Allergic reaction during treatment with oestrogen./nClinical background: A 45-year-old woman with c

Fråga: Allergic reaction during treatment with oestrogen.

Clinical background: A 45-year-old woman with climacterical problems, and also an intractable fibromyalgia, has been treated successfully for two months with transdermal oestradiol patches (Estracomb depot patches I+II) one patch two times/week. After two months of treatment the patient suddenly developed an urticarial reaction including abdominal pain and dyspnoea and was brought to an emergency unit where anaphylactic treatment was administered. After 7-10 days, oral treatment with oestrogen/gestagen (Tablet Cyclabil) 1x1 was started. Within a few days the patient developed a similar reaction including respiratory problems and flush on the chest and she was again brought to hospital and treated successfully. The patient had taken oral oestrogen 25 years ago but discontinued this treatment because of depressive symptoms. No other medication is known. Are these types of reactions documented in the literature? Is it advisable to reintroduce the abovementioned treatment in this patient?

Sammanfattning: Hypersensitivity reactions to oestrogen therapy are rare but not unknown. These reactions can also occur in response to other ingredients in the formulation. However, the only common component in the two dosage forms that the patient has taken is oestradiol. It is possible that she has developed a primary sensitisation to oestrogen via the Estracomb patch, followed by a systemic reaction to the oral oestrogen. In this patient, the risk of a new reaction is judged to be relatively high if the treatment is reintroduced, as the temporal relationship between the previous intake and the symptoms makes a cause-effect relationship likely.

Svar: Estracomb depot patch I contains 4 mg oestradiol. Estracomb depot patch II contains 10 mg oestradiol and 30 mg norethisterone acetate. Other components found in patches I and II are ethanol, paraffin, polyisobutylene, klucel, polyethylene tereftalat, and ethylene-venylacetate copolymer. Cyclabil (white tablets) contain 2 mg oestradiol valerate, sucrose, lactose anhydrous, calcium carbonate, magnesium stearate, starch, talc, macrogol, polyvidone and wax-E (1). These tablets should be taken during the first 11 days of a treatment period, followed by the light brown tablets containing both oestradiol and levonorgestrel which should be taken for the following 10 days. In the present case the patient probably only took the white tablets before development of the described reaction. The common component in these 2 dosage forms (patch and tablet) is oestradiol.

Hypersensitivity reactions during oestrogen replacement therapy are rare but not unknown, as eg urticaria, oedema, slight dyspnoea and other types of allergic reactions have been described (2). Hypersensitivity reactions to oral contraceptives (based on both oestrogen and progestogen) have been observed rarely. Aggravation of bronchial asthma, eczema, rash, angioneurotic oedema, vasomotor rhinitis and urticaria have been reported. It is not known, in these cases, whether in any particular individual the hypersensitivity reaction is due to the hormonal substances themselves or to other ingredients in the tablet (2). In one case report (3) a 26-year-old woman had five documented episodes of life-threatening anaphylaxis during treatment for oligomenorrhea with an oral contraceptive (low dose norethindrone-oestradiol). Most episodes occurred within 10 hours of ingestion. No further episodes occurred after discontinuation of the drug.

When a patient has become primarily sensitised to a drug given through a transdermal patch, the possibility of systemic contact dermatitis from oral administration of the same drug exists. In general, few such reactions have been noted, but most manufacturers do not recommend oral challenge if sensitisation is suspected or confirmed (4). Both type III and type IV reactions can occur (5). In one case report (6) a 32-year-old woman began oestrogen replacement with the Estraderm patch (oestradiol) and, four weeks later, developed generalised urticaria, erythema and oedema. The symptoms resolved upon stopping Estraderm. Premarin (a conjugated oestrogen) 0.625 mg orally was then begun and within five days generalized urticaria, erythema and oedema had recurred. The symptoms resolved upon cessation of Premarin therapy but recurred with Premarin challenge. Estinyl (ethinyloestradiol, a semisynthetic oestrogen) 0.02 mg orally resulted in generalised urticaria and resolved upon stopping Estinyl. In conclusion this patient experienced generalised urticaria caused by oestrogen topically and systemically in three different formulations. As a result of this reaction to all forms of oestrogen, as well as the fact that she required oestrogen replacement, she became desensitised to oestrogen with good effect.

Cutaneous sensitisation to ethanol has been knwon to occur (5), resulting in systemic manifestations in response to drinking alcohol. A 38-year-old woman with no history of allergy developed a localised reaction to oestrogen patches after two months of use. The skin changes suggested contact dermatitis. The patient´s therapy was then switched to oral ethinyloestradiol. Within two days, she suffered a systemic reaction with facial oedema, reddening, generalised itching, and a fine macular rash. Therapy was discontinued, and the generalised reaction subsided within 48 hours. Two weeks later, allergy testing was undertaken. A cutaneous allergy to ethanol was suggested. It was found that the patient had consumed two alcoholic drinks on the evening preceding the reaction. She had never before experienced adverse reactions to alcoholic beverages. The possibility of systemic allergic reaction to ethanol was considered. Subsequent oral alcohol rechallenge lead to further systemic reaction, confirming this suspicion. Oral ethinyloestradiol therapy was restarted without problems.

Allergic contact dermatitis or anaphylactic reactions resulting from treatment with oestradiol has only rarely been implicated amongst the many potential sources of reaction in transdermal therapeutic systems and can be due instead to various ingredients of the formulation (4,7). The manufacturer (8) has 14 case reports on file of anaphylactoid/anaphylactic reactions to treatment with Estraderm patches. Among these there is one case of a 51-year-old woman who developed local urticarial exanthema 24-48 hours after the second patch. This was followed by pruritus and oedema of the pharynx. Later, a placebo plaster was applied, and 20 minutes later, local erythema and pressure in the throat occurred. Skin tests with oestradiol and paraffin were negative. In another case report a woman who used Estraderm developed a spreading rash and hives with itching, and angiooedema of the face, lips and hands. On the fourth day she developed shortness of breath, constriction in her throat and had to be hospitalised.

Consequently, transdermal therapeutic systems are well known for their ability to provoke irritant reactions. By applying oestradiol placebo patches to buttock skin and changing the site of application, the rate of irritant reactions can be reduced to just four per cent of the patches. In contrast, re-applying patches to the same area on the abdomen resulted in irritant reactions in 60 per cent of patches (9).

One case of Quincke´s Oedema and three cases of urticaria have been reported to the Swedish Adverse Drug Reactions Advisory Committee (SADRAC) (1) in relation to Estracomb treatment. Cyclabil treatment (the white tablets containing oestradiol) has been reported as a possible or probable cause of asthmatic bronchiale in one case.

This case should be reported to SADRAC.