Editing Testosterone (section)

===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&nbsp;[[international unit|IU]]/d (10–25&nbsp;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>