What are the symptoms, signs, diagnosis, management, and treatment of progesterone autoimmune urticaria, a subclinical type of chronic autoimmune urticaria (CAU) or chronic spontaneous urticaria (CSU)?

Progesterone Autoimmune Urticaria: Symptoms, Diagnosis, and Treatment

Progesterone autoimmune urticaria, also known as autoimmune progesterone dermatitis (APD) or progestogen hypersensitivity (PH), is best treated with ovulation-suppressing therapies such as continuous combined oral contraceptives, with second-line options including GnRH agonists, omalizumab, or progesterone desensitization. 1, 2, 3

Clinical Presentation

Symptoms and Signs

• Cyclic cutaneous eruptions that occur during the luteal phase of the menstrual cycle (typically 7-10 days before menses)
• Most common presentation is urticaria (seen in approximately 70% of adolescent cases) 2
• Other manifestations include:
  • Angioedema
  • Eczematous eruptions
  • Fixed drug eruption-like lesions
  • Erythema multiforme
  • Vesiculobullous eruptions
  • Recurrent aphthous stomatitis
  • In severe cases, anaphylaxis 4, 3

Timing and Triggers

• Symptoms typically worsen during the luteal phase when progesterone levels peak
• May first appear after:
  • Menarche
  • Pregnancy (14.6% of cases)
  • Hormone therapy (8.9% of cases) 1
• Approximately 45% of patients have history of exposure to exogenous progesterone 1

Diagnosis

The diagnosis of progesterone autoimmune urticaria follows a systematic approach:

1. Clinical history:

   • Document cyclical nature of symptoms in relation to menstrual cycle
   • Establish temporal relationship with progesterone fluctuations
   • Evaluate for previous exposure to exogenous progestins

2. Diagnostic testing:

   • Intradermal progesterone sensitivity test (gold standard)
     • Injection of aqueous progesterone (0.01 mg) intradermally
     • Positive reaction includes wheal, flare, or reproduction of symptoms 1, 4
   • Consider basic tests as recommended for chronic spontaneous urticaria:
     • Differential blood count
     • C-reactive protein/ESR
     • Total IgE levels 5

3. Exclusion of differential diagnoses:

   • Other forms of chronic urticaria
   • Dermatitis herpetiformis
   • Systemic lupus erythematosus
   • Other allergic reactions

Management and Treatment

First-Line Treatment

• Combined oral contraceptives (COCs):
  • Preferably used in continuous daily dosing regimen to suppress ovulation
  • Effectively reduces endogenous progesterone production
  • Successful in controlling symptoms in most cases 2, 3
  • Consider as initial therapy for most patients

Second-Line Options

• Gonadotropin-releasing hormone agonists (GnRHa):

  • Suppresses ovarian function and progesterone production
  • Effective when COCs fail or are contraindicated
  • Limited by potential side effects (bone loss, menopausal symptoms) 2

• Antihistamines:

  • Second-generation H1-antihistamines (fexofenadine, cetirizine, loratadine)
  • May need up to 4 times standard dose as per urticaria guidelines
  • Often provides only partial relief in progesterone-related urticaria 6

• Progesterone desensitization:

  • Involves gradual exposure to increasing doses of progesterone
  • Can be effective for long-term management
  • Requires specialized protocols and monitoring 2, 4

• Omalizumab:

  • Anti-IgE monoclonal antibody
  • Standard dosing: 300mg every 4 weeks (can be increased to 600mg every 2 weeks)
  • Consider for refractory cases 6, 2

Third-Line/Refractory Cases

• Cyclosporine:

  • Dosage up to 5mg/kg body weight
  • Requires monitoring of blood pressure and renal function
  • Consider for cases resistant to other therapies 5, 6

• Surgical options:

  • Bilateral oophorectomy with or without hysterectomy
  • Reserved for severe, refractory cases
  • Provides definitive treatment but has significant implications 3

Monitoring and Follow-up

• Use validated tools like Urticaria Control Test (UCT) and Urticaria Activity Score (UAS7) to monitor disease control 6
• Consider step-down only after at least 3 consecutive months of complete control
• Gradual reduction of medication (not more than 1 tablet per month for antihistamines) 6
• Regular follow-up to assess treatment response and adjust therapy as needed

Clinical Pitfalls and Considerations

• Significant delay in diagnosis is common (average 13.6 months in adolescents) due to the rarity of the condition 2
• Exogenous exposure to progestins is less common in adolescent cases compared to adults 2
• Antihistamines and systemic corticosteroids frequently fail to provide adequate relief when used alone 3
• The condition may resolve spontaneously after menopause when endogenous progesterone production ceases
• Consider the impact of treatment on fertility when managing women of reproductive age