Editing Testosterone (section)

==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&nbsp;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&nbsp;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&nbsp;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>