Goserelin

Synopsis Goserelin is a gonadotrophin-releasing hormone (GnRH) analogue which, during continuous administration, down-regulates the pituitary-ovarian gonadal axis and reduces levels of the gonadotrophins, luteinising hormone and follicle-stimulating hormone. In women, this results in suppression of ovarian steroido-genesis and a decline in estrogen to levels similar to those observed after menopause or following surgical oophorectomy. Thus, goserelin has a useful role in the management of some benign estrogen-dependent gynaecological disorders. Goserelin is available as a biodegradable sustained release depot 3.6mg injection which is administered every 28 days. In women with endometriosis, monthly injections of depot goserelin were effective in achieving resolution of endometriotic implants and in improving pelvic symptoms, including pain and dyspareunia. Randomised clinical comparisons of depot goserelin with danazol indicate that goserelin is at least as effective as danazol and is better tolerated in the treatment of endometriosis. In the management of uterine leiomyomata (fibroids), goserelin depot injections reduce uterine size and the size of uterine leiomyomata, with maximum clinical benefit achieved approximately 3 to 4 months after initiation of treatment. When used as an adjunctive pretreatment for women undergoing surgical removal of uterine leiomyomata, goserelin was associated with technically easier surgical procedures, reduced intraoperative blood loss and reduced transfusion requirements around the time of surgery. As an alternative to surgery, therapeutic use of goserelin is limited by the rapid regrowth of leiomyomata following cessation of treatment. However, goserelin may be a useful treatment for women approaching menopause, in whom uterine leiomyomata shrink naturally as endogenous estrogen levels decline. In women with dysfunctional uterine bleeding, treatment with depot goserelin before surgery facilitates resection and ablative procedures by suppressing endo-metrial growth and thinning the endometrial mucosa. Goserelin is also an effective alternative to surgery in this patient group. As adjuvant therapy for women undergoing assisted reproduction procedures, goserelin is associated with reduced cycle cancellation rates and with an increase in the rate of oocyte retrieval. The tolerability profile of goserelin is characterised by adverse effects typical of hypoestrogenism, including hot flushes, loss of libido and loss of bone mineral density. However, concomitant ‘add-back’ hormone replacement therapy appears to effectively reduce these hypoestrogenic symptoms. In summary, the availability of depot goserelin has broadened the spectrum of effective treatments for benign estrogen-dependent gynaecological disorders. As goserelin is effective as a sustained release depot formulation suitable for administration on a monthly basis, it is also a convenient and practical treatment choice. Pharmacodynamic Properties Goserelin is a gonadotrophin-releasing hormone (GnRH) analogue which is approximately 100 times more potent than endogenous GnRH. In women with benign gynaecological disorders, goserelin initially induces a transient increase in luteinising hormone (LH) and follicle-stimulating hormone (FSH) levels. Continuous administration of goserelin results in down-regulation of the anterior pituitary gland and a subsequent decline in LH and FSH levels. Within 14 days of administration of a depot injection of goserelin 3.6mg, LH and FSH levels decline to levels below baseline and remain suppressed for up to 5 weeks. Since LH and FSH control ovarian steroidogenesis, suppressing the release of these gonadotrophins results in reduced levels of estrogen. In healthy women and those with benign gynaecological disorders, estradiol is reduced to levels similar to those occurring after menopause or after surgical oophorectomy. Limited data are available on the relative hypoestrogenic effects of goserelin and other long- and short-acting GnRH analogues. In a small comparative study, depot goserelin was less effective than depot leuprorelin or depot triptorelin in reducing FSH levels. By the third month of treatment there was evidence of incomplete ovarian suppression, which was more marked with depot goserelin than with depot leuprorelin, depot triptorelin or the short-acting formulation of buserelin. In contrast to danazol, an established treatment of endometriosis, goserelin had no effect on serum insulin or plasma glucagon levels in women with endometriosis. In addition, goserelin had an overall beneficial effect on haemostatic risk factors which resulted in preservation of the fibrinolytic defence mechanism. Pharmacokinetic Properties As goserelin is inactivated by intestinal peptidases when given orally, it is administered by subcutaneous injection. Goserelin is formulated as a sustained release depot injection which contains 3.6mg of the drug dispersed in a biodegradable poly (d, 1-lactide-co-glycolide) polymer rod. The drug is released continuously over a 28-day period, thus avoiding the need for daily injections. The pharmacokinetic properties of goserelin have been determined in men with prostate cancer, healthy volunteers and in women with benign gynaecological disorders. In men with prostate cancer, an initial transient mean serum concentration peak (Cmax) of 0.2 to almost 2.0 μg/L is reached at between 2 and 8 hours, which is followed by a second mean Cmax of approximately 2 to 3 μ/L, 14 to 15 days after administration of a single 3.6mg depot injection. In women with benign gynaecological disorders a mean Cmax value of 1.4 μ/L is reached 15 days after the first and second monthly doses of depot goserelin 3.6mg. There is no evidence of drug accumulation when 3.6mg depot goserelin injections are administered monthly over a period of 6 months. Goserelin is excreted primarily in the urine and has a mean body clearance of 8 L/h. Mean body clearance is reduced and the terminal elimination half-life is prolonged in patients with severe renal impairment, but dosage adjustment is not required. Therapeutic Efficacy In women with endometriosis, goserelin (usually administered as a 3.6mg depot injection every 28 days for a maximum of 6 months) was effective in achieving resolution of endometriotic implants as demonstrated by improvements in lapa-roscopic measurements of mean (revised) American Fertility Society (RAFS) endometriosis classification scores. Goserelin also significantly improved pelvic symptoms, including pain and dyspareunia. Randomised clinical comparisons of depot goserelin with danazol have shown that goserelin is at least as effective as danazol in the treatment of endometriosis. In a comparative study, more marked reductions in mean total RAFS and mean RAFS implant scores were observed in goserelin recipients than in danazol recipients. The addition of concomitant ‘add-back’ estrogen/progesterone hormone replacement therapy (HRT) to goserelin for the treatment of endometriosis did not appear to reduce the therapeutic efficacy of goserelin. Moreover, this therapeutic strategy reduced the hypoestrogenic adverse effects of goserelin treatment. Noncomparative and comparative studies of goserelin in women with uterine leiomyomata have shown the drug to be effective in reducing the size of leiomyomata, thus facilitating surgical removal of these benign neoplasms. Goserelin treatment before surgery was also associated with technically easier surgical procedures (compared with women who had not received goserelin), a reduction in intraoperative blood loss, an increase in haemoglobin levels and, therefore, a reduction in blood transfusion requirements. As an alternative to surgical management of uterine leiomyomata, goserelin appears to be of limited clinical benefit. Although uterine volume is reduced during treatment with goserelin, most shrinkage in volume occurs during the first 4 months’ treatment. Importantly, discontinuation of goserelin treatment is followed by the rapid regrowth of uterine leiomyomata. Thus, goserelin may be most useful as treatment for women approaching menopause in whom these neoplasms might be expected to degenerate naturally. In women with dysfunctional uterine bleeding, surgical pretreatment with goserelin suppressed endometrial growth and reduced uterine size, endometrial thickness and fluid absorption associated with surgical ablation, thus facilitating surgical ablative or resection procedures. Goserelin was also an effective alternative to surgery in women with dysfunctional uterine bleeding, significantly improving evaluated haematological parameters of anaemia. Goserelin was also effective as adjuvant therapy prior to ovarian stimulation in women undergoing assisted reproduction procedures (in vitro fertilisation and gamete intrafallopian transfer). In this clinical setting, goserelin adjuvant treatment was associated with reduced cycle cancellation rates and improved rates of oocyte retrieval. There was a higher pregnancy rate in women who received a single 3.6mg dose of depot goserelin than in recipients of oral clomifene (100 mg/day for 5 days) as adjunctive pretreatment prior to ovarian stimulation with human menopausal gonadotrophin. Tolerability The tolerability profile of goserelin in premenopausal women is characterised by adverse effects typical of a hypoestrogenic state, including hot flushes (reported in 89% of women who received the drug in several clinical studies), vaginal dryness, headaches and loss of libido. In addition, bone mineral density loss of about 4.6% occurs during 6-month courses of goserelin. However, several studies have shown that concomitant ‘add-back’ estrogen/progesterone HRT reduces the incidence of hypoestrogenic adverse effects and bone mineral density loss. Local reactions at the site of injection are observed in approximately 3% of women receiving goserelin. Dosage and Administration In the treatment of women with benign gynaecological disorders the recommended dosage of depot goserelin is 3.6mg, injected subcutaneously into the anterior abdominal wall every 28 days for a maximum of 6 months. Repeat courses of goserelin are not recommended at the present time because of concern regarding bone mineral density loss. Dosage modification of goserelin is not required in women with renal or hepatic impairment. As goserelin is contraindicated in pregnancy, pretreatment examination of fertile women is necessary to exclude pregnancy. In addition, nonhormonal methods of contraception should be used during goserelin treatment. Similar content being viewed by others

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Severe endometriosis treated with gonadotrophin releasing hormone agonist and continuous combined hormone replacement therapy. Br J Obstet Gynaecol 1992 Apr; 99: 344–5 Author information Authors and Affiliations Additional information Various sections of the manuscript reviewed by: M. Y. Dawood, Department of Obstetrics, Gynecology and Reproductive Sciences, Division of Reproductive Endocrinology, The University of Texas Houston Medical School, Houston, Texas, USA; M. Filicori, University of Bologna, Reproductive Endocrinology Center, Department of Obstetrics and Gynecology, Bologna, Italy; I.S. Fraser, Department of Obstetrics and Gynaecology, University of Sydney, Sydney, New South Wales, Australia; T. Kurabayashi, Department of Obstetrics and Gynecology, Niigata University School of Medicine, Niigata, Japan; A. Lemay, Hopital Saint-François d' Assise, Centre de Recherche, Quebec, Quebec, Canada; K.S. Moghissi, Department of Obstetrics and Gynecology, Wayne State University, Detroit, Michigan, USA; R.W. Shaw, Department of Obstetrics and Gynaecology, University of Wales College of Medicine, Cardiff, Wales; J. Tapanainen, Department of Obstetrics and Gynaecology, University of Oulu, Oulu, Finland; E.J. Thomas, Department of Obstetrics and Gynaecology, Princess Anne Hospital, Southampton, England; T. Uemura, Department of Obstetrics and Gynecology, School of Medicine, Yokohama City University, Yokohama, Japan; H.A.I.M. van Leusden, Oosterbeek, The Netherlands; P. Vercellini, Clinica Ostetrica e Ginecologica, Facolta di Medicina, Universita degli Studi di Milano, Milan, Italy. Rights and permissions About this article Cite this article Perry, C.M., Brogden, R.N. Goserelin. Drugs 51, 319–346 (1996). https://doi.org/10.2165/00003495-199651020-00009 Published: Issue date: DOI: https://doi.org/10.2165/00003495-199651020-00009