Delayed type hypersensitivity to human gonadotropin: case report*

Communications-in-brief FERTILITY AND STERILITY Copyright

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Vol. 64, No.4, October 1995 Printed on acid-free paper in U. S. A.

1995 American Society for Reproductive Medicine

Delayed-type hypersensitivity to human gonadotropin: case report*

Allison Redfearn, M.D. t+ Edward G. Hughes, M.D.§ Megan O'Connor, R.N.t Jerry Dolovich, M.D.tll McMaster University, Hamilton, Ontario, Canada

Objective: To investigate adverse reactions to hMG preparations in two women in IVF programs. Design: Two case reports with skin tests for delayed hypersensitivity (DH) to hMG and a biopsy of one delayed reaction. Setting: Allergy and infertility clinics in university medical center. Patients: Two affected patents with a history of local reactions to the injected hMG, one of whom also had fever, and nine control subjects. Interventions: Skin tests and biopsy. Main Outcome Measures: Delayed hypersensitivity skin response to hMG in affected patients indicated by timing and biopsy results. Negative skin test with the purified hFSH, which was also used in treatment with no adverse effects. Conclusion: Use of the purified preparation avoids DH reaction. Fertil Steril 1995;64:855-6 Key Words: Delayed hypersensitivity, adverse reaction, purified hFSH, human menopausal gonadotropin, infertility

The follicle-stimulating hormone preparations that have been available for treatment of infertility are human biologic products containing many constituents. Urofollitropin (hMG, Metrodin-75; Serono Canada Inc., Mississauga, Ontario, Canada), a menopausal urine preparation, has 50% to 65% albumin and 12% to 22% gamma globulin in addition to urine-specific protein (VanLoon K, personal communication). A recent case report describes a woman who experienced local reactions to urine-derived goReceived June 9, 1994; revised and accepted April 21, 1995. * Supported in part by Serono Canada Inc., Mississauga, Ontario, Canada. t Department of Pediatrics. t Present address: Joseph Brant Memorial Hospital, Burlington, Ontario, Canada. § Department of Obstetrics and Gynecology. II Reprint requests: Jerry Dolovich, M.D., Department ofPediatrics, McMaster University Medical Centre, 3V41, 1200 Main Street West, Hamilton, Ontario L8N 3Z5, Canada (FAX: 905521-1703). Vol. 64, No.4, October 1995

nadotropin but no reaction to a highly purified human FSH (hFSH) preparation (1). CASE REPORTS Patient 1

The patient, age 38 years, had infertility for 2.5 years. Menarche was at age 15 years and menses occurred normally every 26 to 30 days. The couple eventually elected to try IVF. Daily 1M injections of hMG (Pergonal; Serono Canada Inc.) were begun on cycle day 3, after 2 days of priming with leuprolide acetate (LA, Lupron; Abbott Laboratories, Montreal, Quebec, Canada). She noted low grade fever during the first 4 days ofinjections of hMG, and by the fourth injection she also noticed malaise and local soreness, swelling, and erythema at the hMG injection site. The injections were discontinued. During her second IVF cycle by the same plan she noted headache, fever above Redfearn et al. Communications-in-brief

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38.5°C, and a similar local reaction by the third injection of hMG, and treatment was stopped. The third treatment cycle by the same plan was stopped after the first injection of hMG due to a similar reaction. There was no pruritus or urticaria. Patient 2 This patient presented with infertility of 3 years at age 33 years. Menarche was at 14 years followed by regular menses for 13 years. Mter 3 years of oral contraception, amenorrhea developed. Mter failure with clomiphene citrate, IVF was tried. By the 5th day of her first course of injections of hMG, there was soreness, erythema, and swelling in a linear band from injection sites in both buttocks anteriorly to the anterior superior iliac spine. She denied arthralgia, pruritus, and fever. Treatment continued for 13 days. In a second cycle, at a double dose of hMG, an identical local response by the 3rd day caused treatment to be stopped. RESULTS

Diagnostic skin tests were performed on both patients with LA, urofollitropin (hMG, Metrodin-75; Serono Canada Inc.) and hCG (Profasi; Serono Canada Inc.) solutions at the concentrations used in the treatment. Intradermal tests, (0.02 mL injected through a 26-gauge needle) to leuprolide acetate showed large wheal and flare responses at 15 minutes, which disappeared in approximately 1 hour. At 24 hours patient 1 reported that the hMG sites (both Metrodin-75 and Pergonal [Serono Canada Inc.]) showed 1.0 and 1.2 cm of induration, respectively. The latter two responses resolved slowly over 2 weeks. In patient 2, the intradermal skin test site for hMG (Pergonal) at 24 hours showed 8 mm of induration and subsided by 48 hours. Skin biopsy at a skin test site at 24 hours in patient 2 showed a mild mast cell number increase in the superficial dermis and mild perivascular lymphocytic infiltration but no immunoglobulin deposition. Nine additional women involved in IVF treatment with the agents tested received these skin tests. Four had been referred for various symptoms considered unlikely to be allergic reactions. Five were healthy IVF patients who volunteered to be control subjects. None had positive delayed skin tests to hMG preparations. Eighteen months after the initial assessment patient 1 returned for allergy skin tests to buffer, highly purified hFSH (Fertinorm HP, Serono Can-

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ada Inc.), and histamine. Again there was a skin test response to hMG (Pergonal) with 6 mm of induration and 21 mm of erythema at 48 hours. The test with highly purified hFSH was negative. Highly purified hFSH (Fertinorm HP) has been used during three treatment cycles with no reaction. Pregnancy has not been achieved. The highly purified hFSH was made available to patient 2 after a negative skin test, and she underwent three treatment cycles without any reaction. She then became pregnant after she stopped taking treatment. DISCUSSION

Human gonadotropin preparations can lead to ovarian hyperstimulation due to pharmacologic effects of the preparations (2). Fever 38.5°C, joint pain and malaise, are reported much less often (personal communication, K VanLoon). In our patients the local redness and swelling at the skin test sites of hMG preparations began after a few hours, were prominent in the 24- to 48-hour time period then gradually subsided. The timing is characteristic of delayed-type hypersensitivity (3). These tests were selective; skin tests with the hMG preparations in nine control subjects were negative. Support for the conclusion that delayed type hypersensitivity is involved was obtained from the skin biopsy. Although IgE-dependent allergic reactions to fertility hormones have been reported (4), there appears to be no report of the immunologic basis of reactions to the urinary menotropins. The tolerance by these patients of highly purified hFSH illustrates that the reactions were not due to FSH. Acknowledgment. We are grateful to the staff of the McMaster Medical Center Infertility Clinic for their work with the presenting patient and control subjects.

REFERENCES 1. Li TC, Hindle JE. Adverse local reaction to intramuscular

injections of urinary-derived gonadotrophins. Hum Reprod 1993;8:1835-6. 2. Compendium of Pharmaceuticals and Specialties. Ottawa, Ontario, Canada: Canadian Pharmaceutical Association, 1993. 3. Miescher PA, Muller-Eberhard HJ. Textbook of immunopathology. 2nd ed. New York: Grune and Stratton, 1976:15777. 4. Foster NG, Jarrell JF, Dolovich JD, Younglai EV. Immunoglobulin-mediated hypersensitivity in response to long-term treatment with gonadorelin hydrochloride (Factrel) in a female patient. Am J Obstet Gynecol 1989; 160:979-83.

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