Published on 19/03/2015 by admin
Filed under Dermatology
Last modified 22/04/2025
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Arif M. Aslam and Ian Coulson
Evidence Levels: A Double-blind study B Clinical trial ≥ 20 subjects C Clinical trial < 20 subjects D Series ≥ 5 subjects E Anecdotal case reports
Autoimmune progesterone dermatitis is an uncommon cyclical pruritic dermatosis affecting women of childbearing age. The diagnosis is suggested by premenstrual flares and improvement during pregnancy. It can present in a variety of morphologies including eczematous, vesicular, and papulovesicular, with urticarial and erythema multiforme-like lesions the commonest. Angioedema or anaphylaxis may accompany the skin eruptions. Hypersensitivity following exposure to exogenous progesterone, usually in the form of an oral contraceptive pill, has been implicated in some cases of autoimmune progesterone dermatitis. Endogenous progesterone may also serve as a trigger for autoimmune progesterone dermatitis in cases arising during menarche or pregnancy. The diagnosis is one of exclusion and is based upon the occurrence of cyclical premenstrual flares, the response to inhibition of ovulation, and the results of intradermal testing and hormone challenge.
The mainstay of treatment is to inhibit endogenous progesterone secretion by suppressing ovulation. Classically, conjugated estrogens 0.625–1.25 mg daily in a 21-day cycle was a mainstay of therapy, but recently this treatment has been supplanted by gonadotropin-releasing hormone (GnRH) agonists. A transient worsening of the skin eruption is expected following initial treatment with GnRH agonists, with improvement thereafter. A major side effect of GnRH agonists is loss of bone density, which generally limits their use to 6 months of therapy. Patients frequently require estrogen replacement while on GnRH agonist therapy.
The antiestrogen tamoxifen, 20 mg daily or 10 mg twice a day, exerts its effect by interfering with clinical estrogen sensitivity, possibly by competitive binding of the estrogen receptors.
Oral contraceptive pills have been implicated in triggering some cases of autoimmune progesterone dermatitis. However, in patients naïve to exogenous progesterone, inducing anovulation with oral contraceptive pills may be successful.
Mild cases of autoimmune progesterone dermatitis may be controlled with short courses of systemic corticosteroids prior to the luteal phase of the menstrual cycle. Very limited disease may respond to potent topical corticosteroids and oral antihistamines.
Danazol 200 mg twice daily for 1 to 2 days prior to menses and continued for 3 days thereafter may prevent the skin eruptions by inhibiting pituitary gonadotropins.
For severe, intractable cases, bilateral oophorectomy is curative.
Autoimmune estrogen dermatitis is a separate entity that can be difficult to distinguish clinically from autoimmune progesterone dermatitis. Intradermal testing that is positive to estrone and negative to progesterone clarifies the diagnosis. Autoimmune estrogen dermatitis responds to tamoxifen, progesterone, and oophorectomy.
Intradermal testing with progesterone
Progesterone challenge
ELISA and ELISpot testing
Different authors have advocated intradermal testing with progesterone in varying amounts and dilutions. One common method of intradermal testing is with 0.1 mL of aqueous progesterone suspension at 100 mg/mL diluted with normal saline to 0.1 mg/mL, 0.01 mg/mL, and 0.001 mg/mL, with normal saline serving as the control. There may be an immediate urticarial reaction within 30 minutes, or a delayed-type hypersensitivity reaction at 24–48 hours.
Progesterone challenge may also be attempted intramuscularly (medroxyprogesterone 10–20 mg) or orally (10 mg) in the first half of the menstrual cycle. Intramuscular skin testing with the depot form of medroxyprogesterone acetate is not advised because of the risk of severe systemic reactions.
ELISA and ELISpot testing can detect elevated levels of IFN-γ-producing peripheral blood mononuclear cells in response to progesterone.
If progesterone testing is negative, consider estrogen sensitivity. Intradermal testing with either estrone (0.1 mL at 1 mg/mL) or conjugated estrogen (0.1 mL of 1, 10, and 100 µg/mL) can be attempted. A positive reaction may be immediate or delayed for several hours, and should persist for more than 24 hours.
The use of a progesterone pessary has recently been proposed as an effective tool in the diagnosis of autoimmune progesterone dermatitis.
Stranahan D, Rausch D, Deng A, Gaspari A. Dermatitis 2006; 17: 39–42.
A case report and a detailed review of the various methods of performing intradermal progesterone testing, highlighting the need for standardization.
Snyder JL, Krishnaswamy G. Ann Allergy Asthma Immunol 2003; 90: 469–77.
A case report and review of the current literature, including a summary table and algorithm for the work-up of cyclical anaphylaxis.
Herzberg AJ, Strohmeyer CR, Cirillio-Hyland VA. J Am Acad Dermatol 1995; 32: 333–8.
A case report accompanied by an excellent review of case reports and current literature.
Cristaudo A, Bordignon V, Palamara F, De Rocco M, Pietravalle M, Picardo M. Clin Exp Dermatol 2007; 32: 439–41.
Describes the ELISpot technique of diagnosing autoimmune progesterone dermatitis.
Kumar A, Georgouras KE. Australas J Dermatol 1999; 40: 96–8.
A case report comparing progesterone dermatitis and estrogen dermatitis, as well as useful information on the technique and interpretation of intradermal testing for both disorders.
Shelley WB, Shelley D, Talanin NY, Santoso-Pham J. J Am Acad Dermatol 1995; 32: 25–31.
An excellent case series and review of estrogen dermatitis, with comparison made to progesterone dermatitis.
Le K, Wood G. Australas J Dermatol 2011; 52: 139–41.
Bandino JP, Thoppil J, Kennedy JS, Hivnor CM. Cutis 2011; 88: 241–3.
A 30-year-old woman, gravida 2, para 1, developed autoimmune progesterone dermatitis 4 days after her third injection of 17-α-hydroxyprogesterone caproate (17P), presenting as an urticarial exanthema. Direct immunofluorescence was negative. The injections were discontinued and lesions resolved within 7 days.
The use of progestational agents, most recently 17P, to reduce preterm labor for patients at risk, may result in more cases of autoimmune progesterone dermatitis being recognized.
Slater JE, Raphael G, Cutler GB, Loriaux DL, Meggs WJ, Kaliner M. Obstet Gynecol 1987; 70: 542–6.
A double-blind, placebo-controlled crossover study of four women with cyclic anaphylaxis associated with progesterone secretion. Two of the subjects experienced dramatic reduction in the severity and number of attacks while receiving an investigational luteinizing hormone-releasing agonist imbzl-D-his6-pro9-NEt-LHRH, 4 µg/kg/day for 4 months. Liaison with a gynecologic endocrinologist may help in the selection of an appropriate GnRH agonist and estrogen combination of therapies.
Baptist AP, Baldwin JL. Clin Mol Allergy 2004; 2: 10.
Successful treatment with nafarelin acetate nasal spray, 200 µg twice daily.
Cocuroccia B, Gisondi P, Gubinelli E, Girolomoni G. Gynecol Endocrinol 2006; 22: 54–6.
Treatment with tamoxifen 20 mg daily produced complete and durable clearing of the eruption after 3 months.
Kakarla N, Zurawin RK. J Pediatr Adolesc Gynecol 2006; 19: 125–9.
A case report describing a patient with no prior exogenous hormone exposure who cleared on oral contraceptive therapy. For patients naïve to exogenous progesterone, an oral contraceptive pill is considered to be first-line therapy (the preparation used contained 30 µg of ethinyl estradiol and 0.15 mg of levonorgestrel).
Anderson RH. Cutis 1984; 33: 490–1.
A case successfully treated with prednisolone 20 mg/day for 10 days during menstruation. The dosage of prednisolone was reduced slowly over several cycles and the patient was eventually managed on topical corticosteroids only.
Jenkins J, Geng A, Robinson-Bostom L. J Am Acad Dermatol 2008; 58: 353–5.
Oral contraceptives and gonadotropin-releasing hormone agonists were contraindicated in this patient undergoing treatment for infertility. The limited disease was well controlled with halobetasol propionate 0.05% cream.
Walling HW, Scupham RK. Int Soc Dermatol 2008; 47: 380–2.
Durable improvement on cetirizine 10 mg every morning and hydroxyzine 10 mg at bedtime taken on the days of the menstrual cycle previously associated with skin eruptions.
Bemanian MH, Gharagozlu M, Farashahi MH, Nabavi M, Shirkhoda Z. Iran J Allergy Asthma Immunol 2007; 6: 97–9.
A case report of a patient with perimenstrual urticaria associated with angioedema and respiratory symptoms, all of which improved on conjugated estrogen 0.625 mg once daily.
Shahar E, Bergman R, Pollack S. Int J Dermatol 1997; 36: 708–11.
Successful prophylactic treatment with danazol in two patients at a dose of 200 mg twice daily, starting one to 2 days before menstruation and continuing for 3 days thereafter.
Warin AP. Clin Exp Dermatol 2001; 26: 107–8.
Successful treatment with azathioprine 100 mg daily.
Medeiros S, Rodrigues-Alves R, Costa M, Afonso A, Rodrigues A, Cardosa J. Clin Exp Dermatol 2010; 35: e12–13.
Bilateral oophorectomy was curative in this case of autoimmune progesterone dermatitis that was unresponsive to oral corticosteroids and GnRH agonist.
Treatment of Skin Disease Comprehensive Therapeutic Strategies 4e
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Gonadotropin-releasing hormone agonists
Tamoxifen
Oral contraceptive pill
Oral corticosteroids
Potent topical corticosteroids
Antihistamines
Conjugated estrogens
Danazol
Azathioprine
Bilateral oophorectomy
