Human gonadotrophin preparations May cause allergic reaction

BMJ 1994; 308 doi: https://doi.org/10.1136/bmj.308.6942.1509b (Published 04 June 1994) Cite this as: BMJ 1994;308:1509
  1. P C DoreC RiceS Killick
  1. Department of Immunology, Kingston General Hospital, Hull HU3 1UR Hull IVF Unit, Princess Royal Hospital, Hull HU8 9HE
  2. Assisted Reproduction Unit, University of Wales College of Medicine, Cardiff CF4 4XN.

    EDITOR, - We were interested in the letter from Aliza Eshkol, of Ares- Serono Group, and Mercia L Page, of Serono Laboratories (UK), regarding extraneous active substances in the old gonadotrophin preparations derived from urine.1 We have noticed that some patients undergoing ovarian stimulation with human menopausal gonadotrophin (Pergonal (Serono)) in our in vitro fertilisation programme develop symptoms that suggest an allergic reaction. The symptoms may be systemic or localised to the injection site, as described by other centres.2 Despite this reaction the patients' ovaries seem to respond normally to stimulation with gonadotrophin, which led us to hypothesise that the non-gonadotrophin proteins (more than 95% of the total protein content3) could be responsible for stimulating an immune response.

    Two of these patients presented for a subsequent cycle of treatment, for which we used a new highly purified follicle stimulating hormone preparation (Metrodin high purity, Serono). Both patients responded well without any symptoms. During cycles in which human menopausal gonadotrophin had been given in combination with a subcutaneous depot of goserelin (case 1) and intranasal buserelin (case 2) they had developed weals at the site of injection of the gonadotrophin, pyrexia, oedema of the face and hands, photophobia (case 1), and fever with flu-like symptoms (case 2). Before treatment with the highly purified follicle stimulating hormone preparation we collected 10 ml plasma for investigation, and an assay was devised to find out whether IgG antibodies to the human menopausal gonadotrophin preparation were present.

    Microtitre plates were coated with the human menopausal gonadotrophin, and serum from the patients was serially diluted (1:10 to 1:2430) across the plates. After two hours' incubation, the plates were washed and a Fab specific, IgG antibody labelled with peroxidase was added at a dilution of 1/300. Substrate was added, and the plates were read with a dual wavelength reader. The two patients had considerably increased levels of IgG antibodies to human menopausal gonadotrophin compared with 10 normal control patients. Higher levels were seen in the patient in case 2, who had not been exposed to the gonadotrophin for 18 months, the patients in case 1 had been exposed to the gonadotrophin five months previously.

    Further studies on patients treated with this human menopausal gonadotrophin without reaction are being pursued. These initial results suggest, however, that components of the preparation - perhaps the biologically active proteins referred to by Eshkol and Page - are antigenic in at least some patients and may provoke an immune response. The adverse effects of this response put further stress on the patient at an already difficult time, and the introduction of a purified gonadotrophin preparation is a welcome development for these patients.


    Use luteinising hormone also

    1. S VineL Gregoryy ChuiC WellsM RumingtonS Walker
    1. Department of Immunology, Kingston General Hospital, Hull HU3 1UR Hull IVF Unit, Princess Royal Hospital, Hull HU8 9HE
    2. Assisted Reproduction Unit, University of Wales College of Medicine, Cardiff CF4 4XN.

      EDITOR, - We wish to comment on the two letters about human gonadotrophin preparations.1,2 Although Metrodin (urofollitrophin) high purity (Serono, Welwyn Garden City) is considered a state of the art drug by the manufactureres,2we have reservations about the use of preparations containing follicle stimulating hormone alone in ovarian stimulation. Luteinising hormone may have a more important role in follicular development than previously considered in supervulated cycles. In this unit we noted a considerable drop in success on changing from human menopausal gonadotrophin (Pergonal; Serono) to urinary follicle stimulating hormone (Metrodin; Serono) and Metrodin high purity. We perform about 160 cycles of in vivo fertilisation a year. In 1993 we started using only intramuscular Metrodin, followed by subcutaneous Metrodin high purity in the latter months of 1993. The case mix, treatment protocol, and stimulation remained unchanged, as did the indications for oocyte retrieval or in vivo fertilisation over that time.

      We noted two significant changes. Firstly, the number of patients ready for oocyte retrieval on the prearranged day fell, and the duration of stimulation and dosage required increased. In 1992 only 9% of patients required additional stimulation and oocyte retrieval to be delayed by seven days or more, whereas in 1993, 22% of oocyte retrievals took place more than seven days after the scheduled date.

      The second change we noted was an appreciable drop in the pregnancy rate. In 1992, while human menopausal gonadotrophin was used, the pregnancy rate per cycle started was 25%, whereas in 1993 the pregnancy rate fell to 11%. The pregnancy rate did not improve on changing from Metrodin to Metrodin high purity. Since the beginning of 1994 we have reverted to human menopausal gonadotrophin (Pergonal). Of the completed in vivo fertilisation cycles from which we know the outcome, the pregnancy rate is 29%.

      Our data suggest that exogenous luteinising hormone may have an important role in follicular development when pituitary desensitisation has been induced, or that the extraneous proteins highlighted recently may include various growth factors,2 which may have an important direct role in follicular development. We suggest that there are clinical indications as well as cost factors1 to support the use of human menopausal gonadotrophin rather than follicle stimulating hormone in ovarian stimulation in all patients receiving assisted conception, and not just the small group of patients with hypogonadotrophic hypogonadism.

      The role of exogenous luteinising hormone and extraneous proteins in ovarian stimulation will be answered only by the development and meticulous clinical and biological evaluation of recombinant follicle stimulating hormone and luteinising hormone preparations.


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