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Leuprorelin

A Review of its Pharmacology and Therapeutic Use in Prostatic Cancer, Endometriosis and Other Sex Hormone-Related Disorders

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Abstract

Synopsis

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.

Pharmacodynamic Properties

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 reduced vertebral bone mineral density, but was at least partially reversible after administration ceased.

While the principal mechanism of action of leuprorelin is pituitary desensitisation resulting in decreased serum levels of gonadotrophins and sex hormones, it is not clear whether this is a result of reduced GnRH receptor binding sites, uncoupling of receptors from intracellular processes, non-GnRH receptor mediated mechanisms, or a combination of these. In vitro data suggest some direct effects of leuprorelin on smooth muscle of the reproductive tract, specific human breast cancer cell lines and possibly ovarian function. It is unclear from pharmacodynamic studies whether leuprorelin has direct antitumour activity in prostatic cancer.

Pharmacokinetic Properties

After oral administration, leuprorelin is almost completely inactivated by in-testinal enzymes, and the drug is therefore administered parenterally in the clinical setting. Single dose administration of leuprorelin 1mg subcutaneously in healthy volunteers and patients with prostatic cancer achieved mean peak plasma drug concentrations of 32 to 35 μg/L within 30 to 60 minutes after administration; bioavailability was 94% compared with intravenous administration, elimination half-life was 3.6 hours and total body clearance was 9.1 L/h.

The sustained release depot formulation releases leuprorelin from biodegradable microspheres at a constant daily rate of 2.8% of the dose for approximately 1 month after subcutaneous or intramuscular administration. Some leuprorelin is apparently leached from microsphere surfaces, resulting in transient peak plasma concentrations of 13.1 and 47.4 μg/L achieved within 3 hours of subcutaneous administration of depot leuprorelin 3.75 and 7.5mg, respectively. However, mean plasma drug concentrations decreased markedly within the first 24 hours and remained between approximately 0.4 and 0.6 μg/L with continued monthly subcutaneous or intramuscular injections. On the basis of available animal and human data, leuprorelin is metabolised to a (5–9) pentapeptide metabolite and probably other peptide metabolites, but is thought to be predominantly excreted in the urine.

Therapeutic Use

Noncomparative studies of men with advanced prostatic cancer treated with monthly depot injections of leuprorelin 3.75 or 7.5mg (or in older studies, daily subcutaneous injections of leuprorelin 1 or 10mg) demonstrated that few patients achieved complete response (usually ⪯ 5%). Partial response and stable disease rates both ranged widely from approximately 20 to 70% and were generally associated with improvements in subjective responses and performance status. Combined therapy with subcutaneous leuprorelin 1 mg/day plus oral administration of the antiandrogen flutamide, 250mg 3 times daily, significantly increased median length of survival (35.6 vs 28.3 months) and progression-free survival (16.5 vs 13.9 months) compared with leuprorelin monotherapy in a large double-blind study of 603 evaluable patients. Data available from the limited number of randomised comparative trials in men with prostatic cancer demonstrated that therapy with monthly subcutaneous injections of depot leuprorelin 3.75mg had equivalent efficacy but was better tolerated than oral administration of fosfestrol 100mg 3 times daily. Daily subcutaneous administration of leuprorelin 1mg achieved comparable response and survival rates to those seen with oral diethyl-stilbestrol 3 mg/day, although leuprorelin was better tolerated.

Women with endometriosis had significant improvements from baseline laparoscopic measurements of mean (revised) American Fertility Society endometriosis classification scores following monthly injections of depot leuprorelin 3.75mg (or in older studies, daily subcutaneous administration of leuprorelin lmg) for up to 2 years. Subjective symptom scores for dysmenorrhoea, pelvic pain, pelvic tenderness and dyspareunia also improved significantly from baseline or compared with placebo after 6 months of depot leuprorelin 3.75mg administered intramuscularly each month. In comparative studies improvements in objective and subjective responses with leuprorelin (usually 3.75mg monthly by depot intramuscular or subcutaneous injection) were similar to those achieved with oral danazol 800 mg/day or intranasal buserelin 900 μg/day. Concomitant ‘add-back’ therapy with estrogen/progesterone or progesterone alone did not influence the efficacy of leuprorelin and helped preserve vertebral bone mineral density.

In a study of 62 children with central precocious puberty, daily subcutaneous administration of leuprorelin 4 to 50 μg/kg for 3.5 to 24.9 months decreased mean growth velocity significantly, from 11.5 cm/year at baseline to 7.4 cm/year during treatment. Predicted adult height of these children increased by 3.5cm with leuprorelin. Similar results were achieved in smaller studies using intramuscular or subcutaneous injections of depot leuprorelin in monthly dosages generally ranging from 3.75 to 15mg. Leuprorelin effectively suppressed levels of gonadotrophins and sex steroids, and usually prevented progression of Tanner staging for breast, genital and pubic hair development.

In studies of women with uterine leiomyomata, monthly intramuscular administration of depot leuprorelin 3.75mg for 6 months markedly reduced uterine volume and improved fibroid-related symptoms in the majority of women. However, as with other GnRH analogues, these effects are transient, as demonstrated by regrowth of fibroids and a return to baseline uterine volume within approximately 24 weeks of discontinuing treatment.

In women receiving controlled ovarian stimulation with menotropins (FSH plus LH) for in vitro fertilisation (IVF) or gamete intrafallopian transfer (GIFT), adjunctive treatment with subcutaneous leuprorelin 0.5 or 1 mg/day was associated with similar or increased numbers of mature oocytes retrieved per cycle and embryos available for transfer compared with cycles in which women did not receive leuprorelin. Pregnancy rates ranged from approximately 15 to 26% of cycles treated with leuprorelin compared with approximately 15 to 22% of cycles not treated with leuprorelin, and were not significantly different between treatment groups. Cycles in which leuprorelin was used usually required a higher total dose of menotropins, but were less likely to be cancelled (for oocyte retrieval) because of premature luteinisation or other factors. In studies comparing outcomes in women receiving adjuvant therapy with leuprorelin 0.25 to 1 mg/day subcutaneously versus Clomifene 50 to 100 mg/day orally, buserelin 300 μg/day subcutaneously or nafarelin 400 μg/day intranasally, no significant differences were noted between treatment groups for pregnancy rates or total number of live births.

Tolerability

The tolerability profile of leuprorelin depends, to some extent, on the patient’s gender and/or clinical condition, since most adverse events are related to changes in circulating levels of sex hormones. Impotence and decreased libido occur in virtually all sexually active men receiving leuprorelin for prostatic cancer, usually within 3 months of initiating treatment. Hot flushes occur in 35 to 71% of men during therapy and approximately 10% experience increased prostatic cancer symptoms (disease flare), usually manifested as bone pain, during the first 2 weeks of treatment. Patients with spinal cord compression should not receive GnRH analogues and those with urinary tract obstruction may not be able to tolerate a transient increase in symptoms associated with an initial increase in serum testosterone levels. Disease flare may be reduced by coadministration of an antiandrogen 1 week before and 1 to 4 weeks after the initial leuprorelin dose. In a large study comparing subcutaneous leuprorelin 1 mg/day with oral diethyl-stilbestrol 3 mg/day in men with prostatic cancer, leuprorelin recipients more frequently experienced flushing (52 vs 11% of patients), but had significantly fewer episodes of gynaecomastia/breast tenderness (3 vs 49%), nausea/vomiting (5 vs 16%) and peripheral oedema (2 vs 16%), and a trend toward fewer serious complications of thrombosis, pulmonary embolus or myocardial infarction (1 vs 7%).

Leuprorelin induces a hypoestrogenic state and suppresses menses in women with endometriosis or uterine leiomyomata. Flushing or vasodilation develops in approximately 80% of women receiving monthly depot injections of leuprorelin 3.75mg. Other adverse events reported frequently among this patient population include headache (͌ 35% of patients), vaginitis/vaginal dryness (29 to 37%), insomnia (17 to 55%) and emotional lability (16 to 45%). In a large study of women with endometriosis, monthly administration of depot leuprorelin 3.75mg caused a significantly lower incidence of weight gain (13 vs 27% of patients) and oedema (5 vs 18%) than oral danazol 800 mg/day, but a higher incidence of hot flushes (84 vs 54%), insomnia (17 vs 6%) and decreased libido (13 vs 4%). Reduction in bone mineral density can occur in women receiving leuprorelin. Although reversible after shorter courses of leuprorelin (e.g. 6 months), sustained bone loss may occur after long term administration (e.g. 2 years). Some protection against this problem can be provided with concomitant ‘add-back’ therapy consisting of estrogen/progesterone or progesterone only.

Adverse events appear to be much less common in children treated with leuprorelin for precocious puberty, although long term effects of leuprorelin on the reproductive system are unknown. The most frequently reported adverse event is a local reaction at the injection site (pain, induration, erythema or abscess) which occurs in about 5% of children receiving daily subcutaneous injections or monthly subcutaneous or intramuscular injections of depot leuprorelin.

Dosage and Administration

In men with prostatic cancer, the recommended dosage of depot leuprorelin is 3.75mg (Europe and Japan) or 7.5mg (US) administered intramuscularly or sub-cutaneously once monthly. As an alternative to the depot formulation, the aqueous formulation of leuprorelin may be administered subcutaneously at a dosage of 1 mg/day.

The recommended dosage of depot leuprorelin for women with endometriosis is 3.75mg intramuscularly or subcutaneously once monthly for 6 months. Treatment for longer periods, or retreatment after recurrence of endometriosis, is not recommended because of potentially irreversible adverse effects on bone mineral density. Leuprorelin dosage in women with uterine leiomyomata is the same as for endometriosis.

The recommended dosage of leuprorelin in children with precocious puberty varies between countries. In the US, depot leuprorelin is initiated at a dosage of 0.3 mg/kg (minimum 7.5mg) or 7.5mg in children weighing ⪯25kg, 11.25mg in those weighing 25 to 37.5kg and 15mg in those weighing >37.5kg. Leuprorelin dosage is titrated upwards by increments of 3.75mg at monthly intervals based on clinical and laboratory assessments. However, in some European countries, the initial recommended dosage of depot leuprorelin is 1.88mg in children weighing ⪯20kg and 3.75mg in those weighing >20kg, administered at monthly intervals. In Japan, the usual monthly dosage of depot leuprorelin is 30 μg/kg which may be increased up to 90 μg/kg depending on the patient’s clinical status. Intramuscular or subcutaneous injection have both been recommended.

As adjuvant therapy in women undergoing in vitro fertilisation (IVF) or gamete intrafallopian transfer (GIFT), leuprorelin dosage varies according to various parameters of response, and is usually administered from the midluteal phase of the previous cycle or the follicular phase of the stimulated cycle until human chorionic gonadotrophin (hCG) administration. In clinical trials, leuprorelin 0.5 to 1 mg/day subcutaneously was commonly used.

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    Greg L. Plosker & Rex N. Brogden

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Various sections of the manuscript reviewed by: H. Akaza, Department of Urology, Institute of Clinical Medicine, University of Tsukuba, Tsukuba, Japan; R.L. Barbieri, Department of Obstetrics and Gynecology, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, USA; A.M. Dlugi, Division of Reproductive Endocrinology, Department of Gynecology-Obstetrics, Henry Ford Hospital, Troy, Michigan, USA; H.M. Fraser, Medical Research Council Reproductive Biology Unit, Centre for Reproductive Biology, Edinburgh, Scotland; A.J. Friedman, Division of Reproductive Endocrinology, Department of Obstetrics and Gynecology, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, USA; T. Kurabayashi, Department of Obstetrics and Gynecology, Niigata University School of Medicine, Niigata, Japan; T. Mazzei, Dipartimento di Farmacología Preclinica e Clinica, Università degli Studi di Firenze, Florence, Italy; E.K. Neely, Department of Pediatrics, Stanford University School of Medicine, Stanford, California, USA; E.S. Surrey, Center for Reproductive Medicine and Surgery, Beverly Hills, California, USA; T. Uemura, Department of Obstetrics and Gynecology, Yokohama City University School of Medicine, Yokohama, Japan.

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Plosker, G.L., Brogden, R.N. Leuprorelin. Drugs 48, 930–967 (1994). https://doi.org/10.2165/00003495-199448060-00008

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