A woman has been treated with implants of goserelin (Zoladex) for breast cancer. She has now develo

Fråga: A woman has been treated with implants of goserelin (Zoladex) for breast cancer. She has now developed a vasculitis, mostly on her legs. Is vasculitis a side-effect of goserelin?

Sammanfattning: GnRH agonists are likely to induce the same side effects. Several cases of apparent allergic reaction have been reported after treatment with gonadorelin, buserelin and goserelin. Only one case described as vasculitis has been reported after goserelin treatment. However, an accurate classification of skin disorders observed during this therapy is difficult to make, especially as no histopathologic information is available in the reports.

Svar: Gosereline which is an agonist of gonadotrophin-releasing hormone (GnRH) is, as gonadorelin and buserelin, a peptide obtained by synthesis. This hypothalamic hormone stimulates the secretion of both lutheinizing hormone and follicle-stimulating hormone. The GnRH agonists are stimulating the secretion when they are given as pulsatile subcutaneous injections but they have an antigonadotrophic action when they are given continuously for prolonged periods (1). The drugs are structurally related and are likely to share the same side-effects (2).

Several cases of apparent allergic reactions have been reported in the literature.

A man was treated with subcutaneous injections of gonadorelin for hypogonadotrophic hypogonadism and experienced generalized pruritus without urticaria or erythema (3). He later received an intravenous test injection and responded with bronchospasm and vascular collapsus. Another male patient was treated for the same syndrome and, although he had tolerated subcutaneous injections well, he responded to an iv injection with malaise, localized pruritus and urticaria in the areas where the subcutaneous doses had been administered (3). A case of anaphylactic reaction was reported in a female patient treated with an iv infusion of gonadorelin for infertility (4). These 3 patients showed a positive reaction to skin testing. A fourth case of apparent allergic reaction involved a woman treated with subcutaneous gonadorelin for hypogonadotrophic hypogonadism (5). After 7 months, the treatment was discontinued because of an urticarial reaction at multiple old injection sites.

In a limited study, 2 patients with previous reaction to buserelin were tested together with 10 healthy subjects (6). As all subjects tested had a positive wheal and flare reaction, the authors conclude that buserelin is likely to be a non-specific histamin releasing compound. The 2 patients included were female patients being treated for sterility. One of them had developed 4 episodes of generalized pruritus within minutes of her 4 injections and the other had presented an urticarial reaction at the injection site during the second injection (6).

Concerning goserelin itself, a clinical study has been reported, involving 75 patients with metastatic prostate cancer, treated with goserelin depot (7). One case of general allergic reaction requiring drug withdrawal was observed.

According to the manufacturer, 2 more cases of urticaria which have not been published have been recorded (8). Two additional cases (one of "allergic reaction" and one of "vasculitis") have been spontaneously reported to the WHO Center (9) during treatment with subcutaneous goserelin. Skin test reactivity to the carrier of the implant tablet (a copolymer) has not been reported.

No histopathologic diagnosis has been performed in the reported cases.

We suggest that this case will be reported to the National Board of Medical Products. 1 Meyler´s, Side effects of drugs. Ed by MNG Dukes. Elsevier, Amsterdam. 1984; 11th ed: 906 2 Martindale, The extra pharmacopoeia. 1989; 29th ed: 1143 3 Popovic V, Milosevic Z, Djukanovic R, Micic D, Nesovic M, Manojlovic D, Djordjevic P, Micic J: Hypersensitivity reaction with intravenous GnRH after pulsatile subcutaneous GnRH treatment in male hypogonadotrophic hypogonadism. Postgrad Med J 1988; 64: 245-246 4 MacLeod TL, Eisen A, Sussman GL: Anaphylactic reaction to synthetic luteinizing hormone-releasing hormone. Fertil Steril 1987; 48: 500-502 5 Seibel MM, Claman P, Oskowitz SP, McARdle C, Weinstein FG: Events surrounding the initiation of puberty with long term subcutaneous pulsatile gonadotropin-releasing hormone in a female patient with Kallman´s syndrome. J Clin Endocrinol Metab 1985; 61: 575-579 6 Bousquet J, Hedon B, Hejjaoui A, Chanal I, Michel FB: Non-specific histamine release activity of busereline, LH-releasing hormone. Allergy 1988; 43: 540-541 7 Debruyne FMJ, Weil EHJ, Fernandez Del MP: Clinical results with the depot preparation of "Zoladex" in prostate cancer. Monograph Series of the European Organization for Research on Treatment of Cancer 1987; 18: pp 255-272 (Hormonal manipulation of cancer: peptides, growth factors and new (anti) steroidal agents, based on an International Symposium, Rotterdam 4-6 Jun, 1986, Editors Klijn JGM, Paridaens R, Foekens JA. 616-21 KLPL) 8 B Ivarsson, ICI Pharma AB, Göteborg, personal communication 9 WHO Collaborating Center for Monitoring Adverse Drug Reactions