Summary
Synopsis
The gonadotrophin releasing hormone (GnRH) [luteinising hormone— releasing hormone (LHRH); gonadorelin] agonist buserelin is a promising new agent in the treatment of a variety of disorders in gynaecology and andrology, paediatrics and oncology. While a single dose of buserelin stimulates the release of pituitary gonadotrophins, multiple doses produce reversible pituitary desensitisation, and this specific blockade of gonadotrophin support to the gonads provides the basis for the drug’s efficacy in conditions dependent on sex hormone secretion. Thus, buserelin provides comparable efficacy to orchidectomy or high dose estrogens in the treatment of hormone-sensitive prostate cancer and exhibits a lower incidence of adverse effects. During the early phase of treatment it may be particularly useful in combination with antiandrogens. Buserelin also appears promising in hormone-sensitive premenopausal breast cancer. Extensive studies have proven the value of buserelin in endometriosis, where it produces a transient remission with gradual recurrence of the disease on cessation of treatment. Surgical intervention is necessary in severe disease after buserelin-induced involution of the lesions. In patients with uterine leiomyoma, preliminary data suggest that buserelin may be beneficial in rendering surgery more conservative by reducing fibroid size, although it appears unlikely to preclude surgical intervention.
The use of buserelin to induce a state of reversible hypogonadotrophism before administration of exogenous gonadotrophins is a promising strategy in the treatment of infertility associated with polycystic ovary syndrome and other conditions of infertility with underlying ovarian dysfunction; such a strategy also clearly enhances the efficiency of in vitro fertilisation programmes. Initial studies suggest its potential usefulness as a female contraceptive when administered intermittently in conjunction with a progestogen. Buserelin represents a first-line treatment of central precocious puberty. In endometriosis the adverse effect profile of buserelin is generally favourable, with hypoestrogenic effects such as hot flushes and vaginal dryness, and decreased libido, predominating. There is no apparent detrimental effect on lipid metabolism. The potential for adverse hypoestrogenic effects on bone mineral content with long term administration remains to be clarified.
Thus, the GnRH agonist buserelin represents an advance in the treatment of a variety of gynaecological and andrological as well as paediatric and oncological conditions, infertility and other sex-hormone dependent conditions, with a low incidence of adverse treatment effects.
Pharmacodynamic Studies
Buserelin is a synthetic analogue of GnRH which is an agonist at pituitary GnRH receptors. When administered as a single dose, buserelin stimulates pituitary gonadotrophin release, whereas multiple doses result in dose-dependent depletion of gonadotrophins.
Peak serum luteinising hormone (LH) and follicle-stimulating hormone (FSH) responses to a single dose of buserelin administered intranasally 6 to 12 days after the midluteal phase in healthy women were observed at 4 and 6 hours, respectively, all levels returning to baseline at 24 hours. Estradiol and progesterone are temporarily increased 10 hours after a dose. Thereafter as gonadotrophin response is blocked, levels of both steroids begin to decrease. At doses of 500μg or more, significant decreases in sex steroid levels and a shortened luteal phase were noted. When given in the early luteal phase, buserelin can induce a deficient luteal phase, while administration in the mid-luteal phase induces luteolysis, leading to early menses. Postovulatory administration does not cause luteolysis in normal women and buserelin has no abortifacient activity in humans. Subcutaneous buserelin 5μg daily starting from days 1 to 3 of the cycle resulted in inhibition of ovulation in healthy women, with decreased pituitary responsiveness preventing the preovulatory gonadotrophin surge; a further study indicated a clear dose response to intranasally administered buserelin.
On daily administration of subcutaneous or intranasal buserelin ovulation is inhibited in normally menstruating women by mechanisms related to suppression of pulsatile LH secretion, and to a reduction in the pituitary LH content which occurs after treatment for 10 to 14 days. Several studies report consistent responses of initially increased LH, followed by sustained decreases in gonadotrophin secretion, reduced sex steroid levels, a state of anovulation, and rapid resumption of normal cycles after discontinuation, following buserelin dosage regimens including 10μg intramuscularly from days 1 to 4, 2.5 to 10μg subcutaneously daily, and 800 to 1200μg intranasally daily. Estrogen provocation in women undergoing long term therapy with intranasal buserelin 400 to 600μg daily produced no gonadotrophin responses, indicating blockade of the effects of endogenous GnRH at pituitary level, which may partially explain the inhibition of ovulation observed with buserelin.
Several studies have noted the effects of low dosages of buserelin on the healthy endometrium. One group has reported an inactive or weakly proliferative endometrium, with no hyperplasia present, after intranasal buserelin 200 to 400μg daily for 2 to 17 months. However, a second group has detected moderate or marked proliferation in about 45% of 92 biopsies from 56 women treated similarly for 1 to 6 months. High dosages of buserelin leading to estrogen suppression usually result in atrophy of the endometrium.
In healthy men, intravenous doses of buserelin 1, 2.5, 5 and 10μg resulted in significant LH but not FSH release at the 2 lower doses, while with the 2 higher doses both LH and FSH increased, and remained elevated for 8 to 10 hours. There was a late stimulating effect on testosterone and estradiol secretion, but no effect on growth hormone, thyroid-stimulating hormone (TSH), prolactin or cortisol. Intravenous buserelin 5μg has been reported to be equipotent, in terms of serum LH release, with intravenous GnRH 25μg or subcutaneous GnRH 100μg. In a series of experiments, single doses of buserelin produced transient increases in serum levels of 17-hydroxyprogesterone, 17β-estradiol and testosterone, followed by a loss of diurnal cyclicity and decreased steroid levels, which returned to normal after several days. Chronic subcutaneous infusion of buserelin to 2 groups of men receiving mean dosages of 118 and 230 μg/day, respectively, resulted in initial rises in LH, FSH and testosterone followed by decreases, which occurred more rapidly in the high dose group. Despite pituitary desensitisation and impaired testicular function, azoospermia did not develop. Similar results were obtained in a further study of long term buserelin treatment, with prolactin levels observed to be unaffected.
Buserelin binds to GnRH receptors with greater affinity and a more prolonged duration of binding than synthetic GnRH. In homogenates of human luteal tissue, binding of buserelin was determined to be of much lower activity than in pituitary membranes, and to vary depending on the stage of the luteal phase in which samples were taken.
The effect of buserelin on the estrogen-sensitive MCF-7 human breast cancer cell line has been investigated in several studies. Buserelin has inhibited cell proliferation in vitro, and in the athymic nude mouse inhibited tumour formation and produced a 30% regression of mature tumours in intact but not ovariectomised animals. Buserelin has also inhibited growth of the prolactin-sensitive T-47-D breast cancer cell line, indicating an inhibition of the prolactin effect in vitro. In male rats with the Dunning R3327 prostatic tumour, buserelin decreased the weights of ventral prostate, seminal vesicles and testes, and tumour. Combination with the antiandrogen nilutamide (anandron) produced further weight reduction and almost complete arrest of tumour growth. Animal studies indicate that antibody formation to buserelin does not occur after long term continuous administration.
Teratogenicity studies in mice and rabbits have revealed no abnormalities in the off-spring of either species after subcutaneous administration of buserelin. No evidence of carcinogenicity was apparent in a 2-year study in rats. Chronic toxicity studies over 26 weeks revealed dose-dependent decreases in testis weight in male rats and dogs, and increased corpora lutea in female rats.
Pharmacokinetic Properties
In healthy volunteers single intranasal doses of buserelin 150, 300 and 450μg, and subcutaneous injection of 5μg resulted in mean maximum plasma concentrations of 66, 117, 111 and 120 ng/L, respectively, 39 to 58 minutes after administration. A single intravenous injection of 500μg in women with endometriosis produced a mean maximum plasma concentration of 101 μg/L, while concentrations of 41.7 and 1.39 μg/L followed repeated administration of 1000μg subcutaneously and 300μg intranasally. In girls with precocious puberty, maximal subcutaneous infusion of 400μg daily produced an average buserelin serum concentration of 1.15 μg/L. Systemic availability after intranasal instillation was 2.5 or 3.3% depending on the formulation studied, and absorption was not influenced by experimental rhinitis. 29 and 57 days after subcutaneous implantation of buserelin 3.3 and 6.6mg in a biodegradable poly (d,L-lactide-co-glycolide) polymer, serum concentrations were 0.38 and 0.43 μg/L, respectively.
In women with endometriosis who were administered buserelin 500μg intravenously, serum analysis showed intact buserelin was the main constituent (90% after 10 minutes, 74% after 2 hours and 52% after 6 hours). The main serum metabolite is the inactive buserelin (5–9) pentapeptide. In urine collected 6 to 24 hours after buserelin treatment, intact buserelin and buserelin (5–9) pentapeptide accounted for 67 and 32% of the recovered dose, respectively. The mean percentage of a dose recovered in urine as immunoreactive buserelin within 24 hours after administration was 16.7%, 12.6% and 0.17% after intravenous, subcutaneous (5μg) and intranasal (300 or 450μg) administration, respectively. Mean elimination half-life has generally been about 72 to 80 minutes regardless of route of administration.
Therapeutic Trials
Several noncomparative trials of buserelin in endometriosis have been conducted, and consistent results have been obtained; buserelin has usually been administered intranasally at a dose of 300μg 3 times daily for 6 months. During treatment there was a progressive disappearance of dysmenorrhoea, pelvic pain and dyspareunia. Repeat laparoscopy at the end of treatment showed a 70 to 80% reduction in active endometrial implant scores. Within a 6-month post-treatment follow-up, symptoms recurred in some patients, mostly those with initially severe disease. Planned pregnancy occurred in 10 to 54% of previously infertile women during the 6-month follow-up, and in 14 to 62% over a longer period. Trials comparing buserelin 900 or 1200 μg/day intranasally or 200 μg/ day subcutaneously with oral danazol 400 to 800 mg/day have demonstrated similar relief of symptoms and percentage decrease in implant score. However, adverse effects with buserelin caused by estrogen deprivation have generally been better tolerated than the anabolic and androgenic effects due to danazol. Pregnancy rates were similar following treatment with either drug, but there was an opposite effect on serum lipids. Whereas danazol increased low density lipoprotein (LDL)-and decreased high density lipoprotein (HDL)-cholesterol, buserelin caused either no change or an increase in the HDL fraction. Buserelin is now established as an alternative to danazol in the medical treatment of endometriosis. Buserelin produces a transient remission with gradual recurrence after stopping treatment, and surgical intervention is necessary in severe endometriosis. In less severe disease repeated treatment courses with intranasal buserelin can be undertaken.
In the treatment of uterine leiomyoma buserelin 200 to 600μg daily has been administered subcutaneously by conventional injection, infusion using a minipump, by intranasal administration of 900 to 1200μg daily and by subcutaneous implantation of a depot preparation containing 6.6mg. By either route buserelin reduced uterine volume by an average of 30 to 49%, fibroid volume by 50 to 71% and uterine cavity by 35%. The major symptoms of menorrhagia, pelvic pain and dysmenorrhoea have consistently been relieved in most patients during treatment. Fibroids often return to pretreatment size within 6 months of stopping buserelin. There is some evidence that buserelin treatment could facilitate surgery by reducing vascularity of the tumour.
Limited investigation of buserelin treatment of polycystic ovary syndrome has been conducted. LH and estrogen levels have been markedly reduced, as well as androstenedione and testosterone levels. Some clinical results are available. Induction of reversible hypogonadotrophism with buserelin plus timed ovarian stimulation with exogenous gonadotrophins appears a promising approach to treatment of infertility associated with polycystic ovary syndrome.
Buserelin is used extensively in the treatment of infertility, suppressing pituitary function and premature luteinisation during regimens based on administration of exogenous gonadotrophins.
Comparative studies have shown that the addition of buserelin to FSH/human chorionic gonadotrophin (HCG) regimens improves oocyte retrieval, fertilisation and pregnancy rates, while direct and indirect comparisons of buserelin/menotropin (human menopausal gonadotrophin)/HCG and clomifene/menotropin/HCG have demonstrated improved oocyte retrieval and embryo transfer, and in some studies, higher pregnancy rates with the buserelin-containing regimens. It is now apparent that pituitary suppression by buserelin followed by gonadotrophin stimulation enhances the success of in vitro fertilisation programmes.
In the treatment of central precocious puberty (mostly in girls), intranasal buserelin 400 to 1800μg daily and subcutaneous administration of 6 to 30 μg/kg daily has often resulted in a reduction in growth rate, decreased progression of bone maturation, arrest of breast development or decreased breast size and cessation of menses in girls, and arrest of testicular and penile development or a reduction of testicular volume in boys. Although some less favourable results have been reported, buserelin should be considered a first-line treatment in children with central precocious puberty, with therapy being individualised according to clinical response.
Treatment of previously untreated patients with prostate cancer stage C and D with subcutaneous or intranasal buserelin is associated with good response rates (in the order of 50 to 95%) according to National Prostatic Cancer Project criteria. Prospective and retrospective comparisons of buserelin 1200μg intranasally (preceded by subcutaneous injections for 3 to 7 days) with diethylstilbestrol (stilboestrol) 3mg daily or orchidectomy have revealed similar complete and partial response rates and no statistically significant differences in progression-free survival, although buserelin was better tolerated. In order to obviate the ‘flare’ of disease which occurs as a result of initially raised plasma testosterone levels with buserelin, and in an attempt to improve overall success, some studies have used buserelin in combination with an antiandrogen. Although disease ‘flare’ has not occurred during combined drug treatment, an advantage for buserelin plus antiandrogen over conventional treatment, with respect to median survival or extent of progression over 12 months, has not been demonstrated. Good results have been obtained in initial studies of subcutaneous implants of buserelin in the treatment of prostate cancer.
To date published clinical evidence on the use of buserelin in premenopausal women with advanced breast cancer is limited. High initial subcutaneous doses of up to 3mg daily, followed by subcutaneous or intranasal maintenance therapy, have elicited objective responses (complete plus partial) in 39 to 42% of patients. One study, which used buserelin 1200 μg/day intranasally in conjunction with antineoplastic therapy, considered the response rate of 82% to be comparable with that historically achieved with surgical castration and antineoplastic therapy. Initial studies of buserelin in postmenopausal breast cancer have produced low response rates.
Intranasal buserelin has been administered daily continuously to healthy women at doses of 200 to 1200 μg/day for up to more than 2 years to assess its potential as a contraceptive agent. In these studies ovulation was inhibited in a total of around 96% of cycles. Regular bleeding was induced by intermittent administration and combination with a progestogen in the second half of the cycle; the most appropriate regimen was buserelin 200μg twice daily or 300 μg once daily for 21 days, in conjunction with a progestogen on days 16 to 22 of the menstrual cycle. Postpartum contraception in breastfeeding women was studied in a few women using continuous daily intranasal administration of buserelin 300 μg/day.
Adverse Effects
Adverse effects of buserelin treatment of endometriosis and uterine leiomyoma were due mainly to estrogen deprivation and included hot flushes (78%), vaginal dryness (19%) and decreased libido (12%). Other effects include headache, nausea, premenstrual syndrome, breast pain, and depression and emotional lability. Withdrawal of treatment due to adverse effects was necessary in about 5% of patients. Loss of bone mineral density, particularly in trabecular bone, occurs after 6 months’ continuous daily administration of buserelin 900 or 1200μg intranasally, but this loss is regained 6 months after stopping treatment. When used as a ‘cyclic’ contraceptive agent, mild local irritation of the nasal mucosa and headaches are the main adverse effects. In the treatment of prostate cancer hot flushes and loss of libido and potency occur in many patients.
Dosage and Administration
Buserelin is normally administered intranasally or subcutaneously, at a variety of dosages depending on the condition treated. These are in general up to 1500 μg/day in divided doses with subcutaneous administration, and normally 900 or 1200 μg/day with intranasal administration. A continuous subcutaneous infusion regimen and depot formulation have also been employed.
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Various sections of the manuscript reviewed by: K. Elkind-Hirsch, Department of Obstetrics and Gynecology, Baylor College of Medicine, Houston, Texas, USA; H.M. Fraser, MRC Unit of Reproductive Biology, Edinburgh, Scotland; J.W. Goldzieher, Endocrine/ Metabolic Research Center, Baylor College of Medicine, Houston, Texas, USA; J.G.M. Klijn, Division of Endocrine Oncology, Dr Daniel den Hoed Cancer Center, Rotterdam, The Netherlands; M. Koutsilieris, Research Center, Hôpital St-Francois d’Assise, Québec, Canada; A. Lemay, Endocrinology of Reproduction Center, Hôpital St-Francois d’Assise, Québec, Canada; T. Niijima, Department of Urology, University of Tokyo, Tokyo, Japan; K. Schmidt-Gollwitzer, Universitäts-Frauenklinik Charlottenburg, Free University of Berlin, Berlin, West Germany; S. Whitehead, Department of Physiology, St George’s Hospital Medical School, University of London, London, England.
Deceased February 1989.
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Brogden, R.N., Buckley, M.M.T. & Ward, A. Buserelin. Drugs 39, 399–437 (1990). https://doi.org/10.2165/00003495-199039030-00007
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DOI: https://doi.org/10.2165/00003495-199039030-00007