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 and infertility. 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.
REPRESENTATIVE TRADE NAMES
Leuprolide – Generic, Lupron®
Product labeling at DailyMed, National Library of Medicine, NIH
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References updated: 22 March 2018
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