref> While the extent of paternal care varies between cultures, higher investment in direct child care has been seen to be correlated with lower average testosterone levels as well as temporary fluctuations.<ref>{{cite journal | vauthors = Gettler LT | title = Applying socioendocrinology to evolutionary models: fatherhood and physiology | journal = Evolutionary Anthropology | volume = 23 | issue = 4 | pages = 146–60 | date = 2014-07-08 | pmid = 25116846 | doi = 10.1002/evan.21412 | s2cid = 438574 }}</ref> For instance, fluctuation in testosterone levels when a child is in distress has been found to be indicative of fathering styles. If a father's testosterone levels decrease in response to hearing their baby cry, it is an indication of empathizing with the baby. This is associated with increased nurturing behavior and better outcomes for the infant.<ref>{{Cite web|url=https://psychcentral.com/news/2015/10/30/parenting-skills-influenced-by-testosterone-levels-empathy/94175.html|title=Parenting Skills Influenced by Testosterone Levels, Empathy| vauthors = Nauert R |date=2015-10-30|website=Psych Central|access-date=December 9, 2018|archive-date=September 30, 2020|archive-url=https://web.archive.org/web/20200930221912/https://psychcentral.com/news/2015/10/30/parenting-skills-influenced-by-testosterone-levels-empathy/94175.html|url-status=dead}}</ref> ====Motivation==== Testosterone levels play a major role in risk-taking during financial decisions.<ref name= "pmid19706398">{{cite journal | vauthors = Sapienza P, Zingales L, Maestripieri D | title = Gender differences in financial risk aversion and career choices are affected by testosterone | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 106 | issue = 36 | pages = 15268–15273 | date = September 2009 | pmid = 19706398 | pmc = 2741240 | doi = 10.1073/pnas.0907352106 | doi-access = free | bibcode = 2009PNAS..10615268S }}</ref><ref name= "Apicella_2008">{{cite journal | vauthors = Apicella CL, Dreber A, Campbell B, Gray PB, Hoffman M, Little AC | title = Testosterone and financial risk preferences | journal = Evolution and Human Behavior | volume = 29 | issue = 6 | pages = 384–90 |date= November 2008 | doi = 10.1016/j.evolhumbehav.2008.07.001 | bibcode = 2008EHumB..29..384A }}</ref> Higher testosterone levels in men reduce the risk of becoming or staying unemployed.<ref>{{cite journal | vauthors = Eibich P, Kanabar R, Plum A, Schmied J | title = In and out of unemployment-Labour market transitions and the role of testosterone | journal = Economics and Human Biology | volume = 46 | pages = 101123 | date = August 2022 | pmid = 35338911 | doi = 10.1016/j.ehb.2022.101123 | s2cid = 245383323 | doi-access = free | hdl = 10419/267153 | hdl-access = free }}</ref> Research has also found that heightened levels of testosterone and [[cortisol]] are associated with an increased risk of impulsive and violent criminal behavior.<ref>{{Cite news |vauthors=Dolan EW |date=2022-12-09 |title=Testosterone and cortisol levels are linked to criminal behavior, according to new research |url=https://www.psypost.org/2022/12/testosterone-and-cortisol-levels-are-linked-to-criminal-behavior-according-to-new-research-64477 |access-date=2023-08-09 |newspaper=Psypost – Psychology News |language=en-US |archive-date=August 10, 2023 |archive-url=https://web.archive.org/web/20230810230437/https://www.psypost.org/2022/12/testosterone-and-cortisol-levels-are-linked-to-criminal-behavior-according-to-new-research-64477 |url-status=live }}</ref> On the other hand, elevated testosterone in men may increase their generosity, primarily to attract a potential mate.<ref>{{cite web | url=https://medicalxpress.com/news/2021-03-testosterone-impact-generosity.amp | title=Study shows that testosterone levels can have an impact on generosity | access-date=April 2, 2023 | archive-date=April 2, 2023 | archive-url=https://web.archive.org/web/20230402012017/https://medicalxpress.com/news/2021-03-testosterone-impact-generosity.amp | url-status=live }}</ref><ref>{{cite journal | vauthors = Dreher JC, Dunne S, Pazderska A, Frodl T, Nolan JJ, O'Doherty JP | title = Testosterone causes both prosocial and antisocial status-enhancing behaviors in human males | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 113 | issue = 41 | pages = 11633–11638 | date = October 2016 | pmid = 27671627 | pmc = 5068300 | doi = 10.1073/pnas.1608085113 | bibcode = 2016PNAS..11311633D | doi-access = free }}</ref> ==== Aggression and criminality {{anchor|Aggression}}{{anchor|Criminality}} ==== {{See also|Aggression#Testosterone|Biosocial criminology}} Most studies support a link between adult criminality and testosterone.<ref name="Armstrong_2022">{{cite journal |vauthors=Armstrong TA, Boisvert DL, Wells J, Lewis RH, Cooke EM, Woeckener M, Kavish N, Vietto N, Harper JM |date=November 2022 |title=Testosterone, cortisol, and criminal behavior in men and women |journal=Hormones and Behavior |volume=146 |pages=105260 |doi=10.1016/j.yhbeh.2022.105260 |pmid=36122515 |s2cid=252285821}}</ref><ref name="pmid1757712">{{cite journal | vauthors = Dabbs JM, Jurkovic GJ, Frady RL | title = Salivary testosterone and cortisol among late adolescent male offenders | journal = Journal of Abnormal Child Psychology | volume = 19 | issue = 4 | pages = 469–78 | date = August 1991 | pmid = 1757712 | doi = 10.1007/BF00919089 | s2cid = 647349 }}</ref><ref>{{cite web | vauthors = Barber N | date = 15 July 2009 | title = Sex, violence, and hormones: Why young men are horny and violent | url = https://www.psychologytoday.com/us/blog/the-human-beast/200907/sex-violence-and-hormones | work = Psychology Today | access-date = May 19, 2023 | archive-date = May 2, 2024 | archive-url = https://web.archive.org/web/20240502041019/https://www.psychologytoday.com/us/blog/the-human-beast/200907/sex-violence-and-hormones | url-status = live }}</ref><ref>{{cite journal | vauthors = Dabbs Jr JM, Carr TS, Frady RL, Riad JK | title = Testosterone, crime, and misbehavior among 692 male prison inmates. | journal = Personality and Individual Differences | date = May 1995 | volume = 18 | issue = 5 | pages = 627–633 | doi = 10.1016/0191-8869(94)00177-T }}</ref> Nearly all studies of juvenile delinquency and testosterone are not significant. Most studies have found testosterone to be associated with behaviors or personality traits linked with [[Antisocial personality disorder|antisocial behavior]]<ref name="pmid24631306">{{cite journal | vauthors = Welker KM, Lozoya E, Campbell JA, Neumann CS, Carré JM | title = Testosterone, cortisol, and psychopathic traits in men and women | journal = Physiology & Behavior | volume = 129 | issue = | pages = 230–6 | date = April 2014 | pmid = 24631306 | doi = 10.1016/j.physbeh.2014.02.057 | s2cid = 23683791 }}</ref> and [[alcoholism]]. Many studies{{Which|date=June 2023}} have been undertaken on the relationship between more general aggressive behavior, and feelings, and testosterone. About half of studies have found a relationship and about half, no relationship.<ref name="isbn0-12-373612-9">{{cite book | vauthors = Wright J, Ellis L, Beaver K | title = Handbook of crime correlates | url = https://archive.org/details/handbookcrimecor00elli | url-access = limited | publisher = Academic Press | location = San Diego | year = 2009 | pages =[https://archive.org/details/handbookcrimecor00elli/page/n8 208]–10 | isbn = 978-0-12-373612-3 }}</ref> Studies have found that testosterone facilitates aggression by modulating [[vasopressin]] receptors in the [[hypothalamus]].<ref>{{cite journal | vauthors = Delville Y, Mansour KM, Ferris CF | s2cid = 23870320 | title = Testosterone facilitates aggression by modulating vasopressin receptors in the hypothalamus | journal = Physiology & Behavior | volume = 60 | issue = 1 | pages = 25–9 | date = July 1996 | pmid = 8804638 | doi = 10.1016/0031-9384(95)02246-5 }}</ref> There are two theories on the role of testosterone in aggression and competition.<ref name="Archer_2006">{{cite journal |vauthors=Archer J |s2cid=26405251 |title=Testosterone and human aggression: an evaluation of the challenge hypothesis |journal=Neuroscience and Biobehavioral Reviews |volume=30 |issue=3 |pages=319–345 |date=2006 |pmid=16483890 |doi=10.1016/j.neubiorev.2004.12.007 |url=http://www.homepage.psy.utexas.edu/homepage/faculty/josephs/pdf_documents/Arch_Chall_NBR.pdf |archive-url=https://web.archive.org/web/20160109111144/http://www.homepage.psy.utexas.edu/HomePage/faculty/josephs/pdf_documents/Arch_Chall_NBR.pdf |archive-date=January 9, 2016 |url-status=dead}}</ref> The first is the [[challenge hypothesis]] which states that testosterone would increase during puberty, thus facilitating reproductive and competitive behavior which would include aggression.<ref name="Archer_2006" /> It is therefore the challenge of competition among males that facilitates aggression and violence.<ref name="Archer_2006" /> Studies conducted have found direct correlation between testosterone and dominance, especially among the most violent criminals in prison who had the highest testosterone.<ref name="Archer_2006" /> The same research found fathers (outside competitive environments) had the lowest testosterone levels compared to other males.<ref name="Archer_2006" /> The second theory is similar and known as "[[Evolutionary neuroandrogenic theory|evolutionary neuroandrogenic (ENA) theory]] of male aggression".<ref name = "Ellis_2015">{{cite journal |vauthors=Ellis L, Hoskin AW |title=The evolutionary neuroandrogenic theory of criminal behavior expanded |url=https://www.researchgate.net/publication/276151720 |journal=Aggression and Violent Behavior |pages=61–74 |volume=24 |doi=10.1016/j.avb.2015.05.002 |year=2015}}</ref><ref>{{cite journal |vauthors=Hoskin AW, Ellis L |title=Fetal Testosterone and Criminality: Test of Evolutionary Neuroandrogenic Theory |url=https://www.researchgate.net/publication/270007761 |journal=Criminology |pages=54–73 |volume=53 |issue=1 |doi=10.1111/1745-9125.12056 |year=2015}}</ref> Testosterone and other androgens have evolved to masculinize a brain to be competitive, even to the point of risking harm to the person and others. By doing so, individuals with masculinized brains as a result of pre-natal and adult life testosterone and androgens, enhance their resource acquiring abilities to survive, attract and copulate with mates as much as possible.<ref name="Ellis_2015" /> The masculinization of the brain is not just mediated by testosterone levels at the adult stage, but also testosterone exposure in the womb. Higher pre-natal testosterone indicated by a low [[digit ratio]] as well as adult testosterone levels increased risk of fouls or aggression among male players in a soccer game.<ref>{{cite journal |vauthors=Perciavalle V, Di Corrado D, Petralia MC, Gurrisi L, Massimino S, Coco M |title=The second-to-fourth digit ratio correlates with aggressive behavior in professional soccer players |journal=Molecular Medicine Reports |volume=7 |issue=6 |pages=1733–1738 |date=Jun 2013 |pmid=23588344 |pmc=3694562 |doi=10.3892/mmr.2013.1426}}</ref> Studies have found higher pre-natal testosterone or lower digit ratio to be correlated with higher aggression.<ref name="Bailey & Hurd 2005">{{cite journal |vauthors=Bailey AA, Hurd PL |s2cid=16606349 |title=Finger length ratio (2D:4D) correlates with physical aggression in men but not in women |journal=Biological Psychology |volume=68 |issue=3 |pages=215–222 |date=Mar 2005 |pmid=15620791 |doi=10.1016/j.biopsycho.2004.05.001}}<br/>Lay summary: {{cite web |title=Finger Length Predicts Aggression in Men |url=http://www.livescience.com/193-finger-length-predicts-aggression-men.html |date=2 March 2005 |website=[[LiveScience]] |access-date=December 30, 2015 |archive-date=September 29, 2017 |archive-url=https://web.archive.org/web/20170929092006/https://www.livescience.com/193-finger-length-predicts-aggression-men.html |url-status=live }}</ref><ref>{{cite journal |vauthors=Benderlioglu Z, Nelson RJ |s2cid=17464657 |title=Digit length ratios predict reactive aggression in women, but not in men |journal=Hormones and Behavior |volume=46 |issue=5 |pages=558–564 |date=Dec 2004 |pmid=15555497 |doi=10.1016/j.yhbeh.2004.06.004}}</ref><ref>{{cite journal |vauthors=Liu J, Portnoy J, Raine A |title=Association between a marker for prenatal testosterone exposure and externalizing behavior problems in children |journal=Development and Psychopathology |volume=24 |issue=3 |pages=771–782 |date=August 2012 |pmid=22781854 |pmc=4247331 |doi=10.1017/S0954579412000363}}</ref><ref>{{cite journal |vauthors=Butovskaya M, Burkova V, Karelin D, Fink B |title=Digit ratio (2D:4D), aggression, and dominance in the Hadza and the Datoga of Tanzania |journal=American Journal of Human Biology |volume=27 |issue=5 |pages=620–627 |date=2015-10-01 |pmid=25824265 |doi=10.1002/ajhb.22718 |s2cid=205303673}}</ref><ref>{{cite journal |vauthors=Joyce CW, Kelly JC, Chan JC, Colgan G, O'Briain D, Mc Cabe JP, Curtin W |title=Second to fourth digit ratio confirms aggressive tendencies in patients with boxers fractures |journal=Injury |volume=44 |issue=11 |pages=1636–1639 |date=Nov 2013 |pmid=23972912 |doi=10.1016/j.injury.2013.07.018}}</ref> The rise in testosterone during competition predicted aggression in males, but not in females.<ref>{{cite journal |vauthors=Carré JM, Olmstead NA |s2cid=32112035 |title=Social neuroendocrinology of human aggression: examining the role of competition-induced testosterone dynamics |journal=Neuroscience |volume=286 |pages=171–186 |date=Feb 2015 |pmid=25463514 |doi=10.1016/j.neuroscience.2014.11.029 |url=http://carrelab.nipissingu.ca/wp-content/uploads/sites/32/2014/10/Carre-Olmstead-2015.pdf |access-date=December 30, 2015 |archive-date=January 26, 2016 |archive-url=https://web.archive.org/web/20160126080124/http://carrelab.nipissingu.ca/wp-content/uploads/sites/32/2014/10/Carre-Olmstead-2015.pdf |url-status=dead }}</ref> Subjects who interacted with handguns and an experimental game showed rise in testosterone and aggression.<ref>{{cite journal |vauthors=Klinesmith J, Kasser T, McAndrew FT |s2cid=33952211 |title=Guns, testosterone, and aggression: an experimental test of a mediational hypothesis |journal=Psychological Science |volume=17 |issue=7 |pages=568–571 |date=July 2006 |pmid=16866740 |doi=10.1111/j.1467-9280.2006.01745.x}}</ref> Natural selection might have evolved males to be more sensitive to competitive and status challenge situations, and that the interacting roles of testosterone are the essential ingredient for aggressive behaviour in these situations.<ref>{{Cite journal|title=The Interacting Roles of Testosterone and Challenges to Status in Human Male Aggression|vauthors=Mcandrew FT|date=2009|journal=Aggression and Violent Behavior|doi=10.1016/j.avb.2009.04.006|volume=14|issue=5|pages=330–335|url=http://faculty.knox.edu/fmcandre/avb_506.pdf|access-date=December 30, 2015|archive-date=November 29, 2020|archive-url=https://web.archive.org/web/20201129104954/http://faculty.knox.edu/fmcandre/avb_506.pdf|url-status=live}}</ref> Testosterone mediates attraction to cruel and violent cues in men by promoting extended viewing of violent stimuli.<ref>{{cite journal |vauthors=Weierstall R, Moran J, Giebel G, Elbert T |title=Testosterone reactivity and identification with a perpetrator or a victim in a story are associated with attraction to violence-related cues |journal=International Journal of Law and Psychiatry |volume=37 |issue=3 |pages=304–312 |date=2014-05-01 |pmid=24367977 |doi=10.1016/j.ijlp.2013.11.016 |url=https://kops.uni-konstanz.de/bitstream/123456789/29513/1/Weierstall_0-269427.pdf |access-date=May 2, 2024 |archive-date=May 2, 2024 |archive-url=https://web.archive.org/web/20240502034815/https://kops.uni-konstanz.de/bitstream/123456789/29513/1/Weierstall_0-269427.pdf |url-status=live }}</ref> Testosterone-specific structural brain characteristic can predict aggressive behaviour in individuals.<ref>{{cite journal |vauthors=Nguyen TV, McCracken JT, Albaugh MD, Botteron KN, Hudziak JJ, Ducharme S |title=A testosterone-related structural brain phenotype predicts aggressive behavior from childhood to adulthood |journal=Psychoneuroendocrinology |volume=63 |pages=109–118 |date=Jan 2016 |pmid=26431805 |pmc=4695305 |doi=10.1016/j.psyneuen.2015.09.021}}</ref> The ''Annals of the New York Academy of Sciences'' has found anabolic steroid use (which increases testosterone) to be higher in teenagers, and this was associated with increased violence.<ref>{{cite journal | vauthors = McGinnis MY | title = Anabolic androgenic steroids and aggression: studies using animal models | journal = Annals of the New York Academy of Sciences | volume = 1036 | pages = 399–415 | date = Dec 2004 | issue = 1 | pmid = 15817752 | doi = 10.1196/annals.1330.024 | bibcode = 2004NYASA1036..399M | s2cid = 36368056 }}</ref> Studies have found administered testosterone to increase verbal aggression and anger in some participants.<ref>{{cite journal | vauthors = von der PB, Sarkola T, Seppa K, Eriksson CJ | title = Testosterone, 5 alpha-dihydrotestosterone and cortisol in men with and without alcohol-related aggression | journal = Journal of Studies on Alcohol | volume = 63 | issue = 5 | pages = 518–26 | date = Sep 2002 | pmid = 12380846 | doi=10.15288/jsa.2002.63.518}}</ref> A few studies indicate that the testosterone derivative [[estradiol]] might play an important role in male aggression.<ref name="isbn0-12-373612-9"/><ref>Goldman D, Lappalainen J, Ozaki N. Direct analysis of candidate genes in impulsive disorders. In: Bock G, Goode J, eds. Genetics of Criminal and Antisocial Behaviour. Ciba Foundation Symposium 194. Chichester: John Wiley & Sons; 1996.</ref><ref>{{cite journal | vauthors = Coccaro E | year = 1996 | title = Neurotransmitter correlates of impulsive aggression in humans. In: Ferris C, Grisso T, eds. Understanding Aggressive Behaviour inn Children | journal = Annals of the New York Academy of Sciences | volume = 794 | issue = 1| pages = 82–89 | doi=10.1111/j.1749-6632.1996.tb32511.x| pmid = 8853594 | bibcode = 1996NYASA.794...82C | s2cid = 33226665 }}</ref><ref name="pmid9253313">{{cite journal | vauthors = Finkelstein JW, Susman EJ, Chinchilli VM, Kunselman SJ, D'Arcangelo MR, Schwab J, Demers LM, Liben LS, Lookingbill G, Kulin HE | title = Estrogen or testosterone increases self-reported aggressive behaviors in hypogonadal adolescents | journal = The Journal of Clinical Endocrinology & Metabolism| volume = 82 | issue = 8 | pages = 2433–38 | year = 1997 | pmid = 9253313 | doi = 10.1210/jcem.82.8.4165 | doi-access = free }}</ref> Estradiol is known to correlate with aggression in male mice.<ref name="pmid18280561">{{cite journal | vauthors = Soma KK, Scotti MA, Newman AE, Charlier TD, Demas GE | s2cid = 32650274 | title = Novel mechanisms for neuroendocrine regulation of aggression | journal = Frontiers in Neuroendocrinology | volume = 29 | issue = 4 | pages = 476–89 | date = Oct 2008 | pmid = 18280561 | doi = 10.1016/j.yfrne.2007.12.003 }}</ref> Moreover, the conversion of testosterone to estradiol regulates male aggression in [[Old World sparrow|sparrows]] during breeding season.<ref name="pmid11016791">{{cite journal | vauthors = Soma KK, Sullivan KA, Tramontin AD, Saldanha CJ, Schlinger BA, Wingfield JC | s2cid = 23990605 | title = Acute and chronic effects of an aromatase inhibitor on territorial aggression in breeding and nonbreeding male song sparrows | journal = Journal of Comparative Physiology A | volume = 186 | issue = 7–8 | pages = 759–69 | year = 2000 | pmid = 11016791 | doi = 10.1007/s003590000129 }}</ref> Rats who were given anabolic steroids that increase testosterone were also more physically aggressive to provocation as a result of "threat sensitivity".<ref>{{cite journal | vauthors = McGinnis MY, Lumia AR, Breuer ME, Possidente B | s2cid = 29969145 | title = Physical provocation potentiates aggression in male rats receiving anabolic androgenic steroids | journal = Hormones and Behavior | volume = 41 | issue = 1 | pages = 101–10 | date = Feb 2002 | pmid = 11863388 | doi = 10.1006/hbeh.2001.1742 }}</ref> The relationship between testosterone and aggression may also function indirectly, as it has been proposed that testosterone does not amplify tendencies towards aggression, but rather amplifies whatever tendencies will allow an individual to maintain social status when challenged. In most animals, aggression is the means of maintaining social status. However, humans have multiple ways of obtaining status. This could explain why some studies find a link between testosterone and pro-social behaviour, if pro-social behaviour is rewarded with social status. Thus the link between testosterone and aggression and violence is due to these being rewarded with social status.<ref name="pmid30619017">{{cite journal | vauthors = Sapolsky RM | title = Doubled-Edged Swords in the Biology of Conflict | journal = Frontiers in Psychology | volume = 9 | pages = 2625 | date = 2018 | pmid = 30619017 | pmc = 6306482 | doi = 10.3389/fpsyg.2018.02625 | doi-access = free }}</ref> The relationship may also be one of a "permissive effect" whereby testosterone does elevate aggression levels, but only in the sense of allowing average aggression levels to be maintained; chemically or physically castrating the individual will reduce aggression levels (though not eliminate them) but the individual only needs a small-level of pre-castration testosterone to have aggression levels to return to normal, which they will remain at even if additional testosterone is added. Testosterone may also simply exaggerate or amplify existing aggression; for example, chimpanzees who receive testosterone increases become more aggressive to chimps lower than them in the social hierarchy, but will still be submissive to chimps higher than them. Testosterone thus does not make the chimpanzee indiscriminately aggressive, but instead amplifies his pre-existing aggression towards lower-ranked chimps.<ref>{{cite book | vauthors = Sapolsky RM | title = The trouble with testosterone. | location = New York | publisher = Simon and Schuster | date = 1998 | pages = 153–55 | isbn = 978-0-684-83891-5 }}</ref> In humans, testosterone appears more to promote status-seeking and social dominance than simply increasing physical aggression. When controlling for the effects of belief in having received testosterone, women who have received testosterone make fairer offers than women who have not received testosterone.<ref name="pmid21616702">{{cite journal | vauthors = Eisenegger C, Haushofer J, Fehr E | title = The role of testosterone in social interaction | journal = Trends in Cognitive Sciences | volume = 15 | issue = 6 | pages = 263–71 | date = June 2011 | pmid = 21616702 | doi = 10.1016/j.tics.2011.04.008 | s2cid = 9554219 | url = http://www.zora.uzh.ch/id/eprint/58008/1/Testosterone_social_interaction_revision_%2812_Apr_11%29.pdf | access-date = December 22, 2020 | archive-date = January 22, 2021 | archive-url = https://web.archive.org/web/20210122153257/https://www.zora.uzh.ch/id/eprint/58008/1/Testosterone_social_interaction_revision_%2812_Apr_11%29.pdf | url-status = live }}</ref> ==== Fairness ==== Testosterone might encourage fair behavior. For one study, subjects took part in a behavioral experiment where the distribution of a real amount of money was decided. The rules allowed both fair and unfair offers. The negotiating partner could subsequently accept or decline the offer. The fairer the offer, the less probable a refusal by the negotiating partner. If no agreement was reached, neither party earned anything. Test subjects with an artificially enhanced testosterone level generally made better, fairer offers than those who received placebos, thus reducing the risk of a rejection of their offer to a minimum. Two later studies have empirically confirmed these results.<ref name="pmid19997098">{{cite journal | vauthors = Eisenegger C, Naef M, Snozzi R, Heinrichs M, Fehr E | s2cid = 1305527 | title = Prejudice and truth about the effect of testosterone on human bargaining behaviour | journal = Nature | volume = 463 | issue = 7279 | pages = 356–59 | year = 2010 | pmid = 19997098 | doi = 10.1038/nature08711 | bibcode = 2010Natur.463..356E }}</ref><ref>{{cite journal | vauthors = van Honk J, Montoya ER, Bos PA, van Vugt M, Terburg D | s2cid = 4383859 | title = New evidence on testosterone and cooperation | journal = Nature | volume = 485 | issue = 7399 | pages = E4–5; discussion E5–6 | date = May 2012 | pmid = 22622587 | doi = 10.1038/nature11136 | bibcode = 2012Natur.485E...4V }}</ref><ref>{{cite journal | vauthors = Eisenegger C, Naef M, Snozzi R, Heinrichs M, Fehr E | s2cid = 4413138 | year = 2012 | title = Eisenegger et al. reply| journal = Nature | volume = 485 | issue = 7399| pages = E5–E6 | doi = 10.1038/nature11137 | bibcode = 2012Natur.485E...5E }}</ref> However men with high testosterone were significantly 27% less generous in an ultimatum game.<ref>{{cite journal | vauthors = Zak PJ, Kurzban R, Ahmadi S, Swerdloff RS, Park J, Efremidze L, Redwine K, Morgan K, Matzner W | title = Testosterone administration decreases generosity in the ultimatum game | journal = PLOS ONE | volume = 4 | issue = 12 | page = e8330 | date = 2009-01-01 | pmid = 20016825 | pmc = 2789942 | doi = 10.1371/journal.pone.0008330 | bibcode = 2009PLoSO...4.8330Z | doi-access = free }}</ref> ==Biological activity== ===Free testosterone=== [[Lipophilic]] [[hormones]] (soluble in [[lipids]] but not in [[water]]), such as [[steroid]] hormones, including testosterone, are transported in water-based [[blood plasma]] through specific and non-specific [[proteins]]. Specific proteins include [[sex hormone-binding globulin]] (SHBG), which binds testosterone, [[dihydrotestosterone]], [[estradiol]], and other [[sex steroids]]. Non-specific binding proteins include [[albumin]]. The part of the total hormone concentration that is not bound to its respective specific carrier protein is the free part. As a result, testosterone which is not bound to SHBG is called ''free testosterone''. Only the free amount of testosterone can bind to an androgenic receptor, which means it has biological activity.<ref name="pmid33553985">{{cite journal |vauthors=Bikle DD |title=The Free Hormone Hypothesis: When, Why, and How to Measure the Free Hormone Levels to Assess Vitamin D, Thyroid, Sex Hormone, and Cortisol Status |journal=[[JBMR Plus]] |volume=5 |issue=1 |pages=e10418 |date=January 2021 |pmid=33553985 |pmc=7839820 |doi=10.1002/jbm4.10418 |url= }}</ref> While a significant portion of testosterone is bound to SHBG, a small fraction of testosterone (1%-2%)<ref name="synevo"/> is bound to albumin and the binding of testosterone to albumin is weak and can be reversed easily;<ref name="pmid30842823"/><ref name="pmid28673039"/> as such, both albumin-bound and unbound testosterone are considered to be bioavailable testosterone.<ref name="pmid30842823"/><ref name="pmid28673039"/> This binding plays an important role in regulating the transport, tissue delivery, bioactivity, and metabolism of testosterone.<ref name="pmid28673039">{{cite journal |vauthors=Goldman AL, Bhasin S, Wu FC, Krishna M, Matsumoto AM, Jasuja R |title=A Reappraisal of Testosterone's Binding in Circulation: Physiological and Clinical Implications |journal=Endocr Rev |volume=38 |issue=4 |pages=302–324 |date=August 2017 |pmid=28673039 |pmc=6287254 |doi=10.1210/er.2017-00025 |url=}}</ref><ref name="pmid30842823">{{cite journal |vauthors=Czub MP, Venkataramany BS, Majorek KA, Handing KB, Porebski PJ, Beeram SR, Suh K, Woolfork AG, Hage DS, Shabalin IG, Minor W |title=Testosterone meets albumin - the molecular mechanism of sex hormone transport by serum albumins |journal=Chem Sci |volume=10 |issue=6 |pages=1607–1618 |date=February 2019 |pmid=30842823 |pmc=6371759 |doi=10.1039/c8sc04397c |url=}}</ref> At the tissue level, testosterone dissociates from albumin and quickly diffuses into the tissues. The percentage of testosterone bound to SHBG is lower in men than in women. Both the free fraction and the one bound to albumin are available at the tissue level (their sum constitutes the bioavailable testosterone), while SHBG effectively and irreversibly inhibits the action of testosterone.<ref name="synevo"><!--sorry, could not find a better source that would have been accessible -->{{cite web|url=https://www.synevo.md/shop/testosteron-liber/|title=Testosteron liber|language=ro|trans-title=Free testosterone|publisher=Synevo Moldova|access-date=March 30, 2024|archive-date=January 29, 2023|archive-url=https://web.archive.org/web/20230129153430/https://www.synevo.md/shop/testosteron-liber/|url-status=live}}</ref> The relationship between sex steroids and SHBG in physiological and pathological conditions is complex, as various factors may influence the levels of plasma SHBG, affecting bioavailability of testosterone.<ref name="pmid4062218">{{cite journal |vauthors=Cunningham SK, Loughlin T, Culliton M, McKenna TJ |title=The relationship between sex steroids and sex-hormone-binding globulin in plasma in physiological and pathological conditions |journal=Ann Clin Biochem |volume=22|issue= 5|pages=489–97 |date=September 1985 |pmid=4062218 |doi=10.1177/000456328502200504 |url=}}</ref><ref name="pmid33139661">{{cite journal |vauthors=Qu X, Donnelly R |title=Sex Hormone-Binding Globulin (SHBG) as an Early Biomarker and Therapeutic Target in Polycystic Ovary Syndrome |journal=Int J Mol Sci |volume=21 |issue=21 |date=November 2020 |page=8191 |pmid=33139661 |pmc=7663738 |doi=10.3390/ijms21218191|doi-access=free }}</ref><ref name="pmid34197576">{{cite journal |vauthors=Aribas E, Kavousi M, Laven JS, Ikram MA, Roeters van Lennep JE |title=Aging, Cardiovascular Risk, and SHBG Levels in Men and Women From the General Population |journal=J Clin Endocrinol Metab |volume=106 |issue=10 |pages=2890–2900 |date=September 2021 |pmid=34197576 |pmc=8475196 |doi=10.1210/clinem/dgab470 }}</ref> ===Steroid hormone activity=== The effects of testosterone in humans and other [[vertebrates]] occur by way of multiple mechanisms: by activation of the [[androgen receptor]] (directly or as dihydrotestosterone), and by conversion to [[estradiol]] and activation of certain [[estrogen receptor]]s.<ref name="pmid18406296">{{cite journal | vauthors = Hiipakka RA, Liao S | s2cid = 23385663 | title = Molecular mechanism of androgen action | journal = Trends in Endocrinology and Metabolism | volume = 9 | issue = 8 | pages = 317–24 | date = Oct 1998 | pmid = 18406296 | doi = 10.1016/S1043-2760(98)00081-2 }}</ref><ref name="pmid11511858">{{cite journal | vauthors = McPhaul MJ, Young M | title = Complexities of androgen action | journal = Journal of the American Academy of Dermatology | volume = 45 | issue = 3 Suppl | pages = S87–94 | date = Sep 2001 | pmid = 11511858 | doi = 10.1067/mjd.2001.117429 }}</ref> Androgens such as testosterone have also been found to bind to and activate [[membrane androgen receptor]]s.<ref name="pmid19931639">{{cite journal | vauthors = Bennett NC, Gardiner RA, Hooper JD, Johnson DW, Gobe GC | title = Molecular cell biology of androgen receptor signalling | journal = Int. J. Biochem. Cell Biol. | volume = 42 | issue = 6 | pages = 813–27 | year = 2010 | pmid = 19931639 | doi = 10.1016/j.biocel.2009.11.013 }}</ref><ref name="pmid25257522">{{cite journal | vauthors = Wang C, Liu Y, Cao JM | title = G protein-coupled receptors: extranuclear mediators for the non-genomic actions of steroids | journal = Int J Mol Sci | volume = 15 | issue = 9 | pages = 15412–25 | year = 2014 | pmid = 25257522 | pmc = 4200746 | doi = 10.3390/ijms150915412 | doi-access = free }}</ref><ref name="pmid23746222">{{cite journal | vauthors = Lang F, Alevizopoulos K, Stournaras C | s2cid = 23918273 | title = Targeting membrane androgen receptors in tumors | journal = Expert Opin. Ther. Targets | volume = 17 | issue = 8 | pages = 951–63 | year = 2013 | pmid = 23746222 | doi = 10.1517/14728222.2013.806491 }}</ref> [[#Free testosterone|Free testosterone]] (T) is transported into the [[cytoplasm]] of target [[Tissue (biology)|tissue]] [[Cell (biology)|cells]], where it can bind to the [[androgen receptor]], or can be reduced to [[Dihydrotestosterone|5α-dihydrotestosterone]] (5α-DHT) by the cytoplasmic enzyme [[5α-reductase]]. 5α-DHT binds to the same androgen receptor even more strongly than testosterone, so that its androgenic potency is about 5 times that of T.<ref name="pmid3762019">{{cite journal | vauthors = Breiner M, Romalo G, Schweikert HU | s2cid = 34846760 | title = Inhibition of androgen receptor binding by natural and synthetic steroids in cultured human genital skin fibroblasts | journal = Klinische Wochenschrift | volume = 64 | issue = 16 | pages = 732–37 | date = August 1986 | pmid = 3762019 | doi = 10.1007/BF01734339 }}</ref> The T-receptor or DHT-receptor complex undergoes a structural change that allows it to move into the [[cell nucleus]] and bind directly to specific [[nucleotide]] sequences of the [[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. 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 [[sexual differentiation|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 [[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).<ref>{{cite book | vauthors = Kelly MJ, Qiu J, Rønnekleiv OK | title = Estrogen signaling in the hypothalamus | volume = 71 | pages = 123–45 | date = 2005-01-01 | pmid = 16112267 | doi = 10.1016/S0083-6729(05)71005-0 | series = Vitamins & Hormones | publisher = Academic Press | isbn = 978-0-12-709871-5 }}</ref>{{Failed verification|date=February 2023}} 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.<ref name="pmid18195084">{{cite journal | vauthors = McCarthy MM | title = Estradiol and the developing brain | journal = Physiological Reviews | volume = 88 | issue = 1 | pages = 91–124 | year = 2008 | pmid = 18195084 | pmc = 2754262 | doi = 10.1152/physrev.00010.2007 }}</ref> ===Neurosteroid activity=== Testosterone, via its [[active metabolite]] [[3α-androstanediol]], is a potent [[positive allosteric modulator]] of the [[GABAA receptor|GABA<sub>A</sub> receptor]].<ref name="KohtzFrye2012">{{cite book | vauthors = Kohtz AS, Frye CA | chapter = Dissociating Behavioral, Autonomic, and Neuroendocrine Effects of Androgen Steroids in Animal Models | title = Psychiatric Disorders | series = [[Methods in Molecular Biology]] | volume = 829 | pages = 397–431 | year = 2012 | publisher = Springer | pmid = 22231829 | doi = 10.1007/978-1-61779-458-2_26 | isbn = 978-1-61779-457-5 }}</ref> Testosterone has been found to act as an [[receptor antagonist|antagonist]] of the [[TrkA]] and [[p75NTR|p75<sup>NTR</sup>]], [[receptor (biochemistry)|receptor]]s for the [[neurotrophin]] [[nerve growth factor]] (NGF), with high [[affinity (pharmacology)|affinity]] (around 5 nM).<ref name="pmid26908835">{{cite journal | vauthors = Prough RA, Clark BJ, Klinge CM | title = Novel mechanisms for DHEA action | journal = J. Mol. Endocrinol. | volume = 56 | issue = 3 | pages = R139–55 | year = 2016 | pmid = 26908835 | doi = 10.1530/JME-16-0013 | doi-access = free }}</ref><ref name="pmid21541365">{{cite journal | vauthors = Lazaridis I, Charalampopoulos I, Alexaki VI, Avlonitis N, Pediaditakis I, Efstathopoulos P, Calogeropoulou T, Castanas E, Gravanis A | title = Neurosteroid dehydroepiandrosterone interacts with nerve growth factor (NGF) receptors, preventing neuronal apoptosis | journal = PLOS Biol. | volume = 9 | issue = 4 | pages = e1001051 | year = 2011 | pmid = 21541365 | pmc = 3082517 | doi = 10.1371/journal.pbio.1001051 | doi-access = free }}</ref><ref name="pmid23074265">{{cite journal | vauthors = Gravanis A, Calogeropoulou T, Panoutsakopoulou V, Thermos K, Neophytou C, Charalampopoulos I | s2cid = 26914550 | title = Neurosteroids and microneurotrophins signal through NGF receptors to induce prosurvival signaling in neuronal cells | journal = Sci Signal | volume = 5 | issue = 246 | pages = pt8 | year = 2012 | pmid = 23074265 | doi = 10.1126/scisignal.2003387 }}</ref> In contrast to testosterone, DHEA and [[DHEA sulfate]] have been found to act as high-affinity [[agonist]]s of these receptors.<ref name="pmid26908835" /><ref name="pmid21541365" /><ref name="pmid23074265" /> Testosterone is an antagonist of the [[sigma-1 receptor]] (K<sub>i</sub> = 1,014 or 201 nM).<ref name="AlbayrakHashimoto2017">{{cite book | vauthors = Albayrak Y, Hashimoto K | series = Advances in Experimental Medicine and Biology | title = Sigma Receptors: Their Role in Disease and as Therapeutic Targets | chapter = Sigma-1 Receptor Agonists and Their Clinical Implications in Neuropsychiatric Disorders | volume = 964 | pages = 153–161 | year = 2017 | publisher = Springer | pmid = 28315270 | doi = 10.1007/978-3-319-50174-1_11 | isbn = 978-3-319-50172-7 }}</ref> However, the concentrations of testosterone required for binding the receptor are far above even total circulating concentrations of testosterone in adult males (which range between 10 and 35 nM).<ref name="Regitz-Zagrosek2012">{{cite book| vauthors = Regitz-Zagrosek V |title=Sex and Gender Differences in Pharmacology|url=https://books.google.com/books?id=J3VxihGDh9wC&pg=PA245|date=2 October 2012|publisher=Springer Science & Business Media|isbn=978-3-642-30725-6|pages=245–}}</ref> ==Biochemistry== [[File:Steroidogenesis.svg|thumb|upright=2|{{vanchor|Figure 1}}: Human [[steroidogenesis]], showing testosterone near bottom<ref name="HäggströmRichfield2014">{{cite journal | vauthors = Häggström M, Richfield D |year=2014|title=Diagram of the pathways of human steroidogenesis|journal=WikiJournal of Medicine|volume=1|issue=1|doi=10.15347/wjm/2014.005|doi-access=free}}</ref>]] ===Biosynthesis=== Like other [[steroid]] hormones, testosterone is derived from [[cholesterol]] {{Crossreference|([[#Figure 1|Figure 1]])}}.<ref name="pmid1307739">{{cite journal | vauthors = Waterman MR, Keeney DS | title = Genes involved in androgen biosynthesis and the male phenotype | journal = Hormone Research | volume = 38 | issue = 5–6 | pages = 217–21 | year = 1992 | pmid = 1307739 | doi = 10.1159/000182546 }}</ref> The first step in the [[biosynthesis]] involves the oxidative cleavage of the side-chain of cholesterol by [[cholesterol side-chain cleavage enzyme]] (P450scc, CYP11A1), a [[mitochondrion|mitochondrial]] [[cytochrome P450]] oxidase with the loss of six carbon atoms to give [[pregnenolone]]. In the next step, two additional carbon atoms are removed by the [[CYP17A1]] (17α-hydroxylase/17,20-lyase) enzyme in the [[endoplasmic reticulum]] to yield a variety of C<sub>19</sub> steroids.<ref name="pmid3535074">{{cite journal | vauthors = Zuber MX, Simpson ER, Waterman MR | title = Expression of bovine 17 alpha-hydroxylase cytochrome P-450 cDNA in nonsteroidogenic (COS 1) cells | journal = Science | volume = 234 | issue = 4781 | pages = 1258–61 | date = Dec 1986 | pmid = 3535074 | doi = 10.1126/science.3535074 | bibcode = 1986Sci...234.1258Z }}</ref> In addition, the 3β-hydroxyl group is oxidized by [[3β-hydroxysteroid dehydrogenase]] to produce [[androstenedione]]. In the final and rate limiting step, the C17 keto group androstenedione is reduced by [[17β-hydroxysteroid dehydrogenase]] to yield testosterone. The largest amounts of testosterone (>95%) are produced by the [[testis|testes]] in men,<ref name="pmid3549275"/> while the [[adrenal gland]]s account for most of the remainder. Testosterone is also synthesized in far smaller total quantities in women by the adrenal glands, [[theca of follicle|thecal cells]] of the [[ovary|ovaries]], and, during [[pregnancy]], by the [[placenta]].<ref name="pmid15507105">{{cite journal | vauthors = Zouboulis CC, Degitz K | title = Androgen action on human skin – from basic research to clinical significance | journal = Experimental Dermatology | volume = 13 | issue = Suppl 4 | pages = 5–10 | year = 2004 | pmid = 15507105 | doi = 10.1111/j.1600-0625.2004.00255.x | s2cid = 34863608 }}</ref> In the testes, testosterone is produced by the [[Leydig cell]]s.<ref name="pmid58744">{{cite journal | vauthors = Brooks RV | title = Androgens | journal = Clinics in Endocrinology and Metabolism | volume = 4 | issue = 3 | pages = 503–20 | date = Nov 1975 | pmid = 58744 | doi = 10.1016/S0300-595X(75)80045-4 }}</ref> The male 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). {{Production rates, secretion rates, clearance rates, and blood levels of major sex hormones}} ====Regulation==== [[File:Hypothalamus pituitary testicles axis.png|thumb|right|{{vanchor|Figure 2}}. Hypothalamic–pituitary–testicular axis]] In males, testosterone is synthesized primarily in [[Leydig cells]]. The number of Leydig cells in turn is regulated by [[luteinizing hormone]] (LH) and [[follicle-stimulating hormone]] (FSH). In addition, the amount of testosterone produced by existing Leydig cells is under the control of LH, which regulates the expression of [[17β-hydroxysteroid dehydrogenase]].<ref name="isbn0-9627422-7-9">{{cite book | vauthors = Payne AH, O'Shaughnessy P |veditors=Payne AH, Hardy MP, Russell LD | title = Leydig Cell | publisher = Cache River Press | location = Vienna [Il] | year = 1996 | pages = 260–85 | isbn = 978-0-9627422-7-9 | chapter = Structure, function, and regulation of steroidogenic enzymes in the Leydig cell }}</ref> The amount of testosterone synthesized is regulated by the [[hypothalamic–pituitary–gonadal axis|hypothalamic–pituitary–testicular axis]] {{crossreference|([[#Figure 2|Figure 2]])}}.<ref name="pmid1377467">{{cite journal | vauthors = Swerdloff RS, Wang C, Bhasin S | title = Developments in the control of testicular function | journal = Baillière's Clinical Endocrinology and Metabolism | volume = 6 | issue = 2 | pages = 451–83 | date = Apr 1992 | pmid = 1377467 | doi = 10.1016/S0950-351X(05)80158-2 }}</ref> When testosterone levels are low, gonadotropin-releasing hormone ([[gonadotropin-releasing hormone|GnRH]]) is released by the [[hypothalamus]], which in turn stimulates the [[pituitary gland]] to release FSH and LH. These latter two hormones stimulate the testis to synthesize testosterone. Finally, increasing levels of testosterone through a negative [[feedback]] loop act on the hypothalamus and pituitary to inhibit the release of GnRH and FSH/LH, respectively. Factors affecting testosterone levels may include: * Age: Testosterone levels gradually reduce as men age.<ref name="pmid25009850">{{cite book | chapter-url = https://www.ncbi.nlm.nih.gov/books/NBK216164/ | title = Testosterone and Aging: Clinical Research Directions. | chapter = Introduction | collaboration = Institute of Medicine (US) Committee on Assessing the Need for Clinical Trials of Testosterone Replacement Therapy | vauthors = Liverman CT, Blazer DG | date = January 1, 2004 | publisher = National Academies Press (US) | via = www.ncbi.nlm.nih.gov | isbn = 978-0-309-09063-6 | doi = 10.17226/10852 | pmid = 25009850 | access-date = September 26, 2016 | archive-date = January 10, 2016 | archive-url = https://web.archive.org/web/20160110170928/http://www.ncbi.nlm.nih.gov/books/NBK216164/ | url-status = live }}</ref><ref name="pmid24407185">{{cite journal | vauthors = Huhtaniemi I | title = Late-onset hypogonadism: current concepts and controversies of pathogenesis, diagnosis and treatment | journal = Asian Journal of Andrology | volume = 16 | issue = 2 | pages = 192–202 | year = 2014 | pmid = 24407185 | pmc = 3955328 | doi = 10.4103/1008-682X.122336 | doi-access = free }}</ref> This effect is sometimes referred to as [[andropause]] or [[late-onset hypogonadism]].<ref name="pmid24793989">{{cite journal | vauthors = Huhtaniemi IT | title = Andropause--lessons from the European Male Ageing Study | journal = Annales d'Endocrinologie | volume = 75 | issue = 2 | pages = 128–31 | year = 2014 | pmid = 24793989 | doi = 10.1016/j.ando.2014.03.005 }}</ref> * Exercise: [[Strength training|Resistance training]] increases testosterone levels acutely,<ref name="Vingren_2010">{{cite journal | vauthors = Vingren JL, Kraemer WJ, Ratamess NA, Anderson JM, Volek JS, Maresh CM | s2cid = 11683565 | title = Testosterone physiology in resistance exercise and training: the up-stream regulatory elements | journal = Sports Medicine | volume = 40 | issue = 12 | pages = 1037–53 | year = 2010 | pmid = 21058750 | doi = 10.2165/11536910-000000000-00000 }}</ref> however, in older men, that increase can be avoided by protein ingestion.<ref name="pmid18455389">{{cite journal | vauthors = Hulmi JJ, Ahtiainen JP, Selänne H, Volek JS, Häkkinen K, Kovanen V, Mero AA | s2cid = 26280370 | title = Androgen receptors and testosterone in men—effects of protein ingestion, resistance exercise and fiber type | journal = The Journal of Steroid Biochemistry and Molecular Biology | volume = 110 | issue = 1–2 | pages = 130–37 | date = May 2008 | pmid = 18455389 | doi = 10.1016/j.jsbmb.2008.03.030 }}</ref> [[Endurance training]] in men may lead to lower testosterone levels.<ref name="pmid16268050">{{cite journal | vauthors = Hackney AC, Moore AW, Brownlee KK | title = Testosterone and endurance exercise: development of the "exercise-hypogonadal male condition" | journal = Acta Physiologica Hungarica | volume = 92 | issue = 2 | pages = 121–37 | year = 2005 | pmid = 16268050 | doi = 10.1556/APhysiol.92.2005.2.3 }}</ref> * Nutrients: [[Vitamin A deficiency]] may lead to sub-optimal plasma testosterone levels.<ref name="pmid12141930">{{cite journal | vauthors = Livera G, Rouiller-Fabre V, Pairault C, Levacher C, Habert R | title = Regulation and perturbation of testicular functions by vitamin A | journal = Reproduction | volume = 124 | issue = 2 | pages = 173–180 | date = August 2002 | pmid = 12141930 | doi = 10.1530/rep.0.1240173 | doi-access = free }}</ref> The secosteroid [[vitamin D]] in levels of 400–1000 [[international unit|IU]]/d (10–25 μg/d) raises testosterone levels.<ref name="pmid21154195">{{cite journal | vauthors = Pilz S, Frisch S, Koertke H, Kuhn J, Dreier J, Obermayer-Pietsch B, Wehr E, Zittermann A | title = Effect of vitamin D supplementation on testosterone levels in men | journal = Hormone and Metabolic Research | volume = 43 | issue = 3 | pages = 223–225 | date = March 2011 | pmid = 21154195 | doi = 10.1055/s-0030-1269854 | s2cid = 206315145 | doi-access = free }}</ref> [[Zinc deficiency]] lowers testosterone levels<ref name="pmid8875519">{{cite journal | vauthors = Prasad AS, Mantzoros CS, Beck FW, Hess JW, Brewer GJ | title = Zinc status and serum testosterone levels of healthy adults | journal = Nutrition | volume = 12 | issue = 5 | pages = 344–348 | date = May 1996 | pmid = 8875519 | doi = 10.1016/S0899-9007(96)80058-X | citeseerx = 10.1.1.551.4971 }}</ref> but over-supplementation has no effect on serum testosterone.<ref name="pmid17882141">{{cite journal | vauthors = Koehler K, Parr MK, Geyer H, Mester J, Schänzer W | title = Serum testosterone and urinary excretion of steroid hormone metabolites after administration of a high-dose zinc supplement | journal = European Journal of Clinical Nutrition | volume = 63 | issue = 1 | pages = 65–70 | date = January 2009 | pmid = 17882141 | doi = 10.1038/sj.ejcn.1602899 | doi-access = free }}</ref> There is limited evidence that [[low-fat diet]]s may reduce total and [[#Free testosterone|free testosterone]] levels in men.<ref>{{cite journal | vauthors = Whittaker J, Wu K | title = Low-fat diets and testosterone in men: Systematic review and meta-analysis of intervention studies | journal = The Journal of Steroid Biochemistry and Molecular Biology | volume = 210 | pages = 105878 | date = June 2021 | pmid = 33741447 | doi = 10.1016/j.jsbmb.2021.105878 | arxiv = 2204.00007 | s2cid = 232246357 }}</ref> * Weight loss: Reduction in weight may result in an increase in testosterone levels. Fat cells synthesize the enzyme aromatase, which converts testosterone, the male sex hormone, into estradiol, the female sex hormone.<ref name="pmid21849026">{{cite journal | vauthors = Håkonsen LB, Thulstrup AM, Aggerholm AS, Olsen J, Bonde JP, Andersen CY, Bungum M, Ernst EH, Hansen ML, Ernst EH, Ramlau-Hansen CH | title = Does weight loss improve semen quality and reproductive hormones? Results from a cohort of severely obese men | journal = Reproductive Health | volume = 8 | issue = 1 | page = 24 | year = 2011 | pmid = 21849026 | pmc = 3177768 | doi = 10.1186/1742-4755-8-24 | doi-access = free }}</ref> However no clear association between [[body mass index]] and testosterone levels has been found.<ref name="pmid19889752">{{cite journal | vauthors = MacDonald AA, Herbison GP, Showell M, Farquhar CM | title = The impact of body mass index on semen parameters and reproductive hormones in human males: a systematic review with meta-analysis | journal = Human Reproduction Update | volume = 16 | issue = 3 | pages = 293–311 | year = 2010 | pmid = 19889752 | doi = 10.1093/humupd/dmp047 | doi-access = free }}</ref> * Miscellaneous: ''Sleep'': ([[REM sleep]]) increases nocturnal testosterone levels.<ref name="pmid18519168">{{cite journal | vauthors = Andersen ML, Tufik S | title = The effects of testosterone on sleep and sleep-disordered breathing in men: its bidirectional interaction with erectile function | journal = Sleep Medicine Reviews | volume = 12 | issue = 5 | pages = 365–79 | date = Oct 2008 | pmid = 18519168 | doi = 10.1016/j.smrv.2007.12.003 }}</ref> * Behavior: Dominance challenges can, in some cases, stimulate increased testosterone release in men.<ref name="pmid10603287">{{cite journal | vauthors = Schultheiss OC, Campbell KL, McClelland DC | s2cid = 6002474 | title = Implicit power motivation moderates men's testosterone responses to imagined and real dominance success | journal = Hormones and Behavior | volume = 36 | issue = 3 | pages = 234–41 | date = Dec 1999 | pmid = 10603287 | doi = 10.1006/hbeh.1999.1542 | citeseerx = 10.1.1.326.9322 }}</ref> * Foods: Natural or man-made [[antiandrogens]] including [[spearmint]] tea reduce testosterone levels.<ref name="pmid17310494">{{cite journal | vauthors = Akdoğan M, Tamer MN, Cüre E, Cüre MC, Köroğlu BK, Delibaş N | title = Effect of spearmint (Mentha spicata Labiatae) teas on androgen levels in women with hirsutism | journal = Phytotherapy Research | volume = 21 | issue = 5 | pages = 444–47 | date = May 2007 | pmid = 17310494 | doi = 10.1002/ptr.2074 | s2cid = 21961390 }}</ref><ref name="pmid18804513">{{cite journal | vauthors = Kumar V, Kural MR, Pereira BM, Roy P | title = Spearmint induced hypothalamic oxidative stress and testicular anti-androgenicity in male rats - altered levels of gene expression, enzymes and hormones | journal = Food and Chemical Toxicology | volume = 46 | issue = 12 | pages = 3563–70 | date = Dec 2008 | pmid = 18804513 | doi = 10.1016/j.fct.2008.08.027 }}</ref><ref name="pmid19585478">{{cite journal | vauthors = Grant P | title = Spearmint herbal tea has significant anti-androgen effects in polycystic ovarian syndrome. A randomized controlled trial | journal = Phytotherapy Research | volume = 24 | issue = 2 | pages = 186–88 | date = Feb 2010 | pmid = 19585478 | doi = 10.1002/ptr.2900 | s2cid = 206425734 }}</ref> [[Licorice]] can decrease the production of testosterone and this effect is greater in females.<ref>{{cite journal | vauthors = Armanini D, Fiore C, Mattarello MJ, Bielenberg J, Palermo M | title = History of the endocrine effects of licorice | journal = Experimental and Clinical Endocrinology & Diabetes | volume = 110 | issue = 6 | pages = 257–61 | date = Sep 2002 | pmid = 12373628 | doi = 10.1055/s-2002-34587 }}</ref> ===Distribution=== The [[plasma protein binding]] of testosterone is 98.0 to 98.5%, with 1.5 to 2.0% free or unbound.<ref name="NieschlagBehre2012">{{cite book |vauthors=Nieschlag E, Behre HM, Nieschlag S |title=Testosterone: Action, Deficiency, Substitution |url=https://books.google.com/books?id=MkrAPaQ4wJkC&pg=PA61 |date=26 July 2012 |publisher=Cambridge University Press |isbn=978-1-107-01290-5 |pages=61– |access-date=March 23, 2018 |archive-date=January 11, 2023 |archive-url=https://web.archive.org/web/20230111143032/https://books.google.com/books?id=MkrAPaQ4wJkC&pg=PA61 |url-status=live }}</ref> It is bound 65% to [[sex hormone-binding globulin]] (SHBG) and 33% bound weakly to [[human serum albumin|albumin]].<ref name="pmid4044776">{{cite journal | vauthors = Cumming DC, Wall SR | title = Non-sex hormone-binding globulin-bound testosterone as a marker for hyperandrogenism | journal = The Journal of Clinical Endocrinology & Metabolism| volume = 61 | issue = 5 | pages = 873–6 | date = November 1985 | pmid = 4044776 | doi = 10.1210/jcem-61-5-873 }}</ref> {{Plasma protein binding of testosterone and dihydrotestosterone}} ===Metabolism=== {{Testosterone metabolism mini|align=right|caption=The [[metabolic pathway]]s involved in the [[metabolism]] of testosterone in humans. In addition to the [[biotransformation|transformation]]s shown in the diagram, [[conjugation (biochemistry)|conjugation]] via [[sulfation]] and [[glucuronidation]] occurs with testosterone and [[metabolite]]s that have one or more available [[hydroxyl group|hydroxyl]] (–OH) [[functional group|group]]s.}} Both testosterone and 5α-DHT are [[metabolism|metabolized]] mainly in the [[liver]].<ref name="MelmedPolonsky2015">{{cite book | vauthors = Melmed S, Polonsky KD, Larsen PR, Kronenberg HM | title = Williams Textbook of Endocrinology | url = https://books.google.com/books?id=YZ8_CwAAQBAJ&pg=PA711 | date = 30 November 2015 | publisher = Elsevier Health Sciences|isbn=978-0-323-29738-7 | pages = 711– }}</ref><ref name="Becker2001">{{cite book | vauthors = Becker KL | title = Principles and Practice of Endocrinology and Metabolism | url = https://books.google.com/books?id=FVfzRvaucq8C&pg=PA1116 | year = 2001 | publisher = Lippincott Williams & Wilkins | isbn = 978-0-7817-1750-2 | pages = 1116, 1119, 1183 | access-date = November 3, 2016 | archive-date = January 11, 2023 | archive-url = https://web.archive.org/web/20230111143043/https://books.google.com/books?id=FVfzRvaucq8C&pg=PA1116 | url-status = live }}</ref> Approximately 50% of testosterone is metabolized via [[conjugation (biochemistry)|conjugation]] into [[testosterone glucuronide]] and to a lesser extent [[testosterone sulfate]] by [[glucuronosyltransferase]]s and [[sulfotransferase]]s, respectively.<ref name="MelmedPolonsky2015" /> An additional 40% of testosterone is metabolized in equal proportions into the [[17-ketosteroid]]s [[androsterone]] and [[etiocholanolone]] via the combined actions of [[5α-reductase|5α-]] and [[5β-reductase]]s, [[3α-hydroxysteroid dehydrogenase]], and 17β-HSD, in that order.<ref name="MelmedPolonsky2015" /><ref name="Becker2001" /><ref name="WeckerWatts2009">{{cite book | vauthors = Wecker L, Watts S, Faingold C, Dunaway G, Crespo L | title = Brody's Human Pharmacology | url = https://books.google.com/books?id=kfsrz_-OrMQC&pg=PA468 | date = 1 April 2009 | publisher = Elsevier Health Sciences | isbn = 978-0-323-07575-6 | pages = 468–469 | access-date = November 3, 2016 | archive-date = January 11, 2023 | archive-url = https://web.archive.org/web/20230111143031/https://books.google.com/books?id=kfsrz_-OrMQC&pg=PA468 | url-status = live }}</ref> Androsterone and etiocholanolone are then [[glucuronidation|glucuronidated]] and to a lesser extent [[sulfation|sulfated]] similarly to testosterone.<ref name="MelmedPolonsky2015" /><ref name="Becker2001" /> The conjugates of testosterone and its hepatic metabolites are released from the liver into [[circulatory system|circulation]] and [[excretion|excreted]] in the [[urine]] and [[bile]].<ref name="MelmedPolonsky2015" /><ref name="Becker2001" /><ref name="WeckerWatts2009" /> Only a small fraction (2%) of testosterone is excreted unchanged in the urine.<ref name="Becker2001" /> In the hepatic 17-ketosteroid pathway of testosterone metabolism, testosterone is converted in the liver by 5α-reductase and 5β-reductase into 5α-DHT and the inactive [[5β-Dihydrotestosterone|5β-DHT]], respectively.<ref name="MelmedPolonsky2015" /><ref name="Becker2001" /> Then, 5α-DHT and 5β-DHT are converted by 3α-HSD into [[3α-androstanediol]] and [[3α-etiocholanediol]], respectively.<ref name="MelmedPolonsky2015" /><ref name="Becker2001" /> Subsequently, 3α-androstanediol and 3α-etiocholanediol are converted by 17β-HSD into androsterone and etiocholanolone, which is followed by their conjugation and excretion.<ref name="MelmedPolonsky2015" /><ref name="Becker2001" /> [[3β-Androstanediol]] and [[3β-etiocholanediol]] can also be formed in this pathway when 5α-DHT and 5β-DHT are acted upon by 3β-HSD instead of 3α-HSD, respectively, and they can then be transformed into [[epiandrosterone]] and [[epietiocholanolone]], respectively.<ref name="pmid20186052">{{cite journal | vauthors = Penning TM | title = New frontiers in androgen biosynthesis and metabolism | journal = Curr Opin Endocrinol Diabetes Obes | volume = 17 | issue = 3 | pages = 233–9 | year = 2010 | pmid = 20186052 | pmc = 3206266 | doi = 10.1097/MED.0b013e3283381a31 }}</ref><ref name="HorskyPresl2012">{{cite book | vauthors = Horsky J, Presl J | title = Ovarian Function and its Disorders: Diagnosis and Therapy | url = https://books.google.com/books?id=7IrpCAAAQBAJ&pg=PA107 | date = 6 December 2012 | publisher = Springer Science & Business Media | isbn = 978-94-009-8195-9 | pages = 107– | access-date = November 5, 2016 | archive-date = January 11, 2023 | archive-url = https://web.archive.org/web/20230111143033/https://books.google.com/books?id=7IrpCAAAQBAJ&pg=PA107 | url-status = live }}</ref> A small portion of approximately 3% of testosterone is [[reversible reaction|reversibly]] converted in the liver into [[androstenedione]] by 17β-HSD.<ref name="WeckerWatts2009" /> In addition to conjugation and the 17-ketosteroid pathway, testosterone can also be [[hydroxylation|hydroxylated]] and [[oxidation|oxidized]] in the liver by [[cytochrome P450]] [[enzyme]]s, including [[CYP3A4]], [[CYP3A5]], [[CYP2C9]], [[CYP2C19]], and [[CYP2D6]].<ref name="Zhou2016">{{cite book | vauthors = Zhou S | title=Cytochrome P450 2D6: Structure, Function, Regulation and Polymorphism | url = https://books.google.com/books?id=UJqmCwAAQBAJ&pg=PA242|date=6 April 2016 | publisher = CRC Press | isbn = 978-1-4665-9788-4 | pages = 242– }}</ref> 6β-Hydroxylation and to a lesser extent 16β-hydroxylation are the major transformations.<ref name="Zhou2016" /> The 6β-hydroxylation of testosterone is catalyzed mainly by CYP3A4 and to a lesser extent CYP3A5 and is responsible for 75 to 80% of cytochrome P450-mediated testosterone metabolism.<ref name="Zhou2016" /> In addition to 6β- and 16β-hydroxytestosterone, 1β-, 2α/β-, 11β-, and 15β-hydroxytestosterone are also formed as minor metabolites.<ref name="Zhou2016" /><ref name="isbn0-3870-8012-0">{{cite book | vauthors = Trager L | title = Steroidhormone: Biosynthese, Stoffwechsel, Wirkung | language = de | publisher = Springer-Verlag | year = 1977 | page = 349 | isbn = 978-0-387-08012-3 }}</ref> Certain cytochrome P450 enzymes such as CYP2C9 and CYP2C19 can also oxidize testosterone at the C17 position to form androstenedione.<ref name="Zhou2016" /> Two of the immediate metabolites of testosterone, 5α-DHT and [[estradiol]], are biologically important and can be formed both in the liver and in extrahepatic tissues.<ref name="Becker2001" /> Approximately 5 to 7% of testosterone is converted by 5α-reductase into 5α-DHT, with circulating levels of 5α-DHT about 10% of those of testosterone, and approximately 0.3% of testosterone is converted into estradiol by [[aromatase]].<ref name="pmid3549275"/><ref name="Becker2001" /><ref name="pmid8092979">{{cite journal | vauthors = Randall VA | title = Role of 5 alpha-reductase in health and disease | journal = Baillière's Clinical Endocrinology and Metabolism | volume = 8 | issue = 2 | pages = 405–31 | date = Apr 1994 | pmid = 8092979 | doi = 10.1016/S0950-351X(05)80259-9 }}</ref><ref name="pmid12428207">{{cite journal | vauthors = Meinhardt U, Mullis PE | title = The essential role of the aromatase/p450arom | journal = Seminars in Reproductive Medicine | volume = 20 | issue = 3 | pages = 277–84 | date = August 2002 | pmid = 12428207 | doi = 10.1055/s-2002-35374 | s2cid = 25407830 }}</ref> 5α-Reductase is highly expressed in the [[male reproductive system|male reproductive organ]]s (including the [[prostate gland]], [[seminal vesicle]]s, and [[epididymides]]),<ref name="Noakes2009">{{cite book | vauthors = Noakes DE | title=Arthur's Veterinary Reproduction and Obstetrics | url = https://books.google.com/books?id=W5TdAwAAQBAJ&pg=PA695 | date = 23 April 2009 | publisher = Elsevier Health Sciences UK | isbn = 978-0-7020-3990-4 | pages = 695– }}</ref> [[skin]], [[hair follicle]]s, and [[brain]]<ref name="NieschlagBehre2004">{{cite book | vauthors = Nieschlag E, Behre HM | title = Testosterone: Action, Deficiency, Substitution | url = https://books.google.com/books?id=ZiZ7MWDqo5oC&pg=PA626 | date = 1 April 2004 | publisher = Cambridge University Press | isbn = 978-1-139-45221-2 | pages = 626– }}</ref> and aromatase is highly expressed in adipose tissue, [[bone]], and the brain.<ref name="Parl2000">{{cite book | vauthors = Parl FF | title = Estrogens, Estrogen Receptor and Breast Cancer | url = https://books.google.com/books?id=v7ai5Mz9TZQC&pg=PA25 | year = 2000 | publisher = IOS Press | isbn = 978-0-9673355-4-4 | pages = 25– }}</ref><ref name="NormanHenry2014">{{cite book | vauthors = Norman AW, Henry HL | title = Hormones|url=https://books.google.com/books?id=_renonjXq68C&pg=PA261 | date=30 July 2014 | publisher = Academic Press | isbn = 978-0-08-091906-5 | pages = 261– }}</ref> As much as 90% of testosterone is converted into 5α-DHT in so-called androgenic tissues with high 5α-reductase expression,<ref name="WeckerWatts2009" /> and due to the several-fold greater potency of 5α-DHT as an AR agonist relative to testosterone,<ref name="MozayaniRaymon2011">{{cite book | vauthors = Mozayani A, Raymon L | title = Handbook of Drug Interactions: A Clinical and Forensic Guide | url = https://books.google.com/books?id=NhBJ6kg_uP0C&pg=PA656 | date = 18 September 2011 | publisher = Springer Science & Business Media | isbn = 978-1-61779-222-9 | pages = 656– }}</ref> it has been estimated that the effects of testosterone are potentiated 2- to 3-fold in such tissues.<ref name="pmid7626464">{{cite journal | vauthors = Sundaram K, Kumar N, Monder C, Bardin CW | s2cid = 32619627 | title = Different patterns of metabolism determine the relative anabolic activity of 19-norandrogens | journal = J. Steroid Biochem. Mol. Biol. | volume = 53 | issue = 1–6 | pages = 253–7 | year = 1995 | pmid = 7626464 | doi = 10.1016/0960-0760(95)00056-6}}</ref> ===Levels=== Total levels of testosterone in the body have been reported as 264 to 916 ng/dL (nanograms per deciliter) in non-obese European and American men age 19 to 39 years,<ref name="pmid28324103">{{cite journal | vauthors = Travison TG, Vesper HW, Orwoll E, Wu F, Kaufman JM, Wang Y, Lapauw B, Fiers T, Matsumoto AM, Bhasin S | title = Harmonized Reference Ranges for Circulating Testosterone Levels in Men of Four Cohort Studies in the United States and Europe | journal = The Journal of Clinical Endocrinology and Metabolism | volume = 102 | issue = 4 | pages = 1161–1173 | date = April 2017 | pmid = 28324103 | pmc = 5460736 | doi = 10.1210/jc.2016-2935 }}</ref> while mean testosterone levels in adult men have been reported as 630 ng/dL.<ref name="Sperling2014" /> Although commonly used as a [[reference range]],<ref>{{cite web |title=Testosterone, total |url=https://www.labcorp.com/tests/004226/testosterone-total |website=LabCorp |access-date=20 December 2021 |archive-date=December 20, 2021 |archive-url=https://web.archive.org/web/20211220171446/https://www.labcorp.com/tests/004226/testosterone-total |url-status=live }}</ref> some physicians have disputed the use of this range to determine [[hypogonadism]].<ref>{{cite journal | vauthors = Morgentaler A | title = Andrology: Testosterone reference ranges and diagnosis of testosterone deficiency | journal = Nature Reviews. Urology | volume = 14 | issue = 5 | pages = 263–264 | date = May 2017 | pmid = 28266512 | doi = 10.1038/nrurol.2017.35 | s2cid = 29122481 }}</ref><ref>{{cite journal | vauthors = Morgentaler A, Khera M, Maggi M, Zitzmann M | title = Commentary: Who is a candidate for testosterone therapy? A synthesis of international expert opinions | journal = The Journal of Sexual Medicine | volume = 11 | issue = 7 | pages = 1636–1645 | date = July 2014 | pmid = 24797325 | doi = 10.1111/jsm.12546 }}</ref> Several professional medical groups have recommended that 350 ng/dL generally be considered the minimum normal level,<ref>{{cite journal | vauthors = Wang C, Nieschlag E, Swerdloff R, Behre HM, Hellstrom WJ, Gooren LJ, Kaufman JM, Legros JJ, Lunenfeld B, Morales A, Morley JE, Schulman C, Thompson IM, Weidner W, Wu FC | title = ISA, ISSAM, EAU, EAA and ASA recommendations: investigation, treatment and monitoring of late-onset hypogonadism in males | journal = International Journal of Impotence Research | volume = 21 | issue = 1 | pages = 1–8 | date = 16 October 208 | pmid = 18923415 | doi = 10.1038/ijir.2008.41 | s2cid = 30430279 | url = https://biblio.ugent.be/publication/631584/file/741306 | url-access = subscription }}</ref> which is consistent with previous findings.<ref>{{cite journal | vauthors = Bhasin S, Pencina M, Jasuja GK, Travison TG, Coviello A, Orwoll E, Wang PY, Nielson C, Wu F, Tajar A, Labrie F, Vesper H, Zhang A, Ulloor J, Singh R, D'Agostino R, Vasan RS | title = Reference ranges for testosterone in men generated using liquid chromatography tandem mass spectrometry in a community-based sample of healthy nonobese young men in the Framingham Heart Study and applied to three geographically distinct cohorts | journal = The Journal of Clinical Endocrinology and Metabolism | volume = 96 | issue = 8 | pages = 2430–2439 | date = August 2011 | pmid = 21697255 | pmc = 3146796 | doi = 10.1210/jc.2010-3012 }}</ref>{{primary source inline|date=December 2021}}{{medical citation needed|date=December 2021}} Levels of testosterone in men decline with age.<ref name="pmid28324103" /> In women, mean levels of total testosterone have been reported to be 32.6 ng/dL.<ref name="Camacho2012">{{cite book|vauthors=Camacho PM|title=Evidence-Based Endocrinology|url=https://books.google.com/books?id=s06wXkPAnfcC&pg=PA217|date=26 September 2012|publisher=Lippincott Williams & Wilkins|isbn=978-1-4511-7146-4|pages=217–|access-date=May 19, 2018|archive-date=January 11, 2023|archive-url=https://web.archive.org/web/20230111143033/https://books.google.com/books?id=s06wXkPAnfcC&pg=PA217|url-status=live}}</ref><ref name="pmid15251757">{{cite journal | vauthors = Steinberger E, Ayala C, Hsi B, Smith KD, Rodriguez-Rigau LJ, Weidman ER, Reimondo GG | title = Utilization of commercial laboratory results in management of hyperandrogenism in women | journal = Endocrine Practice | volume = 4 | issue = 1 | pages = 1–10 | date = 1998 | pmid = 15251757 | doi = 10.4158/EP.4.1.1 }}</ref> In women with [[hyperandrogenism]], mean levels of total testosterone have been reported to be 62.1 ng/dL.<ref name="Camacho2012" /><ref name="pmid15251757" /> {{Testosterone levels in males and females}} {| class="wikitable mw-collapsible mw-collapsed" style="text-align:left; margin-left:auto; margin-right:auto; border:none;" |+ class="nowrap" | Total testosterone levels in males throughout life |- ! Life stage !! Tanner stage !! Age range !! Mean age !! Levels range !! Mean levels |- | Child || Stage I || <10 years || – || <30 ng/dL || 5.8 ng/dL |- | rowspan="4" | Puberty || Stage II || 10–14 years || 12 years || <167 ng/dL || 40 ng/dL |- | Stage III || 12–16 years || 13–14 years || 21–719 ng/dL || 190 ng/dL |- | Stage IV || 13–17 years || 14–15 years || 25–912 ng/dL || 370 ng/dL |- | Stage V || 13–17 years || 15 years || 110–975 ng/dL || 550 ng/dL |- | Adult || – || ≥18 years || – || 250–1,100 ng/dL || 630 ng/dL |- class="sortbottom" | colspan="6" style="width: 1px; background-color:#eaecf0; text-align: center;" | '''Sources:''' <ref name="BajajBerman2011">{{cite book|vauthors=Bajaj L, Berman S|title=Berman's Pediatric Decision Making|url=https://books.google.com/books?id=NPhnHrDQ1_kC&pg=PA160|date=1 January 2011|publisher=Elsevier Health Sciences|isbn=978-0-323-05405-8|pages=160–|access-date=March 25, 2018|archive-date=January 11, 2023|archive-url=https://web.archive.org/web/20230111143033/https://books.google.com/books?id=NPhnHrDQ1_kC&pg=PA160|url-status=live}}</ref><ref name="Styne2016">{{cite book|vauthors=Styne DM|title=Pediatric Endocrinology: A Clinical Handbook|url=https://books.google.com/books?id=akMWDAAAQBAJ&pg=PA191|date=25 April 2016|publisher=Springer|isbn=978-3-319-18371-8|pages=191–|access-date=March 25, 2018|archive-date=January 11, 2023|archive-url=https://web.archive.org/web/20230111143038/https://books.google.com/books?id=akMWDAAAQBAJ&pg=PA191|url-status=live}}</ref><ref name="Sperling2014">{{cite book|vauthors=Sperling MA|title=Pediatric Endocrinology E-Book|url=https://books.google.com/books?id=GgXnAgAAQBAJ&pg=PA488|date=10 April 2014|publisher=Elsevier Health Sciences|isbn=978-1-4557-5973-6|pages=488–|access-date=March 25, 2018|archive-date=January 11, 2023|archive-url=https://web.archive.org/web/20230111143036/https://books.google.com/books?id=GgXnAgAAQBAJ&pg=PA488|url-status=live}}</ref><ref name="PaganaPagana2014">{{cite book |vauthors=Pagana KD, Pagana TJ, Pagana TN |title=Mosby's Diagnostic and Laboratory Test Reference – E-Book |url=https://books.google.com/books?id=J7eXBAAAQBAJ&pg=PA879 |date=19 September 2014 |publisher=Elsevier Health Sciences |isbn=978-0-323-22592-2 |pages=879– |access-date=March 25, 2018 |archive-date=January 11, 2023 |archive-url=https://web.archive.org/web/20230111143038/https://books.google.com/books?id=J7eXBAAAQBAJ&pg=PA879 |url-status=live }}</ref><ref name="HospitalEngorn2014">{{cite book |vauthors=Engorn B, Flerlage J |title=The Harriet Lane Handbook E-Book |url=https://books.google.com/books?id=6cSLAwAAQBAJ&pg=PA240 |date=1 May 2014 |publisher=Elsevier Health Sciences |isbn=978-0-323-11246-8 |pages=240– |access-date=March 25, 2018 |archive-date=January 11, 2023 |archive-url=https://web.archive.org/web/20230111143039/https://books.google.com/books?id=6cSLAwAAQBAJ&pg=PA240 |url-status=live }}</ref> |} {{wide image|Blood values sorted by mass and molar concentration.png|1200px|[[Reference ranges for blood tests]], showing adult male testosterone levels in light blue at center-left}} ==Measurement== In measurements of testosterone in blood samples, different assay techniques can yield different results.<ref>{{Cite journal |title=Challenges in Testosterone Measurement, Data Interpretation, and Methodological Appraisal of Interventional Trials | the Journal of Sexual Medicine | Oxford Academic |journal=The Journal of Sexual Medicine |date=July 2016 |volume=13 |issue=7 |pages=1029–1046 |doi=10.1016/j.jsxm.2016.04.068 |pmid=27209182 |pmc=5516925 | vauthors = Trost LW, Mulhall JP }}</ref><ref>{{Cite journal |url=https://academic.oup.com/humupd/article/18/4/405/665632 |title=Testosterone concentrations, using different assays, in different types of ovarian insufficiency: A systematic review and meta-analysis | Human Reproduction Update | Oxford Academic |journal=Human Reproduction Update |date=July 2012 |volume=18 |issue=4 |pages=405–419 |doi=10.1093/humupd/dms013 |access-date=February 20, 2024 |archive-date=February 20, 2024 |archive-url=https://web.archive.org/web/20240220184429/https://academic.oup.com/humupd/article/18/4/405/665632 |url-status=live | vauthors = Janse F, Tanahatoe SJ, Eijkemans MJ, Fauser BC |pmid=22525963 |url-access=subscription }}</ref> Immunofluorescence assays exhibit considerable variability in quantifying testosterone concentrations in blood samples due to the cross-reaction of structurally similar steroids, leading to overestimating the results. In contrast, the liquid chromatography/tandem mass spectrometry method is more desirable: it offers superior specificity and precision, making it a more suitable choice for this application.<ref name="pmid38311999">{{cite journal |vauthors=Tiulpakov MA, Nagaeva EV, Kalinchenko NY, Bezlepkina OB |title=[A promising approach for therapy control in congenital adrenal hyperplasia. Problems of Endocrinology] |language=Russian |journal=Probl Endokrinol (Mosk) |volume=69 |issue=6 |pages=102–108 |date=January 2024 |pmid=38311999 |pmc=10848187 |doi=10.14341/probl13328}}</ref> Testosterone's bioavailable concentration is commonly determined using the Vermeulen calculation or more precisely using the modified Vermeulen method,<ref name="Jong">{{cite journal | vauthors = de Ronde W, van der Schouw YT, Pols HA, Gooren LJ, Muller M, Grobbee DE, de Jong FH | title = Calculation of bioavailable and free testosterone in men: a comparison of 5 published algorithms | journal = Clinical Chemistry | volume = 52 | issue = 9 | pages = 1777–84 | date = September 2006 | pmid = 16793931 | doi = 10.1373/clinchem.2005.063354 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Hasler J, Herklotz R, Luppa PB, Diver MJ, Thevis M, Metzger J, Savoca R, Jermini F, Huber AR |title=Impact of recent biochemical findings on the determination of free and bioavailable testosterone: evaluation and proposal for clinical use |journal=LaboratoriumsMedizin |date=1 January 2006 |volume=30 |issue=6 |pages=492–505 |doi=10.1515/JLM.2006.050 |doi-access=free }}</ref> which considers the dimeric form of sex hormone-binding globulin.<ref name="PDB">{{Cite journal|url = https://www.rcsb.org/3d-view/1D2S/1|title = RCSB PDB - 1D2S|journal = Crystal Structure of the N-Terminal Laminin G-Like Domain of SHBG in Complex with Dihydrotestosterone|access-date = February 19, 2019|archive-date = June 28, 2021|archive-url = https://web.archive.org/web/20210628012949/https://www.rcsb.org/3d-view/1D2S/1|url-status = live}}</ref> Both methods use chemical equilibrium to derive the concentration of bioavailable testosterone: in circulation, testosterone has two major binding partners, albumin (weakly bound) and sex hormone-binding globulin (strongly bound). These methods are described in detail in the accompanying figure. <gallery> File:Dimeric SHBG.png|Dimeric sex hormone-binding globulin with its testosterone ligands File:Method for determining testosterone.png|Two methods for determining the concentration of bioavailable testosterone </gallery> == Distribution == Testosterone has been detected at variably higher and lower levels among men of various nations and from various backgrounds, explanations for the causes of this have been relatively diverse.<ref>{{cite journal | vauthors = Cohen J, Nassau DE, Patel P, Ramasamy R | title = Low Testosterone in Adolescents & Young Adults | journal = Frontiers in Endocrinology | volume = 10 | pages = 916 | date = 2020-01-10 | pmid = 32063884 | pmc = 6966696 | doi = 10.3389/fendo.2019.00916 | doi-access = free }}</ref><ref>{{cite book |vauthors=Nassar GW, Leslie S |chapter=Physiology, Testosterone |date=2024 |title=StatPearls |chapter-url=http://www.ncbi.nlm.nih.gov/books/NBK526128/ |access-date=2024-03-03 |place=Treasure Island (FL) |publisher=StatPearls Publishing |pmid=30252384 |archive-date=October 2, 2023 |archive-url=https://web.archive.org/web/20231002123403/https://www.ncbi.nlm.nih.gov/books/NBK526128/ |url-status=live }}</ref> People from nations of the [[Eurasian Steppe]] and [[Central Asia]], such as [[Mongolia]], [[Kyrgyzstan]] and [[Uzbekistan]], have consistently been detected to have had significantly elevated levels of testosterone,<ref name="antipufaadmin">{{Cite web |last=antipufaadmin |date=2022-03-04 |title=What Country Has The Highest Testosterone? |url=https://testosteronedecline.com/what-country-has-highest-testosterone/ |access-date=2024-03-03 |website=testosteronedecline.com |archive-date=March 3, 2024 |archive-url=https://web.archive.org/web/20240303234820/https://testosteronedecline.com/what-country-has-highest-testosterone/ |url-status=live }}</ref> while people from [[Central Europe]]an and [[Baltic states|Baltic]] nations such as the [[Czech Republic]], [[Slovakia]], [[Latvia]] and [[Estonia]] have been found to have had significantly decreased levels of testosterone.<ref name="antipufaadmin"/> The region with the highest-ever tested levels of testosterone is [[Chita, Russia]], the people group with the highest ever tested levels of testosterone were the [[Yakuts]].<ref>{{Cite web |date=2021-10-13 |title=Testosterone Levels 100 Years Ago - TestosteroneDecline.com |url=https://testosteronedecline.com/testosterone-levels-100-years-ago/ |access-date=2024-03-03 |website=testosteronedecline.com |archive-date=March 3, 2024 |archive-url=https://web.archive.org/web/20240303234820/https://testosteronedecline.com/testosterone-levels-100-years-ago/ |url-status=live }}</ref> ==History and production== [[File:Lavoslav Ružićka 1939.jpg|thumb|upright=0.8|Nobel Prize winner, [[Leopold Ružička|Leopold Ruzicka]] of Ciba, a pharmaceutical industry giant that synthesized testosterone]] A [[testicular]] action was linked to circulating blood fractions – now understood to be a family of androgenic hormones – in the early work on castration and testicular transplantation in fowl by [[Arnold Adolph Berthold]] (1803–1861).<ref name="Berthold_1849">{{cite journal |vauthors=Berthold AA |title=Transplantation der Hoden |trans-title=Transplantation of testis |language=de |journal=Arch. Anat. Physiol. Wiss. |volume=16 |pages=42–46 |year=1849}}</ref> Research on the action of testosterone received a brief boost in 1889, when the Harvard professor [[Charles-Édouard Brown-Séquard]] (1817–1894), then in Paris, self-injected subcutaneously a "rejuvenating elixir" consisting of an extract of dog and guinea pig testicle. He reported in ''[[The Lancet]]'' that his vigor and feeling of well-being were markedly restored but the effects were transient,<ref name="Brown-Sequard_1889">{{cite journal |vauthors=Brown-Sequard CE |title=The effects produced on man by subcutaneous injections of liquid obtained from the testicles of animals |journal=Lancet |volume=2 |issue=3438 |pages=105–107 |year=1889 |doi=10.1016/S0140-6736(00)64118-1 |url=https://zenodo.org/record/1428532 |access-date=September 16, 2019 |archive-date=March 8, 2021 |archive-url=https://web.archive.org/web/20210308181705/https://zenodo.org/record/1428532 |url-status=live }}</ref> and Brown-Séquard's hopes for the compound were dashed. Suffering the ridicule of his colleagues, he abandoned his work on the mechanisms and effects of androgens in human beings. In 1927, the University of Chicago's Professor of Physiologic Chemistry, Fred C. Koch, established easy access to a large source of bovine testicles – the Chicago stockyards – and recruited students willing to endure the tedious work of extracting their isolates. In that year, Koch and his student, Lemuel McGee, derived 20 mg of a substance from a supply of 40 pounds of bovine testicles that, when administered to castrated roosters, pigs and rats, re-masculinized them.<ref name="Gallagher_Koch_1929">{{cite journal | vauthors = Gallagher TF, Koch FC | title = The testicular hormone |journal = J. Biol. Chem. | volume = 84 | issue = 2 | pages = 495–500 |date=November 1929 | doi = 10.1016/S0021-9258(18)77008-7 | doi-access = free }}</ref> The group of Ernst Laqueur at the University of Amsterdam purified testosterone from bovine testicles in a similar manner in 1934, but the isolation of the hormone from animal tissues in amounts permitting serious study in humans was not feasible until three European pharmaceutical giants – [[Schering AG|Schering]] (Berlin, Germany), [[Organon International|Organon]] (Oss, Netherlands) and [[Novartis|Ciba]] – began full-scale steroid research and development programs in the 1930s. The Organon group in the Netherlands were the first to isolate the hormone, identified in a May 1935 paper "On Crystalline Male Hormone from Testicles (Testosterone)".<ref name="David_1935">{{cite journal | vauthors = David KG, Dingemanse E, Freud JL | title = Über krystallinisches mannliches Hormon aus Hoden (Testosteron) wirksamer als aus harn oder aus Cholesterin bereitetes Androsteron |trans-title=On crystalline male hormone from testicles (testosterone) effective as from urine or from cholesterol | language = de | journal = Hoppe-Seyler's Z Physiol Chem | volume = 233 | issue = 5–6| pages = 281–83 |date=May 1935 | doi = 10.1515/bchm2.1935.233.5-6.281 }}</ref> 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]], at the [[Faculty of Chemistry, Gdańsk University of Technology|''Chemisches Institut'']] of [[Gdańsk University of Technology|Technical University]] in [[Gdańsk]].<ref name="Butenandt_1935a">{{cite journal | vauthors = Butenandt A, Hanisch G | title = Umwandlung des Dehydroandrosterons in Androstendiol und Testosterone; ein Weg zur Darstellung des Testosterons aus Cholestrin |trans-title=About Testosterone. Conversion of Dehydro-androsterons into androstendiol and testosterone; a way for the structure assignment of testosterone from cholesterol | language = de | journal = Hoppe-Seyler's Z Physiol Chem | volume = 237 | issue = 2| pages = 89–97 | year = 1935 | doi = 10.1515/bchm2.1935.237.1-3.89 }}</ref><ref name="pmid11176375">{{cite journal | vauthors = Freeman ER, Bloom DA, McGuire EJ | title = A brief history of testosterone | journal = The Journal of Urology | volume = 165 | issue = 2 | pages = 371–73 | date = Feb 2001 | pmid = 11176375 | doi = 10.1097/00005392-200102000-00004 }}</ref> The [[chemical synthesis]] of testosterone from cholesterol was achieved in August that year by Butenandt and Hanisch.<ref name="Butenandt_1935b">{{cite journal | vauthors = Butenandt A, Hanisch G | title = Uber die Umwandlung des Dehydroandrosterons in Androstenol-(17)-one-(3) (Testosterone); um Weg zur Darstellung des Testosterons auf Cholesterin (Vorlauf Mitteilung). [The conversion of dehydroandrosterone into androstenol-(17)-one-3 (testosterone); a method for the production of testosterone from cholesterol (preliminary communication)] | journal = Chemische Berichte | year = 1935 | volume = 68 | issue = 9 | pages = 1859–62 | language = de | doi = 10.1002/cber.19350680937 }}</ref> Only a week later, the Ciba group in Zurich, [[Leopold Ruzicka]] (1887–1976) and A. Wettstein, published their synthesis of testosterone.<ref name="Ruzicka_1935">{{cite journal | vauthors = Ruzicka L, Wettstein A | title = Uber die kristallinische Herstellung des Testikelhormons, Testosteron (Androsten-3-ol-17-ol) [The crystalline production of the testicle hormone, testosterone (Androsten-3-ol-17-ol)] | journal = Helvetica Chimica Acta | year = 1935 | volume = 18 | pages = 1264–75 | language = de | doi=10.1002/hlca.193501801176}}</ref> These independent partial syntheses of testosterone from a cholesterol base earned both Butenandt and Ruzicka the joint 1939 [[Nobel Prize in Chemistry]].<ref name="pmid11176375"/><ref name="pmid7817189">{{cite journal | vauthors = Hoberman JM, Yesalis CE | title = The history of synthetic testosterone | journal = Scientific American | volume = 272 | issue = 2 | pages = 76–81 | date = Feb 1995 | pmid = 7817189 | doi = 10.1038/scientificamerican0295-76 | bibcode = 1995SciAm.272b..76H }}</ref> Testosterone was identified as 17β-hydroxyandrost-4-en-3-one (C<sub>19</sub>H<sub>28</sub>O<sub>2</sub>), 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 ester]]s permitted the characterization of the hormone's effects, so that Kochakian and Murlin (1936) were able to show that testosterone raised nitrogen retention (a mechanism central to anabolism) in the dog, after which Allan Kenyon's group<ref name="Kenyon _1940">{{cite journal | vauthors = Kenyon AT, Knowlton K, Sandiford I, Koch FC, Lotwin, G | title = A comparative study of the metabolic effects of testosterone propionate in normal men and women and in eunuchoidism | journal = Endocrinology| volume = 26| issue = 1 | pages = 26–45 |date=February 1940| doi = 10.1210/Endo-26-1-26 }}</ref> was able to demonstrate both anabolic and androgenic effects of testosterone propionate in eunuchoidal men, boys, and women. The period of the early 1930s to the 1950s has been called "The Golden Age of Steroid Chemistry",<ref name="pmid10443899">{{cite journal | vauthors = Schwarz S, Onken D, Schubert A | s2cid = 40156824 | title = The steroid story of Jenapharm: from the late 1940s to the early 1970s | journal = Steroids | volume = 64 | issue = 7 | pages = 439–45 | date = July 1999 | pmid = 10443899 | doi = 10.1016/S0039-128X(99)00003-3 }}</ref> and work during this period progressed quickly.<ref name = "de Kruif_1945" >{{cite book | vauthors = de Kruif P | title = The Male Hormone | url = https://archive.org/details/malehormone00dekr | url-access = registration | publisher = Harcourt, Brace | location = New York |year = 1945 }}</ref> Like other androsteroids, testosterone is manufactured industrially from microbial fermentation of plant cholesterol (e.g., from soybean oil). In the early 2000s, the steroid market weighed around one million tonnes and was worth $10 billion, making it the 2nd largest biopharmaceutical market behind antibiotics.<ref>{{Cite journal |last1=Batth |first1=Rituraj |last2=Nicolle |first2=Clément |last3=Cuciurean |first3=Ilenuta Simina |last4=Simonsen |first4=Henrik Toft |date=2020-09-03 |title=Biosynthesis and Industrial Production of Androsteroids |journal=Plants |volume=9 |issue=9 |pages=1144 |doi=10.3390/plants9091144 |issn=2223-7747 |pmc=7570361 |pmid=32899410 |doi-access=free |bibcode=2020Plnts...9.1144B }}</ref> ==Other species== Testosterone is observed in most vertebrates. Testosterone and the classical nuclear [[androgen receptor]] first appeared in [[gnathostome]]s (jawed vertebrates).<ref name="pmid19456336">{{cite journal | vauthors = Guerriero G | title = Vertebrate sex steroid receptors: evolution, ligands, and neurodistribution | journal = Annals of the New York Academy of Sciences | volume = 1163 | issue = 1| pages = 154–68 | year = 2009 | pmid = 19456336 | doi = 10.1111/j.1749-6632.2009.04460.x | bibcode = 2009NYASA1163..154G | s2cid = 5790990 }}</ref> [[Agnathan]]s (jawless vertebrates) such as [[lamprey]]s do not produce testosterone but instead use [[androstenedione]] as a male sex hormone.<ref name="pmid17931674">{{cite journal | vauthors = Bryan MB, Scott AP, Li W | s2cid = 33753909 | title = Sex steroids and their receptors in lampreys | journal = Steroids | volume = 73 | issue = 1 | pages = 1–12 | year = 2008 | pmid = 17931674 | doi = 10.1016/j.steroids.2007.08.011 }}</ref> [[Fish]] make a slightly different form called [[11-ketotestosterone]].<ref name="isbn0-87893-617-3">{{cite book | vauthors = Nelson RF | title = An introduction to behavioral endocrinology | publisher = Sinauer Associates | location = Sunderland, Mass | year = 2005 | page = 143 | isbn = 978-0-87893-617-5 }}</ref> Its counterpart in insects is [[ecdysone]].<ref name="De_Loof_2006">{{cite journal | vauthors = De Loof A | title = Ecdysteroids: the overlooked sex steroids of insects? Males: the black box | journal = Insect Science |date=October 2006 | volume = 13 | issue = 5 | pages = 325–338 | doi = 10.1111/j.1744-7917.2006.00101.x | bibcode = 2006InsSc..13..325D | s2cid = 221810929 }}</ref> The presence of these ubiquitous steroids in a wide range of animals suggest that [[sex hormone]]s have an ancient evolutionary history.<ref name="Mechoulam_1984">{{cite journal | vauthors = Mechoulam R, Brueggemeier RW, Denlinger DL | s2cid = 31950471 | title = Estrogens in insects | journal = Cellular and Molecular Life Sciences |date=September 1984 | volume = 40 | issue = 9 | pages = 942–44 | doi = 10.1007/BF01946450 }}</ref> ==See also== * [[List of androgens/anabolic steroids]] * [[List of human hormones]] ==References== {{Reflist}} ==Further reading== {{Refbegin}} * {{cite book | veditors = Pfaff DW, Etgen AM | vauthors = Fargo KN, Pak TR, Foecking EM, Jones KJ | title = Molecular Mechanisms of Hormone Actions on Behavior | chapter = Molecular Biology of Androgen Action: Perspectives on Neuroprotective and Neurotherapeutic Effects. | publisher = Elsevier Inc. | date = 2010 | pages = 1219–1246 | doi = 10.1016/B978-008088783-8.00036-X | isbn = 978-0-12-374939-0 | chapter-url = https://books.google.com/books?id=Y8jxd5vu6N8C&pg=PA127 }} * {{cite journal | vauthors = Dowd NE | title = Sperm, testosterone, masculinities and fatherhood | journal = Nevada Law Journal | volume = 13 | issue = 2 | page = 8 | url = http://scholars.law.unlv.edu/nlj/vol13/iss2/8 | date = 2013 | access-date = December 10, 2017 | archive-date = March 8, 2021 | archive-url = https://web.archive.org/web/20210308061603/https://scholars.law.unlv.edu/nlj/vol13/iss2/8/ | url-status = live }} * {{cite journal | vauthors = Celec P, Ostatníková D, Hodosy J | title = On the effects of testosterone on brain behavioral functions | journal = Frontiers in Neuroscience | volume = 9 | pages = 12 | date = February 2015 | pmid = 25741229 | pmc = 4330791 | doi = 10.3389/fnins.2015.00012 | doi-access = free }} {{Refend}} {{Portal bar|Chemistry|Biology}} {{Testosterone}} {{Hormones}} {{Endogenous steroids}} {{Androgens and antiandrogens}} {{Navboxes | title = [[Biological activity]] | titlestyle = background:#ccccff | list1 = {{Androgen receptor modulators}} {{Estrogen receptor modulators}} {{GABAA receptor positive modulators}} {{Growth factor receptor modulators}} }} {{Authority control}} [[Category:Testosterone| ]] [[Category:Cyclopentanols]] [[Category:Anabolic–androgenic steroids]] [[Category:Androstanes]] [[Category:Estrogens]]<!--Via metabolism into estradiol and androstanediols--> [[Category:GABAA receptor positive allosteric modulators]]<!--Via metabolism into 3α-androstanediol--> [[Category:Hormones of the testis]] [[Category:Hormones of the ovary]] [[Category:Hormones of the hypothalamus-pituitary-gonad axis]] [[Category:Hormones of the suprarenal cortex]] [[Category:Enones]] [[Category:Neuroendocrinology]] [[Category:Human hormones]] [[Category:Sex hormones]]
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