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LiverTox: Clinical and Research Information on Drug-Induced Liver Injury [Internet]. Bethesda (MD): National Institute of Diabetes and Digestive and Kidney Diseases; 2012-.

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LiverTox: Clinical and Research Information on Drug-Induced Liver Injury [Internet].

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Last Update: May 28, 2023.



Leuprolide is a parenterally administered, gonadotropin releasing hormone (GnRH) agonist which causes an inhibition of estrogen and androgen production and is used predominantly to treat advanced prostate cancer. Leuprolide has been associated with a modest rate of serum enzyme elevations during therapy, but has not been convincingly linked to instances of clinically apparent acute liver injury.


Leuprolide (loo' proe lide), also called leuprorelin (loo" proe rel' in), is a nonapeptide analogue of gonadotropin releasing hormone (GnRH) that acts as a partial agonist of the gonadotropin receptors in the pituitary that induce secretion of luteinizing hormone (LH) and follicle stimulating hormone (FSH). These gonadotropins cause production and secretion of testosterone by the male testes and estrogen by the female ovaries. The continued receptor occupancy by leuprolide, however, ultimately causes a down-regulation of production of LH and FSH and a resultant decrease in testosterone and estrogen levels. Leuprolide, alone or in combination with other antiandrogens, has been found to be palliative in advanced prostate cancer. Leuprolide was approved for use in the United States in 1989 and is still widely used, being considered a first line therapy in management of prostate cancer, the GnRH agonists having largely replaced surgical castration in the medical management of prostate cancer. Leuprolide is also used off label for hormonally sensitive benign conditions such as endometriosis, uterine fibroids, precocious puberty, infertility, and gender affirming therapy. Leuprolide is available generically and under the brand name Lupron in solution for daily subcutaneous injections (1 mg) or in long acting depot forms which are administered intramuscularly every 1 (7.5 mg), 3 (22.5 mg), 4 (30 mg) or 6 (45 mg) months. Leuprolide and the other GnRH analogues cause a profound hypogonadism ("chemical castration") and its common side effects are typical of androgen deprivation, including hot flashes, loss of libido, erectile dysfunction, depression, nausea, diarrhea, weight gain and fluid retention. Rare, but potentially severe adverse events include immediate hypersensitivity reactions, pituitary apoplexy and, with long term use, weight gain, metabolic changes, diabetes and osteoporosis.


Leuprolide has been associated with mild serum enzyme elevations during therapy in 3% to 5% of patients, but values above 3 times the upper limit of normal are rare, being reported in less than 1% of recipients. The serum enzyme elevations during leuprolide therapy have generally been transient and asymptomatic, resolving even with drug continuation and rarely requiring dose modification or discontinuation. Despite use for several decades, leuprolide has not been linked to convincing cases of clinically apparent liver injury. Routine monitoring of patients for liver test abnormalities is not recommended.

Likelihood score: E (unlikely cause of clinically apparent liver injury).

Mechanism of Injury

The cause of liver test abnormalities during leuprolide therapy is not known. Leuprolide is a short polypeptide and is metabolized locally in many tissues. It is not metabolized by the hepatic cytochrome P450 system and has not been associated with significant drug-drug interactions. Some serum enzyme elevations may be caused by nonalcoholic fatty liver, arising because of weight gain or metabolic changes caused by the androgen deprivation state induced by the GnRH agonist.

Outcome and Management

The serum enzyme elevations that occur on leuprolide therapy usually do not require dose adjustment or drug discontinuation, but should lead to a search for other causes of liver disease. There is no evidence to indicate that there is cross sensitivity to liver injury among the various GnRH analogues.

Drug Class: Antineoplastic Agents, GnRH Analogues

Other Drugs in the Subclass, GnRH Analogues: Degarelix, Goserelin, Histrelin, Relugolix, Triptorelin



Leuprolide – Generic, Lupron®


Antineoplastic Agents


Product labeling at DailyMed, National Library of Medicine, NIH


Leuprolide 53714-56-0 C59-H84-N16-O12 image 135004318 in the ncbi pubchem database


References updated: 28 May 2023

Abbreviations: FSH, follicle stimulating hormone; GnRH, gonadotropin releasing hormone; LH, luteinizing hormone; PSA, prostate specific antigen.

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    (Among 27 patients who received one and 24 who receive two leuprolide implants with controlled drug delivery, testosterone suppression was maintained for a year and adverse events included hot flashes [75%], depression [10%], impotence [6%] and fatigue [8%]; no mention of ALT elevations or hepatotoxicity).
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    (60 year old man with prostate cancer developed headaches and neurologic symptoms within 24 hours of a first injection of leuprolide, and subsequent evaluation revealed a previously unsuspected nonfunctioning pituitary adenoma).
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    (Among 160 men with advanced prostate cancer treated with leuprolide [3.75 mg by subcutaneous depot injection] monthly for 6 months, the major side effects were hot flashes [45%] and injection site reactions [18%]; "All changes from baseline or shifts in routine laboratory values...were judged not clinically significant").
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    (Review of results on two GnRH agonist depot formulations for advanced prostate cancer that allow for every 6-month administration [leuprolide and triptorelin], both provide sustained testosterone suppression and have adverse side effects similar to other GnRH agonist formulations; mentions a single episode of ALT and AST elevation in a patient receiving triptorelin).
  • Lee PA, Klein K, Mauras N, Neely EK, Bloch CA, Larsen L, Mattia-Goldberg C, Chwalisz K. Efficacy and safety of leuprolide acetate 3-month depot 11.25 milligrams or 30 milligrams for the treatment of central precocious puberty. J Clin Endocrinol Metab. 2012;97:1572–80. [PubMed: 22344198]
    (Among 84 children with precocious puberty treated with leuprolide 3-month depot injections [11.25 versus 30 mg], hormonal suppression was better with the higher dose and adverse events were similar, including injection site pain [23%], headache [20%] and weight gain [8%]; no mention of ALT elevations or hepatotoxicity).
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    (Among 243 Belgian men with prostate cancer treated with either 1- or 3-month depot formulations of leuprolide, the most common adverse events were injection site pain [19%], hot flashes [9%] and transient tumor flares [5%]; no mention of ALT elevations or hepatotoxicity).
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    (Among 72 children followed in 20 pediatric centers for precocious puberty who were treated with the 3-month depot formulations of leuprolide [11.25 or 30 mg] for up to 3 years, hormonal suppression was similar with the two doses as were adverse events, and "no new or unexpected safety concerns were identified based on laboratory testing").
  • Miller K, Simson G, Goble S, Persson BE. Efficacy of degarelix in prostate cancer patients following failure on luteinizing hormone-releasing hormone agonist treatment: results from an open-label, multicentre, uncontrolled, phase II trial(CS27). Ther Adv Urol. 2015;7:105–15. [PMC free article: PMC4485413] [PubMed: 26161141]
    (Among 37 patients with advanced prostate cancer who had failed therapy with a GnRH agonist [including leuprolide], switching to degarelix for up to 1 year yielded a low rate of response [8%], with poor tolerance and a high dropout rate; changes in clinical chemistry results were "small, with no consistent trends").
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    (Among 899 cases of drug induced liver injury enrolled in a US prospective study between 2004 and 2013, none were attributed to leuprolide or any of the GnRH analogues).
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    (Among 40 trans-women treated with cyproterone or leuprolide combined with transdermal estrogens for 12 months, suppression of gonadotrophins was achieved in both groups and no major adverse events occurred; no mention of ALT elevations or hepatotoxicity).
  • Shiba E, Yamashita H, Kurebayashi J, Noguchi S, Iwase H, Ohashi Y, Sasai K, et al. A randomized controlled study evaluating safety and efficacy of leuprorelin acetate every-3-months depot for 2 versus 3 or more years with tamoxifen for 5 years as adjuvant treatment in premenopausal patients with endocrine-responsive breast cancer. Breast Cancer. 2016;23:499–509. [PMC free article: PMC4839052] [PubMed: 25655898]
    (Among 222 premenopausal Japanese women with breast cancer treated with tamoxifen and adjuvant leuprorelin for 2 vs 3 or more years, estrogen levels remained suppressed with continued therapy and disease-free survival remained high, while adverse events were similar; 1 subject developed ALT elevations above 5 times ULN and rates of hepatic steatosis were 10% [2 years only] vs 14% [3 years or more]).
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    (Among 167 premenopausal women with breast cancer treated with tamoxifen and leuprorelin [depot injections every 3 or 6 months], adverse events included hot flush [55%], injection site pain [30%], headache [24%] and back pain [12%] and one patient in each group discontinued therapy because of liver enzyme elevations).
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    (Systematic review of literature on relative efficacy and safety of different GnRH agonists, indicates that there is little evidence of superiority of any of the four, largely because of lack of adequately powered, controlled studies comparing them).
  • Cornford P, Jefferson K, Cole O, Gilbody J. Effects of initiating or switching to a six-monthly triptorelin formulation on prostate cancer patient-healthcare interactions and hospital resource use: a real-world, retrospective, non-interventional study. Oncol Ther. 2018;6:173–187. [PMC free article: PMC7359994] [PubMed: 32700031]
    (Among 41 adults with advanced prostate cancer who were switched from every 1 or 3 monthly GnRH regimen to 6 monthly triptorelin, healthcare visits, injections and PSA testing were less as were adverse side effects including fatigue [12% vs 26%], urinary frequency [9% vs 32%], and bone pain [7% vs 14%]; no mention of ALT elevations or hepatotoxicity).
  • Shore ND, Saad F, Cookson MS, George DJ, Saltzstein DR, Tutrone R, Akaza H, et al. HERO Study Investigators. Oral relugolix for androgen-deprivation therapy in advanced prostate cancer. N Engl J Med. 2020;382:2187–2196. [PubMed: 32469183]
    (Among 930 men with advanced prostate cancer treated with relugolix [120 mg daily by mouth] or leuprolide [by injection every 3 months] for 48 weeks, sustained suppression of testosterone to castration levels was achieved by 97% on relugolix vs 89% on leuprolide while common adverse event rates were similar with ALT elevations above 3 times ULN in 1.4% vs 1.3%, although major adverse cardiovascular events arose in 2.8% vs 5.6%).
  • Sawazaki H, Kitamura Y, Yagi K, Arai Y. Impact of androgen deprivation therapy on non-alcoholic fatty liver disease in patients with prostate cancer: a CT evaluation. Urol Int. 2020;104:425–430. [PubMed: 32396918]
    (Among 77 patients with prostate cancer treated with androgen deprivation therapy [32 with leuprolide and 45 degarelix] for 6 months, computerized tomography demonstrated development of fatty liver in 7 patients but little change in body weight).
  • Wallach JD, Deng Y, McCoy RG, Dhruva SS, Herrin J, Berkowitz A, Polley EC, et al. Real-world cardiovascular outcomes associated with degarelix vs leuprolide for prostate cancer treatment. JAMA Netw Open. 2021;4:e2130587. [PMC free article: PMC8536955] [PubMed: 34677594]
    (Among 2226 men with advanced prostate cancer who initiated degarelix or leuprolide therapy between 2007 and 2019 who were propensity-matched for risk factors, major adverse cardiovascular event [MACE] rates were similar in the two groups [10.2 vs 8.6 per 100-patient years], although degarelix was associated with a high rate of death from any cause).
  • Lopes RD, Higano CS, Slovin SF, Nelson AJ, Bigelow R, Sørensen PS, Melloni C, et al. PRONOUNCE Study Investigators. Cardiovascular safety of degarelix versus leuprolide in patients with prostate cancer: the primary results of the PRONOUNCE randomized trial. Circulation. 2021;144:1295–1307. [PMC free article: PMC9004319] [PubMed: 34459214]
    (Among 545 men with prostate cancer and concurrent atherosclerosis cardiovascular disease treated with degarelix or leuprolide for at least one year, major cardiovascular adverse events [MACE} arose in 5.5% vs 4.1% and rates of testosterone suppression, disease progression, discontinuations for adverse events and serious adverse event rates were similar in both groups).
  • Lambertini M, Boni L, Michelotti A, Magnolfi E, Cogoni AA, Mosconi AM, Giordano M, et al. GIM study group. Long-term outcomes with pharmacological ovarian suppression during chemotherapy in premenopausal early breast cancer patients. J Natl Cancer Inst. 2022;114:400–408. [PMC free article: PMC8902441] [PubMed: 34850043]
    (Among 281 women with early onset breast cancer treated with chemotherapy with or without a GnRH analogue to preserve ovarian function, disease-free and overall survival were similar in the two groups and those given the GnRH analogue were slightly more likely to have a successful pregnancy during follow up [6.5% vs 3.2%]; no mention of other adverse events, ALT levels or hepatotoxicity).
  • Popovic J, Geffner ME, Rogol AD, Silverman LA, Kaplowitz PB, Mauras N, Zeitler P, et al. Gonadotropin-releasing hormone analog therapies for children with central precocious puberty in the United States. Front Pediatr. 2022;10:968485. [PMC free article: PMC9577333] [PubMed: 36268040]
    (Review of the 3 GnRH analogues used to treat children with precocious puberty including leuprolide, triptorelin, and histrelin which have different regimens of administration [intramuscular and subcutaneous] and durations of action [1-12 months]; no mention of liver adverse events).
  • Bahl A, Rajappa S, Rawal S, Bakshi G, Murthy V, Patil K. A review of clinical evidence to assess differences in efficacy and safety of luteinizing hormone-releasing hormone (LHRH) agonist (goserelin) and LHRH antagonist (degarelix). Indian J Cancer. 2022;59 Supplement:S160–S174. [PubMed: 35343199]
    (Systematic review of studies comparing the efficacy and safety of the 3 GnRH analogues used in therapy of prostate cancer identified 12 studies which showed overall no differences in efficacy in reducing serum testosterone levels and, in 4 studies reporting data on safety, similar degrees of tolerance and rates of adverse events: no mention of ALT elevations or hepatotoxicity).


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