View source for Pharmacology of cyproterone acetate

{{Use dmy dates|date=February 2020}}
{{Drugbox
| drug_name = {{Font|size=95%|Pharmacology of cyproterone acetate}}
| image = Cyproterone acetate.svg
| width = 230px

<!--Clinical data-->
| routes_of_administration = [[Oral administration|By mouth]], [[intramuscular injection]]
| class = [[Steroidal antiandrogen]]; [[Progestin]]; [[Progestogen]]; [[Progestogen ester]]; [[Antigonadotropin]]

<!--Pharmacokinetic data-->
| bioavailability = Oral: 68–100%<ref name="pmid16112947">{{cite journal | vauthors = Kuhl H | title = Pharmacology of estrogens and progestogens: influence of different routes of administration | journal = Climacteric | volume = 8 | issue = Suppl 1 | pages = 3–63 | year = 2005 | pmid = 16112947 | doi = 10.1080/13697130500148875 | s2cid = 24616324 | url = http://hormonebalance.org/images/documents/Kuhl%2005%20%20Pharm%20Estro%20Progest%20Climacteric_1313155660.pdf}}</ref><ref name="pmid2977383" />
| protein_bound = [[Human serum albumin|Albumin]]: 93%<br />Free: 7%<ref name="BińkowskaWoroń2015" /><ref name="SchindlerCampagnoli2003">{{cite journal | vauthors = Schindler AE, Campagnoli C, Druckmann R, Huber J, Pasqualini JR, Schweppe KW, Thijssen JH | title = Classification and pharmacology of progestins | journal = Maturitas | volume = 46 | issue = Suppl 1 | pages = S7–S16 | date = December 2003 | pmid = 14670641 | doi = 10.1016/j.maturitas.2003.09.014 | url = http://www.kalbemed.com/Portals/6/KOMELIB/GENITO-URINARY%20SYSTEM/Obsgyn/Anore/2.pdf | quote = Since there is no binding of CPA to SHBG and CBG in the serum, 93% of the compound is bound to serum albumin. }}{{dead link|date=July 2018 |bot=MutchyMan112 |fix-attempted=yes }}</ref><ref name="WakelinMaibach2002">{{cite book | vauthors = Wakelin SH, Maibach HI, Archer CB |title=Systemic Drug Treatment in Dermatology: A Handbook|url=https://books.google.com/books?id=F1ZiAgAAQBAJ&pg=PA32|date=1 June 2002|publisher=CRC Press|isbn=978-1-84076-013-2|pages=32–|quote=It is almost exclusively bound to plasma albumin.}}</ref><ref name="HammondLähteenmäki1982">{{cite journal | vauthors = Hammond GL, Lähteenmäki PL, Lähteenmäki P, Luukkainen T | title = Distribution and percentages of non-protein bound contraceptive steroids in human serum | journal = Journal of Steroid Biochemistry | volume = 17 | issue = 4 | pages = 375–80 | date = October 1982 | pmid = 6215538 | doi = 10.1016/0022-4731(82)90629-X }}</ref>
| metabolism = [[Liver|Hepatic]] ([[CYP3A4]])<ref name="Dickman2012">{{cite book| vauthors = Dickman A | title = Drugs in Palliative Care|url=https://books.google.com/books?id=LKrZINavapAC&pg=PA138|date=27 September 2012|publisher=OUP Oxford|isbn=978-0-19-966039-1|pages=137–138}}</ref><ref name="BoarderNewby2010">{{cite book | vauthors = Boarder M, Newby D, Navti P | title=Pharmacology for Pharmacy and the Health Sciences: A Patient-centred Approach|url=https://books.google.com/books?id=KVicAQAAQBAJ&pg=PA632|date=25 March 2010|publisher=OUP Oxford|isbn=978-0-19-955982-4|pages=632–}}</ref>
| metabolites = • {{abbrlink|15β-OH-CPA|15β-Hydroxycyproterone acetate}} (major)<ref name="pmid16112947" /><ref name="pmid3160716" /><br /> • [[Cyproterone]] (minor)<ref name="Weber2015">{{cite book| vauthors = Weber GF |title=Molecular Therapies of Cancer|url=https://books.google.com/books?id=dhs_CgAAQBAJ&pg=PA316|date=22 July 2015|publisher=Springer|isbn=978-3-319-13278-5|pages=316–|quote=The terminal half-life is about 38 h. A portion of the drug is metabolized by hydrolysis to cyproterone and acetic acid. However, in contrast to many other steroid esters hydrolysis is not extensive, and much of the pharmacological activity is exerted by the acetate form. Excretion is about 70% in the feces, mainly in the form of glucuronidated metabolites, and about 30% in the urine, predominantly as non-conjugated metabolites.}}</ref><br />• [[Acetic acid]] (minor)<ref name="Weber2015" />
| elimination_half-life = Oral: 1.6–4.3 days<ref name="Weber2015" /><ref name="pmid7919640">{{cite journal | vauthors = Barradell LB, Faulds D | title = Cyproterone. A review of its pharmacology and therapeutic efficacy in prostate cancer | journal = Drugs Aging | volume = 5 | issue = 1 | pages = 59–80 | date = July 1994 | pmid = 7919640 | doi = 10.2165/00002512-199405010-00006 }}</ref><ref name="BradfordKaye1998">{{cite book|title=AAPL Newsletter | year =1998|publisher=The Academy| url = http://courtpsychiatrist.com/pdf/pharmacological%20treatment%20sex%20offenders.pdf|quote=CPA is 100% bioavailable when taken orally with a half life of 38 hours. The injectable form reaches maximum plasma levels in 82 hours and has a half life of about 72 hours.}}</ref><br />{{abbr|IM|Intramuscular injection}}: 3–4.3 days<ref name="pmid2977383" /><ref name="Weber2015" /><ref name="BradfordKaye1998" />
| excretion = [[Feces]]: 70%<ref name="Weber2015" /><br />[[Urine]]: 30%<ref name="Weber2015" />
}}

The '''pharmacology of cyproterone acetate''' ('''CPA''') concerns the  [[pharmacology]] ([[pharmacodynamics]], [[pharmacokinetics]], and [[routes of administration]]) of the [[steroidal antiandrogen]] and [[progestin]] medication [[cyproterone acetate]].

CPA blocks the effects of [[androgen]]s like [[testosterone]] in the body, which it does by preventing them from interacting with their [[biological target]], the [[androgen receptor]] (AR), and by reducing their [[biosynthesis|production]] by the [[gonad]]s and hence their concentrations in the body.<ref name="pmid16112947" /><ref name="pmid8005205">{{cite journal | vauthors = Neumann F | title = The antiandrogen cyproterone acetate: discovery, chemistry, basic pharmacology, clinical use and tool in basic research | journal = Exp. Clin. Endocrinol. | volume = 102 | issue = 1 | pages = 1–32 | year = 1994 | pmid = 8005205 | doi = 10.1055/s-0029-1211261 | doi-access = free }}</ref><ref name="Berek2007">{{cite book | vauthors = Berek JS |title=Berek & Novak's Gynecology |url=https://books.google.com/books?id=P3erI0J8tEQC&pg=PA1085 |year=2007 |publisher=Lippincott Williams & Wilkins |isbn=978-0-7817-6805-4 |page=1085}}</ref> In addition, it has [[progesterone]]-like effects by activating the [[progesterone receptor]] (PR).<ref name="pmid16112947" /><ref name="pmid8005205" /> By activating the PR, CPA has [[antigonadotropic]] effects and can inhibit [[fertility]] and suppress [[sex hormone]] [[biosynthesis|production]] in both men and women. CPA can also produce weak and partial [[cortisol]]-like effects at very high doses under certain circumstances by activating the [[glucocorticoid receptor]] (GR).<ref name="pmid16112947" />

CPA can be taken [[oral administration|by mouth]] or by [[intramuscular injection|injection into muscle]]. It has near-complete oral [[bioavailability]], is highly and exclusively bound to [[human serum albumin|albumin]] in terms of [[plasma protein binding]], is [[metabolism|metabolized]] in the [[liver]] by [[hydroxylation]] and [[conjugation (biochemistry)|conjugation]], has [[15β-hydroxycyproterone acetate]] (15β-OH-CPA) as a single major [[active metabolite]], has a long [[elimination half-life]] of about 2 to 4&nbsp;days regardless of route of administration, and is [[excretion|excreted]] in [[feces]] primarily and to a lesser extent in [[urine]].

==Pharmacodynamics==
CPA has [[antiandrogen]]ic activity,<ref name="pmid16112947" /><ref name="FiggChau2010">{{cite book | vauthors = Figg W, Chau CH, Small EJ | title = Drug Management of Prostate Cancer |url=https://books.google.com/books?id=4KDrjeWA5-UC&pg=PA71 |date=14 September 2010 |publisher=Springer |isbn=978-1-60327-829-4 |page=71}}</ref> [[progestogen]]ic activity,<ref name="pmid16112947" /><ref name="FiggChau2010" /> weak [[partial agonist|partial]] [[glucocorticoid]] activity,<ref name="pmid12695529">{{cite journal | vauthors = Honer C, Nam K, Fink C, Marshall P, Ksander G, Chatelain RE, Cornell W, Steele R, Schweitzer R, Schumacher C | title = Glucocorticoid receptor antagonism by cyproterone acetate and RU486 | journal = Molecular Pharmacology | volume = 63 | issue = 5 | pages = 1012–20 | date = May 2003 | pmid = 12695529 | doi = 10.1124/mol.63.5.1012 | s2cid = 23872584 }}</ref> weak [[steroidogenesis inhibitor]] activity,<ref name="pmid2956461">{{cite journal | vauthors = Ayub M, Levell MJ | title = Inhibition of rat testicular 17 alpha-hydroxylase and 17,20-lyase activities by anti-androgens (flutamide, hydroxyflutamide, RU23908, cyproterone acetate) in vitro | journal = Journal of Steroid Biochemistry | volume = 28 | issue = 1 | pages = 43–7 | date = July 1987 | pmid = 2956461 | doi = 10.1016/0022-4731(87)90122-1 }}</ref> and [[agonist]] activity at the [[pregnane X receptor]].<ref name="HanDavis2010">{{cite book | vauthors = Han C, Davis CB, Wang B | title = Evaluation of Drug Candidates for Preclinical Development: Pharmacokinetics, Metabolism, Pharmaceutics, and Toxicology|url=https://books.google.com/books?id=2TsQKxRdRVEC&pg=PA92|date=6 January 2010|publisher=John Wiley & Sons|isbn=978-0-470-57488-1|pages=92–}}</ref><ref name="pmid9727070">{{cite journal | vauthors = Lehmann JM, McKee DD, Watson MA, Willson TM, Moore JT, Kliewer SA | title = The human orphan nuclear receptor PXR is activated by compounds that regulate CYP3A4 gene expression and cause drug interactions | journal = The Journal of Clinical Investigation | volume = 102 | issue = 5 | pages = 1016–23 | date = September 1998 | pmid = 9727070 | pmc = 508967 | doi = 10.1172/JCI3703 }}</ref><ref name="pmid16863430">{{cite journal | vauthors = Christians U, Schmitz V, Haschke M | title = Functional interactions between P-glycoprotein and CYP3A in drug metabolism | journal = Expert Opinion on Drug Metabolism & Toxicology | volume = 1 | issue = 4 | pages = 641–54 | date = December 2005 | pmid = 16863430 | doi = 10.1517/17425255.1.4.641 | s2cid = 17742146 }}</ref> It has no [[estrogen (medication)|estrogen]]ic or [[antimineralocorticoid]] activity.<ref name="pmid16112947" /> In terms of [[potency (pharmacology)|potency]], CPA is described as a highly potent progestogen, a moderately potent antiandrogen, and a weak glucocorticoid.<ref name="Hammerstein1990" /><ref name="pmid10352926">{{cite journal | vauthors = Rittmaster RS | title = Antiandrogen treatment of polycystic ovary syndrome | journal = Endocrinol. Metab. Clin. North Am. | volume = 28 | issue = 2 | pages = 409–21 | date = June 1999 | pmid = 10352926 | doi = 10.1016/S0889-8529(05)70077-3 }}</ref><ref name="pmid10495361">{{cite journal | vauthors = Diamanti-Kandarakis E | title = Current aspects of antiandrogen therapy in women | journal = Curr. Pharm. Des. | volume = 5 | issue = 9 | pages = 707–23 | date = September 1999 | doi = 10.2174/1381612805666230111201150 | pmid = 10495361 | url = https://books.google.com/books?id=9rfNZL6oEO0C&pg=PA707}}</ref>

{| class="wikitable center sortable mw-collapsible mw-collapsed" style="width:475px; text-align:left; margin-left:auto; margin-right:auto; border:none;"
|+ class="nowrap" | Relative affinities (%) of cyproterone acetate
|-
! '''Progestogen''' !! '''{{abbrlink|PR|Progesterone receptor}}''' !! '''{{abbrlink|AR|Androgen receptor}}''' !! '''{{abbrlink|ER|Estrogen receptor}}''' !! '''{{abbrlink|GR|Glucocorticoid receptor}}''' !! '''{{abbrlink|MR|Mineralocorticoid receptor}}'''
|-
| Cyproterone acetate || 90 || 6 || 0 || 6 || 8
|- class="sortbottom"
| colspan="6" style="width: 1px; background-color:#eaecf0; text-align: center;" | '''Notes:''' Values are percentages (%). Reference [[ligand (biochemistry)|ligand]]s (100%) were [[promegestone]] for the {{abbrlink|PR|progesterone receptor}}, [[metribolone]] for the {{abbrlink|AR|androgen 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}}. '''Sources:''' <ref name="pmid16112947" />
|}

{{Parenteral potencies and durations of progestogens}}

===Antiandrogenic activity===
{{Affinities of selected androgen receptor ligands}}

{{Relative potencies of selected antiandrogens in rats}}

CPA is a [[potency (pharmacology)|potent]] [[competitive antagonist]] of the [[androgen receptor]] (AR), the [[biological target]] of [[androgen]]s such as [[testosterone]] and [[dihydrotestosterone]] (DHT).<ref name="FiggChau2010" /> It was at one time the most potent known AR antagonist of the [[steroidal antiandrogen]]s,<ref name="Pratt1994">{{cite book| vauthors = Pratt WB |title=The Anticancer Drugs|url=https://books.google.com/books?id=nPR1L4K5HuEC&pg=PA219|year=1994|publisher=Oxford University Press|isbn=978-0-19-506739-2|pages=219–}}</ref> out of hundreds of other compounds.<ref name="PlewigKligman2012">{{cite book | vauthors =  Plewig G, Kligman AM |title=ACNE and ROSACEA|url=https://books.google.com/books?id=0cD-CAAAQBAJ&pg=PA685|date=6 December 2012|publisher=Springer Science & Business Media|isbn=978-3-642-59715-2|pages=662, 685}}</ref> CPA has the highest antiandrogenic activity of any other clinically used progestin.<ref name="Kuhl2011">{{cite journal | vauthors = Kuhl H | title = Pharmacology of Progestogens | journal = J Reproduktionsmed Endokrinol | year = 2011 | volume = 8 | issue = 1 | pages = 157–177 | url = http://www.kup.at/kup/pdf/10168.pdf}}</ref><ref name="pmid14644837">{{cite journal | vauthors = Schneider HP | title = Androgens and antiandrogens | journal = Ann. N. Y. Acad. Sci. | volume = 997 | issue = 1| pages = 292–306 | date = November 2003 | pmid = 14644837 | doi = 10.1196/annals.1290.033 | bibcode = 2003NYASA.997..292S | s2cid = 8400556 }}</ref> It directly blocks endogenous androgens like testosterone and DHT from binding to and activating the AR, and thus prevents them from exerting their androgenic effects, such as [[masculinization]] and [[prostate gland]] [[cell growth|growth]], in the body.<ref name="pmid8252496">{{cite journal | vauthors = Schröder FH | title = Cyproterone acetate--mechanism of action and clinical effectiveness in prostate cancer treatment | journal = Cancer | volume = 72 | issue = 12 Suppl | pages = 3810–5 | date = December 1993 | pmid = 8252496 | doi = 10.1002/1097-0142(19931215)72:12+<3810::AID-CNCR2820721710>3.0.CO;2-O | s2cid = 221762 | doi-access = free }}</ref><ref name="Kuhl2011" />

A comparative study of binding inhibition to the AR in rat prostate cytosol AR found [[half-maximal inhibitory concentration|IC<sub>50</sub>]] values of 3&nbsp;nM for DHT, 24&nbsp;nM for [[cyproterone acetate]], and 67&nbsp;nM for spironolactone.<ref name="pmid6887871">{{cite journal | vauthors = Liang T, Rasmusson GH, Brooks JR | title = 12. Androgens: Pharmacodynamics and antagonists. Biochemical and biological studies with 4-aza-steroidal 5 alpha-reductase inhibitors | journal = J. Steroid Biochem. | volume = 19 | issue = 1A | pages = 385–90 | date = July 1983 | pmid = 6887871 | doi = 10.1016/s0022-4731(83)80051-x }}</ref>

{| class="wikitable sortable floatright" style="text-align:left; margin-left:auto; margin-right:auto; border:none;"
|+ class="nowrap" | Affinities of selected ligands at the androgen receptor
|-
! Compound !! {{abbrlink|AR|Androgen receptor}} {{abbrlink|RBA|Relative binding affinity}} (%) || {{abbrlink|AR|Androgen receptor}} K<sub>i</sub> (nM)
|-
| {{No selflink|Metribolone}} || 100 || 1.18
|-
| {{No selflink|Androstanolone|Dihydrotestosterone}} || 136 || 0.87
|-
| {{No selflink|Testosterone (medication)|Testosterone}} || 117 || 1.01
|-
| {{No selflink|Spironolactone}} || 67.0 || 1.76
|-
<!--| {{No selflink|Danazol}} || 41.4 || 2.85
|--->
| {{No selflink|Trimethyltrienolone}} || 14.8 || 8.0
|-
| {{No selflink|Megestrol acetate}} || 13.6 || 8.7
|-
| {{No selflink|Cyproterone acetate}} || 12.5 || 9.5
|-
<!--| {{No selflink|Medroxyprogesterone acetate}} || 11.6 || 10
|--->
| {{No selflink|Progesterone (medication)|Progesterone}} || 6.6 || 18
|-
| {{No selflink|Estradiol (medication)|Estradiol}} || 4.9 || 24
|-
| {{No selflink|Androstenedione}} || 2.0 || 58
|-
| {{No selflink|Canrenone}} || 0.84 || 140
|-
<!--| {{No selflink|Formestane}} || 0.79 || 150
|-
| {{No selflink|17α-Hydroxyprogesterone}} || 0.42 || 280
|--->
| {{No selflink|Flutamide}} || 0.079 || 1200
|-
<!--| {{No selflink|Testolactone}} || 0.0029 || 41000
|--->
| {{No selflink|Cimetidine}} || 0.00084 || 140,000
|- class="sortbottom"
| colspan="3" style="width: 1px; background-color:#eaecf0; text-align: center;" | '''Notes:''' (1) Human skin [[fibroblast]]s used for assays. (2) Situation ''in vivo'' is different for flutamide and spironolactone due [[biotransformation]]. (3) Conflicting findings for spironolactone. '''Sources:''' ''Main:'' <ref name="Hammerstein1990">{{cite book| vauthors = Hammerstein J |title=Hair and Hair Diseases|chapter=Antiandrogens: Clinical Aspects|year=1990|pages=827–886|publisher=Springer |doi=10.1007/978-3-642-74612-3_35|isbn=978-3-642-74614-7}}</ref><ref name="pmid6725525">{{cite journal | vauthors = Eil C, Edelson SK | title = The use of human skin fibroblasts to obtain potency estimates of drug binding to androgen receptors | journal = J. Clin. Endocrinol. Metab. | volume = 59 | issue = 1 | pages = 51–5 | date = July 1984 | pmid = 6725525 | doi = 10.1210/jcem-59-1-51 }}</ref> ''Related:'' <ref name="pmid6457421">{{cite journal | vauthors = Brown TR, Rothwell SW, Sultan C, Migeon CJ | title = Inhibition of androgen binding in human foreskin fibroblasts by antiandrogens | journal = Steroids | volume = 37 | issue = 6 | pages = 635–48 | date = June 1981 | pmid = 6457421 | doi = 10.1016/S0039-128X(81)90173-2 | s2cid = 88959 }}</ref><ref name="pmid3762019">{{cite journal | vauthors = Breiner M, Romalo G, Schweikert HU | 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 = 732–7 | date = August 1986 | pmid = 3762019 | doi = 10.1007/BF01734339 | s2cid = 34846760 }}</ref><ref name="BreinerRomalo1986">{{cite journal| vauthors = Breiner M, Romalo G, Schweikert HU |title=Inhibition of androgen receptor binding by drugs in cultured human genital skin fibroblasts|journal=Acta Endocrinologica|volume=113|issue=1_Suppl|year=1986|pages=S152|issn=0804-4643|doi=10.1530/acta.0.111S152}}</ref>
|}

====Antiandrogenic efficacy and potency====
[[File:Androgen receptor antagonistic potency of spironolactone, cyproterone acetate, and flutamide in male rats.png|thumb|right|400px|Androgen receptor antagonistic potency of [[spironolactone]], CPA, and [[flutamide]] in castrated male rats treated with exogenous testosterone (as measured by inhibition of androgen-dependent ventral prostate weight).<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 | date = February 2004 | pmid = 14751673 | doi = 10.1016/j.tox.2003.09.012 | bibcode = 2004Toxgy.195..177Y | url = }}</ref>]]

The antiandrogenic activity of CPA is dose-dependent.<ref name="Kuhl2011" /><ref name="Springer2012" /> Although CPA is a potent antiandrogen, relatively high doses of CPA are nonetheless required for clinically important AR antagonism.<ref name="pmid9476091" /><ref name="Springer2012" /><ref name="Hammerstein1990" /> The clinical antiandrogenic efficacy of birth control pills containing CPA, which have only low doses of CPA in them (2&nbsp;mg/day), often can't be distinguished from that of birth control pills containing other progestins.<ref name="pmid9476091" /> It is likely that the antiandrogenic effects of CPA-containing birth control pills are due mostly to the ethinylestradiol component and/or suppression of androgen levels, rather than the antiandrogenic activity of the small doses of CPA present in them.<ref name="GräfBrotherton1974" /><ref name="Hammerstein1990" /><ref name="MarsdenShuster1989" /><ref name="Thomson1989" /><ref name="Springer2012" />

CPA has been found to decrease inflammatory [[acne]] lesions in males by about 15% at 5&nbsp;mg/day, by 45% at 25&nbsp;mg/day, and by 73% at 100&nbsp;mg/day.<ref name="WardBrogden1984">{{cite journal | vauthors = Ward A, Brogden RN, Heel RC, Speight TM, Avery GS | title = Isotretinoin. A review of its pharmacological properties and therapeutic efficacy in acne and other skin disorders | journal = Drugs | volume = 28 | issue = 1 | pages = 6–37 | date = July 1984 | pmid = 6235105 | doi = 10.2165/00003495-198428010-00002 }}</ref> A dosage of 100&nbsp;mg/day CPA can achieve a 65 to 70% reduction in [[sebum excretion rate]] in males within 4&nbsp;weeks of treatment, but doses of 10&nbsp;mg/day CPA or less are said to have a negligible effect.<ref name="GräfBrotherton1974" /><ref name="MarsdenShuster1989">{{cite book | vauthors = Marsden JR, Shuster S | chapter = The Treatment of Acne | veditors = Malcolm Greaves MW, Shuster S| title = Pharmacology of the Skin II | volume = 87/2 |year=1989|pages=473–481 |doi=10.1007/978-3-642-74054-1_35| series = Handbook of Experimental Pharmacology | publisher = Springer | isbn = 978-3-642-74056-5 }}</ref> On the basis of these findings, it has estimated that the threshold dosage of CPA to reduce sebum production may be 5&nbsp;mg/day in males.<ref name="Hammerstein1990" /> In other studies, 25&nbsp;mg/day CPA resulted in substantial improvement or complete clearance of severe acne in almost all males, whereas 12.5&nbsp;mg/day was ineffective.<ref name="Cormanevan der Meeren1981">{{cite journal| vauthors = Cormane RH, Van Der Meeren HL |title=Cyproteronacetate in the management of severe acne in males|journal=Archives of Dermatological Research |volume=271 |issue=2 |year=1981 |pages=183–187 |issn=0340-3696 |doi=10.1007/BF00412545 |s2cid=12153042}}</ref><ref name="MischDolman1986">{{cite journal | vauthors = Misch KJ, Dolman WF, Neild V, Rhodes EL | title = Response of male acne to antiandrogen therapy with cyproterone acetate | journal = Dermatologica | volume = 173 | issue = 3 | pages = 139–142 | year = 1986 | pmid = 2945742 | doi = 10.1159/000249236 }}</ref>

CPA has been found to be strongly [[catabolic]] in young healthy males.<ref name="GräfBrotherton1974" /><ref name="pmid5161488">{{cite journal | vauthors = van Wayjen RG, van den Ende A | title = Clinical-pharmacological investigation of cyproterone acetate | journal = Gynecol Invest | volume = 2 | issue = 1 | pages = 282–9 | date = 1971 | pmid = 5161488 | doi = 10.1159/000301868 }}</ref> It was shown to result in a mean negative [[nitrogen balance]] of 1.2&nbsp;g at 50&nbsp;mg/day, 1.4&nbsp;g at 100&nbsp;mg/day, and 2.5&nbsp;g at 200&nbsp;mg/day.<ref name="GräfBrotherton1974" /><ref name="pmid5161488" /> This corresponded to mean losses of [[lean body mass|lean tissue]] of 780, 945, and 1,515&nbsp;g, respectively.<ref name="pmid5161488" /> Conversely, the catabolic effect was much less in an older male, and no such effect was observed in adult females consuming a diet with sufficient calories and protein.<ref name="GräfBrotherton1974" /><ref name="pmid5161488" /> The catabolic effects of CPA were found to be greater than those of [[corticosteroid]]s.<ref name="pmid5161488" />

Although higher doses of CPA are necessary for considerable systemic AR antagonistic activity, it is notable that even low doses of oral CPA appear to be able to significantly antagonize AR signaling in the [[liver]] in women.<ref name="pmid15063480">{{cite journal | vauthors = Sitruk-Ware R | title = Pharmacological profile of progestins | journal = Maturitas | volume = 47 | issue = 4 | pages = 277–83 | date = April 2004 | pmid = 15063480 | doi = 10.1016/j.maturitas.2004.01.001 }}</ref> This may be related to the hepatic [[first-pass effect]] of [[oral administration]], and is evidenced by the fact that whereas combined birth control pills containing CPA increase SHBG levels by 300 to 400%, combined birth control pills containing various other progestins, with either androgenic or antiandrogenic activity, increase SHBG levels by only 50 to 300%.<ref name="pmid15063480" /> This is relevant as estrogens stimulate hepatic SHBG production while androgens inhibit hepatic SHBG production, and vice versa for their antagonists.<ref name="pmid16112947" /><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=PA1152 |year=2001|publisher=Lippincott Williams & Wilkins|isbn=978-0-7817-1750-2|pages=1152–}}</ref> The antiandrogenic activity of CPA may also be responsible for the relatively greater risk of [[venous thromboembolism]] with CPA-containing birth control pills compared to those containing other progestins.<ref name="pmid15063481">{{cite journal | vauthors = Kuhl H | title = Mechanisms of sex steroids. Future developments | journal = Maturitas | volume = 47 | issue = 4 | pages = 285–91 | date = April 2004 | pmid = 15063481 | doi = 10.1016/j.maturitas.2003.11.010 }}</ref>

In rats, a dosage of CPA of 25&nbsp;mg/kg/day results in complete regression of prostate gland growth in gonadally intact males.<ref name="pmid8252496" /> The equivalent dosage in humans, on the basis of body surface (conversion factor from rat to human of 6), was estimated to be approximately 4&nbsp;mg/kg/day, or around 300&nbsp;mg/day CPA for a 75&nbsp;kg (165&nbsp;lb) man.<ref name="pmid8252496" /> Other techniques for determining the dosage of CPA have validated this extrapolation, for instance affinity studies and prostatic CPA levels.<ref name="pmid8252496" /> The affinity of CPA for the AR is around 20-fold lower than that of DHT, and an excess of CPA levels of around 20 to 30&nbsp;times those of DHT would hence be expected to maximally neutralize androgen signaling.<ref name="pmid8252496" /> In accordance, different publications have stated based on preclinical experiments that a 2- to 5-fold excess of CPA can inhibit the effects of testosterone by 50%, a 3- to 10-fold excess of CPA can reduce the effects of "potent androgens" (presumably testosterone and/or DHT) by 50%, and a 10-fold excess of CPA can inhibit the effects of testosterone by "almost 100%".<ref name="pmid2941191">{{cite journal | vauthors = Miller JA, Jacobs HS | title = Treatment of hirsutism and acne with cyproterone acetate | journal = Clin Endocrinol Metab | volume = 15 | issue = 2 | pages = 373–89 | date = May 1986 | pmid = 2941191 | doi = 10.1016/S0300-595X(86)80031-7
 }}</ref><ref name="NeumannJacobi1982" /><ref name="JacobiNeumann1988">{{cite journal | vauthors = Jacobi G, Neumann F | title = The Case for Cyproterone Acetate | journal = Baillière's Clinical Oncology: International Practice and Research | date = November 1988 | volume = 2 | issue = 3 | pages = 571–580 | issn = 0950-3560 | url = https://scholar.google.com/scholar?cluster=10064506544781395690}}</ref> High-dose CPA has been found to achieve prostatic levels that are at least 30-fold those of DHT.<ref name="pmid8252496" /> One study found that levels of CPA in the prostate gland in men being treated with 200&nbsp;mg/day oral CPA were about 28&nbsp;times those of DHT.<ref name="pmid8252496" /> In accordance with the preceding findings, it has been stated that oral doses of CPA of at least 300&nbsp;mg/day may achieve a [[combined androgen blockade]] action in the treatment of prostate cancer.<ref name="pmid9088277">{{cite journal | vauthors = Newling DW | title = The palliative therapy of advanced prostate cancer, with particular reference to the results of recent European clinical trials | journal = British Journal of Urology | volume = 79 | issue = Suppl 1 | pages = 72–81 | date = March 1997 | pmid = 9088277 | doi = 10.1111/j.1464-410X.1997.tb00805.x }}</ref> At a dosage of CPA of 100&nbsp;mg/day in men with prostate cancer, circulating levels of CPA (e.g., 350&nbsp;ng/mL) are on the order of 200-fold higher than circulating levels of testosterone (e.g., 100&nbsp;ng/dL).<ref name="TunnGraff1982" /> In men who have undergone orchiectomy, 50&nbsp;mg/day oral CPA results in a 500-fold excess of circulating CPA relative to circulating testosterone.<ref name="TunnGraff1982" />

In accordance with such findings, high-dose CPA shows equivalent effects on the prostate gland in men relative to high-dose [[diethylstilbestrol]] or [[buserelin]], which both achieve castrate levels of testosterone.<ref name="pmid8252496" /> However, a lower dosage of 50&nbsp;mg/day CPA has been found to produce a reduction in prostate volume in men with [[benign prostatic hyperplasia]] that is reportedly comparable to that observed with surgical or medical castration.<ref name="pmid8252496" /> In accordance, the dosage of CPA that achieves complete inhibition of the secretory function of the healthy prostate gland is around 50 to 100&nbsp;mg/day, which is less than the dosage of 200 to 300&nbsp;mg/day CPA that is used to treat prostate cancer.<ref name="Neumann1996" /> It has been said that in combined androgen blockade regimens with castration and CPA as the AR antagonist for prostate cancer, due to the marked reduction in androgen levels, lower dosages of CPA than those used as a monotherapy would seem to be equally effective.<ref name="pmid8252496" /> Relative to the 200 to 300&nbsp;mg/day dosage of CPA used as a monotherapy in prostate cancer, the recommended dosage in combined androgen blockade is 100 to 200&nbsp;mg/day.<ref name="Neumann1996" /> It has been stated that this dosage should be more than necessary to inhibit the effects of the remaining adrenal androgens in castrated men.<ref name="Neumann1996" />

Despite considerable suppression of testosterone levels, only a modest suppression of [[spermatogenesis]] typically occurs with 5 to 10&nbsp;mg/day CPA, and [[azoospermia]] occurs only occasionally.<ref name="pmid9203050">{{cite journal | vauthors = Meriggiola MC, Bremner WJ | title = Progestin-androgen combination regimens for male contraception | journal = J. Androl. | volume = 18 | issue = 3 | pages = 240–4 | date = 1997 | pmid = 9203050 | doi = 10.1002/j.1939-4640.1997.tb01913.x | s2cid = 25874511 | doi-access = free }}</ref> Conversely, a combination of [[testosterone enanthate]] injections with 12.5 to 100&nbsp;mg/day CPA results in azoospermia in most men.<ref name="pmid9203050" /><ref name="pmid12185103">{{cite journal | vauthors = Meriggiola MC, Costantino A, Bremner WJ, Morselli-Labate AM | title = Higher testosterone dose impairs sperm suppression induced by a combined androgen-progestin regimen | journal = J. Androl. | volume = 23 | issue = 5 | pages = 684–90 | date = 2002 | pmid = 12185103 | doi = 10.1002/j.1939-4640.2002.tb02311.x | hdl = 1773/4474 | s2cid = 2400041 | hdl-access = free }}</ref> The rates of azoospermia increased with greater CPA dosage, which was attributed to the additional AR antagonism of higher doses of CPA.<ref name="pmid9203050" /><ref name="pmid12185103" /> Significant [[spermatogenesis]] still occurs with 50&nbsp;mg/day CPA alone, but spermatogenesis is significantly reduced compared to normal.<ref name="pmid1177426">{{cite journal | vauthors = Laschet U, Laschet L | title = Antiandrogens in the treatment of sexual deviations of men | journal = J. Steroid Biochem. | volume = 6 | issue = 6 | pages = 821–6 | date = June 1975 | pmid = 1177426 | doi = 10.1016/0022-4731(75)90310-6 }}</ref> At a dosage of 200&nbsp;mg/day, CPA has been found to produce azoospermia ([[sperm count]] of less than 1&nbsp;million/mL) in men within 8 to 10&nbsp;weeks of treatment.<ref name="pmid1177426" /> However, [[fertility]] is generally lost even at a lower dosage of CPA of 100&nbsp;mg/day because there is complete inhibition of the [[male accessory gland|accessory sex gland]]s and hence an absence of [[semen]] production and [[ejaculate]] upon [[orgasm]].<ref name="pmid1177426" /><ref name="Neumann1996" /><ref name="GräfBrotherton1974" /> Ejaculate volume decreases at a dosage of 50&nbsp;mg/day and decreases to almost zero after 6&nbsp;weeks of high-dose CPA therapy.<ref name="GräfBrotherton1974" /><ref name="NeumannJacobi1982" /> The effects of CPA on fertility are completely reversible.<ref name="Neumann1996" /> This has been demonstrated in clinical studies of male adolescents and adults treated with CPA continuously for 6 to 7&nbsp;years.<ref name="Neumann1996" />

====Weak partial androgenic activity====
CPA, like [[spironolactone]] and other steroidal antiandrogens such as [[chlormadinone acetate]] and [[megestrol acetate]], is actually not a pure antagonist of the AR – that is, a [[silent antagonist]] – but rather appears to be a very weak [[partial agonist]].<ref name="pmid9476091" /><ref name="FiggChau2010" /><ref name="pmid8252497">{{cite journal | vauthors = Labrie F | title = Mechanism of action and pure antiandrogenic properties of flutamide | journal = Cancer | volume = 72 | issue = 12 Suppl | pages = 3816–27 | date = December 1993 | pmid = 8252497 | doi = 10.1002/1097-0142(19931215)72:12+<3816::AID-CNCR2820721711>3.0.CO;2-3 | s2cid = 2195250 | doi-access = free }}</ref><ref name="pmid1525065">{{cite journal | vauthors = Simental JA, Sar M, Wilson EM | title = Domain functions of the androgen receptor | journal = The Journal of Steroid Biochemistry and Molecular Biology | volume = 43 | issue = 1–3 | pages = 37–41 | date = September 1992 | pmid = 1525065 | doi =  10.1016/0960-0760(92)90185-L| s2cid = 43177646 }}</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 | date = November 1988 | pmid = 2462135 | doi = 10.1016/0022-4731(88)90295-6 }}</ref><ref name="pmid10715537">{{cite journal | vauthors = Térouanne B, Tahiri B, Georget V, Belon C, Poujol N, Avances C, Orio F, Balaguer P, Sultan C | title = A stable prostatic bioluminescent cell line to investigate androgen and antiandrogen effects | journal = Molecular and Cellular Endocrinology | volume = 160 | issue = 1–2 | pages = 39–49 | date = February 2000 | pmid = 10715537 | doi = 10.1016/s0303-7207(99)00251-8 | s2cid = 13737435 }}</ref><ref name="FritzSperoff2010">{{cite book | vauthors = Fritz MA, Speroff L | title = Clinical Gynecologic Endocrinology and Infertility |url=https://books.google.com/books?id=Ll73ZsBKLkwC&pg=PA80 |access-date=27 May 2012 |date=20 December 2010 |publisher=Lippincott Williams & Wilkins |isbn=978-0-7817-7968-5 |page=80}}</ref> Clinically, CPA generally functions purely as an antiandrogen, as it displaces much more efficacious endogenous androgens such as testosterone and DHT from interacting with the receptor and thus its net effect is virtually always to lower physiological androgenic activity.<ref name="pmid8252496" /><ref name="pmid11379383">{{cite journal | vauthors = Schneider HP | title = The role of antiandrogens in hormone replacement therapy | journal = Climacteric | volume = 3 | issue = Suppl 2 | pages = 21–7 | date = December 2000 | pmid = 11379383 }}</ref> But unlike silent antagonists of the AR like [[nonsteroidal antiandrogen]]s such as [[flutamide]], [[bicalutamide]], and [[enzalutamide]], CPA, by virtue of its slight [[intrinsic activity]] at the AR, may be unable to fully inhibit androgenic signaling in the body, which may persist to an extent in some tissues such as the prostate gland.<ref name="pmid9476091" />

In accordance with its albeit weak capacity for activation of the AR, CPA has been found to stimulate androgen-sensitive [[carcinoma]] growth in the absence of other androgens, an effect which could be blocked by co-treatment with flutamide.<ref name="pmid9476091" /><ref name="pmid2462135" /><ref name="pmid10715537" /> In one study in rodents, DHT-stimulated prostate weight remained 40% above controls with administration of CPA even at the highest dosage, while flutamide was able to completely block the stimulatory effects of DHT.<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 = 283–288 | date = October 1985 | pmid = 3930312 | doi = 10.1016/0303-7207(85)90059-0 | s2cid = 24746807 }}</ref> In addition, CPA alone increased prostate weight by 60%, whereas flutamide had no effect.<ref name="PoyetLabrie1985" /> As a result of its weak intrinsic androgenicity, CPA may not be as effective in the treatment of certain androgen-sensitive conditions such as [[prostate cancer]] compared to nonsteroidal antiandrogens with a silent antagonist profile at the AR.<ref name="FiggChau2010" /><ref name="Kampel2012">{{cite book | vauthors = Kampel LJ |title=Dx/Rx: Prostate Cancer: Prostate Cancer |url=https://books.google.com/books?id=oU1rl6LKbJkC&pg=PA169 |date=20 March 2012 |publisher=Jones & Bartlett Publishers |isbn=978-1-4496-8695-6 |page=169}}</ref> Indeed, CPA has never been found to extend life in prostate cancer patients when added to castration relative to castration alone, unlike nonsteroidal antiandrogens.<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 = 211–247 | date = February 2000 | pmid = 10637363 | doi = 10.2174/0929867003375371 | quote = When compared to flutamide, [cyproterone acetate] has significant intrinsic androgenic and estrogenic activities. [...] The effects of flutamide and the steroidal derivatives, cyproterone acetate, chlormadinone acetate, megestrol acetate and medroxyprogesterone acetate were compared in vivo in female nude mice bearing androgen-sensitive Shionogi tumors. All steroidal compounds stimulated tumor growth while flutamide had no stimulatory effect [51]. Thus, CPA due to its intrinsic properties stimulates androgen-sensitive parameters and cancer growth. Cyproterone acetate added to castration has never been shown in any controlled study to prolong disease-free survival or overall survival in prostate cancer when compared with castration alone [152-155]. }}</ref> As such, it is thought that the partial androgenic activity of CPA and other steroidal antiandrogens underlies the superior antiandrogenic efficacy of silent-antagonist nonsteroidal antiandrogens like flutamide.<ref name="pmid8252497" /> However, the clinical significance of the weak androgenic activity of CPA has also been disputed.<ref name="pmid8252496" /><ref name="El EtrebyHabenicht1987">{{cite journal | vauthors = el Etreby MF, Habenicht UF, Louton T, Nishino Y, Schröder HG | title = Effect of cyproterone acetate in comparison to flutamide and megestrol acetate on the ventral prostate, seminal vesicle, and adrenal glands of adult male rats | journal = The Prostate | volume = 11 | issue = 4 | pages = 361–375 | year = 1987 | pmid = 2960960 | doi = 10.1002/pros.2990110408 | s2cid = 86447179 }}</ref><ref name="HabenichtDüsterberg1985">{{cite journal | vauthors = Habenicht UF, Düsterberg B, El Etreby MF, Neumann F   |title=Does cyproterone acetate have an androgen agonistic effect?|journal=Acta Endocrinologica|volume=110|issue=1_Suppla|year=1985|pages=S152–S153|issn=0804-4643|doi=10.1530/acta.0.109S152-a}}</ref> In fact, some studies have found little or no stimulating effect of CPA on the prostate gland or [[seminal vesicle]]s of male rats even with very high circulating concentrations of CPA.<ref name="El EtrebyHabenicht1987" /><ref name="HabenichtDüsterberg1985" />

Nonsteroidal antiandrogens like flutamide and bicalutamide are more efficacious as antiandrogens than CPA in castrated animals due to their superior AR antagonistic activity.<ref name="Neumann1996" /><ref name="SchröderRadlmaier2009" /> Conversely, CPA is a much more potent antiandrogen than nonsteroidal antiandrogens like flutamide and bicalutamide in gonadally intact male animals, which is due to its antigonadotropic effects and consequent suppression of testosterone levels (nonsteroidal antiandrogens do not suppress testosterone levels).<ref name="Neumann1996">{{cite book| vauthors = Neumann F |title=Antiandrogens in Prostate Cancer|chapter=Pharmacology of Cyproterone Acetate — A Short Review|year=1996|pages=31–44|doi=10.1007/978-3-642-45745-6_3|isbn=978-3-642-45747-0}}</ref><ref name="SchröderRadlmaier2009" />

CPA at high doses (e.g., 25–50{{nbsp}}mg/day) has been reported to suppress SHBG levels, and may have a partial androgenic effect on hepatic SHBG production at such doses.<ref name="pmid36201493">{{cite journal | vauthors = Collet S, Gieles N, Wiepjes CM, Heijboer AC, Reyns T, Fiers T, Lapauw B, den Heijer M, T'Sjoen G | display-authors = 6 | title = Changes in serum testosterone and adrenal androgen levels in transgender women with and without gonadectomy | journal = The Journal of Clinical Endocrinology and Metabolism | volume =  108| issue =  2| date = October 2022 | pages = 331–338 | pmid = 36201493 | doi = 10.1210/clinem/dgac576 | pmc = 9844963 | s2cid = 252737129 }}</ref><ref name="pmid32454455">{{cite journal | vauthors = Khalil R, Antonio L, Laurent MR, David K, Kim NR, Evenepoel P, Eisenhauer A, Heuser A, Cavalier E, Khosla S, Claessens F, Vanderschueren D, Decallonne B | display-authors = 6 | title = Early effects of androgen deprivation on bone and mineral homeostasis in adult men: a prospective cohort study | journal = European Journal of Endocrinology | volume = 183 | issue = 2 | pages = 181–189 | date = August 2020 | pmid = 32454455 | doi = 10.1530/EJE-20-0348 | s2cid = 218910292 | url = https://oceanrep.geomar.de/id/eprint/49793/1/%5B1479683X%20-%20European%20Journal%20of%20Endocrinology%5D%20Early%20effects%20of%20androgen%20deprivation%20on%20bone%20and%20mineral%20homeostasis%20in%20adult%20men_%20a%20prospective%20cohort%20study.pdf }}</ref><ref name="pmid2530403">{{cite journal | vauthors = Vincens M, Mercier-Bodard C, Mowszowicz I, Kuttenn F, Mauvais-Jarvis P | title = Testosterone-estradiol binding globulin (TeBG) in hirsute patients treated with cyproterone acetate (CPA) and percutaneous estradiol | journal = Journal of Steroid Biochemistry | volume = 33 | issue = 4A | pages = 531–534 | date = October 1989 | pmid = 2530403 | doi = 10.1016/0022-4731(89)90037-x }}</ref><ref name="Elger1995">{{cite journal | vauthors = Elger W | title = Pharmacology of antiandrogens and their clinical application | journal = Current Science | date = 1995 | volume = 68 | issue = 4 | pages = 459–469 | jstor = 24096450 | url = https://www.jstor.org/stable/24096450}}</ref> Similar effects are known for related androgenic progestins like [[medroxyprogesterone acetate]] and [[megestrol acetate]].<ref name="pmid16112947" /> CPA has also been reported to lower [[HDL cholesterol]] levels, another effect associated with androgens.<ref name="pmid3318361">{{cite journal | vauthors = Godsland IF, Wynn V, Crook D, Miller NE | title = Sex, plasma lipoproteins, and atherosclerosis: prevailing assumptions and outstanding questions | journal = American Heart Journal | volume = 114 | issue = 6 | pages = 1467–1503 | date = December 1987 | pmid = 3318361 | doi = 10.1016/0002-8703(87)90552-7 }}</ref><ref name="pmid">{{cite journal | vauthors = Coleman E, Radix AE, Bouman WP, Brown GR, de Vries AL, Deutsch MB, Ettner R, Fraser L, Goodman M, Green J, Hancock AB, Johnson TW, Karasic DH, Knudson GA, Leibowitz SF, Meyer-Bahlburg HF, Monstrey SJ, Motmans J, Nahata L, Nieder TO, Reisner SL, Richards C, Schechter LS, Tangpricha V, Tishelman AC, Van Trotsenburg MA, Winter S, Ducheny K, Adams NJ, Adrián TM, Allen LR, Azul D, Bagga H, Başar K, Bathory DS, Belinky JJ, Berg DR, Berli JU, Bluebond-Langner RO, Bouman MB, Bowers ML, Brassard PJ, Byrne J, Capitán L, Cargill CJ, Carswell JM, Chang SC, Chelvakumar G, Corneil T, Dalke KB, De Cuypere G, de Vries E, Den Heijer M, Devor AH, Dhejne C, D'Marco A, Edmiston EK, Edwards-Leeper L, Ehrbar R, Ehrensaft D, Eisfeld J, Elaut E, Erickson-Schroth L, Feldman JL, Fisher AD, Garcia MM, Gijs L, Green SE, Hall BP, Hardy TL, Irwig MS, Jacobs LA, Janssen AC, Johnson K, Klink DT, Kreukels BP, Kuper LE, Kvach EJ, Malouf MA, Massey R, Mazur T, McLachlan C, Morrison SD, Mosser SW, Neira PM, Nygren U, Oates JM, Obedin-Maliver J, Pagkalos G, Patton J, Phanuphak N, Rachlin K, Reed T, Rider GN, Ristori J, Robbins-Cherry S, Roberts SA, Rodriguez-Wallberg KA, Rosenthal SM, Sabir K, Safer JD, Scheim AI, Seal LJ, Sehoole TJ, Spencer K, St Amand C, Steensma TD, Strang JF, Taylor GB, Tilleman K, T'Sjoen GG, Vala LN, Van Mello NM, Veale JF, Vencill JA, Vincent B, Wesp LM, West MA, Arcelus J | display-authors = 6 | title = Standards of Care for the Health of Transgender and Gender Diverse People, Version 8 | journal = International Journal of Transgender Health | volume = 23 | issue = Suppl 1 | pages = S1–S259 | date = 19 August 2022 | pmid = 36238954 | pmc = 9553112 | doi = 10.1080/26895269.2022.2100644 | doi-access = free }}</ref> Accordingly, CPA shows weak androgenic effects in the liver in rodents which can be blocked by [[flutamide]].<ref name="pmid3320549">{{cite journal | vauthors = Lax ER | title = Mechanisms of physiological and pharmacological sex hormone action on the mammalian liver | journal = Journal of Steroid Biochemistry | volume = 27 | issue = 4–6 | pages = 1119–1128 | date = 1987 | pmid = 3320549 | doi = 10.1016/0022-4731(87)90198-1 }}</ref><ref name="pmid6578932">{{cite journal | vauthors = Lax ER, Baumann P, Schriefers H | title = Antiandrogenic effects of oestradiol on enzyme activities of hepatic steroid metabolism | journal = Experimental and Clinical Endocrinology | volume = 82 | issue = 2 | pages = 145–152 | date = August 1983 | pmid = 6578932 | doi = 10.1055/s-0029-1210270 }}</ref>

====Other androgenic and antiandrogenic actions====
A paradoxical effect occurs with certain prostate cancer cells which have [[genetic mutation]]s in their ARs.<ref name="MiyamotoRahman2004">{{cite journal | vauthors = Miyamoto H, Rahman MM, Chang C | title = Molecular basis for the antiandrogen withdrawal syndrome | journal = Journal of Cellular Biochemistry | volume = 91 | issue = 1 | pages = 3–12 | date = January 2004 | pmid = 14689576 | doi = 10.1002/jcb.10757 | s2cid = 5773128 }}</ref><ref name="PaulBreul2000">{{cite journal | vauthors = Paul R, Breul J | title = Antiandrogen withdrawal syndrome associated with prostate cancer therapies: incidence and clinical significance | journal = Drug Safety | volume = 23 | issue = 5 | pages = 381–390 | date = November 2000 | pmid = 11085345 | doi = 10.2165/00002018-200023050-00003 | s2cid = 7402525 }}</ref><ref name="SellaFlex1998">{{cite journal | vauthors = Sella A, Flex D, Sulkes A, Baniel J | title = Antiandrogen withdrawal syndrome with cyproterone acetate | journal = Urology | volume = 52 | issue = 6 | pages = 1091–1093 | date = December 1998 | pmid = 9836560 | doi = 10.1016/S0090-4295(98)00354-9 }}</ref> These altered ARs can be activated, rather than inhibited, by CPA.<ref name="MiyamotoRahman2004" /><ref name="PaulBreul2000" /><ref name="SellaFlex1998" /> In such cases, withdrawal of CPA may result in a reduction in [[cancer]] growth, rather than the reverse.<ref name="MiyamotoRahman2004" /><ref name="PaulBreul2000" /><ref name="SellaFlex1998" /> This is known as [[antiandrogen withdrawal syndrome]].<ref name="MiyamotoRahman2004" /><ref name="PaulBreul2000" /><ref name="SellaFlex1998" />

CPA may also have a slight direct inhibitory effect on [[5α-reductase]], though the evidence for this is sparse and conflicting.<ref name="pmid11075290">{{cite journal | vauthors = Rabe T, Kowald A, Ortmann J, Rehberger-Schneider S | title = Inhibition of skin 5 alpha-reductase by oral contraceptive progestins in vitro | journal = Gynecological Endocrinology | volume = 14 | issue = 4 | pages = 223–30 | date = August 2000 | pmid = 11075290 | doi = 10.3109/09513590009167685 | s2cid = 72220210 }}</ref><ref name="pmid1009901">{{cite journal | vauthors = Stárka L, Sulcová J, Broulík P | title = Effect of cyproterone acetate on the action and metabolism of testosterone in the mouse kidney | journal = Endokrinologie | volume = 68 | issue = 2 | pages = 155–63 | year = 1976 | pmid = 1009901 }}</ref><ref name="pmid12600226">{{cite journal | vauthors = Raudrant D, Rabe T | title = Progestogens with antiandrogenic properties | journal = Drugs | volume = 63 | issue = 5 | pages = 463–92 | year = 2003 | pmid = 12600226 | doi = 10.2165/00003495-200363050-00003 | s2cid = 28436828 }}</ref> Most studies however suggest that CPA does not produce important inhibition of 5α-reductase.<ref name="NeumannJacobi1982">{{cite book | vauthors = Neumann F, Jacobi GH | chapter = Antiandrogens in tumour therapy | pages = 41–64 | title = Clinics in Oncology | volume = 1 | issue = 1 | date = March 1982 }}</ref><ref name="NeumannSteinbeck1974">{{cite book | vauthors = Neumann F, Steinbeck H |chapter=Antiandrogens|year=1974|pages=235–484|doi=10.1007/978-3-642-80859-3_6|title=Androgens II and Antiandrogens / Androgene II und Antiandrogene|publisher=Springer |isbn=978-3-642-80861-6}}</ref><ref name="Thomson1989">{{cite book| vauthors = Thomson DS |chapter=Pharmacology of Anti-androgens in the Skin|volume=87 / 2|year=1989|pages=483–493|issn=0171-2004|doi=10.1007/978-3-642-74054-1_36|title=Pharmacology of the Skin II|series=Handbook of Experimental Pharmacology|publisher=Springer |isbn=978-3-642-74056-5}}</ref> The combination of birth control pills containing CPA with [[finasteride]], a well-established, selective [[5α-reductase inhibitor]], has been found to result in significantly improved effectiveness in the treatment of hirsutism relative to CPA-containing birth control pills alone.<ref name="pmid10731531">{{cite journal | vauthors = Tartagni M, Schonauer LM, De Salvia MA, Cicinelli E, De Pergola G, D'Addario V | title = Comparison of Diane 35 and Diane 35 plus finasteride in the treatment of hirsutism | journal = Fertility and Sterility | volume = 73 | issue = 4 | pages = 718–23 | date = April 2000 | pmid = 10731531 | doi = 10.1016/s0015-0282(99)00633-0 | doi-access = free }}</ref><ref name="pmid11239530">{{cite journal | vauthors = Sahin Y, Dilber S, Keleştimur F | title = Comparison of Diane 35 and Diane 35 plus finasteride in the treatment of hirsutism | journal = Fertility and Sterility | volume = 75 | issue = 3 | pages = 496–500 | date = March 2001 | pmid = 11239530 | doi = 10.1016/s0015-0282(00)01764-7 | doi-access = free }}</ref>

In addition to its AR antagonistic activity and suppression of gonadal sex-hormone production, high-dose CPA has been found to suppress the levels of the [[adrenal androgen]] [[dehydroepiandrosterone sulfate]] (DHEA-S), which is due to exertion of [[negative feedback]] by CPA on [[adrenocorticotropic hormone]] (ACTH) [[secretion]] via the [[glucocorticoid]] activity of CPA.<ref name="pmid9476091">{{cite journal | vauthors = Pucci E, Petraglia F | title = Treatment of androgen excess in females: yesterday, today and tomorrow | journal = Gynecol. Endocrinol. | volume = 11 | issue = 6 | pages = 411–33 | date = December 1997 | pmid = 9476091 | doi = 10.3109/09513599709152569 }}</ref><ref name="pmid2941191" /><ref name="pmid10495361" />

===Progestogenic activity===
CPA is a highly potent progestogen.<ref name="FritzSperoff2011">{{cite book | vauthors = Fritz MA, Speroff L |title= Clinical Gynecologic Endocrinology and Infertility |url=https://books.google.com/books?id=Ll73ZsBKLkwC&pg=PA561 |year=2011 |publisher=Lippincott Williams & Wilkins |isbn=978-0-7817-7968-5 |pages=561–}}</ref> It is described as the most potent progestin of the [[17α-hydroxyprogesterone]] group, being about 1,200-fold more potent than [[hydroxyprogesterone acetate]], 12-fold more potent than [[medroxyprogesterone acetate]], and 3-fold more potent than [[chlormadinone acetate]] in animal [[bioassay]]s.<ref name="GräfBrotherton1974">{{cite book| vauthors = Gräf KJ, Brotherton J, Neumann F |chapter=Clinical Uses of Antiandrogens|year=1974|pages=485–542|doi=10.1007/978-3-642-80859-3_7|title=Androgens II and Antiandrogens / Androgene II und Antiandrogene|publisher=Springer |isbn=978-3-642-80861-6}}</ref><ref name="RunnebaumRabe2012" /> Based on results in the [[Clauberg test|animal bioassay]]s, CPA has also been said to be the most potent progestin known, with 1,000&nbsp;times the potency of [[progesterone (medication)|progesterone]].<ref name="GräfBrotherton1974" /> With [[oral administration]] in humans however, CPA is distinctly less potent as a progestogen than various other progestins such as the [[19-nortestosterone]] [[chemical derivative|derivative]]s.<ref name="pmid16112947" /> The effective dosage of CPA needed to inhibit [[ovulation]] by itself in women (i.e., to act as a contraceptive) is 1&nbsp;mg/day,<ref name="pmid16112947" /> and the medication is marketed as a contraceptive (combined with low-dose [[ethinylestradiol]]) at a dosage of 2&nbsp;mg/day.<ref name="Hammerstein1990" /><ref name="FritzSperoff2011" /><ref name="Springer2012">{{cite book |title=Pharmacology of the Skin II: Methods, Absorption, Metabolism and Toxicity, Drugs and Diseases |url=https://books.google.com/books?id=GvDxCAAAQBAJ&pg=PA474 |date=6 December 2012 |publisher=Springer Science & Business Media |isbn=978-3-642-74054-1 |pages=474, 489}}</ref> For comparison, the ovulation-inhibiting dosage of [[levonorgestrel]] is 50&nbsp;μg/day.<ref name="pmid16112947" />

At the dosages typically used clinically, CPA is described as a "strong" and "powerful" progestogen.<ref name="pmid2976627">{{cite journal | vauthors = Reed MJ, Franks S | title = Anti-androgens in gynaecological practice | journal = Baillière's Clin Obstet Gynaecol | volume = 2 | issue = 3 | pages = 581–95 | date = September 1988 | pmid = 2976627 | doi = 10.1016/S0950-3552(88)80045-2 }}</ref><ref name="Hammerstein1990" /><ref name="Hammerstein1979">{{cite book| vauthors = Hammerstein J |chapter=Cyproterone acetate|title=Advances in Gynaecological Endocrinology: Proceedings of the Sixth Study Group of the Royal College of Obstetricians and Gynaecologists, 18th and 19th October, 1978|url=https://books.google.com/books?id=waMTAQAAMAAJ|year=1979|publisher=The College|isbn=978-0-87489-225-3|pages=367–368, 374|quote=CPA may be characterized endocrinologically as possessing strong progestational, moderate anti-androgenic and limited anti-gonadotropic potencies. [...] Its progestational activity, in terms of the transformation dose in the oestrogen-primed human endometrium, is 20–30 mg which is comparable to that of chlormadinone acetate and other strong progestogens (Table I). To take full clinical advantage of its anti-androgenicity not less than 50–100 mg CPA must be taken orally per day, which totals 2 to 3 times the progestational activity the female organism is exposed to throughout a complete ovulatory menstrual cycle. Thus unless much lower and less efficacious doses of CPA are used, a tremendous progestational overdosage must be accepted. [...] As already pointed out CPA is endocrinologically not a well-balanced compound because of the strong preponderance of the progestational over the anti-androgenic potency. A way to avoid the heavy progestogen overdosage inherent with the high-dose reverse sequential therapy would be to combine the low-dose contraceptive formulation just mentioned with a pure anti-androgen such as free cyproterone (Table 2).}}</ref> Its [[endometrial transformation]] dosage is 20 to 30&nbsp;mg per cycle and its [[menstrual delay test]] dosage has been estimated to be less than 1&nbsp;mg/day.<ref name="Hammerstein1990" /> CPA is not well-balanced in terms of its activities; relative to the progestogenic potency of CPA, its potency as an androgen receptor antagonist is quite weak.<ref name="Hammerstein1990" /> In order to take full advantage of its antiandrogenic activity, CPA must be administered at a dosage of 50 to 100&nbsp;mg per day, which is 2 to 3&nbsp;times the cyclical endometrial transformation dose ''per day''.<ref name="Hammerstein1990" /><ref name="pmid126335">{{cite journal | vauthors = Hammerstein J, Meckies J, Leo-Rossberg I, Moltz L, Zielske F | title = Use of cyproterone acetate (CPA) in the treatment of acne, hirsutism and virilism | journal = J. Steroid Biochem. | volume = 6 | issue = 6 | pages = 827–36 | date = June 1975 | pmid = 126335 | doi = 10.1016/0022-4731(75)90311-8 }}</ref><ref name="Hammerstein1979" /> As such, the total dosage of CPA per month is as much as 30&nbsp;times the physiological equivalent of progesterone production during the normal menstrual cycle, and is notably equivalent to the total production of progesterone by a [[corpus luteum]] throughout the course of a woman's entire cyclic life.<ref name="Hammerstein1990" /><ref name="pmid126335" /><ref name="Hammerstein1979" /> Consequently, there is profound overdosage of progestogenic effect (and by extension progestogenic side effects) when CPA is used as an antiandrogen at high doses.<ref name="pmid126335" /><ref name="Hammerstein1979" /> For this reason, it has been said that CPA cannot be considered an ideal antiandrogen.<ref name="pmid126335" /><ref name="Hammerstein1979" />

Through its action as a progestogen, CPA has been found to significantly increase [[prolactin]] secretion and to induce extensive [[lobuloalveolar]] development of the [[mammary gland]]s of female [[rhesus macaque]]s.<ref name="pmid411573">{{cite journal | vauthors = Herbert DC, Schuppler J, Poggel A, Günzel P, El Etreby MF | title = Effect of cyproterone acetate on prolactin secretion in the female Rhesus monkey | journal = Cell Tissue Res. | volume = 183 | issue = 1 | pages = 51–60 | year = 1977 | pmid = 411573 | doi = 10.1007/bf00219991| s2cid = 25943599 }}</ref> In accordance, a study found that CPA, in all cases, induced full lobuloalveolar development of the [[breast]]s in transgender women treated with the medication in combination with estrogen for a prolonged period of time.<ref name="pmid10632490">{{cite journal | vauthors = Kanhai RC, Hage JJ, van Diest PJ, Bloemena E, Mulder JW | title = Short-term and long-term histologic effects of castration and estrogen treatment on breast tissue of 14 male-to-female transsexuals in comparison with two chemically castrated men | journal = The American Journal of Surgical Pathology | volume = 24 | issue = 1 | pages = 74–80 | date = January 2000 | pmid = 10632490 | doi = 10.1097/00000478-200001000-00009 | s2cid = 37752666 | doi-access = free }}</ref><ref name="Lawrence2007">{{cite book | vauthors = Lawrence AA |chapter= Transgender Health Concerns |year=2007 |pages=473–505 |doi= 10.1007/978-0-387-31334-4_19 |title=The Health of Sexual Minorities|isbn=978-0-387-28871-0 }}</ref><ref name="Rosen2009">{{cite book | vauthors = Rosen PP |title=Rosen's Breast Pathology |url=https://books.google.com/books?id=_swaovkfRMMC&pg=PA31 |year=2009 |publisher=Lippincott Williams & Wilkins |isbn=978-0-7817-7137-5 |pages=31–}}</ref> [[Pregnancy]]-like [[breast hyperplasia]] was observed in two of the subjects.<ref name="Rosen2009" /> In contrast, the same study found that men with prostate cancer treated with a non-progestogenic antiandrogen like flutamide or bicalutamide and no estrogen produced moderate but incomplete lobuloalveolar development of the breasts.<ref name="pmid10632490" /> Based on the above research, it was concluded by the study authors that combined estrogenic and progestogenic action is required in transgender women for fully mature female-like histologic breast development (i.e., that includes complete lobuloalveolar maturation).<ref name="pmid10632490" /><ref name="Lawrence2007" /> Also, it was observed that lobuloalveolar maturation reverses upon discontinuation of CPA after surgical castration, similarly to the case of [[Involution (medicine)#Mammary gland|mammary gland involution]] in [[postpartum]] women, indicating that continued progestogen treatment is necessary to maintain the histology.<ref name="pmid10632490" /> It should be noted however that although these findings may have important implications in the context of [[lactation]] and [[breastfeeding]], [[epithelium|epithelial tissue]] accounts for approximately only 10% of breast volume with the bulk of the breasts (80–90%) being represented by [[stroma (animal tissue)|stromal]] or [[adipose tissue|adipose]] tissue,<ref name="pmid16728564">{{cite journal | vauthors = Lorincz AM, Sukumar S | title = Molecular links between obesity and breast cancer | journal = Endocrine-Related Cancer | volume = 13 | issue = 2 | pages = 279–92 | year = 2006 | pmid = 16728564 | doi = 10.1677/erc.1.00729 | quote = Adipocytes make up the bulk of the human breast, with epithelial cells accounting for only approximately 10% of human breast volume.| doi-access = free }}</ref><ref name="pmid11149569">{{cite journal | vauthors = Howard BA, Gusterson BA | title = Human breast development | journal = Journal of Mammary Gland Biology and Neoplasia | volume = 5 | issue = 2 | pages = 119–37 | year = 2000 | pmid = 11149569 | doi = 10.1023/a:1026487120779 | s2cid = 10819224 | quote = In the stroma, there is an increase in the amount of fibrous and fatty tissue, with the adult nonlactating breast consisting of 80% or more of stroma.}}</ref><ref name="Sperling2014">{{cite book | vauthors = Sperling MA | title = Pediatric Endocrinology|url=https://books.google.com/books?id=GgXnAgAAQBAJ&pg=PA598|date=10 April 2014|publisher=Elsevier Health Sciences|isbn=978-1-4557-5973-6|pages=598–|quote=Estrogen stimulates the nipples to grow, mammary terminal duct branching to progress to the stage at which ductules are formed, and fatty stromal growth to increase until it constitutes about 85% of the mass of the breast. [...] Lobulation appears around menarche, when multiple blind saccular buds form by branching of the terminal ducts. These effects are due to the presence of progesterone. [...] Full alveolar development normally only occurs during pregnancy under the influence of additional progesterone and prolactin.}}</ref><ref name="pmid22206682">{{cite journal | vauthors = Hagisawa S, Shimura N, Arisaka O | title = Effect of excess estrogen on breast and external genitalia development in growth hormone deficiency | journal = Journal of Pediatric and Adolescent Gynecology | volume = 25 | issue = 3 | pages = e61–3 | year = 2012 | pmid = 22206682 | doi = 10.1016/j.jpag.2011.11.005 | quote = Estrogen stimulates growth of the nipples, progression of mammary duct branching to the stage at which ductiles are formed, and fatty stromal growth until it constitutes about 85% of the mass of the breast.}}</ref> and it is uncertain to what extent, if any, that development of lobuloalveolar structures (a type of [[epithelium|epithelial]] tissue) contributes to breast size or shape.<ref name="WierckxGooren2014">{{cite journal | vauthors = Wierckx K, Gooren L, T'Sjoen G | title = Clinical review: Breast development in trans women receiving cross-sex hormones | journal = The Journal of Sexual Medicine | volume = 11 | issue = 5 | pages = 1240–7 | date = May 2014 | pmid = 24618412 | doi = 10.1111/jsm.12487}}</ref>

CPA has been found to increase prolactin levels in humans both alone and in combination with an estrogen.<ref name="pmid27561756">{{cite journal | vauthors = Nota NM, Dekker MJ, Klaver M, Wiepjes CM, van Trotsenburg MA, Heijboer AC, den Heijer M | title = Prolactin levels during short- and long-term cross-sex hormone treatment: an observational study in transgender persons | journal = Andrologia | volume = 49 | issue = 6 | pages = e12666| date = August 2017 | pmid = 27561756 | doi = 10.1111/and.12666 | s2cid = 25268468 | doi-access = free }}</ref>

====Antigonadotropic effects====
CPA has potent [[antigonadotropic]] effects via its progestogenic activity.<ref name="pmid8005205" /><ref name="IversenMelezinek2001">{{cite journal | vauthors = Iversen P, Melezinek I, Schmidt A | title = Nonsteroidal antiandrogens: a therapeutic option for patients with advanced prostate cancer who wish to retain sexual interest and function | journal = BJU International | volume = 87 | issue = 1 | pages = 47–56 | date = January 2001 | pmid = 11121992 | doi = 10.1046/j.1464-410x.2001.00988.x | s2cid = 28215804 | doi-access = free }}</ref><ref name="FritzSperoff2011" /><ref name="FiggChau2010" /> It blunts the [[gonadotropin releasing hormone]] (GnRH)-induced secretion of [[gonadotropin]]s, and accordingly, markedly suppresses circulating levels of [[luteinizing hormone]] (LH) and [[follicle-stimulating hormone]] (FSH) at sufficiently high doses.<ref name="pmid8005205" /><ref name="pmid769466">{{cite journal | vauthors = Donald RA, Espiner EA, Cowles RJ, Fazackerley JE | title = The effect of cyproterone acetate on the plasma gonadotrophin response to gonadotrophin releasing hormone | journal = Acta Endocrinologica | volume = 81 | issue = 4 | pages = 680–4 | date = April 1976 | pmid = 769466 | doi =  10.1530/acta.0.0810680}}</ref> Consequently, levels of [[progesterone]], [[androstenedione]], testosterone, DHT, and [[estradiol]] are also markedly lowered at sufficiently high dosages, while an elevation in [[sex hormone-binding globulin]] (SHBG) and [[prolactin]] levels is observed.<ref name="pmid6771095">{{cite journal | vauthors = Moltz L, Römmler A, Post K, Schwartz U, Hammerstein J | title = Medium dose cyproterone acetate (CPA): effects on hormone secretion and on spermatogenesis in men | journal = Contraception | volume = 21 | issue = 4 | pages = 393–413 | date = April 1980 | pmid = 6771095 | doi = 10.1016/s0010-7824(80)80017-5 }}</ref><ref name="pmid6458025">{{cite journal | vauthors = Rost A, Schmidt-Gollwitzer M, Hantelmann W, Brosig W | title = Cyproterone acetate, testosterone, LH, FSH, and prolactin levels in plasma after intramuscular application of cyproterone acetate in patients with prostatic cancer | journal = The Prostate | volume = 2 | issue = 3 | pages = 315–22 | year = 1981 | pmid = 6458025 | doi = 10.1002/pros.2990020310 | s2cid = 22364184 }}</ref><ref name="pmid6777092">{{cite journal | vauthors = Jeffcoate WJ, Matthews RW, Edwards CR, Field LH, Besser GM | title = The effect of cyproterone acetate on serum testosterone, LH, FSH, and prolactin in male sexual offenders | journal = Clinical Endocrinology | volume = 13 | issue = 2 | pages = 189–95 | date = August 1980 | pmid = 6777092 | doi = 10.1111/j.1365-2265.1980.tb01041.x | s2cid = 10145079 }}</ref><ref name="pmid8719011">{{cite journal | vauthors = Grunwald K, Rabe T, Schlereth G, Runnebaum B | title = [Serum hormones before and during therapy with cyproterone acetate and spironolactone in patients with androgenization] | language = de | journal = Geburtshilfe und Frauenheilkunde | volume = 54 | issue = 11 | pages = 634–45 | date = November 1994 | pmid = 8719011 | doi = 10.1055/s-2007-1022355 }}</ref><ref name="pmid6237068">{{cite journal | vauthors = Salva P, Morer F, Ordoñez J, Rodriguez J | title = Treatment of idiopathic hirsute women with two combinations of cyproterone acetate | journal = International Journal of Clinical Pharmacology Research | volume = 3 | issue = 2 | pages = 129–35 | year = 1983 | pmid = 6237068 }}</ref>

The effective dosage of CPA for inhibition of [[ovulation]] in women, this being an antigonadotropic effect, is 1&nbsp;mg/day.<ref name="pmid16112947" /> CPA alone has been found to suppress ovulation in 3 of 5 women at a dose of 0.5&nbsp;mg/day and in 5 of 5 women at a dose of 1&nbsp;mg/day in studies.<ref name="pmid22078182">{{cite journal | vauthors = Endrikat J, Gerlinger C, Richard S, Rosenbaum P, Düsterberg B | title = Ovulation inhibition doses of progestins: a systematic review of the available literature and of marketed preparations worldwide | journal = Contraception | volume = 84 | issue = 6 | pages = 549–57 | date = December 2011 | pmid = 22078182 | doi = 10.1016/j.contraception.2011.04.009 | url = }}</ref><ref name="pmid393050">{{cite journal | vauthors = Spona J, Schneider WH, Bieglmayer C, Schroeder R, Pirker R | title = Ovulation inhibition with different doses of levonorgestrel and other progestogens: clinical and experimental investigations | journal = Acta Obstet Gynecol Scand | volume = 88 | issue = Suppl | pages = 7–15 | date = 1979 | pmid = 393050 | doi = 10.3109/00016347909157223 | s2cid = 30486799 }}</ref><ref name="pmid3093307">{{cite journal | vauthors = Spona J, Huber J, Schmidt JB | title = 	Inhibierung der Ovulation mit 35 μg Athinylöstradiol und 2 mg Cyproteronazetat (Diane-35) | trans-title = Inhibition of ovulation with 35 micrograms of ethinyl estradiol and 2 mg of cyproterone acetate (Diane 35) | language = German | journal = Geburtshilfe Frauenheilkd | volume = 46 | issue = 7 | pages = 435–8 | date = July 1986 | pmid = 3093307 | doi = 10.1055/s-2008-1026659 | url = }}</ref><ref name="pmid2954886">{{cite journal | vauthors = Spona J, Huber J | title = Efficacy of low-dose oral contraceptives containing levonorgestrel, gestoden and cyproterone acetate | journal = Gynecol Obstet Invest | volume = 23 | issue = 3 | pages = 184–93 | date = 1987 | pmid = 2954886 | doi = 10.1159/000298860 | url = }}</ref><ref name="SponaHuber1987">{{cite book | vauthors = Spona J, Huber J, Schmidt JB | veditors = Schindler AE | title=Antiandrogen-Estrogen Therapy for Signs of Androgenization | chapter=Ovulation inhibitory effect of SH B 209 AE (Diane-35)—a new antiandrogen-estrogen combination | publisher=De Gruyter | publication-place=Berlin, Boston | date=1987-12-31 | doi=10.1515/9783110866902-006 | pages=51–58| isbn=9783110866902 }}</ref><ref name="Hammerstein1990" /> Ovulation inhibition with 1–2&nbsp;mg/day CPA in combination with 1–2&nbsp;mg/day [[estradiol valerate]] as a [[birth control pill]] (brand name Femilar) occurred in 94.4% of 108 women during the third treatment cycle in one study and in almost 100% of 26 women over 12 treatment cycles in another study (except for one woman who ovulated during her first treatment cycle).<ref name="pmid22468839">{{cite journal | vauthors = Fruzzetti F, Trémollieres F, Bitzer J | title = An overview of the development of combined oral contraceptives containing estradiol: focus on estradiol valerate/dienogest | journal = Gynecol Endocrinol | volume = 28 | issue = 5 | pages = 400–8 | date = May 2012 | pmid = 22468839 | pmc = 3399636 | doi = 10.3109/09513590.2012.662547 | url = }}</ref><ref name="pmid7731379">{{cite journal | vauthors = Hirvonen E, Allonen H, Anttila M, Kulmala Y, Ranta T, Rautiainen H, Sipilä P, Ylöstalo P | title = Oral contraceptive containing natural estradiol for premenopausal women | journal = Maturitas | volume = 21 | issue = 1 | pages = 27–32 | date = January 1995 | pmid = 7731379 | doi = 10.1016/0378-5122(94)00856-3 | url = }}</ref><ref name="pmid2972897">{{cite journal | vauthors = Hirvonen E, Stenman UH, Mälkönen M, Rasi V, Vartiainen E, Ylöstalo P | title = New natural oestradiol/cyproterone acetate oral contraceptive for pre-menopausal women | journal = Maturitas | volume = 10 | issue = 3 | pages = 201–13 | date = October 1988 | pmid = 2972897 | doi = 10.1016/0378-5122(88)90023-0 | url = }}</ref>

Oral CPA has been studied at low dosages of 5 to 20&nbsp;mg/day as a potential [[male hormonal contraceptive]].<ref name="PayneHardy2007">{{cite book| vauthors = Payne AH, Hardy MP |title=The Leydig Cell in Health and Disease|url=https://books.google.com/books?id=x4ttqKIAOg0C&pg=PA426|date=28 October 2007|publisher=Springer Science & Business Media|isbn=978-1-59745-453-7|pages=426–}}</ref><ref name="NieschlagHabenicht2013">{{cite book| vauthors = Nieschlag E, Habenicht UF |title=Spermatogenesis — Fertilization — Contraception: Molecular, Cellular and Endocrine Events in Male Reproduction|url=https://books.google.com/books?id=PAXtCAAAQBAJ&pg=PA485|date=17 April 2013|publisher=Springer Science & Business Media|isbn=978-3-662-02815-5|pages=485–}}</ref> A dosage of as low as 5 to 10&nbsp;mg/day oral CPA has been found to suppress circulating testosterone levels in men by 50 to 70%.<ref name="pmid3075164">{{cite journal | vauthors = Wu FC | title = Male contraception: current status and future prospects | journal = Clinical Endocrinology | volume = 29 | issue = 4 | pages = 443–465 | date = October 1988 | pmid = 3075164 | doi = 10.1111/j.1365-2265.1988.tb02894.x | quote = Cyproterone acetate (CPA) is an antiandrogen with progestational effects. It was originally intended as an antifertility agent through its antiandrogen action on the epididymis (Prasad et al., 1970). However, it subsequently became clear that CPA acted as a gestagen to suppress gonadotrophins and testosterone even at the low doses of 5 to 10 mg daily (Wang & Yeung, 1980). | s2cid = 36608203 }}</ref><ref name="pmid6771095" /><ref name="pmid949890" /><ref name="pmid6771091">{{cite journal | vauthors = Wang C, Yeung KK | title = Use of low-dosage oral cyproterone acetate as a male contraceptive | journal = Contraception | volume = 21 | issue = 3 | pages = 245–272 | date = March 1980 | pmid = 6771091 | doi = 10.1016/0010-7824(80)90005-0 }}</ref> For comparison with lower dosages, the suppression of circulating testosterone levels in men with a dosage of 100&nbsp;mg/day oral CPA was 77% and with a dosage of 300&nbsp;mg/week intramuscular CPA was 76%.<ref name="pmid7000222" /><ref name="pmid6237116">{{cite journal | vauthors = Knuth UA, Hano R, Nieschlag E | title = Effect of flutamide or cyproterone acetate on pituitary and testicular hormones in normal men | journal = The Journal of Clinical Endocrinology and Metabolism | volume = 59 | issue = 5 | pages = 963–969 | date = November 1984 | pmid = 6237116 | doi = 10.1210/jcem-59-5-963 }}</ref> Dosages of CPA of 12.5 to 25&nbsp;mg/day have been used as a maintenance dosage for testosterone suppression in men with sexual deviance after initial administration of higher CPA dosages, without recurrence of symptoms.<ref name="GijsGooren1996">{{cite journal| vauthors = Gijs L, Gooren L |title=Hormonal and psychopharmacological interventions in the treatment of paraphilias: An update|journal=Journal of Sex Research|volume=33|issue=4|year=1996|pages=273–290|issn=0022-4499|doi=10.1080/00224499609551845|quote=Some researchers have recommended never stopping medication, but continuing the use of 12.5 to 25 mg CPA a day as a maintenance dose (Bradford & Pawlak, 1993a).}}</ref><ref name="BradfordPawlak1993">{{cite journal | vauthors = Bradford JM, Pawlak A | title = Double-blind placebo crossover study of cyproterone acetate in the treatment of the paraphilias | journal = Archives of Sexual Behavior | volume = 22 | issue = 5 | pages = 383–402 | date = October 1993 | pmid = 8239971 | doi = 10.1007/BF01542555 | quote = A number of individuals (not included in this study), who have been on CPA for longer periods and then remained on very low dosages of CPA (12.5 to 25 mg per day), have reported no recurrence of the deviant sexual fantasies and no paraphiliac behavior ever reoccurred. Some of these individuals have remained in treatment for a number of years without any further paraphilic behavior. | s2cid = 9472016 }}</ref> CPA is generally able to maximally suppress circulating testosterone levels by 70 to 80% in men.<ref name="GräfBrotherton1974" /><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–}}</ref><ref name="SchröderRadlmaier2009"/><!--relies on transcluded template ref {{cite book | vauthors = Schröder FH, Radlmaier A | chapter = Steroidal Antiandrogens | pages = [https://archive.org/details/hormonetherapybr00crai/page/n328 325]–346 | doi = 10.1007/978-1-59259-152-7_15 | title = Hormone Therapy in Breast and Prostate Cancer | url = https://archive.org/details/hormonetherapybr00crai | url-access = limited | veditors = Jordan VC, Furr BJ | year = 2009 | publisher = Humana Press | isbn = 978-1-60761-471-5}}</ref>--> However, in spite of strong suppression of testosterone levels, CPA, at least by itself (e.g., without estrogen), is not usually able to reduce testosterone levels into the [[castration|castrate]]/female range (<50&nbsp;ng/dL) at any dosage, and testosterone levels generally remain just above it at levels of roughly 50 to 200&nbsp;ng/dL.<ref name="GräfBrotherton1974" /><ref name="WenderothJacobi1983">{{cite journal| vauthors = Wenderoth UK, Jacobi GH |title=Gonadotropin-releasing hormone analogues for palliation of carcinoma of the prostate|journal=World Journal of Urology|volume=1|issue=1|year=1983|pages=40–48|issn=0724-4983|doi=10.1007/BF00326861|s2cid=23447326}}</ref><ref name="SchröderRadlmaier2009" /><ref name="pmid7000222" /><ref name="FourcadeMcLeod2015" /> However, studies have reported that a very high dosage of CPA of 300&nbsp;mg/day may suppress testosterone levels to around 50&nbsp;ng/dL in men.<ref name="JacobiNeumann1988" /><ref name="D'AgataGulizia1979">{{cite journal | vauthors = D'Agata R, Gulizia S, Vicari E, Aliffi A, Polosa P | title = Effect of cyproterone acetate acutely administered on the pituitary-testicular axis | journal = Hormone Research | volume = 11 | issue = 3 | pages = 109–114 | year = 1979 | pmid = 488903 | doi = 10.1159/000179046 | doi-broken-date = 10 November 2024 }}</ref> CPA also suppresses estradiol levels in men, with one study finding about a 65% decrease in estradiol levels (from about 27&nbsp;pg/mL to around 10&nbsp;pg/mL) with 100&nbsp;mg/day CPA.<ref name="JacobiNeumann1988" />

CPA has been found to maximally suppress testosterone and estradiol levels in young men within 7&nbsp;days of continuous administration.<ref name="pmid7919640" /> Following discontinuation of CPA, the recovery of testosterone levels is variable and may require 14&nbsp;days to 6&nbsp;months for completion.<ref name="pmid2941191" /> An escape or recovery phenomenon, in which testosterone levels increase over time, has been observed with long-term CPA monotherapy.<ref name="Saborowski1988">{{cite thesis | vauthors = Saborowski KJ | title = Konservative Therapie mit Cyproteronacetat und Estradiolundecylat beim Fortgeschrittenen Prostatacarcinom: Eine 5-Jahres-Studie | trans-title = Conservative Therapy with Cyproterone Acetate and Estradiol Undecylate in Advanced Prostate Cancer: A 5-Year Study | language = de | year = 1988 | publisher = Bochum, Univ. | degree= Ph.D. | oclc = 917571781 | url = https://books.google.com/books?id=9JeKGwAACAAJ}}</ref><ref name="TunnGraff1982" /> In one study in aged men with prostate cancer, testosterone levels were initially suppressed by 70%, but increased to 50% of baseline levels between 6 and 12&nbsp;months, remaining stable thereafter up to 24&nbsp;months of therapy.<ref name="Saborowski1988" /><ref name="TunnGraff1982" />

The combination of progestogens like CPA with an estrogen is synergistic in terms of antigonadotropic effect, and is able to fully suppress gonadal testosterone production even with very small doses of the estrogen.<ref name="SchröderRadlmaier2009" /><ref name="pmid3552544">{{cite journal | vauthors = Melamed AJ | title = Current concepts in the treatment of prostate cancer | journal = Drug Intell Clin Pharm | volume = 21 | issue = 3 | pages = 247–54 | date = March 1987 | pmid = 3552544 | doi = 10.1177/106002808702100302 | s2cid = 7482144 | quote = [Megestrol acetate] produces a transient reduction in plasma testosterone to levels somewhat higher than those in castrated men. When used in a dose of 40 mg tid, in combination with estradiol 0.5–1.5 mg/d, it acts synergistically to suppress pituitary gonadotropins and maintain plasma testosterone at castration levels for periods up to one year.}}</ref><ref name="pmid27916515">{{cite journal | vauthors = Tangpricha V, den Heijer M | title = Oestrogen and anti-androgen therapy for transgender women | journal = Lancet Diabetes Endocrinol | volume = 5 | issue = 4 | pages = 291–300 | date = April 2017 | pmid = 27916515 | pmc = 5366074 | doi = 10.1016/S2213-8587(16)30319-9 }}</ref><ref name="FungHellstern-Layefsky2017" /><ref name="CheungOoi2018">{{cite journal | vauthors = Cheung AS, Ooi O, Davidoff D, Leemaqz SY, Cundill P, Silberstein N, Bretherton I, Grossmann M, Zajac JD | title = Cyproterone vs spironolactone as anti-androgen therapy for transgender females receiving oestradiol therapy | journal = Clinical Endocrinology | year = 2018 | volume = 89 | pages = 4–94 | issn = 0300-0664 | doi = 10.1111/cen.13727 | pmid = 29952008 | s2cid = 243882715 }}</ref> One study found that 100 to 300&nbsp;mg/day CPA combined with an "extremely low" dosage of [[diethylstilbestrol]] (0.1&nbsp;mg/day), a [[nonsteroidal estrogen]], suppressed testosterone levels into the castrate range (to 30&nbsp;ng/dL) in men with prostate cancer.<ref name="SchröderRadlmaier2009" /><ref name="pmid2973529">{{cite journal | vauthors = Goldenberg SL, Bruchovsky N, Rennie PS, Coppin CM | title = The combination of cyproterone acetate and low dose diethylstilbestrol in the treatment of advanced prostatic carcinoma | journal = J. Urol. | volume = 140 | issue = 6 | pages = 1460–5 | date = December 1988 | pmid = 2973529 | doi = 10.1016/S0022-5347(17)42073-8 }}</ref><ref name="pmid8677581">{{cite journal | vauthors = Goldenberg SL, Bruchovsky N, Gleave ME, Sullivan LD | title = Low-dose cyproterone acetate plus mini-dose diethylstilbestrol--a protocol for reversible medical castration | journal = Urology | volume = 47 | issue = 6 | pages = 882–4 | date = June 1996 | pmid = 8677581 | doi = 10.1016/S0090-4295(96)00048-9 }}</ref> Discontinuation of diethylstilbestrol at 5&nbsp;months resulted in a rapid 6-fold increase in testosterone levels (to 135&nbsp;ng/dL) and then further (to almost 200&nbsp;ng/dL) by 12&nbsp;months.<ref name="pmid2973529" /> Another study likewise found that the combination of 160&nbsp;mg/day oral [[megestrol acetate]], a progestin closely related to CPA, with 0.5 to 1.5&nbsp;mg/day oral [[estradiol (medication)|estradiol]] suppressed testosterone levels into the castrate range in men with prostate cancer.<ref name="pmid3552544" /> A study by Fung and colleagues (2017) found no difference in suppression of circulating testosterone levels (~95% suppression) in transgender women by the combination of either 25&nbsp;mg/day oral CPA or 50&nbsp;mg/day oral CPA with a moderate dosage of oral or [[transdermal]] estradiol (mean 3.3&nbsp;mg/day oral, 3.4&nbsp;g/day [[transdermal gel|gel]], or 95.6&nbsp;μg/day [[transdermal patch|patch]]es).<ref name="FungHellstern-Layefsky2017">{{cite journal| vauthors = Fung R, Hellstern-Layefsky M, Lega I |title=Is a lower dose of cyproterone acetate as effective at testosterone suppression in transgender women as higher doses?|journal=International Journal of Transgenderism|volume=18|issue=2|year=2017|pages=123–128|issn=1553-2739|doi=10.1080/15532739.2017.1290566|s2cid=79095497}}</ref>

A high dosage of CPA given starting 7&nbsp;days prior to initiation of GnRH agonist therapy was found to prevent the GnRH agonist-induced flare in testosterone levels.<ref name="pmid7919640" /> The combination of 100&nbsp;mg/day CPA and 0.1&nbsp;mg/day diethylstilbestrol given starting 4&nbsp;weeks before GnRH-agonist introduction has also been found to prevent the GnRH agonist-induced testosterone flare.<ref name="pmid7688656">{{cite journal | vauthors = Bruchovsky N, Goldenberg SL, Akakura K, Rennie PS | title = Luteinizing hormone-releasing hormone agonists in prostate cancer. Elimination of flare reaction by pretreatment with cyproterone acetate and low-dose diethylstilbestrol | journal = Cancer | volume = 72 | issue = 5 | pages = 1685–91 | date = September 1993 | pmid = 7688656 | doi = 10.1002/1097-0142(19930901)72:5<1685::AID-CNCR2820720532>3.0.CO;2-3 | s2cid = 21824595 | doi-access = free }}</ref> CPA should be given continuously for at least a week prior to GnRH agonist initiation for an optimal preventative effect on the GnRH agonist-induced testosterone flare.<ref name="pmid7919640" />

{{Testosterone levels with cyproterone acetate}}

===Glucocorticoid activity===
CPA is an agonist of the [[glucocorticoid receptor]] (GR), and has weak and [[partial agonist|partial]] [[glucocorticoid]] activity at high doses.<ref name="pmid16112947" /><ref name="pmid2941191" /><ref name="Neumann1996" /> In animals, CPA suppresses the [[secretion]] of [[adrenocorticotropic hormone]] (ACTH) from the [[pituitary gland]], suppresses the production of [[corticosteroid]]s like [[cortisol]] and [[corticosterone]] by the [[adrenal cortex|adrenal cortices]], and decreases the weights of the [[adrenal gland]]s and [[thymus]].<ref name="NeumannJacobi1982" /><ref name="Neumann1996" /> Conversely however, CPA shows no [[anti-inflammatory]] or [[eosinophilic]] effects in animals.<ref name="NeumannJacobi1982" /><ref name="Neumann1996" /> As such, CPA, as well as related antiandrogens, show only some of the typical effects of glucocorticoids.<ref name="NeumannJacobi1982" /><ref name="Neumann1996" /> CPA may produce mild glucucorticoid actions at high doses of more than 100&nbsp;mg/day in humans.<ref name="pmid1801674">{{cite journal | vauthors = Eden JA | title = Progestogens: an occasional review | journal = Asia-Oceania Journal of Obstetrics and Gynaecology | volume = 17 | issue = 4 | pages = 289–95 | date = December 1991 | pmid = 1801674 | doi = 10.1111/j.1447-0756.1991.tb00276.x | quote = CPA is a progestogen which is anti-oestrogenic but also antiandrogenic and in high doses (higher than 100 mg) has mild glucocorticoid actions.}}</ref> Clinically, the glucocorticoid effects of CPA appear to be relevant only at high doses in people with small body sizes (CPA exposure of more than 80 to 100&nbsp;mg/m<sup>2</sup>), namely in the treatment of children with precocious puberty.<ref name="NeumannJacobi1982" /><ref name="Neumann1996" /> No signs of secondary [[adrenal insufficiency]] have been observed with CPA.<ref name="NeumannJacobi1982" /><ref name="Neumann1996" /> While various studies have clearly shown reduced cortisol and ACTH levels and ACTH responsiveness in humans with CPA therapy, some studies contradict these findings and report no such effects even with high doses of CPA.<ref name="pmid6266428" /><ref name="pmid6257015">{{cite journal | vauthors = van Wayjen RG, van den Ende A | title = Effect of cyproterone acetate on pituitary-adrenocortical function in man | journal = Acta Endocrinol. | volume = 96 | issue = 1 | pages = 112–22 | year = 1981 | pmid = 6257015 |doi= 10.1530/acta.0.0960112}}</ref><ref name="pmid2421511">{{cite journal | vauthors = Schürmeyer T, Graff J, Senge T, Nieschlag E | title = Effect of oestrogen or cyproterone acetate treatment on adrenocortical function in prostate carcinoma patients | journal = Acta Endocrinol. | volume = 111 | issue = 3 | pages = 360–7 | year = 1986 | pmid = 2421511 | doi = 10.1530/acta.0.1110360}}</ref><ref name="pmid7584530">{{cite journal | vauthors = van Wayjen RG, van den Ende A | title = Experience in the long-term treatment of patients with hirsutism and/or acne with cyproterone acetate-containing preparations: efficacy, metabolic and endocrine effects | journal = Exp. Clin. Endocrinol. Diabetes | volume = 103 | issue = 4 | pages = 241–51 | year = 1995 | pmid = 7584530 | doi = 10.1055/s-0029-1211357 }}</ref><ref name="pmid6227191">{{cite journal | vauthors = Holdaway IM, Croxson MS, Evans MC, France J, Sheehan A, Wilson T, Ibbertson HK | title = Effect of cyproterone acetate on glucocorticoid secretion in patients treated for hirsutism | journal = Acta Endocrinol. | volume = 104 | issue = 2 | pages = 222–6 | year = 1983 | pmid = 6227191 |doi= 10.1530/acta.0.1040222}}</ref><ref name="El EtrebyHabenicht1987" />

Due to [[negative feedback]] on the [[hypothalamic–pituitary–adrenal axis|hypothalamic–pituitary-adrenal]] (HPA) [[hypothalamic-pituitary-adrenal axis|axis]], administration of [[exogenous]] [[glucocorticoid]]s such as [[prednisone]] and [[dexamethasone]] suppress the secretion of [[adrenocorticotropic hormone]] (ACTH) from the [[pituitary gland]] and the production of [[cortisol]] from the [[adrenal gland]]s. This results in adrenal suppression and [[atrophy]] and, upon glucocorticoid discontinuation, temporary [[adrenal insufficiency]]. Similarly, CPA both in animals and humans can weakly reduce ACTH and cortisol levels and decrease adrenal gland weight as well as cause adrenal insufficiency with discontinuation. These findings suggest that CPA possesses weak glucocorticoid properties.<ref name="Azziz2007">{{cite book| vauthors = Azziz R |title=Androgen Excess Disorders in Women|url=https://books.google.com/books?id=Ch-BsGAOtucC&pg=PA382|date=8 November 2007|publisher=Springer Science & Business Media|isbn=978-1-59745-179-6|pages=382–}}</ref><ref name="pmid233676">{{cite journal | vauthors = Girard J, Baumann JB, Bühler U, Zuppinger K, Haas HG, Staub JJ, Wyss HI | title = Cyproteroneacetate and ACTH adrenal function | journal = J. Clin. Endocrinol. Metab. | volume = 47 | issue = 3 | pages = 581–6 | year = 1978 | pmid = 233676 | doi = 10.1210/jcem-47-3-581 }}</ref><ref name="pmid438696">{{cite journal | vauthors = Panesar NS, Herries DG, Stitch SR | title = Effects of cyproterone and cyproterone acetate on the adrenal gland in the rat: studies in vivo and in vitro | journal = J. Endocrinol. | volume = 80 | issue = 2 | pages = 229–38 | year = 1979 | pmid = 438696 | doi = 10.1677/joe.0.0800229}}</ref><ref name="pmid487397">{{cite journal | vauthors = El Etreby MF | title = Effect of cyproterone acetate, levonorgestrel and progesterone on adrenal glands and reproductive organs in the beagle bitch | journal = Cell Tissue Res. | volume = 200 | issue = 2 | pages = 229–43 | year = 1979 | pmid = 487397 | doi = 10.1007/bf00236416| s2cid = 20443285 }}</ref><ref name="pmid6260040">{{cite journal | vauthors = Savage DC, Swift PG | title = Effect of cyproterone acetate on adrenocortical function in children with precocious puberty | journal = Arch. Dis. Child. | volume = 56 | issue = 3 | pages = 218–22 | year = 1981 | pmid = 6260040 | pmc = 1627152 | doi = 10.1136/adc.56.3.218}}</ref><ref name="pmid6279337">{{cite journal | vauthors = Stivel MS, Kauli R, Kaufman H, Laron Z | title = Adrenocortical function in children with precocious sexual development during treatment with cyproterone acetate | journal = Clin. Endocrinol. | volume = 16 | issue = 2 | pages = 163–9 | year = 1982 |pmid= 6279337 |doi= 10.1111/j.1365-2265.1982.tb03160.x| s2cid = 21454179 }}</ref><ref name="pmid6216913">{{cite journal | vauthors = Hague WM, Munro DS, Sawers RS, Duncan SL, Honour JW | title = Long-term effects of cyproterone acetate on the pituitary adrenal axis in adult women | journal = Br J Obstet Gynaecol | volume = 89 | issue = 12 | pages = 981–4 | year = 1982 | pmid = 6216913 |doi= 10.1111/j.1471-0528.1982.tb04650.x| s2cid = 40574520 }}</ref> CPA has been reported to be an [[receptor antagonist|antagonist]] of the [[glucocorticoid receptor]] (GR) ''[[in vitro]]''<ref name="pmid12695529"/><ref name="pmid2875214">{{cite journal | vauthors = Mercier L, Miller PA, Simons SS | title = Antiglucocorticoid steroids have increased agonist activity in those hepatoma cell lines that are more sensitive to glucocorticoids | journal = J. Steroid Biochem. | volume = 25 | issue = 1 | pages = 11–20 | year = 1986 | pmid = 2875214 |doi= 10.1016/0022-4731(86)90275-x}}</ref><ref name="pmid1645605">{{cite journal | vauthors = Poulin R, Baker D, Poirier D, Labrie F | title = Multiple actions of synthetic 'progestins' on the growth of ZR-75-1 human breast cancer cells: an in vitro model for the simultaneous assay of androgen, progestin, estrogen, and glucocorticoid agonistic and antagonistic activities of steroids | journal = Breast Cancer Research and Treatment | volume = 17 | issue = 3 | pages = 197–210 | year = 1991 | pmid = 1645605 | doi = 10.1007/BF01806369 | s2cid = 26083052 }}</ref> and may reduce adrenal cortisol and [[corticosterone]] production by weakly [[enzyme inhibitor|inhibiting]] the [[enzyme]]s [[3β-hydroxysteroid dehydrogenase]] and [[21-hydroxylase]].<ref name="pmid438696" /><ref name="pmid6237971">{{cite journal | vauthors = Pham-Huu-Trung MT, de Smitter N, Bogyo A, Girard F | title = Effects of cyproterone acetate on adrenal steroidogenesis in vitro | journal = Horm. Res. | volume = 20 | issue = 2 | pages = 108–15 | year = 1984 | pmid = 6237971 | doi = 10.1159/000179982| doi-broken-date = 10 November 2024 }}</ref><ref name="pmid2988566">{{cite journal | vauthors = Lambert A, Mitchell RM, Robertson WR | title = On the site of action of the anti-adrenal steroidogenic effect of cyproterone acetate | journal = Biochem. Pharmacol. | volume = 34 | issue = 12 | pages = 2091–5 | year = 1985 | pmid = 2988566 | doi = 10.1016/0006-2952(85)90400-9}}</ref><ref name="pmid208851">{{cite journal | vauthors = Heinze F, Teller WM, Fehm HL, Joos A | title = The effect of cyproterone acetate on adrenal cortical function in children with precocious puberty | journal = Eur. J. Pediatr. | volume = 128 | issue = 2 | pages = 81–8 | year = 1978 | pmid = 208851 | doi = 10.1007/bf00496993| s2cid = 25215020 }}</ref> These are [[antiglucocorticoid]] actions. However, [[metabolite]]s of CPA, for instance [[15β-hydroxycyproterone acetate]], may have differing activities.<ref name="pmid3160716">{{cite journal | vauthors = Frith RG, Phillipou G | title = 15-Hydroxycyproterone acetate and cyproterone acetate levels in plasma and urine | journal = J. Chromatogr. | volume = 338 | issue = 1 | pages = 179–86 | year = 1985 | pmid = 3160716 | doi = 10.1016/0378-4347(85)80082-7}}</ref><ref name="pmid413211">{{cite journal | vauthors = Bhargava AS, Seeger A, Günzel P | title = Isolation and identification of 15-beta-hydroxy cyproterone acetate as a new metabolite of cyproterone acetate in dog, monkey and man | journal = Steroids | volume = 30 | issue = 3 | pages = 407–18 | year = 1977 | pmid = 413211 | doi = 10.1016/0039-128x(77)90031-9| s2cid = 54373018 }}</ref><ref name="pmid6266428">{{cite journal | vauthors = Bhargava AS, Kapp JF, Poggel HA, Heinick J, Nieuweboer B, Günzel P | title = Effect of cyproterone acetate and its metabolites on the adrenal function in man, rhesus monkey and rat | journal = Arzneimittelforschung | volume = 31 | issue = 6 | pages = 1005–9 | year = 1981 | pmid = 6266428 }}</ref> Both [[cyproterone]] and CPA have been found to possess glucocorticoid effects, and based on studies in mice, it has been suggested that CPA has approximately one-fifth of the potency of [[prednisone]] as a glucocorticoid.<ref name="pmid1204803">{{cite journal | vauthors = Broulik PD, Starka L | title = Corticosteroid-like effect of cyproterone and cyproterone acetate in mice | journal = Experientia | volume = 31 | issue = 11 | pages = 1364–5 | year = 1975 | pmid = 1204803 | doi = 10.1007/bf01945829| s2cid = 11452300 }}</ref> The glucocorticoid effects of CPA in humans appear to be less significant than those in animals.<ref name="pmid6266428" />

[[Megestrol acetate]], [[medroxyprogesterone acetate]], and [[chlormadinone acetate]] are all steroidal progestins of the [[17α-hydroxyprogesterone]] family and close [[structural analog|analogue]]s of CPA which similarly possess glucocorticoid properties and the potential for producing adrenal insufficiency upon discontinuation.<ref name="Thomas1997">{{cite book | vauthors = Thomas JA |title=Endocrine Toxicology, Second Edition |url=https://books.google.com/books?id=URc5JMoNirgC&pg=PA152 |date=12 March 1997 |publisher=CRC Press |isbn=978-1-4398-1048-4 |pages=152–}}</ref><ref name="Panay2015">{{cite book | vauthors = Panay N |title=Managing the Menopause |url=https://books.google.com/books?id=l0pLCgAAQBAJ&pg=PA126 |date=31 August 2015 |publisher=Cambridge University Press |isbn=978-1-107-45182-7 |pages=126–}}</ref>

===Other activities===

====Estrogenic and antiestrogenic activities====
CPA does not bind to the [[estrogen receptor]]s.<ref name="pmid16112947" /> Accordingly, pre-treatment with CPA does not block the retention of [[estradiol (medication)|estradiol]] in the [[brain]] in mice.<ref name="pmid1260424">{{cite journal | vauthors = Luttge WG, Gray HE, Hughes JR | title = Regional and subcellular [3h]estradiol localization in selected brain regions and pituitary of female mice: effects of unlabeled estradiol and various anti-hormones | journal = Brain Res. | volume = 104 | issue = 2 | pages = 273–81 | date = March 1976 | pmid = 1260424 | doi = 10.1016/0006-8993(76)90619-3 | s2cid = 10297027 }}</ref> CPA has no [[estrogen (medication)|estrogen]]ic or direct [[antiestrogen]]ic activity.<ref name="pmid16112947" /> However, CPA has been reported to produce weak estrogenic effects in rodents.<ref name="pmid612093">{{cite journal | vauthors = Arya M, Lohiya NK | title = Estrogenic and antifertility effect of cyproterone acetate in female gerbils, meriones hurriane Jerdon | journal = Acta Biol. Med. Ger. | volume = 36 | issue = 7–8 | pages = 1133–41 | date = 1977 | pmid = 612093 }}</ref><ref name="pmid94736">{{cite journal | vauthors = Lohika NK, Arya M | title = Effect of cyproterone acetate on the genital organs of female rats | journal = Acta Eur. Fertil. | volume = 10 | issue = 2 | pages = 57–65 | date = June 1979 | pmid = 94736 }}</ref><ref name="pmid6172270">{{cite journal | vauthors = Lohiya NK, Arya M | title = Oestrogenic activity of cyproterone acetate in female mice | journal = Endokrinologie | volume = 78 | issue = 1 | pages = 21–7 | date = October 1981 | pmid = 6172270 }}</ref> In any case, CPA has prominent indirect antiestrogenic effects via its progestogenic activity.<ref name="pmid16112947" /> This includes PR-mediated antiestrogenic activity in certain tissues like the [[uterus]] and [[vagina]] as well as suppression of [[estrogen]] levels via its PR-mediated [[antigonadotropic]] activity.<ref name="pmid16112947" /> CPA also has indirect estrogenic activity in the breasts via its antiandrogenic activity, as [[androgen]]s have strong functional antiestrogenic effects in this part of the body.{{Citation needed|date=June 2020}} This underlies the slight gynecomastia that can occur with CPA in men.

====Opioid receptors====
CPA has been found to bind to several of the [[opioid receptor]]s, including the [[μ-opioid receptor|μ-]], [[δ-opioid receptor|δ-]], and [[κ-opioid receptor]] subtypes.<ref name="pmid9203575">{{cite journal | vauthors = Gutiérrez M, Menéndez L, Ruiz-Gayo M, Hidalgo A, Baamonde A | title = Cyproterone acetate displaces opiate binding in mouse brain | journal = European Journal of Pharmacology | volume = 328 | issue = 1 | pages = 99–102 | date = June 1997 | pmid = 9203575 | doi = 10.1016/s0014-2999(97)83034-8 }}</ref><ref name="pmid14670648">{{cite journal | vauthors = Gruber CJ, Huber JC | title = Differential effects of progestins on the brain | journal = Maturitas | volume = 46 | issue = Suppl 1 | pages = S71–5 | date = December 2003 | pmid = 14670648 | doi = 10.1016/j.maturitas.2003.09.021 }}</ref> However, this binding is very weak relative to its other actions (IC<sub>50</sub> for inhibition of <nowiki>[</nowiki><sup>3</sup>H<nowiki>]</nowiki>[[diprenorphine]] binding = 1.62 ± 0.33 μM).<ref name="pmid9203575" /><ref name="pmid14670648" /> It has been suggested that activation of opioid receptors might be involved in the [[sedation]] that is reportedly sometimes seen with high doses of CPA or in its reported effectiveness in the treatment of [[cluster headache]]s.<ref name="pmid9203575" />

====Aryl hydrocarbon receptor antagonist====
CPA has been identified as an antagonist of the [[aryl hydrocarbon receptor]] and this action may be involved in its liver toxicity.<ref name="pmid33750846">{{cite journal | vauthors = Chen CS, Gao GL, Ho DR, Lin CY, Chou YT, Chen SC, Huang MC, Kao WY, Su JJ | title = Cyproterone acetate acts as a disruptor of the aryl hydrocarbon receptor | journal = Sci Rep | volume = 11 | issue = 1 | pages = 5457 | date = March 2021 | pmid = 33750846 | doi = 10.1038/s41598-021-84769-7 | pmc = 7943802 | bibcode = 2021NatSR..11.5457C | url = }}</ref>

==Pharmacokinetics==

===Absorption===
The [[oral administration|oral]] [[bioavailability]] of CPA is 68 to 100%.<ref name="pmid16112947" /><ref name="pmid2977383" /> The [[absorption (pharmacokinetics)|absorption]] of oral CPA is slow but complete, and the medication is not subject to a significant [[first-pass metabolism|first-pass effect]].<ref name="pmid2941191" /><ref name="Mylan-CyproteroneLabel">{{cite web | title = Mylan-Cyproterone Label | url = https://pdf.hres.ca/dpd_pm/00011374.PDF}}</ref> The mean [[absorption half-life]] of oral CPA is about 1.5&nbsp;hours.<ref name="pmid2941191" /> [[Steady-state (pharmacokinetics)|Steady-state levels]] of CPA occur with oral CPA after about 8&nbsp;days of continuous administration, with a 2- to 3-fold gradual accumulation in CPA levels.<ref name="pmid2941191" /> Oral CPA is taken daily and intramuscular CPA is administered weekly or biweekly.<ref name="SalehGrudzinskas2009">{{cite book| vauthors = Saleh FM, Grudzinskas AJ, Bradford JM |title=Sex Offenders: Identification, Risk Assessment, Treatment, and Legal Issues|url=https://books.google.com/books?id=df0RDAAAQBAJ&pg=PA197|date=11 February 2009|publisher=Oxford University Press, USA|isbn=978-0-19-517704-6|pages=197–}}</ref>

Following a single low oral dose of 2&nbsp;mg CPA in combination with 35 or 50&nbsp;μg ethinylestradiol in premenopausal women, mean [[Cmax (pharmacology)|peak levels]] of CPA of 7.2 to 15.2&nbsp;ng/mL<!--7.2, 11.0, and 15.2 ng/mL--> (17–36.5&nbsp;nmol/L) have been recorded after 1.6 to 3.7&nbsp;hours.<ref name="Kuhl2011" /><ref name="pmid880829">{{cite journal | vauthors = Hümpel M, Wendt H, Schulze PE, Dogs G, Weiss C, Speck U | title = Bioavailability and pharmacokinetics of cyproterone acetate after oral administration of 2.0 mg cyproterone acetate in combination with 50 micrograms ethinyloestradiol to 6 young women | journal = Contraception | volume = 15 | issue = 5 | pages = 579–88 | date = May 1977 | pmid = 880829 | doi = 10.1016/0010-7824(77)90108-1 }}</ref><ref name="HümpelWendt1977">{{cite journal| vauthors = Hümpel M, Wendt H, Dogs G, Weiss C, Rietz S, Speck U |title=Intraindividual comparison of pharmacokinetic parameters of d-norgestrel, lynestrenol and cyproterone acetate in 6 women|journal=Contraception|volume=16|issue=2|year=1977|pages=199–215|issn=0010-7824|doi=10.1016/0010-7824(77)90087-7}}</ref><ref name="pmid294111">{{cite journal | vauthors = Düsterberg B, Hümpel M, Wendt H | title = Plasma levels of active ingredients after single and repeated administration of a new oral contraceptive containing 2 mg of cyproterone acetate and 50 micrograms of ethinyl estradiol (DIANE) to five young women | journal = Acta Obstet Gynecol Scand | issue = Suppl | volume = 88 | pages = 27–31 | date = 1979 | pmid = 294111 | doi = 10.3109/00016347909157226 | s2cid = 12805693 }}</ref><ref name="pmid8131397">{{cite journal | vauthors = Kuhnz W, Staks T, Jütting G | title = Pharmacokinetics of cyproterone acetate and ethinylestradiol in 15 women who received a combination oral contraceptive during three treatment cycles | journal = Contraception | volume = 48 | issue = 6 | pages = 557–75 | date = December 1993 | pmid = 8131397 | doi = 10.1016/0010-7824(93)90118-Q }}</ref> In healthy men, a single high oral dose of 100&nbsp;mg CPA produced maximal CPA levels of 254&nbsp;ng/mL (609&nbsp;nmol/L) after 2.6&nbsp;hours.<ref name="pmid9349934">{{cite journal | vauthors = Kuhnz W, Kulmann H, Fuhrmeister A | title = Investigation into the age-dependence of the pharmacokinetics of cyproterone acetate in healthy male volunteers | journal = Eur. J. Clin. Pharmacol. | volume = 53 | issue = 1 | pages = 75–80 | date = 1997 | pmid = 9349934 | doi = 10.1007/s002280050340 | s2cid = 25219124 }}</ref> In aged men with [[prostate cancer]], continuous oral CPA therapy resulted in CPA levels of 132 ± 18&nbsp;ng/mL at 25&nbsp;mg/day, 246 ± 13&nbsp;ng/mL at 50&nbsp;mg/day, and 348 ± 23&nbsp;ng/mL at 100&nbsp;mg/day.<ref name="TunnGraff1982">{{cite book | vauthors = Tunn UW, Graff J, Senge T | date = June 1982 | chapter = Treatment of inoperable prostatic cancer with cyproterone acetate | veditors = Schröder FH | title = Proceedings Androgens and Anti-androgens, International Symposium, Utrecht, June 5th, 1982 | pages = 149–159 | publisher = Schering Nederland BV | isbn = 978-9090004327 | oclc = 11786945}}</ref> Similarly, in healthy young women, a single high oral dose of 100&nbsp;mg CPA resulted in peak CPA levels of 255&nbsp;ng/mL (612&nbsp;nmol/L) within 2 to 3&nbsp;hours.<ref name="pmid2977383">{{cite journal | vauthors = Huber J, Zeillinger R, Schmidt J, Täuber U, Kuhnz W, Spona J | title = Pharmacokinetics of cyproterone acetate and its main metabolite 15 beta-hydroxy-cyproterone acetate in young healthy women | journal = Int J Clin Pharmacol Ther Toxicol | volume = 26 | issue = 11 | pages = 555–61 | date = November 1988 | pmid = 2977383 }}</ref><ref name="Ching2006" /> During continuous treatment with high oral doses of CPA in women with hirsutism, levels of CPA were 199 to 228&nbsp;ng/mL (477–547&nbsp;nmol/L) with 50&nbsp;mg/day CPA and were 436 to 520&nbsp;ng/mL (1050–1250&nbsp;nmol/L) with 100&nbsp;mg/day CPA.<ref name="pmid7421247">{{cite journal | vauthors = Frölich M, Vader HL, Walma ST, de Rooy HA | title = Cyproterone acetate in blood of hirsute women during long-term treatment. The absorption and elimination after oral application | journal = J. Steroid Biochem. | volume = 13 | issue = 9 | pages = 1097–100 | date = September 1980 | pmid = 7421247 | doi = 10.1016/0022-4731(80)90142-9 }}</ref>

After a single [[intramuscular injection]] of 300&nbsp;mg CPA in healthy young women, maximal levels of CPA of 191&nbsp;ng/mL (458&nbsp;nmol/L) and of 15β-OH-CPA of 164&nbsp;ng/mL occurred after 2 to 4&nbsp;days.<ref name="pmid2977383" /><ref name="Ching2006" /> During continuous weekly intramuscular injections of CPA in men with prostate cancer, mean levels of CPA roughly doubled from 170&nbsp;ng/mL (408&nbsp;nmol/L) after the first injection to 310&nbsp;ng/mL (744&nbsp;nmol/L) after the fifth injection, and were projected to increase to 350 to 400&nbsp;ng/mL (840–960&nbsp;nmol/L) after around 8 to 12&nbsp;injections.<ref name="pmid6458025" /> The [[area-under-the-curve (pharmacokinetics)|area-under-the-curve]] (AUC; total exposure) levels of CPA with 100&nbsp;mg/day oral CPA and 300&nbsp;mg/week intramuscular CPA may be approximately equivalent.<ref name="pmid6458025" />

{{Gallery
| title=[[Cyproterone acetate]] levels with oral and intramuscular cyproterone acetate
| width=300 | height=250
| align=center
| style="font-size:small;"

| File:Cyproterone acetate levels with a single oral dose of 100 mg cyproterone acetate in men.png | CPA levels after a single oral dose of 100&nbsp;mg CPA in men.<ref name="pmid9349934" /><ref name="NeumannHümpel1982" />

| File:Cyproterone acetate levels after a 100 mg oral dose of cyproterone acetate (Androcur or Ciproterone) in healthy men.png | CPA levels after a single oral dose of 100&nbsp;mg CPA (Androcur or Ciproterone) in men.<ref name="pmid16438790">{{cite journal | vauthors = Pereira AS, Mendes GD, Oliveira LS, Valle HF, De Nucci G | title = Atmospheric pressure photoionization applied to quantitation of cyproterone acetate in human plasma | journal = J Chromatogr Sci | volume = 43 | issue = 10 | pages = 513–7 | date = 2005 | pmid = 16438790 | doi = 10.1093/chromsci/43.10.513 | url = | doi-access = free }}</ref>

| File:Cyproterone acetate levels with 100 mg oral cyproterone acetate per day in women.png | Cyproterone acetate levels with 100&nbsp;mg oral cyproterone acetate per day in women.<ref name="pmid2967500">{{cite journal | vauthors = Neumann F, Wiechert R | title = Das Antiandrogen Cyproteronacetat Seine Geschichte von der Entdeckung bis zur Marktreife | trans-title = The antiandrogen cyproterone acetate. Its history from discovery to marketing | language = de | journal = Pharmazie in unserer Zeit | volume = 17 | issue = 2 | pages = 33–50 | date = March 1988 | issn = 0048-3664 | pmid = 2967500 | doi = 10.1002/pauz.19880170202 }}</ref><ref name="pmid6224974">{{cite journal | vauthors = Hammerstein J, Moltz L, Schwartz U | title = Antiandrogens in the treatment of acne and hirsutism | journal = J. Steroid Biochem. | volume = 19 | issue = 1B | pages = 591–7 | date = July 1983 | pmid = 6224974 | doi = 10.1016/0022-4731(83)90223-6 }}</ref><ref name="Hammerstein1990" /> Administration was stopped at day 10.<ref name="pmid2967500" /><ref name="pmid6224974" /><ref name="Hammerstein1990" />

| File:Cyproterone acetate and testosterone levels with 300 mg per week cyproterone acetate by intramuscular injection in men.png | CPA and testosterone levels with continuous 300&nbsp;mg/week CPA in oil solution by intramuscular injection in men.<ref name="pmid6458025"/> Five injections were administered total but CPA and testosterone levels were determined only for the 1st, 3rd, and 5th injections.<ref name="pmid6458025" />

| File:Cyproterone acetate levels with 300 mg cyproterone acetate per week by intramuscular injection in men.png | CPA levels with continuous 300&nbsp;mg/week CPA in oil solution by intramuscular injection in men.<ref name="NeumannHümpel1982">{{cite book | vauthors = Neumann F, Hümpel M, Senge T, Schenck B, Tunn U | chapter = Cyproterone Acetate—Biochemical and Biological Basis for Treatment of Prostatic Cancer | veditors = Jacobi GH, Hohenfellner R | title = Prostate Cancer | url = https://books.google.com/books?id=4HNrAAAAMAAJ | date = 1 December 1982 | publisher = Williams & Wilkins | isbn = 978-0-683-04354-9 | pages = 269–303}}</ref> The first injection was at week 1 and the injection for week 23 was skipped.<ref name="NeumannHümpel1982" /> The dashed line shows average levels.<ref name="NeumannHümpel1982" />

}}

===Distribution===
With oral CPA, there is a probable [[distribution (pharmacology)|distribution]] phase of CPA into [[tissue (biology)|tissue]]s which lasts about 12&nbsp;hours and has a [[distribution half-life|half-life]] of 3&nbsp;hours.<ref name="pmid2941191" /> CPA is very [[lipophilic]], and it is sequestered into fat, which provides a [[depot (medicine)|depot effect]].<ref name="pmid7919640" /><ref name="pmid2941191" /><ref name="Kuhl2011" /> The [[volume of distribution]] of CPA is 20.6 ± 3.5&nbsp;L/kg.<ref name="pmid2977383" /><ref name="Ching2006">{{cite thesis | type = Ph.D. | vauthors = Ching RC | title = Avaliação de bioquivalência de comprimidos contendo 100 mg de acetato de ciproterona | date = 2006 | publisher = Universidade de São Paulo | language = pt | url = http://www.teses.usp.br/teses/disponiveis/9/9139/tde-23112017-171517/publico/RUTE_CHUANG_K_CHING_MESTRADO.pdf| archive-url = https://web.archive.org/web/20190501170601/http://www.teses.usp.br/teses/disponiveis/9/9139/tde-23112017-171517/publico/RUTE_CHUANG_K_CHING_MESTRADO.pdf | archive-date = 1 May 2019 }}</ref> CPA crosses the [[blood–brain barrier]], which is evidenced by the suppression of gonadotropin secretion that is observed during therapy with it (the site of action of this effect being the [[pituitary gland]], a part of the [[brain]]).<ref name="pmid12044015">{{cite journal | vauthors = Denmeade SR, Isaacs JT | title = A history of prostate cancer treatment | journal = Nat. Rev. Cancer | volume = 2 | issue = 5 | pages = 389–96 | date = May 2002 | pmid = 12044015 | pmc = 4124639 | doi = 10.1038/nrc801 }}</ref> In terms of [[plasma protein binding]], CPA does not bind to SHBG or [[corticosteroid-binding globulin]]<ref name="FRCOG2015">{{cite book |veditors=Carp HJ |vauthors=Schindler AE |chapter=Pharmacology of Progestogens |title=Progestogens in Obstetrics and Gynecology |chapter-url=https://books.google.com/books?id=Ik8SCAAAQBAJ&pg=PA38 |date=2015 |publisher=Springer |isbn=978-3-319-14385-9 |pages=38–}}</ref> and is instead bound exclusively to [[albumin]] (93%), with the remainder (7%) circulating free or unbound.<ref name="pmid16112947" /><ref name="BińkowskaWoroń2015" /><ref name="SchindlerCampagnoli2003" /><ref name="WakelinMaibach2002" /><ref name="HammondLähteenmäki1982" /> The affinity of CPA for SHBG is very low at about 0.006% of that of testosterone or DHT.<ref name="pmid2941191" />

===Metabolism===
[[File:Metabolic pathways of cyproterone acetate in humans.png|thumb|right|200px|[[Metabolism]] of CPA.<ref name="pmid29617576">{{cite journal | vauthors = Barra F, Scala C, Ferrero S | title = Current understanding on pharmacokinetics, clinical efficacy and safety of progestins for treating pain associated to endometriosis | journal = Expert Opin Drug Metab Toxicol | volume = 14 | issue = 4 | pages = 399–415 | date = April 2018 | pmid = 29617576 | doi = 10.1080/17425255.2018.1461840 | hdl = 11567/912822 | s2cid = 4731449 | hdl-access = free }}</ref><ref name="Kuhl2011" /><ref name="RabeAlbring2015">{{cite journal | vauthors = Rabe T, Albring C, Blume-Peytavi U, Egarter C, Geisthövel F, König K, Kuhl H, Merkle E, Mueck AO, Reisch N, Schüring A, Stute P, Toth B, Wildt L, Zouboulis CC | title = Hirsutismus – Medikamentöse Therapie Gemeinsame Stellungnahme der Deutschen Gesellschaft für Gynäkologische Endokrinologie und Fortpflanzungsmedizin e.V. und des Berufsverbands der Frauenärzte e.V. | trans-title = Hirsutism – Medicinal treatment. Joint statement of the German Society of Gynaecological Endocrinology and Reproductive Medicine and the Professional Association of Gynaecologists | journal = Journal für Reproduktionsmedizin und Endokrinologie | year = 2015 | volume = 12 | issue = 3 | pages = 102–149 | language = de | issn = 1810-2107 | url = https://www.kup.at/journals/summary/12989.html}}</ref>]]

CPA is [[metabolism|metabolized]] primarily by [[hydroxylation]] via [[CYP3A4]], forming the major [[active metabolite]] [[15β-hydroxycyproterone acetate]].<ref name="pmid16112947" /><ref name="pmid3160716" /> This [[metabolite]] circulates at concentrations approximately twice those of CPA, and has similar antiandrogen activity to that of CPA but only 10% of its activity as a progestogen.<ref name="pmid16112947" /><ref name="pmid3160716" /><ref>{{cite book | vauthors = Fischl FH |chapter=Pharmacology of Estrogens and Gestagens |title=Menopause andropause |veditors = Fischl FH |year=2001 |pages=33–50 |isbn=978-3-901299-34-6 |chapter-url= http://www.kup.at/kup/pdf/4975.pdf |type= PDF |publisher= Krause und Pachernegg |location= Gablitz}}</ref><ref>{{cite web |author1=New Zealand Medicines |author2=Medical Devices Safety Authority |title=Data Sheet: Diane 35 ED |date=2005-12-09 |url=http://www.medsafe.govt.nz/Profs/Datasheet/d/Diane35EDtab.htm |url-status=dead |archive-url=https://web.archive.org/web/20070108191008/http://medsafe.govt.nz/Profs/Datasheet/d/Diane35EDtab.htm |archive-date=2007-01-08 }}</ref> As a result, the co-administration of CPA with drugs which inhibit CYP3A4 may increase its potency as a progestogen.<ref name="BińkowskaWoroń2015">{{cite journal | vauthors = Bińkowska M, Woroń J | title = Progestogens in menopausal hormone therapy | journal = Przegla̜d Menopauzalny = Menopause Review | volume = 14 | issue = 2 | pages = 134–43 | date = June 2015 | pmid = 26327902 | doi = 10.5114/pm.2015.52154 | pmc=4498031}}</ref>

Some CPA is reportedly metabolized by [[hydrolysis]] into [[cyproterone]] and [[acetic acid]].<ref>{{cite web |author=Medicines and Healthcare products Regulatory Authority |title=Cyproterone Acetate |date=2006-04-11 |url=http://www.mhra.gov.uk/home/groups/l-unit1/documents/websiteresources/con2023735.pdf |access-date=23 December 2018 |archive-url=https://web.archive.org/web/20070928010520/http://www.mhra.gov.uk/home/groups/l-unit1/documents/websiteresources/con2023735.pdf |archive-date=28 September 2007 |url-status=dead }}</ref> However, unlike many other steroid [[ester]]s, CPA is not extensively hydrolyzed, and much of the pharmacological activity of the drug is attributable to CPA itself in its unchanged form.<ref name=Berlex>{{cite web |author=Berlex Canada, Inc. |title=Cyproterone Acetate Tablets and Injections Product Monographs (revised version) |date=2003-02-10 |url=http://www.berlex.ca/html/docs/en/AndrocurEn.pdf |url-status=dead |archive-url=https://web.archive.org/web/20060924152720/http://www.berlex.ca/html/docs/en/AndrocurEn.pdf |archive-date=2006-09-24 }}</ref> Cyproterone has approximately one-third the potency of CPA as an antiandrogen<ref>{{cite journal | vauthors = Giorgi EP, Shirley IM, Grant JK, Stewart JC | title = Androgen dynamics in vitro in the human prostate gland. Effect of cyproterone and cyproterone acetate | journal = The Biochemical Journal | volume = 132 | issue = 3 | pages = 465–74 | date = March 1973 | pmid = 4125095 | pmc = 1177610 | doi=10.1042/bj1320465}}</ref> and is devoid of progestogenic activity.<ref name="GräfBrotherton1974" />

The [[biological half-life|elimination half-life]] of oral CPA is relatively long at approximately 1.6 to 2.2&nbsp;days (38 to 53&nbsp;hours), but possibly as long as 3.6 to 4.3&nbsp;days (86 to 100&nbsp;hours).<ref name="pmid16112947" /><ref name="pmid7919640" /><ref name="pmid12603397">{{cite journal | vauthors = Anderson J | title = The role of antiandrogen monotherapy in the treatment of prostate cancer | journal = BJU Int. | volume = 91 | issue = 5 | pages = 455–61 | date = March 2003 | pmid = 12603397 | doi = 10.1046/j.1464-410X.2003.04026.x | s2cid = 8639102 | doi-access = free }}</ref><ref name="pmid2977383" /><ref name="Ching2006" /> The half-life of 15β-OH-CPA with oral administration of CPA is 2.6&nbsp;days.<ref name="pmid2977383" /><ref name="Ching2006" /> The elimination half-life of CPA is prolonged in [[obese]] patients, which may be due to relatively greater storage of CPA in fat.<ref name="pmid2941191" /> The elimination half-life of CPA is also longer in older individuals; it is approximately twice as long in elderly men than in younger men (95&nbsp;hours and 45&nbsp;hours, respectively).<ref name="pmid9349934" /> When given via [[depot injection|depot]] [[intramuscular injection]], CPA has an elimination half-life of 3 to 4.3&nbsp;days while 15β-OH-CPA has a half-life of 5.2&nbsp;days.<ref name="pmid2977383" /><ref name="Weber2015" /><ref name="BradfordKaye1998" /><ref name="Ching2006" /> The [[duration of action]] of a single intramuscular injection of CPA is about 14 to 20&nbsp;days.<ref name="WrightBurgess2012" /><ref name="BeckerDüsterberg1980" /><ref name="MoltzHaase2008" /> The serum total [[clearance (pharmacology)|clearance]] of CPA is approximately 2.32 ± 0.38&nbsp;mL/min/kg.<ref name="pmid2977383" /><ref name="Ching2006" /> Levels of CPA and 15β-OH-CPA with oral administration decrease biphasically over a period of 24 to 120&nbsp;hours.<ref name="pmid2977383" /><ref name="Ching2006" />

The elimination of CPA appears to be biphasic.<ref name="pmid6415998">{{cite journal | vauthors = Foegh M | title = Evaluation of steroids as contraceptives in men | journal = Acta Endocrinol Suppl (Copenh) | volume = 260 | issue = 3_Supplb| pages = 3–48 | date = 1983 | pmid = 6415998 | doi = 10.1530/acta.0.104S009 | url = }}</ref> In one study, a peak at 3.4{{nbsp}}hours post-dose with an initial half-life of 3.4{{nbsp}}hours and later half-life of 1.6{{nbsp}}days was observed following a single 50{{nbsp}}mg oral dose of CPA.<ref name="pmid6415998" /> The high lipophilicity and fat storage of CPA may be the reason for its longer subsequent half-life.<ref name="pmid6415998" />

===Excretion===
CPA is [[excretion|excreted]] 70% in [[feces]] and 30% in [[urine]].<ref name="Weber2015" />

==References==
{{Reflist}}

{{Cyproterone acetate}}
{{Androgens and antiandrogens}}
{{Progestogens and antiprogestogens}}
{{Navboxes
| title = [[Pharmacodynamics]]
| titlestyle = background:#ccccff
| list1 = 
{{Androgen receptor modulators}}
{{Aryl hydrocarbon receptor modulators}}
{{Glucocorticoid receptor modulators}}
{{Opioid receptor modulators}}
{{Progesterone receptor modulators}}
{{Xenobiotic-sensing receptor modulators}}
}}

[[Category:Cyproterone acetate]]
[[Category:Medication pharmacology|cyproterone acetate]]