{"paper_id":"f5d8ea1f-47a6-4a93-a30d-8114a861d969","body_text":"BioMed Central\nPage 1 of 5\n(page number not for citation purposes)\nClinical and Molecular Allergy\nOpen AccessCase Report\nAutoimmune progesterone dermatitis in a patient with \nendometriosis: case report and review of the literature\nAlan P Baptist* and James L Baldwin\nAddress: Division of Allergy/Immunology, Department of Internal Medicine, University of Michigan, 3918 Taubman Center, #0380, 1500 E \nMedical Center Drive, Ann Arbor, MI 48109-0380, USA\nEmail: Alan P Baptist* - abaptist@umich.edu; James L Baldwin - jbaldwin@umich.edu\n* Corresponding author    \nAbstract\nAutoimmune progesterone derm atitis (APD) is a condition in which the menstrual cycle is\nassociated with a number of skin findings such as urticaria, eczema, angioedema, and others. In\naffected women, it occurs 3–10 days prior to the onset of menstrual flow, and resolves 2 days into\nmenses. Women with irregular menses may not have this clear correlation, and therefore may be\nmissed. We present a case of APD in a woman with irregular menses and urticaria/angioedema for\nover 20 years, who had not been diagnosed or correctly treated due to the variable timing of skin\nmanifestations and menses. In addition, we review  the medical literature in regards to clinical\nfeatures, pathogenesis, diagnosis, and treatment options.\nIntroduction\nWhile many women complain of worsening acne and\nwater retention during their menstrual cycle, there exist a\nsmall number in whom the menstrual cycle is associated\nwith a variety of other skin manifestations such as urti-\ncaria, eczema, folliculitis, and angioedema. This condi-\ntion is known as autoimmune progesterone dermatitis\n(APD) due to the fact that progesterone is most frequently\nidentified as the etiologic agent. In women with irregular\nmenses, the diagnosis may remain elusive for years. We\npresent a case of APD, and review the current literature in\nregards to clinical features, pathogenesis, diagnosis, and\ntreatment options.\nCase\nA 33y/o woman with a history of endometriosis presented\nwith complaints of chronic urticaria. The patient noted\nthat the urticaria began at the age of 12, and did not seem\nto have any obvious trigger. Each individual lesion would\nlast from 12–24 hours, and the entire episode would last\n5–10 days. Lesions would usually start on the chest and\nthen spread over the entire body. She had seen multiple\nphysicians, including allergists and dermatologists, and\nhad been treated with a variety of medications including\ncertirizine, desloratadine, hydroxyzine, montelukast, ran-\nitidine, and diphenhydramine without relief. Prednisone\nat high doses would provide temporary relief, and she had\nrequired multiple courses of prednisone over the past 20\nyears. In addition, she complained of occasional\nangioedema, usually at the same time as the hives but\noccasionally occurring when hives were not present. The\npatient also had acne that had been very difficult to con-\ntrol since her teenage years, and she noted that the acne\nwould also respond to prednisone.\nMultiple lab tests over the years had been unremarkable.\nThese included SSA/SSB, anti-Smith, ACE level, C3/C4,\nhepatitis B, ANA, anti double-stranded DNA, immu-\nnoglobulins, SPEP, C1 esterase inhibitor level and func-\ntion, chemistry panel, liver tests, TSH, T4, thyroid\nPublished: 02 August 2004\nClinical and Molecular Allergy 2004, 2:10 doi:10.1186/1476-7961-2-10\nReceived: 15 June 2004\nAccepted: 02 August 2004\nThis article is available from: http://www.clinicalmolecularallergy.com/content/2/1/10\n© 2004 Baptist and Baldwin; licensee BioMed Central Ltd. This is an open-access article distributed under the terms of the Creative Commons Attribution \nLicense (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original \nwork is properly cited.\n\nClinical and Molecular Allergy 2004, 2:10 http://www.clinicalmolecularallergy.com/content/2/1/10\nPage 2 of 5\n(page number not for citation purposes)\nantibodies, rheumatoid factor, ESR, and CBC. Skin biopsy\nof a lesion had been read as \"chronic urticaria\".\nUpon further questioning, it was learned that due to the\npatient's endometriosis, she had very irregular menstrual\ncycles in terms of length and timing. It was determined\nthat the hives and/or angioedema would begin approxi-\nmately 4 days prior to the onset of menses, and would last\nabout 2 days into menses. The symptoms would not occur\nwith every episode of menses. The patient's acne would\noften occur on her face during the urticarial episodes. Of\nnote, the patient had 2 children, and during each preg-\nnancy her hives, acne, and angioedema had been mark-\nedly improved. Because of her endometriosis, she had\nbeen started on Depo-Provera (medroxyprogesterone ace-\ntate) in her twenties. After 1 injection, she developed\nsevere hives that lasted over 2 months and required mul-\ntiple courses of prednisone. Due to the urticaria, Depo-\nProvera was discontinued after one injection. As the\npatient complained of acne, Ortho Tri-Cyclen (norgesti-\nmate/ethinyl estradiol) was initiated by her dermatolo-\ngist. This treatment modality did not have any effect on\nthe urticaria, angioedema, or acne.\nThe patient was evaluated in our clinic. Physical examina-\ntion was essentially normal, and no hives were noted.\nAllergy skin testing was performed with progesterone 50\nmg/mL in normal saline. Prick test was normal, but a full\nstrength intradermal test revealed a 7 mm wheal with ery-\nthema. The histamine control showed a 9 mm wheal with\nerythema, and saline control was negative for wheal and\nerythema. Two healthy controls also underwent intrader-\nmal testing to exclude irritant reaction, and were found to\nbe negative\nBased on the above results, the patient was diagnosed\nwith autoimmune progesterone dermatitis. The patient\nwas started on a GnRH agonist (nafarelin acetate nasal\nspray, 200 mcg twice a day). Within one month, she noted\ndramatic improvement in her urticaria and angioedema.\nAcne was still occasionally present, but much improved.\nShe did complain of mild hot flashes, but felt these were\ntolerable.\nDiscussion\nIn a small group of women, the menstrual cycle has been\nassociated with a spectrum of dermatologic diseases\nincluding eczema, erythema multiforme, stomatitis,\npapulopustular lesions, folliculitis, angioedema, urticaria,\nand others (Table 1) [1-8]. As progesterone sensitivity has\nbeen the most commonly identified cause, dermatologic\ndiseases associated with the menstrual cycle have been\nlabeled autoimmune progesterone dermatitis (APD) [4].\nThe first documented case of APD was in 1921, in which\na patient's premenstrual serum caused acute urticarial\nlesions. In addition, it was shown that the patient's pre-\nmenstrual serum could be used to desensitize and\nimprove her symptoms [9]. Since 1921, approximately 50\ncases of APD have been published in the medical\nliterature.\nClinical Features\nThe clinical symptoms of APD (eczema, urticaria,\nangioedema, etc.) usually begin 3–10 days prior to the\nonset of menstrual flow, and end 1–2 days into menses.\nSeverity of symptoms can vary from nearly undetectable\nto anaphylactic in nature, and symptoms can be progres-\nsive [10,11]. There are no specific histological features on\nbiopsy in APD [12]. The age of onset is variable, with the\nearliest age reported at menarche [13]. Some studies have\nnoted that a majority of patients had taken an oral contra-\nceptive (OCP) prior to the onset of APD [14], but multiple\ncases exist in which women have never been exposed to\nexogenous progesterone [15-17].\nThe symptoms of APD correlate with progesterone levels\nduring the luteal phase of the menstrual cycle.\nProgesterone begins to rise 14 days prior to the onset of\nmenses, peaks 7 days prior to menses, and returns to a low\nbaseline level 1–2 days after menses begins. In studies\nwhere an etiologic agent has been sought, progesterone\nhas been found most frequently. However, estrogen, pros-\ntacyclin, and gonadotropin levels have correlated with\nsymptoms in some cases [18-21].\nSymptoms may first appear, improve, or worsen during\npregnancy and the peripartum period [2,22-24]. In addi-\ntion, APD during pregnancy has been associated with\nspontaneous abortions [2,25]. Pregnancy is associated\nwith an increase of maternal progesterone levels, which\nmay explain the initiation or worsening of symptoms. In\nregards to an improvement of symptoms during preg-\nnancy, a number of theories have emerged. Explanations\ninclude a slow rise of progesterone during pregnancy that\nTable 1: Dermatologic manifestations of autoimmune \nprogesterone dermatitis\n- Urticaria\n- Angioedema\n- Eczema\n- Erythema multiforme\n- Stomatitis\n- Folliculitis\n- Papulopustular/papulovesicular lesions\n- Stephens-Johnson syndrome\n- Vesiculobullous reactions\n- Dermatitis herpetiformis-like rash\n- Mucosal lesions\n\nClinical and Molecular Allergy 2004, 2:10 http://www.clinicalmolecularallergy.com/content/2/1/10\nPage 3 of 5\n(page number not for citation purposes)\nacts as a method of desensitization, a decrease in maternal\nimmune response during pregnancy, or an increased pro-\nduction of anti-inflammatory glucocorticoids [13,25,26].\nPathogenesis\nThe exact pathogenesis of APD is unknown. If exogenous\nprogesterones (i.e. OCPs) are initially used, it is conceiva-\nble that uptake by antigen presenting cells and presenta-\ntion to TH2 cells could result in subsequent IgE synthesis;\nhowever this mechanism would not explain the patho-\ngenesis in patients such as ours who have the onset of\nAPD prior to exogenous progesterone exposure. Some\nauthors have suggested that hydrocortisone or 17- α-\nhydroxyprogesterone have cross-sensitivity with proges-\nterone and may cause initial sensitization, but this has not\nbeen observed in all studies [27,28].\nTo further delineate the pathogenesis, antibodies against\nprogesterone have been investigated. Using immunofluo-\nrescent techniques and basophil degranulation tests, stud-\nies have found that such antibodies do exist in certain\npatients with APD [1,13,29]. However, negative results\nlooking for antibodies have also been reported [24]. In\naddition, skin test results with progesterone have shown\nimmediate reactions (within 30 minutes), delayed reac-\ntions (24–48 hours later), and reactions with features of\nboth immediate and delayed features [13,14,30,31]. This\npresumably indicates both type I and type IV hypersensi-\ntivity reactions. Progesterone has also been reported to\nhave a direct histamine releasing effect on mast cells, yet\nvery little research has been done to support this hypoth-\nesis [32]. Additionally, one study found an in vitro\nincrease of an interferon-γ release assay, possibly implying\na role for TH1-type cytokines in APD [33].\nEosinophils may also be involved in the pathogenesis of\nAPD. Eosinophilia has been correlated with cutaneous\nsymptoms in some cases, and studies have found a\ndecrease in total eosinophil count after therapy\n[13,29,34]. Whether increased eosinophils are a response\nto cytokines from lymphocytes or play a primary mecha-\nnistic role in APD remains to be determined.\nDiagnosis\nThe diagnosis of APD requires an appropriate clinical his-\ntory accompanied by an intradermal injection test with\nprogesterone. An aqueous suspension or aqueous alcohol\nsolution of progesterone is the preferable vehicle of test-\ning as progesterone in oil can cause an irritant reaction\n[35], though many published case reports have used pro-\ngesterone in oil for testing. Various authors have advo-\ncated different amounts of progesterone or\nmedroxyprogesterone to be used for testing [12,33,36]. As\nhad been done in some prior studies, the patient pre-\nsented here was tested with progesterone in aqueous solu-\ntion at a concentration of 50 mg/mL.\nAs mentioned above, APD may be due to an immediate or\ndelayed hypersensitivity reaction. Therefore, intradermal\ntesting may not become positive until 24–48 hours later\n[14,24]. In addition, some authors have advocated patch\ntesting with progesterone to further evaluate for a hyper-\nsensitivity reaction [33]. Of note, intradermal testing has\nbeen negative in some patients with typical clinical symp-\ntoms of APD and who improved after APD treatment\n[2,3,24].\nSome authors have recommended further tests to evaluate\nthe immunologic evidence in APD. These include circulat-\ning antibodies to progesterone, basophil granulation\ntests, direct and indirect immunofluorescence to luteiniz-\ning cells of the corpus luteum, in vitro interferon-γ release,\nand circulating antibodies to 17- α-hydroxyprogesterone\n[1,7,13,29,33,36]. However, most case reports in the\nmedical literature do not routinely check for serologic evi-\ndence of APD, and when checked these markers have not\nalways been found to be reliable. This is most likely due\nto the fact that, as mentioned above, the pathogenesis of\nAPD is incompletely understood.\nTreatment\nAutoimmune progesterone dermatitis is usually resistant\nto conventional therapy such as antihistamines. The use\nof systemic glucocorticoids, usually in high doses, has\nbeen reported to control the cutaneous lesions of APD is\nsome studies, but not in others [3,10,37]. Early reports of\nAPD describe attempts of progesterone desensitization,\nand some authors even attempted injections derived from\nthe corpus luteum [18,24,38]. However, results were usu-\nally temporary, and such methods of treatment have now\nfallen out of favor.\nCurrent therapeutic modalities often attempt to inhibit\nthe secretion of endogenous progesterone by the suppres-\nsion of ovulation. Table 2 lists some of the pharmacologic\nstrategies used in APD. Oral contraceptives (OCPs) are\noften tried as initial therapy, but have had limited success,\npossibly due to the fact that virtually all OCPs have a pro-\ngesterone component. Conjugated estrogens have also\nbeen used in the treatment of APD. These did show\nimprovement in many of the patients, but often required\nhigh doses [2,16,22]. However, due to the increased risk\nof endometrial carcinoma with unopposed conjugated\nestrogens, this treatment is not commonly used today\n[39].\nVarious other therapy modalities are currently used in\nAPD, and there is no clear treatment of choice. GnRH ago-\nnists, such as buserelin and triptorelin, have been used to\n\nClinical and Molecular Allergy 2004, 2:10 http://www.clinicalmolecularallergy.com/content/2/1/10\nPage 4 of 5\n(page number not for citation purposes)\ninduce remission of symptoms by causing ovarian sup-\npression [7,11,15]. However, side effects include symp-\ntoms of estrogen deficiency (hot flashes, vaginal dryness,\ndecreased bone mineral density), and estrogen supple-\nmentation may be needed [40]. Alkaylated steroids such\nas stanozol have been used to successfully suppress ovula-\ntion, sometimes in combination with chronic low doses\nof corticosteroids [37]. Side effects of alkaylated steroids\ninclude abnormal facial or body hair growth, hepatic dys-\nfunction, and mood disorders, any of which may limit\ntheir use. To decrease the risk of side effects, some authors\nhave recommended using the alkaylated steroid only in\nthe perimenstrual period [37]. Another therapeutic\noption used in APD has been the antiestrogen tamoxifen,\nwhich also can suppress ovulation [3,5]. As with GnRH\nagonists, patients on tamoxifen may experience symp-\ntoms of estrogen deficiency. In addition, tamoxifen has\nbeen associated with an increased risk of venous throm-\nbosis and cataract formation. In some patients with unre-\nmitting symptoms of APD, bilateral oopherectomy has\nbeen required [10,15,24]. While this definitive treatment\nhas been successful in controlling symptoms, today it is\nrarely used before all medical options have been\nexhausted.\nConclusion\nAutoimmune progesterone dermatitis is a condition seen\nin a small number of women who present with eczema,\nerythema multiforme, stomatitis, papulopustular lesions,\nfolliculitis, angioedema, urticaria, and other skin manifes-\ntations in relation to the menstrual cycle. It is usually seen\n3–10 days prior to the onset of menstrual flow, but may\nbe difficult to recognize in women with irregular menses.\nThe exact pathogenesis is unknown, and is thought to\ninvolve a hypersensitivity reaction to progesterone. The\ndiagnosis of APD is made by an appropriate clinical his-\ntory accompanied by an intradermal injection test with\nprogesterone. Current treatment modalities often attempt\nto inhibit the secretion of endogenous progesterone, but\nmay be unsuccessful. More research is needed into the\npathogenesis of APD to most appropriately care for these\npatients.\nReferences\n1. Jones WN, Gordon VH: Auto-immune progesterone eczema.\nAn endogenous progeste rone hypersensitivity. Arch Dermatol\n1969, 99:57-59.\n2. Wojnarowska F, Greaves MW, Pe achey RD, Drury PL, Besser GM:\nProgesterone-induced erythema multiforme.  J R Soc Med\n1985, 78:407-408.\n3. Stephens CJ, Wojnarowska FT, Wilkinson JD: Autoimmune pro-\ngesterone dermatitis responding to Tamoxifen. Br J Dermatol\n1989, 121:135-137.\n4. Stone J, Downham T: Autoimmune progesterone dermatitis.\nInt J Dermatol 1981, 20:50-51.\n5. Moghadam BK, Hers ini S, Barker BF: Autoimmune progesterone\ndermatitis and stomatitis.  Oral Surg Oral Med Oral Pathol Oral\nRadiol Endod 1998, 85:537-541.\n6. Wilkinson SM, Beck  MH, Kingston TP: Progesterone-induced\nurticaria--need it be autoimmune?  Br J Dermatol  1995,\n133:792-794.\n7. Yee KC, Cunliffe WJ: Progesterone-induced urticaria: response\nto buserelin. Br J Dermatol 1994, 130:121-123.\nTable 2: Treatment options used in autoimmune progesterone dermatitis\nTreatment Option Advantages Disadvantages\nOral Contraceptives (OCPs) - Usually trie d as initial therapy - Limited success due to the progesterone component \nof OCPs\n- Fewer side effects than other most other therapies\nAntihistamines - Well tolerated, few side effects - Rarely effective as monotherapy\n- Does not address underlying mechanism\nConjugated Estrogens - Avoids progesterone component of OCPs - Increased risk of endometrial cancer, not commonly \nused today\n- Often require high doses\nGlucocorticoids - Able to suppress mu ltiple components of the immune \nsystem\n- Usually not effective alone\n- Can be combined with other therapies - Often require high doses\nGnRH Agonists - Often used if OC Ps and glucocorticoids are not \neffective\n- Can cause symptoms of estrogen deficiency (hot \nflashes, decreased bone mineral density)\nAlkaylated Steroids - Can be combined with low dose ster oids - Can cause symptoms of excess androgens (facial hair, \nhepatic dysfunction, mood disorders)\n- Interferes with gonadal hormone receptors\nTamoxifen - Has been used successf ully in patients unresponsive to \nconjugated estrogen\n- Can cause symptoms of estrogen deficiency\n- Increased risk of venous thrombosis and cataract \nformation\nBilateral oopherectomy - Definitive treatment, used if medical options \nunsuccessful\n- Surgical procedure, associated morbidity\n- Symptoms of estrogen deficiency\n\nPublish with BioMed Central   and  every \nscientist can read your work free of charge\n\"BioMed Central will be the most significant development for \ndisseminating the results of biomedical research in our lifetime.\"\nSir Paul Nurse, Cancer Research UK\nYour research papers will be:\navailable free of charge to the entire biomedical community\npeer reviewed and published immediately upon acceptance\ncited in PubMed and archived on PubMed Central \nyours — you keep the copyright\nSubmit your manuscript here:\nhttp://www.biomedcentral.com/info/publishing_adv.asp\nBioMedcentral\nClinical and Molecular Allergy 2004, 2:10 http://www.clinicalmolecularallergy.com/content/2/1/10\nPage 5 of 5\n(page number not for citation purposes)\n8. 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Acta Derm Venereol 1989, 69:308-310.\n30. Katayama I, Nishioka K: Autoimmune progesterone dermatitis\nwith persistent amenorrhoea. Br J Dermatol 1985, 112:487-491.\n31. Georgouras K: Autoimmune progesterone dermatitis. Australas\nJ dermatol 1981, 12(3):109-112.\n32. Slater JE, Kaliner M: Effects of sex hormones on basophil hista-\nmine release in recurrent idiopathic anaphylaxis. J Allergy Clin\nImmunol 1987, 80:285-290.\n33. Halevy S, Cohen AD, Lunenfeld E, Grossman N: Autoimmune pro-\ngesterone dermatitis manifested as erythema annulare cen-\ntrifugum: Confirmation of progesterone sensitivity by in\nvitro interferon -gamma release.  J Am Acad Dermatol  2002,\n47:311-313.\n34. Mittman RJ, Bernstein DI, Steinberg DR, Enrione M, Bernstein IL:\nProgesterone-responsive ur ticaria and eosinophilia.  J Allergy\nClin Immunol 1989, 84:304-310.\n35. Zondek B, Bromberg YM: Endocrine allergy: allergic sensitivity\nto endogenous hormones. J Allergy 1945, 16:1-16.\n36. Herzberg AJ, Strohmeyer CR, Cirillo-Hyland VA: Autoimmune\nprogesterone dermatitis. J Am Acad Dermatol 1995, 32:333-338.\n37. Brestel EP, Thrush LB: The treatment of glucocorticosteroid-\ndependent chronic urtica ria with stanozolol.  J Allergy Clin\nImmunol 1988, 82:265-269.\n38. Guy WH, Jacob FM, Guy WB: Sex hormone sensitization (cor-\npus luteum). AMA Arch Derm Syphilol 1951, 63:377-378.\n39. Ziel HK, Finkle WD: Increased risk of e ndometrial carcinoma\namong users of conj ugated estrogens.  N Engl J Med  1975,\n293:1167-1170.\n40. Matta WH, Shaw RW, Hesp R, Katz D: Hypogonadism induced by\nluteinising ho rmone releasing hormone agonist analogues:\neffects on bone density in premenopausal women.  Br Med J\n(Clin Res Ed) 1987, 294:1523-1524.\n41. Shahar E, Bergman R, Pollack S: Autoimmune progesterone der-\nmatitis: effective prophylactic treatment with danazol.  Int J\nDermatol 1997, 36:708-711.","source_license":"CC0","license_restricted":false}