View source for Biology:Medroxyprogesterone acetate

{{Short description|Injectible form of birth control}}
{{Infobox drug
| Verifiedfields = verified
| Watchedfields = verified
| verifiedrevid = 307255781
| IUPAC_name = [(6''S'',8''R'',9''S'',10''R'',13''S'',14''S'',17''R'')-17-acetyl-6,10,13-trimethyl-3-oxo-2,6,7,8,9,11,12,14,15,16-decahydro-1''H''-cyclopenta[''a'']phenanthren-17-yl] acetate
| image = Medroxyprogesterone acetate.svg
| width = 250px
| image2 = Medroxyprogesterone acetate molecule ball.png
| width2 = 235px

<!--Clinical data-->
| pronounce = {{IPAc-en|m|ɛ|ˌ|d|r|ɒ|k|s|i|p|r|oʊ|ˈ|dʒ|ɛ|s|t|ər|oʊ|n|_|ˈ|æ|s|ɪ|t|eɪ|t}} {{respell|me|DROKS|ee|proh|JES|tər|ohn|_|ASS|i|tayt}}<ref name="Drugs.com-2">{{Cite web|url=https://www.drugs.com/medroxyprogesterone.html|title = Medroxyprogesterone Uses, Dosage & Side Effects}}</ref>
| tradename = Provera, Depo-Provera, Depo-SubQ Provera 104, Curretab, Cycrin, Farlutal, Gestapuran, Perlutex, Veramix, others<ref name="IndexNominum2000">{{cite book|title=Index Nominum 2000: International Drug Directory|url=https://books.google.com/books?id=5GpcTQD_L2oC&pg=PA638|date=January 2000|publisher=Taylor & Francis|isbn=978-3-88763-075-1|pages=638–|url-status=live|archive-url=https://web.archive.org/web/20130619010022/http://books.google.com/books?id=5GpcTQD_L2oC&pg=PA638|archive-date=19 June 2013}}</ref>
| Drugs.com = {{drugs.com|monograph|medroxyprogesterone-acetate}}
| MedlinePlus = a604039
| pregnancy_AU = <!-- A / B1 / B2 / B3 / C / D / X -->
| legal_AU = S4
| legal_UK = <!-- GSL / P / POM / CD -->
| legal_US = Rx-only
| legal_status = Rx-only
| routes_of_administration = [[Medicine:Oral administration|By mouth]], [[Medicine:Sublingual administration|sublingual]], [[Biology:Intramuscular injection|intramuscular injection]], [[Medicine:Subcutaneous injection|subcutaneous injection]]
| class = [[Chemistry:Progestogen (medication)|Progestogen]]; [[Chemistry:Progestin|Progestin]]; [[Chemistry:Progestogen ester|Progestogen ester]]; [[Chemistry:Antigonadotropin|Antigonadotropin]]; [[Biology:Steroidal antiandrogen|Steroidal antiandrogen]]

<!--Pharmacokinetic data-->
| bioavailability = By mouth: ~100%<ref name="pmid16112947" /><ref name="pmid19434889" />
| protein_bound = 88% (to [[Biology:Serum albumin|albumin]])<ref name="pmid19434889">{{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 = 61 | issue = 1–2 | pages = 171–80 | year = 2008 | pmid = 19434889 | doi = 10.1016/j.maturitas.2008.11.013 }}</ref>
| metabolism = [[Biology:Liver|Liver]] ([[Biology:Hydroxylation|hydroxylation]] ([[Biology:CYP3A4|CYP3A4]]), [[Chemistry:Redox|reduction]], [[Chemistry:Conjugation (biochemistry)|conjugation]])<ref name="ProveraLabel" /><ref name="pmid16112947" /><ref name="pmid26291834" />
| metabolites =
| elimination_half-life = By mouth: 12–33 hours<ref name="ProveraLabel">{{cite web|title=Provera|url=https://www.accessdata.fda.gov/drugsatfda_docs/label/2015/011839s079s080lbl.pdf|website=FDA|access-date=31 March 2018|date=2015|archive-url=https://web.archive.org/web/20170211092207/http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/011839s079s080lbl.pdf|archive-date=11 February 2017|url-status=dead}}</ref><ref name="pmid16112947" /><br />{{abbr|IM|Intramuscular injection}} ({{abbrlink|aq. susp.|aqueous suspension}}): ~50 days<ref name="DepoProveraLabel">{{cite web|title=Depo_Provera|url=https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/020246s058lbl.pdf|website=FDA|access-date=31 March 2018|date=2016}}</ref><br />{{abbr|SC|Subcutaneous injection}} ({{abbr|aq. susp.|aqueous suspension}}): ~40 days<ref name="DepoSubQProveraLabel">{{cite web|title=depo-subQ Provera|url=https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/021583s023lbl.pdf|website=FDA|access-date=31 March 2018|date=2017}}</ref>
| onset =
| duration_of_action =
| excretion = [[Biology:Urine|Urine]] (as [[Chemistry:Conjugation (biochemistry)|conjugate]]s)<ref name="ProveraLabel" />

<!--Identifiers-->
| CAS_number = 71-58-9
| ATC_prefix = G03
| ATC_suffix = AC06
| ATC_supplemental = {{ATC|G03|DA02}}, {{ATC|L02|AB02}}
| PubChem = 6279
| IUPHAR_ligand = 2879
| DrugBank = DB00603
| ChemSpiderID = 6043
| ChEBI = 6716
| UNII = C2QI4IOI2G
| KEGG_Ref = {{keggcite|correct|kegg}}
| KEGG = C08150
| ChEMBL_Ref = {{ebicite|correct|EBI}}
| ChEMBL = 717
| synonyms = MPA; DMPA; Methylhydroxy<wbr />progesterone acetate; Methylacetoxy<wbr />progesterone; MAP; Methypregnone; Metipregnone; 6α-Methyl-17α-hydroxyprogesterone acetate; 6α-Methyl-17α-acetoxyprogesterone; 6α-Methyl-17α-hydroxypregn-4-ene-3,20-dione acetate; NSC-26386

<!--Chemical data-->
| C=24 | H=34 | O=4
| SMILES = C[C@H]1C[C@@H]2[C@H](CC[C@]3([C@H]2CC[C@@]3(C(=O)C)OC(=O)C)C)[C@@]4(C1=CC(=O)CC4)C
| StdInChI_Ref =
| StdInChI = InChI=1S/C24H34O4/c1-14-12-18-19(22(4)9-6-17(27)13-21(14)22)7-10-23(5)20(18)8-11-24(23,15(2)25)28-16(3)26/h13-14,18-20H,6-12H2,1-5H3/t14-,18+,19-,20-,22+,23-,24-/m0/s1
| StdInChIKey_Ref =
| StdInChIKey = PSGAAPLEWMOORI-PEINSRQWSA-N
| melting_point = 207
| melting_high = 209
}}
<!-- Definition and medical uses -->
'''Medroxyprogesterone acetate''' ('''MPA'''), also known as '''depot medroxyprogesterone acetate''' ('''DMPA''') in [[Medicine:Injection|injectable]] form and sold under the brand name '''Depo-Provera''' among others, is a hormonal medication of the [[Chemistry:Progestin|progestin]] type.<ref name=AHFS2016/><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> It is used as a method of birth control and as a part of menopausal hormone therapy.<ref name=AHFS2016/><ref name="pmid16112947" /> It is also used to treat [[Medicine:Endometriosis|endometriosis]], [[Medicine:Abnormal uterine bleeding|abnormal uterine bleeding]], [[Medicine:Paraphilia|paraphilia]], and certain types of [[Medicine:Cancer|cancer]].<ref name=AHFS2016/> The medication is available both alone and in combination with an [[Chemistry:Estrogen (medication)|estrogen]].<ref name="Drugs.com"/><ref name="Martindale"/> It is taken [[Medicine:Oral administration|by mouth]], used [[Medicine:Sublingual administration|under the tongue]], or by [[Biology:Intramuscular injection|injection into a muscle]] or [[Medicine:Subcutaneous injection|fat]].<ref name=AHFS2016>{{cite web|title=Medroxyprogesterone Acetate|url=https://www.drugs.com/monograph/medroxyprogesterone-acetate.html|publisher=The American Society of Health-System Pharmacists|access-date=8 December 2016|url-status=live|archive-url=https://web.archive.org/web/20161224100359/https://www.drugs.com/monograph/medroxyprogesterone-acetate.html|archive-date=24 December 2016}}</ref>

<!-- Side effect and mechanism -->
Common [[Medicine:Side effect|side effect]]s include menstrual disturbances such as [[Medicine:Amenorrhea|absence of periods]], [[Medicine:Abdominal pain|abdominal pain]], and [[Medicine:Headache|headache]]s.<ref name=AHFS2016/> More serious side effects include [[Medicine:Osteoporosis|bone loss]], blood clots, allergic reactions, and liver problems.<ref name=AHFS2016/> Use is not recommended during [[Medicine:Pregnancy|pregnancy]] as it may [[Chemistry:Teratogen|harm the baby]].<ref name=AHFS2016/> MPA is an artificial [[Chemistry:Progestogen (medication)|progestogen]], and as such [[Biology:Agonist|activates]] the [[Biology:Progesterone receptor|progesterone receptor]], the [[Biology:Biological target|biological target]] of [[Chemistry:Progesterone|progesterone]].<ref name="pmid16112947" /> It also has [[Biology:Androgen|androgen]]ic activity and weak [[Chemistry:Glucocorticoid|glucocorticoid]] activity. Due to its progestogenic activity, MPA decreases the body's release of [[Biology:Gonadotropin|gonadotropin]]s and can suppress [[Biology:Sex hormone|sex hormone]] levels.<ref name="Genazzani1993" /> It works as a form of birth control by preventing ovulation.<ref name=AHFS2016/>

<!-- History, society, and culture -->
MPA was discovered in 1956 and was introduced for medical use in the United States in 1959.<ref name="Roberts2013">{{cite book| vauthors = Roberts SM |title=Introduction to Biological and Small Molecule Drug Research and Development: Chapter 12. Hormone replacement therapy|url=https://books.google.com/books?id=GR11DAAAQBAJ&pg=PP9|date=7 May 2013|publisher=Elsevier Science|isbn=978-0-12-806202-9|pages=9–|quote=[...] medroxyprogesterone acetate, also known as Provera (discovered simultaneously by Searle and Upjohn in 1956) [..]}}</ref><ref name=Sneader2005>{{cite book | vauthors = Sneader W | title = Drug discovery: a history | publisher = Wiley | location = New York | year = 2005 | page = 204 | isbn = 0-471-89980-1 | chapter = Chapter 18: Hormone analogs }}</ref><ref name=AHFS2016/> It is on the [[Medicine:WHO Model List of Essential Medicines|World Health Organization's List of Essential Medicines]].<ref name="WHO21st">{{cite book | vauthors = ((World Health Organization)) | title = World Health Organization model list of essential medicines: 21st list 2019 | year = 2019 | hdl = 10665/325771 |  publisher = World Health Organization | location = Geneva | id = WHO/MVP/EMP/IAU/2019.06. License: CC BY-NC-SA 3.0 IGO | hdl-access=free }}</ref> MPA is the most widely used progestin in menopausal hormone therapy and in progestogen-only birth control.<ref name="Meikle1999">{{cite book| vauthors = Meikle AW |title=Hormone Replacement Therapy|url=https://books.google.com/books?id=ja2nBgAAQBAJ&pg=PA383|date=1 June 1999|publisher=Springer Science & Business Media|isbn=978-1-59259-700-0|pages=383–}}</ref><ref name="Organization)Organization2002">{{cite book|author1=Special Programme of Research, Development, and Research Training in Human Reproduction (World Health Organization)|author2=World Health Organization|title=Research on Reproductive Health at WHO: Biennial Report 2000-2001|url=https://books.google.com/books?id=cvKaqyMOGjUC&pg=PP17|year=2002|publisher=World Health Organization|isbn=978-92-4-156208-9|pages=17–}}</ref> DMPA is approved for use as a form of long-acting birth control in more than 100&nbsp;countries.<ref name="BagadePawar2014c" /><ref name="Gunasheela2011" /> In 2021, it was the 238th most commonly prescribed medication in the United States, with more than 1{{nbsp}}million prescriptions.<ref>{{cite web | title=The Top 300 of 2021 | url=https://clincalc.com/DrugStats/Top300Drugs.aspx | website=ClinCalc | access-date=14 January 2024 | archive-date=15 January 2024 | archive-url=https://web.archive.org/web/20240115223848/https://clincalc.com/DrugStats/Top300Drugs.aspx | url-status=live }}</ref><ref>{{cite web | title = Medroxyprogesterone - Drug Usage Statistics | website = ClinCalc | url = https://clincalc.com/DrugStats/Drugs/Medroxyprogesterone | access-date = 14 January 2024}}</ref>

==Medical uses==
The most common use of MPA is in the form of DMPA as a long-acting [[Chemistry:Progestogen-only injectable contraceptive|progestogen-only injectable contraceptive]] to prevent pregnancy in women. It is an extremely effective contraceptive when used with relatively high doses to prevent ovulation. MPA is also used in combination with an estrogen in menopausal hormone therapy in postmenopausal women to treat and prevent menopausal symptoms such as hot flashes, vaginal atrophy, and [[Medicine:Osteoporosis|osteoporosis]].<ref name="pmid16112947" /> It is used in menopausal hormone therapy specifically to prevent endometrial hyperplasia and [[Medicine:Endometrial cancer|cancer]] that would otherwise be induced by prolonged unopposed estrogen therapy in women with intact [[Biology:Uterus|uterus]]es.<ref name="pmid16112947" /><ref name="pmid22895916">{{cite journal | vauthors = Furness S, Roberts H, Marjoribanks J, Lethaby A | title = Hormone therapy in postmenopausal women and risk of endometrial hyperplasia | journal = The Cochrane Database of Systematic Reviews | issue = 8 | pages = CD000402 | date = August 2012 | volume = 2012 | pmid = 22895916 | doi = 10.1002/14651858.CD000402.pub4 | pmc = 7039145 }}</ref> In addition to contraception and menopausal hormone therapy, MPA is used in the treatment of gynecological and menstrual disorders such as [[Medicine:Dysmenorrhea|dysmenorrhea]], [[Medicine:Amenorrhea|amenorrhea]], and [[Medicine:Endometriosis|endometriosis]].<ref name=Medline>{{cite web | title = Medroxyprogesterone | url = https://www.nlm.nih.gov/medlineplus/druginfo/meds/a682470.html | access-date = 2 July 2010 | date = 9 January 2008 | website = [[Social:MedlinePlus|MedlinePlus]] | url-status = live | archive-url = https://web.archive.org/web/20100712043213/http://www.nlm.nih.gov/medlineplus/druginfo/meds/a682470.html | archive-date = 12 July 2010 }}</ref> Along with other progestins, MPA was developed to allow for oral progestogen therapy, as [[Chemistry:Progesterone (medication)|progesterone]] (the progestogen hormone made by the human body) could not be taken orally for many decades before the process of [[Physics:Micronization|micronization]] was developed and became feasible in terms of [[Medicine:Pharmaceutical manufacturing|pharmaceutical manufacturing]].<ref name = Panay2010>{{cite journal | vauthors = Panay N, Fenton A | title = Bioidentical hormones: what is all the hype about? | journal = Climacteric | volume = 13 | issue = 1 | pages = 1–3 | date = February 2010 | pmid = 20067429 | doi = 10.3109/13697130903550250 | s2cid = 244295 }}</ref>

DMPA reduces sex drive in men and is used as a form of chemical castration to control inappropriate or unwanted sexual behavior in those with [[Medicine:Paraphilia|paraphilia]]s or [[Medicine:Hypersexuality|hypersexuality]], including in convicted sex offenders.<ref name="pmid16575429">{{cite journal | vauthors = Light SA, Holroyd S | title = The use of medroxyprogesterone acetate for the treatment of sexually inappropriate behaviour in patients with dementia | journal = Journal of Psychiatry & Neuroscience | volume = 31 | issue = 2 | pages = 132–4 | date = March 2006 | pmid = 16575429 | pmc = 1413960 | url = http://www.cma.ca/multimedia/staticContent/HTML/N0/l2/jpn/vol-31/issue-2/pdf/pg132.pdf | url-status = live | archive-url = https://web.archive.org/web/20160307005616/https://www.cma.ca/multimedia/staticContent/HTML/N0/l2/jpn/vol-31/issue-2/pdf/pg132.pdf | archive-date = 7 March 2016 }}</ref><ref name="Salon2000">{{cite web | url = http://archive.salon.com/health/feature/2000/03/01/castration/ | title = The chemical knife | access-date = 22 January 2009 | url-status = dead | archive-url = https://web.archive.org/web/20090107134347/http://archive.salon.com/health/feature/2000/03/01/castration/ | archive-date = 7 January 2009 }}</ref> DMPA has also been used to treat [[Medicine:Benign prostatic hyperplasia|benign prostatic hyperplasia]], as a palliative appetite stimulant for [[Medicine:Cancer|cancer]] patients, and at high doses (800&nbsp;mg per day) to treat certain hormone-dependent cancers including [[Medicine:Endometrial cancer|endometrial cancer]], renal cancer, and [[Medicine:Breast cancer|breast cancer]].<ref name="Drugs@FDA-Depo-Provera" /><ref name = Meyler/><ref name="pmid390798">{{cite journal | vauthors = Ganzina F | title = High-dose medroxyprogesterone acetate (MPA) treatment in advanced breast cancer. A review | journal = Tumori | volume = 65 | issue = 5 | pages = 563–85 | date = October 1979 | pmid = 390798 | doi = 10.1177/030089167906500507| s2cid = 23378403 }}</ref><ref name="pmid2974757">{{cite journal | vauthors = Kjaer M | title = The role of medroxyprogesterone acetate (MPA) in the treatment of renal adenocarcinoma | journal = Cancer Treat. Rev. | volume = 15 | issue = 3 | pages = 195–209 | date = September 1988 | pmid = 2974757 | doi = 10.1016/0305-7372(88)90003-5}}</ref><ref name="pmid1534051">{{cite journal | vauthors = Vanderstappen D, Bonte J | title = New trends in the use of medroxyprogesterone acetate as a chemotherapeutic agent in gynecologic malignancies | journal = Eur. J. Gynaecol. Oncol. | volume = 13 | issue = 2 | pages = 113–23 | date = 1992 | pmid = 1534051 }}</ref> MPA has also been prescribed in feminizing hormone therapy for transgender women due to its [[Chemistry:Progestogen (medication)|progestogen]]ic and functional [[Biology:Antiandrogen|antiandrogen]]ic effects.<ref name="pmid16286768">{{cite journal | vauthors = Gooren L | title = Hormone treatment of the adult transsexual patient | journal = Horm. Res. | volume = 64 | issue = Suppl 2 | pages = 31–6 | date = 2005 | pmid = 16286768 | doi = 10.1159/000087751 | s2cid = 42507159 }}</ref> It has been used to delay puberty in children with [[Medicine:Precocious puberty|precocious puberty]] but is not satisfactory for this purpose as it is not able to completely suppress puberty.<ref name="SachdevaDutta2012">{{cite book| vauthors = Sachdeva A, Dutta AK |title=Advances in Pediatrics|url=https://books.google.com/books?id=I2FHFyCaDeIC&pg=PA1202|date=31 August 2012|publisher=JP Medical Ltd|isbn=978-93-5025-777-7|pages=1202–}}</ref> DMPA at high doses has been reported to be definitively effective in the treatment of hirsutism as well.<ref name="Hammerstein1990">{{cite book| vauthors = Hammerstein J |title=Hair and Hair Diseases|chapter=Antiandrogens: Clinical Aspects|year=1990|pages=827–886|doi=10.1007/978-3-642-74612-3_35|isbn=978-3-642-74614-7}}</ref>

Though not used as a treatment for [[Medicine:Epilepsy|epilepsy]], MPA has been found to reduce the frequency of seizures and does not interact with [[Chemistry:Anticonvulsant|antiepileptic]] medications. MPA does not interfere with blood clotting and appears to improve blood parameters for women with sickle cell anemia. Similarly, MPA does not appear to affect [[Biology:Liver|liver]] [[Biology:Metabolism|metabolism]], and may improve primary biliary cirrhosis and [[Medicine:Hepatitis|chronic active hepatitis]]. Women taking MPA may experience spotting shortly after starting the medication but is not usually serious enough to require medical intervention. With longer use [[Medicine:Amenorrhea|amenorrhea]] (absence of [[Medicine:Menstruation|menstruation]]) can occur as can irregular menstruation which is a major source of dissatisfaction, though both can result in improvements with iron deficiency and risk of [[Medicine:Pelvic inflammatory disease|pelvic inflammatory disease]] and often do not result in discontinuation of the medication.<ref name = Meyler/>

===Birth control===
{{Infobox birth control
| name = Depot medroxyprogesterone acetate (DMPA)
| image = Prikpil.JPG
| width = 250px
| caption =
| bc_type = Hormonal
| tradename = Depo-Provera, Depo-SubQ Provera 104, others
| Drugs.com = {{drugs.com|parent|depo-provera}}
| date_first_use = 1969<ref name="Nadakavukaren2011" />
| rate_type = Failure
| perfect_failure% = 0.2
| typical_failure% = 6
| typical_failure_ref =<ref name="Trussell 2011"/>
| duration_effect = 3 months<br />(12–14 weeks)
| reversibility = 3–18 months
| user_reminders = Maximum interval is just under 3 months
| clinic_interval = 12 weeks
| STD_protection_YesNo = No
| periods_advantage = Usually no periods from 2nd injection
| benefits = Especially good if poor pill compliance.<br />Reduced endometrial cancer risk.
| periods_disadvantage = Especially in first injection may be frequent spotting
| risks = Reduced bone density, which may reverse after discontinuation
| medical_notes = For those intending to start family, suggest switch 6 months prior to alternative method (e.g. POP) allowing more reliable return fertility.
}}

DMPA, under brand names such as Depo-Provera and Depo-SubQ Provera 104, is used in hormonal birth control as a long-lasting progestogen-only injectable contraceptive to prevent pregnancy in women.<ref name="pmid18470526" /><ref name="westhoff" /> It is given by [[Biology:Intramuscular injection|intramuscular]] or [[Medicine:Subcutaneous injection|subcutaneous injection]] and forms a long-lasting [[Medicine:Depot injection|depot]], from which it is slowly released over a period of several months. It takes one week to take effect if given after the first five days of the period cycle, and is effective immediately if given during the first five days of the period cycle. Estimates of first-year failure rates are about 0.3%.<ref name="trussell 2004a">{{cite book | vauthors = Trussell J | year = 2004 |chapter=Contraceptive Efficacy | veditors =  Hatcher RA, Trussell J, Stewart FH, Nelson AL, Cates Jr W, Guest F, Kowal D |title=Contraceptive Technology |edition=18th rev. |pages=773–845 |location=New York |publisher=Ardent Media |isbn=0-9664902-5-8}}</ref>

====Effectiveness====
Trussell's estimated ''perfect use'' first-year failure rate for DMPA as the average of failure rates in seven clinical trials at 0.3%.<ref name="trussell 2004a"/><ref name="trussell 2004b">{{cite journal | vauthors = Trussell J | title = Contraceptive failure in the United States | journal = Contraception | volume = 70 | issue = 2 | pages = 89–96 | date = August 2004 | pmid = 15288211 | doi = 10.1016/j.contraception.2004.03.009 | pmc = 3638209 }}</ref> It was considered ''perfect use'' because the clinical trials measured efficacy during actual use of DMPA defined as being no longer than 14 or 15 weeks after an injection (i.e., no more than 1 or 2 weeks late for a next injection).

Prior to 2004, Trussell's ''typical use'' failure rate for DMPA was the same as his ''perfect use'' failure rate: 0.3%.<ref>{{cite journal | vauthors = Trussell J, Hatcher RA, Cates W, Stewart FH, Kost K | title = A guide to interpreting contraceptive efficacy studies | journal = Obstetrics and Gynecology | volume = 76 | issue = 3 Pt 2 | pages = 558–67 | date = September 1990 | pmid = 2199875 }}</ref>
* DMPA estimated ''typical use'' first-year failure rate = 0.3% in:
** ''Contraceptive Technology, 16th revised edition'' (1994)<ref name="trussell 1994">{{cite book | vauthors = Trussell J | year = 1994 | chapter = Contraceptive Failure Rates | veditors = Hatcher RA, Trussell J, Nelson AL, Cates W, Kowal D, Policar MS | title = Contraceptive Technology | edition = 16th rev. | pages = [https://archive.org/details/isbn_9780829031713/page/637 637]–688 | location = New York | publisher = Irvington Publishers | isbn = 0-8290-3171-5 | url = https://archive.org/details/isbn_9780829031713 | url-access = registration }}</ref>
** ''Contraceptive Technology, 17th revised edition'' (1998)<ref name="trussell 1998">{{cite book | vauthors = Trussell J | year = 1998 | chapter = Contraceptive Efficacy | veditors = Hatcher RA, Trussell J, Stewart F, Cates W, Stewart GK, Guest F, Kowal D | title = Contraceptive Technology | edition = 17th rev. | pages = [https://archive.org/details/contraceptivetec00hatc/page/779 779]–844 | location = New York | publisher = Ardent Media | isbn = 0-9664902-0-7 | chapter-url = https://archive.org/details/contraceptivetec00hatc | chapter-url-access = registration }}</ref>
*** Adopted in 1998 by the [[Organization:Food and Drug Administration|FDA]] for its current ''Uniform Contraceptive Labeling'' guidance<ref name="fda guidance">{{cite web |author=FDA |year=1998 |title=Guidance for Industry - Uniform Contraceptive Labeling |website=[[Organization:Food and Drug Administration|Food and Drug Administration]] |url=https://www.fda.gov/cdrh/ode/contrlab.pdf |access-date=21 June 2007 |archive-url = https://web.archive.org/web/20070225182414/https://www.fda.gov/cdrh/ode/contrlab.pdf |archive-date = 25 February 2007 |}}</ref>

In 2004, using the 1995 NSFG failure rate, Trussell increased (by 10 times) his ''typical use'' failure rate for DMPA from 0.3% to 3%.<ref name="trussell 2004a"/><ref name="trussell 2004b"/>
* DMPA estimated ''typical use'' first-year failure rate = 3% in:
** ''Contraceptive Technology, 18th revised edition'' (2004)<ref name="trussell 2004a"/>
** ''Contraceptive Technology, 19th revised edition'' (2007)<ref name="trussell 2007">{{cite book | vauthors = Trussell J  | name-list-style = vanc | year = 2007 | chapter = Contraceptive Efficacy | veditors = Hatcher RA, Trussell J, Nelson AL, Cates W, Stewart FH, Kowal D | title = Contraceptive Technology | edition = 19th rev. | location = New York | publisher = Ardent Media | chapter-url = http://www.contraceptivetechnology.com/table.html | access-date = 21 June 2007 | url-status = dead | archive-url = https://web.archive.org/web/20080531095926/http://www.contraceptivetechnology.com/table.html | archive-date = 31 May 2008 }}</ref>

Trussell did not use 1995 NSFG failure rates as ''typical use'' failure rates for the other two then newly available long-acting contraceptives, the Norplant implant (2.3%) and the ParaGard copper T 380A [[Medicine:Intrauterine device|IUD]] (3.7%), which were (as with DMPA) an order of magnitude higher than in clinical trials. Since Norplant and ParaGard allow no scope for user error, their much higher 1995 NSFG failure rates were attributed by Trussell to contraceptive overreporting at the time of a conception leading to a live birth.<ref name="trussell 2004a"/><ref name="trussell 1999">{{cite journal | vauthors = Trussell J, Vaughan B | title = Contraceptive failure, method-related discontinuation and resumption of use: results from the 1995 National Survey of Family Growth | journal = Family Planning Perspectives | volume = 31 | issue = 2 | pages = 64–72, 93 | year = 1999 | pmid = 10224544 | doi = 10.2307/2991641 | url = http://www.guttmacher.org/pubs/journals/3106499.pdf | jstor = 2991641 | url-status = live | archive-url = https://web.archive.org/web/20081202020036/https://www.guttmacher.org/pubs/journals/3106499.pdf | archive-date = 2 December 2008 }}</ref><ref name="trussell 2004b"/>

====Advantages====
DMPA has a number of advantages and benefits:<ref name="hatcher"/><ref name="speroff"/><ref name="westhoff">{{cite journal | vauthors = Westhoff C | title = Depot-medroxyprogesterone acetate injection (Depo-Provera): a highly effective contraceptive option with proven long-term safety | journal = Contraception | volume = 68 | issue = 2 | pages = 75–87 | date = August 2003 | pmid = 12954518 | doi = 10.1016/S0010-7824(03)00136-7 }}</ref><ref name="mishell">{{cite book | vauthors = Mishell DR | year = 2004 | veditors = Strauss III JF, Barbieri RL | title = Yen and Jaffe's Reproductive Endocrinology |edition=5th |publisher=Elsevier Saunders |location=Philadelphia |isbn=0-7216-9546-9 |pages=899–938 |chapter=Contraception}}</ref>
* Highly effective at preventing pregnancy.
* Injected every 12 weeks. The only continuing action is to book subsequent follow-up injections every twelve weeks, and to monitor side effects to ensure that they do not require medical attention.
* No [[Chemistry:Estrogen (medication)|estrogen]]. No increased risk of [[Medicine:Deep vein thrombosis|deep vein thrombosis]], [[Medicine:Pulmonary embolism|pulmonary embolism]], [[Medicine:Stroke|stroke]], or [[Medicine:Myocardial infarction|myocardial infarction]].
* Minimal [[Medicine:Drug interaction|drug interaction]]s (compared to other hormonal contraceptives).
* Decreased risk of [[Medicine:Endometrial cancer|endometrial cancer]]. DMPA reduces the risk of endometrial cancer by 80%.<ref name=Kaunitz>{{cite journal | vauthors = Kaunitz AM | title = Current options for injectable contraception in the United States | journal = Seminars in Reproductive Medicine | volume = 19 | issue = 4 | pages = 331–7 | date = December 2001 | pmid = 11727175 | doi = 10.1055/s-2001-18641 | s2cid = 39556669 }}</ref><ref name="BrJFP_Bigrigg1999">{{cite journal | vauthors = Bigrigg A, Evans M, Gbolade B, Newton J, Pollard L, Szarewski A, Thomas C, Walling M | title = Depo Provera. Position paper on clinical use, effectiveness and side effects | journal = The British Journal of Family Planning | volume = 25 | issue = 2 | pages = 69–76 | date = July 1999 | pmid = 10454658 }}</ref><ref name="WHO DMPA EC">{{cite journal | title = Depot-medroxyprogesterone acetate (DMPA) and risk of endometrial cancer. The WHO Collaborative Study of Neoplasia and Steroid Contraceptives | journal = International Journal of Cancer | volume = 49 | issue = 2 | pages = 186–90 | date = September 1991 | pmid = 1831802 | doi = 10.1002/ijc.2910490207 | s2cid = 221776781 }}</ref> The reduced risk of endometrial cancer in DMPA users is thought to be due to both the direct anti-proliferative effect of progestogen on the endometrium and the indirect reduction of estrogen levels by suppression of ovarian follicular development.<ref name=Santen>{{cite book | vauthors = Santen RJ | veditors = Strauss III JF, Barbieri RL | title = Yen and Jaffe's Reproductive Endocrinology |edition=5th |year=2004 |publisher=Elsevier Saunders |location=Philadelphia |isbn=0-7216-9546-9 |pages=787–809 |chapter=Endocrinology of Breast and Endometrial Cancer}}</ref>
* Decreased risk of iron deficiency anemia, [[Medicine:Pelvic inflammatory disease|pelvic inflammatory disease (PID)]], [[Medicine:Ectopic pregnancy|ectopic pregnancy]],<ref name="Bartz 2011">{{cite book | vauthors = Bartz D, Goldberg AB | year = 2011 | chapter = Injectable contraceptives | veditors = Hatcher RA, Trussell J, Nelson AL, Cates W Jr, Kowal D, Policar MS | title =Contraceptive technology | edition = 20th revised | location = New York | publisher = Ardent Media | isbn = 978-1-59708-004-0 | oclc = 781956734 | pages = 212–213 | quote = Advantages of DMPA Injectables. 5. Reduced risk of ectopic pregnancy. Compared with women who use no contraceptive at all, women who use DMPA have a reduced risk for having an ectopic pregnancy. Although the overall risk of pregnancy and thus ectopic pregnancy is lowered by DMPA, the possibility of an ectopic pregnancy should be excluded if a woman using DMPA becomes pregnant. One study showed that 1.5% of women who got pregnant on DMPA had an ectopic pregnancy, the same ectopic rate as women who conceived while not using contraception.<sup>27</sup>}}</ref><ref>{{cite journal | vauthors = Borgatta L, Murthy A, Chuang C, Beardsley L, Burnhill MS | title = Pregnancies diagnosed during Depo-Provera use | journal = Contraception | volume = 66 | issue = 3 | pages = 169–72 | date = September 2002 | pmid = 12384205 | doi = 10.1016/S0010-7824(02)00340-2 }}</ref> and uterine fibroidsNote: this is no longer considered valid. Progesterones have been found to be the critical mitogen for uterine fibroid tumours.<ref>J. Julie Kim, Takeshi Kurita, Serdar E. Bulun, Progesterone Action in Endometrial Cancer, Endometriosis, Uterine Fibroids, and Breast Cancer, Endocrine Reviews, Volume 34, Issue 1, 1 February 2013, Pages 130–162, https://doi.org/10.1210/er.2012-1043 <nowiki><ref></nowiki>

* Decreased symptoms of [[Medicine:Endometriosis|endometriosis]].
* Decreased incidence of [[Medicine:Dysmenorrhea|primary dysmenorrhea]], [[Medicine:Mittelschmerz|ovulation pain]], and [[Medicine:Ovarian cyst|functional ovarian cysts]].
* Decreased incidence of seizures in women with [[Medicine:Epilepsy|epilepsy]]. Additionally, unlike most other hormonal contraceptives, DMPA's contraceptive effectiveness is not affected by [[Biology:Enzyme induction and inhibition|enzyme-inducing]] antiepileptic drugs.<nowiki></ref name="obrien"></nowiki>{{cite journal |vauthors=O'Brien MD, Guillebaud J |date=September 2006 |title=Contraception for women with epilepsy |journal=Epilepsia |volume=47 |issue=9 |pages=1419–22 |doi=10.1111/j.1528-1167.2006.00671.x |pmid=16981856 |s2cid=22284176 |doi-access=free}}</ref>
* Decreased incidence and severity of sickle cell crises in women with sickle-cell disease.<ref name="westhoff"/>

The United Kingdom Department of Health has actively promoted Long Acting Reversible Contraceptive use since 2008, particularly for young people;<ref>{{cite news |title=Increasing use of long-acting reversible contraception |publisher=Nursing Times.net |url=https://www.nursingtimes.net/clinical-archive/sexual-health/increasing-use-of-long-acting-reversible-contraception-21-10-2008/ |date=21 October 2008 |access-date=19 June 2009 |url-status=live |archive-url=https://web.archive.org/web/20090826233650/https://www.nursingtimes.net/clinical-archive/sexual-health/increasing-use-of-long-acting-reversible-contraception-21-10-2008/ |archive-date=26 August 2009 }}</ref> following on from the October 2005 National Institute for Health and Clinical Excellence guidelines.<ref>{{cite web|title=CG30 Long-acting reversible contraception: quick reference guide |url=http://www.nice.org.uk/nicemedia/pdf/cg030quickrefguide.pdf |publisher=National Institute for Health and Clinical Excellence |access-date=19 June 2009 |url-status=dead |archive-url=https://web.archive.org/web/20090920091647/http://www.nice.org.uk/nicemedia/pdf/cg030quickrefguide.pdf |archive-date=20 September 2009 }}</ref> Giving advice on these methods of contraception has been included in the 2009 Quality and Outcomes Framework "good practice" for primary care.<ref>{{cite web |title=Sexual Health Ruleset |work=New GMS Contract Quality and Outcome Framework - Implementation Dataset and Business Rules |url=http://www.pcc.nhs.uk/uploads/QOF/Business%20Rules%20v14/sexual_health_ruleset_r4_v14_0.pdf |publisher=Primary Care Commissioning |date=1 May 2009 |access-date=19 June 2009 |url-status=live |archive-url=https://web.archive.org/web/20110810074228/http://www.pcc.nhs.uk/uploads/QOF/Business%20Rules%20v14/sexual_health_ruleset_r4_v14_0.pdf |archive-date=10 August 2011 }}<br />'''Summarized at'''<br />* {{cite web |title=Contraception - Management QOF indicators |url=http://cks.library.nhs.uk/contraception/management/goals_and_outcome_measures/qof_indicators |work=NHS Clinical Knowledge Summaries |publisher=NHS Institute for Innovation and Improvement |access-date=19 June 2009 }}{{dead link|date=June 2017 |bot=InternetArchiveBot |fix-attempted=yes }}</ref>

===Comparison===
Proponents of [[Unsolved:Bioidentical hormone replacement therapy|bioidentical hormone therapy]] believe that progesterone offers fewer side effects and improved quality of life compared to MPA.<ref name=Holtorf2009>{{cite journal|vauthors=Holtorf K |title=The bioidentical hormone debate: are bioidentical hormones (estradiol, estriol, and progesterone) safer or more efficacious than commonly used synthetic versions in hormone replacement therapy? |journal=Postgraduate Medicine |volume=121 |issue=1 |pages=73–85 |date=January 2009 |pmid=19179815 |doi=10.3810/pgm.2009.01.1949 |s2cid=2060730 |url=http://www.bobmehrpharmacies.com/images/_content/bio-identical/The%20Bioidentical%20Hormone%20Debate-%20Ken%20Holtorf%20MD.pdf |url-status=dead |archive-url=https://web.archive.org/web/20110708075449/http://www.bobmehrpharmacies.com/images/_content/bio-identical/The%20Bioidentical%20Hormone%20Debate-%20Ken%20Holtorf%20MD.pdf |archive-date=8 July 2011 }}</ref> The evidence for this view has been questioned; MPA is better absorbed when taken by mouth, with a much longer elimination half-life leading to more stable blood levels<ref name=Cirigliano>{{cite journal|vauthors=Cirigliano M |title=Bioidentical hormone therapy: a review of the evidence |journal=Journal of Women's Health |volume=16 |issue=5 |pages=600–31 |date=June 2007 |pmid=17627398 |doi=10.1089/jwh.2006.0311 |url=http://www.solaltech.com/doctors/3/Bioidentical%20Hormone%20Therapy--%20Cirigliano.pdf |url-status=dead |archive-url=https://web.archive.org/web/20110106204000/http://www.solaltech.com/doctors/3/Bioidentical%20Hormone%20Therapy--%20Cirigliano.pdf |archive-date=6 January 2011 }}</ref> though it may lead to greater breast tenderness and more sporadic vaginal bleeding.<ref name = Holtorf2009/> The two compounds do not differentiate in their ability to suppress endometrial hyperplasia,<ref name = Holtorf2009/> nor does either increase the risk of [[Medicine:Pulmonary embolism|pulmonary embolism]].<ref>{{cite journal | vauthors = Boothby LA, Doering PL | title = Bioidentical hormone therapy: a panacea that lacks supportive evidence | journal = Current Opinion in Obstetrics and Gynecology | volume = 20 | issue = 4 | pages = 400–7 | date = August 2008 | pmid = 18660693 | doi = 10.1097/GCO.0b013e3283081ae9 | s2cid = 22449765 }}</ref> The two medications have not been adequately compared in direct tests to clear conclusions about safety and superiority.<ref name="Panay2010"/>

===Available forms===

MPA is available alone in the form of 2.5, 5, and 10&nbsp;mg [[Medicine:Oral administration|oral]] [[Medicine:Tablet (pharmacy)|tablet]]s, as a 150&nbsp;mg/mL (1&nbsp;mL) or 400&nbsp;mg/mL (2.5&nbsp;mL) [[Earth:Microcrystalline|microcrystalline]] aqueous suspension for [[Biology:Intramuscular injection|intramuscular injection]], and as a 104&nbsp;mg (0.65&nbsp;mL of 160&nbsp;mg/mL) microcrystalline aqueous suspension for [[Medicine:Subcutaneous injection|subcutaneous injection]].<ref name="Drugs@FDA" /><ref name="HospitalEngorn2014">{{cite book | vauthors = Engorn B, Flerlage J |title=The Harriet Lane Handbook E-Book|url=https://books.google.com/books?id=6cSLAwAAQBAJ&pg=PA846|date=1 May 2014|publisher=Elsevier Health Sciences|isbn=978-0-323-11246-8|pages=846–}}</ref> It has also been marketed in the form of 100, 200, 250, 400, and 500&nbsp;mg oral tablets; 500 and 1,000&nbsp;mg oral suspensions; and as a 50&nbsp;mg/mL microcrystalline aqueous suspension for intramuscular injection.<ref name="Tiziani2013">{{cite book| vauthors = Tiziani AP |title=Havard's Nursing Guide to Drugs|url=https://books.google.com/books?id=XpzQAgAAQBAJ&pg=PA989|date=1 June 2013|publisher=Elsevier Health Sciences|isbn=978-0-7295-8162-2|pages=989–}}</ref><ref name="Leidenberger2013">{{cite book| vauthors = Leidenberger FA |title=Klinische Endokrinologie für Frauenärzte|url=https://books.google.com/books?id=YTiuBgAAQBAJ&pg=PA528|date=17 April 2013|publisher=Springer-Verlag|isbn=978-3-662-08110-5|pages=528–}}</ref> A 100&nbsp;mg/mL microcrystalline aqueous suspension for intramuscular injection was previously available as well.<ref name="Drugs@FDA" /> In addition to single-drug formulations, MPA is available in the form of oral tablets in combination with [[Biology:Conjugated estrogens|conjugated estrogens]] (CEEs), [[Chemistry:Estradiol (medication)|estradiol]], and [[Chemistry:Estradiol valerate|estradiol valerate]] for use in menopausal hormone therapy, and is available in combination with [[Chemistry:Estradiol cypionate|estradiol cypionate]] in a microcrystalline aqueous suspension as a combined injectable contraceptive.<ref name="Drugs.com" /><ref name="Martindale" /><ref name="Drugs@FDA" /><ref name="BagadePawar2014c" />

Depo-Provera is the brand name for a 150&nbsp;mg microcrystalline aqueous suspension of DMPA that is administered by intramuscular injection. The shot must be injected into thigh, buttock, or deltoid muscle four times a year (every 11 to 13&nbsp;weeks), and provides pregnancy protection instantaneously after the first injection.<ref name="Depo Provera: The Birth Control Shot">Stacey, Dawn. [http://contraception.about.com/od/prescriptionoptions/a/depoprovera.htm ''Depo Provera: The Birth Control Shot''] {{webarchive|url=https://web.archive.org/web/20081010212054/http://contraception.about.com/od/prescriptionoptions/a/depoprovera.htm |date=10 October 2008}} Accessed 13 October 2009.</ref> Depo-subQ Provera 104 is a variation of the original intramuscular DMPA that is instead a 104&nbsp;mg microcrystalline dose in aqueous suspension administered by subcutaneous injection. It contains 69% of the MPA found in the original intramuscular DMPA formulation. It can be injected using a smaller injection needle inserting the medication just below the skin, instead of into the muscle, in either the abdomen or thigh. This subcutaneous injection claims to reduce the side effects of DMPA while still maintaining all the same benefits of the original intramuscular DMPA.

==Contraindications==
MPA is not usually recommended because of unacceptable health risk or because it is not indicated in the following cases:<ref name="who mec">{{cite book |author=WHO |year=2004 |chapter=Progestogen-only contraceptives |title=Medical Eligibility Criteria for Contraceptive Use |edition=3rd |location=Geneva |publisher=Reproductive Health and Research, WHO |isbn=92-4-156266-8 |chapter-url=https://www.who.int/reproductive-health/publications/mec/pocs.html |url-status=live |archive-url=https://web.archive.org/web/20090531160312/http://www.who.int/reproductive-health/publications/mec/pocs.html |archive-date=31 May 2009}}</ref><ref name="ffprhc mec">{{cite web |author=FFPRHC | year=2006 |title=The UK Medical Eligibility Criteria for Contraceptive Use (2005/2006) |url=http://www.ffprhc.org.uk/admin/uploads/UKMEC200506.pdf |access-date=11 January 2007 |archive-url = https://web.archive.org/web/20070619230102/http://www.ffprhc.org.uk/admin/uploads/UKMEC200506.pdf |archive-date = 19 June 2007 |author-link= Royal College of Obstetricians and Gynaecologists}}</ref>

Conditions where the theoretical or proven risks usually outweigh the advantages of using DMPA:
* Multiple risk factors for arterial [[Medicine:Cardiovascular disease|cardiovascular disease]]
* Current [[Medicine:Deep vein thrombosis|deep vein thrombosis]] or pulmonary embolus
* Migraine headache with [[Unsolved:Aura (symptom)|aura]] while using DMPA
* Before evaluation of unexplained vaginal bleeding suspected of being a serious condition
* A history of [[Medicine:Breast cancer|breast cancer]] and no evidence of current disease for five years
* Active liver disease: (acute [[Medicine:Viral hepatitis|viral hepatitis]], severe decompensated [[Medicine:Cirrhosis|cirrhosis]], benign or [[Medicine:Hepatocellular carcinoma|malignant]] liver tumours)
* Conditions of concern for estrogen deficiency and reduced HDL levels theoretically increasing cardiovascular risk:
** [[Medicine:Hypertension|Hypertension]] with [[Medicine:Vascular disease|vascular disease]]
** Current and history of ischemic heart disease
** History of [[Medicine:Stroke|stroke]]
** [[Medicine:Diabetes|Diabetes]] for over 20 years or with [[Medicine:Diabetic nephropathy|nephropathy]]/[[Medicine:Diabetic retinopathy|retinopathy]]/[[Medicine:Diabetic neuropathy|neuropathy]] or [[Medicine:Vascular disease|vascular disease]]

Conditions which represent an unacceptable health risk if DMPA is used:
* Current or recent [[Medicine:Breast cancer|breast cancer]] (a hormonally sensitive tumour)

Conditions where use is not indicated and should not be initiated:
* [[Medicine:Pregnancy|Pregnancy]]

MPA is not recommended for use prior to [[Biology:Menarche|menarche]] or before or during recovery from [[Medicine:Surgery|surgery]].<ref name=Merck>{{cite web | publisher = Merck Manual | url = http://www.merck.com/mmpe/lexicomp/medroxyprogesterone.html | title = MedroxyPROGESTERone: Drug Information Provided by Lexi-Comp | access-date = 8 July 2010 | date = 1 December 2009 | url-status = live | archive-url = https://web.archive.org/web/20100724182722/http://www.merck.com/mmpe/lexicomp/medroxyprogesterone.html | archive-date = 24 July 2010}}</ref>

==Side effects==
In women, the most common [[Medicine:Adverse effect|adverse effect]]s of MPA are acne, changes in menstrual flow, drowsiness, and can cause [[Medicine:Birth defect|birth defect]]s if taken by pregnant women. Other common side effects include breast tenderness, increased facial hair, decreased scalp hair, difficulty falling or remaining asleep, stomach pain, and weight loss or gain.<ref name = Medline/> Lowered [[Philosophy:Libido|libido]] has been reported as a side effect of MPA in women.<ref name="King2012">{{cite book | vauthors = King SR | title = Neurosteroids and the Nervous System | url = https://books.google.com/books?id=D1fOTC6CP3kC&pg=PA45 | date = 9 November 2012 | publisher = Springer Science & Business Media | isbn = 978-1-4614-5559-2 | pages = 45– | url-status = live | archive-url = https://web.archive.org/web/20171105200514/https://books.google.com/books?id=D1fOTC6CP3kC&pg=PA45 | archive-date = 5 November 2017}}</ref> DMPA can affect menstrual bleeding. After a year of use, 55% of women experience [[Medicine:Amenorrhea|amenorrhea]] (missed periods); after two years, the rate rises to 68%. In the first months of use "irregular or unpredictable bleeding or spotting, or, rarely, heavy or continuous bleeding" was reported.<ref name="depo us patient info">{{cite web |author=Pfizer |date=October 2004 |title=Depo-Provera Contraceptive Injection, US patient labeling |url=http://www.pfizer.com/pfizer/download/ppi_depo_provera_contraceptive.pdf |access-date=21 February 2007 |url-status=dead |archive-url=https://web.archive.org/web/20070206044043/http://www.pfizer.com/pfizer/download/ppi_depo_provera_contraceptive.pdf |archive-date=6 February 2007 |author-link=Pfizer }}</ref> MPA does not appear to be associated with [[Medicine:Vitamin B12 deficiency|vitamin B<sub>12</sub> deficiency]].<ref name="pmid720068">{{cite journal | vauthors = Amatayakul K, Sivasomboon B, Thanangkul O | title = Vitamin and trace mineral metabolism in medroxyprogesterone acetate users | journal = Contraception | volume = 18 | issue = 3 | pages = 253–69 | date = September 1978 | pmid = 720068 | doi = 10.1016/s0010-7824(78)80019-5 }}</ref> Data on weight gain with DMPA likewise are inconsistent.<ref name="Nelson2014" /><ref name="Aronson2015" />

At high doses for the treatment of breast cancer, MPA can cause weight gain and can worsen [[Medicine:Diabetes mellitus|diabetes mellitus]] and [[Medicine:Edema|edema]] (particularly of the face). Adverse effects peak at five weeks, and are reduced with lower doses. Less frequent effects may include [[Medicine:Thrombosis|thrombosis]] (though it is not clear if this is truly a risk, it cannot be ruled out), painful urination, [[Medicine:Headache|headache]], nausea, and [[Medicine:Vomiting|vomiting]]. When used as a form of [[Chemistry:Androgen deprivation therapy|androgen deprivation therapy]] in men, more frequent complaints include reduced [[Philosophy:Libido|libido]], impotence, reduced [[Medicine:Ejaculation|ejaculate]] volume, and within three days, chemical castration. At extremely high doses (used to treat cancer, not for contraception) MPA may cause adrenal suppression and may interfere with carbohydrate metabolism, but does not cause [[Medicine:Diabetes mellitus|diabetes]].<ref name=Meyler>{{cite book | vauthors = Meyler L | title = Meyler's side effects of endocrine and metabolic drugs | publisher = [[Company:Elsevier|Elsevier Science]] | location = Amsterdam | year = 2009 | url = https://books.google.com/books?id=BWMeSwVwfTkC&pg=PA281 | pages = 281–284] | isbn = 978-0-444-53271-8 | url-status = live | archive-url = https://web.archive.org/web/20141023181123/http://books.google.com/books?id=BWMeSwVwfTkC&pg=PA281 | archive-date = 23 October 2014 }}</ref>

When used as a form of injected birth control, there is a delayed return of fertility. The average return to fertility is 9 to 10 months after the last injection, taking longer for overweight or obese women. By 18 months after the last injection, fertility is the same as that in former users of other contraceptive methods.<ref name="hatcher"/><ref name="speroff"/> [[Biology:Fetus|Fetus]]es exposed to progestogens have demonstrated higher rates of genital abnormalities, low birth weight, and increased [[Medicine:Ectopic pregnancy|ectopic pregnancy]] particularly when MPA is used as an injected form of long-term birth control. A study of accidental pregnancies among poor women in Thailand found that infants who had been exposed to DMPA during pregnancy had a higher risk of low birth weight and an 80% greater-than-usual chance of dying in the first year of life.<ref>{{cite journal | title = Exposure to DMPA in pregnancy may cause low birth weight | journal = Progress in Human Reproduction Research | issue = 23 | pages = 2–3 | year = 1992 | pmid = 12286194 }}</ref>

===Mood changes===
There have been concerns about a possible risk of [[Medicine:Depression (mood)|depression]] and mood changes with progestins like MPA, and this has led to reluctance of some clinicians and women to use them.<ref name="Lobo2007">{{cite book| vauthors = Lobo RA |title=Treatment of the Postmenopausal Woman: Basic and Clinical Aspects|url=https://books.google.com/books?id=gywV9hkcyOMC&pg=PA211|date=5 June 2007|publisher=Elsevier|isbn=978-0-08-055309-2|pages=211–}}</ref><ref name="pmid10338269">{{cite journal | vauthors = Kaunitz AM | title = Long-acting hormonal contraception: assessing impact on bone density, weight, and mood | journal = Int J Fertil Womens Med | volume = 44 | issue = 2 | pages = 110–7 | date = 1999 | pmid = 10338269 | quote = Despite the efficacy and increasing acceptability of these long-term methods, some clinicians and women are reluctant to use them because of concerns regarding reduction in bone density with DMPA, and depressive symptoms and body weight issues with both injectables and implants. Recent multicenter experience showed no increase in depressive symptoms after 1 year's DMPA use and 2 years' Norplant use, even among users with the highest mean depressive symptom scores pre-therapy.}}</ref> However, contrary to widely-held beliefs, most research suggests that progestins do not cause adverse psychological effects such as depression or [[Medicine:Anxiety|anxiety]].<ref name="Lobo2007" /> A 2018 systematic review of the relationship between progestin-based contraception and depression included three large studies of DMPA and reported no association between DMPA and depression.<ref name="pmid29496297">{{cite journal | vauthors = Worly BL, Gur TL, Schaffir J | title = The relationship between progestin hormonal contraception and depression: a systematic review | journal = Contraception | volume = 97| issue = 6| pages = 478–489| date = February 2018 | pmid = 29496297 | doi = 10.1016/j.contraception.2018.01.010 | s2cid = 3644828 }}</ref> According to a 2003 review of DMPA, the majority of published clinical studies indicate that DMPA is not associated with depression, and the overall data support the notion that the medication does not significantly affect mood.<ref name="pmid12954518">{{cite journal | vauthors = Westhoff C | title = Depot-medroxyprogesterone acetate injection (Depo-Provera): a highly effective contraceptive option with proven long-term safety | journal = Contraception | volume = 68 | issue = 2 | pages = 75–87 | date = August 2003 | pmid = 12954518 | doi = 10.1016/s0010-7824(03)00136-7| quote = Another common patient tolerability concern reported with hormonal contraception is the effect on mood [95]. The majority of published reports indicate that DMPA does not cause depressive symptoms. In a large, 1-year, clinical trial of DMPA in 3857 US women, fewer than 2% of users reported depression [15]. Other reports in various settings, including a private practice [96], adolescent clinics [97,98], a psychiatric hospital [99] and inner-city family-planning clinics [100,101], have not found an adverse effect of DMPA on depression. [...] Using a variety of objective indices for depressive symptoms, the overall data for both OCs and DMPA are supportive that these agents have no significant effect on mood. Although history of mood symptoms prior to OC use may predispose a subgroup of women to negative mood changes, the data for DMPA suggest that even women who have depressive symptoms prior to treatment can tolerate therapy with no exacerbation of these symptoms.}}</ref>

In the largest study to have assessed the relationship between MPA and depression to date, in which over 3,900&nbsp;women were treated with DMPA for up to 7&nbsp;years, the incidence of depression was infrequent at 1.5% and the discontinuation rate due to depression was 0.5%.<ref name="pmid29496297" /><ref name="pmid18470526">{{cite journal | vauthors = Bakry S, Merhi ZO, Scalise TJ, Mahmoud MS, Fadiel A, Naftolin F | title = Depot-medroxyprogesterone acetate: an update | journal = Arch. Gynecol. Obstet. | volume = 278 | issue = 1 | pages = 1–12 | date = July 2008 | pmid = 18470526 | doi = 10.1007/s00404-007-0497-z | s2cid = 11340062 }}</ref><ref name="pmid9649914">{{cite journal | vauthors = Westhoff C, Truman C, Kalmuss D, Cushman L, Davidson A, Rulin M, Heartwell S | title = Depressive symptoms and Depo-Provera | journal = Contraception | volume = 57 | issue = 4 | pages = 237–40 | date = April 1998 | pmid = 9649914 | doi = 10.1016/s0010-7824(98)00024-9| doi-access = free }}</ref> This study did not include baseline data on depression,<ref name="pmid9649914" /> and due to the incidence of depression in the study, the FDA required package labeling for DMPA stating that women with depression should be observed carefully and that DMPA should be discontinued if depression recurs.<ref name="pmid29496297" /> A subsequent study of 495&nbsp;women treated with DMPA over the course of 1&nbsp;year found that the mean depression score slightly decreased in the whole group of continuing users from 7.4 to 6.7 (by 9.5%) and decreased in the quintile of that group with the highest depression scores at baseline from 15.4 to 9.5 (by 38%).<ref name="pmid9649914" /> Based on the results of this study and others, a consensus began emerging that DMPA does not in fact increase the risk of depression nor worsen the severity of pre-existing depression.<ref name="Aronson2015">{{cite book| vauthors = Aronson JK |title=Meyler's Side Effects of Drugs: The International Encyclopedia of Adverse Drug Reactions and Interactions|url=https://books.google.com/books?id=NOKoBAAAQBAJ&pg=RA2-PA836|date=15 October 2015|publisher=Elsevier Science|isbn=978-0-444-53716-4|pages=2–|quote=Perhaps surprisingly, a consensus seems to be emerging that depot medroxyprogesterone acetate implants do not in fact result in an increase in the incidence of depression or in the severity of pre-existing depression, even after 1 or 2 years, nor do they cause significant weight gain.}}</ref><ref name="pmid9649914" /><ref name="pmid18470526" />

Similarly to the case of DMPA for hormonal contraception, the Heart and Estrogen/Progestin Replacement Study (HERS), a study of 2,763 postmenopausal women treated with 0.625&nbsp;mg/day oral CEEs plus 2.5&nbsp;mg/day oral MPA or placebo for 36&nbsp;months as a method of menopausal hormone therapy, found no change in depressive symptoms.<ref name="FinkPfaff2011">{{cite book| vauthors = Fink G, Pfaff DW, Levine J |title=Handbook of Neuroendocrinology|url=https://books.google.com/books?id=Disx7IryLxUC&pg=PA564|date=31 August 2011|publisher=Academic Press|isbn=978-0-12-378554-1|pages=564–}}</ref><ref name="Ryden2009">{{cite book| vauthors = Ryden J |title=Practical Gynecology: A Guide for the Primary Care Physician|url=https://books.google.com/books?id=Nxct2LPHIsEC&pg=PA379|year=2009|publisher=ACP Press|isbn=978-1-934465-05-9|pages=379–}}</ref><ref name="pmid11829697">{{cite journal | vauthors = Hlatky MA, Boothroyd D, Vittinghoff E, Sharp P, Whooley MA | title = Quality-of-life and depressive symptoms in postmenopausal women after receiving hormone therapy: results from the Heart and Estrogen/Progestin Replacement Study (HERS) trial | journal = JAMA | volume = 287 | issue = 5 | pages = 591–7 | date = February 2002 | pmid = 11829697 | doi = 10.1001/jama.287.5.591 | doi-access = free }}</ref> However, some small studies have reported that progestins like MPA might counteract beneficial effects of estrogens against depression.<ref name="Lobo2007" /><ref name="pmid16112947" /><ref name="pmid15358281">{{cite journal | vauthors = Wiegratz I, Kuhl H | title = Progestogen therapies: differences in clinical effects? | journal = Trends Endocrinol. Metab. | volume = 15 | issue = 6 | pages = 277–85 | date = August 2004 | pmid = 15358281 | doi = 10.1016/j.tem.2004.06.006 | s2cid = 35891204 }}</ref>

===Long-term effects===
The [[Medicine:Women's Health Initiative|Women's Health Initiative]] investigated the use of a combination of oral CEEs and MPA compared to placebo. The study was prematurely terminated when previously unexpected risks were discovered, specifically the finding that though the all-cause mortality was not affected by the hormone therapy, the benefits of menopausal hormone therapy (reduced risk of [[Medicine:Hip fracture|hip fracture]], [[Medicine:Colorectal cancer|colorectal]] and [[Medicine:Endometrial cancer|endometrial cancer]] and all other causes of death) were offset by increased risk of coronary heart disease, [[Medicine:Breast cancer|breast cancer]], [[Medicine:Stroke|stroke]]s and [[Medicine:Pulmonary embolism|pulmonary embolism]].<ref>{{cite journal | vauthors = Rossouw JE, Anderson GL, [[Biography:Ross Prentice|Prentice RL]], LaCroix AZ, Kooperberg C, Stefanick ML, Jackson RD, Beresford SA, Howard BV, Johnson KC, Kotchen JM, Ockene J | title = Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results From the Women's Health Initiative randomized controlled trial | journal = JAMA | volume = 288 | issue = 3 | pages = 321–33 | date = July 2002 | pmid = 12117397 | doi = 10.1001/jama.288.3.321 | s2cid = 20149703 | url = https://escholarship.org/content/qt3mr6f93p/qt3mr6f93p.pdf?t=prll4c }}</ref>

When combined with CEEs, MPA has been associated with an increased risk of breast cancer, [[Medicine:Dementia|dementia]], and [[Medicine:Thrombus|thrombus]] in the eye. In combination with estrogens in general, MPA may increase the risk of [[Medicine:Cardiovascular disease|cardiovascular disease]], with a stronger association when used by [[Medicine:Menopause|postmenopausal]] women also taking CEEs. It was because of these unexpected interactions that the [[Medicine:Women's Health Initiative|Women's Health Initiative]] study was ended early due to the extra risks of menopausal hormone therapy,<ref>{{cite journal | vauthors = Prentice RL, Anderson GL | title = The women's health initiative: lessons learned | journal = Annual Review of Public Health | volume = 29 | pages = 131–50 | year = 2008 | pmid = 18348708 | doi = 10.1146/annurev.publhealth.29.020907.090947 | doi-access = free }}</ref> resulting in a dramatic decrease in both new and renewal prescriptions for hormone therapy.<ref>{{cite journal | vauthors = Buist DS, Newton KM, [[Biography:Diana Miglioretti|Miglioretti DL]], Beverly K, Connelly MT, Andrade S, Hartsfield CL, Wei F, Chan KA, Kessler L | title = Hormone therapy prescribing patterns in the United States | journal = Obstetrics and Gynecology | volume = 104 | issue = 5 Pt 1 | pages = 1042–50 | date = November 2004 | pmid = 15516400 | doi = 10.1097/01.AOG.0000143826.38439.af | s2cid = 31593637 }}</ref>

Long-term studies of users of DMPA have found slight or no increased overall risk of breast cancer. However, the study population did show a slightly increased risk of breast cancer in recent users (DMPA use in the last four years) under age 35, similar to that seen with the use of [[Chemistry:Combined oral contraceptive pill|combined oral contraceptive pill]]s.<ref name="depo us patient info"/>

{{Health risks in the conjugated estrogens and medroxyprogesterone acetate substudy of the Women's Health Initiative}}

====Blood clots====
DMPA has been associated in multiple studies with a higher risk of venous thromboembolism (VTE) when used as a form of progestogen-only birth control in premenopausal women.<ref name="pmid30008249">{{cite journal | vauthors = Beyer-Westendorf J, Bauersachs R, Hach-Wunderle V, Zotz RB, Rott H | title = Sex hormones and venous thromboembolism - from contraception to hormone replacement therapy | journal = VASA. Zeitschrift für Gefässkrankheiten | volume = 47 | issue = 6 | pages = 441–450 | date = October 2018 | pmid = 30008249 | doi = 10.1024/0301-1526/a000726 | s2cid = 51628832 }}</ref><ref name="pmid21559819">{{cite journal | vauthors = DeLoughery TG | title = Estrogen and thrombosis: controversies and common sense | journal = Reviews in Endocrine & Metabolic Disorders | volume = 12 | issue = 2 | pages = 77–84 | date = June 2011 | pmid = 21559819 | doi = 10.1007/s11154-011-9178-0 | s2cid = 28053690 }}</ref><ref name="ManthaKarp2012">{{cite journal | vauthors = Mantha S, Karp R, Raghavan V, Terrin N, Bauer KA, Zwicker JI | title = Assessing the risk of venous thromboembolic events in women taking progestin-only contraception: a meta-analysis | journal = BMJ | volume = 345 | issue = aug07 2 | pages = e4944 | date = August 2012 | pmid = 22872710 | pmc = 3413580 | doi = 10.1136/bmj.e4944 }}</ref><ref name="pmid30741807">{{cite journal | vauthors = Tepper NK, Jeng G, Curtis KM, Boutot ME, Boulet SL, Whiteman MK | title = Venous Thromboembolism Among Women Initiating Depot Medroxyprogesterone Acetate Immediately Postpartum | journal = Obstetrics and Gynecology | volume = 133 | issue = 3 | pages = 533–540 | date = March 2019 | pmid = 30741807 | doi = 10.1097/AOG.0000000000003135 | doi-access = free }}</ref> The increase in incidence of VTE ranges from 2.2-fold to 3.6-fold.<ref name="pmid30008249" /><ref name="pmid21559819" /><ref name="ManthaKarp2012" /><ref name="pmid30741807" /> Elevated risk of VTE with DMPA is unexpected, as DMPA has little or no effect on coagulation and fibrinolytic factors,<ref name="Van Hylckama VliegMiddeldorp2011">{{cite journal | vauthors = van Hylckama Vlieg A, Middeldorp S | title = Hormone therapies and venous thromboembolism: where are we now? | journal = Journal of Thrombosis and Haemostasis | volume = 9 | issue = 2 | pages = 257–266 | date = February 2011 | pmid = 21114755 | doi = 10.1111/j.1538-7836.2010.04148.x | s2cid = 32394836 | doi-access = free }}</ref><ref name="BenagianoPrimiero1983">{{cite journal | vauthors = Benagiano G, Primiero FM | title = Long acting contraceptives. Present status | journal = Drugs | volume = 25 | issue = 6 | pages = 570–609 | date = June 1983 | pmid = 6223801 | doi = 10.2165/00003495-198325060-00003 | s2cid = 45898359 }}</ref> and progestogens by themselves normally do not increase the risk of thrombosis.<ref name="pmid21559819" /><ref name="ManthaKarp2012" /> It has been argued that the higher incidence with DMPA has reflected preferential prescription of DMPA to women considered to be at an increased risk of VTE.<ref name="pmid21559819" /> Alternatively, it is possible that MPA may be an exception among progestins in terms of VTE risk.<ref name="pmid30669160">{{cite journal | vauthors = Rott H | title = Birth Control Pills and Thrombotic Risks: Differences of Contraception Methods with and without Estrogen | journal = Hamostaseologie | volume = 39 | issue = 1 | pages = 42–48 | date = February 2019 | pmid = 30669160 | doi = 10.1055/s-0039-1677806 | s2cid = 58947063 }}</ref><ref name="pmid29570359">{{cite journal | vauthors = Scarabin PY | title = Progestogens and venous thromboembolism in menopausal women: an updated oral versus transdermal estrogen meta-analysis | journal = Climacteric | volume = 21 | issue = 4 | pages = 341–345 | date = August 2018 | pmid = 29570359 | doi = 10.1080/13697137.2018.1446931 | s2cid = 4229701 }}</ref><ref name="pmid21538049">{{cite journal | vauthors = Sitruk-Ware R, Nath A | title = Metabolic effects of contraceptive steroids | journal = Reviews in Endocrine & Metabolic Disorders | volume = 12 | issue = 2 | pages = 63–75 | date = June 2011 | pmid = 21538049 | doi = 10.1007/s11154-011-9182-4 | s2cid = 23760705 }}</ref> A 2018 [[Meta-analysis|meta-analysis]] reported that MPA was associated with a 2.8-fold higher risk of VTE than other progestins.<ref name="pmid29570359" /> It is possible that the [[Chemistry:Glucocorticoid|glucocorticoid]] activity of MPA may increase the risk of VTE.<ref name="pmid16112947" /><ref name="Kuhl2011" /><ref name="pmid21538049" />

====Bone density====
DMPA may cause reduced [[Physics:Bone density|bone density]] in premenopausal women and in men when used without an estrogen, particularly at high doses, though this appears to be reversible to a normal level even after years of use.

On 17 November 2004, the United States [[Organization:Food and Drug Administration|Food and Drug Administration]] put a [[Medicine:Boxed warning|black box warning]] on the label, indicating that there were potential adverse effects of loss of bone mineral density.<ref>{{cite web |url=http://www.acog.org |title=Depot medroxyprogesterone acetate and bone effects. Committee Opinion #602 |date=June 2014 |access-date=3 May 2015 |url-status=live |archive-url=https://web.archive.org/web/20150430112715/http://www.acog.org/ |archive-date=30 April 2015}}</ref><ref name="FDA2004-Warning">{{cite web |author=FDA |date=17 November 2004 |url=https://www.fda.gov/bbs/topics/ANSWERS/2004/ANS01325.html |title=Black Box Warning Added Concerning Long-Term Use of Depo-Provera Contraceptive Injection |website=[[Organization:Food and Drug Administration|Food and Drug Administration]] |access-date=12 May 2006 |archive-url=https://web.archive.org/web/20051221195621/https://www.fda.gov/bbs/topics/ANSWERS/2004/ANS01325.html |archive-date=21 December 2005}}</ref> While it causes temporary [[Medicine:Osteoporosis|bone loss]], most women fully regain their bone density after discontinuing use.<ref name="Nelson2014">{{cite journal| vauthors = Nelson AL |title=DMPA: battered and bruised but still needed and used in the USA|journal=Expert Review of Obstetrics & Gynecology|volume=5|issue=6|year=2014|pages=673–686|issn=1747-4108|doi=10.1586/eog.10.60}}</ref> The [[Organization:World Health Organization|World Health Organization]] (WHO) recommends that the use not be restricted.<ref name="WHO2005">{{cite web | author =World Health Organization |author-link =World Health Organization | date =September 2005 | url =https://www.who.int/reproductive-health/family_planning/bone_health.html |title =Hormonal contraception and bone health | work =Family Planning | access-date =12 May 2006 |url-status=dead |archive-url =https://web.archive.org/web/20060514022320/http://www.who.int/reproductive-health/family_planning/bone_health.html |archive-date =14 May 2006 }}</ref><ref name="Contraception2006-Curtis">{{cite journal | vauthors = Curtis KM, Martins SL | title = Progestogen-only contraception and bone mineral density: a systematic review | journal = Contraception | volume = 73 | issue = 5 | pages = 470–87 | date = May 2006 | pmid = 16627031 | doi = 10.1016/j.contraception.2005.12.010 | url = https://zenodo.org/record/1258855 }}</ref> The American College of Obstetricians and Gynecologists notes that the potential adverse effects on BMD be balanced against the known negative effects of unintended pregnancy using other birth control methods or no method, particularly among adolescents.

Three studies have suggested that bone loss is reversible after the discontinuation of DMPA.<ref>{{cite journal | vauthors = Cundy T, Cornish J, Evans MC, Roberts H, Reid IR | title = Recovery of bone density in women who stop using medroxyprogesterone acetate | journal = BMJ | volume = 308 | issue = 6923 | pages = 247–8 | date = January 1994 | pmid = 8111260 | pmc = 2539337 | doi = 10.1136/bmj.308.6923.247 }}</ref><ref name="Scholes2002">{{cite journal | vauthors = Scholes D, LaCroix AZ, Ichikawa LE, Barlow WE, Ott SM | title = Injectable hormone contraception and bone density: results from a prospective study | journal = Epidemiology | volume = 13 | issue = 5 | pages = 581–7 | date = September 2002 | pmid = 12192229 | doi = 10.1097/00001648-200209000-00015 | doi-access = free }}</ref><ref name="Scholes2005">{{cite journal | vauthors = Scholes D, LaCroix AZ, Ichikawa LE, Barlow WE, Ott SM | title = Change in bone mineral density among adolescent women using and discontinuing depot medroxyprogesterone acetate contraception | journal = Archives of Pediatrics & Adolescent Medicine | volume = 159 | issue = 2 | pages = 139–44 | date = February 2005 | pmid = 15699307 | doi = 10.1001/archpedi.159.2.139 | doi-access = free }}</ref> Other studies have suggested that the effect of DMPA use on postmenopausal bone density is minimal,<ref>{{cite journal | vauthors = Orr-Walker BJ, Evans MC, Ames RW, Clearwater JM, Cundy T, Reid IR | title = The effect of past use of the injectable contraceptive depot medroxyprogesterone acetate on bone mineral density in normal post-menopausal women | journal = Clinical Endocrinology | volume = 49 | issue = 5 | pages = 615–8 | date = November 1998 | pmid = 10197077 | doi = 10.1046/j.1365-2265.1998.00582.x | s2cid = 22565912 }}</ref> perhaps because DMPA users experience less bone loss at menopause.<ref>{{cite journal | vauthors = Cundy T, Cornish J, Roberts H, Reid IR | title = Menopausal bone loss in long-term users of depot medroxyprogesterone acetate contraception | journal = American Journal of Obstetrics and Gynecology | volume = 186 | issue = 5 | pages = 978–83 | date = May 2002 | pmid = 12015524 | doi = 10.1067/mob.2002.122420 }}</ref> Use after peak bone mass is associated with increased bone turnover but no decrease in bone mineral density.<ref>{{cite journal | vauthors = Walsh JS, Eastell R, Peel NF | title = Depot medroxyprogesterone acetate use after peak bone mass is associated with increased bone turnover but no decrease in bone mineral density | journal = Fertility and Sterility | volume = 93 | issue = 3 | pages = 697–701 | date = February 2010 | pmid = 19013564 | doi = 10.1016/j.fertnstert.2008.10.004 | doi-access = free }}</ref>

The FDA recommends that DMPA not be used for longer than two years, unless there is no viable alternative method of contraception, due to concerns over bone loss.<ref name="FDA2004-Warning"/> However, a 2008 Committee Opinion from the American Congress of Obstetricians and Gynecologists (ACOG) advises healthcare providers that concerns about bone mineral density loss should neither prevent the prescription of or continuation of DMPA beyond two years of use.<ref name="pmid18757687">{{cite journal | title = ACOG Committee Opinion No. 415: Depot medroxyprogesterone acetate and bone effects | journal = Obstetrics and Gynecology | volume = 112 | issue = 3 | pages = 727–30 | date = September 2008 | pmid = 18757687 | doi = 10.1097/AOG.0b013e318188d1ec | author1 = American College of Obstetricians Gynecologists Committee on Gynecologic Practice | doi-access = free }}</ref>

===HIV risk===
There is uncertainty regarding the risk of HIV acquisition among DMPA users; some observational studies suggest an increased risk of HIV acquisition among women using DMPA, while others do not.<ref>{{cite journal | vauthors = Polis CB, Phillips SJ, Curtis KM, Westreich DJ, Steyn PS, Raymond E, Hannaford P, Turner AN | title = Hormonal contraceptive methods and risk of HIV acquisition in women: a systematic review of epidemiological evidence | journal = Contraception | volume = 90 | issue = 4 | pages = 360–90 | date = October 2014 | pmid = 25183264 | doi = 10.1016/j.contraception.2014.07.009 | url = http://www.contraceptionjournal.org/article/S0010-7824(14)00571-X/pdf | doi-access = free | hdl = 2164/4151 | hdl-access = free }}</ref> The World Health Organization issued statements in February 2012 and July 2014 saying the data did not warrant changing their recommendation of no restriction – Medical Eligibility for Contraception (MEC) category 1 – on the use of DMPA in women at high risk for HIV.<ref>{{cite web|author=WHO Department of Reproductive Health and Research|date=16 February 2012|title=Technical Statement: Hormonal contraception and HIV|location=Geneva|publisher=World Health Organization|url=https://www.who.int/reproductivehealth/publications/family_planning/rhr_12_8/en/|url-status=dead|archive-url=https://web.archive.org/web/20150130063224/http://www.who.int/reproductivehealth/publications/family_planning/rhr_12_8/en/|archive-date=30 January 2015}}</ref><ref>{{cite web|author=WHO Department of Reproductive Health and Research|date=23 July 2014|title=2014 Guidance Statement: Hormonal contraceptive methods for women at high risk of HIV and living with HIV|location=Geneva|publisher=World Health Organization|url=http://apps.who.int/iris/bitstream/10665/128537/1/WHO_RHR_14.24_eng.pdf|url-status=dead|archive-url=https://web.archive.org/web/20150130063143/http://apps.who.int/iris/bitstream/10665/128537/1/WHO_RHR_14.24_eng.pdf|archive-date=30 January 2015}}</ref> Two meta-analyses of observational studies in sub-Saharan Africa were published in January 2015.<ref>{{cite web|author=AVAC|date=27 January 2015|title=News from the HC-HIV front: it's raining meta (analyses)!|location=New York|publisher=AIDS Vaccine Advocacy Coalition|url=http://www.avac.org/blog/news-hc-hiv-front|url-status=live|archive-url=https://web.archive.org/web/20150130053427/http://www.avac.org/blog/news-hc-hiv-front|archive-date=30 January 2015}}</ref> They found a 1.4- to 1.5-fold increase risk of HIV acquisition for DMPA users relative to no hormonal contraceptive use.<ref>{{cite journal | vauthors = Ralph LJ, McCoy SI, Shiu K, Padian NS | title = Hormonal contraceptive use and women's risk of HIV acquisition: a meta-analysis of observational studies | journal = The Lancet. Infectious Diseases | volume = 15 | issue = 2 | pages = 181–9 | date = February 2015 | pmid = 25578825 | doi = 10.1016/S1473-3099(14)71052-7 | pmc=4526270}}</ref><ref>{{cite journal | vauthors = Morrison CS, Chen PL, Kwok C, Baeten JM, Brown J, Crook AM, Van Damme L, Delany-Moretlwe S, Francis SC, Friedland BA, Hayes RJ, Heffron R, Kapiga S, Karim QA, Karpoff S, Kaul R, McClelland RS, McCormack S, McGrath N, Myer L, Rees H, van der Straten A, Watson-Jones D, van de Wijgert JH, Stalter R, Low N | title = Hormonal contraception and the risk of HIV acquisition: an individual participant data meta-analysis | journal = PLOS Medicine | volume = 12 | issue = 1 | page = e1001778 | date = January 2015 | pmid = 25612136 | pmc = 4303292 | doi = 10.1371/journal.pmed.1001778 | doi-access = free }}</ref> In January 2015, the Faculty of Sexual & Reproductive Healthcare of the Royal College of Obstetricians and Gynaecologists issued a statement reaffirming that there is no reason to advise against use of DMPA in the United Kingdom even for women at 'high risk' of HIV infection.<ref>{{cite web|author1=Faculty of Sexual Reproductive Healthcare|date=January 2015|title=CEU Statement: Depot medroxyprogesterone acetate (DMPA, Depo-Provera) and risk of HIV acquisition|location=London|publisher=Royal College of Obstetricians and Gynaecologists|url=http://www.fsrh.org/pdfs/CEUStatementDMPAandHIV.pdf|url-status=dead|archive-url=https://web.archive.org/web/20150130073139/http://www.fsrh.org/pdfs/CEUStatementDMPAandHIV.pdf|archive-date=30 January 2015}}</ref> A systematic review and meta-analysis of risk of HIV infection in DMPA users published in fall of 2015 stated that "the epidemiological and biological evidence now make a compelling case that DMPA adds significantly to the risk of male-to-female HIV transmission."<ref name="pmid26710371">{{cite journal | vauthors = Brind J, Condly SJ, Mosher SW, Morse AR, Kimball J | title = Risk of HIV Infection in Depot-Medroxyprogesterone Acetate (DMPA) Users: A Systematic Review and Meta-analysis | journal = Issues Law Med | volume = 30 | issue = 2 | pages = 129–39 | date = 2015 | pmid = 26710371 }}</ref> In 2019, a randomized controlled trial found no significant association between DMPA use and HIV.<ref name=ECHO2019>{{cite journal |author=ECHO Trial Consortium | title = HIV incidence among women using intramuscular depot medroxyprogesterone acetate, a copper intrauterine device, or a levonorgestrel implant for contraception: a randomised, multicentre, open-label trial | journal = The Lancet | volume = 394| issue = 10195| pages = 303–313|date=13 June 2019 |doi=10.1016/S0140-6736(19)31288-7 | pmid = 31204114 |doi-access=free | pmc=6675739}}</ref>

==Breastfeeding==
MPA may be used by [[Social:Breastfeeding|breastfeeding]] mothers. Heavy bleeding is possible if given in the immediate postpartum time and is best delayed until six weeks after birth. It may be used within five days if not breast feeding. While a study showed "no significant difference in birth weights or incidence of birth defects" and "no significant alternation of immunity to infectious disease caused by breast milk containing DMPA", a subgroup of babies whose mothers started DMPA at two days postpartum had a 75% higher incidence of doctor visits for infectious diseases during their first year of life.<ref>{{cite journal | vauthors = Dahlberg K | title = Some effects of depo-medroxyprogesterone acetate (DMPA): observations in the nursing infant and in the long-term user | journal = International Journal of Gynaecology and Obstetrics | volume = 20 | issue = 1 | pages = 43–8 | date = February 1982 | pmid = 6126406 | doi = 10.1016/0020-7292(82)90044-3 | s2cid = 8295162 }}</ref>

A larger study with longer follow-up concluded that "use of DMPA during pregnancy or breastfeeding does not adversely affect the long-term growth and development of children". This study also noted that "children with DMPA exposure during pregnancy and lactation had an increased risk of suboptimal growth in height," but that "after adjustment for socioeconomic factors by multiple logistic regression, there was no increased risk of impaired growth among the DMPA-exposed children." The study also noted that effects of DMPA exposure on puberty require further study, as so few children over the age of 10 were observed.<ref>{{cite journal | vauthors = Pardthaisong T, Yenchit C, Gray R | title = The long-term growth and development of children exposed to Depo-Provera during pregnancy or lactation | journal = Contraception | volume = 45 | issue = 4 | pages = 313–24 | date = April 1992 | pmid = 1387602 | doi = 10.1016/0010-7824(92)90053-V }}</ref>

==Overdose==
MPA has been studied at "massive" dosages of up to 5,000&nbsp;mg per day orally and 2,000&nbsp;mg per day via intramuscular injection, without major [[Medicine:Tolerability|tolerability]] or [[Medicine:Drug safety|safety]] issues described.<ref name="pmid1390312" /><ref name="pmid350387">{{cite journal | vauthors = Pannuti F, Martoni A, Lenaz GR, Piana E, Nanni P | title = A possible new approach to the treatment of metastatic breast cancer: massive doses of medroxyprogesterone acetate | journal = Cancer Treat Rep | volume = 62 | issue = 4 | pages = 499–504 | date = April 1978 | pmid = 350387 }}</ref><ref name="pmid9452274">{{cite journal | vauthors = Simons JP, Schols AM, Hoefnagels JM, Westerterp KR, ten Velde GP, Wouters EF | title = Effects of medroxyprogesterone acetate on food intake, body composition, and resting energy expenditure in patients with advanced, nonhormone-sensitive cancer: a randomized, placebo-controlled trial | journal = Cancer | volume = 82 | issue = 3 | pages = 553–60 | date = February 1998 | pmid = 9452274 | doi = 10.1002/(sici)1097-0142(19980201)82:3<553::aid-cncr18>3.0.co;2-0| doi-access = free }}</ref> Overdose is not described in the [[Organization:Food and Drug Administration|Food and Drug Administration]] (FDA) product labels for injected MPA (Depo-Provera or Depo-SubQ Provera 104).<ref name="DepoProveraLabel" /><ref name="DepoSubQProveraLabel" /> In the FDA product label for oral MPA (Provera), it is stated that overdose of an estrogen and progestin may cause nausea and [[Medicine:Vomiting|vomiting]], breast tenderness, [[Medicine:Dizziness|dizziness]], [[Medicine:Abdominal pain|abdominal pain]], drowsiness, fatigue, and withdrawal bleeding.<ref name="ProveraLabel" /> According to the label, treatment of overdose should consist of discontinuation of MPA therapy and symptomatic care.<ref name="ProveraLabel" />

==Interactions==
MPA increases the risk of [[Medicine:Breast cancer|breast cancer]], [[Medicine:Dementia|dementia]], and [[Medicine:Thrombus|thrombus]] when used in combination with CEEs to treat menopausal symptoms.<ref name = Merck/> When used as a contraceptive, MPA does not generally [[Medicine:Drug interaction|interact]] with other medications. The combination of MPA with [[Chemistry:Aminoglutethimide|aminoglutethimide]] to treat [[Medicine:Metastasis|metastases]] from breast cancer has been associated with an increase in [[Medicine:Depression (mood)|depression]].<ref name = Meyler/> [[Biology:Hypericum perforatum|St John's wort]] may decrease the effectiveness of MPA as a contraceptive due to acceleration of its [[Biology:Metabolism|metabolism]].<ref name = Merck/>

==Pharmacology==

===Pharmacodynamics===
MPA acts as an [[Biology:Agonist|agonist]] of the [[Biology:Progesterone receptor|progesterone]], [[Biology:Androgen receptor|androgen]], and [[Biology:Glucocorticoid receptor|glucocorticoid receptor]]s (PR, AR, and GR, respectively),<ref name="pmid19434889" /> activating these receptors with [[Chemistry:EC50|EC<sub>50</sub>]] values of approximately 0.01 nM, 1 nM, and 10 nM, respectively.<ref name="Organization2004">{{cite book | author = World Health Organization | title = Residues of Some Veterinary Drugs in Animals and Food: Monographs Prepared by the Sixty-second Meeting of the Joint FAO/WHO Expert Committee on Food Additives, Rome, 4-12 February 2004 | url = https://books.google.com/books?id=4cmezxyAHGUC&pg=PA49 | year = 2004 | publisher = Food & Agriculture Org. | isbn = 978-92-5-105195-5 | page = 49 | url-status = live | archive-url = https://web.archive.org/web/20140617202257/http://books.google.com/books?id=4cmezxyAHGUC&pg=PA49 | archive-date = 17 June 2014 }}</ref> It has negligible affinity for the [[Biology:Estrogen receptor|estrogen receptor]].<ref name="pmid19434889" /> The medication has relatively high affinity for the [[Biology:Mineralocorticoid receptor|mineralocorticoid receptor]], but in spite of this, it has no [[Chemistry:Mineralocorticoid|mineralocorticoid]] or [[Chemistry:Antimineralocorticoid|antimineralocorticoid]] activity.<ref name="pmid16112947" /> The [[Chemistry:Intrinsic activity|intrinsic activities]] of MPA in activating the PR and the AR have been reported to be at least equivalent to those of progesterone and [[Chemistry:Dihydrotestosterone|dihydrotestosterone]] (DHT), respectively, indicating that it is a full agonist of these receptors.<ref name="pmid10077001">{{cite journal | vauthors = Kemppainen JA, Langley E, Wong CI, Bobseine K, Kelce WR, Wilson EM | title = Distinguishing androgen receptor agonists and antagonists: distinct mechanisms of activation by medroxyprogesterone acetate and dihydrotestosterone | journal = Molecular Endocrinology | volume = 13 | issue = 3 | pages = 440–54 | date = March 1999 | pmid = 10077001 | doi = 10.1210/mend.13.3.0255 | doi-access = free }}</ref><ref name="pmid10509795">{{cite journal | vauthors = Bentel JM, Birrell SN, Pickering MA, Holds DJ, Horsfall DJ, Tilley WD | title = Androgen receptor agonist activity of the synthetic progestin, medroxyprogesterone acetate, in human breast cancer cells | journal = Molecular and Cellular Endocrinology | volume = 154 | issue = 1–2 | pages = 11–20 | date = August 1999 | pmid = 10509795 | doi = 10.1016/S0303-7207(99)00109-4 | s2cid = 25584803 }}</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 MPA and related steroids
|-
! {{center|'''Progestogen'''}} !! '''{{abbrlink|PR|Progesterone receptor}}''' !! '''{{abbrlink|AR|Androgen receptor}}''' !! '''{{abbrlink|ER|Estrogen receptor}}''' !! '''{{abbrlink|GR|Glucocorticoid receptor}}''' !! '''{{abbrlink|MR|Mineralocorticoid receptor}}'''
|-
| [[Chemistry:Progesterone (medication)|Progesterone]] || 50 || 0 || 0 || 10 || 100
|-
| [[Chemistry:Chlormadinone acetate|Chlormadinone acetate]] || 67 || 5 || 0 || 8 || 0
|-
| [[Chemistry:Cyproterone acetate|Cyproterone acetate]] || 90 || 6 || 0 || 6 || 8
|-
| Medroxyprogesterone acetate || 115 || 5 || 0 || 29 || 160
|-
| [[Biology:Megestrol acetate|Megestrol acetate]] || 65 || 5 || 0 || 30 || 0
|- class="sortbottom"
| colspan="6" style="width: 1px; background-color:#eaecf0; text-align: center;" | '''Notes:''' Values are percentages (%). Reference [[Biology:Ligand (biochemistry)|ligand]]s (100%) were [[Chemistry:Promegestone|promegestone]] for the {{abbrlink|PR|progesterone receptor}}, [[Chemistry:Metribolone|metribolone]] for the {{abbrlink|AR|androgen receptor}}, [[Chemistry:Estradiol (medication)|estradiol]] for the {{abbrlink|ER|estrogen receptor}}, [[Biology:Dexamethasone|dexamethasone]] for the {{abbrlink|GR|glucocorticoid receptor}}, and [[Chemistry:Aldosterone|aldosterone]] for the {{abbrlink|MR|mineralocorticoid receptor}}. '''Sources:''' <ref name="pmid16112947" />
|}

====Progestogenic activity====
MPA is a potent [[Biology:Agonist|agonist]] of the [[Biology:Progesterone receptor|progesterone receptor]] with similar affinity and [[Chemistry:Intrinsic activity|efficacy]] relative to [[Chemistry:Progesterone (medication)|progesterone]].<ref name="pmid16784762">{{cite journal | vauthors = Pullen MA, Laping N, Edwards R, Bray J | title = Determination of conformational changes in the progesterone receptor using ELISA-like assays | journal = Steroids | volume = 71 | issue = 9 | pages = 792–8 | date = September 2006 | pmid = 16784762 | doi = 10.1016/j.steroids.2006.05.009 | s2cid = 24703323 }}</ref> While both MPA and its deacetylated analogue [[Chemistry:Medroxyprogesterone|medroxyprogesterone]] bind to and agonize the PR, MPA has approximately 100-fold higher [[Chemistry:Dissociation constant|binding affinity]] and [[Biology:Transactivation|transactivation]] potency in comparison.<ref name="pmid16784762" /> As such, unlike MPA, medroxyprogesterone is not used clinically, though it has seen some use in [[Medicine:Veterinary medicine|veterinary medicine]].<ref name="IndexNominum2000" /> The oral dosage of MPA required to inhibit ovulation (i.e., the effective contraceptive dosage) is 10&nbsp;mg/day, whereas 5&nbsp;mg/day was not sufficient to inhibit ovulation in all women.<ref name="pmid6233840">{{cite journal | vauthors = Wikström A, Green B, Johansson ED | title = The plasma concentration of medroxyprogesterone acetate and ovarian function during treatment with medroxyprogesterone acetate in 5 and 10 mg doses | journal = Acta Obstetricia et Gynecologica Scandinavica | volume = 63 | issue = 2 | pages = 163–8 | year = 1984 | pmid = 6233840 | doi = 10.3109/00016348409154654 | s2cid = 45767999 }}</ref> In accordance, the dosage of MPA used in oral contraceptives in the past was 10&nbsp;mg per tablet.<ref name="Blum2013" /> For comparison to MPA, the dosage of [[Chemistry:Progesterone (medication)|progesterone]] required to inhibit ovulation is 300&nbsp;mg/day, whereas that of the 19-nortestosterone derivatives [[Chemistry:Norethisterone|norethisterone]] and [[Chemistry:Norethisterone acetate|norethisterone acetate]] is only 0.4 to 0.5&nbsp;mg/day.<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 }}</ref>

The mechanism of action of progestogen-only contraceptives like DMPA depends on the progestogen activity and dose. High-dose progestogen-only contraceptives, such as DMPA, inhibit [[Biology:Follicular phase|follicular development]] and prevent ovulation as their primary mechanism of action.<ref name="glasier">{{cite book | vauthors = Glasier A |  veditors = DeGroot LJ, Jameson JL | title = Endocrinology | edition = 5th | year = 2006 | publisher = Elsevier Saunders | location = Philadelphia | isbn = 978-0-7216-0376-6 | pages = 2993–3003 | chapter = Contraception }}</ref><ref name="loose">{{cite book | vauthors = Loose DS, Stancel GM | veditors = Loose DS, Stancel GM | year = 2006 | chapter = Estrogens and Progestins |title=Goodman & Gilman's The Pharmacological Basis of Therapeutics |edition=11th |pages=1541–1571 |location=New York |publisher=McGraw-Hill |isbn=0-07-142280-3}}</ref> The progestogen decreases the pulse frequency of [[Biology:Gonadotropin-releasing hormone|gonadotropin-releasing hormone]] (GnRH) release by the [[Biology:Hypothalamus|hypothalamus]], which decreases the release of [[Biology:Follicle-stimulating hormone|follicle-stimulating hormone]] (FSH) and [[Biology:Luteinizing hormone|luteinizing hormone]] (LH) by the [[Medicine:Anterior pituitary|anterior pituitary]]. Decreased levels of FSH inhibit follicular development, preventing an increase in [[Chemistry:Estradiol|estradiol]] levels. Progestogen [[Negative feedback|negative feedback]] and the lack of [[Biology:Estrogen|estrogen]] [[Positive feedback|positive feedback]] on LH release prevent a LH surge. Inhibition of follicular development and the absence of a LH surge prevent ovulation.<ref name="hatcher">{{cite book | vauthors = Hatcher RA | year = 2004 |chapter=Depo-Provera Injections, Implants, and Progestin-Only Pills (Minipills) | veditors = Hatcher RA, Trussell J, Stewart F, Cates W, Stewart GK, Guest F, Kowal D |title=Contraceptive Technology |edition=18th rev. |pages=461–494 |location=New York |publisher=Ardent Media |isbn=0-9664902-5-8}}</ref><ref name="speroff">{{cite book | vauthors = Speroff L, Darney PD | year = 2005 | chapter = Injectable Contraception | title = A Clinical Guide for Contraception | edition = 4th | pages = 201–220 | location = Philadelphia | publisher = Lippincott Williams & Wilkins | isbn = 0-7817-6488-2 }}</ref> A secondary mechanism of action of all progestogen-containing contraceptives is inhibition of [[Biology:Spermatozoon|sperm]] penetration by changes in the cervical mucus.<ref name="rivera">{{cite journal | vauthors = Rivera R, Yacobson I, Grimes D | title = The mechanism of action of hormonal contraceptives and intrauterine contraceptive devices | journal = American Journal of Obstetrics and Gynecology | volume = 181 | issue = 5 Pt 1 | pages = 1263–9 | date = November 1999 | pmid = 10561657 | doi = 10.1016/S0002-9378(99)70120-1 }}</ref> Inhibition of ovarian function during DMPA use causes the endometrium to become thin and atrophic. These changes in the endometrium could, theoretically, prevent implantation. However, because DMPA is highly effective in inhibiting ovulation and sperm penetration, the possibility of fertilization is negligible. No available data support prevention of implantation as a mechanism of action of DMPA.<ref name="rivera"/>

{| class="wikitable sortable mw-collapsible mw-collapsed" style="text-align:left; margin-left:auto; margin-right:auto; border:none;"
|+ class="nowrap" | MPA and related steroids at the progesterone receptor
|-
! Compound !! {{abbr|K<sub>i</sub>|Inhibitory constant}} (nM) !! {{abbrlink|EC<sub>50</sub>|Half-maximal effective concentration}} (nM)<sup>a</sup> !! {{abbrlink|EC<sub>50</sub>|Half-maximal effective concentration}} (nM)<sup>b</sup>
|-
| [[Chemistry:Progesterone (medication)|Progesterone]] || 4.3 || 0.9 || 25
|-
| [[Chemistry:Medroxyprogesterone|Medroxyprogesterone]] || 241 || 47 || 32
|-
| Medroxyprogesterone acetate || 1.2 || 0.6 || 0.15
|- class="sortbottom"
| colspan="4" style="width: 1px; background-color:#eaecf0; text-align: center;" | '''Footnotes:''' <sup>a</sup> = Coactivator recruitment. <sup>b</sup> = Reporter cell line. '''Sources:''' <ref name="pmid16784762" />
|}

{| class="wikitable center sortable mw-collapsible mw-collapsed" style="width:650px; text-align:left; margin-left:auto; margin-right:auto; border:none;"
|+ class="nowrap" | Oral potencies of MPA and related steroids
|-
! Progestogen !! {{abbr|OID|Ovulation-inhibiting dosage}}<br /><small>(mg/day)</small> !! {{abbr|TFD|Endometrial transformation dosage}}<br /><small>(mg/cycle)</small> !! {{abbr|TFD|Endometrial transformation dosage}}<br /><small>(mg/day)</small> !! {{abbr|ODP|Oral dosage in commercial contraceptive preparations}}<br /><small>(mg/day)</small> !! {{abbr|ECD|Estimated comparable dosage}}<br /><small>(mg/day)</small>
|-
| [[Chemistry:Progesterone (medication)|Progesterone]] || 300 || 4200 || 200–300 || – || 200
|-
| [[Chemistry:Chlormadinone acetate|Chlormadinone acetate]] || 1.7 || 20–30 || 10 || 2.0 || 5–10
|-
| [[Chemistry:Cyproterone acetate|Cyproterone acetate]] || 1.0 || 20 || 1.0 || 2.0 || 1.0
|-
| Medroxyprogesterone acetate || 10 || 50 || 5–10 || ? || 5.0
|-
| [[Biology:Megestrol acetate|Megestrol acetate]] || ? || 50 || ? || ? || 5.0
|- class="sortbottom"
| colspan="6" style="width: 1px; background-color:#eaecf0; text-align: center;" | '''Abbreviations:''' OID = ovulation-inhibiting dosage (without additional estrogen). TFD = endometrial transformation dosage. ODP = oral dosage in commercial contraceptive preparations. ECD = estimated comparable dosage. '''Sources:''' <ref name="SchindlerCampagnoli2003" /><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 | url-status = live | archive-url = https://web.archive.org/web/20161011060809/http://www.kup.at/kup/pdf/10168.pdf | archive-date = 11 October 2016 }}</ref><ref name="FritzSperoff2012">{{cite book | vauthors = Fritz MA, Speroff L | title = Clinical Gynecologic Endocrinology and Infertility | url = https://books.google.com/books?id=KZLubBxJEwEC&pg=PA761 | date = 28 March 2012 | publisher = Lippincott Williams & Wilkins | isbn = 978-1-4511-4847-3 | pages = 761– }}</ref>
|}


====Antigonadotropic and anticorticotropic effects====
MPA suppresses the [[Medicine:Hypothalamic–pituitary–adrenal axis|hypothalamic–pituitary–adrenal]] (HPA) and hypothalamic–pituitary–gonadal (HPG) axes at sufficient dosages, resulting decreased levels of [[Biology:Gonadotropin|gonadotropin]]s, [[Biology:Androgen|androgen]]s, [[Biology:Estrogen|estrogen]]s, [[Biology:Adrenocorticotropic hormone|adrenocorticotropic hormone]] (ACTH), and [[Chemistry:Cortisol|cortisol]], as well as levels of sex hormone-binding globulin (SHBG).<ref name="Genazzani1993">{{cite book | vauthors = Genazzani AR | title = Frontiers in Gynecologic and Obstetric Investigation | url = https://books.google.com/books?id=vNZ8Xb8lDF4C&pg=PA320 | date = 15 January 1993 | publisher = Taylor & Francis | isbn = 978-1-85070-486-7 | page = 320 | url-status = live | archive-url = https://web.archive.org/web/20160520164420/https://books.google.com/books?id=vNZ8Xb8lDF4C&pg=PA320 | archive-date = 20 May 2016 }}</ref> There is evidence that the suppressive effects of MPA on the HPG axis are mediated by activation of both the PR and the AR in the [[Medicine:Pituitary gland|pituitary gland]].<ref name="pmid2525057">{{cite journal | vauthors = Poulin R, Baker D, Poirier D, Labrie F | title = Androgen and glucocorticoid receptor-mediated inhibition of cell proliferation by medroxyprogesterone acetate in ZR-75-1 human breast cancer cells | journal = Breast Cancer Research and Treatment | volume = 13 | issue = 2 | pages = 161–72 | date = March 1989 | pmid = 2525057 | doi = 10.1007/bf01806528 | s2cid = 26116247 }}</ref><ref name="pmid12641635">{{cite journal | vauthors = Brady BM, Anderson RA, Kinniburgh D, Baird DT | title = Demonstration of progesterone receptor-mediated gonadotrophin suppression in the human male | journal = Clinical Endocrinology | volume = 58 | issue = 4 | pages = 506–12 | date = April 2003 | pmid = 12641635 | doi = 10.1046/j.1365-2265.2003.01751.x | s2cid = 12567639 | doi-access = free }}</ref> Due to its effects on androgen levels, MPA can produce strong functional [[Biology:Antiandrogen|antiandrogen]]ic effects, and is used in the treatment of [[Chemistry:Androgen-dependent condition|androgen-dependent condition]]s such as [[Medicine:Precocious puberty|precocious puberty]] in boys and [[Medicine:Hypersexuality|hypersexuality]] in men.<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=K2Tpk3qHkwcC&pg=PA44 | date = 11 February 2009 | publisher = Oxford University Press | isbn = 978-0-19-517704-6 | page = 44 | url-status = live | archive-url = https://web.archive.org/web/20140617204821/http://books.google.com/books?id=K2Tpk3qHkwcC&pg=PA44 | archive-date = 17 June 2014 }}</ref> In addition, since the medication suppresses estrogen levels as well, MPA can produce strong functional [[Chemistry:Antiestrogen|antiestrogen]]ic effects similarly, and has been used to treat [[Chemistry:Estrogen-dependent condition|estrogen-dependent condition]]s such as precocious puberty in girls and [[Medicine:Endometriosis|endometriosis]] in women. Due to low estrogen levels, the use of MPA without an estrogen poses a risk of decreased bone mineral density and other symptoms of estrogen deficiency.<ref name="WHO2008">{{cite book | title = WHO Model Formulary 2008 | year = 2009 | isbn = 9789241547659 | vauthors = ((World Health Organization)) | veditors = Stuart MC, Kouimtzi M, Hill SR | hdl = 10665/44053 |  publisher = World Health Organization | page = 368 }}</ref>

Oral MPA has been found to suppress testosterone levels in men by about 30% (from 831&nbsp;ng/dL to 585&nbsp;ng/dL) at a dosage of 20&nbsp;mg/day, by about 45 to 75% (average 60%; to 150–400&nbsp;ng/dL) at a dosage of 60&nbsp;mg/day,<ref name="Lothstein1996">{{cite journal| vauthors = Lothstein LM |title=Antiandrogen treatment for sexual disorders: Guidelines for establishing a standard of care|journal=Sexual Addiction & Compulsivity|volume=3|issue=4|year=1996|pages=313–331|issn=1072-0162|doi=10.1080/10720169608400122}}</ref><ref name="APA1999" /><ref name="pmid8891323">{{cite journal | vauthors = Kravitz HM, Haywood TW, Kelly J, Liles S, Cavanaugh JL | title = Medroxyprogesterone and paraphiles: do testosterone levels matter? | journal = The Bulletin of the American Academy of Psychiatry and the Law | volume = 24 | issue = 1 | pages = 73–83 | date = 1996 | pmid = 8891323 | url = http://jaapl.org/content/24/1/73 }}</ref> and by about 70 to 75% (from 832 to 862&nbsp;ng/dL to 214 to 251&nbsp;ng/dL) at a dosage of 100&nbsp;mg/day.<ref name="pmid6449127">{{cite journal | vauthors = Novak E, Hendrix JW, Chen TT, Seckman CE, Royer GL, Pochi PE | title = Sebum production and plasma testosterone levels in man after high-dose medroxyprogesterone acetate treatment and androgen administration | journal = Acta Endocrinologica | volume = 95 | issue = 2 | pages = 265–270 | date = October 1980 | pmid = 6449127 | doi = 10.1530/acta.0.0950265 }}</ref><ref name="pmid5066846">{{cite journal | vauthors = Kirschner MA, Schneider G | title = Suppression of the pituitary-Leydig cell axis and sebum production in normal men by medroxyprogesterone acetate (provera) | journal = Acta Endocrinologica | volume = 69 | issue = 2 | pages = 385–393 | date = February 1972 | pmid = 5066846 | doi = 10.1530/acta.0.0690385 }}</ref> Dosages of oral MPA of 2.5 to 30&nbsp;mg/day in combination with estrogens have been used to help suppress testosterone levels in transgender women.<ref name="AsschemanGooren1993">{{cite journal| vauthors = Asscheman H, Gooren LJ | name-list-style = vanc |title=Hormone Treatment in Transsexuals|journal=Journal of Psychology & Human Sexuality|volume=5|issue=4|year=1993|pages=39–54|issn=0890-7064|doi=10.1300/J056v05n04_03|s2cid=144580633 }}</ref><ref name="pmid25692882">{{cite journal | vauthors = Meriggiola MC, Gava G | title = Endocrine care of transpeople part II. A review of cross-sex hormonal treatments, outcomes and adverse effects in transwomen | journal = Clinical Endocrinology | volume = 83 | issue = 5 | pages = 607–615 | date = November 2015 | pmid = 25692882 | doi = 10.1111/cen.12754 | s2cid = 39706760 | hdl = 11585/541921 }}</ref><ref name="pmid17986639">{{cite journal | vauthors = Gooren LJ, Giltay EJ, Bunck MC | title = Long-term treatment of transsexuals with cross-sex hormones: extensive personal experience | journal = The Journal of Clinical Endocrinology and Metabolism | volume = 93 | issue = 1 | pages = 19–25 | date = January 2008 | pmid = 17986639 | doi = 10.1210/jc.2007-1809 | doi-access = free }}</ref><ref name="Deutsch2016">{{cite web | vauthors = Deutsch M | title = Guidelines for the Primary and Gender-Affirming Care of Transgender and Gender Nonbinary People | date = 17 June 2016 | edition = 2nd | publisher = Center of Excellence for Transgender Health | location = University of California, San Francisco | page = 28 | url = http://transhealth.ucsf.edu/pdf/Transgender-PGACG-6-17-16.pdf}}</ref><ref name="DahlFeldman2015">{{cite web | vauthors = Dahl M, Feldman JL, Goldberg J, Jaberi A  | title = Endocrine Therapy for Transgender Adults in British Columbia: Suggested Guidelines | publisher = Vancouver Coastal Health | date = 2015 | access-date = 15 August 2018 | url = http://www.phsa.ca/transcarebc/Documents/HealthProf/BC-Trans-Adult-Endocrine-Guidelines-2015.pdf}}</ref><ref name="pmid29756046">{{cite journal | vauthors = Leinung MC, Feustel PJ, Joseph J | title = Hormonal Treatment of Transgender Women with Oral Estradiol | journal = Transgender Health | volume = 3 | issue = 1 | pages = 74–81 | date = 2018 | pmid = 29756046 | pmc = 5944393 | doi = 10.1089/trgh.2017.0035 }}</ref> One study of injectable MPA in men with [[Medicine:Benign prostatic hyperplasia|benign prostatic hyperplasia]] reported that a single 150&nbsp;mg dose suppressed testosterone levels into the defined male castrate range (<58&nbsp;ng/dL) within 7&nbsp;days and that castration levels of testosterone were maintained for 3&nbsp;months.<ref name="pmid">{{cite journal | vauthors = Onu PE | title = Depot medroxyprogesterone in the management of benign prostatic hyperplasia | journal = European Urology | volume = 28 | issue = 3 | pages = 229–235 | date = 1995 | pmid = 8536777 | doi = 10.1159/000475056 }}</ref> Very high doses of intramuscular MPA of 150 to 500&nbsp;mg per week (but up to 900&nbsp;mg per week) have similarly been reported to suppress testosterone levels to less than 100&nbsp;ng/dL.<ref name="Lothstein1996" /><ref name="MeyerWalker1985">{{cite journal | vauthors = Meyer WJ, Walker PA, Emory LE, Smith ER | title = Physical, metabolic, and hormonal effects on men of long-term therapy with medroxyprogesterone acetate | journal = Fertility and Sterility | volume = 43 | issue = 1 | pages = 102–109 | date = January 1985 | pmid = 3155506 | doi = 10.1016/S0015-0282(16)48326-3 | doi-access = free }}</ref> The typical initial dose of intramuscular MPA for testosterone suppression in men with paraphilias is 400 or 500&nbsp;mg per week.<ref name="Lothstein1996" />

====Androgenic activity====
MPA is a potent full agonist of the AR. Its activation of the AR may play an important and major role in its antigonadotropic effects and in its beneficial effects against [[Medicine:Breast cancer|breast cancer]].<ref name="pmid2525057" /><ref name="pmid10819508">{{cite journal | vauthors = Birrell SN, Hall RE, Tilley WD | title = Role of the androgen receptor in human breast cancer | journal = Journal of Mammary Gland Biology and Neoplasia | volume = 3 | issue = 1 | pages = 95–103 | date = January 1998 | pmid = 10819508 | doi = 10.1023/A:1018730519839 | s2cid = 12044431 }}</ref><ref name="pmid16166329">{{cite journal | vauthors = Buchanan G, Birrell SN, Peters AA, Bianco-Miotto T, Ramsay K, Cops EJ, Yang M, Harris JM, Simila HA, Moore NL, Bentel JM, Ricciardelli C, Horsfall DJ, Butler LM, Tilley WD | title = Decreased androgen receptor levels and receptor function in breast cancer contribute to the failure of response to medroxyprogesterone acetate | journal = Cancer Research | volume = 65 | issue = 18 | pages = 8487–96 | date = September 2005 | pmid = 16166329 | doi = 10.1158/0008-5472.CAN-04-3077 | doi-access = free }}</ref> However, although MPA may produce androgenic side effects such as [[Engineering:Acne|acne]] and hirsutism in some women,.<ref name="ReesHope2005">{{cite book | vauthors = Rees MC, Hope S, Ravnikar V | title = The Abnormal Menstrual Cycle | url = https://books.google.com/books?id=B6eFjomeMFcC&pg=PA213 | date = 12 August 2005 | publisher = Taylor & Francis | isbn = 978-1-84214-212-7 | page = 213 | url-status = live | archive-url = https://web.archive.org/web/20131231191143/http://books.google.com/books?id=B6eFjomeMFcC&pg=PA213 | archive-date = 31 December 2013 }}</ref><ref name="Aronson2009">{{cite book | vauthors = Aronson JK |  title = Meyler's Side Effects of Endocrine and Metabolic Drugs | url = https://books.google.com/books?id=BWMeSwVwfTkC&pg=PA283 | date = 20 January 2009 | publisher = Elsevier | isbn = 978-0-444-53271-8 | page = 283 | url-status = live | archive-url = https://web.archive.org/web/20131231191208/http://books.google.com/books?id=BWMeSwVwfTkC&pg=PA283 | archive-date = 31 December 2013 }}</ref> In fact, likely due to its suppressive actions on androgen levels, it has been reported that MPA is generally highly effective in improving pre-existing symptoms of hirsutism in women with the condition.<ref name="pmid590535">{{cite journal | vauthors = Ettinger B, Golditch IM | title = Medroxyprogesterone acetate for the evaluation of hypertestosteronism in hirsute women | journal = Fertility and Sterility | volume = 28 | issue = 12 | pages = 1285–8 | date = December 1977 | pmid = 590535 | doi = 10.1016/S0015-0282(16)42970-5| doi-access = free }}</ref><ref name="pmid1200527">{{cite journal | vauthors = Correa de Oliveira RF, Novaes LP, Lima MB, Rodrigues J, Franco S, Khenaifes AI, Francalanci CP | title = A new treatment for hirsutism | journal = Annals of Internal Medicine | volume = 83 | issue = 6 | pages = 817–9 | date = December 1975 | pmid = 1200527 | doi = 10.7326/0003-4819-83-6-817 }}</ref> However, MPA has been seen to cause androgenic effects in children with precocious puberty.<ref name="pmid4332067">{{cite journal | vauthors = Richman RA, Underwood LE, French FS, Van Wyk JJ | title = Adverse effects of large doses of medroxyprogesterone (MPA) in idiopathic isosexual precocity | journal = The Journal of Pediatrics | volume = 79 | issue = 6 | pages = 963–71 | date = December 1971 | pmid = 4332067 | doi = 10.1016/s0022-3476(71)80191-9 }}</ref> The reason for the general lack of [[Biology:Virilization|virilizing]] effects with MPA, despite it binding to and activating the AR with high affinity and this action potentially playing an important role in many of its physiological and therapeutic effects, is not entirely clear. However, MPA has been found to interact with the AR differently compared to other agonists of the receptor such as [[Chemistry:Dihydrotestosterone|dihydrotestosterone]] (DHT).<ref name="pmid10077001"/> The result of this difference appears to be that MPA binds to the AR with a similar affinity and intrinsic activity to that of DHT, but requires about 100-fold higher concentrations for a comparable induction of gene transcription, while at the same time not antagonizing the transcriptional activity of normal androgens like DHT at any concentration.<ref name="pmid10077001" /> Thus, this may explain the low propensity of MPA for producing androgenic side effects.<ref name="pmid10077001" />

MPA shows weak androgenic effects on liver protein synthesis, similarly to other weakly androgenic progestins like [[Biology:Megestrol acetate|megestrol acetate]] and 19-nortestosterone [[Chemistry:Chemical derivative|derivative]]s.<ref name="pmid16112947" /><ref name="pmid26291834" /> While it does not antagonize estrogen-induced increases in levels of [[Chemistry:Triglyceride|triglyceride]]s and HDL cholesterol, DMPA every other week may decrease levels of HDL cholesterol.<ref name="pmid16112947" /> In addition, MPA has been found to suppress sex hormone-binding globulin (SHBG) production by the [[Biology:Liver|liver]].<ref name="pmid26291834" /><ref name="Luciano1992">{{cite journal|last1=Luciano|first1=A. A.|title=Endometriosis—the role of medroxyprogesterone acetate|journal=Journal of Obstetrics and Gynaecology|volume=12|issue=sup2|year=1992|pages=S38–S44|issn=0144-3615|doi=10.3109/01443619209045611}}</ref><ref name="pmid10914617">{{cite journal | vauthors = Nachtigall LE, Raju U, Banerjee S, Wan L, Levitz M | title = Serum estradiol-binding profiles in postmenopausal women undergoing three common estrogen replacement therapies: associations with sex hormone-binding globulin, estradiol, and estrone levels | journal = Menopause | volume = 7 | issue = 4 | pages = 243–250 | date = 2000 | pmid = 10914617 | doi = 10.1097/00042192-200007040-00006 | s2cid = 3076514 }}</ref> At a dosage of 10&nbsp;mg/day oral MPA, it has been found to decrease circulating SHBG levels by 14 to 18% in women taking 4&nbsp;mg/day oral [[Chemistry:Estradiol valerate|estradiol valerate]].<ref name="pmid26291834" /> Conversely, in a study that combined 2.5&nbsp;mg/day oral MPA with various oral estrogens, no influence of MPA on estrogen-induced increases in SHBG levels was discerned.<ref name="pmid10914617" /> In another, higher-dose study, SHBG levels were lower by 59% in a group of women treated with 50&nbsp;mg/day oral MPA alone relative to an untreated control group of women.<ref name="Luciano1992" /> In massive-dose studies of oral or injectable MPA (e.g., 500–1,000&nbsp;mg/day), the medication decreased SHBG levels by about 80%.<ref name="pmid2362454">{{cite journal | vauthors = Lundgren S, Lønning PE, Utaaker E, Aakvaag A, Kvinnsland S | title = Influence of progestins on serum hormone levels in postmenopausal women with advanced breast cancer--I. General findings | journal = Journal of Steroid Biochemistry | volume = 36 | issue = 1–2 | pages = 99–104 | date = June 1990 | pmid = 2362454 | doi = 10.1016/0022-4731(90)90118-c }}</ref><ref name="pmid2141886">{{cite journal | vauthors = Lundgren S, Lønning PE | title = Influence of progestins on serum hormone levels in postmenopausal women with advanced breast cancer--II. A differential effect of megestrol acetate and medroxyprogesterone acetate on serum estrone sulfate and sex hormone binding globulin | journal = Journal of Steroid Biochemistry | volume = 36 | issue = 1–2 | pages = 105–109 | date = June 1990 | pmid = 2141886 | doi = 10.1016/0022-4731(90)90119-d }}</ref><ref name="pmid2968646">{{cite journal | vauthors = Tomić R, Ljungberg B, Damber JE | title = Hormonal effects of high dose medroxyprogesterone acetate treatment in males with renal or prostatic adenocarcinoma | journal = Scandinavian Journal of Urology and Nephrology | volume = 22 | issue = 1 | pages = 15–18 | date = 1988 | pmid = 2968646 | doi = 10.1080/00365599.1988.11690377 }}</ref>

Unlike the related steroids [[Biology:Megestrol acetate|megestrol acetate]] and [[Chemistry:Cyproterone acetate|cyproterone acetate]], MPA is not an [[Biology:Receptor antagonist|antagonist]] of the AR and does not have direct [[Biology:Antiandrogen|antiandrogen]]ic activity.<ref name="pmid16112947" /> As such, although MPA is sometimes described as an [[Biology:Antiandrogen|antiandrogen]], it is not a "true" antiandrogen (i.e., AR antagonist).<ref name="APA1999">{{cite book|title=Dangerous Sex Offenders: A Task Force Report of the American Psychiatric Association|url=https://books.google.com/books?id=PbC8kWQ-n1sC&pg=PA112|year=1999|publisher=American Psychiatric Pub|isbn=978-0-89042-280-9|pages=112–144}}</ref>

====Glucocorticoid activity====
As an agonist of the GR, MPA has [[Chemistry:Glucocorticoid|glucocorticoid]] activity, and as a result can cause symptoms of [[Medicine:Cushing's syndrome|Cushing's syndrome]],<ref>{{cite journal | vauthors = Merrin PK, Alexander WD | title = Cushing's syndrome induced by medroxyprogesterone | journal = BMJ | volume = 301 | issue = 6747 |page = 345 | date = August 1990 | pmid = 2144198 | pmc = 1663616 | doi = 10.1136/bmj.301.6747.345-a }}</ref> steroid diabetes, and adrenal insufficiency at sufficiently high doses.<ref>{{citation | url = http://www.medscape.org/viewarticle/549746 | title = Systemic Effects of Oral Glucocorticoids | url-status = live | archive-url = https://web.archive.org/web/20140128153658/http://www.medscape.org/viewarticle/549746 | archive-date = 28 January 2014 }}</ref> It has been suggested that the glucocorticoid activity of MPA may contribute to bone loss.<ref name="pmid12181616">{{cite journal | vauthors = Ishida Y, Ishida Y, Heersche JN | title = Pharmacologic doses of medroxyprogesterone may cause bone loss through glucocorticoid activity: an hypothesis | journal = Osteoporos Int | volume = 13 | issue = 8 | pages = 601–5 | date = August 2002 | pmid = 12181616 | doi = 10.1007/s001980200080 | s2cid = 23343761 }}</ref> The glucocorticoid activity of MPA may also result in an [[Biology:Downregulation and upregulation|upregulation]] of the [[Biology:Thrombin receptor|thrombin receptor]] in [[Biology:Blood vessel|blood vessel]] walls, which may contribute to procoagulant effects of MPA and risk of venous thromboembolism and [[Medicine:Atherosclerosis|atherosclerosis]].<ref name="pmid16112947"/> The relative glucocorticoid activity of MPA is among the highest of the clinically used progestins.<ref name="pmid16112947" />


====Steroidogenesis inhibition====

MPA has been found to act as a [[Chemistry:Competitive inhibition|competitive]] [[Biology:Enzyme inhibitor|inhibitor]] of rat 3α-hydroxysteroid dehydrogenase (3α-HSD).<ref name="pmid6213817">{{cite journal | vauthors = Sunde A, Rosness PA, Eik-Nes KB | title = Effects in vitro of medroxyprogesterone acetate on steroid metabolizing enzymes in the rat: selective inhibition of 3 alpha-hydroxysteroid oxidoreductase activity | journal = Journal of Steroid Biochemistry | volume = 17 | issue = 2 | pages = 197–203 | date = August 1982 | pmid = 6213817 | doi = 10.1016/0022-4731(82)90122-4 }}</ref><ref name="pmid2933398">{{cite journal | vauthors = Penning TM, Sharp RB, Krieger NR | title = Purification and properties of 3 alpha-hydroxysteroid dehydrogenase from rat brain cytosol. Inhibition by nonsteroidal anti-inflammatory drugs and progestins | journal = The Journal of Biological Chemistry | volume = 260 | issue = 28 | pages = 15266–72 | date = December 1985 | doi = 10.1016/S0021-9258(18)95730-3 | pmid = 2933398 | doi-access = free }}</ref><ref name="pmid15181090">{{cite journal | vauthors = Pazol K, Wilson ME, Wallen K | title = Medroxyprogesterone acetate antagonizes the effects of estrogen treatment on social and sexual behavior in female macaques | journal = The Journal of Clinical Endocrinology and Metabolism | volume = 89 | issue = 6 | pages = 2998–3006 | date = June 2004 | pmid = 15181090 | pmc = 1440328 | doi = 10.1210/jc.2003-032086 }}</ref><ref name="pmid18291663">{{cite journal | vauthors = Meyer L, Venard C, Schaeffer V, Patte-Mensah C, Mensah-Nyagan AG | title = The biological activity of 3alpha-hydroxysteroid oxido-reductase in the spinal cord regulates thermal and mechanical pain thresholds after sciatic nerve injury | journal = Neurobiology of Disease | volume = 30 | issue = 1 | pages = 30–41 | date = April 2008 | pmid = 18291663 | doi = 10.1016/j.nbd.2007.12.001 | s2cid = 5830825 }}</ref> This [[Biology:Enzyme|enzyme]] is essential for the [[Biology:Biotransformation|transformation]] of [[Chemistry:Progesterone|progesterone]], [[Biology:Deoxycorticosterone|deoxycorticosterone]], and DHT into inhibitory [[Biology:Neurosteroid|neurosteroid]]s such as [[Biology:Allopregnanolone|allopregnanolone]], {{abbrlink|THDOC|tetrahydrodeoxycorticosterone}}, and 3α-androstanediol, respectively.<ref name="pmid11750861">{{cite journal | vauthors = Mellon SH, Griffin LD | title = Neurosteroids: biochemistry and clinical significance | journal = Trends in Endocrinology and Metabolism | volume = 13 | issue = 1 | pages = 35–43 | year = 2002 | pmid = 11750861 | doi = 10.1016/s1043-2760(01)00503-3 | s2cid = 11605131 }}</ref> MPA has been described as very potent in its inhibition of rat 3α-HSD, with an [[Chemistry:IC50|IC<sub>50</sub>]] of 0.2&nbsp;μM and a K<sub>i</sub> (in rat testicular homogenates) of 0.42&nbsp;μM.<ref name="pmid6213817" /><ref name="pmid2933398" /> However, inhibition of 3α-HSD by MPA does not appear to have been confirmed using human proteins yet, and the concentrations required with rat proteins are far above typical human therapeutic concentrations.<ref name="pmid6213817" /><ref name="pmid2933398" />

MPA has been identified as a competitive inhibitor of human 3β-hydroxysteroid dehydrogenase/Δ<sup>5-4</sup> isomerase II (3β-HSD II).<ref name="pmid10372718">{{cite journal | vauthors = Lee TC, Miller WL, Auchus RJ | title = Medroxyprogesterone acetate and dexamethasone are competitive inhibitors of different human steroidogenic enzymes | journal = The Journal of Clinical Endocrinology and Metabolism | volume = 84 | issue = 6 | pages = 2104–10 | date = June 1999 | pmid = 10372718 | doi = 10.1210/jcem.84.6.5646 | doi-access = free }}</ref> This enzyme is essential for the [[Biology:Biosynthesis|biosynthesis]] of [[Biology:Sex steroid|sex steroid]]s and [[Biology:Corticosteroid|corticosteroid]]s.<ref name="pmid10372718" /> The K<sub>i</sub> of MPA for inhibition of 3β-HSD II is 3.0&nbsp;μM, and this concentration is reportedly near the circulating levels of the medication that are achieved by very high therapeutic dosages of MPA of 5 to 20&nbsp;mg/kg/day (dosages of 300 to 1,200&nbsp;mg/day for a 60&nbsp;kg (132&nbsp;lb) person).<ref name="pmid10372718" /> Aside from 3β-HSD II, other human steroidogenic enzymes, including [[Biology:Cholesterol side-chain cleavage enzyme|cholesterol side-chain cleavage enzyme]] (P450scc/CYP11A1) and [[Biology:CYP17A1|17α-hydroxylase/17,20-lyase]] (CYP17A1), were not found to be inhibited by MPA.<ref name="pmid10372718" /> MPA has been found to be effective in the treatment of gonadotropin-independent precocious puberty and in [[Medicine:Breast cancer|breast cancer]] in [[Medicine:Menopause|postmenopausal]] women at high dosages, and inhibition of 3β-HSD II could be responsible for its effectiveness in these conditions.<ref name="pmid10372718" />

====GABA<sub>A</sub> receptor allosteric modulation====
[[Chemistry:Progesterone (medication)|Progesterone]], via transformation into [[Biology:Neurosteroid|neurosteroid]]s such as 5α-dihydroprogesterone, 5β-dihydroprogesterone, [[Biology:Allopregnanolone|allopregnanolone]], and [[Chemistry:Pregnanolone|pregnanolone]] (catalyzed by the enzymes [[Chemistry:5α-reductase|5α-]] and 5β-reductase and 3α- and 3β-HSD), is a positive allosteric modulator of the [[Biology:GABAA receptor|GABA<sub>A</sub> receptor]], and is associated with a variety of effects mediated by this property including [[Medicine:Dizziness|dizziness]], [[Medicine:Sedation|sedation]], [[Chemistry:Hypnotic|hypnotic]] [[Philosophy:Altered state of consciousness|state]]s, mood changes, anxiolysis, and cognitive/memory impairment, as well as effectiveness as an [[Chemistry:Anticonvulsant|anticonvulsant]] in the treatment of catamenial epilepsy.<ref name="pmid11750861" /><ref name="pmid14644065">{{cite journal | vauthors = Söderpalm AH, Lindsey S, Purdy RH, Hauger R, Wit de H | title = Administration of progesterone produces mild sedative-like effects in men and women | journal = Psychoneuroendocrinology | volume = 29 | issue = 3 | pages = 339–54 | date = April 2004 | pmid = 14644065 | doi = 10.1016/s0306-4530(03)00033-7 | s2cid = 21796848 }}</ref> It has also been found to produce [[Medicine:Anesthesia|anesthesia]] via this action in animals when administered at sufficiently high dosages.<ref name="pmid14644065" /> MPA was found to significantly reduce [[Medicine:Seizure|seizure]] incidence when added to existing anticonvulsant regimens in 11 of 14 women with uncontrolled [[Medicine:Epilepsy|epilepsy]], and has also been reported to induce anesthesia in animals, raising the possibility that it might modulate the GABA<sub>A</sub> receptor similarly to progesterone.<ref name="pmid8516376">{{cite journal | vauthors = McAuley JW, Kroboth PD, Stiff DD, Reynolds IJ | title = Modulation of [3H]flunitrazepam binding by natural and synthetic progestational agents | journal = Pharmacology Biochemistry and Behavior | volume = 45 | issue = 1 | pages = 77–83 | date = May 1993 | pmid = 8516376 | doi = 10.1016/0091-3057(93)90089-c | s2cid = 42764270 }}</ref><ref name="Weizman2008">{{cite book | vauthors = Weizman A | title = Neuroactive Steroids in Brain Function, Behavior and Neuropsychiatric Disorders: Novel Strategies for Research and Treatment | url = https://books.google.com/books?id=uABKkFdPjhkC&pg=PA104 | date = 1 February 2008 | publisher = Springer Science & Business Media | isbn = 978-1-4020-6854-6 | pages = 104, 107, 112 }}</ref>

MPA shares some of the same [[Biology:Metabolic pathway|metabolic routes]] of progesterone and, analogously, can be transformed into metabolites such as 5α-dihydro-MPA (DHMPA) and 3α,5α-tetrahydro-MPA (THMPA).<ref name="pmid8516376" /> However, unlike the reduced metabolites of progesterone, DHMPA and THMPA have been found not to modulate the GABA<sub>A</sub> receptor.<ref name="pmid8516376" /> Conversely, unlike progesterone, MPA itself actually modulates the GABA<sub>A</sub> receptor, although notably not at the neurosteroid binding site.<ref name="pmid8516376" /> However, rather than act as a potentiator of the receptor, MPA appears to act as a negative allosteric modulator.<ref name="pmid8516376" /> Whereas the reduced metabolites of progesterone enhance binding of the [[Chemistry:Benzodiazepine|benzodiazepine]] [[Chemistry:Flunitrazepam|flunitrazepam]] to the GABA<sub>A</sub> receptor ''[[In vitro|in vitro]]'', MPA can partially inhibit the binding of flunitrazepam by up to 40% with half-maximal inhibition at 1&nbsp;μM.<ref name="pmid8516376" /> However, the concentrations of MPA required for inhibition are high relative to therapeutic concentrations, and hence, this action is probably of little or no clinical relevance.<ref name="pmid8516376" /> The lack of potentiation of the GABA<sub>A</sub> receptor by MPA or its metabolites is surprising in consideration of the apparent anticonvulsant and anesthetic effects of MPA described above, and they remain unexplained.<ref name="pmid8516376" />

Clinical studies using massive dosages of up to 5,000&nbsp;mg/day oral MPA and 2,000&nbsp;mg/day intramuscular MPA for 30 days in women with advanced breast cancer have reported "no relevant side effects", which suggests that MPA has no meaningful direct action on the GABA<sub>A</sub> receptor in humans even at extremely high dosages.<ref name="pmid1390312">{{cite journal | vauthors = Muss HB, Cruz JM | title = High-dose progestin therapy for metastatic breast cancer | journal = Annals of Oncology | volume = 3 | issue = Suppl 3 | pages = 15–20 | date = August 1992 | pmid = 1390312 | doi = 10.1093/annonc/3.suppl_3.S15 | doi-access = free }}</ref>

====Appetite stimulation====
Although MPA and the closely related medication [[Biology:Megestrol acetate|megestrol acetate]] are effective appetite stimulants at very high dosages,<ref name="HofbauerAnker2005">{{cite book | vauthors = Hofbauer KG, Anker SD, Inui A, Nicholson JR|title=Pharmacotherapy of Cachexia|url=https://books.google.com/books?id=I6cf05LaCakC&pg=PA292|date=22 December 2005|publisher=CRC Press|isbn=978-1-4200-4895-7|pages=292–|quote=Medroxyprogesterone [acetate] has similarly been shown to increase appetite and food intake with stabilization of body weight at a dose of 1000 mg (500 mg twice daily).13 Although the drug may be used at 500 to 4000 mg daily, side effects increase above oral doses of 1000 mg daily.16}}</ref> the [[Chemistry:Mechanism of action|mechanism of action]] of their beneficial effects on [[Medicine:Appetite|appetite]] is not entirely clear. However, [[Chemistry:Glucocorticoid|glucocorticoid]], [[Biology:Cytokine|cytokine]], and possibly anabolic-related mechanisms are all thought to possibly be involved, and a number of downstream changes have been implicated, including stimulation of the release of [[Biology:Neuropeptide Y|neuropeptide Y]] in the [[Biology:Hypothalamus|hypothalamus]], modulation of [[Biology:Calcium channel|calcium channel]]s in the ventromedial hypothalamus, and inhibition of the secretion of [[Biology:Proinflammatory cytokine|proinflammatory cytokine]]s including IL-1α, IL-1β, IL-6, and TNF-α, actions that have all been linked to an increase in appetite.<ref name="DoyleHanks2005">{{cite book | vauthors = Doyle D, Hanks G, Cherny NI | title = Oxford Textbook Of Palliative Medicine | url = https://books.google.com/books?id=1n93PGjL0IMC&pg=PA553 | date = 3 February 2005 | publisher = Oxford University Press | isbn = 978-0-19-856698-4 | page = 553 | url-status = live | archive-url = https://web.archive.org/web/20130618070049/http://books.google.com/books?id=1n93PGjL0IMC&pg=PA553 | archive-date = 18 June 2013 }}</ref>

====Other activity====
MPA weakly stimulates the [[Biology:Cell proliferation|proliferation]] of [[Biology:MCF-7|MCF-7]] [[Medicine:Breast cancer|breast cancer]] [[Biology:Cell|cell]]s ''[[In vitro|in vitro]]'', an action that is independent of the classical PRs and is instead mediated via the progesterone receptor membrane component-1 (PGRMC1).<ref name="pmid23758160">{{cite journal | vauthors = Neubauer H, Ma Q, Zhou J, Yu Q, Ruan X, Seeger H, Fehm T, Mueck AO | title = Possible role of PGRMC1 in breast cancer development | journal = Climacteric | volume = 16 | issue = 5 | pages = 509–13 | date = October 2013 | pmid = 23758160 | doi = 10.3109/13697137.2013.800038 | s2cid = 29808177 }}</ref> Certain other progestins are also active in this assay, whereas [[Chemistry:Progesterone (medication)|progesterone]] acts neutrally.<ref name="pmid23758160" /> It is unclear if these findings may explain the different risks of breast cancer observed with progesterone, [[Chemistry:Dydrogesterone|dydrogesterone]], and other progestins such as medroxyprogesterone acetate and [[Chemistry:Norethisterone|norethisterone]] in [[Engineering:Clinical trial|clinical studies]].<ref name="pmid31512725">{{cite journal | vauthors = Trabert B, Sherman ME, Kannan N, Stanczyk FZ | title = Progesterone and breast cancer | journal = Endocr. Rev. | volume = 41| issue = 2| pages = 320–344| date = September 2019 | pmid = 31512725 | doi = 10.1210/endrev/bnz001 | pmc = 7156851 }}</ref>

===Pharmacokinetics===

====Absorption====
Surprisingly few studies have been conducted on the [[Medicine:Pharmacokinetics|pharmacokinetics]] of MPA at postmenopausal replacement dosages.<ref name="pmid24291402" /><ref name="pmid16112947" /> The [[Chemistry:Bioavailability|bioavailability]] of MPA with [[Medicine:Oral administration|oral administration]] is approximately 100%.<ref name="pmid16112947" /> A single oral dose of 10&nbsp;mg MPA has been found to result in peak MPA levels of 1.2 to 5.2&nbsp;ng/mL within 2&nbsp;hours of administration using [[Biology:Radioimmunoassay|radioimmunoassay]].<ref name="pmid24291402">{{cite journal | vauthors = Stanczyk FZ, Bhavnani BR | title = Use of medroxyprogesterone acetate for hormone therapy in postmenopausal women: is it safe? | journal = The Journal of Steroid Biochemistry and Molecular Biology | volume = 142 | pages = 30–38 | date = July 2014 | pmid = 24291402 | doi = 10.1016/j.jsbmb.2013.11.011 | s2cid = 22731802 }}</ref><ref name="VictorJohansson1976">{{cite journal | vauthors = Victor A, Johansson ED | title = Pharmacokinetic observations on medroxyprogesterone acetate administered orally and intravaginally | journal = Contraception | volume = 14 | issue = 3 | pages = 319–329 | date = September 1976 | pmid = 975821 | doi = 10.1016/0010-7824(76)90099-8 }}</ref> Following this, levels of MPA decreased to 0.09 to 0.35&nbsp;ng/mL 12&nbsp;hours post-administration.<ref name="pmid24291402" /><ref name="VictorJohansson1976" /> In another study, peak levels of MPA were 3.4 to 4.4&nbsp;ng/mL within 1 to 4&nbsp;hours of administration of 10&nbsp;mg oral MPA using radioimmunoassay.<ref name="pmid24291402" /><ref name="HiroiStanczyk1975">{{cite journal | vauthors = Hiroi M, Stanczyk FZ, Goebelsmann U, Brenner PF, Lumkin ME, Mishell DR | title = Radioimmunoassay of serum medroxyprogesterone acetate (Provera) in women following oral and intravaginal administration | journal = Steroids | volume = 26 | issue = 3 | pages = 373–386 | date = September 1975 | pmid = 1198624 | doi = 10.1016/0039-128X(75)90082-3 | s2cid = 24777672 }}</ref> Subsequently, MPA levels fell to 0.3 to 0.6&nbsp;ng/mL 24&nbsp;hours after administration.<ref name="pmid24291402" /><ref name="HiroiStanczyk1975" /> In a third study, MPA levels were 4.2 to 4.4&nbsp;ng/mL after an oral dose of 5&nbsp;mg MPA and 6.0&nbsp;ng/mL after an oral dose of 10&nbsp;mg MPA, both using radioimmunoassay as well.<ref name="pmid24291402" /><ref name="SvenssonJohnson1994">{{cite journal | vauthors = Svensson LO, Johnson SH, Olsson SE | title = Plasma concentrations of medroxyprogesterone acetate, estradiol and estrone following oral administration of Klimaxil, Trisequence/Provera and Divina. A randomized, single-blind, triple cross-over bioavailability study in menopausal women | journal = Maturitas | volume = 18 | issue = 3 | pages = 229–238 | date = March 1994 | pmid = 8015506 | doi = 10.1016/0378-5122(94)90129-5 }}</ref>

Treatment of postmenopausal women with 2.5 or 5&nbsp;mg/day MPA in combination with estradiol valerate for two weeks has been found to rapidly increase circulating MPA levels, with steady-state concentrations achieved after three days and peak concentrations occurring 1.5 to 2&nbsp;hours after ingestion.<ref name="pmid16112947" /><ref name="JärvinenKainulainen2004" /> With 2.5&nbsp;mg/day MPA, levels of the medication were 0.3&nbsp;ng/mL (0.8&nbsp;nmol/L) in women under 60 years of age and 0.45&nbsp;ng/mL (1.2&nbsp;nmol/L) in women 65 years of age or over, and with 5&nbsp;mg/day MPA, levels were 0.6&nbsp;ng/mL (1.6&nbsp;nmol/L) in women under 60 years of age and in women 65 years of age or over.<ref name="pmid16112947" /><ref name="JärvinenKainulainen2004" /> Hence, area-under-curve levels of the medication were 1.6 to 1.8&nbsp;times higher in those who were 65&nbsp;years of age or older relative to those who were 60&nbsp;years of age or younger.<ref name="pmid26291834" /><ref name="JärvinenKainulainen2004" /> As such, levels of MPA have been found to vary with age, and MPA may have an increased risk of side effects in elderly postmenopausal women.<ref name="pmid26291834" /><ref name="pmid16112947" /><ref name="JärvinenKainulainen2004" /> This study assessed MPA levels using liquid-chromatography–tandem mass spectrometry (LC–MS/MS), a more accurate method of blood determinations.<ref name="JärvinenKainulainen2004">{{cite journal | vauthors = Järvinen A, Kainulainen P, Nissilä M, Nikkanen H, Kela M | title = Pharmacokinetics of estradiol valerate and medroxyprogesterone acetate in different age groups of postmenopausal women | journal = Maturitas | volume = 47 | issue = 3 | pages = 209–217 | date = March 2004 | pmid = 15036491 | doi = 10.1016/j.maturitas.2003.01.001 }}</ref>

Oral MPA tablets can be administered [[Medicine:Sublingual administration|sublingually]] instead of orally.<ref name="PDR-MPA">{{cite web | title = Medroxyprogesterone Acetate - Drug Summary | url = https://www.pdr.net/drug-summary/Provera-medroxyprogesterone-acetate-1015 | website = Prescribers' Digital Reference (PDR) | publisher = ConnectiveRx | archive-url = https://web.archive.org/web/20181007065946/https://www.pdr.net/drug-summary/Provera-medroxyprogesterone-acetate-1015 | access-date = 17 June 2019 | archive-date = 7 October 2018 | quote = When needed, tablets may be administered sublingually†; absorption is adequate by this route.}}</ref><ref name="pmid1101759">{{cite journal | vauthors = Sutton FD, Zwillich CW, Creagh CE, Pierson DJ, Weil JV | title = Progesterone for outpatient treatment of Pickwickian syndrome | journal = Annals of Internal Medicine | volume = 83 | issue = 4 | pages = 476–479 | date = October 1975 | pmid = 1101759 | doi = 10.7326/0003-4819-83-4-476 | quote = The sublingual route was chosen to avoid any irregular absorption that might result from simultaneous food intake. }}</ref><ref name="pmid31127826">{{cite journal | vauthors = Jain J, Kwan D, Forcier M | title = Medroxyprogesterone Acetate in Gender-Affirming Therapy for Transwomen: Results From a Retrospective Study | journal = The Journal of Clinical Endocrinology and Metabolism | volume = 104 | issue = 11 | pages = 5148–5156 | date = November 2019 | pmid = 31127826 | doi = 10.1210/jc.2018-02253 | doi-access = free }}</ref> [[Medicine:Rectal administration|Rectal administration]] of MPA has also been studied.<ref name="pmid1884566">{{cite journal | vauthors = van Hoogdalem EJ, de Boer AG, Breimer DD | title = Pharmacokinetics of rectal drug administration, Part II. Clinical applications of peripherally acting drugs, and conclusions | journal = Clinical Pharmacokinetics | volume = 21 | issue = 2 | pages = 110–128 | date = August 1991 | pmid = 1884566 | doi = 10.2165/00003088-199121020-00003 | s2cid = 11720029 }}</ref>

With intramuscular administration of 150&nbsp;mg [[Earth:Microcrystalline|microcrystalline]] MPA in aqueous suspension, the medication is detectable in the circulation within 30&nbsp;minutes, serum concentrations vary but generally plateau at 1.0&nbsp;ng/mL (2.6&nbsp;nmol/L) for 3&nbsp;months.<ref name="Mishell">{{cite journal | vauthors = Mishell DR | title = Pharmacokinetics of depot medroxyprogesterone acetate contraception | journal = The Journal of Reproductive Medicine | volume = 41 | issue = 5 Suppl | pages = 381–390 | date = May 1996 | pmid = 8725700 | url = http://www.reproductivemedicine.com/toc/auto_abstract.php?id=540 }}</ref> Following this, there is a gradual decline in MPA levels, and the medication can be detected in the circulation for as long as 6 to 9&nbsp;months post-injection.<ref name="Mishell" /> The [[Chemistry:Particle size|particle size]] of MPA crystals significantly influences its rate of absorption into the body from the local tissue [[Medicine:Depot injection|depot]] when used as a microcrystalline aqueous suspension via intramuscular injection.<ref name="pmid8013220d">{{cite journal | vauthors = Sang GW | title = Pharmacodynamic effects of once-a-month combined injectable contraceptives | journal = Contraception | volume = 49 | issue = 4 | pages = 361–385 | date = April 1994 | pmid = 8013220 | doi = 10.1016/0010-7824(94)90033-7 }}</ref><ref name="pmid1958567">{{cite journal | vauthors = Garza-Flores J, Hall PE, Perez-Palacios G | title = Long-acting hormonal contraceptives for women | journal = The Journal of Steroid Biochemistry and Molecular Biology | volume = 40 | issue = 4–6 | pages = 697–704 | date = 1991 | pmid = 1958567 | doi = 10.1016/0960-0760(91)90293-e | s2cid = 26021562 }}</ref><ref name="GabelnickHall1987">{{cite journal| vauthors = Gabelnick HL, Hall PE |title=Long-acting methods for fertility regulation|journal=Journal of Controlled Release|volume=6|issue=1|year=1987|pages=387–394|issn=0168-3659|doi=10.1016/0168-3659(87)90092-7}}</ref> Smaller crystals dissolve faster and are absorbed more rapidly, resulting in a shorter duration of action.<ref name="pmid8013220d" /><ref name="pmid1958567" /><ref name="GabelnickHall1987" /> Particle sizes can differ between different formulations of MPA, potentially influencing clinical efficacy and tolerability.<ref name="pmid8013220d" /><ref name="pmid1958567" /><ref name="GabelnickHall1987" /><ref name="AntalDick1989">{{cite journal| vauthors = Antal EJ, Dick CF, Wright III CE, Welshman IR, Block EM |title=Comparative bioavailability of two medroxyprogesterone acetate suspensions|journal=International Journal of Pharmaceutics|volume=54|issue=1|year=1989|pages=33–39|issn=0378-5173|doi=10.1016/0378-5173(89)90162-2}}</ref>

====Distribution====
The [[Biology:Plasma protein binding|plasma protein binding]] of MPA is 88%.<ref name="pmid16112947" /><ref name="pmid26291834" /> It is weakly bound to [[Biology:Human serum albumin|albumin]] and is not bound to sex hormone-binding globulin or corticosteroid-binding globulin.<ref name="pmid16112947" /><ref name="pmid26291834" />

====Metabolism====
The elimination half-life of MPA via oral administration has been reported as both 11.6 to 16.6&nbsp;hours<ref name="ProveraLabel" /> and 33&nbsp;hours,<ref name="pmid16112947" /> whereas the elimination half-lives with [[Biology:Intramuscular injection|intramuscular]] and [[Medicine:Subcutaneous injection|subcutaneous injection]] of microcrystalline MPA in aqueous suspension are 50 and 40&nbsp;days, respectively.<ref name="DepoProveraLabel" /><ref name="DepoSubQProveraLabel" /> The [[Biology:Metabolism|metabolism]] of MPA is mainly via [[Biology:Hydroxylation|hydroxylation]], including at positions C6β, C21, C2β, and C1β, mediated primarily via [[Biology:CYP3A4|CYP3A4]], but 3- and 5-dihydro and 3,5-tetrahydro [[Biology:Metabolite|metabolite]]s of MPA are also formed.<ref name="pmid16112947" /><ref name="pmid26291834" /> Deacetylation of MPA and its metabolites (into, e.g., [[Chemistry:Medroxyprogesterone|medroxyprogesterone]]) has been observed to occur in non-human primate research to a substantial extent as well (30 to 70%).<ref name="pmid1271819">{{cite journal | vauthors = Ishihara M, Kirdani Y, Osawa Y, Sandberg AA | title = The metabolic fate of medroxyprogesterone acetate in the baboon | journal = Journal of Steroid Biochemistry | volume = 7 | issue = 1 | pages = 65–70 | date = January 1976 | pmid = 1271819 | doi = 10.1016/0022-4731(76)90167-9 }}</ref> MPA and/or its metabolites are also metabolized via [[Chemistry:Conjugation (biochemistry)|conjugation]].<ref name="Merck" /> The C6α [[Chemistry:Methyl group|methyl]] and C17α acetoxy [[Chemistry:Functional group|group]]s of MPA make it more resistant to metabolism and allow for greater bioavailability than oral [[Chemistry:Progesterone (medication)|progesterone]].<ref name="pmid26291834">{{cite journal | vauthors = Stanczyk FZ, Bhavnani BR | title = Reprint of "Use of medroxyprogesterone acetate for hormone therapy in postmenopausal women: Is it safe?" | journal = J. Steroid Biochem. Mol. Biol. | volume = 153 | pages = 151–9 | date = September 2015 | pmid = 26291834 | doi = 10.1016/j.jsbmb.2015.08.013 | s2cid = 23985966 }}</ref>

====Elimination====
MPA is [[Biology:Elimination (pharmacology)|eliminated]] 20 to 50% in [[Biology:Urine|urine]] and 5 to 10% in [[Biology:Feces|feces]] following intravenous administration.<ref name="Jr.Lawrence2015">{{cite book | vauthors = DeVita VT, Lawrence TS, Rosenberg SA |title=DeVita, Hellman, and Rosenberg's Cancer: Principles & Practice of Oncology|url=https://books.google.com/books?id=HEAYBgAAQBAJ&pg=PT1149|date=7 January 2015|publisher=Wolters Kluwer Health|isbn=978-1-4698-9455-3|pages=1149–}}</ref> Less than 3% of a dose is [[Biology:Excretion|excreted]] in [[Chemistry:Conjugation (biochemistry)|unconjugated]] form.<ref name="Jr.Lawrence2015" />

====Level–effect relationships====
With intramuscular administration, the high levels of MPA in the blood inhibit [[Biology:Luteinizing hormone|luteinizing hormone]] and ovulation for several months, with an accompanying decrease in serum progesterone to below 0.4&nbsp;ng/mL.<ref name="Mishell" /> Ovulation resumes when once blood levels of MPA fall below 0.1&nbsp;ng/mL.<ref name="Mishell" /> Serum estradiol remains at approximately 50&nbsp;pg/mL for approximately four months post-injection (with a range of 10–92&nbsp;pg/mL after several years of use), rising once MPA levels fall below 0.5&nbsp;ng/mL.<ref name="Mishell" />

Hot flashes are rare while MPA is found at significant blood levels in the body, and the [[Biology:Vagina|vagina]]l [[Biology:Epithelium|lining]] remains moist and creased. The endometrium undergoes [[Medicine:Atrophy|atrophy]], with small, straight glands and a stroma that is decidualized. Cervical mucus remains [[Physics:Viscosity|viscous]]. Because of its steady blood levels over the long term and multiple effects that prevent fertilization, MPA is a very effective means of birth control.<ref name = Mishell/>

====Time–concentration curves====
{{Gallery
| title=Hormone levels with medroxyprogesterone acetate
| width=300 | height=300
| align=center
| style="font-size:small;"

| File:Levels of medroxyprogesterone acetate with 2.5 or 5 mg per day oral medroxyprogesterone acetate in postmenopausal women.png | MPA levels with 2.5 or 5 mg/day [[Medicine:Oral administration|oral]] MPA in combination with 1 or 2&nbsp;mg/day [[Chemistry:Estradiol valerate|estradiol valerate]] (Indivina) in postmenopausal women<ref name="JärvinenKainulainen2004"/>

| File:Medroxyprogesterone acetate levels after a single 150 mg intramuscular injection of medroxyprogesterone acetate in women.png | MPA levels after a single 150&nbsp;mg [[Biology:Intramuscular injection|intramuscular injection]] of MPA (Depo-Provera) in aqueous suspension in women<ref name="Goebelsmann1986e">{{cite book| vauthors = Goebelsmann U |title=Contraceptive Steroids |chapter=Pharmacokinetics of Contraceptive Steroids in Humans| veditors = Gregoire AT, Blye RP |chapter-url=https://books.google.com/books?id=7dnTBwAAQBAJ&pg=PA67|date=1986|publisher=Springer Science & Business Media|isbn=978-1-4613-2241-2|pages=67–111|doi=10.1007/978-1-4613-2241-2_4}}</ref><ref name="pmid833262">{{cite journal | vauthors = Ortiz A, Hirol M, Stanczyk FZ, Goebelsmann U, Mishell DR | title = Serum medroxyprogesterone acetate (MPA) concentrations and ovarian function following intramuscular injection of depo-MPA | journal = J. Clin. Endocrinol. Metab. | volume = 44 | issue = 1 | pages = 32–8 | date = January 1977 | pmid = 833262 | doi = 10.1210/jcem-44-1-32}}</ref>

| File:Medroxyprogesterone acetate levels after a single intramuscular injection of different doses of medroxyprogesterone acetate in women.png | MPA levels after a single 25 to 150&nbsp;mg [[Biology:Intramuscular injection|intramuscular injection]] of MPA (Depo-Provera) in aqueous suspension in women<ref name="Goebelsmann1986e" /><ref name="pmid6451351">{{cite journal | vauthors = Fotherby K, Koetsawang S, Mathrubutham M | title = Pharmacokinetic study of different doses of Depo Provera | journal = Contraception | volume = 22 | issue = 5 | pages = 527–36 | date = November 1980 | pmid = 6451351 | doi = 10.1016/0010-7824(80)90105-5}}</ref>

| File:Medroxyprogesterone acetate levels with a subcutaneous injection of 104 mg medroxyprogesterone acetate in women.png | MPA levels after a single 104&nbsp;mg [[Medicine:Subcutaneous injection|subcutaneous injection]] of MPA (Depo-SubQ Provera) in aqueous suspension in women<ref name="DepoSubQProveraLabel"/>

}}

==Chemistry==

MPA is a synthetic [[Chemistry:Pregnane|pregnane]] [[Biology:Steroid|steroid]] and a [[Chemistry:Chemical derivative|derivative]] of [[Chemistry:Progesterone (medication)|progesterone]] and 17α-hydroxyprogesterone.<ref name="Elks2014" /><ref name="IndexNominum2000" /> Specifically, it is the 17α-[[Chemistry:Acetate|acetate]] [[Chemistry:Ester|ester]] of [[Chemistry:Medroxyprogesterone|medroxyprogesterone]] or the 6α-[[Biology:Methylation|methylated]] analogue of [[Chemistry:Hydroxyprogesterone acetate|hydroxyprogesterone acetate]].<ref name="Elks2014" /><ref name="IndexNominum2000" /> MPA is known chemically as 6α-methyl-17α-acetoxyprogesterone or as 6α-methyl-17α-acetoxypregn-4-ene-3,20-dione, and its generic name is a contraction of 6α-methyl-17α-hydroxyprogesterone acetate.<ref name="Elks2014" /><ref name="IndexNominum2000" /> MPA is closely related to other 17α-hydroxyprogesterone derivatives such as [[Chemistry:Chlormadinone acetate|chlormadinone acetate]], [[Chemistry:Cyproterone acetate|cyproterone acetate]], and [[Biology:Megestrol acetate|megestrol acetate]], as well as to [[Chemistry:Medrogestone|medrogestone]] and [[Chemistry:Nomegestrol acetate|nomegestrol acetate]].<ref name="Elks2014" /><ref name="IndexNominum2000" /> 9α-fluoromedroxyprogesterone acetate (FMPA), the C9α fluoro analogue of MPA and an [[Biology:Angiogenesis inhibitor|angiogenesis inhibitor]] with two orders of magnitude greater potency in comparison to MPA, was investigated for the potential treatment of [[Medicine:Cancer|cancer]]s but was never marketed.<ref name="pmid19158035">{{cite journal | vauthors = Ademuyiwa FO, Miller KD | title = Incorporation of antiangiogenic therapies in the treatment of metastatic breast cancer | journal = Clin. Breast Cancer | volume = 8 | issue = Suppl 4 | pages = S151–6 | date = December 2008 | pmid = 19158035 | doi = 10.3816/CBC.2008.s.011}}</ref><ref name="AdisInsight-FMPA">{{Cite web|url=https://adisinsight.springer.com/drugs/800011224|title=FMPA - AdisInsight|website=adisinsight.springer.com}}</ref>

==History==
MPA was independently discovered in 1956 by Syntex and the Upjohn Company.<ref name="Roberts2013" /><ref name="Sneader2005"/><ref name="FR1295307">{{ cite patent | country = FR | number = 1295307 | status = | title = Procédé de préparation de dérivés cyclopentano-phénanthréniques | pubdate = 8 June 1962 | gdate = | fdate = | pridate = 8 September 1956 | inventor = | assign1 = Syntex SA | assign2 = | class = }}</ref><ref name="US3377364">{{ cite patent | country = US | number = 3377364 | status = granted | title = 6-methyl-17alpha-hydroxyprogesterone, the lower fatty acid 17-acylates and methods for producing the same | pubdate = 9 April 1968 | gdate = | fdate = | pridate = 23 November 1956 | inventor = Spero G | assign1 = Upjohn Company |assign2= |class=}}</ref> It was first introduced on 18 June 1959 by Upjohn in the {{wipe|United States}} under the brand name Provera (2.5, 5, and 10&nbsp;mg tablets) for the treatment of [[Medicine:Amenorrhea|amenorrhea]], metrorrhagia, and [[Medicine:Recurrent miscarriage|recurrent miscarriage]].<ref name="Green1987">{{cite journal | vauthors = Green W | title = Odyssey of Depo-Provera: Contraceptives, Carcinogenic Drugs, and Risk-Management Analyses | journal = Food Drug Cosmetic Law Journal | year = 1987 | issue = 42 | pages = 567–587 | location = Chicago | quote = Depo-Provera is a drug, manufactured by The Upjohn Co., whose active ingredient is medroxyprogesterone acetate (MPA). FDA first approved the drug in 1959 to treat amenorrhea,5 irregular uterine bleeding, and threatened and habitual abortion.}}</ref><ref name="pmid23617013">{{cite book | vauthors = Hartmann KE, Jerome RN, Lindegren ML, Potter SA, Shields TC, Surawicz TS, Andrews JC | title = Primary Care Management of Abnormal Uterine Bleeding | chapter = Labeled Indications for Drugs Included in Review | year = 2013 | publisher = Agency for Healthcare Research and Quality (US) | pmid = 23617013 | url = https://www.ncbi.nlm.nih.gov/books/NBK132498/}}</ref> An intramuscular formulation of MPA, now known as DMPA (400&nbsp;mg/mL MPA), was also introduced, under the brand name brand name Depo-Provera, in 1960 in the U.S. for the treatment of [[Medicine:Endometrial cancer|endometrial]] and renal cancer.<ref name="Drugs@FDA-Depo-Provera">{{citation | title = Depo-Provera (medroxyprogesterone acetate) (NDA # 012541) - Drugs@FDA: FDA Approved Drug Products | url = https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&ApplNo=012541 | access-date = 2 April 2018 | quote = Original Approvals or Tentative Approvals: 09/23/1960.}}</ref> MPA in combination with [[Chemistry:Ethinylestradiol|ethinylestradiol]] was introduced in 1964 by Upjohn in the U.S. under the brand name Provest (10&nbsp;mg MPA and 50&nbsp;μg ethinylestradiol tablets) as an oral contraceptive, but this formulation was discontinued in 1970.<ref name="Gelijns1991">{{cite book | vauthors = Gelijns A | title = Innovation in Clinical Practice: The Dynamics of Medical Technology Development | url = https://books.google.com/books?id=MZkrAAAAYAAJ&pg=PA167 | year = 1991 | publisher = National Academies|pages=167–|id=NAP:13513}}</ref><ref name="Publishing2013">{{cite book|author=William Andrew Publishing|title=Pharmaceutical Manufacturing Encyclopedia|url=https://books.google.com/books?id=_J2ti4EkYpkC&pg=PA1501|date=22 October 2013|publisher=Elsevier|isbn=978-0-8155-1856-3|pages=1501–}}</ref><ref name="Blum2013">{{cite book | vauthors = Blum RW | title = Adolescent Health Care: Clinical Issues | url = https://books.google.com/books?id=36PpAgAAQBAJ&pg=PA216 | date = 22 October 2013 | publisher = Elsevier Science | isbn = 978-1-4832-7738-7 | pages = 216–}}</ref> This formulation was marketed by Upjohn outside of the U.S. under the brand names Provestral and Provestrol, while Cyclo-Farlutal (or Ciclofarlutal) and Nogest-S<ref>{{cite book | url = http://pdf.usaid.gov/pdf_docs/pnaap426.pdf | title = Population/fertility control thesaurus | year = 1976 | vauthors = Kolbe HK | publisher = Population Information Program, Science Communication Division, Dept. of Medical and Public Affairs, George Washington University | url-status = live | archive-url = https://web.archive.org/web/20161009213403/http://pdf.usaid.gov/pdf_docs/pnaap426.pdf | archive-date = 9 October 2016}}</ref> were formulations available outside of the U.S. with a different dosage (5&nbsp;mg MPA and 50 or 75&nbsp;μg ethinylestradiol tablets).<ref name="Lee1966">{{cite book | vauthors = Bolivar De Lee J | title = The ... Year Book of Obstetrics and Gynecology|url=https://books.google.com/books?id=hBU-AQAAIAAJ|year=1966|publisher=Year Book Publishers|page=339|quote=One of these is medroxyprogesterone acetate, which is sold in the United States by Upjohn as Provest, and is obtainable abroad as Provestral, Provestrol, Cyclo-Farlutal, and the more frankly suggestive Nogest.}}</ref><ref>{{cite book | vauthors = Fínkelstein M | title=Research on Steroids|url=https://books.google.com/books?id=Hg5rAAAAMAAJ|year=1966|publisher=Pergamon|pages=469, 542}}</ref>

Following its development in the late 1950s, DMPA was first assessed in clinical trials for use as an injectable contraceptive in 1963.<ref name="Li2009">{{cite book| vauthors = Li C |title=Breast Cancer Epidemiology|url=https://books.google.com/books?id=m3MtuTKbkbUC&pg=PA110|date=11 November 2009|publisher=Springer Science & Business Media|isbn=978-1-4419-0685-4|pages=110–}}</ref> Upjohn sought {{abbrlink|FDA|Food and Drug Administration}} approval of intramuscular DMPA as a long-acting contraceptive under the brand name Depo-Provera (150&nbsp;mg/mL MPA) in 1967, but the application was rejected.<ref name="Levitt2015">{{cite book | vauthors = Levitt JI | title = Black Women and International Law: Deliberate Interactions, Movements and Actions | url = https://books.google.com/books?id=emwaCAAAQBAJ&pg=PA231|date=30 April 2015|publisher=Cambridge University Press|isbn=978-1-316-29840-4|pages=230–231}}</ref><ref name="Women1998">{{cite book|title=Documentation on Women's Concerns|url=https://books.google.com/books?id=ItQcAQAAMAAJ|date=January 1998|publisher=Library and Documentation Centre, All India Association for Christian Higher Education | quote = Upjohn meanwhile, had been repeatedly seeking FDA approval for use of DMPA as a contraceptive, but applications were rejected in 1967, 1978 and yet again in 1983, [...]}}</ref> However, this formulation was successfully introduced in countries outside of the United States for the first time in 1969, and was available in over 90&nbsp;countries worldwide by 1992.<ref name="Nadakavukaren2011">{{cite book| vauthors = Nadakavukaren A |title=Our Global Environment: A Health Perspective, Seventh Edition|url=https://books.google.com/books?id=NXkbAAAAQBAJ&pg=PA63|date=28 February 2011|publisher=Waveland Press|isbn=978-1-4786-0976-6|pages=63–}}</ref> Upjohn attempted to gain FDA approval of DMPA as a contraceptive again in 1978, and yet again in 1983, but both applications failed similarly to the 1967 application.<ref name="Levitt2015" /><ref name="Women1998" /> However, in 1992, the medication was finally approved by the FDA, under the brand name Depo-Provera, for use in contraception.<ref name="Levitt2015" /> A subcutaneous formulation of DMPA was introduced in the United States as a contraceptive under the brand name Depo-SubQ Provera 104 (104&nbsp;mg/0.65&nbsp;mL MPA) in December 2004, and subsequently was also approved for the treatment of [[Medicine:Endometriosis|endometriosis]]-related pelvic pain.<ref name="ShoupeJr.2015">{{cite book | vauthors = Shoupe D, Mishell DR | title = The Handbook of Contraception: A Guide for Practical Management|url=https://books.google.com/books?id=ZQehCgAAQBAJ&pg=PA126|date=28 September 2015|publisher=Humana Press|isbn=978-3-319-20185-6|pages=126–}}</ref>

MPA has also been marketed widely throughout the world under numerous other brand names such as Farlutal, Perlutex, and Gestapuran, among others.<ref name="IndexNominum2000" /><ref name="Drugs.com" />

==Society and culture==

===Generic names===
''Medroxyprogesterone acetate'' is the generic name of the drug and its {{abbrlink|INN|International Nonproprietary Name|INN}}, {{abbrlink|USAN|United States Adopted Name}}, {{abbrlink|BAN|British Approved Name|BANM}}, and {{abbrlink|JAN|Japanese Accepted Name}}, while ''medrossiprogesterone'' is the {{abbrlink|DCIT|Denominazione Comune Italiana}} and ''médroxyprogestérone'' the {{abbrlink|DCF|Dénomination Commune Française}} of its free alcohol form.<ref name="Elks2014">{{cite book|vauthors=Elks J|title=The Dictionary of Drugs: Chemical Data: Chemical Data, Structures and Bibliographies|url=https://books.google.com/books?id=0vXTBwAAQBAJ&pg=RA1-PA187|date=14 November 2014|publisher=Springer|isbn=978-1-4757-2085-3|page=657|url-status=live|archive-url=https://web.archive.org/web/20171105200514/https://books.google.com/books?id=0vXTBwAAQBAJ&pg=RA1-PA187|archive-date=5 November 2017}}</ref><ref name="Martindale">{{cite book |editor=Sweetman, Sean C. |chapter=Sex hormones and their modulators |title=Martindale: The Complete Drug Reference |edition=36th |year=2009 |pages=2113–2114 |publisher=Pharmaceutical Press |location=London|isbn=978-0-85369-840-1|chapter-url=https://www.medicinescomplete.com/mc/martindale/2009/9062-p.htm}}</ref><ref name="IndexNominum2000" /><ref name="MortonHall1999">{{cite book| vauthors = Morton IK, Hall JM |title=Concise Dictionary of Pharmacological Agents: Properties and Synonyms|url=https://books.google.com/books?id=mqaOMOtk61IC&pg=PA173|date=31 October 1999|publisher=Springer Science & Business Media|isbn=978-0-7514-0499-9|pages=173–}}</ref><ref name="Drugs.com">{{Cite web|url=https://www.drugs.com/medroxyprogesterone.html|title=Medroxyprogesterone Uses, Dosage & Side Effects|website=Drugs.com}}</ref> It is also known as ''6α-methyl-17α-acetoxyprogesterone'' (''MAP'') or ''6α-methyl-17α-hydroxyprogesterone acetate''.<ref name="Elks2014" /><ref name="Martindale" /><ref name="IndexNominum2000" /><ref name="Drugs.com" />

===Brand names===
MPA is marketed under a large number of brand names throughout the world.<ref name="Drugs.com" /><ref name="Martindale" /><ref name="IndexNominum2000" /> Its most major brand names are Provera as oral tablets and Depo-Provera as an aqueous suspension for intramuscular injection.<ref name="Drugs.com" /><ref name="Martindale" /><ref name="IndexNominum2000" /> A formulation of MPA as an aqueous suspension for subcutaneous injection is also available in the {{wipe|United States}} under the brand name Depo-SubQ Provera 104.<ref name="Drugs.com" /><ref name="Martindale" /> Other brand names of MPA formulated alone include Farlutal and Sayana for clinical use and Depo-Promone, Perlutex, Promone-E, and Veramix for veterinary use.<ref name="Drugs.com" /><ref name="Martindale" /><ref name="IndexNominum2000" /> In addition to single-drug formulations, MPA is marketed in combination with the estrogens CEEs, estradiol, and estradiol valerate.<ref name="Drugs.com" /><ref name="Martindale" /><ref name="IndexNominum2000" /> Brand names of MPA in combination with CEEs as oral tablets in different countries include Prempro, Premphase, Premique, Premia, and Premelle.<ref name="Drugs.com" /><ref name="Martindale" /><ref name="IndexNominum2000" /> Brand names of MPA in combination with estradiol as oral tablets include Indivina and Tridestra.<ref name="Drugs.com" /><ref name="Martindale" /><ref name="IndexNominum2000" />

===Availability===
Oral MPA and DMPA are widely available throughout the world.<ref name="Drugs.com" /> Oral MPA is available both alone and in combination with the estrogens CEEs, estradiol, and estradiol valerate.<ref name="Drugs.com" /> DMPA is registered for use as a form of birth control in more than 100&nbsp;countries worldwide.<ref name="BagadePawar2014c">{{cite journal | vauthors = Bagade O, Pawar V, Patel R, Patel B, Awasarkar V, Diwate S | title = Increasing use of long-acting reversible contraception: safe, reliable, and cost-effective birth control | journal = World J Pharm Pharm Sci | volume = 3 | issue = 10 | pages = 364–392 | year = 2014 | issn = 2278-4357 | url = http://www.wjpps.com/download/article/1412071798.pdf | access-date = 2 August 2018 | archive-url = https://web.archive.org/web/20170810000242/http://www.wjpps.com/download/article/1412071798.pdf | archive-date = 10 August 2017 | url-status = dead }}</ref><ref name="Gunasheela2011">{{cite book| vauthors = Gunasheela S |title=Practical Management of Gynecological Problems|url=https://books.google.com/books?id=gZB-h_gqgS8C&pg=PA39|date=14 March 2011|publisher=JP Medical Ltd|isbn=978-93-5025-240-6|pages=39–}}</ref><ref name="Drugs.com" /> The combination of injected MPA and estradiol cypionate is approved for use as a form of birth control in 18&nbsp;countries.<ref name="BagadePawar2014c" />

====United States====

{{As of|2016|11}}, MPA is available in the {{wipe|United States}} in the following formulations:<ref name="Drugs@FDA">{{cite web | title = Drugs@FDA: FDA Approved Drug Products | publisher = United States Food and Drug Administration | access-date = 31 March 2018 | url = http://www.accessdata.fda.gov/scripts/cder/daf/ | url-status = live | archive-url = https://web.archive.org/web/20161116164727/http://www.accessdata.fda.gov/scripts/cder/daf/ | archive-date = 16 November 2016 }}</ref>
* Oral pills: Amen, Curretab, Cycrin, Provera – 2.5&nbsp;mg, 5&nbsp;mg, 10&nbsp;mg
* Aqueous suspension for intramuscular injection: Depo-Provera – 150&nbsp;mg/mL (for contraception), 400&nbsp;mg/mL (for cancer)
* Aqueous suspension for subcutaneous injection: Depo-SubQ Provera 104 – 104&nbsp;mg/0.65&nbsp;mL (for contraception)

It is also available in combination with an estrogen in the following formulations:
* Oral pills: CEEs and MPA (Prempro, Prempro (Premarin, Cycrin), Premphase (Premarin, Cycrin 14/14), Premphase 14/14, Prempro/Premphase) – 0.3&nbsp;mg / 1.5&nbsp;mg; 0.45&nbsp;mg / 1.5&nbsp;mg; 0.625&nbsp;mg / 2.5&nbsp;mg; 0.625&nbsp;mg / 5&nbsp;mg

While the following formulations have been discontinued:
* Oral pills: ethinylestradiol and MPA (Provest) – 50&nbsp;μg / 10&nbsp;mg
* Aqueous suspension for intramuscular injection: estradiol cypionate and MPA (Lunelle) – 5&nbsp;mg / 25&nbsp;mg (for contraception)

The state of Louisiana permits sex offenders to be given MPA.<ref>{{Cite web|url=http://www.legis.la.gov/legis/Law.aspx?d=508441|title=§43.6. Administration of medroxyprogesterone acetate (MPA) to certain sex offenders|last=Louisiana State Legislature|website=Louisiana Revised Statutes|access-date=8 July 2019}}</ref>

===Generation===
Progestins in birth control pills are sometimes grouped by generation.<ref name="UnzeitigLunsen2000">{{cite book | vauthors = Unzeitig V, van Lunsen RH |title=Contraceptive Choices and Realities: Proceedings of the 5th Congress of the European Society of Contraception |url= https://books.google.com/books?id=-FliV0TxtEEC&pg=PA73 |date=15 February 2000|publisher=CRC Press|isbn=978-1-85070-067-8|pages=73–}}</ref><ref name="HumansOrganization2007">{{cite book|author1=IARC Working Group on the Evaluation of Carcinogenic Risks to Humans|author2=World Health Organization|author3=International Agency for Research on Cancer|title=Combined Estrogen-progestogen Contraceptives and Combined Estrogen-progestogen Menopausal Therapy|url=https://books.google.com/books?id=aGDU5xibtNgC&pg=PA434|year=2007|publisher=World Health Organization|isbn=978-92-832-1291-1|pages=44}}</ref> While the 19-nortestosterone progestins are consistently grouped into generations, the [[Chemistry:Pregnane|pregnane]] progestins that are or have been used in birth control pills are typically omitted from such classifications or are grouped simply as "miscellaneous" or "pregnanes".<ref name="UnzeitigLunsen2000" /><ref name="HumansOrganization2007" /> In any case, based on its date of introduction in such formulations of 1964, MPA could be considered a "first-generation" progestin.<ref name="Gordon2007">{{cite book| vauthors = Gordon JD |title=Obstetrics, Gynecology & Infertility: Handbook for Clinicians|url=https://books.google.com/books?id=2JLC6yiA7fcC&pg=PA228|year=2007|publisher=Scrub Hill Press, Inc.|isbn=978-0-9645467-7-6|pages=228–}}</ref>

===Controversy===

====Outside the United States====
* In 1994, when DMPA was approved in India, India's ''Economic and Political Weekly'' reported that "The FDA finally licensed the drug in 1990 in response to concerns about the population explosion in the third world and the reluctance of third world governments to license a drug not licensed in its originating country."<ref>{{cite journal|title=Contraceptives. Case for public enquiry|journal=Economic and Political Weekly|year=1994|volume=29|issue=15|id=Popline database document number 096527|pages=825–6}}</ref> Some scientists and women's groups in India continue to oppose DMPA.<ref>{{cite journal| vauthors = Sorojini NB |title=Why women's groups oppose injectable contraceptives |journal=Indian Journal of Medical Ethics |volume=13 |issue=1 |date=January–March 2005 |url=http://www.issuesinmedicalethics.org/131di008.html |url-status=dead |archive-url=https://web.archive.org/web/20060506074850/http://www.issuesinmedicalethics.org/131di008.html |archive-date=6 May 2006 }}</ref> In 2016, India introduced DMPA depo-medroxyprogesterone IM preparation in the public health system.<ref>{{cite web |url=https://nhm.gov.in/New_Updates_2018/NHM_Components/RMNCHA/Family_planning/Schemes_&_Guidelines/Injectable_Contraceptive_MPA.pdf |access-date=26 February 2020|title=Reference Manual for Injectable Contraceptive (MPA)|website=nhm.gov.in}}</ref>
* The Canadian Coalition on Depo-Provera, a coalition of women's health professional and advocacy groups, opposed the approval of DMPA in Canada.<ref>{{cite web | vauthors = Boscoe M | title=Canadian Coalition on Depo-Provera letter to The Honorable Benoit Bouchard, National Minister of Health and Welfare | url=http://www.cwhn.ca/resources/birth_control/depoLetter.html |date=6 December 1991 |publisher=Canadian Women's Health Network | access-date=22 August 2006|archive-url=https://web.archive.org/web/20070205105907/http://www.cwhn.ca/resources/birth_control/depoLetter.html|archive-date=5 February 2007}}</ref> Since the approval of DMPA in Canada in 1997, a $700 million class-action lawsuit has been filed against Pfizer by users of DMPA who developed [[Medicine:Osteoporosis|osteoporosis]]. In response, Pfizer argued that it had met its obligation to disclose and discuss the risks of DMPA with the Canadian medical community.<ref>{{cite web | title=Class action suit filed over birth control drug | url=http://www.ctv.ca/servlet/ArticleNews/story/CTVNews/20051219/depo_provera_051219/20051219?hub=TopStories | publisher=CTV.ca | date=19 December 2005 | access-date=22 August 2006 | url-status=dead | archive-url=https://web.archive.org/web/20060813180129/http://www.ctv.ca/servlet/ArticleNews/story/CTVNews/20051219/depo_provera_051219/20051219?hub=TopStories | archive-date=13 August 2006 }}</ref>
* Clinical trials for this medication regarding women in Zimbabwe were controversial with regard to human rights abuses and Medical Experimentation in Africa.
* A controversy erupted in [[Place:Israel|Israel]] when the government was accused of giving DMPA to Ethiopian immigrants without their consent. Some women claimed they were told it was a vaccination. The Israeli government denied the accusations but instructed the four health maintenance organizations to stop administering DMPA injections to women "if there is the slightest doubt that they have not understood the implications of the treatment".<ref>"{{cite news |url=http://www.haaretz.com/news/israel/israeli-minister-appointing-team-to-probe-ethiopian-birth-control-shot-controversy-1.506266 |title=Israeli minister appointing team to probe Ethiopian birth control shot controversy |newspaper=Haaretz |access-date=20 June 2015 |url-status=live |archive-url=https://web.archive.org/web/20150620062920/http://www.haaretz.com/news/israel/israeli-minister-appointing-team-to-probe-ethiopian-birth-control-shot-controversy-1.506266 |archive-date=20 June 2015 }}</ref>

====United States====
There was a long, controversial history regarding the approval of DMPA by the U.S. [[Organization:Food and Drug Administration|Food and Drug Administration]]. The original manufacturer, Upjohn, applied repeatedly for approval. FDA advisory committees unanimously recommended approval in 1973, 1975 and 1992, as did the FDA's professional medical staff, but the FDA repeatedly denied approval. Ultimately, on 29 October 1992, the FDA approved DMPA for birth control, which had by then been used by over 30 million women since 1969 and was approved and being used by nearly 9&nbsp;million women in more than 90&nbsp;countries, including the {{wipe|United Kingdom}}, {{wipe|France}}, {{wipe|Germany}}, Sweden, Thailand, [[Earth:New Zealand|New Zealand]] and Indonesia.<ref name=Leary1992>{{cite journal | vauthors = Leary WE | title = U.S. approves injectable drug as birth control | journal = The New York Times on the Web | pages = A1, A14 | date = October 1992 | pmid = 11646958 | url = https://query.nytimes.com/gst/fullpage.html?sec=health&res=9E0CE1DD123BF933A05753C1A964958260 | url-status = live | archive-url = https://web.archive.org/web/20081208133159/http://query.nytimes.com/gst/fullpage.html?sec=health&res=9E0CE1DD123BF933A05753C1A964958260 | archive-date = 8 December 2008 }}</ref> Points in the controversy included:
* Animal testing for carcinogenicity – DMPA caused breast cancer tumors in dogs. Critics of the study claimed that dogs are more sensitive to artificial progesterone, and that the doses were too high to extrapolate to humans. The FDA pointed out that all substances carcinogenic to humans are carcinogenic to animals as well, and that if a substance is not carcinogenic it does not register as a carcinogen at high doses. Levels of DMPA which caused malignant mammary tumors in dogs were equivalent to 25 times the amount of the normal luteal phase progesterone level for dogs. This is lower than the pregnancy level of progesterone for dogs, and is species-specific.<ref>{{cite web|url=http://www.inchem.org/documents/iarc/suppl7/progestins.html|title=Progestins (IARC Summary & Evaluation, Supplement7, 1987)|access-date=15 October 2016|url-status=live|archive-url=https://web.archive.org/web/20171107030422/http://www.inchem.org/documents/iarc/suppl7/progestins.html|archive-date=7 November 2017}}</ref><br />DMPA caused endometrial cancer in monkeys – 2 of 12 monkeys tested, the first ever recorded cases of endometrial cancer in rhesus monkeys.<ref name="MM_Goodman1985">{{Cite journal | vauthors = Goodman A  | title=The Case Against Depo-Provera - Problems in the U.S | journal=Multinational Monitor | date=February–March 1985 | volume=6 | issue=2 & 3 | url=http://www.multinationalmonitor.org/hyper/issues/1985/02/problems-us.html | url-status=live | archive-url=https://web.archive.org/web/20061003000448/http://www.multinationalmonitor.org/hyper/issues/1985/02/problems-us.html | archive-date=3 October 2006 }}</ref> However, subsequent studies have shown that in humans, DMPA ''reduces'' the risk of endometrial cancer by approximately 80%.<ref name="Kaunitz"/><ref name="BrJFP_Bigrigg1999"/><ref name="WHO DMPA EC"/><br />Speaking in comparative terms regarding animal studies of carcinogenicity for medications, a member of the FDA's Bureau of Drugs testified at an agency DMPA hearing, "...Animal data for this drug is more worrisome than any other drug we know of that is to be given to well people."
* Cervical cancer in Upjohn/NCI studies. Cervical cancer was found to be increased as high as 9-fold in the first human studies recorded by the manufacturer and the [[Organization:National Cancer Institute|National Cancer Institute]].<ref>{{cite journal | title = Controversy over Depo-Provera | journal = Washington Drug & Device Letter | volume = 9 | issue = 1 |page = 2 | date = January 1977 | pmid = 12335988 }}</ref> However, numerous larger subsequent studies have shown that DMPA use does not increase the risk of cervical cancer.<ref>{{cite journal | vauthors = Thomas DB, Ye Z, Ray RM | title = Cervical carcinoma in situ and use of depot-medroxyprogesterone acetate (DMPA). WHO Collaborative Study of Neoplasia and Steroid Contraceptives | journal = Contraception | volume = 51 | issue = 1 | pages = 25–31 | date = January 1995 | pmid = 7750280 | doi = 10.1016/0010-7824(94)00007-J }}</ref><ref>{{cite journal | title = Depot-medroxyprogesterone acetate (DMPA) and risk of invasive squamous cell cervical cancer. The WHO Collaborative Study of Neoplasia and Steroid Contraceptives | journal = Contraception | volume = 45 | issue = 4 | pages = 299–312 | date = April 1992 | pmid = 1387601 | doi = 10.1016/0010-7824(92)90052-U }}</ref><ref>{{cite journal | vauthors = Thomas DB, Ray RM | title = Depot-medroxyprogesterone acetate (DMPA) and risk of invasive adenocarcinomas and adenosquamous carcinomas of the uterine cervix. WHO Collaborative Study of Neoplasia and Steroid Contraceptives | journal = Contraception | volume = 52 | issue = 5 | pages = 307–12 | date = November 1995 | pmid = 8585888 | doi = 10.1016/0010-7824(95)00215-V }}</ref><ref>{{cite journal | vauthors = Shapiro S, Rosenberg L, Hoffman M, Kelly JP, Cooper DD, Carrara H, Denny LE, du Toit G, Allan BR, Stander IA, Williamson AL | title = Risk of invasive cancer of the cervix in relation to the use of injectable progestogen contraceptives and combined estrogen/progestogen oral contraceptives (South Africa) | journal = Cancer Causes & Control | volume = 14 | issue = 5 | pages = 485–95 | date = June 2003 | pmid = 12946044 | doi = 10.1023/A:1024910808307 | s2cid = 34683749 }}</ref><ref>{{cite journal | vauthors = Kaunitz AM | title = Depot medroxyprogesterone acetate contraception and the risk of breast and gynecologic cancer | journal = The Journal of Reproductive Medicine | volume = 41 | issue = 5 Suppl | pages = 419–27 | date = May 1996 | pmid = 8725705 }}</ref>
* Coercion and lack of informed consent. Testing or use of DMPA was focused almost exclusively on women in developing countries and poor women in the United States,<ref name="albion" /> raising serious questions about coercion and lack of informed consent, particularly for the illiterate<ref>{{cite journal | title = Sterilization of minors leads to controversy | journal = Family Planning/Population Reporter; A Review of State Laws and Policies | volume = 2 | issue = 4 | pages = 77–8 | date = August 1973 | pmid = 12257656 }}</ref> and for mentally disabled people, who in some reported cases were given DMPA long-term for reasons of "menstrual hygiene", although they were not sexually active.<ref>{{cite journal | vauthors = Egan TM, Siegert RJ, Fairley NA | title = Use of hormonal contraceptives in an institutional setting: reasons for use, consent and safety in women with psychiatric and intellectual disabilities | journal = The New Zealand Medical Journal | volume = 106 | issue = 961 | pages = 338–41 | date = August 1993 | pmid = 8341476 }}</ref>
* Atlanta/Grady Study – Upjohn studied the effect of DMPA for 11 years in Atlanta, mostly on black women who were receiving public assistance, but did not file any of the required follow-up reports with the FDA. Investigators who eventually visited noted that the studies were disorganized. "They found that data collection was questionable, consent forms and protocol were absent; that those women whose consent had been obtained at all were not told of possible side effects. Women whose known medical conditions indicated that use of DMPA would endanger their health were given the shot. Several of the women in the study died; some of cancer, but some for other reasons, such as suicide due to depression. Over half the 13,000 women in the study were [[Medicine:Lost to follow-up|lost to followup]] due to sloppy record keeping." Consequently, no data from this study was usable.<ref name="albion"/>
* WHO Review – In 1992, the WHO presented a review of DMPA in four developing countries to the FDA. The National Women's Health Network and other women's organizations testified at the hearing that the WHO was not objective, as the WHO had already distributed DMPA in developing countries. DMPA was approved for use in United States on the basis of the WHO review of previously submitted evidence from countries such as Thailand, evidence which the FDA had deemed insufficient and too poorly designed for assessment of cancer risk at a prior hearing.
* The Alan Guttmacher Institute has speculated that United States approval of DMPA may increase its availability and acceptability in developing countries.<ref name="albion">{{cite web| vauthors = Hawkins K, Elliott J |date=5 May 1996 |url=http://www.monitor.net/monitor/controlled/bc-depohearing.html |archive-date=21 November 2015 |url-status=dead |archive-url=https://web.archive.org/web/20151121180041/http://www.monitor.net/monitor/controlled/bc-depohearing.html |title=Seeking Approval |work=Albion Monitor |access-date=20 November 2006 }}</ref><ref>{{cite journal | vauthors = Singh S | title = Adolescent knowledge and use of injectable contraceptives in developing countries | journal = The Journal of Adolescent Health | volume = 16 | issue = 5 | pages = 396–404 | date = May 1995 | pmid = 7662691 | doi = 10.1016/S1054-139X(94)00060-R }}</ref>
* In 1995, several women's health groups asked the FDA to put a moratorium on DMPA, and to institute standardized informed consent forms.<ref>{{cite journal | title = Clinicians clash with consumer groups over possible Depo ban | journal = Contraceptive Technology Update | volume = 16 | issue = 1 | pages = 11–4 | date = January 1995 | pmid = 12319319 }}</ref>

==Research==
DMPA was studied by Upjohn for use as a [[Chemistry:Progestogen-only injectable contraceptive|progestogen-only injectable contraceptive]] in women at a dose of 50&nbsp;mg once a month but produced poor cycle control and was not marketed for this use at this dosage.<ref name="pmid865726">{{cite journal | vauthors = Toppozada M | title = The clinical use of monthly injectable contraceptive preparations | journal = Obstet Gynecol Surv | volume = 32 | issue = 6 | pages = 335–47 | date = June 1977 | pmid = 865726 | doi = 10.1097/00006254-197706000-00001 }}</ref> A combination of DMPA and [[Chemistry:Polyestradiol phosphate|polyestradiol phosphate]], an [[Chemistry:Estrogen (medication)|estrogen]] and long-lasting [[Chemistry:Prodrug|prodrug]] of [[Chemistry:Estradiol (medication)|estradiol]], was studied in women as a combined injectable contraceptive for use by [[Biology:Intramuscular injection|intramuscular injection]] once every three months.<ref name="GoldzieherFotherby1994">{{cite book| vauthors = Goldzieher JW, Fotherby K |title=Pharmacology of the contraceptive steroids|url=https://books.google.com/books?id=bJRsAAAAMAAJ|year=1994|publisher=Raven Press|isbn=978-0-7817-0097-9|page=154}}</ref><ref name="pmid5925038">{{cite journal | vauthors = Zañartu J, Rice-Wray E, Goldzieher JW | title = Fertility control with long-acting injectable steroids. A preliminary report | journal = Obstet Gynecol | volume = 28 | issue = 4 | pages = 513–5 | date = October 1966 | pmid = 5925038 | url = https://journals.lww.com/greenjournal/citation/1966/10000/fertility_control_with_long_acting_injectable.11.aspx}}</ref><ref name="Beckman1967">{{cite book| vauthors = Beckman H |title=The Year Book of Drug Therapy|url=https://books.google.com/books?id=sRc-AQAAIAAJ|year=1967|publisher=Year Book Publishers}}</ref>

High-dose oral and intramuscular MPA monotherapy has been studied in the treatment of prostate cancer but was found to be inferior to monotherapy with [[Chemistry:Cyproterone acetate|cyproterone acetate]] or [[Chemistry:Diethylstilbestrol|diethylstilbestrol]].<ref name="PiotrowskiGreenberg2016">{{cite book| vauthors = Piotrowski Z, Greenberg RE |title=Prostate Cancer |chapter=Antiandrogen Monotherapy in the Treatment of Prostate Cancer|year=2016|pages=515–521|publisher=Academic Press |doi=10.1016/B978-0-12-800077-9.00055-4|isbn=9780128000779}}</ref><ref name="pmid11842755">{{cite book | vauthors = Forster TH, Stoffel F, Gasser TC | title = Controversies in Uro-Oncology | chapter = Hormone therapy in advanced prostate cancer | volume = 36 | pages = 49–65 | date = 2002 | pmid = 11842755 | doi = 10.1159/000061329 | isbn = 3-8055-7217-4 | series = Frontiers of Radiation Therapy and Oncology | issue = 5 }}</ref><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 | doi-access = free }}</ref> High-dose oral MPA has been studied in combination with diethylstilbestrol and CEEs as an addition to [[Chemistry:High-dose estrogen|high-dose estrogen]] therapy for the treatment of [[Medicine:Prostate cancer|prostate cancer]] in men, but was not found to provide better effectiveness than diethylstilbestrol alone.<ref name="DenisGriffiths1999">{{cite book | vauthors = Denis LJ, Griffiths K, Kaisary AV, Murphy GP |title=Textbook of Prostate Cancer: Pathology, Diagnosis and Treatment: Pathology, Diagnosis and Treatment|url=https://books.google.com/books?id=GreZlojD-tYC&pg=PA296|date=1 March 1999|publisher=CRC Press|isbn=978-1-85317-422-3|pages=296–}}</ref>

DMPA has been studied for use as a potential male hormonal contraceptive in combination with the [[Biology:Androgen|androgen]]s/[[Chemistry:Anabolic steroid|anabolic steroid]]s [[Chemistry:Testosterone (medication)|testosterone]] and [[Chemistry:Nandrolone|nandrolone]] (19-nortestosterone) in men.<ref name="pmid20933120">{{cite journal | vauthors = Nieschlag E | title = Clinical trials in male hormonal contraception | journal = Contraception | volume = 82 | issue = 5 | pages = 457–70 | year = 2010 | pmid = 20933120 | doi = 10.1016/j.contraception.2010.03.020 | url = http://www.kup.at/kup/pdf/10172.pdf}}</ref> However, it was never approved for this indication.<ref name="pmid20933120" />

MPA was investigated by InKine Pharmaceutical, Salix Pharmaceuticals, and the [[Organization:University of Pennsylvania|University of Pennsylvania]] as a potential [[Chemistry:Anti-inflammatory|anti-inflammatory]] medication for the treatment of [[Medicine:Autoimmune hemolytic anemia|autoimmune hemolytic anemia]], [[Medicine:Crohn's disease|Crohn's disease]], idiopathic thrombocytopenic purpura, and [[Medicine:Ulcerative colitis|ulcerative colitis]], but did not complete clinical development and was never approved for these indications.<ref name="AdisInsight-MPA-AI">{{Cite web|url=https://adisinsight.springer.com/drugs/800008646|title=Medroxyprogesterone - InKine - AdisInsight}}</ref><ref name="pmid15102587">{{cite journal | vauthors = Srinivasan R, Lichtenstein GR | title = Recent developments in the pharmacological treatment of Crohn's disease | journal = Expert Opin Investig Drugs | volume = 13 | issue = 4 | pages = 373–91 | date = April 2004 | pmid = 15102587 | doi = 10.1517/13543784.13.4.373 | s2cid = 22533823 }}</ref> It was formulated as an oral medication at very high dosages, and was thought to inhibit the signaling of [[Biology:Proinflammatory cytokine|proinflammatory cytokine]]s such as interleukin 6 and [[Biology:Tumor necrosis factor alpha|tumor necrosis factor alpha]], with a [[Chemistry:Mechanism of action|mechanism of action]] that was said to be similar to that of [[Biology:Corticosteroid|corticosteroid]]s.<ref name="AdisInsight-MPA-AI" /><ref name="pmid15102587" /> The formulation of MPA had the tentative brand names Colirest and Hematrol for these indications.<ref name="AdisInsight-MPA-AI" />

MPA has been found to be effective in the treatment of [[Medicine:Mania|manic]] symptoms in women with [[Medicine:Bipolar disorder|bipolar disorder]].<ref name="SaxenaScaini2017">{{cite journal | vauthors = Saxena A, Scaini G, Bavaresco DV, Leite C, Valvassori SS, Carvalho AF, Quevedo J | title = Role of Protein Kinase C in Bipolar Disorder: A Review of the Current Literature | journal = Molecular Neuropsychiatry | volume = 3 | issue = 2 | pages = 108–124 | date = November 2017 | pmid = 29230399 | pmc = 5701269 | doi = 10.1159/000480349 }}</ref>

==Veterinary use==
MPA has been used to reduce [[Philosophy:Aggression|aggression]] and spraying in male cats.<ref name="pmid12701517">{{cite journal | vauthors = Simpson BS, Papich MG | title = Pharmacologic management in veterinary behavioral medicine | journal = Vet. Clin. North Am. Small Anim. Pract. | volume = 33 | issue = 2 | pages = 365–404, vii | date = March 2003 | pmid = 12701517 | doi = 10.1016/S0195-5616(02)00130-4 }}</ref> It may be particularly useful for controlling such behaviors in [[Medicine:Neutering|neutered]] male cats.<ref name="pmid12701517" /> The medication can be administered in cats as an injection once per month.<ref name="pmid12701517" />

==See also==
* Conjugated estrogens/medroxyprogesterone acetate
* Estradiol/medroxyprogesterone acetate
* Estradiol cypionate/medroxyprogesterone acetate
* Polyestradiol phosphate/medroxyprogesterone acetate
{{Notelist}}
{{Notefoot}}

==References==
{{Reflist}}

==External links==
* {{cite web| url = https://druginfo.nlm.nih.gov/drugportal/name/medroxyprogesterone%20acetate | publisher = U.S. National Library of Medicine| work = Drug Information Portal| title = Medroxyprogesterone acetate }}

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