Editing Antiandrogen (section)

==Mechanism of action==

===Androgen receptor antagonists===
{| class="wikitable sortable floatright"
|+ Antiandrogens at steroid hormone receptors
|-
! rowspan="2" | {{No selflink|Antiandrogen}} || colspan="5" | Relative binding affinities
|-
! {{abbrlink|AR|Androgen receptor}} || {{abbrlink|PR|Progesterone receptor}} || {{abbrlink|ER|Estrogen receptor}} || {{abbrlink|GR|Glucocorticoid receptor}} || {{abbrlink|MR|Mineralocorticoid receptor}}
|-
| {{No selflink|Cyproterone acetate}} || 8–10 || 60 || <0.1 || 5 || 1
|-
| {{No selflink|Chlormadinone acetate}} || 5 || 175 || <0.1 || 38 || 1
|-
| {{No selflink|Megestrol acetate}} || 5 || 152 || <0.1 || 50 || 3
|-
| {{No selflink|Spironolactone}} || 7<!--26 for 30 min--> || 0.4<sup>a</sup> || <0.1 || 2<sup>a</sup> || 182
|-
| {{No selflink|Trimethyltrienolone}} || 3.6 || <1 || <1 || <1 || <1
|-
| {{No selflink|Inocoterone}} || 0.8 || <0.1 || <0.1 || <0.1 || <0.1
|-
| {{No selflink|Inocoterone acetate}} || <0.1 || <0.1 || <0.1 || <0.1 || <0.1
|-
| {{No selflink|Flutamide}} || <0.1 || <0.1 || <0.1 || <0.1 || <0.1
|-
| {{No selflink|Hydroxyflutamide}} || 0.5–0.8 || <0.1 || <0.1 || <0.1 || <0.1
|-
| {{No selflink|Nilutamide}} || 0.5–0.8 || <0.1 || <0.1 || <0.1 || <0.1
|-
| {{No selflink|Bicalutamide}} || 1.8 || <0.1 || <0.1 || <0.1 || <0.1
|- class="sortbottom"
| colspan="6" style="width: 1px; background-color:#eaecf0; text-align: center;" | <small>'''Notes:''' (1): Reference [[ligand (biochemistry)|ligand]]s (100%) were [[testosterone (medication)|testosterone]] for the {{abbrlink|AR|androgen receptor}}, [[progesterone (medication)|progesterone]] for the {{abbrlink|PR|progesterone receptor}}, [[estradiol (medication)|estradiol]] for the {{abbrlink|ER|estrogen receptor}}, [[dexamethasone]] for the {{abbrlink|GR|glucocorticoid receptor}}, and [[aldosterone]] for the {{abbrlink|MR|mineralocorticoid receptor}}. (2): Tissues were rat prostate (AR), rabbit uterus (PR), mouse uterus (ER), rat thymus (GR), and rat kidney (MR). (3): Incubation times (0&nbsp;°C) were 24 hours (AR, <sup>a</sup>), 2 hours (PR, ER), 4 hours (GR), and 1 hour (MR). (4): Assay methods were different for bicalutamide for receptors besides the AR. '''Sources:'''<ref name="pmid3059062">{{cite journal | vauthors = Moguilewsky M, Bouton MM | title = How the study of the biological activities of antiandrogens can be oriented towards the clinic | journal = Journal of Steroid Biochemistry | volume = 31 | issue = 4B | pages = 699–710 | date = October 1988 | pmid = 3059062 | doi = 10.1016/0022-4731(88)90021-0 }}</ref><ref name="pmid1992602">{{cite journal | vauthors = Gaillard-Moguilewsky M | title = Pharmacology of antiandrogens and value of combining androgen suppression with antiandrogen therapy | journal = Urology | volume = 37 | issue = 2 Suppl | pages = 5–12 | date = 1991 | pmid = 1992602 | doi = 10.1016/0090-4295(91)80095-O }}</ref><ref name="pmid3009970">{{cite journal | vauthors = Moguilewsky M, Fiet J, Tournemine C, Raynaud JP | title = Pharmacology of an antiandrogen, anandron, used as an adjuvant therapy in the treatment of prostate cancer | journal = Journal of Steroid Biochemistry | volume = 24 | issue = 1 | pages = 139–46 | date = January 1986 | pmid = 3009970 | doi = 10.1016/0022-4731(86)90043-9 }}</ref><ref name="pmid8136296">{{cite journal | vauthors = Teutsch G, Goubet F, Battmann T, Bonfils A, Bouchoux F, Cerede E, Gofflo D, Gaillard-Kelly M, Philibert D | title = Non-steroidal antiandrogens: synthesis and biological profile of high-affinity ligands for the androgen receptor | journal = The Journal of Steroid Biochemistry and Molecular Biology | volume = 48 | issue = 1 | pages = 111–9 | date = January 1994 | pmid = 8136296 | doi = 10.1016/0960-0760(94)90257-7 | s2cid = 31404295 }}</ref><ref name="RaynaudFortin1986">{{cite book| vauthors = Raynaud JP, Fortin M, Hunt P, Ojasoo T, Doré JC, Surcouf E, Mornon JP | veditors = Gotto AM, O'Malley BW, Liliane FP |chapter=Approaches to drug development using receptors|title=The Role of Receptors in Biology and Medicine: Proceedings of the Ninth Argenteuil Symposium|url=https://books.google.com/books?id=ORFrAAAAMAAJ|year=1986|publisher=Raven Press|isbn=978-0-88167-161-2|pages=65–77}}</ref><ref name="RaynaudOjasoo1981">{{cite book| vauthors = Raynaud JP, Ojasoo T, Labrie F |title=Mechanisms of Steroid Action|chapter=Steroid hormones—agonists and antagonists|year=1981|pages=145–158|publisher=Macmillan Education UK |doi=10.1007/978-1-349-81345-2_11|isbn=978-1-349-81347-6}}</ref><ref name="pmid7421203">{{cite journal | vauthors = Raynaud JP, Bouton MM, Moguilewsky M, Ojasoo T, Philibert D, Beck G, Labrie F, Mornon JP | title = Steroid hormone receptors and pharmacology | journal = Journal of Steroid Biochemistry | volume = 12 | pages = 143–57 | date = January 1980 | pmid = 7421203 | doi = 10.1016/0022-4731(80)90264-2 }}</ref><ref name="pmid359134">{{cite journal | vauthors = Ojasoo T, Raynaud JP | title = Unique steroid congeners for receptor studies | journal = Cancer Research | volume = 38 | issue = 11 Pt 2 | pages = 4186–98 | date = November 1978 | pmid = 359134 | url = http://cancerres.aacrjournals.org/content/38/11_Part_2/4186.short | access-date = 2021-10-31 | archive-date = 2020-11-27 | archive-url = https://web.archive.org/web/20201127182040/https://cancerres.aacrjournals.org/content/38/11_Part_2/4186.short | url-status = live }}</ref><ref name="pmid171505">{{cite journal | vauthors = Raynaud JP, Bonne C, Bouton MM, Moguilewsky M, Philibert D, Azadian-Boulanger G | title = Screening for anti-hormones by receptor studies | journal = Journal of Steroid Biochemistry | volume = 6 | issue = 5 | pages = 615–22 | date = May 1975 | pmid = 171505 | doi = 10.1016/0022-4731(75)90042-4 }}</ref><ref name="pmid14600402">{{cite journal | vauthors = Hanada K, Furuya K, Yamamoto N, Nejishima H, Ichikawa K, Nakamura T, Miyakawa M, Amano S, Sumita Y, Oguro N | title = Bone anabolic effects of S-40503, a novel nonsteroidal selective androgen receptor modulator (SARM), in rat models of osteoporosis | journal = Biol. Pharm. Bull. | volume = 26 | issue = 11 | pages = 1563–9 | date = November 2003 | pmid = 14600402 | doi = 10.1248/bpb.26.1563 | doi-access = free }}</ref></small>
|}
{{Relative potencies of selected antiandrogens in rats}}

AR antagonists act by directly binding to and competitively displacing androgens like testosterone and DHT from the AR, thereby preventing them from activating the receptor and mediating their biological effects.<ref name="pmid10637363" /><ref name="ShenTaplin2010" /> AR antagonists are classified into two types, based on [[chemical structure]]: steroidal and nonsteroidal.<ref name="SchröderRadlmaier2009" /><ref name="KolvenbagFurr2009" /><ref name="pmid10637363" /><ref name="ShenTaplin2010" /><ref name="LemkeWilliams2012">{{cite book| vauthors = Lemke TL, Williams DA |title=Foye's Principles of Medicinal Chemistry|url=https://books.google.com/books?id=Sd6ot9ul-bUC&pg=PA1372|date=24 January 2012|publisher=Lippincott Williams & Wilkins|isbn=978-1-60913-345-0|pages=228–231, 1371–1372}}</ref> Steroidal AR antagonists are structurally related to [[steroid hormone]]s like testosterone and [[progesterone]], whereas nonsteroidal AR antagonists are not steroids and are structurally distinct. Steroidal AR antagonists tend to have [[off-target activity|off-target hormonal actions]] due to their structural similarity to other steroid hormones.<ref name="LemkeWilliams2012" /> In contrast, nonsteroidal AR antagonists are selective for the AR and have no off-target hormonal activity.<ref name="LemkeWilliams2012" /> For this reason, they are sometimes described as "pure" antiandrogens.<ref name="LemkeWilliams2012" />

Although they are described as antiandrogens and indeed show only such effects generally, most or all steroidal AR antagonists are actually not [[silent antagonist]]s of the AR but rather are weak [[partial agonist]]s and are able to activate the receptor in the absence of more potent AR agonists like testosterone and DHT.<ref name="pmid10637363" /><ref name="FiggChau2010" /><ref name="PoyetLabrie1985">{{cite journal | vauthors = Poyet P, Labrie F | title = Comparison of the antiandrogenic/androgenic activities of flutamide, cyproterone acetate and megestrol acetate | journal = Molecular and Cellular Endocrinology | volume = 42 | issue = 3 | pages = 283–8 | date = October 1985 | pmid = 3930312 | doi = 10.1016/0303-7207(85)90059-0 | s2cid = 24746807 }}</ref><ref name="pmid2462135">{{cite journal | vauthors = Luthy IA, Begin DJ, Labrie F | title = Androgenic activity of synthetic progestins and spironolactone in androgen-sensitive mouse mammary carcinoma (Shionogi) cells in culture | journal = Journal of Steroid Biochemistry | volume = 31 | issue = 5 | pages = 845–52 | year = 1988 | pmid = 2462135 | doi = 10.1016/0022-4731(88)90295-6}}</ref> This may have clinical implications in the specific context of prostate cancer treatment.<ref name="pmid10637363" /><ref name="PoyetLabrie1985" /> As an example, steroidal AR antagonists are able to increase prostate weight and accelerate prostate cancer cell growth in the absence of more potent AR agonists,<ref name="pmid10637363" /><ref name="PoyetLabrie1985" /> and spironolactone has been found to accelerate progression of prostate cancer in case reports.<ref name="pmid22665559">{{cite journal | vauthors = Sundar S, Dickinson PD | title = Spironolactone, a possible selective androgen receptor modulator, should be used with caution in patients with metastatic carcinoma of the prostate | journal = BMJ Case Rep | volume = 2012 | pages = bcr1120115238| year = 2012 | pmid = 22665559 | pmc = 3291010 | doi = 10.1136/bcr.11.2011.5238 }}</ref><ref name="pmid27641657">{{cite journal | vauthors = Flynn T, Guancial EA, Kilari M, Kilari D | title = Case Report: Spironolactone Withdrawal Associated With a Dramatic Response in a Patient With Metastatic Castrate-Resistant Prostate Cancer | journal = Clin Genitourin Cancer | volume = 15| issue = 1| pages = e95–e97| year = 2016 | pmid = 27641657 | doi = 10.1016/j.clgc.2016.08.006 | s2cid = 38441469 }}</ref> In addition, whereas cyproterone acetate produces ambiguous genitalia via feminization in male fetuses when administered to pregnant animals,<ref name="JamesPasqualini2013">{{cite book | vauthors = James VH, Pasqualini JR | title = Hormonal Steroids: Proceedings of the Sixth International Congress on Hormonal Steroids | url = https://books.google.com/books?id=1VMJAwAAQBAJ&pg=PA391 | date = 22 October 2013 | publisher = Elsevier Science | isbn = 978-1-4831-9067-9 | pages = 391–}}</ref> it has been found to produce masculinization of the genitalia of female fetuses of pregnant animals.<ref name="pmid10637363" /> In contrast to steroidal AR antagonists, nonsteroidal AR antagonists are silent antagonists of the AR and do not activate the receptor.<ref name="pmid9000189">{{cite journal |vauthors=Caubet JF, Tosteson TD, Dong EW, Naylon EM, Whiting GW, Ernstoff MS, Ross SD |title=Maximum androgen blockade in advanced prostate cancer: a meta-analysis of published randomized controlled trials using nonsteroidal antiandrogens |journal=Urology |volume=49 |issue=1 |pages=71–8 |year=1997 |pmid=9000189 |doi=10.1016/S0090-4295(96)00325-1 |quote=Because steroidal antiandrogens such as cyproterone acetate have intrinsic androgenic activity and lower antiandrogenic activity than the NSAAs such as flutamide and nilutamide,39–43 it is not surprising that the two classes of antiandrogens may have different efficacies.}}</ref><ref name="FiggChau2010"/><ref name=SinghGauthier2000>{{cite journal |vauthors=Singh SM, Gauthier S, Labrie F |title=Androgen receptor antagonists (antiandrogens): structure-activity relationships |journal=Current Medicinal Chemistry |volume=7 |issue=2 |pages=211–47 |date=February 2000 |pmid=10637363 |doi=10.2174/0929867003375371}}</ref><ref name="PoyetLabrie1985" /> This may be why they have greater efficacy than steroidal AR antagonists in the treatment of prostate cancer and is an important reason as to why they have largely replaced them for this indication in medicine.<ref name="pmid9000189" /><ref name="FiggChau2010" /><ref name=SinghGauthier2000 /><ref name="PoyetLabrie1985" />

Nonsteroidal antiandrogens have relatively low [[affinity (pharmacology)|affinity]] for the AR compared to steroidal AR ligands.<ref name="FiggChau2010" /><ref name="SinghGauthier2000" /><ref name="pmid2788775v">{{cite journal | vauthors = Ayub M, Levell MJ | title = The effect of ketoconazole related imidazole drugs and antiandrogens on [3H] R 1881 binding to the prostatic androgen receptor and [3H]5 alpha-dihydrotestosterone and [3H]cortisol binding to plasma proteins | journal = J. Steroid Biochem. | volume = 33 | issue = 2 | pages = 251–5 | date = August 1989 | pmid = 2788775 | doi = 10.1016/0022-4731(89)90301-4 }}</ref> For example, bicalutamide has around 2% of the affinity of DHT for the AR and around 20% of the affinity of CPA for the AR.<ref name="pmid2788775v" /> Despite their low affinity for the AR however, the lack of weak partial agonist activity of NSAAs appears to improve their potency relative to steroidal antiandrogens.<ref name="pmid2788775v" /><ref name="pmid14751673">{{cite journal | vauthors = Yamasaki K, Sawaki M, Noda S, Muroi T, Takakura S, Mitoma H, Sakamoto S, Nakai M, Yakabe Y | title = Comparison of the Hershberger assay and androgen receptor binding assay of twelve chemicals | journal = Toxicology | volume = 195 | issue = 2–3 |pages=177–86 |year = 2004 | pmid = 14751673 | doi = 10.1016/j.tox.2003.09.012| bibcode = 2004Toxgy.195..177Y }}</ref> For example, although flutamide has about 10-fold lower affinity for the AR than CPA, it shows equal or slightly greater potency to CPA as an antiandrogen in [[bioassay]]s.<ref name="pmid2788775v" /><ref name="pmid14751673" /> In addition, circulating therapeutic concentrations of nonsteroidal antiandrogens are very high, on the order of thousands of times higher than those of testosterone and DHT, and this allows them to efficaciously compete and block AR signaling.<ref name="Pratt1994">{{cite book| vauthors = Pratt WB |title= The Anticancer Drugs|url=https://books.google.com/books?id=nPR1L4K5HuEC&pg=PA220 |year=1994 |publisher=Oxford University Press |isbn=978-0-19-506739-2 |pages=220– |quote=In patients receiving flutamide at the usual dosage of 250 mg every 8 hours, the minimal plasma concentration of hydroxyflutamide is about 5 uM, which is 5,000 times the plasma concentration of testosterone (1 nM) in patients treated with an LHRH agonist.127 As hydroxyflutamide is only one percent as potent as testosterone in competing for binding to the androgen receptor,126 a plasma level of 5 uM hydroxyflutamide is required to ensure effective competition.127 [...] Both cyproterone acetate and flutamide have been demonstrated to be effective therapy (roughly equivalent to an estrogen) when used alone in the treatment of carcinoma of the prostate.123}}</ref>

AR antagonists may not bind to or block [[membrane androgen receptor]]s (mARs), which are distinct from the classical nuclear AR.<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 | 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 | s2cid = 23918273 }}</ref> However, the mARs do not appear to be involved in [[virilization|masculinization]]. This is evidenced by the perfectly [[female]] [[phenotype]] of women with [[complete androgen insensitivity syndrome]].<ref name="PescovitzEugster2004">{{cite book| vauthors = Pescovitz OH, Eugster EA |title=Pediatric Endocrinology: Mechanisms, Manifestations, and Management|url=https://books.google.com/books?id=9gvBlktAT6YC&pg=PA248|year=2004|publisher=Lippincott Williams & Wilkins|isbn=978-0-7817-4059-3|pages=248–}}</ref><ref name="BuonocoreBracci2012">{{cite book| vauthors = Buonocore G, Bracci R, Weindling M |title=Neonatology: A Practical Approach to Neonatal Diseases|url=https://books.google.com/books?id=n_L2XpJbhLoC&pg=PA1012|date=28 January 2012|publisher=Springer Science & Business Media|isbn=978-88-470-1405-3|pages=1012–}}</ref> These women have a 46,XY [[karyotype]] (i.e., are genetically "male") and high levels of androgens but possess a defective AR and for this reason never masculinize.<ref name="PescovitzEugster2004" /><ref name="BuonocoreBracci2012" /> They are described as highly feminine, both physically as well as mentally and behaviorally.<ref name="Jordan-Young2011">{{cite book| vauthors = Jordan-Young RM |title=Brain Storm|url=https://books.google.com/books?id=2V9UuOWMXOMC&pg=PA82|date=7 January 2011|publisher=Harvard University Press|isbn=978-0-674-05879-8|pages=82–}}</ref><ref name="BlakemoreBerenbaum2013">{{cite book| vauthors = Blakemore JE, Berenbaum SA, Liben LS |title=Gender Development |url=https://books.google.com/books?id=PQ3Ylt6KnA4C&pg=PT115 |date=13 May 2013|publisher=Psychology Press|isbn=978-1-135-07932-1|pages=115–}}</ref><ref name="Maggi2012">{{cite book| vauthors = Maggi M |title= Hormonal Therapy for Male Sexual Dysfunction|url=https://books.google.com/books?id=o_A9DnMVi3cC&pg=PA6|date=30 January 2012|publisher=John Wiley & Sons|isbn=978-0-470-65760-7|pages=6–}}</ref>

====N-Terminal domain antagonists====
[[Peptide antiandrogen|N-Terminal domain AR antagonist]]s are a new type of AR antagonist that, unlike all currently marketed AR antagonists, bind to the [[N-terminal domain]] (NTD) of the AR rather than the [[ligand-binding domain]] (LBD).<ref name="ImamuraSadar2016">{{cite journal | vauthors = Imamura Y, Sadar MD | title = Androgen receptor targeted therapies in castration-resistant prostate cancer: Bench to clinic | journal = International Journal of Urology | volume = 23 | issue = 8 | pages = 654–665 | date = August 2016 | pmid = 27302572 | pmc = 6680212 | doi = 10.1111/iju.13137 }}</ref> Whereas conventional AR antagonists bind to the LBD of the AR and [[competitive antagonist|competitively]] displace androgens, thereby preventing them from [[Receptor (biochemistry)#Binding and activation|activating]] the receptor, AR NTD antagonists bind [[covalent bond|covalently]] to the NTD of the AR and prevent [[protein–protein interaction]]s subsequent to activation that are required for [[transcription (biology)|transcriptional activity]].<ref name="ImamuraSadar2016" /> As such, they are [[non-competitive antagonist|non-competitive]] and [[irreversible antagonist]]s of the AR.<ref name="De MolFenwick2016">{{cite journal | vauthors = De Mol E, Fenwick RB, Phang CT, Buzón V, Szulc E, de la Fuente A, Escobedo A, García J, Bertoncini CW, Estébanez-Perpiñá E, McEwan IJ, Riera A, Salvatella X | display-authors = 6 | title = EPI-001, A Compound Active against Castration-Resistant Prostate Cancer, Targets Transactivation Unit 5 of the Androgen Receptor | journal = ACS Chemical Biology | volume = 11 | issue = 9 | pages = 2499–2505 | date = September 2016 | pmid = 27356095 | pmc = 5027137 | doi = 10.1021/acschembio.6b00182 }}</ref> Examples of AR NTD antagonists include [[bisphenol A diglycidyl ether]] (BADGE) and its derivatives [[EPI-001]], [[ralaniten]] (EPI-002), and [[ralaniten acetate]] (EPI-506).<ref name="ImamuraSadar2016" /><ref name="pmid26389532">{{cite journal | vauthors = Martinez-Ariza G, Hulme C | title = Recent advances in allosteric androgen receptor inhibitors for the potential treatment of castration-resistant prostate cancer | journal = Pharmaceutical Patent Analyst | volume = 4 | issue = 5 | pages = 387–402 | year = 2015 | pmid = 26389532 | doi = 10.4155/ppa.15.20 }}</ref> AR NTD antagonists are under investigation for the potential treatment of prostate cancer, and it is thought that they may have greater [[efficacy]] as antiandrogens relative to conventional AR antagonists.<ref name="ImamuraSadar2016" /> In accordance with this notion, AR NTD antagonists are active against [[splice variant]]s of the AR, which conventional AR antagonists are not, and AR NTD antagonists are immune to [[gain-of-function mutation]]s in the AR LBD that convert AR antagonists into AR agonists and commonly occur in prostate cancer.<ref name="ImamuraSadar2016" />

====Androgen receptor degraders====
[[Selective androgen receptor degrader]]s (SARDs) are another new type of antiandrogen that has recently been developed.<ref name="pmid27885283">{{cite journal | vauthors = Lai AC, Crews CM | title = Induced protein degradation: an emerging drug discovery paradigm | journal = Nature Reviews. Drug Discovery | volume = 16 | issue = 2 | pages = 101–114 | date = February 2017 | pmid = 27885283 | pmc = 5684876 | doi = 10.1038/nrd.2016.211 }}</ref>  They work by enhancing the [[downregulation|degradation]] of the AR, and are analogous to [[selective estrogen receptor degrader]]s (SERDs) like [[fulvestrant]] (a drug used to treat [[hormone receptor positive breast tumor|estrogen receptor-positive]] [[breast cancer]]).<ref name="pmid27885283" /> Similarly to AR NTD antagonists, it is thought that SARDs may have greater efficacy than conventional AR antagonists, and for this reason, they are under investigation for the treatment of prostate cancer.<ref name="pmid23219429">{{cite journal | vauthors = Lai KP, Huang CK, Chang YJ, Chung CY, Yamashita S, Li L, Lee SO, Yeh S, Chang C | display-authors = 6 | title = New therapeutic approach to suppress castration-resistant prostate cancer using ASC-J9 via targeting androgen receptor in selective prostate cells | journal = The American Journal of Pathology | volume = 182 | issue = 2 | pages = 460–473 | date = February 2013 | pmid = 23219429 | pmc = 3562731 | doi = 10.1016/j.ajpath.2012.10.029 }}</ref> An example of a SARD is [[dimethylcurcumin]] (ASC-J9), which is under development as a [[topical medication]] for the potential treatment of acne.<ref name="AdisInsight-ASC-J9">{{Cite web | url = http://adisinsight.springer.com/drugs/800028542 | title = ASCJ 9 | work = AdisInsight | publisher = Springer Nature Switzerland AG | access-date = 2017-12-24 | archive-date = 2018-03-04 | archive-url = https://web.archive.org/web/20180304204526/http://adisinsight.springer.com/drugs/800028542 | url-status = live }}</ref> SARDs like dimethylcurcumin differ from conventional AR antagonists and AR NTD antagonists in that they may not necessarily bind directly to the AR.<ref name="pmid23219429" />

===Androgen synthesis inhibitors===
{{Main|Androgen synthesis inhibitor}}

Androgen synthesis inhibitors are [[enzyme inhibitor]]s that prevent the [[biosynthesis]] of androgens.<ref name="FiggChau2010" /> This process occurs mainly in the [[gonad]]s and [[adrenal gland]]s, but also occurs in other tissues like the [[prostate gland]], [[skin]], and [[hair follicle]]s. These drugs include aminoglutethimide, ketoconazole,<ref name = "pmid2652864">{{cite journal |vauthors=Witjes FJ, Debruyne FM, Fernandez del Moral P, Geboers AD | title = Ketoconazole high dose in management of hormonally pretreated patients with progressive metastatic prostate cancer. Dutch South-Eastern Urological Cooperative Group | journal = Urology | volume = 33 | issue = 5 | pages = 411–5 |date=May 1989 | pmid = 2652864 | doi = 10.1016/0090-4295(89)90037-X }}</ref> and abiraterone acetate.<ref name="IIIBarbieri2013" /><ref name="FiggChau2010" /><ref name="Held-Warmkessel2006">{{cite book| vauthors = Held-Warmkessel J |title= Contemporary Issues in Prostate Cancer: A Nursing Perspective|url=https://books.google.com/books?id=dZe4ZSVDdBsC&pg=PA275|year=2006|publisher=Jones & Bartlett Learning|isbn=978-0-7637-3075-8|pages=275–}}</ref> Aminoglutethimide inhibits cholesterol side-chain cleavage enzyme, also known as P450scc or CYP11A1, which is responsible for the conversion of [[cholesterol]] into [[pregnenolone]] and by extension the production of all steroid hormones, including the androgens.<ref name="IIIBarbieri2013" /> Ketoconazole and abiraterone acetate are inhibitors of the enzyme CYP17A1, also known as 17α-hydroxylase/17,20-lyase, which is responsible for the conversion of [[pregnane]] steroids into androgens, as well as the conversion of [[mineralocorticoid]]s into glucocorticoids.<ref name="IIIBarbieri2013" /><ref name="FiggChau2010" /> Because these drugs all prevent the formation of glucocorticoids in addition to androgens, they must be combined with a glucocorticoid like [[prednisone]] to avoid [[adrenal insufficiency]].<ref name="Held-Warmkessel2006" /> A newer drug currently under development for treatment of prostate cancer, [[seviteronel]], is selective for inhibition of the 17,20-lyase functionality of CYP17A1, and for this reason, unlike earlier drugs, does not require concomitant treatment with a glucocorticoid.<ref name="pmid27154414">{{cite journal | vauthors = Bird IM, Abbott DH | title = The hunt for a selective 17,20 lyase inhibitor; learning lessons from nature | journal = J. Steroid Biochem. Mol. Biol. | volume = 163 | pages = 136–46 | year = 2016 | pmid = 27154414 | doi = 10.1016/j.jsbmb.2016.04.021 | pmc=5046225}}</ref>

====5α-Reductase inhibitors====
5α-Reductase inhibitors such as finasteride and dutasteride are inhibitors of [[5α-reductase]], an enzyme that is responsible for the formation of DHT from testosterone.<ref name = Flores>{{Cite journal |vauthors=Flores E, Bratoeff E, Cabeza M, Ramirez E, Quiroz A, Heuze I | title = Steroid 5alpha-reductase inhibitors | journal = Mini-Reviews in Medicinal Chemistry | volume = 3 | pages = 225–37 |date=May 2003 | pmid = 12570838 | issue = 3 | doi=10.2174/1389557033488196}}</ref> DHT is between 2.5- and 10-fold more potent than testosterone as an androgen<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> and is produced in a [[tissue-selective]] manner based on [[gene expression|expression]] of 5α-reductase.<ref name="Bhagavan2002">{{cite book| vauthors = Bhagavan NV |title=Medical Biochemistry|url=https://books.google.com/books?id=b7Dc9bOs9uAC&pg=PA787 |year=2002|publisher=Academic Press|isbn=978-0-12-095440-7|pages=787–}}</ref> Tissues in which DHT forms at a high rate include the [[prostate gland]], [[skin]], and [[hair follicle]]s.<ref name="BologniaJorizzo" /><ref name="Bhagavan2002" /> In accordance, DHT is involved in the [[pathophysiology]] of benign prostatic hyperplasia, pattern hair loss, and hirsutism, and 5α-reductase inhibitors are used to treat these conditions.<ref name="BologniaJorizzo" /><ref name="Bhagavan2002" /><ref name="pmid27672412">{{cite journal | vauthors = Hirshburg JM, Kelsey PA, Therrien CA, Gavino AC, Reichenberg JS | title = Adverse Effects and Safety of 5-alpha Reductase Inhibitors (Finasteride, Dutasteride): A Systematic Review | journal = J Clin Aesthet Dermatol | volume = 9 | issue = 7 | pages = 56–62 | year = 2016 | pmid = 27672412 | pmc = 5023004 }}</ref>

===Antigonadotropins===
[[File:Estradiol and testosterone levels with a single intramuscular injection of 320 mg polyestradiol phosphate in men.png|thumb|right|300px|class=skin-invert-image|Estradiol and testosterone levels following a single intramuscular injection of 320&nbsp;mg [[polyestradiol phosphate]], a [[polymer]]ic estradiol ester and prodrug, in men with prostate cancer.<ref name="pmid8610057">{{cite journal | vauthors = Stege R, Gunnarsson PO, Johansson CJ, Olsson P, Pousette A, Carlström K | title = Pharmacokinetics and testosterone suppression of a single dose of polyestradiol phosphate (Estradurin) in prostatic cancer patients | journal = Prostate | volume = 28 | issue = 5 | pages = 307–10 | year = 1996 | pmid = 8610057 | doi = 10.1002/(SICI)1097-0045(199605)28:5<307::AID-PROS6>3.0.CO;2-8 | s2cid = 33548251 }}</ref>]]
[[File:Testosterone and luteinizing hormone levels with 100 mg per day oral cyproterone acetate in men.png|thumb|right|300px|class=skin-invert-image|Testosterone and luteinizing hormone levels with 100&nbsp;mg/day oral [[cyproterone acetate]] in men.<ref name="FourcadeMcLeod2015">{{cite journal| vauthors = Fourcade RO, McLeod D |title=Tolerability of Antiandrogens in the Treatment of Prostate Cancer|journal=UroOncology|volume=4|issue=1|year=2015|pages=5–13|issn=1561-0950|doi=10.1080/1561095042000191655}}</ref>]]

[[Antigonadotropin]]s are drugs that suppress the GnRH-mediated [[secretion]] of [[gonadotropin]]s from the [[pituitary gland]].<ref name="FarmerWalker2012" /> Gonadotropins include [[luteinizing hormone]] (LH) and [[follicle-stimulating hormone]] (FSH) and are [[peptide hormone]]s that signal the [[gonad]]s to produce [[sex hormone]]s. By suppressing gonadotropin secretion, antigonadotropins suppress gonadal sex hormone production and by extension circulating androgen levels.<ref name="FarmerWalker2012" /> [[GnRH modulator]]s, including both [[GnRH agonist]]s and [[GnRH antagonist]]s, are powerful antigonadotropins that are able to suppress androgen levels by 95% in men.<ref name="Urotext2001">{{cite book|author=Urotext|title=Urotext-Luts: Urology|url=https://books.google.com/books?id=6zjtA37qDsMC&pg=PA71|date=1 January 2001|publisher=Urotext|isbn=978-1-903737-03-3|pages=71–|access-date=2016-12-27|archive-date=2023-01-11|archive-url=https://web.archive.org/web/20230111061908/https://books.google.com/books?id=6zjtA37qDsMC&pg=PA71|url-status=live}}</ref> In addition, estrogens and progestogens are antigonadotropins via exertion of [[negative feedback]] on the [[hypothalamic–pituitary–gonadal axis]] (HPG axis).<ref name="Brueggemeier2006" /><ref name="pmid10997774">{{cite journal |vauthors=de Lignières B, Silberstein S | title = Pharmacodynamics of oestrogens and progestogens | journal = Cephalalgia: An International Journal of Headache | volume = 20 | issue = 3 | pages = 200–7 |date=April 2000 | pmid = 10997774 | doi = 10.1046/j.1468-2982.2000.00042.x| s2cid = 40392817 | doi-access = free }}</ref><ref name="pmid368741">{{cite journal | vauthors = Neumann F | title = The physiological action of progesterone and the pharmacological effects of progestogens--a short review | journal = Postgraduate Medical Journal | volume = 54 | issue = Suppl 2 | pages = 11–24 | year = 1978 | pmid = 368741 }}</ref> High-dose estrogens are able to suppress androgen levels to castrate levels in men similarly to GnRH modulators,<ref name="pmid7000222">{{cite journal | vauthors = Jacobi GH, Altwein JE, Kurth KH, Basting R, Hohenfellner R | title = Treatment of advanced prostatic cancer with parenteral cyproterone acetate: a phase III randomised trial | journal = Br J Urol | volume = 52 | issue = 3 | pages = 208–15 | year = 1980 | pmid = 7000222 | doi = 10.1111/j.1464-410x.1980.tb02961.x}}</ref> while high-dose progestogens are able to suppress androgen levels by up to approximately 70 to 80% in men.<ref name="WeinKavoussi2011">{{cite book|vauthors=Wein AJ, Kavoussi LR, Novick AC, Partin AW, Peters CA|title=Campbell-Walsh Urology: Expert Consult Premium Edition: Enhanced Online Features and Print, 4-Volume Set|url=https://books.google.com/books?id=fu3BBwAAQBAJ&pg=PA2938|date=25 August 2011|publisher=Elsevier Health Sciences|isbn=978-1-4160-6911-9|pages=2938–|access-date=27 December 2016|archive-date=11 January 2023|archive-url=https://web.archive.org/web/20230111061407/https://books.google.com/books?id=fu3BBwAAQBAJ&pg=PA2938|url-status=live}}</ref><ref name="pmid519881">{{cite journal | vauthors = Kjeld JM, Puah CM, Kaufman B, Loizou S, Vlotides J, Gwee HM, Kahn F, Sood R, Joplin GF | title = Effects of norgestrel and ethinyloestradiol ingestion on serum levels of sex hormones and gonadotrophins in men | journal = Clinical Endocrinology | volume = 11 | issue = 5 | pages = 497–504 | year = 1979 | pmid = 519881 | doi = 10.1111/j.1365-2265.1979.tb03102.x| s2cid = 5836155 }}</ref>

Examples of GnRH agonists include [[leuprorelin]] (leuprolide) and [[goserelin]], while an example of a GnRH antagonist is [[cetrorelix]].<ref name="LemkeWilliams2012" /> Estrogens that are or that have been used as antigonadotropins include estradiol, [[estradiol ester]]s like [[estradiol valerate]], [[estradiol undecylate]], and [[polyestradiol phosphate]], conjugated estrogens, ethinylestradiol, diethylstilbestrol (no longer widely used), and [[bifluranol]].<ref name="pmid18268497">{{cite journal | vauthors = Norman G, Dean ME, Langley RE, Hodges ZC, Ritchie G, Parmar MK, Sydes MR, Abel P, Eastwood AJ | title = Parenteral oestrogen in the treatment of prostate cancer: a systematic review | journal = Br. J. Cancer | volume = 98 | issue = 4 | pages = 697–707 | year = 2008 | pmid = 18268497 | pmc = 2259178 | doi = 10.1038/sj.bjc.6604230 }}</ref><ref name="pmid6258683">{{cite journal | vauthors = Dekanski JB | title = Anti-prostatic activity of bifluranol, a fluorinated bibenzyl | journal = Br. J. Pharmacol. | volume = 71 | issue = 1 | pages = 11–6 | year = 1980 | pmid = 6258683 | pmc = 2044395 | doi = 10.1111/j.1476-5381.1980.tb10903.x}}</ref> Progestogens that are used as antigonadotropins include [[chlormadinone acetate]], cyproterone acetate, gestonorone caproate,<ref name="pmid694436">{{cite journal | vauthors = Sander S, Nissen-Meyer R, Aakvaag A | title = On gestagen treatment of advanced prostatic carcinoma | journal = Scand. J. Urol. Nephrol. | volume = 12 | issue = 2 | pages = 119–21 | year = 1978 | pmid = 694436 | doi = 10.3109/00365597809179977}}</ref> [[hydroxyprogesterone caproate]], medroxyprogesterone acetate, [[megestrol acetate]], and oxendolone.<ref name="Brueggemeier2006" /><ref name="PrentkyBurgess2000">{{cite book| vauthors = Prentky RA, Burgess AW |title= Forensic Management of Sexual Offenders|url=https://books.google.com/books?id=-50Of8_n_TAC&pg=PA219 |date=31 July 2000|publisher=Springer Science & Business Media|isbn=978-0-306-46278-8|pages=219–}}</ref><ref name="pmid294107">{{cite journal | vauthors = Sudo K, Yamazaki I, Masuoka M, Nakayama R | title = Anti-androgen TSAA-291. IV. Effects of the anti-androgen TSAA-291 (16 beta-ethyl-17 beta-hydroxy-4-oestren-3-one) on the secretion of gonadotrophins | journal = Acta Endocrinol Suppl (Copenh) | volume = 229 | pages = 53–66 | year = 1979 | pmid = 294107 | doi = 10.1530/acta.0.092s053}}</ref>

===Miscellaneous===

====Sex hormone-binding globulin modulators====
In addition to their antigonadotropic effects, estrogens are also functional antiandrogens by decreasing free concentrations of androgens via increasing the [[liver|hepatic]] production of [[sex hormone-binding globulin]] (SHBG) and by extension circulating SHBG levels.<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=PA62 |date=26 July 2012|publisher=Cambridge University Press|isbn=978-1-107-01290-5|pages=62–}}</ref><ref name="HumansOrganization2007">{{cite book|author1=IARC Working Group on the Evaluation of Carcinogenic Risks to Humans|author2=World Health Organization|author3=International Agency for Research on Cancer|title=Combined Estrogen-progestogen Contraceptives and Combined Estrogen-progestogen Menopausal Therapy|url=https://books.google.com/books?id=aGDU5xibtNgC&pg=PA157|year=2007|publisher=World Health Organization|isbn=978-92-832-1291-1|pages=157–}}</ref><ref name="pmid22294742">{{cite journal | vauthors = Coss CC, Jones A, Parke DN, Narayanan R, Barrett CM, Kearbey JD, Veverka KA, Miller DD, Morton RA, Steiner MS, Dalton JT | title = Preclinical characterization of a novel diphenyl benzamide selective ERα agonist for hormone therapy in prostate cancer | journal = Endocrinology | volume = 153 | issue = 3 | pages = 1070–81 | year = 2012 | pmid = 22294742 | doi = 10.1210/en.2011-1608 | doi-access = free }}</ref> [[Combined oral contraceptive]]s containing ethinylestradiol have been found to increase circulating SHBG levels by 2- to 4-fold in women and to reduce free testosterone concentrations by 40 to 80%.<ref name="HumansOrganization2007" /> However, combined oral contraceptives that contain the particularly androgenic progestin [[levonorgestrel]] have been found to increase SHBG levels by only 50 to 100%,<ref name="HumansOrganization2007" /> which is likely because activation of the AR in the liver has the opposite effect of estrogen and suppresses production of SHBG.<ref name="KrishnaR.2000">{{cite book| vauthors = Krishna UR, Sheriar NK |title=Adolescent Gynecology (pb)|url=https://books.google.com/books?id=B8hcC17D154C&pg=PA121|date=1 January 2000|publisher=Orient Blackswan|isbn=978-81-250-1793-6|pages=121–}}</ref> Levonorgestrel and certain other [[19-nortestosterone]] progestins used in combined oral contraceptives like [[norethisterone]] also directly bind to and displace androgens from SHBG, which may additionally antagonize the functional antiandrogenic effects of ethinylestradiol.<ref name="KrishnaR.2000"/><ref name="FilshieGuillebaud2013">{{cite book| vauthors = Filshie M, Guillebaud J |title=Contraception: Science and Practice|url=https://books.google.com/books?id=Ug3-BAAAQBAJ&pg=PA26 |date=22 October 2013 |publisher=Elsevier Science |isbn=978-1-4831-6366-6 |pages=26–}}</ref> In men, a study found that treatment with a relatively low dosage of 20&nbsp;μg/day ethinylestradiol for 5&nbsp;weeks increased circulating SHBG levels by 150% and, due to the accompanying decrease free testosterone levels, increased total circulating levels of testosterone by 50% (via reduced negative feedback by androgens on the HPG axis).<ref name="NieschlagBehre2012" />

====Corticosteroid-binding globulin modulators====
[[Estrogen (medication)|Estrogens]] at high doses can partially suppress adrenal androgen production.<ref name="Oettel1999">{{cite book | vauthors = Oettel M | title=Estrogens and Antiestrogens II | series=Handbook of Experimental Pharmacology | chapter=Estrogens and Antiestrogens in the Male | publisher=Springer Berlin Heidelberg | publication-place=Berlin, Heidelberg | year=1999 | volume=135 / 2 | issn=0171-2004 | doi=10.1007/978-3-642-60107-1_25 | pages=505–571| isbn=978-3-642-64261-6 }}</ref><ref name="MargiorisChrousos2001">{{cite book| vauthors = Margioris AN, Chrousos GP |title=Adrenal Disorders|url=https://books.google.com/books?id=XB73BwAAQBAJ&pg=PA84|date=20 April 2001|publisher=Springer Science & Business Media|isbn=978-1-59259-101-5|pages=84–}}</ref><ref name="pmid7586614">{{cite journal | vauthors = Polderman KH, Gooren LJ, van der Veen EA | title = Effects of gonadal androgens and oestrogens on adrenal androgen levels | journal = Clin. Endocrinol. (Oxf) | volume = 43 | issue = 4 | pages = 415–21 | date = October 1995 | pmid = 7586614 | doi = 10.1111/j.1365-2265.1995.tb02611.x  | s2cid = 6815423 }}</ref><ref name="pmid2958420">{{cite journal | vauthors = Stege R, Eriksson A, Henriksson P, Carlström K | title = Orchidectomy or oestrogen treatment in prostatic cancer: effects on serum levels of adrenal androgens and related steroids | journal = Int. J. Androl. | volume = 10 | issue = 4 | pages = 581–7 | date = August 1987 | pmid = 2958420 | doi = 10.1111/j.1365-2605.1987.tb00357.x | doi-access = free }}</ref><ref name="pmid2734983">{{cite journal | vauthors = Pousette A, Carlström K, Stege R | title = Androgens during different modes of endocrine treatment of prostatic cancer | journal = Urol. Res. | volume = 17 | issue = 2 | pages = 95–8 | date = 1989 | pmid = 2734983 | doi = 10.1007/BF00262027 | s2cid = 25309877 }}</ref><ref name="pmid7500443">{{cite journal | vauthors = Cox RL, Crawford ED | title = Estrogens in the treatment of prostate cancer | journal = J. Urol. | volume = 154 | issue = 6 | pages = 1991–8 | date = December 1995 | pmid = 7500443 | doi = 10.1016/S0022-5347(01)66670-9 }}</ref> A study found that treatment with a high-dose [[ethinylestradiol]] (100&nbsp;μg/day) reduced levels of major circulating [[adrenal androgen]]s by 27 to 48% in [[transgender women]].<ref name="Oettel1999" /><ref name="MargiorisChrousos2001" /><ref name="pmid7586614" /> Decreased adrenal androgens with estrogens is apparent with [[oral administration|oral]] and [[synthetic compound|synthetic]] estrogens like [[ethinylestradiol]] and [[estramustine phosphate]] but is minimal with [[parenteral administration|parenteral]] [[bioidentical]] [[estradiol (medication)|estradiol]] forms like [[polyestradiol phosphate]].<ref name="pmid2734983" /> It is thought to be mediated via a [[liver|hepatic]] mechanism, probably increased [[corticosteroid-binding globulin]] (CBG) [[biosynthesis|production]] and levels and compensatory changes in adrenal steroid production (e.g., shunting of adrenal androgen synthesis to [[cortisol]] production).<ref name="pmid2734983" /><ref name="pmid7500443" /> It is notable in this regard that oral and synthetic estrogens, due to the oral [[first pass effect|first pass]] and resistance to hepatic [[metabolism]], have much stronger influences on [[liver protein synthesis]] than parenteral estradiol.<ref name="pmid2664738">{{cite journal | vauthors = von Schoultz B, Carlström K, Collste L, Eriksson A, Henriksson P, Pousette A, Stege R | title = Estrogen therapy and liver function--metabolic effects of oral and parenteral administration | journal = Prostate | volume = 14 | issue = 4 | pages = 389–95 | date = 1989 | pmid = 2664738 | doi = 10.1002/pros.2990140410 | s2cid = 21510744 | url = }}</ref> The decrease in adrenal androgen levels with high-dose estrogen therapy may be beneficial in the treatment of [[prostate cancer]].<ref name="pmid7586614" /><ref name="pmid7500443" />

====Anticorticotropins====
[[Anticorticotropin]]s such as [[glucocorticoid]]s and [[mineralocorticoid]]s work by exerting [[negative feedback]] on the [[hypothalamic–pituitary–adrenal axis]] (HPA axis), thereby inhibiting the secretion of [[corticotropin-releasing hormone]] (CRH) and hence [[adrenocorticotropic hormone]] (ACTH; corticotropin) and consequently suppressing the production of [[androgen prohormone]]s like [[dehydroepiandrosterone]] (DHEA), [[dehydroepiandrosterone sulfate]] (DHEA-S), and [[androstenedione]] in the [[adrenal gland]].<ref name="MelmedPolonsky2011">{{cite book| vauthors = Melmed S, Polonsky KS, Larsen PR, Kronenberg HM |title= Williams Textbook of Endocrinology E-Book|url=https://books.google.com/books?id=nbg1QOAObicC&pg=PA753|date=12 May 2011|publisher=Elsevier Health Sciences|isbn=978-1-4377-3600-7|pages=753–}}</ref><ref name="KumarAbbas2009">{{cite book | vauthors = Kumar V, Abbas AK, Fausto N, Aster JC |title=Robbins & Cotran Pathologic Basis of Disease E-Book|url=https://books.google.com/books?id=_1Zmvm4JVNcC&pg=PA1154|date=10 June 2009|publisher=Elsevier Health Sciences|isbn=978-1-4377-2015-0|pages=1154–}}</ref> They are rarely used clinically as functional antiandrogens, but are used as such in the case of [[congenital adrenal hyperplasia]] in girls and women, in which there are excessive production and levels of adrenal androgens due to glucocorticoid deficiency and hence HPA axis overactivity.<ref name="MelmedPolonsky2011" /><ref name="KumarAbbas2009" />

====Insulin sensitizers====
In women with [[insulin resistance]], such as those with [[polycystic ovary syndrome]], androgen levels are often elevated.<ref name="NikolakisKyrgidis2019">{{cite journal | vauthors = Nikolakis G, Kyrgidis A, Zouboulis CC | title = Is There a Role for Antiandrogen Therapy for Hidradenitis Suppurativa? A Systematic Review of Published Data | journal = American Journal of Clinical Dermatology | volume = 20 | issue = 4 | pages = 503–513 | date = August 2019 | pmid = 31073704 | doi = 10.1007/s40257-019-00442-w | s2cid = 149443722 }}</ref> [[Metformin]], an [[insulin-sensitizing medication]], has indirect antiandrogenic effects in such women, decreasing [[testosterone]] levels by as much as 50% secondary to its beneficial effects on insulin sensitivity.<ref name="NikolakisKyrgidis2019" /><ref name="pmid28058854">{{cite journal | vauthors = Patel R, Shah G | title = Effect of metformin on clinical, metabolic and endocrine outcomes in women with polycystic ovary syndrome: a meta-analysis of randomized controlled trials | journal = Current Medical Research and Opinion | volume = 33 | issue = 9 | pages = 1545–1557 | date = September 2017 | pmid = 28058854 | doi = 10.1080/03007995.2017.1279597 | s2cid = 4391302 }}</ref><ref name="pmid33014044">{{cite journal | vauthors = Guan Y, Wang D, Bu H, Zhao T, Wang H | title = The Effect of Metformin on Polycystic Ovary Syndrome in Overweight Women: A Systematic Review and Meta-Analysis of Randomized Controlled Trials | journal = International Journal of Endocrinology | volume = 2020 | issue =  | pages = 5150684 | date = 2020 | pmid = 33014044 | pmc = 7519180 | doi = 10.1155/2020/5150684 | doi-access = free }}</ref>

====Immunogens and vaccines====
[[Ovandrotone albumin]] (Fecundin, Ovastim) and [[Androvax]] (androstenedione albumin) are [[immunogen]]s and [[vaccine]]s against [[4-androstenedione|androstenedione]] that are used in [[veterinary medicine]] to improve [[fecundity]] (reproductive rate) in ewes (adult female sheep).<ref name="SreenanDiskin2012">{{cite book| vauthors = Sreenan JM, Diskin MG |title=Embryonic Mortality in Farm Animals |url= https://books.google.com/books?id=QKFyBgAAQBAJ&pg=PA172 |date=6 December 2012|publisher=Springer Science & Business Media|isbn=978-94-009-5038-2|pages=172–}}</ref><ref name="JindalSharma2010">{{cite book| vauthors = Jindal SK, Sharma MC |title=Biotechnology in Animal Health and Production |url= https://books.google.com/books?id=e9yFom2LWTcC&pg=PA77|year=2010|publisher=New India Publishing|isbn=978-93-80235-35-6|pages=77–}}</ref> The generation of [[antibodies]] against androstenedione by these agents is thought to decrease circulating levels of androstenedione and its metabolites (e.g., testosterone and estrogens), which in turn increases the activity of the HPG axis via reduced negative feedback and increases the rate of [[ovulation]], resulting in greater [[fertility]] and fecundity.<ref name="SreenanDiskin2012" /><ref name="JindalSharma2010" />