Progestogen hypersensitivity

Abstract

Progestogen hypersensitivity (PH) is a heterogeneous disease characterized by diverse cutaneous manifestations, bronchospasm, and/or anaphylaxis. Possible triggers include ovarian progesterone and exogenous progestogens. The timing of symptoms is critical to diagnose PH: during the luteal phase of the menstrual cycle for the endogenous form and after exposure to progestins for exogenous PH. Diagnostic modalities, such as progesterone skin testing, have low sensitivity and specificity for PH. If exogenous PH is suspected, the allergist should consider a progestogen challenge. Treatment strategies should be tailored for each patient, including symptom-directed therapies, ovulation suppression, and progesterone desensitization. Future studies should explore the mechanisms of PH, validation of diagnostic criteria, and standardization of treatment strategies.

Introduction

Almost a century ago, Bernhard Zondek and Y. M. Bromberg first published their studies investigating an “allergic sensitivity to endogenous hormones” and proposed the name “endocrine allergy” to define this condition (1, 2). Subsequently, the term “autoimmune progesterone dermatitis” was coined to describe the cutaneous and mucosal manifestations associated with an increase in progesterone during the luteal phase of the menstrual cycle (3). “Autoimmune progesterone dermatitis” is a misnomer as, in most cases, there is no evidence of autoimmunity. Furthermore, it does not encompass the non-dermatological manifestations of the disease, such as bronchospasm and anaphylaxis. More recently, the term “progestogen hypersensitivity” (PH) was proposed to accurately include all the different hypersensitivity mechanisms involved in the disease. In addition, the term progestogen encompasses the entire class of hormones that bind to the progesterone receptor, including endogenous progesterones and synthetic progestins (Table 1) (4).

Table 1.

Selected terminology used in the management of progestogen hypersensitivity.

Terminology	Definitions
Progestogen	Class of steroid hormones that bind to the progesterone receptor, umbrella term that encompasses both progesterone and progestins.
Progesterone	Endogenous steroid hormone or an exogenous form of the hormone originating from soy, yam or animal sources
Progestin	Synthetic progestogen preparations commonly used in oral contraceptives that may have different pharmacologic properties based on the compound source from which they are modified. Examples include 21-carbon compound derivatives (medroxyprogesterone acetate, megestrol acetate, nomegestrol) and 19-nortestosterone compounds (norethindrone, norethindrone acetate, levonorgestrel).

The prevalence and incidence of PH are unknown, but it is considered a rare disease. The hallmarks of PH include a flare during the second half of the menstrual cycle (luteal phase) and improvement in symptoms with the onset of menses and with inhibition of ovulation. Other clinical and laboratory characteristics are highly heterogeneous, which may contribute to the underdiagnosis or misdiagnosis of PH. However, allergists and dermatologists should be familiar with the broad spectrum of this disease, especially given the significant impact on the patients’ quality of life and fertility. Furthermore, the need to recognize and treat PH will only increase in the coming decades as infertility continues to affect individuals (5).

Here we review hypotheses regarding PH pathogenesis, key clinical and laboratory findings, and diagnostic and therapeutic options for disease management. Given the limited research in this area, this review cites many case reports and small case series and draws on the expert consensus opinion of the authors.

Pathogenesis

Studies that directly explore the mechanisms involved in PH are scant. Most of the hypotheses proposed for the pathogenesis of PH (Figure 1) have been inferred by examining the existing epidemiological, clinical, and laboratory data of women affected by this condition. For example, PH has not been reported in postmenopausal women receiving progestins as part of hormone replacement therapy. This observation suggests that progestogen exposure is required but not sufficient for developing PH. Therefore, a multiple-hit hypothesis may be most plausible. Epidemiological data shows that, on average, PH first manifests during a woman’s peak reproductive years (4, 6), suggesting there might be a progestogen dose-response effect. This effect is further supported by the relative lack of PH cases in men (7), even though serum progesterone levels in men are similar to those in postmenopausal women (8).

Figure 1.

Mechanisms contributing to the pathogenesis of progestogen hypersensitivity include: (A) Type I (immediate); (B) type III (immune complex); and (C) type IV (cell-mediated or delayed) hypersensitivity reactions.

The hormonal milieu present in women during the peak reproductive years may significantly contribute to the development of PH. A detailed description of the varied effects of female sex hormones on the immune system is beyond the scope of this review but has been described elsewhere (9, 10). Most relevant to the pathogenesis of PH, estrogen promotes the differentiation of dendritic cells and the production of T helper 2 (Th2) cytokines (11, 12). In addition, estrogen inhibits B cell apoptosis and tolerance induction of naïve B cells (13, 14). These mechanisms drive a Th2-prone environment in women of reproductive age, which may contribute to progestogen sensitization and progestogen-specific immunoglobulin E (IgE) production. Evidence for a genetic predisposition to PH is lacking (15).

Notably, in 58% of women with PH, the initial symptoms are triggered by an exogenous progestogen (4). These exogenous progestogen triggers include synthetic progestins used for oral and intrauterine contraceptive methods and progesterone used for in vitro fertilization treatment. The widespread use of such exogenous progestogens is likely contributing to the higher number of PH cases being reported. The difference in allergenicity of an acute exogenous progestogen exposure, in contrast to a cyclic endogenous exposure, remains an area of active investigation.

Clinical and laboratory data also provide clues to the underlying mechanisms of PH. Some of the most common clinical findings of PH include cyclical urticaria, angioedema, and anaphylaxis, suggesting a mechanistic role for immediate hypersensitivity. The utility of progesterone skin testing is questionable, as 50% of patients with PH have a positive result (4). Ghosh and colleagues reported that 6 out of 17 patients with suspected PH had high progesterone-specific IgE levels (16). Overall, these findings highlight the contributions of progestogen-specific IgE production and progestogen-induced mast cell degranulation to the pathogenesis of PH.

Other dermatological manifestations, such as maculopapular rashes, plaques, and vesiculobullous lesions, suggest that progestogen-induced type IV (cell-mediated) hypersensitivity reactions may contribute to some forms of PH. In one published case, a Stevens-Johnson syndrome-type rash recurred during the luteal phase of the menstrual cycle and resolved after bilateral oophorectomy, pointing to cell-mediated response pathways (17). Several other cases describing delayed reactions to progesterone skin testing provide additional evidence for T cell activation as a possible mechanism (15, 18, 19). Interestingly, peripheral blood mononuclear cells (PBMCs) of patients with PH that were exposed to progesterone had a higher release of IFN-γ compared to the PBMCs from healthy controls (20). These results indicate that T helper 1 (Th1) responses might also contribute to the pathogenesis of PH. Other reports suggest that the immune responses involved in PH might be dynamic, as exemplified by a case of PH that initially presented with anaphylaxis (Th2) and later developed a fixed drug eruption-like rash (Th1) (21). Finally, a type III hypersensitivity reaction or immune complex disease has also been implicated in PH. This is supported by the report of a PH patient with circulating 17-hydroxyprogesterone-binding IgG (22).

Current epidemiological, clinical, and laboratory data support a multiple-hit hypothesis for the development of PH. Future studies are warranted to directly examine the mechanisms involved in the pathogenesis of this disease. These investigations should focus on (1) the cellular processes and signaling components of the various hypersensitivity reactions associated with PH, (2) tolerance mechanisms to progestogens in unaffected women and men, (3) the Th2-prone environment during women’s peak reproductive years, (4) the allergenicity of progestogens and their metabolites, and (5) the presence of possible adjuvants in exogenous progestogens. A better understanding of the pathogenesis of PH will enable investigators to develop more effective interventions for prevention and treatment.

Clinical manifestations

PH presents with heterogeneous manifestations of either immediate or delayed hypersensitivity (Figure 2). Cutaneous manifestations are common: dermatitis and urticaria are most frequently reported, but other reported dermatologic manifestations include angioedema, fixed drug eruption, bullous lesions, erythema multiforme, and Stevens-Johnson-like syndrome (3, 17, 21, 23–31). Multiple cutaneous manifestations have been reported in the same patient (32). Non-cutaneous symptoms, including bronchospasm and anaphylaxis, have also been reported in women with PH (4, 21, 33, 34), and may co-exist with cutaneous manifestations.

Figure 2.

The (A) timing and (B) clinical manifestations of progestogen hypersensitivity.

The timing of progestogen exposure, either endogenous or exogenous, in relationship to symptoms is a critical component of the clinical history. For patients with PH triggered by endogenous, ovarian progesterone, the clinical symptoms present during the luteal phase of the menstrual cycle at the time progesterone levels peak, usually 3 – 10 days prior to the start of menses. The clinical presentation of PH in women with polycystic ovarian syndrome and other menstrual cycle irregularities is limited to case reports (34). In such presentations, it is expected that symptoms would occur in the 3 – 10 days prior to the onset of menses when progesterone concentration is highest; however, more research is needed to understand the timing of PH symptoms in women with irregular menstrual cycles. Patients with endogenous PH may tolerate exogenous progestogens, such as progestins in oral contraceptive pills (OCPs). In contrast, for women with symptoms triggered by exogenous progestins, symptoms temporally correlate with exogenous progestin treatment for contraception or as part of fertility treatments (4). Patients with exogenous PH may have symptoms with one specific progestogen, but able to tolerate others (e.g., symptoms to a specific progestin, but able to tolerate other progestins or progesterone).

In the authors’ experience, PH should be carefully differentiated from typical premenstrual symptoms, including bloating, abdominal cramps, mood changes, and fatigue secondary to premenstrual syndrome or premenstrual dysphoric disorder (35, 36). Isolated GI symptoms or mood changes are not consistent with PH. The differential diagnosis is discussed in detail below.

Endogenous PH in relation to pregnancy is not well-studied. PH may start during pregnancy though symptoms should be carefully distinguished from other pregnancy-related symptoms. It is hypothesized that intrapartum rising progesterone levels may trigger symptoms. For some patients, PH symptoms resolve following pregnancy, while for other women symptoms persist after delivery (19, 37, 38). For women with PH pre-pregnancy, symptoms may improve during pregnancy, possibly due to auto-desensitization in the setting of gradually rising levels of progesterone (39, 40).

Approaches to diagnosis

Proposed criteria

The diagnosis of PH is primarily based on a clinical history integrating progestogen exposure, symptoms, and timing (Table 2). In the authors’ experience, the following three criteria are required for diagnosis of PH:

Table 2.

Evaluation of progestogen hypersensitivity history.

Progestogen Allergy History
Initial Visit	Follow Up Visit
Patient age at symptom onset	-
Symptoms	•
Symptom timeline	•
Start and start dates relative to menses	•
Period of no symptoms?	•
Response to treatment, e.g., histamine-targeted	•
Identifiable trigger/onset	•
Exogenous exposures, tolerated vs. not tolerated	•
Prior hives or rashes	New hives or rashes
New medications	•
NSAID use	-
History of NSAID sensitivity	-
History of clots or other contraindications to OCP use	-
History of autoimmune disease	New medical diagnoses
Planning for future pregnancy	•
Review of symptoms	•

1. Symptoms compatible with PH – cutaneous symptoms (i.e., dermatitis, urticaria, vesiculobullous disease, fixed drug eruption) and/or bronchospasm and/or anaphylaxis.

   1. Alternative etiologies for symptoms ruled out (i.e., chronic idiopathic urticaria, uncontrolled atopic dermatitis, medication allergy)

2. Timing consistent with the luteal phase of menstrual cycle or in the setting of exogenous progestin exposure.

3. Response to inhibitors of ovulation.

Classifying the type of progestogen exposure facilitates subsequent approaches to diagnosis and management (4). Endogenous sources of progesterone include menses and pregnancy. Exogenous sources include supplemental progestogens used in oral, injected, or implantable forms commonly used for contraception control or fertility treatment. Patients may present with an initial reaction to an exogenous exposure, with subsequent reactions to endogenous progesterone sources; this is referred to as a “mixed” subtype (Table 3).

Table 3.

Progestogen hypersensitivity classification.

Trigger	Classification	Examples	Consider progestogen challenge?
OCP	Exogenous	Symptoms only with OCP ingestion or injection, or starting post-implantation	Yes
Emergency contraception		Symptoms only with Plan B use	Yes
IVF		Symptoms only with injections, ingestion, or intravaginal use	Yes
Any of the above triggers	Mixed	Symptoms starting with exogenous trigger, but continuing with monthly, pre-menstrual symptoms	Yes
Menses	Endogenous	Cyclical, pre-menstrual symptoms only ending with menstruation	No
Pregnancy		Start of cyclical, pre-menstrual symptoms only following non-IVF pregnancy	No

^*OCP = oral contraceptive pill; IVF = in vitro fertilization

^**Direct or to alternative progestogen

Diagnostic modalities

Skin testing

Progesterone requires a non-aqueous diluent for skin testing preparation. Benzyl alcohol, sesame, olive, and peanut oil have been used. However, current progesterone skin testing protocols are neither sensitive nor specific for PH (41). Diluents may additionally contribute to false positive results. Therefore, a negative result cannot rule out PH in the context of a convincing history, and a positive result should not be used to justify intervention. Based on this, we no longer use progesterone skin testing to make the diagnosis of PH. Progestogen challenge should be considered in all patients where confirmation of a suspected diagnosis is necessary and safe.

Biopsy

In the absence of skin testing, alternative diagnostic modalities can support the consideration of a PH diagnosis. Skin lesion biopsy can help rule out PH mimics as discussed in the section below (Differential diagnosis of PH). As the spectrum of rash in PH varies widely, there is no consensus regarding characteristic pathology for PH. In a review of 39 patients, a histologic finding of a perivascular inflammatory infiltrate was described in 72% of cases; a non-specific inflammatory infiltrate was described in 31% of cases, with eosinophilic and neutrophilic components also reported. Biopsies suggestive of a hypersensitivity reaction should also trigger an evaluation for drug allergy and allergic contact dermatitis culprits (42). Therefore, although biopsy is more invasive than skin testing, it may better inform alternative diagnoses and thus targeted management strategies and should be considered in patients with atypical or recalcitrant symptoms, or with non-respiratory systemic features, including evidence of musculoskeletal, gastrointestinal, and/or renal involvement.

Progestogen Challenges

As with other drugs, a graded challenge can be used to exclude exogenous PH (Table 4) or to inform the selection of an alternative progestogen in the context of a prior positive response or strong history (3, 31). The same principles and contraindications applied to graded challenges for suspect drugs apply to progestogens including that they should be performed by an allergy expert, in an environment equipped to manage allergic reactions, and without pre-medications. While not studied in the context of PH, a placebo-controlled challenge may be useful in complex cases.

Table 4.

Progestogen challenge protocols.

Progestogen Type	Example	Observation time
Intravaginal progesterone	Crinone gel (vaginal progesterone)
	50% of applicator	Observe 30 minutes
	50% of applicator	Observe 1 hour
Oral progestin	Loestrin* combination oral contraceptive pill
	10%	Observe 30 minutes
	90%	Observe 1 hour

^*Progesterone component: norethindrone acetate 1mg (combined with ethinyl estradiol 10mg)

A positive response to one progestin does not exclude all progestins; however, an alternative progestin should be chosen for the subsequent challenge. Reactions to implantable progestins can be challenged with oral or intravaginal formulations.

Hormonal suppression

Empiric suppression of ovulation with low dose combined oral contraceptives can be considered a diagnostic tool for endogenous PH in patients not actively planning for pregnancy (40, 43). This approach may be useful in cases where the cyclical character of the symptoms is unclear. However, it is less useful in differentiating between other non-hypersensitivity, menses-linked symptoms such as premenstrual syndrome (PMS). Alternative options lacking any progestins include analogues of gonadotropin-releasing hormone (GnRH) or GnRH receptor blockade. Agent selection, management, and patient education regarding risks of use should be conducted in collaboration with the patients’ primary gynecologist, as discussed in the Treatment section below.

Investigational Assays

A case report of PH reported the use of two in vitro investigational assays: 1) Serum specific-progesterone immunoglobulin (Ig)G and IgE and 2) Direct leukocyte histamine release from basophils (16, 34). Currently, in vitro testing for PH is not available. Validated patch testing is also not available (44).

Differential diagnosis of PH

The differential diagnosis of PH is broad. Monthly exposures to medications (drug allergy to NSAIDs or migraine medications for premenstrual symptoms) and personal care products (contact allergy to hair dyes, nail salon, epilation) should be considered in the context of cyclical symptoms. Similarly, exogenous exposures to hormone-based oral contraceptive pills can cause a constellation of symptoms, including fatigue, headache, and vaginal discomfort that resolve with menses (placebo pill week). These symptoms are consistent with off-target effects or intolerances to hormonal contraception and not with exogenous or endogenous PH.

Premenstrual exacerbations of chronic or subacute dermatoses are common PH mimics. Clarifying if the patient is “ever completely clear” of the rash between the onset of menstruation and the onset of the luteal phase can help to differentiate PH from an acute on chronic, or acute on subacute presentation of a non-PH diagnosis (45, 46). Patients do not typically have active symptoms when progesterone is back to baseline levels. Chronic urticaria, with sparse lesions during the month but more active disease pre-menses, may be mistaken for PH, particularly given similar demographics between the two diseases. Mast cell activation syndrome, with positive mediators, may also be considered in the differential.

Other syndromes associated with menses may be mislabeled as PH. These can be differentiated based on a detailed timeline (47). Catamenial syndromes correlate with the onset of menses (48, 49). Estrogen hypersensitivity should proceed the luteal phase and may be bimodal. The proposed pathophysiology of these syndromes is discussed elsewhere (50–52). Perimenstrual asthma presents in patients with preexisting asthma, with noticeable symptoms worsening days -26 to 4 of the menstrual cycle. Concern for possible perimenstrual asthma should be considered when a patient presents with a history of near-fatal asthma. Perimenstrual asthma events in a patient with severe asthma and chronic rhinosinusitis with nasal polyps should trigger an evaluation for undiagnosed aspirin-exacerbated respiratory disease (AERD) (53, 54).

Finally, it can be challenging to distinguish PH from premenstrual syndrome (PMS), a syndrome of physical and behavioral or affective symptoms with its own set of diagnostic criteria, and theories of pathogenesis that are not representative of a hypersensitivity reaction to progesterone.

De-labeling

The variability in PH presentation, and non-specific nature of progesterone skin testing, can result in misdiagnosis of PH. New symptoms or changes in presentation provide an opportunity for the allergist to reevaluate the PH diagnosis. Follow-up visits for PH should repeat many of the same initial history-taking questions (Table 2). Interval medical diagnoses should be recorded as early symptoms may be part of a later-diagnosed, non-PH syndrome. Challenges should be considered for patients with a PH diagnosis, including those with a history of positive skin testing but who have never received a challenge.

Approach to treatment

The approach to the treatment of PH is often multimodal, employing standard-of-care management of symptom-directed therapy and in some cases, therapies directed at suppression of ovulation or desensitization to progesterone (Figure 3). A multi-disciplinary approach with care coordination between allergy, obstetrics/gynecology, reproductive endocrinology, and dermatology is often needed to optimize patient outcomes.

Figure 3:

Progestogen hypersensitivity management decision tree. A goal-based guide for a systematic approach to manage PH based on patients’ preference/expectations, specifically symptom control versus the need for progestogens for fertility treatments. PH = Progestogen hypersensitivity

Standard-of-care treatment of atopic disease

In patients with mild-to-moderate symptoms, it is recommended to start with first-line therapies for the patient’s presenting symptom(s). For example, in some patients with mild cyclical urticaria or pruritus, treatment with second-generation H1 blockers may be sufficiently efficacious for the management of symptoms (32), although the response can be variable (55). Targeting dermatitis, urticaria, or respiratory symptoms with standard-of-care management should not be delayed, even when a diagnosis of PH is suspected.

Oral contraceptives with continuous cycling

In patients who do not respond to standard-of-care allergy treatment, a trial of an oral contraceptive with a constant dose of progesterone administered continuously can ameliorate symptoms in some patients (56). This treatment is hypothesized to work by suppressing the surge of endogenous progesterone that occurs during the luteal phase of the menstrual cycle (57). Combined and progestin-only oral contraceptives can be utilized and generally are prescribed under the supervision of a gynecologist, primary care doctor, or endocrinologist. Oral contraceptives are not recommended for women with a history of anaphylaxis or severe cutaneous reactions and should be avoided in women with a history of exacerbation of symptoms with oral contraceptives. While generally well tolerated by most patients, anaphylaxis to oral contraceptives has been reported (57). In women with mild cutaneous symptoms, we allow patients to start the oral contraceptive pill at home. Alternative approaches should be considered for women who are planning for pregnancy.

Progesterone desensitization

Progesterone desensitization can be utilized for patients with PH to exogenous progestins who require high-dose progesterone for fertility treatments such as in vitro fertilization (4, 26, 39). Both rapid intramuscular (4) (Table E1) and intravaginal (26) protocols have been successful. Coordination of care with the reproductive endocrinologist is necessary to time desensitization with the planned start of high-dose progesterone supplementation. The rapid desensitization protocols should be carried out in centers equipped to treat anaphylaxis.

Desensitization has also been reported to improve uncontrolled symptoms in patients who cannot otherwise tolerate hormonal contraceptives (4, 55, 58). In this setting, a slow (Table E2) or rapid (Table E3) oral desensitization can be employed, which can be initiated at the start of the patient’s menstrual cycle. Like desensitization to other drugs, progesterone desensitization requires continuous exposure to the drug to maintain the desensitized state. Patients must receive clear guidance on taking the medication daily, or they risk re-sensitization. This is particularly important for many combined oral contraceptives, where a week of placebo pills is included in the blister pack.

Omalizumab

Omalizumab has been used to treat urticaria, angioedema, or anaphylaxis in the setting of PH (55, 59). This therapy may be of particular interest to women desiring fertility, given the reassuring omalizumab pregnancy registry findings (60, 61). We do not typically start omalizumab during pregnancy for women with mild PH symptoms; however, there may be cases of severe PH symptoms where the benefits of omalizumab outweigh the risks and should be considered in shared decision-making with the patient. Omalizumab may also be an adjuvant for progesterone desensitization in patients with a history of failed desensitization, as it has been used for other medications (62).

Gonadotropin-releasing hormone (GnRH) agonists, selective estrogen receptor modulators, and oophorectomy

In patients with severe symptoms refractory to first-line symptom management, continuously cycled oral contraceptives, and progesterone desensitization, GnRH agonists and selective estrogen receptor modulators can be considered after all other management options have failed. GnRH agonists such as leuprolide acetate have been used to treat women with refractory PH (33, 34, 43, 58, 63). GnRH agonists cause paradoxical downregulation of the pituitary GnRH receptor, leading to decreased luteinizing hormone (LH) and follicle stimulating hormone (FSH) secretion. This, in turn, suppresses the growth of ovarian follicles and, ultimately ovulation, and is associated with lower circulating progesterone and estrogen levels. In patients where PH is suspected, treatment with GnRH agonists can confirm the diagnosis and be therapeutic.

However, physicians and patients should employ shared decision-making given the significant hypoestrogenic side effects of GnRH agonists, including vasomotor symptoms, insomnia, amenorrhea, decreased libido, vaginitis, and bone loss (64). A gynecologist or reproductive endocrinologist generally supervises the use of GnRH agonists and administration of other hormone replacement such as supplemental estrogen.

Tamoxifen, a selective estrogen receptor modulator, has been reported to successfully treat several cases of PH (31, 65, 66). Like the GnRH agonists, daily tamoxifen use induces amenorrhea and can be associated with significant side effects, including hot flashes, thromboembolic events, and uterine hyperplasia (67, 68).

Lastly, there are case reports and series describing patients who undergo bilateral oophorectomy for treatment of PH (3, 17, 39, 63, 69, 70). Many of these cases pre-date the introduction of newer therapeutic approaches discussed above. This option would be contraindicated for women who desire fertility; for women who have completed childbearing, the procedure has significant morbidity associated with premature menopause and associated symptoms. Of note, women with PH who undergo oophorectomy may not tolerate hormone replacement after PH, typically used to treat post-oophorectomy hypoestrogenism (39).

Prognosis

The natural history of PH is not well defined. In patients who only exhibit symptoms when exposed to exogenous progestins, the symptoms are expected to resolve upon withdrawal of the offending drugs (4). In women with symptoms due to endogenous PH, spontaneous resolution of symptoms has not been reported until patients reach menopause. At menopause symptoms are expected to remit. While it is possible that symptoms could occur in a postmenopausal woman secondary to exogenous progesterone exposure in the setting of hormone replacement therapy, this has not been reported.

Generally, patients do very well with a personalized approach based on their specific goals (i.e., symptom relief, tolerance of high-dose progestins for fertility treatments). There are no validated patient-reported outcome tools to assess PH symptom control to guide treatment escalation or de-escalation. As with other allergic diseases, treatment should be periodically de-escalated to assess for continued necessity. Close care coordination with a multi-disciplinary team is often required to optimize outcomes (26).

Conclusion

Diagnosis, management, and treatment of PH exemplifies the important role that allergists can serve in women’s health. Core allergy tools, such as drug challenges, merit wider use in the diagnosis of PH and may assist in de-labeling as well as avoidance of unnecessary interventions. However, the lack of robust evidence in this area also highlights the need for funding and research for women’s health in allergy and clinical immunology. Future studies should explore the mechanisms of PH, validation of the proposed diagnostic criteria, and standardization of treatment strategies.