Review
Presentation and natural history of progestogen hypersensitivity

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Abstract

Objective

To review the published medical literature on the clinical presentation, risk factors, and natural history of hypersensitivity reactions to progestogens.

Data Sources

Through the use of PubMed, we conducted a review of allergy, dermatology, and obstetric literature for cases and case series of patients with hypersensitivity reactions to exogenous or endogenous progestogens. There are no longitudinal, prospective studies related to progestogen hypersensitivity.

Study Selections

Publications were selected that described cases that were clinically consistent with progesterone hypersensitivity and positive test results or clear symptoms with exposure to progestogens to confirm the diagnosis.

Results

Progestogen hypersensitivity symptoms can be triggered by endogenous progesterone or exogenous progestins used for contraception or fertility treatments. Symptoms are varied and include dermatitis, urticaria, asthma, and anaphylaxis.

Conclusion

Although the medical literature on progestogen hypersensitivity is limited to case reports and small case series, significant heterogeneity exists in clinical presentation among patients.

Introduction

Progestogen hypersensitivity (PH), also referred to as autoimmune progesterone dermatitis, is a rare hypersensitivity reaction to endogenous progesterone and/or synthetic progestins. The presentation of PH is heterogeneous and can start at any time from menarche to menopause in reproductive-aged women. Here we will review progesterone biology, theories of PH pathogenesis, risk factors for PH, clinical presentations of PH, and natural history of PH.

Section snippets

Progesterone Biology

Progesterone is a steroid hormone derived from cholesterol with a wide breadth of metabolic and physiologic functions related to the menstrual cycle, pregnancy, embryogenesis, and lactation.1 In addition to reproductive functions, progesterone also has anti-inflammatory properties and can regulate T-lymphocyte–mediated immune responses.1 During the menstrual cycle, progesterone levels increase immediately before ovulation and peak during the luteal phase at approximately day 21 of a 28-day

Pathogenesis of PH

The pathogenesis of PH is unclear, but given the heterogeneity of clinical manifestations and triggers for PH, multiple mechanisms are likely involved. The term autoimmune progesterone dermatitis, initially used by Shelley and colleagues,5 who first described the syndrome in 1964, was used because the patient described reacted to endogenous progesterone. However, there is limited evidence that this is an autoimmune condition. There is also evidence that PH may start after allergic sensitization

Risk Factors for PH

Although no large-scale epidemiologic studies have conclusively identified risk factors for PH, there are many case reports of patients who have developed PH after being exposed to exogenous progestins used in contraception6, 24 or high-dose progesterone used for in vitro fertilization.17, 25 Given increased use of progestins for contraception, fertility treatment, and hormone replacement therapy, we anticipate that the incidence of PH may increase as women have increased exposures to

Epidemiology

Progestogen-based medications are used by millions of women.26, 27 However, there are fewer than 200 cases of PH in the literature, with the largest case series reporting only 24 cases over the span of 10 years.6 Cases are almost exclusively in women of reproductive age.24 This finding correlates with likely maximal exposure to both endogenous and exogenous progestogens. Although hormone therapy is used in the postmenopausal population, there have been no incident cases reported in this group.

Clinical Presentation

Onset and timing of symptoms are useful components of the medical history for diagnosis of endogenous PH. Cyclical symptoms peak in the luteal phase in the 14 days preceding menses.3, 31 Notably, hypersensitivity to endogenous progesterone may be difficult to establish in patients with irregular menstrual cycles.21 The timing of symptoms in catamenial anaphylaxis and dermatoses differ from PH in that symptoms correlate with the onset of menses not the progesterone surge of the luteal phase.32

Prognosis

Medical management and desensitization are the mainstays of treatment for PH. Untreated symptoms have not been reported to spontaneously remit, other than during pregnancy as described above or at menopause.48 Because there have been no longitudinal prospective studies on patients with PH, the natural history is poorly understood. Symptomatic treatment with antihistamines or topical corticosteroids may be helpful. Omalizumab may represent a treatment option for patients with recurrent urticaria

Conclusion

PH is an underrecognized diagnosis with important implications for women of reproductive age. The underlying pathogenesis of the disease is unknown but is likely multifactorial given the broad range of symptoms patients with PH. The clinical manifestations are heterogeneous and include cutaneous findings, such as dermatitis, urticaria, erythema multiforme, and fixed drug eruption, and other immediate hypersensitivity symptoms, such as bronchospasm or anaphylaxis. Relating timing of the symptoms

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    • Disclosures: The authors have nothing to disclose.

    Funding Sources: Dr Foer is supported by grant T32 AI 7306-31 from the National Institutes of Health (Joshua Boyce, principal investigator).

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    © 2018 American College of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.