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Taiwanese Journal of Obstetrics & Gynecology 53 (2014) 420e422

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Taiwanese Journal of Obstetrics & Gynecology

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Research Letter Autoimmune progesterone dermatitis

* Ikbal Kaygusuz a, , Ilknur Inegol Gumus a, Evren Sarifakioglu b, Ayla Eser a, Bulent Bozkurt c, Hasan Kafali a € a Department of Obstetrics and Gynecology, School of Medicine, Turgut Ozal University, Ankara, Turkey € b Department of Dermatology, School of Medicine, Turgut Ozal University, Ankara, Turkey € c Division of Allergy, Department of Chest Medicine, School of Medicine, Turgut Ozal University, Ankara, Turkey

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Article history: The patient's obstetrical history consisted of two pregnancies Accepted 23 December 2013 resulting in two normal vaginal deliveries. She reported no epi- sodes of skin lesions during pregnancy or during the breast-feeding period. Pelvic examination and ultrasound assessment were essentially normal. Following the diagnosis of APD, initiation of appropriate treatment was planned. The patient was informed about treatment options and possible side effects. She received four Autoimmune progesterone dermatitis (APD) is a rare autoim- weekly intramuscular injections (depot) of the gonadotropin- mune response to endogenous progesterone, characterized by cy- releasing hormone (GnRH) analog Lucrin (3.75 mg leuprolide ace- clic cutaneous and mucosal lesions at the end of the luteal phase tate; Abbott, Istanbul, Turkey). Her symptoms improved dramati- when progesterone levels are elevated. These lesions usually cally within 1 month. She continued with this treatment for 3 e disappear 1 2 days after menstruation ceases [1]. The clinical months. She had mild hot flashes, but felt that these were tolerable. presentation of APD can vary in severity from urticaria to Two months after cessation of therapy, she still had no skin lesions. anaphylaxis [2]. We herein report three cases of APD and review the A 30-year-old virgin woman was admitted to the gynecology current literature with regard to its clinical features, pathogenesis, clinic with complaints of hypomenorrhea, frequent menstruation diagnosis, and treatment options. (25-day cycles), and hirsutism. She had also experienced herpetic A 38-year-old woman was admitted to the dermatology clinic lesions during every menstrual period for the last 5 years. The pa- with a complaint of intermittent rash on her body for 3 years. The tient noted that the lesions began at the age of 25 and usually recent lesions on her face and neck appeared 1 week before her appeared on her face near the lips. She had thought that these le- admission. Physical examination revealed erythematous papules in sions were herpes and occurred because of stress. Her pelvic ex- the V region of the neck and edema of the face with urticarial amination and ultrasound assessment were normal. For the skin appearance (Fig. 1). She had no remarkable medical history. After a lesions, she was referred to a dermatology specialist. Her physical detailed discussion with the patient, it was understood that these examination revealed round, hyperpigmented lesions on the left lesions occurred 3 days before her menses and ended when the cheek and over the lips. Complete blood count, urea and electrolytes, menstruation ceased. She was investigated by an allergist for a liver function, fasting glucose levels, and herpes simplex virus 1 and possible autoimmune hypersensitivity caused by increased levels of 2 antibodies test results were all normal. Allergy skin testing was progesterone. An intradermal testing with 50 mg/mL progesterone performed with progesterone (50 mg/mL) in normal saline and the fi was performed, which con rmed the clinical diagnosis. Normal result was positive. Because the patient complained of frequent saline was used as a negative control. Fifteen minutes after an in- menstruation and hirsutism, her gynecologist recommended com- tradermal injection of the progesterone solution, an immediate bined oral contraceptive (COC) therapy with 30 mg of ethinyl estra- reaction was observed (i.e., a 9-mm wheal was noted; Fig. 2). Based diol and 0.15 mg of levonorgestrel. Subsequently, her skin lesions on this result, the patient was diagnosed with APD and was referred resolved completely. to a gynecologist. The patient was evaluated in the gynecology A 24-year-old woman was admitted to the gynecology clinic for clinic. She reported 28-day menstrual cycles and had experienced an annual control. She had cyclic eczematous eruptions that skin lesions during every premenstrual period in the last 3 years. occurred 1 year gynecologic after menarche. She had no significant medical history. She was referred to a dermatology clinic for the treatment of monthly skin lesions. The lesions occurred about 5 days * Corresponding author. Department of Obstetrics and Gynecology, School of € before menses and disappeared 1e2 days after the menstruation Medicine, Turgut Ozal University, Ciftlik Street, Number 57 06510, Emek, Ankara, Turkey. ceased. Physical examination revealed several erythematous mac- E-mail address: [email protected] (I. Kaygusuz). ules and patches on the pretibial areas, forearms, elbows, and

http://dx.doi.org/10.1016/j.tjog.2013.12.007 1028-4559/Copyright © 2014, Taiwan Association of Obstetrics & Gynecology. Published by Elsevier Taiwan LLC. All rights reserved. I. Kaygusuz et al. / Taiwanese Journal of Obstetrics & Gynecology 53 (2014) 420e422 421

response. Following the diagnosis, the patient received COC therapy with drospirenone (3 mg) and ethinyl estradiol (0.02 mg). Following the treatment, no recurrences of the skin lesions occurred, but she complained of a slight eruption in the arm in the region where al- lergy testing was performed during every premenstrual period. The eruption was treated with an antihistamine gel. APD was first described in 1921 with acute urticarial lesions during the premenstrual period [3], and since then approximately 70 cases have been published in the international literature. The earliest age reported has been during menarche [4]. In general, it is seen in the third decade of life [5] and in ovulatory women. How- ever, it has also been reported in postmenopausal women receiving hormone replacement therapy [6] and raloxifene [7]. Table 1 pre- sents the reports on APD patients published in the last 3 years [1,8e13]. The morphology of these lesions is variable and includes ery- thema multiforme, urticaria, eczematous patches, angioedema, papulopustular/papulovesicular lesions, stomatitis, folliculitis, Ste- venseJohnson syndrome, vesiculobullous reactions, dermatitis herpetiformis-like rash, and mucosal lesions [2]. The lesions can be localized or generalized, and are most commonly found on the face, but have also been reported on the body, hands, and mucosa of the oropharynx. Vulvovaginal APD has also been reported as well [14]. Symptoms correlate with progesterone levels and occur during Fig. 1. Edema of the face with urticarial appearance. the luteal phase of the menstrual cycle [15] and resolve 1e2 days after menstruation. The pathogenesis of APD is unknown. It may occur in women with a previous history of exogenous progesterone intake, suggesting that synthetic progesterone may induce a cross- reaction against the endogenous hormone, or rarely with exposure to endogenous progesterone during menarche or pregnancy as an autoimmune reaction [16]. The diagnosis is made with appropriate clinical history as well as confirmation with an intradermal skin test to progesterone [9], intramuscular and oral challenge with progesterone [16],ordetection of circulating antibodies to progesterone. In many cases detection of antibodies to progesterone has been reported to be negative, and therefore this is not essential for making a diagnosis [14].Theother criterion for diagnosing APD is prevention of progesterone-induced skin eruption by inhibiting ovulation [7]. APD should be differenti- ated from recurrent eczemas. Differential diagnosis and treatment of recurrent eczema are presented in Table 2 [17]. Fig. 2. Intradermal testing with progesterone. APD is caused by a reaction to the endogenous production of progesterone, and thus treatment modalities are generally based on buttocks. She reported that she had used antihistamines for treat- drugs that suppress ovulation. Antihistamine therapy is usually ment 2 years previously, but this treatment had not improved her unsuccessful and high doses of steroids are needed to suppress symptoms. Skin prick tests were negative for representative symptoms [1]. At present, the first-line therapy is COC. Other inhalant allergens. Intradermal testing with progesterone (50 mg/ medical options are GnRH analogs, tamoxifen, danazol, and con- fi mL) con rmed the clinical diagnosis with a positive immediate jugated estrogens. Because of the adverse side effects of these

Table 1 Reports of APD patients published in the last 3 years.

Case Age (y) Appearance Localization Duration Intradermal Therapy test

Lahmam Bennani et al [8] 23 Pruritic papular-vesicular eruption Trunk Since puberty þ COC George and Badawy [9] 38 Erythema multiforme, urticaria 1 y after menarche COC Le and Wood [10] 34 Papular and eczematous eruption Inner forearms and 2y Topical steroid bilateral palms Toms-Whittle et al [11] 34 Pruritic eruption Legs 8 y GnRH analog Lee et al [1] 48 Eczematous eruption Legs, forearms, 6y þ GnRH analog and buttocks García-Ortega and Scorza [12] 35 Generalized erythematous pruritic Face and limbs 7 y þ With pregnancy near wheals, and areas of edema clearance of the lesions Medeiros et al [13] 42 Multiple pruritic and erythematous Face, neckline area, Onset during þ Unresponsive to medical papules and plaques with crusted trunk, and limbs pregnancy (5 y) treatment erosions Oophorectomy

APD ¼ autoimmune progesterone dermatitis; COC ¼ combined oral contraceptive; GnRH ¼ gonadotropin-releasing hormone. 422 I. Kaygusuz et al. / Taiwanese Journal of Obstetrics & Gynecology 53 (2014) 420e422

Table 2 Differential diagnoses and treatment of recurrent eczema.a

Diagnosis Description (clinical features) Treatment

Allergic contact dermatitis A hypersensitivity reaction exists after sensitization to Corticosteroids: Topical/systemic specific substances in areas exposed directly to the allergen. Topical immunomodulators [calcineurin inhibitors Contact dermatitis is an erythematous, papular dermatitis, (pimecrolimus and tacrolimus)] often with areas of vesiculation. Localization may suggest Phototherapy this diagnosis, but patch tests are needed to definitely Immunosuppressive agents establish it. Oral antihistamines Irritant contact dermatitis Nonspecific response of the skin to direct irritants (e.g., Removal of any potential causal agents soaps and detergents). It is manifested by erythema, mild Use of ceramide creams or bland emollients and bland edema, and scaling. The hands are the most important barrier creams location. Topical corticosteroids Angioedema Angioedema typically affects the skin and mucosal tissues of Second-generation antihistamines the face, lips, and mouth; however, angioedema may affect Systemic corticosteroids other parts of the body, including respiratory and Fresh frozen plasma, antifibrinolytics, C1 esterase gastrointestinal mucosa. It may occur in isolation, inhibitor accompanied by urticaria, or as a component of anaphylaxis. Immunosuppressants such as calcineurin inhibitors Drug eruptions The morphologies of drug eruptions are numerous and Discontinue the medication if possible include morbilliform, urticarial, papulosquamous, pustular, Systemic antihistamines and bullous. Pruritus and dysesthesia without an obvious Topical corticosteroids eruption can also be seen. These dermatoses may or may Intravenous immunoglobulin not be pruritic. Cyclosporine Insect bites After insect bites, secondary eczematous lesions may Removal of the bee stinger, compress, applying ice packs develop in the area of the bites, especially on the limbs, and Epinephrine may be confused with atopic dermatitis. Systemic antihistamines Systemic corticosteroids

a Adapted from Fitzpatrick's dermatology in general medicine. drugs, long-term use is limited [1]. For cases that are unresponsive [2] Baptist AP, Baldwin JL. Autoimmune progesterone dermatitis in a patient with to medical treatment, bilateral oophorectomy is recommended; endometriosis: case report and review of the literature. Clin Mol Allergy 2004;2:10. however, this is only for those who no longer desire fertility [13].In [3] Geber H. Einege daten zur pathologie dur urtecaria menstruationalis. Der- some patients, the disorder completely resolves spontaneously [5]. matol Z 1921;32:143e50. Other therapeutic agents, such as azathioprine, hydroxy- [4] Farah FS, Shbaklu Z. Autoimmune progesterone urticaria. J Allergy Clin Immunol 1971;48:257e61. chloroquine, dapsone, or cyclosporine, have also been described in [5] Kakarla N, Zurawin RK. A case of autoimmune progesterone dermatitis in an the literature. However, their use is limited because they appear adolescent female. J Pediatr Adolesc Gynecol 2006;19:125e9. ineffective or have significant side effects [18]. [6] Bolaji II, O'Dwyer EM. Post-menopausal cyclic eruptions: autoimmune pro- gesterone dermatitis. Eur J Obstet Gynecol Reprod Biol 1992;47:169e71. In our cases, treatment with the GnRH analog and COC pills was [7] Warin AP. Case 2. Diagnosis: erythema multiforme as a presentation of effective. The long-term use of GnRH analogs induces some side autoimmune progesterone dermatitis. Clin Exp Dermatol 2001;26:107e8. effects, and therefore we prescribed the drug for only 3 months. [8] Lahmam Bennani Z, El Fekih N, Baccouche D, Khaled A, Zaglaoui F, Fazaa B. Autoimmune progesterone dermatitis. Ann Dermatol Venereol 2012;139: Symptoms disappeared with the treatment in all the cases. Two 832e5 [Article in French]. months after cessation of therapy, the patients still had no skin [9] George R, Badawy SZ. Autoimmune progesterone dermatitis: a case report. lesions. Case Rep Obstet Gynecol 2012;2012:1e2. In conclusion, APD is a rare autoimmune response to endoge- [10] Le K, Wood G. A case of autoimmune progesterone dermatitis diagnosed by progesterone pessary. Australas J Dermatol 2011;52:139e41. nous progesterone seen 3e10 days before the onset of menstrua- [11] Toms-Whittle LM, John LH, Griffiths DJ, Buckley DA. Autoimmune proges- tion, when progesterone levels are elevated. It can present in terone dermatitis: a diagnosis easily missed. Clin Exp Dermatol 2011;36: e different morphological forms. Premenstrual flare, positive intra- 378 80. [12] García-Ortega P, Scorza E. Progesterone autoimmune dermatitis with positive dermal skin test with progesterone, and prevention of lesions with autologous serum skin test result. Obstet Gynecol 2011;117:495e8. inhibition of ovulation are the main criteria for the diagnosis of [13] Medeiros S, Rodrigues-Alves R, Costa M, Afonso A, Rodrigues A, Cardoso J. APD. There are different treatment modalities and they generate Autoimmune progesterone dermatitis: treatment with oophorectomy. Clin Exp Dermatol 2010;35:e.12e3. variable response in affected patients. [14] Banerjee AK, de Chazal R. Chronic vulvovaginal pruritus treated successfully with GnRH analogue. Postgrad Med J 2006;82:e22. [15] Snyder JL, Krishnaswamy G. Autoimmune progesterone dermatitis and its Conflicts of interest manifestation as anaphylaxis: a case report and literature review. Ann Allergy Asthma Immunol 2003;90:469e77. The authors have no conflicts of interest relevant to this article. [16] Kasperska-Zajac A, Brzoza Z, Rogala B. Sex hormones and urticaria. J Dermatol Sci 2008;52:79e86. [17] Wolff K, Goldsmith LA, Katz SI, Gilchrest BA, Paller AS, Leffell DJ, editors. Fitzpatrick's dermatology in general medicine. 7th ed. New York: McGraw- References Hill Medical; 2008. [18] Dedecker F, Graesslin O, Quereux C, Gabriel R, Salmon-Ehr V. Autoimmune [1] Lee MK, Lee WY, Yong SJ, Shin KC, Lee SN, Lee SJ, et al. A case of autoimmune progesterone dermatitis: a rare pathology. Eur J Obstet Gynecol Reprod Biol progesterone dermatitis misdiagnosed as allergic contact dermatitis. Allergy 2005;123:120e1. Asthma Immunol Res 2011;3:141e4.