Leuprorelin

Abstract

Leuprorelin (leuprolide acetate) is a gonadotrophin-releasing hormone (GnRH) analogue used to treat a wide range of sex hormone-related disorders including advanced prostatic cancer, endometriosis and precocious puberty. It acts primarily on the anterior pituitary, inducing a transient early rise in gonadotrophin release. With continued use, leuprorelin causes pituitary desensitisation and/or down-regulation, leading to suppressed circulating levels of gonadotrophins and sex hormones. Clinical trials in men with advanced prostatic cancer demonstrate that leuprorelin (usually monthly depot injections of 3.75 or 7.5mg) is less likely to cause serious adverse cardiovascular effects than diethylstilbestrol, and has comparable efficacy to bilateral orchiectomy or other GnRH analogues. Therefore, the choice between leuprorelin and orchiectomy may be made on the basis of the patients treatment preference, along with specific patient characteristics and cost implications. Monthly intramuscular or subcutaneous administration of depot leuprorelin 3.75mg was superior to placebo, and comparable to oral danazol 800 mg/day or intranasal buserelin 900 μg/day, in achieving objective and subjective responses in women with endometriosis. Thus, leuprorelin is an effective alternative to other treatments for women with endometriosis, but the recommended duration of its use in this clinical setting is limited to 6 months because it reduces bone mineral density. In children with central precocious puberty, leuprorelin (usually monthly intramuscular or subcutaneous injections of depot leuprorelin 3.75 to 15mg) decreases mean growth velocity and signs of sexual maturation and increases predicted adult height compared with baseline measurements. Although effects on final adult height are predicted from available data and require confirmation in long term follow-up studies, the absence of effective alternatives to GnRH analogues makes leuprorelin a first-line therapy for children with this rare disease. In women with uterine leiomyomata, monthly intramuscular administration of depot leuprorelin 3.75mg for 6 months markedly reduces uterine volume and fibroid-related symptoms, but, as with other GnRH analogues, these effects dissipate following discontinuation of the drug. As adjuvant therapy in women undergoing in vitro fertilisation or gamete intrafallopian transfer, leuprorelin (usually 0.5 to 1 mg/day subcutaneously) reduces the risk of cancelled cycles for oocyte retrieval by preventing premature luteinisation. While some studies demonstrate an improvement in intermediate end-points such as increased number of mature oocytes retrieved and embryos available for transfer, a significant effect has not been demonstrated on the rate of live births per stimulated cycle. The tolerability profile of leuprorelin varies somewhat depending on the patients gender and/or disease state because most adverse effects associated with leuprorelin result from changes in levels of circulating sex hormones. In men with prostatic cancer receiving leuprorelin, impotence and decreased libido occur almost universally, hot flushes are reported by 35 to 71 % of men and exacerbation of symptoms (disease flare) occurs in approximately 10%. Hot flushes occur in approximately 80% of women receiving leuprorelin for endometriosis and other common adverse events include headache, vaginitis/vaginal dryness, insomnia and emotional lability. Children with precocious puberty appear to tolerate leuprorelin well, although long term effects on the reproductive system are unknown. The most frequently reported problem in this patient population is local reaction at the injection site, which develops in approximately 5% of children receiving leuprorelin. In general, few notable differences have been demonstrated between leuprorelin and other GnRH analogues in the limited number of comparative clinical trials conducted in patients with sex hormone-related disorders. While monthly injections of depot leuprorelin may be preferable to daily administration of other GnRH analogues in some patients, other GnRH analogues are also available in depot formulations. Thus, leuprorelin offers effective therapy for a number of sex hormone-related disorders with daily subcutaneous administration of the aqueous solution or convenient monthly injections of the depot formulation. Leuprorelin (leuprolide acetate) is a potent agonist analogue of gonadotrophin-releasing hormone (GnRH) which initially induces release of gonadotrophins [luteinising hormone (LH) and follicle-stimulating hormone (FSH)] from the anterior pituitary, but with continued use causes pituitary desensitisation and/or down-regulation. Since gonadotrophins control release of testosterone from testicular Leydig cells in males and estrogens from the ovaries in females, leuprorelin effectively suppresses circulating sex hormone levels within about 2 to 4 weeks (after an initial transient rise in levels) and these remain suppressed for the duration of treatment. Thus, leuprorelin has been used in the treatment of various sex hormone-related diseases such as prostatic cancer, endometriosis, precocious puberty and uterine leiomyomata. Leuprorelin has also been used as adjunctive therapy, primarily to prevent LH surge before satisfactory oocyte maturation, in women undergoing in vitro fertilisation. Histological evaluations have demonstrated that long term (up to 24 months) subcutaneous administration of leuprorelin 1 to 10 mg/day to men with prostatic cancer markedly suppressed spermatogenesis and Leydig cell activity and caused peritubular membrane thickening. In a rat model of endometriosis, transplanted endometrial tissue growth was suppressed by leuprorelin in a dose-dependent manner, and appeared to be associated with suppression of serum estradiol levels. Monthly subcutaneous administration of depot leuprorelin 1 mg/kg for up to 12 months in the rat significantly...