Autoimmune Progesterone Dermatitis

By Cocuroccia, Barbara; Gisondi, Paolo; Gubinelli, Emanuela; Girolomoni, Giampiero


Autoimmune progesterone dermatitis (APD) is a rare disorder characterized by recurrent polymorphous skin manifestations, which appear or are exacerbated during the Iuteal phase of the menstrual cycle. The hallmarks for diagnosis include premenstrual flare, its prevention with the inhibition of ovulation, and positive skin reaction to intradermal injection of progesterone. The mainstay of treatment is to inhibit the secretion of endogenous progesterone by suppressing ovulation. Bilateral oophorectomy may be necessary in patients with severe and refractory symptoms. We report herein the case of a 38-year-old woman who developed recurrent and cyclic vesiculobullous eruptions clinically suggestive of erythema multiforme or autoimmune bullous diseases. The skin manifestations turned out to be APD. The patient was treated with tamoxifen 20 mg daily with complete symptom remission after 4 months.

Keywords: Autoimmune progesterone dermatitis, hormone-induced dermatitis, progesterone-induced anaphylaxis


Autoimmune progesterone dermatitis (APD) is a rare disorder characterized by recurrent cyclic skin eruptions which appear or are exacerbated during the luteal phase of the menstrual cycle and resolve totally or partially after menses [1,2]. The skin manifestations are polymorphous and more commonly include erythematous and eczematous patches and plaques, urticaria, angioedema and erythema multiforme-like eruptions.

Progesterone-induced anaphylaxis has been also reported [3]. APD is considered a hypersensitivity reaction to increased levels of endogenous progesterone during the luteal phase of the menstrual cycle [4]. Exposure to exogenous progesterone may play a role in triggering APD in some patients [5]. Similar eruptions have been reported in relation to exogenous or endogenous estrogens [6]. Positive skin tests to progesterone or its derivatives, reproduction of symptoms with intramuscular hormonal challenges and detection of antibodies to progesterone or its derivatives have suggested an autoimmune basis for the syndrome [3,7].

Case report

A 38-year-old woman presented with a 3-year history of cyclic dermatosis involving the extremities and the oral and genital regions. The eruption usually began approximately 1 week before her menstrual period and improved 2-3 days into the menstrual flow, with some active lesions persisting throughout. The disease was interpreted elsewhere as erythema multiforme. Continuous therapy with oral acyclovir for 6 months was inefficacious. Oral prednisone at high doses (> 1 mg/kg daily) was effective in preventing the manifestations, but the eruption relapsed at daily doses of 0.5 mg/ kg or less, in coincidence with the luteal phase of her menstrual cycle. She had been taking the contraceptive pill for 5 years and denied intake, even occasionally, of other drugs.

At the time of presentation, eroded and crusted lesions were present on the oral mucosa, lips, vulva and perineal area. Moreover, target erythematous plaques with overlying vesiculobullous lesions, symmetrically distributed on the upper and lower extremities, were present (Figure 1). Routine laboratory investigations, as well as serum complement levels and autoantibodies against nuclear antigens, native DNA and extractable nuclear antigens, were normal or absent. A search for serum immunoglobulin M antibodies against herpes simplex virus 1 and 2, Epstein-Barr virus and Mycoplasma pneumoniae was negative. Serum antibodies against the 180-kDa bullous pemphigoid antigen, desmoglein 1 and 3 were absent. Indirect immunofluorescence on normal and salt-split skin was negative. The chest X-ray as well as abdominal and pelvic echo scans did not reveal abnormalities. A biopsy specimen was obtained for histology and direct immunofluorescence studies. Histological examination showed necrotic keratinocytes at the basal layer of the epidermis and upper dermal infiltrates of lymphocytes, neutrophils and rare eosinophils. Moreover, the lymphocytic infiltrate extended into the epidermis in some areas (Figure 2). Direct immunofluorescence test performed on perilesional skin did not reveal deposits of immunoglobulins, complement or fibrinogen. Intradermal testing with progesterone (0.1 ml of an aqueous suspension at 1 mg/ml) on the left forearm resulted in a 10-mm area of erythema and edema 8 h after injection. The control intradermal testing with distillate water was negative. Intradermal testing with estrogen benzoates (0.1 ml of an aqueous suspension at 1 mg/ml) was negative. The contraceptive pill was discontinued without benefit. Therapy with tamoxifen 20 mg daily induced progressive amelioration with complete and durable clearing of the eruption after 3 months. The patient spontaneously discontinued treatment with relapse of the eruption. Further therapy with tamoxifen resulted in complete disease regression after 2 months. At a 6-month follow-up and continuous therapy, the patient was disease-free.

Figure 1. Multiple eroded and crusted elements on the lips (A). Target erythematous and vesiculobullous lesions on the upper arms (B) and knees (C).

Figure 2. Lesional skin showing necrotic keratinocytes at the basal layer of the epidermis and a perivascular infiltrate of lymphocytes, neutrophils and rare eosinophils in the upper dermis. In some areas, lymphocytes emigrate into the epidermis.


APD is a rare cyclic reaction to progesterone produced during the luteal phase of a woman’s menstrual cycle which can present with a variety of skin manifestations often resulting in delayed diagnosis. Other than eczematous lesions, urticaria, angioedema and erythema multiforme-like eruptions, vesicular, bullous or papulopustular lesions, deeptype erythema annulare centrifugum-like manifestations and fixed drug eruption have been described [3,8-10]. Moreover, anaphylactic reactions with urticaria, flushing, laryngeal edema, bronchospasm, hypotension and shock have been reported [11-13]. In many cases, APD occurs in women taking or having taken oral contraceptives, which may act as disease trigger [3]. Similar eruptions have been reported in relation to exogenous or endogenous estrogens [6]. The diagnosis of hormone-induced dermatitis in the present case was suspected in view of the premenstrual recurrent cyclic eruptions and previous exposure to exogenous sexual hormones. Physical and histological examination was very suggestive of erythema multiforme, but the absence of recurrent herpes simplex, history of drug intake or associated diseases militated against this diagnosis. Negative skin immunofluorescence and the absence of autoantibodies to skin components excluded an autoimmune bullous disorder. Positive intradermal test with progesterone, but not estrogens, and resolution of the manifestations with tamoxifen confirmed the diagnosis of APD. It is important to suspect the diagnosis of autoimmune hormone dermatitis in women who present with a skin eruption that waxes and wanes in relation to the menstrual cycle. Systemic corticosteroids may temporarily improve symptoms [3,7]. The mainstay of treatment, however, is to inhibit the secretion of endogenous progesterone by the suppression of ovulation and includes gonadotropin-releasing hormone/luteinizing hormone- releasing hormone analogs, danazol, tamoxifen and conjugated estrogens [14-16]. Bilateral salpingo-oophorectomy may be necessary in patients with refractory and severe symptoms [1,17,18].


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1 Istituto Dermopatico dell’Immacolata, IRCCS, Rome, Italy, and 2 Department of Biomdical and Surgical Sciences, Section of Dermatology, University of Verona, Verona, Italy

(Received 1 February 2005; revised 1 June 2005; accepted 7 June 2005)

Correspondence: G. Girolomoni, Department of Biomedical and Surgical Sciences, Section of Dermatology, University of Verona, Piazzale A. Stefani 1, 1-37126 Verona, Italy. Tel: 39 45 8072547. Fax: +39 45 8300521. E-mail: [email protected]

Copyright Taylor & Francis Ltd. Jan 2006