Progestogen Hypersensitivity: presentation and natural history

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 with positive testing or clear symptoms with exposure to progestogens to confirm the diagnosis.

Results:

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

Conclusions:

While the medical literature of progestogen hypersensitivity is limited to case reports and small case series, there exists significant heterogeneity in clinical presentation between patients.

Introduction:

Progestogen hypersensitivity (PH), also referred to as autoimmune progesterone dermatitis (APD), 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.

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 rise just prior to ovulation and peak during the luteal phase at approximately day 21 of a 28-day menstrual cycle, generally one week prior to the start of menstruation.² Progesterone is initially made by the ovarian corpus luteum and has an important role in facilitating endometrial changes to prepare the uterus for embryo implantation. If implantation does not occur, the corpus luteum will regress and the subsequent drop in progesterone will trigger menstruation.³ If pregnancy does occur, progesterone levels rise throughout the pregnancy, first produced by the corpus luteum, but eventually the placenta will take over as the dominant source of progesterone in pregnancy. During gestation, progesterone contributes to decreased maternal immune responses facilitating pregnancy and other physiologic effects including decreased uterine smooth muscle contractility and inhibition of lactation during pregnancy.¹

Interestingly, mast cells in both humans and mice are known to express progesterone receptors (PRA and PRB). Human mast cell lines treated with physiologic concentrations of progesterone and estradiol had significant release of the main mast cell protease tryptase.⁴ If and how this may contribute to the pathobiology of PH is unknown.

Pathogenesis of progesterone hypersensitivity:

The pathogenesis of PH is unclear, but given the heterogeneity of clinical manifestations and triggers for PH, there are likely multiple mechanisms involved in pathogenesis. The term “autoimmune progesterone dermatitis”, initially used by Shelley and colleagues who first described the syndrome in 1964, was used because the patient described reacted to endogenous progesterone.⁵ However, there is limited evidence that this is an autoimmune condition. There is also evidence that PH may start after allergic sensitization to progestins. Thus the term “progestogen hypersensitivity” was recently proposed as an alternative to APD, as it encompasses hypersensitivity reactions to both endogenous and exogenous progesterone, as well as progestins which are closely structurally related.⁶

Evidence that immediate/Type I hypersensitivity plays a role in PH is supported by the presence of positive skin testing in some patients with PH.^6,7 While positive testing may help support a diagnosis of PH, the positive and negative predictive value of progesterone skin testing is unknown, and not required for a diagnosis of PH. Mast cell and basophil activation seen with functional assays also supports an IgE-mediated immune response in PH.^8,9 There are also reports of delayed reactions to progesterone skin prick or intradermal testing,^10–12 implicating that a delayed, Type IV, cell-mediated mechanism may also be involved in pathogenesis. There is a report of a Stevens-Johnson-like syndrome attributed to PH, which suggests a form of cell-mediated reaction.¹³

There are reports of patients with progesterone-specific immunoglobulin G (IgG) antibodies with immune complex deposition consistent with a Type III reaction in PH.^14,15 One report describes a patient with cyclic oral and perineal rashes during the luteal phase of the menstrual cycle who was found to have circulating immunoglobulin directed against 17-hydroxyprogesterone with an IgG fraction containing a progesterone binding-component.¹⁴ A different report describes a patient with recurrent erythema multiforme during the luteal phase progesterone surge, who was found to have immune complexes following challenge with medroxyprogesterone.¹⁵

PH can present with symptoms consistent with an immediate hypersensitivity reaction as described below in Clinical Manifestations. In these cases, it is unclear how sensitization to progestogen occurs. One theory of allergic sensitization in PH is that exogenous progestins, used for contraception and fertility treatment, may be recognized as foreign by the immune system. Progestogen-specific immunoglobulin E (IgE) antibodies may be formed in susceptible patients following exposure to exogenous progestins. When patients are subsequently exposed to exogenous or endogenous progestogens, they may react due to cross-linking of the IgE antibodies.^6,16 High-dose progesterone used for fertility treatments leading to subsequent development of PH has been described,^17,18 raising the possibility of allergic sensitization to synthetic progestins.

While exogenous progestin exposure may result in PH in some patients, there are multiple reports of patients with PH who were never exposed to exogenous progestins, but instead have only reacted to endogenously produced progesterone during the luteal phase of the menstrual cycle.^19–22 A proposed mechanism to explain this phenomenon is steroid cross-sensitization by steroids with similar structures to progesterone, as patients with hydrocortisone allergy may have cross-sensitization to 17-α-progesterone and symptoms consistent with PH.²³ However, there are many patients with spontaneous development of PH to endogenous progesterone without an obvious trigger for sensitization, in whom a direct effect on progesterone mast cell receptors may play a role.

Risk factors for progestogen hypersensitivity:

While there are no large-scale epidemiologic studies that 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 contraception^6,24 or high-dose progesterone used for in vitro fertilization (IVF).^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 progestins. A proposed classification tool for PH is based on the initial trigger of endogenous progesterone or exogenous progestogens and helps to facilitate diagnosis of PH by focusing attention to exposures and timing of symptoms rather than the symptoms, which can be nonspecific (Table 1).

Table 1:

PH Classification, adapted from Foer et al.⁶

Classification	Trigger	Symptom timing
Endogenous	Menses	Premenstrual symptoms
	Pregnancy	Starts during pregnancy and may persist post-partum
Exogenous	Supplemental progestins for fertility or contraception	Starts following exposure to exogenous progestins
Mixed	Supplemental progestins for fertility or contraception	Starts after exogenous progestin exposure, but persists with premenstrual and/or pregnancy symptoms

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 10 years.⁶ Cases are almost exclusively in women of reproductive age.²⁴ This correlates with likely maximal exposure to both endogenous and exogenous progestogens. While hormone therapy is utilized in the post-menopausal population, there have been no incident cases reported in this group. There is a single case report of rash and skin test positivity to megestrol acetate in a male receiving progestins as an appetite stimulant.²⁸ There are no cases reported in the setting of transgender hormone therapy. The heterogeneity of symptoms, as discussed below, may also lead to delayed or missed diagnoses and underreporting of disease.^29,30

Clinical Presentation:

Onset and timing of symptoms are a useful component 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 While the etiology of catamenial anaphylaxis is not clearly understood, it has been proposed that the symptoms may be triggered by endometrial release of prostaglandins at the onset of menses.^33,34

Pregnancy may trigger,³⁵ exacerbate¹⁵ or mitigate^22,29 PH symptoms. When PH begins during pregnancy, it may or may not resolve following childbirth.^11,35,36 The reason for improvement during pregnancy in some patients is unclear, but it has been proposed that improvement may be due to auto-desensitization as systemic levels of progesterone gradually rise during pregnancy^15,25 or due to reduction in maternal immune responses during pregnancy.³⁷ PH can also start in the postpartum period, which suggests sensitization to high-levels of progesterone during pregnancy.^5,37,38

In contrast, symptoms from exogenous progestogens may correlate temporally with exposure but will not be associated with the luteal phase of the menstrual cycle. Synthetic progestin exposure trigger PH symptoms in patients with PH to both endogenous and exogenous progestogens or in patients who only experience PH symptoms upon exposure to exogenous progestogens.⁶ There are a variety of progestins used for contraception and fertility treatment. PH has been triggered by oral contraceptive pills,^25,39,40 long-acting depot progestin injections,^21,29,32 contraceptive vaginal rings,⁴¹ and progestin-containing intrauterine devices.⁶ High-dose progesterone required to support pregnancy for patients undergoing in vitro fertilization can trigger PH, which can be a limiting factor to achieve a desired pregnancy for patients with infertility.²⁵ A thorough medication history is important in all patients with a suspicion of PH to exclude alternative diagnoses as well as to establish temporality with symptoms.

Symptom heterogeneity is a hallmark of PH and refers to both the type of symptoms across the PH spectrum as well as the reported tendency for symptoms to change over time for a single individual. Symptom type includes cutaneous, respiratory and systemic manifestations.³⁰ Reports of cutaneous symptoms include maculopapular and papulovesicular rashes,^5,37 eczematous dermatitis,^9,25 fixed drug eruption,⁴² petechiae/purpura,⁴³ urticaria and erythema multiforme.³⁹ Mucosal involvement may present with vulvovaginal pruritus,⁴⁴ and stomatitis.^13,45 (Figure 1 Cutaneous manifestations of PH). In 113 patients with reported PH, 102 (90%) had urticaria and/or angioedema, 71 (63%) had dermatitis (including eczema and/or maculopapular eruption), 15 (13%) had vesiculobullous eruptions, 10 (9%) had erythema multiforme, two (2%) had purpura/petechiae, and less than 1% (one patient each) had fixed drug eruption and stomatitis.^{24, 6}

Figure 1A-D.

Cutaneous manifestations of Progestogen Hypersensitivity (PH)

Systemic reactions are less common than cutaneous symptoms, but when present can be severe. Respiratory and vascular involvement ranges from bronchospasm⁶ to anaphylaxis.^7,40,46 Cutaneous symptoms may be concurrently present^22,40,47 or absent. There are no reports of isolated gastrointestinal symptoms (GI), or GI and cutaneous symptoms without respiratory involvement.

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 As there have been no longitudinal prospective studies following 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 or anaphylaxis.^7,49 PH can delay fertility and patient preference regarding conception is an important decision point in PH management. Inducing anovulation is an option for women who do not want to conceive,^21,40,46 but is associated with undesirable long-term sequelae. Oophorectomy has been used in extreme situations and largely prior to the advent of desensitization.^5,19,50 Desensitization has successfully resulted in live births but requires close inter-specialty coordination with allergy, reproductive endocrinology and obstetrics and gynecology to safely target the follicular phase and optimize embryo transfer.^6,17 Desensitization can also be used safely for symptom management in patients who prefer to avoid the adverse effects of long-term steroid or leuprolide use.⁶

Conclusion:

Progestogen hypersensitivity is an under-recognized diagnosis with important implications for women of reproductive age. The underlying pathobiology 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 to endogenous or exogenous progesterone exposure is crucial for recognizing the syndrome. Further study into PH pathobiology, risk factors, and natural history are needed to better understand this complex and poorly understood syndrome.

Key messages:

• Progestogen hypersensitivity is a heterogeneous syndrome with multiple clinical manifestations including dermatitis, urticaria, asthma, and anaphylaxis.

• Progestogen hypersensitivity symptoms can be triggered by ovarian or placental endogenous progesterone or by exogenous progestins used for contraception or fertility treatments.

• The underlying pathobiology of progestogen hypersensitivity is poorly understood, but is likely multifactorial given the variety of triggers and clinical manifestations seen in progestogen hypersensitivity.

• Medical management and desensitization are the mainstays of treatment for Progestogen hypersensitivity particularly for patients interested in fertility and conception.