Leuprorelin

Gonadotropin releasing hormone analogs (goserelin, buserelin, leuprorelin, triptorelin) inhibit gonadotropin release and thus lower testosterone or estrogen levels. They are used to treat breast cancer and prostate cancer. 

Recently, a Japanese research group published preclinical safety and efficacy data of an oral antiestrogen (TZE-5323) (Saito et al. 2003). This drug has been shown to have a strong affinity for human ERa and ER/i and a dose-dependent capacity to inhibit estradiol-stimulated transcriptional activation (Saito et al. 2003). In the experimental endometriosis model in rats, TZE-5323 dose-dependently reduced the volume of the endometrial implant with an effectiveness similar to that of danazol and leuprorelin acetate without causing significant changes in bone mineral density and in serum estradiol levels (Saito et al. 2003). 

Sharifi R, Ratanawong C, Jung A, et al. Therapeutic effects of leuprorelin microspheres in prostate cancer. Adv Drug Delia Rev 1997 28 121-38. 

Leuprorelin acetate Nafarelin acetate C2H5-NH-Pro-Arg-Leu-D-Leu-Tyr-Ser-Trp-His-5oxo pro NH2-Gly-Pro-Arg-Leu-D-Ala-Tyr-Ser-Try-His-5oxo pro 1... 

Management of endometriosis, uterine leiomyomata (Fibroids) CAS Registry 53714-56-0 (leuprorelin) 74381-53-6 (leuprorelin acetate) 5-oxo-L-prolyl-L-his tidyl-L-tryptophyl-L- seryl-L-tyrosyl-D-le ucyl-L-leucyl-L-argi nyl-A-ethyl-L-prolin amide acetate NA... 

A 61-year-old man with a 7-year history of diabetes, well-controlled with diet and acarbose, developed prostate cancer and was given leuprorelin acetate and flutamide. After the second injection of leuprorelin his fasting glucose and hemoglobin Alc concentrations were markedly raised (23 mmol/1 and 11% respectively). 

An 81-year-old man with no history of diabetes developed diabetes mellitus after using leuprorelin for prostate carcinoma for 6 months. His fasting glucose was 19 mmol/1 and his HbAlc was 9.9%. 

Of 65 women with idiopathic hirsutism who took either finasteride 5 mg/day or the long-acting gonadorelin agonist leuprorelin (3.75 mg monthly as an intramuscular depot), none had either menstrual abnormalities or... 

In 67 premenopausal Japanese women randomized to 4-weekly, low-dose buserelin 1.8 mg or leuprorelin 1.88 mg, women given leuprorelin had a more rapid clinical response and a higher rate of hot flushes (2). 

Of 547 men randomized to leuprorelin plus flutamide for 3 or 8 months, those treated for 8 months had a higher overall rate of adverse events, and 87% had hot flushes, compared with 72% of those who were treated for 3 months (4). 

A 75-year-old man developed a high fever and cough immediately after an injection of leuprorelin acetate 3.75 mg and 8 days after starting flutamide 375 mg/ day (7). He died of respiratory failure after a month, and interstitial pneumonitis was confirmed postmortem. 

There has been one previous report of seizure exacerbation during leuprorelin treatment, in a girl with preexisting brain damage (14), and a case of de novo seizures has also been reported (15). 

A 13-year-old girl, who had previously had surgery and radiotherapy for a medulloblastoma, developed atypical absence seizures for the first time after 3 months of therapy with leuprorelin. The seizures stopped 1 month after treatment was withdrawn and did not recur until 30 months later. The seizures were not related to estradiol concentrations or the menstrual cycle. 

Injection site reactions are common with gonadorelin receptor agonists. In 119 women randomized to subcutaneous triptorelin a local reaction (redness, pain, or bruising) was present after 1 hour in 24% and persisted for 24 hours in 9.5% (41). In another study in 105 women randomized to leuprorelin acetate, moderate local reactions occurred in 24% and severe reactions in 1% (42). 

A 78-year-old man treated with subcutaneous leuprorelin acetate had repeated local reactions, with erythema, induration, abscesses, and an ulcer on one hip (44). 

In the second case the lactic acid/glycolic acid vehicle may have caused the reaction rather than leuprorelin. 

Epithelioid granulomata have been attributed to leuprorelin (45). 

A 73-year-old man with prostate cancer received leuprorelin acetate injections and developed a subcutaneous nodule at the injection site. Histology showed epithelioid granulomata with multinuclear giant cells. 

Three further cases of granulomatous reactions at leuprorelin injection sites in Japanese men have led to speculation that they occur more often in Japan because of the use of subcutaneous injection rather than intramuscular injection, which is used in Western countries (46). The exact mechanism of this reaction is unknown, and whether it is due to the co-polymer or leuprorelin itself is debated. Local reactions can cause reduced efficacy (47). 

A 44-year-old woman with no previous history of widespread pain, depression, or anxiety developed a diffuse pain syndrome consistent with fibromyalgia after leuprorelin treatment. Her symptoms increased in severity with three successive monthly injections, and persisted for several months (53). 

A 29-year-old woman with polycystic ovary syndrome had her first in vitro fertilization cycle of leuprorelin acetate, FSH, and human chorionic gonadotropin (hCG) (67). Within 2 days she complained of abdominal distension, shortness of breath, and abdominal pain. Over the next few days she developed massive ovarian enlargement, ascites, hyponatremia, respiratory failure, and renal insufficiency. This was further complicated by duodenal perforation, probably due to severe physical stress. 

Ovarian hyperstimulation syndrome occurred in a woman with polycystic ovarian syndrome, 3 weeks after an intramuscular injection of leuprorelin acetate for endometriosis (68). She was later given further courses of the drug without this complication. 

A previously healthy 34-year-old woman who underwent ovulation induction with leuprorelin acetate and FSH developed abdominal ascites due to OHSS, followed by acute aphasia and right hemiparesis (76). The stroke was caused by a large intracardiac thrombus. 

Azuma T, Kurimoto S, Mikami K, Oshi M. Interstitial pneumonitis related to leuprorelin acetate and flutamide. J Urol 1999 161(1) 221. 

Minagawa K, Sueoka H. [Seizure exacerbation by the use of leuprorelin acetate for treatment of central precocious puberty in a female patient with symptomatic localization-related epilepsy. ]No To Hattatsu 1999 31(5) 466-8. 

Tanaka T, Niimi H, Matsuo N, Fujieda K, Tachibana K, Ohyama K, Satoh M, Kugu K. Results of long-term followup after treatment of central precocious puberty with leuprorelin acetate evaluation of effectiveness of treatment and recovery of gonadal function. The TAP-144-SR Japanese study group on central precocious puberty. J Clin Endocrinol Metab 2005 90 1371-6. 

Yamano Z, Kusuda Y, Hara S, Shimogaki H, Hamani G. Cutaneous epithelioid granulomas caused by subcutaneous infusion of leuprorelin acetate. A case report. Acta Urol Japan 2004 50 199-202. 

Yasukawa K, Sawamura D, Sugawara H, Kato N. Leuprorelin acetate granulomas case reports and review of the literature. Br J Dermatol 2005 152 1045-7. 

Periti, P.,T. Mazzei, and E. Mini. 2002. Clinical pharmacokinetics of depot leuprorelin. Clin. Pharmacokinet. 41 485-504. 

Common Name Leuprolide acetate Leuprorelin acetate... 

Based on these limitations, only a limited number of drug delivery systems based on biodegradable polymers have so far been successfully commercialized. One example is Lupron Depot one-month injectable microspheres of PLGA containing leuprorelin acetate (LH-RH agonist) for the treatment of endometriosis and prostatic cancer [31,32]. 

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