Leuprorelin

{{Short description|Manufactured (artificial) injectable hormone}} {{cs1 config|name-list-style=vanc}} {{Use dmy dates|date=March 2023}} {{Drugbox | Verifiedfields = changed | Watchedfields = changed | verifiedrevid = 411878260 | image = Leuprorelin.svg | image_class = skin-invert-image | width = 250 | alt = | image2 = Leuprorelin ball-and-stick.png | image_class2 = bg-transparent | width2 = 250 | alt2 = | caption =

| pronounce = | tradename = Lupron, Eligard, Lucrin, Lupaneta, others | Drugs.com = {{drugs.com|monograph|leuprolide-acetate}} | MedlinePlus = a685040 | DailyMedID = Leuprolide | pregnancy_AU = D | pregnancy_AU_comment = | pregnancy_category= | routes_of_administration = implant, subcutaneous, intramuscular | class = GnRH analogue; GnRH agonist; Antigonadotropin | ATC_prefix = L02 | ATC_suffix = AE02 | ATC_supplemental =

| legal_AU = S4 | legal_AU_comment =<ref>[https://www.tga.gov.au/resources/prescription-medicines-registrations/eligard-mundipharma-pty-ltd ELIGARD (Mundipharma Pty Ltd)] Department of Health and Aged Care. Retrieved 30 March 2023</ref> | legal_BR =  | legal_BR_comment = | legal_CA = Rx-only | legal_CA_comment = <ref>{{cite web | title=Product monograph brand safety updates | website=Health Canada | date=February 2024 | url=https://www.canada.ca/en/health-canada/services/drugs-health-products/drug-products/drug-product-database/label-safety-assessment-update/product-monograph-brand-safety-updates.html | access-date=24 March 2024}}</ref><ref>{{cite web | title=Regulatory Decision Summary for Eligard | website=Drug and Health Products Portal | date=21 September 2023 | url=https://dhpp.hpfb-dgpsa.ca/review-documents/resource/RDS1708632207803 | access-date=2 April 2024}}</ref> | legal_DE =  | legal_DE_comment = | legal_NZ =  | legal_NZ_comment = | legal_UK =  | legal_UK_comment = | legal_US = Rx-only | legal_US_comment = <ref name="Lupron FDA label" /><ref name="Eligard FDA label" /><ref name="Fensolvi FDA label" /><ref name="Viadur FDA label" /><ref name="Lupron Depot FDA label" /> | legal_EU = Rx-only | legal_EU_comment = <ref name="Camcevi EPAR">{{cite web | title=Camcevi EPAR | website=European Medicines Agency (EMA) | date=22 March 2022 | url=https://www.ema.europa.eu/en/medicines/human/EPAR/camcevi | access-date=21 June 2022}}</ref> | legal_UN =  | legal_UN_comment = | legal_status = Rx-only

| CAS_number_Ref = {{cascite|correct|??}} | CAS_number = 53714-56-0 | CAS_supplemental = {{CAS|74381-53-6}} (acetate) | PubChem = 657181 | IUPHAR_ligand = 1175 | DrugBank_Ref = {{drugbankcite|correct|drugbank}} | DrugBank = DB00007 | ChemSpiderID_Ref = {{chemspidercite|changed|chemspider}} | ChemSpiderID = 571356 | UNII_Ref = {{fdacite|changed|FDA}} | UNII = EFY6W0M8TG | KEGG_Ref = {{keggcite|correct|kegg}} | KEGG = D08113 | ChEBI_Ref = | ChEBI = | ChEMBL_Ref = {{ebicite|changed|EBI}} | ChEMBL = 1201199 | NIAID_ChemDB = | PDB_ligand = | synonyms = leuprolide, leuprolidine, A-43818, Abbott-43818, DC-2-269, TAP-144

| IUPAC_name = ''N''-<nowiki>[1-[[1-[[1-[[1-[[1-[[1-[[5-</nowiki>(diaminomethylideneamino)-1- [2-(ethylcarbamoyl)pyrrolidin-1-yl]-1-oxo-pentan-2- yl]carbamoyl]-3-methyl-butyl]carbamoyl]-3-methyl- butyl]carbamoyl]-2-(4-hydroxyphenyl)ethyl] carbamoyl]-2-hydroxy-ethyl]carbamoyl]-2-(1''H''-indol-3- yl)ethyl]carbamoyl]-2-(3''H''-imidazol-4-yl)ethyl]-5-oxo- pyrrolidine-2-carboxamide | C=59 | H=84 | N=16 | O=12 | SMILES = CCNC(=O)[C@@H]1CCCN1C(=O)[C@H](CCCNC(=N)N)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](CC(C)C)NC(=O)[C@H](Cc2ccc(cc2)O)NC(=O)[C@H](CO)NC(=O)[C@H](Cc3c[nH]c4c3cccc4)NC(=O)[C@H](Cc5c[nH]cn5)NC(=O)[C@@H]6CCC(=O)N6 | StdInChI_Ref = {{stdinchicite|changed|chemspider}} | StdInChI=1S/C59H84N16O12/c1-6-63-57(86)48-14-10-22-75(48)58(87)41(13-9-21-64-59(60)61)68-51(80)42(23-32(2)3)69-52(81)43(24-33(4)5)70-53(82)44(25-34-15-17-37(77)18-16-34)71-56(85)47(30-76)74-54(83)45(26-35-28-65-39-12-8-7-11-38(35)39)72-55(84)46(27-36-29-62-31-66-36)73-50(79)40-19-20-49(78)67-40/h7-8,11-12,15-18,28-29,31-33,40-48,65,76-77H,6,9-10,13-14,19-27,30H2,1-5H3,(H,62,66)(H,63,86)(H,67,78)(H,68,80)(H,69,81)(H,70,82)(H,71,85)(H,72,84)(H,73,79)(H,74,83)(H4,60,61,64)/t40-,41-,42-,43+,44-,45-,46-,47-,48-/m0/s1 | StdInChIKey_Ref = {{stdinchicite|changed|chemspider}} | StdInChIKey = GFIJNRVAKGFPGQ-LIJARHBVSA-N | density = | density_notes = | melting_point = | melting_high = | melting_notes = | boiling_point = | boiling_notes = | solubility = | sol_units = | specific_rotation = }}

'''Leuprorelin''', also known as '''leuprolide''', is a manufactured version of a hormone used to treat prostate cancer, breast cancer, endometriosis, uterine fibroids, for early puberty, as part of transgender hormone therapy, or to perform chemical castration of violent sex offenders.<ref name="AHFS2016">{{cite web|title=Leuprolide Acetate|url=https://www.drugs.com/monograph/leuprolide-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/20161223133754/https://www.drugs.com/monograph/leuprolide-acetate.html|archive-date=23 December 2016}}</ref><ref name="WHO21st" /><ref>{{cite journal |vauthors=Silvani M, Mondaini N, Zucchi A |date=September 2015 |title=Androgen deprivation therapy (castration therapy) and pedophilia: What's new |journal=Archivio Italiano di Urologia, Andrologia |volume=87 |issue=3 |pages=222–226 |doi=10.4081/aiua.2015.3.222 |pmid=26428645 |s2cid=5181746 |doi-access=free |hdl-access=free |hdl=11568/1073189}}</ref> It is given by injection into a muscle or under the skin.<ref name=AHFS2016/>

Leuprorelin is in the gonadotropin-releasing hormone (GnRH) analogue family of medications.<ref name=AHFS2016/> It works by decreasing gonadotropins, thereby decreasing testosterone and estradiol.<ref name=AHFS2016/> Common side effects include hot flashes, unstable mood, trouble sleeping, headaches, and pain at the site of injection.<ref name=AHFS2016/> Other side effects may include high blood sugar, allergic reactions, and problems with the pituitary gland.<ref name=AHFS2016/> Use during pregnancy may harm foetal development.<ref name=AHFS2016/>

Leuprorelin was patented in 1973 and approved for medical use in the United States in 1985.<ref name=AHFS2016/><ref name=Fis2006>{{cite book | vauthors = Fischer J, Ganellin CR |title=Analogue-based Drug Discovery |date=2006 |publisher=John Wiley & Sons |isbn=978-3-527-60749-5 |page=514 |url=https://books.google.com/books?id=FjKfqkaKkAAC&pg=PA514 |language=en |access-date=19 September 2020 |archive-date=20 June 2021 |archive-url=https://web.archive.org/web/20210620041512/https://books.google.com/books?id=FjKfqkaKkAAC&pg=PA514 |url-status=live }}</ref> It is on the 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 | author-link = World Health Organization | 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> It is sold under the brand name '''Lupron''', among others.<ref name=AHFS2016/>

==Medical uses== Leuprorelin may be used in the treatment of hormone-responsive cancers such as prostate cancer and breast cancer. It may also be used for estrogen-dependent conditions such as endometriosis<ref name="pmid16176939">{{cite journal |vauthors=Crosignani PG, Luciano A, Ray A, Bergqvist A |title=Subcutaneous depot medroxyprogesterone acetate versus leuprolide acetate in the treatment of endometriosis-associated pain |journal=Human Reproduction |volume=21 |issue=1 |pages=248–56 |date=January 2006 |pmid=16176939 |doi=10.1093/humrep/dei290 |doi-access=free }}</ref> or uterine fibroids.

It may be used for precocious puberty in both males and females,<ref name="pmid16449344">{{cite journal |vauthors=Badaru A, Wilson DM, Bachrach LK, etal |title=Sequential comparisons of one-month and three-month depot leuprolide regimens in central precocious puberty |journal=The Journal of Clinical Endocrinology and Metabolism |volume=91 |issue=5 |pages=1862–67 |date=May 2006 |pmid=16449344 |doi=10.1210/jc.2005-1500 |doi-access= }}</ref> and to prevent premature ovulation in cycles of controlled ovarian stimulation for in vitro fertilization (IVF). This use is controversial since the Lupron label advises against using the drug when one is considering pregnancy, due to a risk of birth defects.<ref>{{cite web |title=Lupron, used to halt puberty in children, may cause lasting health problems |url=https://www.statnews.com/2017/02/02/lupron-puberty-children-health-problems/ |website=STAT |access-date=7 December 2020 |date=2 February 2017 |archive-date=7 December 2020 |archive-url=https://web.archive.org/web/20201207124710/https://www.statnews.com/2017/02/02/lupron-puberty-children-health-problems/ |url-status=live }}</ref>

It may be used to reduce the risk of premature ovarian failure in women receiving cyclophosphamide for chemotherapy.<ref>{{cite journal | vauthors = Clowse ME, Behera MA, Anders CK, Copland S, Coffman CJ, Leppert PC, Bastian LA | title = Ovarian preservation by GnRH agonists during chemotherapy: a meta-analysis | journal = Journal of Women's Health | volume = 18 | issue = 3 | pages = 311–19 | date = March 2009 | pmid = 19281314 | pmc = 2858300 | doi = 10.1089/jwh.2008.0857 }}</ref>

Along with triptorelin and goserelin, it has been used to delay puberty in transgender youth until they are old enough to begin hormone replacement therapy.<ref name="WolfeMash2008">{{cite book| vauthors = Wolfe DA, Mash EJ |title=Behavioral and Emotional Disorders in Adolescents: Nature, Assessment, and Treatment|url=https://books.google.com/books?id=nRzMWqpj-pcC&pg=PA556|access-date=24 March 2012|year=2008|publisher=Guilford Press|isbn=978-1-60623-115-9|pages=556–|url-status=live|archive-url=https://web.archive.org/web/20140702151233/http://books.google.com/books?id=nRzMWqpj-pcC&pg=PA556|archive-date=2 July 2014}}</ref> Researchers have recommended puberty blockers after age 12, when the person has developed to Tanner stages 2–3, and then cross-sex hormones treatment at age 16.

They are also sometimes used as alternatives to antiandrogens like spironolactone and cyproterone acetate for suppressing testosterone production in transgender women.<ref>{{cite journal | vauthors = Gava G, Mancini I, Alvisi S, Seracchioli R, Meriggiola MC | title = A comparison of 5-year administration of cyproterone acetate or leuprolide acetate in combination with estradiol in transwomen | journal = European Journal of Endocrinology | volume = 183 | issue = 6 | pages = 561–569 | date = December 2020 | pmid = 33055297 | doi = 10.1530/EJE-20-0370 | s2cid = 222832326 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Gava G, Cerpolini S, Martelli V, Battista G, Seracchioli R, Meriggiola MC | title = Cyproterone acetate vs leuprolide acetate in combination with transdermal oestradiol in transwomen: a comparison of safety and effectiveness | journal = Clinical Endocrinology | volume = 85 | issue = 2 | pages = 239–246 | date = August 2016 | pmid = 26932202 | doi = 10.1111/cen.13050 | s2cid = 30150360 }}</ref><ref>{{cite web | work = NHS Guideline | title = Hormone Therapy in Gender Dysphoria | quote = Table 1 | url = https://www.elmmb.nhs.uk/_resources/assets/attachment/full/0/20242.pdf | access-date = 22 April 2022 | archive-date = 5 June 2022 | archive-url = https://web.archive.org/web/20220605035115/https://www.elmmb.nhs.uk/_resources/assets/attachment/full/0/20242.pdf | url-status = dead }}</ref> It also is used for suppressing estrogen production in transgender men.<ref>{{cite journal | journal = NHS Guideline | title = Hormone Therapy in Gender Dysphoria | quote = Table 1 | url = https://www.lancsmmg.nhs.uk/media/1517/trans-male-gender-dysphoria-prescribing-information-sheet.pdf }}</ref>

It is considered a possible treatment for paraphilias.<ref>{{cite journal |vauthors=Saleh FM, Niel T, Fishman MJ |title=Treatment of paraphilia in young adults with leuprolide acetate: a preliminary case report series |journal=Journal of Forensic Sciences |volume=49 |issue=6 |pages=1343–48 |year=2004 |pmid=15568711 |doi=10.1520/JFS2003035 }}</ref> Leuprorelin has been tested as a treatment for reducing sexual urges in pedophiles and other cases of paraphilia.<ref>{{cite journal |vauthors=Schober JM, Byrne PM, Kuhn PJ |title=Leuprolide acetate is a familiar drug that may modify sex-offender behaviour: the urologist's role |journal=BJU International |volume=97 |issue=4 |pages=684–86 |year=2006 |pmid=16536753 |doi=10.1111/j.1464-410X.2006.05975.x |s2cid=19365144 |doi-access= }}</ref><ref>{{cite journal |vauthors=Schober JM, Kuhn PJ, Kovacs PG, Earle JH, Byrne PM, Fries RA |title=Leuprolide acetate suppresses pedophilic urges and arousability |journal=Archives of Sexual Behavior |volume=34 |issue=6 |pages=691–705 |year=2005 |pmid=16362253 |doi=10.1007/s10508-005-7929-2 |s2cid=24065433 }}</ref>

==Side effects== Common side effects of leuprorelin injection include redness/burning/stinging/pain/bruising at the injection site, hot flashes (flushing), increased sweating, night sweats, tiredness, headache, upset stomach, nausea, diarrhea, impotence, testicular shrinkage,<ref name="Lupron Depot FDA label" /> constipation, stomach pain, breast swelling or tenderness, acne, joint/muscle aches or pain, trouble sleeping (insomnia), reduced sexual interest, vaginal discomfort/dryness/itching/discharge, vaginal bleeding, swelling of the ankles/feet, increased urination at night, dizziness, breakthrough bleeding in a female child during the first two months of leuprorelin treatment, weakness, chills, clammy skin, skin redness, itching, or scaling, testicular pain, impotence, depression, or memory problems.<ref>{{cite web |url=http://www.rxlist.com/lupron-side-effects-drug-center.htm |title=Common Side Effects of Lupron (Leuprolide Acetate Injection) Drug Center |access-date=26 July 2015 |url-status=live |archive-url=https://web.archive.org/web/20150729185809/http://www.rxlist.com/lupron-side-effects-drug-center.htm |archive-date=29 July 2015 }}{{full citation needed|date=February 2017}}</ref> The rates of gynecomastia with leuprorelin have been found to range from 3 to 16%.<ref name="pmid16321765">{{cite journal | vauthors = Di Lorenzo G, Autorino R, Perdonà S, De Placido S | title = Management of gynaecomastia in patients with prostate cancer: a systematic review | journal = Lancet Oncol. | volume = 6 | issue = 12 | pages = 972–79 | date = December 2005 | pmid = 16321765 | doi = 10.1016/S1470-2045(05)70464-2 }}</ref>

A cohort of women that were prescribed leuprorelin to delay precocious puberty as children has developed osteoporosis and brittle teeth at an unexpected rate; However, the FDA has not established that these conditions were caused by leuprorelin.<ref>{{cite news| vauthors = Jewett C |date=2 February 2017|title=Women Fear Drug They Used To Halt Puberty Led To Health Problems|url=https://khn.org/news/women-fear-drug-they-used-to-halt-puberty-led-to-health-problems/|work=Kaiser Health Network|access-date=17 November 2022}}</ref>

===Lupron "flare"=== During the initial phase of luteinizing hormone-releasing hormone (LHRH) agonist therapy in male patients, there is a notable phenomenon known as the "flare." This occurs when testosterone levels temporarily surge by approximately 50% within the first 1 to 2 weeks of therapy. This increase is a response to the initial stimulation of luteinizing hormone (LH) by the LHRH agonist, leading to a rise in testosterone levels before they begin to decrease as intended. For individuals receiving LHRH agonists as part of gender-affirming care, this temporary increase in testosterone can be particularly distressing, exacerbating gender dysphoria and discomfort. To manage and mitigate these effects, healthcare providers often prescribe antiandrogens during this phase to help block the unwanted increase in testosterone and alleviate the associated distress.<ref>{{cite journal |last1=Thompson |first1=Ian |title=Flare Associated with LHRH-Agonist Therapy |journal=Reviews in Urology |date=2001 |volume=3 Suppl 3 |issue=Suppl 3 |pages=S10–S14 |pmid=16986003|pmc=1476081 }}</ref>

==Pharmacology==

===Mechanism of action=== Leuprorelin is a gonadotropin-releasing hormone (GnRH) analogue acting as an agonist at pituitary GnRH receptors. GnRH receptor agonists initially increase the secretion of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) by the anterior pituitary and increased serum estradiol and testosterone levels via the hypothalamic–pituitary–gonadal axis (HPG axis). However, normal functioning of this axis requires pulsatile release of GnRH from the hypothalamus. Continuous exposure to an agonist such as leuprorelin for several weeks causes pituitary GnRH receptors to become desensitised and no longer responsive (downregulation). This desensitisation is the objective of leuprorelin therapy because it ultimately reduces LH and FSH secretion, leading to hypogonadism and a dramatic reduction in estradiol and testosterone levels regardless of sex.<ref name="Mutschler">{{Cite book| vauthors = Mutschler E, Schäfer-Korting M |title= Arzneimittelwirkungen |language=de|location=Stuttgart|publisher=Wissenschaftliche Verlagsgesellschaft|year=2001|edition=8|pages=372–73|isbn=978-3-8047-1763-3}}</ref><ref>{{cite journal | vauthors = Wuttke W, Jarry H, Feleder C, Moguilevsky J, Leonhardt S, Seong JY, Kim K | title = The neurochemistry of the GnRH pulse generator | journal = Acta Neurobiologiae Experimentalis | volume = 56 | issue = 3 | pages = 707–13 | year = 1996 | doi = 10.55782/ane-1996-1176 | pmid = 8917899 | url = http://www.ane.pl/linkout.php?vol=56&no=3&fpp=707 | archive-url = https://web.archive.org/web/20151208053059/http://www.ane.pl/linkout.php?vol=56&no=3&fpp=707 | url-status = live | archive-date = 8 December 2015 | doi-access = free }}</ref>

===Available forms=== Leuprorelin is available in the following forms, among others:<ref name="pmid22335366">{{cite journal | vauthors = Teutonico D, Montanari S, Ponchel G | title = Leuprolide acetate: pharmaceutical use and delivery potentials | journal = Expert Opin Drug Deliv | volume = 9 | issue = 3 | pages = 343–54 | date = March 2012 | pmid = 22335366 | doi = 10.1517/17425247.2012.662484 | s2cid = 30843402 }}</ref><ref name="ButlerGovindan2010">{{cite book| vauthors = Butler SK, Govindan R |title=Essential Cancer Pharmacology: The Prescriber's Guide|url=https://books.google.com/books?id=ZC0oMwt1ZKgC&pg=PA262|year=2010|publisher=Lippincott Williams & Wilkins|isbn=978-1-60913-704-5|pages=262–|access-date=29 August 2018|archive-date=13 June 2021|archive-url=https://web.archive.org/web/20210613025013/https://books.google.com/books?id=ZC0oMwt1ZKgC&pg=PA262|url-status=live}}</ref><ref name="LehneRosenthal2014">{{cite book| vauthors = Lehne RA, Rosenthal R | chapter = Anticancer drugs II: Hormonal agents, targeted drugs, and other noncytotoxic anticancer drugs |title=Pharmacology for Nursing Care | chapter-url= https://books.google.com/books?id=udTsAwAAQBAJ&pg=PA1296|year=2014|publisher=Elsevier Health Sciences|isbn=978-0-323-29354-9 |pages=1296– |access-date=29 August 2018|archive-date=11 August 2021|archive-url=https://web.archive.org/web/20210811042959/https://books.google.com/books?id=udTsAwAAQBAJ&pg=PA1296|url-status=live}}</ref><ref name="Demos2011">{{cite book | vauthors = Su X, Hapani S, Wu S | chapter = An Update on Androgen-Deprivation Therapy for Advanced Prostate Cancer| title=Prostate Cancer|chapter-url=https://books.google.com/books?id=WJkjgbRJe3EC&pg=PA503|year=2011|publisher=Demos Medical Publishing|isbn=978-1-935281-91-7|pages=503–512 |access-date=29 August 2018|archive-date=13 June 2021|archive-url=https://web.archive.org/web/20210613025018/https://books.google.com/books?id=WJkjgbRJe3EC&pg=PA503|url-status=live}}</ref><ref>{{Cite web|date=21 May 2020|title=Leuprolide Long-acting – Medical Mutual|url=https://provider.medmutual.com/PDF/RxMgmt/DrugClass/Leuprolide%20ER.pdf?t=7/10/2020%2011:20:16%20AM|access-date=11 August 2021|archive-date=11 August 2021|archive-url=https://web.archive.org/web/20210811042931/https://www.medmutual.com/for-providers|url-status=live}}</ref> * Short-acting daily intramuscular injection (Lupron)<ref name="Lupron FDA label">{{cite web | title=Lupron- leuprolide acetate lupron- leuprolide acetate injection, solution | website=DailyMed | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=319f0af7-6cc7-4a91-a28a-9ceea37d0ca8 | access-date=27 May 2021 | archive-date=27 May 2021 | archive-url=https://web.archive.org/web/20210527044148/https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=319f0af7-6cc7-4a91-a28a-9ceea37d0ca8 | url-status=live }}</ref> * Long-acting depot intramuscular injection (Lupron Depot)<ref name="Lupron Depot FDA label">{{cite web | title=Lupron Depot- leuprolide acetate kit | website=DailyMed | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=cbc8f94e-7330-4465-05ad-16d64493a5dd | access-date=27 May 2021 | archive-date=27 May 2021 | archive-url=https://web.archive.org/web/20210527044144/https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=cbc8f94e-7330-4465-05ad-16d64493a5dd | url-status=live }}</ref><ref>{{cite web | title=Lupron Depot- leuprolide acetate kit | website=DailyMed | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=00c486b0-bd7b-4898-834d-8c656e5e73cb | access-date=27 May 2021 | archive-date=27 May 2021 | archive-url=https://web.archive.org/web/20210527044146/https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=00c486b0-bd7b-4898-834d-8c656e5e73cb | url-status=live }}</ref><ref>{{cite web | title=Lupron Depot- leuprolide acetate kit | website=DailyMed | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=60aad237-e1da-4705-cbbb-b3ca79e89ad8 | access-date=27 May 2021 | archive-date=27 May 2021 | archive-url=https://web.archive.org/web/20210527044153/https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=60aad237-e1da-4705-cbbb-b3ca79e89ad8 | url-status=live }}</ref><ref>{{cite web | title=Lupron Depot-Ped- leuprolide acetate kit | website=DailyMed | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=e99f47d2-da10-3127-ecb3-e5d942ae6e81 | access-date=27 May 2021 | archive-date=27 May 2021 | archive-url=https://web.archive.org/web/20210527044149/https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=e99f47d2-da10-3127-ecb3-e5d942ae6e81 | url-status=live }}</ref> * Long-acting depot subcutaneous injection ('''Eligard''')<ref name="Eligard FDA label" /> * Long-acting subcutaneous injection (Fensolvi)<ref name="Fensolvi FDA label" /> * Long-acting subcutaneous implant (Viadur)<ref name="Viadur FDA label" /> * Long-acting leuprolide mesylate (Camcevi) for the treatment of advanced prostate cancer.<ref name="FDA letter">{{Cite web |url=https://www.accessdata.fda.gov/drugsatfda_docs/appletter/2021/211488Orig1s000ltr.pdf | vauthors = Ibrahim A |title= Camcevi (leuprolide) NDA Approval | date = 25 May 2021 | work = U.S. Food and Drug Administration |access-date = 27 May 2021 |archive-date=27 May 2021 |archive-url=https://web.archive.org/web/20210527031734/https://www.accessdata.fda.gov/drugsatfda_docs/appletter/2021/211488Orig1s000ltr.pdf |url-status=dead }}</ref> * Leuprolide acetate and norethindrone acetate co-packaged pack (Lupaneta Pack)<ref>{{cite web | title=Lupaneta Pack- leuprolide acetate and norethindrone acetate kit | website=DailyMed | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=f6709069-6a58-625b-d090-53a2c5cc6f3b | access-date=27 May 2021 | archive-date=27 May 2021 | archive-url=https://web.archive.org/web/20210527044151/https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=f6709069-6a58-625b-d090-53a2c5cc6f3b | url-status=live }}</ref><ref>{{cite web | title=Lupaneta Pack- leuprolide acetate and norethindrone acetate kit | website=DailyMed | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=77addaa2-4d81-c2d0-2efd-7280aa4a8ccf | access-date=27 May 2021 | archive-date=27 May 2021 | archive-url=https://web.archive.org/web/20210527044156/https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=77addaa2-4d81-c2d0-2efd-7280aa4a8ccf | url-status=live }}</ref>

==Chemistry== The peptide sequence is Pyr-His-Trp-Ser-Tyr-D-Leu-Leu-Arg-Pro-NHEt (Pyr = L-pyroglutamyl).

==History== Leuprorelin was discovered and first patented in 1973 and was introduced for medical use in 1985.<ref name="Leal2013">{{cite book| vauthors = Jamil GL |title=Rethinking the Conceptual Base for New Practical Applications in Information Value and Quality|url=https://books.google.com/books?id=heOWBQAAQBAJ&pg=PA111|year=2013|publisher=IGI Global|isbn=978-1-4666-4563-9|pages=111–|access-date=27 August 2018|archive-date=13 June 2021|archive-url=https://web.archive.org/web/20210613025015/https://books.google.com/books?id=heOWBQAAQBAJ&pg=PA111|url-status=live}}</ref><ref name="Hara2003">{{cite book| vauthors = Hara T |title=Innovation in the Pharmaceutical Industry: The Process of Drug Discovery and Development|url=https://books.google.com/books?id=aYP-AQAAQBAJ&pg=PA106|year=2003|publisher=Edward Elgar Publishing|isbn=978-1-84376-566-0|pages=106–07|access-date=27 August 2018|archive-date=13 June 2021|archive-url=https://web.archive.org/web/20210613025020/https://books.google.com/books?id=aYP-AQAAQBAJ&pg=PA106|url-status=live}}</ref> It was initially marketed only for daily injection, but a depot injection formulation was introduced in 1989.<ref name="Hara2003" />

===Approvals=== * Lupron injection was approved by the FDA for treatment of advanced prostate cancer on 9 April 1985.<ref>{{Cite web |url=https://www.accessdata.fda.gov/drugsatfda_docs/nda/pre96/019010Orig1s000rev.pdf |title=Lupron (Leuprolide acetate) NDA approval | vauthors = Esber EC | work = U.S. Food and Drug Administration | date = 21 May 1985 |access-date= 27 May 2021 |archive-date= 10 April 2021 |archive-url= https://web.archive.org/web/20210410034236/https://www.accessdata.fda.gov/drugsatfda_docs/nda/pre96/019010Orig1s000rev.pdf |url-status=dead }}</ref><ref name="Lupron FDA label" /><ref name="Leal2013" /><ref name="Hara2003" /> * Lupron depot for monthly intramuscular injection was approved by the FDA for palliative treatment of advanced prostate cancer on 26 January 1989.<ref name="Lupron Depot FDA label" /> * Viadur was approved by the FDA for palliative treatment of advanced prostate cancer on 6 March 2000.<ref name="Viadur FDA label" /> * Eligard was approved by the FDA for palliative treatment of advanced prostate cancer on 24 January 2002.<ref name="Eligard FDA label" /> * Fensolvi was approved by the FDA for children with central precocious puberty on 4 May 2020.<ref name="Fensolvi FDA label" /><ref>{{Cite news| vauthors = Ernst D |date=4 May 2020|title=Fensolvi Approved for Central Precocious Puberty|url= https://www.empr.com/home/news/fensolvi-approved-for-central-precocious-puberty/ |website=MPR|access-date=19 August 2020|archive-date=5 November 2020|archive-url=https://web.archive.org/web/20201105015119/https://www.empr.com/home/news/fensolvi-approved-for-central-precocious-puberty/|url-status=live}}</ref>

==Society and culture==

=== Legal status === On 24 March 2022, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) adopted a positive opinion, recommending the granting of a marketing authorization for the medicinal product Camcevi, intended for the treatment of the cancer of the prostate in adult men when the cancer is "hormone-dependent", which means that it responds to treatments that reduce the levels of the hormone testosterone.<ref name="Camcevi: Pending EC decision" /> The applicant for this medicinal product is Accord Healthcare S.L.U.<ref name="Camcevi: Pending EC decision">{{cite web | title=Camcevi: Pending EC decision | website=European Medicines Agency (EMA) | date=24 March 2022 | url=https://www.ema.europa.eu/en/medicines/human/summaries-opinion/camcevi | access-date=28 March 2022 | archive-date=29 March 2022 | archive-url=https://web.archive.org/web/20220329163708/https://www.ema.europa.eu/en/medicines/human/summaries-opinion/camcevi | url-status=dead }} Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.</ref> Leuprorelin was approved for medical use in the European Union in May 2022.<ref name="Camcevi EPAR" /><ref>{{cite web | title=Camcevi Product information | website=Union Register of medicinal products | url=https://ec.europa.eu/health/documents/community-register/html/h1647.htm | access-date=3 March 2023}}</ref>

===Names=== Leuprorelin is the generic name of the drug and its {{abbrlink|INN|International Nonproprietary Name}} and {{abbrlink|BAN|British Approved Name}}, while leuprorelin acetate is its {{abbrlink|BANM|British Approved Name}} and {{abbrlink|JAN|Japanese Accepted Name}}, leuprolide acetate is its {{abbrlink|USAN|United States Adopted Name}} and {{abbrlink|USP|United States Pharmacopeia}}, leuprorelina is its {{abbrlink|DCIT|Denominazione Comune Italiana}}, and leuproréline is its {{abbrlink|DCF|Dénomination Commune Française}}.<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=PA730|year=2014|publisher=Springer|isbn=978-1-4757-2085-3|pages=730–|access-date=25 February 2018|archive-date=13 June 2021|archive-url=https://web.archive.org/web/20210613025020/https://books.google.com/books?id=0vXTBwAAQBAJ&pg=PA730|url-status=live}}</ref><ref name="IndexNominum2000">{{cite book|title=Index Nominum 2000: International Drug Directory|url=https://books.google.com/books?id=5GpcTQD_L2oC&pg=PA599|year=2000|publisher=Taylor & Francis|isbn=978-3-88763-075-1|pages=599–|access-date=25 February 2018|archive-date=13 June 2021|archive-url=https://web.archive.org/web/20210613025018/https://books.google.com/books?id=5GpcTQD_L2oC&pg=PA599|url-status=live}}</ref><ref name="MortonHall2012">{{cite book| vauthors = Morton IK, Hall JM |title=Concise Dictionary of Pharmacological Agents: Properties and Synonyms|url=https://books.google.com/books?id=tsjrCAAAQBAJ&pg=PA164|year=2012|publisher=Springer Science & Business Media|isbn=978-9-401144-39-1|pages=164–|access-date=25 February 2018|archive-date=13 June 2021|archive-url=https://web.archive.org/web/20210613025016/https://books.google.com/books?id=tsjrCAAAQBAJ&pg=PA164|url-status=live}}</ref><ref name="Drugs.com">{{Cite web | url=https://www.drugs.com/international/leuprorelin.html | title=Leuprorelin | work = Drugs.com | access-date=25 February 2018 | archive-date=25 February 2018 | archive-url=https://web.archive.org/web/20180225205554/https://www.drugs.com/international/leuprorelin.html | url-status=live }}</ref> It is also known by its developmental code names A-43818, Abbott-43818, DC-2-269, and TAP-144.<ref name="Elks2014" /><ref name="IndexNominum2000" /><ref name="MortonHall2012" /><ref name="Drugs.com" />

Leuprorelin is marketed by Bayer AG under the brand name Viadur,<ref name="Viadur FDA label">{{cite web | title=Viadur- leuprolide acetate | website=DailyMed | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=82c5998f-2253-4880-9be5-feaba553d5d1 | access-date=26 May 2021 | archive-date=27 May 2021 | archive-url=https://web.archive.org/web/20210527044151/https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=82c5998f-2253-4880-9be5-feaba553d5d1 | url-status=live }}</ref> by Tolmar under the brand names Eligard and Fensolvi,<ref name="Eligard FDA label">{{cite web | title=Eligard- leuprolide acetate kit | website=DailyMed | date=26 March 2020 | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=b78d1919-9dee-44fa-90f9-e0a26d32481d | access-date=20 August 2020 | archive-date=10 August 2020 | archive-url=https://web.archive.org/web/20200810000049/https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=b78d1919-9dee-44fa-90f9-e0a26d32481d | url-status=live }}</ref><ref name="Fensolvi FDA label">{{cite web | title=Fensolvi- leuprolide acetate kit | website=DailyMed | date=3 June 2020 | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=dfb6e01c-f138-471d-bf5b-2be38247e3f0 | access-date=20 August 2020 | archive-date=26 October 2020 | archive-url=https://web.archive.org/web/20201026130238/https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=dfb6e01c-f138-471d-bf5b-2be38247e3f0 | url-status=live }}</ref> and by TAP Pharmaceuticals (1985–2008), by Varian Pharmed( Previously named Varian Darou Pajooh) under the brand name Leupromer and Abbott Laboratories (2008–present) under the brand name Lupron.

===Legal history=== In October 2001, the US Department of Justice, states attorneys general, and TAP Pharmaceutical Products, a subsidiary of Abbott Laboratories, settled criminal and civil charges against TAP related to federal and state medicare fraud and illegal marketing of the drug leuprorelin.<ref>{{cite journal | vauthors = Charatan F | title = Drug companies defrauded Medicare of millions | journal = BMJ | volume = 323 | issue = 7317 | pages = 828 | date = October 2001 | pmid = 11597964 | pmc = 1121385 | doi = 10.1136/bmj.323.7317.828a }}</ref> TAP paid a total of $875 million, which was a record high at the time.<ref name=":1">{{Cite news | vauthors = Petersen M |date=4 October 2001 |title=2 Drug Makers to Pay $875 Million to Settle Fraud Case |language=en-US |work=The New York Times |url=https://www.nytimes.com/2001/10/04/business/2-drug-makers-to-pay-875-million-to-settle-fraud-case.html |access-date=24 January 2022 |issn=0362-4331}}</ref><ref name=":2">{{Cite web |title=#513: 10-03-01 TAP PHARMACEUTICAL PRODUCTS INC. AND SEVEN OTHERS CHARGED WITH HEALTH CARE CRIMES COMPANY AGREES TO PAY $875 MILLION TO SETTLE CHARGES |url=https://www.justice.gov/archive/opa/pr/2001/October/513civ.htm |access-date=24 January 2022 |website=www.justice.gov}}</ref> The $875 million settlement broke down to $290 million for violating the Prescription Drug Marketing Act, $559.5 million to settle federal fraud charges for overcharging Medicare, and $25.5 million reimbursement to 50 states and Washington, D.C., for filing false claims with the states' Medicaid programs.<ref name=":2" /> The case arose under the False Claims Act with claims filed by Douglas Durand, a former TAP vice president of sales, and Joseph Gerstein, a doctor at Tufts University's HMO practice.<ref name=":1" /> Durand, Gerstein, and Tufts shared $95 million of the settlement.<ref name=":1" />

There have since been various suits concerning leuprorelin use, none successful.<ref>{{Cite web |date=8 May 2021 |title=What You Should Know About Lupron Class Action Lawsuit |url=https://lawanswer.org/what-you-should-know-about-lupron-class-action-lawsuit/ |access-date=28 February 2022 |website=Law Answer |language=en-US |archive-date=28 February 2022 |archive-url=https://web.archive.org/web/20220228112017/https://lawanswer.org/what-you-should-know-about-lupron-class-action-lawsuit/ |url-status=dead }}</ref><ref>{{Cite web |title=Abbott, AbbVie Defeat Long-Running Lupron Bone, Joint Suit (1) |url=https://news.bloomberglaw.com/product-liability-and-toxics-law/abbott-abbvie-defeat-long-running-lupron-bone-joint-lawsuit |access-date=28 February 2022 |website=news.bloomberglaw.com |language=en}}</ref> They either concern the oversubscription of the drug or undue warning about the side effects. Between 2010 and 2013, the FDA updated the Lupron drug label to include new safety information on the risk of thromboembolism, loss of bone density and convulsions.<ref>{{Cite web |date=12 February 2019 |title=More women come forward with complaints about Lupron side effects |url=https://www.ktnv.com/news/investigations/more-women-come-forward-with-complaints-about-lupron-side-effects |access-date=28 February 2022 |website=KTNV |language=en}}</ref> The FDA then asserted that the benefits of leuprorelin outweigh its risks when used according to its approved labeling. Since 2017, the FDA has been evaluating leuprorelin's connection to pain and discomfort in musculoskeletal and connective tissue.<ref>{{Cite journal | author = Center for Drug Evaluation and Research |date=30 September 2019 |title=January - March 2017 {{!}} Potential Signals of Serious Risks/New Safety Information Identified by the FDA Adverse Event Reporting System (FAERS) |url=https://www.fda.gov/drugs/fdas-adverse-event-reporting-system-faers/january-march-2017-potential-signals-serious-risksnew-safety-information-identified-fda-adverse |journal=FDA |language=en}}</ref>

==Research== {{As of|2006}}, leuprorelin was under investigation for possible use in the treatment of mild to moderate Alzheimer's disease.<ref>{{cite journal |vauthors=Doraiswamy PM, Xiong GL |title=Pharmacological strategies for the prevention of Alzheimer's disease |journal=Expert Opinion on Pharmacotherapy |volume=7 |issue=1 |pages=1–10 |year=2006 |pmid=16370917 |doi=10.1517/14656566.7.1.S1 |s2cid=5546284 }}</ref>{{update inline|date=August 2020}}

A by mouth formulation of leuprorelin is under development for the treatment of endometriosis.<ref name="AdisInsight-Oral">{{cite web |title=Leuprorelin oral - Enteris BioPharma |url= http://adisinsight.springer.com/drugs/800023068 | work = Adis Insight | publisher = Springer Nature Switzerland AG |access-date=16 July 2018 |language=en |archive-date=4 November 2017 |archive-url= https://web.archive.org/web/20171104163213/http://adisinsight.springer.com/drugs/800023068 |url-status=live }}</ref> It was also under development for the treatment of precocious puberty, prostate cancer, and uterine fibroids, but development for these uses was discontinued.<ref name="AdisInsight-Oral" /> The formulation has the tentative brand name Ovarest.<ref name="AdisInsight-Oral" /> As of July 2018, it is in phase II clinical trials for endometriosis.<ref name="AdisInsight-Oral" />{{update inline|date=August 2020}}

==Veterinary use== Leuprorelin is frequently used in ferrets for the treatment of adrenal disease. Its use has been reported in a ferret with concurrent primary hyperaldosteronism,<ref>{{cite journal |vauthors=Desmarchelier M, Lair S, Dunn M, Langlois I |title=Primary hyperaldosteronism in a domestic ferret with an adrenocortical adenoma |journal=Journal of the American Veterinary Medical Association |volume=233 |issue=8 |pages=1297–301 |year=2008 |pmid=19180717 |doi=10.2460/javma.233.8.1297 }}</ref> and one with concurrent diabetes mellitus.<ref>{{cite journal |vauthors=Boari A, Papa V, Di Silverio F, Aste G, Olivero D, Rocconi F |title=Type 1 diabetes mellitus and hyperadrenocorticism in a ferret |journal=Veterinary Research Communications |volume=34 |issue=Suppl 1 |pages=S107–10 |year=2010 |pmid=20446034 |doi=10.1007/s11259-010-9369-2 |doi-access=free }}</ref> It is also used to treat pet parrots with chronic egg laying behavior.<ref name="yarmouth">{{cite web |title=Treatment of Chronic Egg Laying |url=https://yarmouthvetcenter.com/egg-laying-treatment-of-chronic-egg-laying.pml |website=Yarmouth Veterinary Center |access-date=29 December 2020 |archive-date=24 November 2020 |archive-url=https://web.archive.org/web/20201124004845/https://www.yarmouthvetcenter.com/egg-laying-treatment-of-chronic-egg-laying.pml |url-status=live }}</ref>

==References== {{Reflist}}

==Further reading== {{refbegin}} * {{cite journal | vauthors = Shajnfeld A, Krueger RB | title=Reforming (Purportedly) Non-Punitive Responses to Sexual Offending | website=Developments in Mental Health Law | date=July 2006 | volume=25 | page=81 | ssrn=1077282}} {{refend}}

Category:Drugs developed by AbbVie Category:Gonadotropin-releasing hormone agonists Category:Hormonal antineoplastic drugs Category:Masculinizing hormone therapy Category:Peptide therapeutics Category:Puberty blockers Category:Drugs developed by Takeda Pharmaceutical Company Category:Feminizing hormone therapy Category:World Health Organization essential medicines Category:Wikipedia medicine articles ready to translate