Are You Confident of the Diagnosis?

Autoimmune progesterone dermatitis (APD) is an uncommon disease characterized by the appearance of a cyclic rash that develops premenstrually. It is considered a hypersensitivity reaction to either endogenous or exogenous progesterone and has a variable cutaneous presentation. Shelley et al are credited with the first description of APD in an article in which they report on a 27-year-old woman with a cyclic pruritic vesicular eruption.

  • Characteristic findings on physical examination

The morphology of cutaneous lesions of APD may include urticarial papules and plaques, a vesicobullous eruption, mucosal lesions, eczematous dermatitis, erythema multiforme-like lesions, a gyrate erythema and a fixed drug eruption. The lesions are generally pruritic and may be painful. When urticarial lesions predominate, they may be generalized and there have been reports of laryngospasm and anaphylactoid reactions as well.

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  • Expected results of diagnostic studies

There is no pathognomonic histopathology but rather it varies with the clinical presentation, ranging from nonspecific to consistent with hypersensitivity dermatitis, erythema multiforme, or lichen simplex chronicus.

  • Diagnosis confirmation

The criteria for the diagnosis of APD includes:

  • Cyclic cutaneous lesions related to the menstrual cycle

  • A positive progesterone skin test or a positive oral/intramuscular challenge to progesterone

  • Demonstration of a circulating antibody to the progesterone or basophil degranulation tests

Criteria 2 and 3 refer to testing to document the suspected hypersensitivity to progesterone. The more common test is the intradermal progesterone challenge in which 0.01mL of aqueous progesterone suspension (50mg/mL) is injected intradermally. A positive reaction may be immediate (within 30 minutes) or delayed (24-96 hr). Due to the unavailability of progesterone in an aqueous solution in Hungary, investigators there used intravaginal progesterone to provoke a flare in order to confirm the diagnosis in one patient.

Autoimmune estrogen dermatitis was first described in 1995 in seven women who had cyclical exacerbations of papulovesicular lesions, urticaria, eczema, or generalized pruritus. As in autoimmune progesterone dermatitis, the clinical presentation is varied and the histologic findings are nonspecific. However, as in APD, it usually presents as a cyclic cutaneous disorder that may be urticarial, eczematous, papular or bullous and is usually characterized by pruritus. The histology usually correlates with the individual’s clinical presentation, so that patients with eczematous eruptions show a spongiotic dermatitis and those with lesions mimicking erythema multiforme show histologic findings consistent with EM.

Who is at Risk for Developing this Disease?

APD usually occurs in adult women after menarche and rarely has been reported in pregnancy or the postmenopausal period. The majority of women affected by APD report a history of exposure to exogenous progesterone, such as in oral contraceptives (OCPs). There are also reports of APD occurring during infertility treatment.

Because the treatment course in infertility may require multiple injections given at defined intervals, one must be aware of the possible progression in severity of the cutaneous reaction with subsequent injections (personal communication). In these cases, the use of injectable progesterone may need to be abandoned or pre-treatment with corticosteroids may be considered.

As one would expect, estrogen dermatitis also occurs in women; given the limited number of case reports, there is no known exact incidence for this disease. Given its varied clinical presentation and lack of pathognomonic histology, it is likely that it often goes undiagnosed.

What is the Cause of the Disease?

  • Etiology

  • Pathophysiology

Autoimmune progesterone dermatitis is an uncommon disease characterized by exacerbations during the luteal phase of the menstrual cycle. The luteal phase is the second half of the menstrual cycle triggered by a surge of luteinizing hormone (LH), which induces the ovum to mature and be released. The luteal phase is characterized by the high levels of progesterone being produced by the corpus luteum, the solid body formed in an ovary after the egg has been released by the ovary into the fallopian tube.

Progesterone plays a key role in preparing the endometrium for implantation of the blastocyst and support of the early pregnancy. Progesterone also causes an increase in the woman’s basal body temperature that can be used as a tool to enhance the likelihood of conception.

Similarly, it is believed that autoimmune estrogen dermatitis is essentially a hypersensitivity to circulating estrogen either endogenous or exogenous.

Systemic Implications and Complications

In general, there are no systemic symptoms or complications associated with APD or AED other than symptoms such as pruritus, pain of dyspigmentation with the cutaneous eruption. Patients with autoimmune progesterone dermatitis may develop reactions to progesterone used in infertility treatments; cases of anaphylaxis have been reported, as well as the use of progesterone desensitization to achieve viable pregnancies.

There is a report of a patient who developed APD during two separate pregnancies, both of which ended with a spontaneous abortion in the first trimester; the significance of this finding is unknown.

Treatment Options

Although mild flares of APD may respond to topical steroid and oral antihistamine therapy, definitive treatment of APD is aimed at the suppression of secretion of progesterone by inhibiting ovulation. Various agents have been tried with success:


Systemic glucocorticoids may be used to control the cutaneous lesions and symptoms of APD but with varying success. The long-term side effects of steroids limit their usefulness. There is no standard dosing regimen for the use of prednisone. Systemic glucocorticoids in high doses have been reported to control the lesions in some – but not all – studies. Another author has reported the use of prednisolone at a dose of 40mg daily during menstruation to successfully control symptoms.

Oral contraceptives (OCPs) may be used to suppress ovulation. Side effects include the increased risk of deep venous thrombosis, especially in women over 40 years old and smokers.

Danazol, an anabolic steroid, the later generation stanozolol have been reported to be helpful, but treatment may be complicated by elevation of liver function tests and masculinization. In attempt to avoid these side effects, danazol may be used prophylactically. In one case report, two patients were treated successfully with danazol in a dose of 200mg twice daily, starting 1-2 days before the expected date of each menses and continuing for 3 days thereafter.

Different gonadotropin-releasing hormone (GnRH / LH-RH) agonists, such as leuprorelin and buserelin, have also been used to induce remission by causing ovarian suppression. Side effects include symptoms of estrogen deficiency such as hot flashes, vaginal dryness, and decreased bone mineral density. The negative aspects of GnRH therapy include the need for estrogen supplementation to counteract the side effects as well as the expense. Additionally, an oral progesterone add-back challenge may be performed after treatment with a GnRH agonist to confirm the diagnosis.

Tamoxifen, a nonsteroidal antiestrogen drug, suppresses ovulation and the postovulation rise in endogenous progesterone levels. It has also been used to induce remission of APD, but side effects include amenorrhea, decreased bone mineral density, increase risk of deep vein thrombosis and cataract formation.

Conjugated estrogens also suppress ovulation but the high doses required are associated with an increased risk of endometrial carcinoma and are, therefore, not used today.


There are several reports of the successful use of oophorectomy as the treatment of intractable APD. Given the invasive nature and implications for childbearing, any surgical option would need to be considered after medical therapy options were exhausted and childbearing is complete.


APD has also been reported to resolve without treatment and during pregnancy.

The treatment of autoimmune estrogen dermatitis is aimed at the suppression of circulating estrogen. This includes:

Elimination of Exogenous Estrogen Therapy

Review of patient’s medication list to identify and eliminate any estrogen

Anti-estrogen therapy

Tamoxifen has been used successfully in several reports to induce remission of the cyclic disease. The mechanism and potential side effects are listed above.

Surgical therapy

Intractable cases may be treated with bilateral oophorectomy.

Optimal Therapeutic Approach for this Disease

For autoimmune progesterone dermatitis:

  • Identify the possibility of APD by a history of the cyclic nature of the recurrent eruptions.

  • Investigate by clinical history the possible source of exogenous progesterone, eg, OCPs.

  • Consider and rule out, if possible, the possibility of other cutaneous eruptions that may flare premenstrually, such as acne, dermatitis herpetiformis, erythema multiforme, lichen planus, and estrogen dermatitis.

  • Perform a intradermal skin test reaction to progesterone with a control subject as well.

  • Once confirmed, initiate therapy to suppress ovulation and therefore inhibit the secretion of endogenous progesterone.

For autoimmune estrogen dermatitis:

  • Identify the possibility of AED by a history of the cyclic nature of the recurrent eruptions.

  • Investigate by clinical history the possible source of exogenous estrogens, such as estrogen replacement therapy.

  • Consider and rule out, if possible, the possibility of other cutaneous eruptions that may flare cyclically such as acne, dermatitis herpetiformis, erythema multiforme, lichen planus and autoimmune progesterone dermatitis.

  • Perform a intradermal skin test reaction to estrogen. A papule lasting longer than 24 hours or an immediate urticarial wheal (in clinical cases with urticaria) is considered a positive reaction. Injections of progesterone should be negative in order to rule out APD. One may also consider a patch test to an estrogen patch eg Estraderm and a prick test with an alcohol solution of estrone. Serum testing for anti-ethinyl-estradiol antibodies may be done but are considered less reliable.

  • Once confirmed, initiate therapy to suppress the secretion of endogenous estrogen is the mainstay – usually the use of Tamoxifen.

Patient Management

Given the variability in terms of the morphology of the cutaneous lesions, as well as the similarity to other common skin conditions such as chronic idiopathic urticaria, erythema multiforme, and other eczematous or urticarial eruptions, patients may have been seen by multiple physicians prior to the diagnoses being considered and confirmed. Understandably, there may be significant frustration on the part of the patient.

Discuss with the patient what is known about APD, specifically that the disease appears to be an autoimmunity toward the patient’s own progesterone. The intradermal skin testing is helpful in both confirming the diagnosis and demonstrating to the patient that progesterone is, in fact, causal in the elicitation of their dermatitis.

Patients should be reassured that, although frustrating in its chronicity and often difficult in terms of its associated potential symptoms, such as pruritus or pain, APD does not have any known association with other systemic diseases such as other autoimmune diseases or malignancy.

Patients should be reassured regarding the benign nature of this condition, its treatability and potential for cure. First-line therapy, provided there are no contraindications, is the use of an oral contraceptive to suppress ovulation. Conjugated estrogen, leuprolide acetate, danazol and tamoxifen may also be effective in some cases. A detailed medical history needs to be taken including tobacco history, risk for thromboses and personal or family history of estrogen-dependent cancers prior to initiating estrogen therapy.

Although reports of success and duration of therapy are anecdotal, several case studies suggest suppression with medical therapy for 6 months may lead to prolonged remission; others have shown exacerbation of disease with cessation of therapy.

In discussing AED with patients, the conversation would be similar in terms of discussion of the autoimmune etiology, in this case to estrogen, as well as to its benign, albeit frustrating, nature. Again the patient should be reassured by the reports of successful treatment and, in some cases, remission.

Unusual Clinical Scenarios to Consider in Patient Management

There may be many women who suffer from APD/AED and not realize it. There are no support groups for patients suffering from these conditions.