Autoimmune progesterone dermatitis and stomatitis

Autoimmune progesterone dermatitis and stomatitis Behjat K. H. Moghadam, DDS, DScD, a Sia Hersini, DMD, b and Bruce E Barker, DDS, Kansas City, Mo. UNIVERSITYOF MISSOURI-KANSASCITY SCHOOLOF DENTISTRY Autoimmune progesterone dermatitis is a rare clinical condition associated with variable cutaneous and mucosal eruptions such as urticaria, erythema multiforme, and eczema. Exacerbation is influenced by hormonal changes of the menstrual cycle. The patient described in this report had recurrent cyclic lesions on the skin, oral mucosa, and lips that appeared just before regular menstruation and persisted until a few days after. During each cycle, the eruptions appeared at the previously affected sites, mimicking the clinical feature of a fixed drug eruption. This rare phenomenon is attributed to an autoimmune reaction to female sex hormones. The condition failed to respond to therapy with prednisone, but improved with the use of an antiestrogen drug, tamoxifen. This medication suppresses ovulation and the post-ovulation rise in endogenous progesterone levels. (Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1998;85:537-41)

Hypersensitivity reaction to the female sex hormones is a rare clinical condition appearing with variable manifestations. 118 The most common symptoms reported in the literature are urticaria, 1,6,11-13,16 erythema multiforme-like reaction, 24,14,t8 and eczematous eruptions. 5,7,16,17 Oral mucosal lesions such as ulcerative stomatitis and erosive stomatitis have been reported in some cases. 1,15,1s These eruptions typically reappear within a few days before the onset of menses, with spontaneous resolution occurring after menstruation. 1-18 One of the most serious clinical conditions related to the female sex hormones was a case of severe anaphylactic-like patterns and shock in the course of menstrnation. 8 After the patient underwent oophorohysterectomy, all related symptoms disappeared completely. Cure by oophorectomy also has been reported in a severe case of vesiculobullous eruptions with cyclic premenstrual exacerbation in a young female. 4 Additional episodes of premenstrual worsening of atopic dermatitis and flaring of the existing cutaneous eruptions just before or during menstruation have been reported. 4-6,9 Exacerbation of other clinical conditions, such as bronchial asthma and vascular rhinitis, has also been reported in the course of menstruations. 19,2° The mechanism by which endogenous progesterone or other normal secretory components of females becomes antigenic is unknown. It has been suggested that an altered form of the hormone may exist in persons with an autoimmune progesterone reactivity. 6 These altered molecules may not be considered self and aAssociate Professor, Department of Diagnostic Sciences. bThird-year Resident, Oral Medicine Post-Graduate Program, Department of Diagnostic Sciences. cprofessor, Department of Oral and Maxillofacial Pathology. Received for publication June 9, 1997;returned for revisionAug. 14, 1997; accepted for publication Dec. 1, 1997. Copyright © 1998 by Mosby, Inc. 10792-2104/98/$5.00 + 0 7/13/88524

may elicit an autoimmune reaction mediated by either antibody-dependent or cell-mediated responses. 6,8 Type 1 IgE-mediated allergy has been proposed as a cause of an autoimmune progesterone dermatitis because of an immediate induction of positive skin test with progesterone, 1,4,6-8,12 degranulation of basophils, 4,5 and the presence of a serum factor that binds rabbit corpus luteum. 6 In some affected individuals, the positive skin test with progesterone injection had a feature of delayed hypersensitivity reaction with erythema and induration peaking 24 to 48 hours after onset. 5,13,16 More rarely, the hypersensitivity reaction associated with menstruation may appear as a fixed drug eruption (FDE). 2 The concept of FDE was first introduced by Brocq 21 in 1894. Clinically FDE is characterized by round erythematous patches on the skin or mucous membranes. The cutaneous lesions may appear in different forms. They are usually characterized by sharply demarcated, erythematous patches recurring at the same locations each time the offending drug is used. 22-31 A large number of drugs such as antiinflammatory agents (acetylsalicylic acid), 26 antimicrobial agents (tetracyclines, sulfonamides), 27 sedatives, 2829 and chlorhexidine-containing mouth washes can trigger FDE. 30 We report a rare case of an autoimmune progesterone dermatitis and stomatitis with the feature of FDE in a young female. The intraoral ulcerations and cutaneous eruptions appeared at the same locations immediately before or during each menstruation and disappeared after menses. The possibility of autoimmune progesterone dermatitis was raised because of the cyclic nature of the condition. The eruptions were recurrent during the luteal phase of the menstrual cycle when the serum progesterone level is elevated.

CASE REPORT A 29-year-old woman was referred to the Department of 537

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Fig. 1. Large erythematous ulceration of soft palate. This lesion healed without scarring or residual pigmentation.

Fig. 2. Both upper and lower lips were swollen and red and had areas of exfoliation. Large vesicle is located at vermillion skin junction (arrows).

Diagnostic Sciences at the University of Missouri-Kansas City School of Dentistry because of intraoral ulcerations and soreness in her lips. These lesions were very painful, and she had had difficulty eating and talking during the preceding 24 hours. Routine medical and dental diagnostic procedures revealed that she had a history of hay fever and sinusitis. She had taken no medication over the counter or by prescription. The first onset of disease was 1 year earlier, when the patient was 28 years of age; she had developed fever, malaise, and an acute episode of gingivostomatitis 1 day before her menstruation. At that time her condition was diagnosed and treated as a primary herpes infection. The second onset developed 4 weeks later with the similar clinical manifestation and less severe symptoms that lasted for a few days. These symptoms reappeared in the initiation of each menstruation and healed without any treatment. She had remained asymptomatic during the time between menses. The most recent onset developed less than 24 hours after an episode of mild fever and malaise on the first day of her menstrual cycle. The intraoral lesions were a large erythematous ulceration on the palate (Fig. 1) and two small ulcerations at

Fig. 3. Itchy erythematous patch on patient's finger.

the border of her tongue. Both the upper and lower lips were swollen and red and had several small vesicles, ulcerations, and areas of exfoliation (Fig. 2). Several erythematous macular eruptions were on her face, finger (Fig. 3), and shoulder. Melanotic pigmentation was absent in the lesions. Cytologic smears taken from a large fresh vesicle at the vermillion border of the lower lip (Fig. 2) were negative for the presence of multinucleated giant cells found in viral infections. The tentative diagnosis at that time was a mild form of erythema multiforme possibly secondary to a herpes infection. The patient was placed on 20 mg of prednisone for 4 days; this was followed by 10 mg for the next 4 days and then 5 mg for the next 4 days. The therapeutic effects of the prednisone were minimal, and several weeks later the patient reported a recurrence of lesions in the same areas, starting on her face and extending onto the trunk and extremities. The erythematous macular lesions on her face, shoulder, and trunk had developed hyperpigmentation, which flared with each subsequent mensm~al cycle. Intraoral lesions were minimal, with no pigmentary changes. The lip lesions persisted and were heavily pigmented (Fig. 4). The patient consulted with a dermatologist, and a diagnosis of probable fixed-drug eruptiontype reaction secondary to her menstrual cycle was made. This clinical diagnosis was confirmed by a biopsy taken from a shoulder lesion. Microscopic examination revealed a predominantly superficial perivascular dermatitis with spongiosis and pigmentary incontinence (Fig. 5). A Fontana-Masson stain was strongly positive for melanin, which was present in the superficial dermis both within histiocytes and in the surrounding connective tissue (Fig. 6). The clinical and histologic information relating to this patient was strongly suggestive of an autoimmune reaction to elevated progesterone levels during the luteal phase of menstmation. During a follow-up visit, skin testing with estrogen (1 mg/ml) and Depo-Provera (1 mg/ml), a derivative of progesterone, was performed without complication; no reaction in eruptive or noneruptive skin areas developed after 48-hour evaluation. Following a consultation with her gynecologist, the patient was first placed on 50-mg spironolactone

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Fig. 4. Heavy pigmentation developed around lip lesions during later course of disease.

Fig. 5. Biopsy showed superficial perivascular dermatitis with spongiosis and pigmentary incontinence (hematoxylineosin, original magnification xl00).

(Aldactone), an antidiuretic hormone given to control the premenstrual symptoms, daily for 10 days, with no benefit. The medication dosage was then increased to 100 mg/day for 3 weeks, but no significant effect was detected. Tamoxifen (Nolvadex), an antiestrogen agent, was then prescribed at a dosage of 20 mg/day for 2 months. The patient reported that her clinical symptoms began to decline gradually over a few weeks, but the cutaneous pigmentations persisted (Fig. 4). For 13 months the patient has not taken any medication and has not had a recurrence. The hyperpigmented skin areas are present but are gradually fading.

DISCUSSION Herzberg et al. 1° reported a case of autoimmune progesterone dermatitis with papulovesicular eruptions and reviewed 42 other cases of a similar condition. An additional case not included in that review was a case of anaphylactic-like reaction in the course of menstruation reported by Basomba et al. 8 The autoimmune reaction to endogenous progesterone is a rare clinical condition associated with several dermatologic reactions appearing as chronic urticaria, 1,6,11-13,16 cyclic erythema multiforme, 2:4,14,18 atopic eczema, 5,7,16,17 or FDE-type reaction resembling erythema multiforme. 2 These eruptions are characterized by recurrence a few days before the menses with spontaneous resolution after menstruation. 1-28 The term autoimmune progesterone dermatitis was used to describe these lesions when exacerbation of an eczematous reaction developed after progesterone challenges. 4 Further evidence incriminating progesterone as a principal causative factor includes rapid induction of urticaria and erythema multiforme by progesterone injection, 1,4,6-s,12 inhibition of urticaria by administration of an antiovulatory agent, 6 complete remission of anaphylactic reactions after oophorohysterectomy, 4,8 and demonstration of serum antibodies to progesterone by indirect immunofluorescence. 6,1° The positive

Fig. 6. Melanin pigment within superficial dermis, both within histiocytes and free in tissue (Fontana-Masson, original magnification x200).

immunofluorescence reaction m one study was localized around the cell membrane of the luteinizing cells of the corpus luteum, the location of progesterone before secretion. 6 The direct immunofluorescence test was negative in some cases. 1° Progesterone antibodies to endogenous 17-hydroxy progesterone also have been demonstrated in the serum of a patient with a history of recurrent oral and perineal rashes since menarche. 15 In vitro studies on autoimmune progesterone antibodies include degranulation of rabbit basophils 4,5 and morphologic alteration of rat mast cells in the presence of patient serum (suspected antibody) and progesterone (suspected antigen). 14 Administration of synthetic progesterone has been recognized as a cause of cyclic erythema multiforme 2-4,14,18 and FDE 2 in several cases. However, the onset of autoimmune progesterone dermatitis was not always linked to a specific condition such as exogenous progesterone intake. 1° In addition to these cases and our

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present case, a case of anaphylactic-like reaction during menstruation in a patient with no history of hormone therapy has been reported. 8 The principal hallmark for the diagnosis of autoimmune progesterone dermatitis in many cases was a history of luteal phase skin and oral lesions, which was recurrent on cyclic basis. Such a diagnosis had been made even though the patient's test result with progesterone or immunofluorescence examination was negative. In autoimmune progesterone dermatitis, patient age at onset ranged from 16 to 48 years, with most patients in their twenties. 1° In many of these cases the trigger mechanism that contributed to the formation of circulating antibodies against endogenous progesterone remained undetermined. 1° One possibility is a crossreaction between endogenous progesterone and circulating antibodies formed against other potential antigens such as viral infections, medications, or food products. 8 In one case the patient had her first acute urticaria attack at age 37 years; it was attributed to seafood intake. Later, at age 40 years, she showed a pattern of anaphylactic-like reaction in the course of menstruation. A possible explanation in this case was a crossreaction between endogenous progesterone and antibodies formed against food proteins, s In our case the patient had a history of herpes simplex stomatitis at age 28 years that was associated with her menstruation and could have served as a trigger for her later autoimmune condition at age 29 years. This may explain why there had been no onset of autoimmune condition after menarche before age 29 years either in the present case or in many of the other reported cases. The initial cutaneous and mucosal lesions in our patient had been similar to a mild form of cyclic erythema multiforme secondary to an episode of herpes infection and menses. Cutaneous itchy erythematous plaques, 1 to 2 cm in diameter, developed on her face, hand, and shoulder early in her menstruation. The individual lesions lasted about 2 weeks and healed without scarring or pigmentation. The typical "target" lesion was absent. The intraoral ulcerations were principally localized on her soft palate, the border of her tongue, and the vermilion border of her lips. These lesions also healed without scarring or pigmentation. During the later course of the disease, lesions recurred at previously affected sites and began to heal with pigmentation. Because recurrent lesions in erythema multiforme usually show no predilection for previously involved sites, z FDE-type reaction was suspected and further confirmed by histologic observation of melanin incontinence throughout the dermis. Melanin-laden macrophages also have been reported in a few other cases of autoim-

mune progesterone dermatitis with the clinical features of erythema multiforme. 4,1°,14 Occasionally, FDE occurs without inducing pigmentation. 3°,31 The histology of FDE typically shows hydropic degeneration of epidermal basal cells with dermal perivascular infiltrates.2,13 FDE and erythema multiforme share some common clinical and histologic characteristics, which makes it difficult to distinguish between them. 2,13 Erythema multiforme can be due to a wide variety of causes and can be triggered by menstrual-associated herpes simplex condition. When associated with menstruation, it can be a manifestation of autoimmune progesterone dermatitis.1 Some investigators believe that FDE is a rare variant of erythema multiforme. 2 Skin and oral mucosa are most commonly involved in autoimmune progesterone responses, inasmuch as.both tissues express specific binding sites for progesterone. 32 Most affected individuals have a positive skin test reaction to progesterone challenges with afeature of immediate 7,8,12 or delayed 5,13,16 immune reaction. Negative skin test reaction also has been reported in some cases.3,4,17 The failure to demonstrate visible changes after skin testing indicates that test agents must be modified in some way to elicit a response in susceptible skin. 6 These observations may explain why intradermal tests with estrogen and Depo-Provera were negative in this patient. In addition, the cutaneous and oral lesions reappeared at the same anatomic location before each menstruation, suggesting an FDE reaction. The result of skin testing with the causative agent on both lesional and unaffected skin sites may or may not be positive in patients with FOE. 22 Because of its rarity and resemblance to erythema multiforme, FDE is usually difficult to diagnose, and errors are possible. 2,13 Although gray areas exist in the difference between these two conditions, we believe that most clinical and histologic features in this case favor FDE. The therapeutic possibilities of autoimmune progesterone dermatitis include the use of conjugated estrogens (Premarin), which suppress ovulation and therefore progesterone production. 1,7,11-14,18 Administration of systemic steroids has been successful in some cases, 15A6 but the condition is commonly unresponsive to conventional therapy with topical steroids and antihistamines. Our patient responded to a course of therapy with tamoxifen, an antiestrogen agent. This medication also has been effective in two other cases. 3,17 The clearing of autoimmune progesterone dermatitis during tamoxifen therapy is related to the decrease in endogenous semrn progesterone levels. The drug has a peripheral anfiestrogenic effect, and suppresses ovula-

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tion and the post-ovulation rise in progesterone by interfering with the pituitary/hypothalamic feedback mechanism. 3,17 However, the reason for the prolongation of the beneficial effects of tamoxifen in our patient is unclear. After therapy was stopped the patient maintained her regular menstruation without recurrence. Improvement in the present case could be related to an undetermined factor, such as structural modification of endogenous progesterone, gradual desensitization, or some adjustment in the patient's immune system. Some cases of autoimmune progesterone dermatitis have resolved without treatment, 1,1° and some severe conditions have been cured by oophorohysterectomy. 4,8 In patients with a cyclic eruption related to the menses, the possibility of autoimmune progesterone dermatitis should be strongly considered.

13. Georgouras K. Autoimmuue progesterone dermatitis. Aust J Dermatol 1981;22:109-12. 14. Stone J, Downham T. Autoimmune progesterone dermatitis. Int J Dermatol 1981 ;20:50-1. 15. Cheesman KL, Gaynor LV, Chatterton RT Jr, Radvany RM. Identification of a 17-hydroxyprogesterone-binding immunoglobulin in the serum of a woman with periodic rashes. J Clin Endocrinol Metab 1982;55:597-9. 16. Anderson RH. Autoimmune progesterone dermatitis. Cutis 1984;33:490-1. 17. Stephens CJM, Wojnarowska FT, Willkinson JD. Autoimmune progesterone dermatitis responding to tamoxifen. Br J Dermatol 1989;121:135-7. 18. Teelucksingh S, Edwards CRW. Autoimmune progesterone dermatitis. J Intern Med 1990;22:143-4. 19. Efiasson O, Scherzer HH. Recurrent respiratory failure in premenstrual asthma. Corm Med 1984;48:777-8. 20. Beynon HLC, Garbett ND, Barnes PJ. Severe premenstrual exacerbations of asthma: effect of intramuscular progesterone. Lancet 1988;2:370-2. 21 Brocq L, Eruption 6ryth~mato-pigment~e fix due a I'antipyrine. Ann Derma Syph 1894;3:308-13. 22. Alanko K. Topical Provocation of fixed drug eruption. Contact Dermatitis 1994;31:25-7. 23. Lisi R Stingeni L. Fixed drug eruption: bullous form. Clin Dermatol 1993;11:461-6. 24. Kanwar AJ, Dhar S, Ghosh S, Kaur S. Mucosal fixed drug eruption. Dermatology 1994;188:171. 25. Dhar S, Amrinder JK. Fixed drug eruption on the tongue of a 4year-old boy. Pediatr Dermatol 1995;12:51-2. 26. Naldi L, Ferri C, Locati F, Cainelli T, Cutaneous reactions to analgesic antipyretics and nonsteroidal anti-inflammatory drugs. Dermatology 1993;186:164-9. 27. VanArsdel PP Jr. Allergy and adverse drug reactions. J AmAcad Dermatol 1982;34:319-30. 28. Rademacher D, Gerhardt G, Brasch J. Fixed drug eruption caused by chlormezanone. Contact Dermatitis 1995;32:117-8. 29. Fujimoto Y, Hayakawa R, Suzuki M, Ogino Y. Fixed drug eruption due to allylisopropyl-acetylurea. Contact Dermatitis 1993;28:82-4. 30. Moghadam B, Drisko C, Gier R. Chlorhexidine mouthwashinduced fixed drug eruption. Oral Surg Oral Med Oral Pathol 1991;71:431-4. 31. Krivda MJ, Benson PM. Nonpigmenting fixed drug eruption. J Am Acad Dermatol 1994;31:291-2. 32. Shughrue PJ, Stumpf WE, Madhabananda S. The distribution of progesterone receptor in the 20-day-old fetal mouse: an autoradiographic study with [125I] progestin. Endocrinology 1988;123:2382-9.

Drs. David Kaplan and Frank A. Mantz aided in the diagnosis and management of the patient. Ms. Lisa Cabra prepared the manuscript, and Mr. Jim Thomas provided photographic assistance.

REFERENCES 1. Hart R. Autoimmune progesterone dermatitis. Arch Dermatol 1977; 113:426-30. 2. Sowden JM, Smith AG. Multifocal fixed drug eruption mimicking erythema multiforme. Clin Exp Dermatol 1990;15:387-8. 3. Wojnarowska F, Greaves MW, Peachy RDC, Drury PL, Besser GM. Progesterone induced erythema multiforme. J R Soc Med 1985;78:407-8. 4. ShelleyWB, Preucel RW, Spoont SS.Autoimmune progesterone dermatitis: cure by oophorectomy. JAMA 1964;190:35-8. 5. Jones WN, Gordon VH. Autoimmune progesterone eczema: an endogenous progesterone hypersensitivity. Arch Dermatol 1969;99:57-9. 6. Farah FS, Shbaklu Z. Autoimmune progesterone urticaria. J Allergy Clin Immunol 1991;48:257-61. 7. Katayama I, Nishioka K. Autoimmune progesterone dermatitis with persistent amenorrhoea. Br J Dermatol 1985; 112:487-91. 8. Basomba A, Guerrero M, Campos A, Villalmanzo IG. Grave anaphylactic-like reaction in the course of menstruation: a case report. Allergy 1987;42:477-9. 9. Kemmett D, Tidman M. The influence of the menstrual cycle and pregnancy on atopic dermatitis. Br J Dermatol 1991; 125:5961. 10. Herzberg AJ, Strohmeyer CR, Cirillo-Hyland VA. Autoimmune progesterone dermatitis. J Am Acad Dermatol 1995;32:335-8. 11. Berger H. Ulcerative stomatitis caused by endogenous progesterone. Ann Intern Med 1955;42:205-8. 12. Tromovitch T, Heggli WE Autoimmune progesterone urticaria. Calif Med 1967;106:211-2.

Reprint requests: Behjat K. H. Moghadam, DDS, DScD Department of Diagnostic Sciences UMKC School of Dentistry 650 E. 25th Street Kansas City, MO 64108