Progestogen hypersensitivity

INTRODUCTION — Hypersensitivity reactions to progestogens occur in women of reproductive age and can present with a heterogeneous group of cutaneous and/or systemic allergic reactions that correlate temporally with relative peaks in serum progesterone levels. These reactions can be associated with endogenous or exogenous sources of progesterone. This topic will discuss the different types of reactions that have been attributed to progesterone hypersensitivity, what is known about pathogenesis, approaches to diagnosis, and interventions to alleviate symptoms.

TERMINOLOGY — Progesterone is a steroid hormone derived from cholesterol and is the main progestogen in the human body. The term "progestogen" refers to any natural or synthetic form of progesterone. The term "progestin" is specific for synthetic progestogens. Progestins are functionally similar but structurally different from natural progesterone.

A variety of terms have been used in the medical literature to describe hypersensitivity reactions to progestogens, including "autoimmune progesterone dermatitis," "progesterone allergy," and "progesterone hypersensitivity." The most commonly used term is "autoimmune progesterone dermatitis," which was introduced in 1964 [1]. However, dermatitis is just one component in the range of reactions that have been reported, and progestogen hypersensitivity (PH) is not associated with other autoimmune diseases. Thus, the term "progestogen hypersensitivity" was subsequently proposed as a more accurate description of the multiple and varied reactions attributed to various forms of progesterone [2].

EPIDEMIOLOGY — PH predominantly affects women of reproductive age, with an average age of onset in the late 20s among cases described in the literature. There is a single reported case of hypersensitivity in a male patient receiving the progestin, megestrol acetate [3]. PH appears to be rare, with fewer than 200 reported cases, although it may be under-recognized, and there are no published estimates of incidence or prevalence [2,4]. PH has not been reported to develop in postmenopausal women treated with progestins as part of hormone replacement therapy (HRT).

PROGESTERONE BIOLOGY — Progesterone has multiple metabolic and physiologic effects related to the menstrual cycle, embryogenesis, pregnancy, and lactation [5]. In addition to its role in reproduction, progesterone has anti-inflammatory properties and regulates T lymphocyte-mediated immune responses [5].

In the normal menstrual cycle, progesterone is released from the corpus luteum during the luteal phase and contributes to changes in the endometrium that prepare the uterus for implantation (figure 1). Progesterone levels begin to rise 24 to 48 hours prior to ovulation and reach maximum levels on day 20 to 21 of a 28-day cycle [6-8]. If pregnancy does not occur, progesterone levels decrease, resulting in menstruation. (See "Normal menstrual cycle".)

If implantation occurs, progesterone remains elevated and suppresses the maternal immune response to facilitate pregnancy [5]. Increased progesterone during gestation may also contribute to relaxation of uterine smooth muscle contractility and inhibition of lactation. Decreasing progesterone levels are believed to precipitate labor and lactation.

CLINICAL MANIFESTATIONS — Symptoms of PH include both cutaneous and noncutaneous signs and symptoms. Patients typically have either cutaneous or systemic symptoms, although the patient's reaction can evolve over time. In addition, a single patient may have more than one type of cutaneous reaction, such as erythema multiforme and urticaria [9]. Signs and symptoms can vary somewhat from month to month.

Cutaneous manifestations — The cutaneous manifestations of PH may take several forms (picture 1):

●Eczematous dermatitis [10,11]

●Maculopapular rash [12,13]

●Urticaria with or without angioedema [14-19]

●Papules and plaques [12,13]

●Vesiculobullous and vesiculopustular lesions [1,7,13]

●Petechiae and purpura [20,21]

●Fixed drug eruption (picture 2) [22,23]

●Vulvovaginal pruritus [24]

●Stomatitis [25,26]

●Erythema multiforme [27,28]

●Stevens-Johnson like syndrome (SJS) [29,30]

In each of the reports cited above, evidence for PH was provided through either positive progesterone skin testing (ie, epicutaneous and intracutaneous with immediate reading, intracutaneous with delayed reading, or patch testing), a challenge with progesterone that elicited the implicated symptoms, or a clear response to treatment (such as suppression of ovulation or oophorectomy).

Note that cutaneous PH is distinct from irritant reactions to injected progesterone. Progesterone formulated for injection is suspended in various oils (commonly sesame or peanut), and patients can have local reactions to these injections. This would not be considered a form of PH. The irritant effects of the oils also need to be taken into account if skin testing is performed. (See 'Skin testing' below.)

Asthma or anaphylaxis — PH can also present with asthma or anaphylaxis, with or without other cutaneous manifestations [2,17,22,31-34].

●In one detailed report, a 26-year-old woman was started on an estrogen-progestin oral contraceptive (OC) for management of oligomenorrhea and polycystic ovary syndrome and developed facial and lip angioedema, bronchospasm, and hypotension within two days [33]. The OC was discontinued and restarted two weeks later, resulting in a similar reaction, followed by three additional episodes of anaphylaxis of increasing severity while she remained on the OC. Several years later, she developed a maculopapular dermatitis of her face and neck that appeared cyclically with her menstrual cycle.

●In a series of 24 cases, 13 percent had asthma symptoms that were either perimenstrual or induced by an exogenous progestogen [2].

Onset of symptoms — In women exposed only to their endogenous progesterone, PH can begin at any point after menarche, without a clear triggering event. In some patients, cyclical symptoms begin after completion of a normal pregnancy.

For women exposed to exogenous progestogens, symptoms can begin any time after that exposure and can be elicited only by the exogenous source or by both the exogenous progestogen and by their normal cycles.

Timing of symptoms — Symptoms correlate temporally with progestogen exposure and differ with endogenous and exogenous progestogens.

In relation to the menstrual cycle — For women reacting to endogenous progesterone, the cyclical nature of the reactions relative to the menstrual cycle is a key diagnostic feature. Signs and symptoms appear during the peak progesterone levels of the luteal phase, most commonly 3 to 10 days before the onset of menses (figure 1) [2,4]. Symptoms usually resolve after the first few days of menstruation, although they can persist throughout the month. Patterns may be difficult to detect in women with irregular menses [16].

The diagnosis of PH can be challenging to make in women with irregular cycles due to the difficulty in establishing correlations with progesterone surges. Cycles longer than 45 days tend to be anovulatory or oligo-ovulatory. Other causes should be considered in these patients.

In relation to exogenous progestins — In women being treated with exogenous progestins as part of contraception or fertility treatments, there may be no correlation to the underlying menstrual cycle, with symptoms corresponding instead to the administration of the exogenous progestogens.

During pregnancy — During pregnancy, PH can begin intrapartum and may or may not resolve following childbirth [35-37]. There are reports of patients with PH who developed worsening of symptoms during pregnancy as systemic progesterone levels rose [11,27]. Conversely, there are descriptions of patients with PH before pregnancy who improved in the intrapartum period [17,38]. It has been proposed that improvement during pregnancy may be due to either autodesensitization to progesterone as levels gradually rise during pregnancy or an attenuation of maternal immune responses during pregnancy [13]. PH has also been reported to begin during the postpartum period [1,13,39].

THEORIES OF PATHOGENESIS — The heterogeneity of clinical manifestations suggests that multiple mechanisms may be involved and that mechanisms may differ among patients.

Exposure to exogenous progestins or endogenous progesterone — PH is usually reported in patients exposed to exogenous progestogens. Less commonly, the only known exposure has been the patient's own endogenous progesterone.

●Common sources of exogenous progestins include oral contraceptive (OC) pills [7,11,33], long-acting depot progestin preparations (eg, medroxyprogesterone acetate [16,38]), progestin-containing vaginal rings [40], progestin-containing intrauterine devices (IUDs) [2], and vaginal preparations used to support pregnancy [41]. The high-dose progesterone used during in vitro fertilization (IVF) is also associated with PH, and the resulting symptoms can limit the patient's ability to tolerate ongoing fertility treatment [11]. In addition, there are reports of patients with symptoms following emergency contraception [2].

●Endogenous progesterone is produced by the ovarian corpus luteum during the luteal phase of the menstrual cycle [16,42]. During pregnancy, progesterone is produced by the corpus luteum and/or the placenta [43,44]. (See 'Timing of symptoms' above.)

Proposed immunologic mechanisms — Immunologic drug reactions can be classified by mechanism (table 1).

●Some presentations of PH may be type I, immediate hypersensitivity reactions (table 1). Classic mast cell-mediated symptoms include urticaria, angioedema, and anaphylaxis. In this model, progestogen-specific immunoglobulin E (IgE) antibodies are formed, usually following exposure to exogenous progesterone or synthetic progestins used for contraception or hormonal supplementation. Most synthetic progestins are derived from adding or modifying the side chains of 19-nortestosterone, 17-alpha-hydroxyprogesterone, or 17-acetoxyprogesterone, so it is plausible that these compounds are sufficiently different from natural progesterone as to be recognized as foreign by the immune system. When subsequent exposure to a progestogen occurs, patients react due to cross-linking of these IgE antibodies on the surface of mast cell and/or basophils and activation of these cells. This mechanism is consistent with the observation that many cases of PH develop following exposure to the high doses of progesterone used in fertility treatments [2,14,15].

Evidence that immediate hypersensitivity plays a role in some cases of PH is supported by the presence of positive skin testing results to progesterone in some patients [14,34]. (See 'Skin testing' below.)

Evidence of basophil and mast cell activation using functional assays also supports an IgE-mediated immune response [1,10,45]. In patients with immediate-type symptoms suggestive of PH but with negative skin prick testing to progesterone, it has been proposed that progesterone may modulate mast cell and/or basophil reactivity, causing direct hormone-induced mast cell activation and release of bioactive mediators. However, studies evaluating the effect of estrogen and progesterone on basophil histamine release found that neither hormone influenced basophil histamine release. Mast cells have been shown to express receptors for both estradiol and progesterone [46,47]. However, the effect of hormones on mast cells has not been studied directly [48].

●Some forms of PH may result from delayed, cell-mediated (type IV) reactions (table 1). Some cases were supported by delayed reactions to skin prick or intracutaneous testing with progesterone [35,43,49]. (See 'Skin testing' below.)

Patch testing is a form of testing that can provide information about contact allergies. In a study of 19 patients with contact dermatitis to hydrocortisone, 5 of the 19 patients had positive patch testing to 17-alpha-progesterone. The authors posited that cross-sensitization to progesterone resulted from primary sensitization to corticosteroids with similar structures. However, only two of the five patch test-positive patients in this study had symptoms consistent with PH [50]. Furthermore, sensitivity to topical or oral corticosteroids does not seem to be a common finding among patients with PH, and these medications are sometimes used in the treatment of PH.

Severe reactions consistent with cyclical Stevens-Johnson like syndrome (SJS), which have been attributed to PH, are also considered a form of cell-mediated reaction [29]. Testing is generally not performed for SJS like reactions.

●The formation of progesterone-specific immunoglobulin G (IgG) antibodies, with immune complex formation and tissue deposition (a type III immunologic reaction), has also been implicated in PH. In a case report, a patient with cyclical oral and perineal rashes was shown to have circulating IgG directed against 17-hydroxyprogesterone [51]. However, the rate of asymptomatic IgG antibody formation in patients treated with progesterone has not been studied. In another report, a patient with recurrent erythema multiforme during the luteal phase of the menstrual cycle had detectable cutaneous IgG immune complexes following challenge with medroxyprogesterone [27].

Possible risk factors — Epidemiologic studies to conclusively identify risk factors have not been performed, but clinical experience suggests that exposure to exogenous progesterone, particularly in OCs or at high doses used in IVF, is a risk factor for the development of PH [2,4,11,15]. One review of 89 cases found that 45 percent had known prior exposure to exogenous progestogen [4]. However, exogenous progesterone exposure is not always present, and many patients experience symptoms only with endogenous progesterone exposure during menstruation or pregnancy [20,52].

PH is not believed to be a familial disorder, although there is one case report of three sisters with PH, which unfortunately did not provide details about each woman's progesterone exposure [49].

EVALUATION — The evaluation may involve some form of skin testing, depending upon the type of reaction. In addition, there may be situations in which a progesterone challenge is helpful, although these are infrequent.

Referral — If PH is suspected but there is uncertainty about the diagnosis, the patient should be referred to an allergy specialist, if possible. Epicutaneous and intradermal skin testing are sometimes used in the evaluation of suspected immunoglobulin E (IgE)-mediated (type I) hypersensitivity. Skin testing for type I reactions should be performed by an allergist or clinician specifically trained in the safe performance and interpretation of this technique. (See "Overview of skin testing for IgE-mediated allergic disease".)

We also recommend involving an allergist for patients presenting with any type of blistering skin reaction (eg, suspected Stevens-Johnson syndrome [SJS]) for further treatment recommendations. For patients with blistering reactions caused by exogenous progestogens, further exposure may be dangerous and should be avoided until the patient is evaluated further.

Patients with suspected IgE-mediated reactions — Immunoglobulin E (IgE)-mediated reactions involve signs and symptoms suggestive of mast cell-mediator release, such as pruritus, urticaria, angioedema, bronchospasm, hypotension, and/or anaphylaxis.

Skin testing — Skin prick (also known as epicutaneous) and intracutaneous testing with progesterone have been proposed as diagnostic tests to confirm suspected type I PH. However, there are several issues with validity, and not all allergy experts believe that skin testing is worthwhile [2,14,19,53]. We suggest limiting the performance of progesterone skin testing to patients with symptoms suggestive of an IgE-mediated reaction that begins a few days before the onset of menses and resolves during or after the completion of menses.

If performed, a positive skin testing result supports the diagnosis of PH in a patient with a compatible clinical history. However, the positive and negative predictive values of progesterone skin testing are unknown. Therefore, a negative skin test result does not exclude the diagnosis, and there can be an irritant false-positive response. In addition, only a small number of asymptomatic, progesterone-exposed women have been skin tested as controls.

A few studies provide information about the performance of progesterone skin testing as a diagnostic test. Among patients with suggestive symptoms in one study, 50 percent had positive skin tests [2]. In a review of cases reported in the literature, 64 of 67 cases had positive skin testing, but this would very likely represent a highly select population [4]. One paper included a group of 12 control women in whom progesterone skin testing was performed to make sure that women without symptoms would not test positive, and all had negative results [54]. In summary, data are very limited, and improved diagnostic tests are needed.

●We use full concentration pharmaceutical grade progesterone (50 mg/mL) for skin prick testing.

At one author's (KB) center, a bio-identical progesterone compounded with olive oil is used for skin testing.

●If skin prick testing is negative, intradermal testing is performed next, with dilutions starting at a 0.05 mg/mL solution and increasing stepwise if negative with 0.5 and 5 mg/mL solutions [2,15]. Higher concentrations can produce false-positive irritant responses. Progesterone is not soluble in water or saline but can be suspended at the desired concentration in one of several oils (olive, sesame, peanut, or palm) or in ethanol.

●Because these diluents can lead to false-positive irritant reactions in some patients, it is important to include the ethanol or oil diluent at the same concentration (but without progesterone) as a control, in addition to appropriate saline (negative) and histamine (positive) controls [2,55].

A general discussion of skin testing techniques is found separately. (See "Overview of skin testing for IgE-mediated allergic disease", section on 'Skin testing methods'.)

Graded challenge — Progesterone challenge has been used in the diagnosis of PH [1,27]. Challenge could be considered in a patient with a negative or suspected irritant response to progesterone skin testing to confirm that the patient does not react. However, there are several issues that limit the safety or utility of progesterone challenge, such that it is usually not performed in clinical practice. Issues include the following:

●Challenge should not be performed in a patient with past anaphylaxis attributed to progesterone.

●Some patients with PH may not react to a single dose, so challenge may need to involve multiple doses.

●Some patients with PH can react with severe rashes that take weeks to resolve.

●Depending on the clinical syndrome, a placebo-controlled challenge may be needed for definitive interpretation.

●Patients with severe dermatitis as the manifestation of PH can react with an eruption that takes weeks to resolve.

In vitro testing (investigational) — There are no commercially available in vitro tests for PH, although commercial assays are in development. Investigational in vitro assays that have been reported to be potentially useful in PH include direct leukocyte histamine release (LHR) assays performed on basophils and progesterone-specific IgE demonstrated by enzyme-linked immunosorbent assay (ELISA), although this is not commercially available [33]. Interferon-gamma-release assay has also been proposed as a way to assess progesterone-related T cell activity [39,56].

Patients with other reactions — We do not advocate the use of delayed readings of intracutaneous tests or progesterone patch testing for patients with possible PH, because the data are limited, and these techniques require further validation.

We do not perform any type of testing or re-expose patients with erythema multiforme, SJS, or toxic epidermal necrolysis (TEN) to progesterone, as even minor exposures can trigger a recurrence of symptoms.

Challenge with a GnRH agent — Gonadotropin-releasing hormone (GnRH) agonists, such as leuprolide acetate, can be given for two or three months as a diagnostic intervention if patients are accepting of the possible adverse effects. Alternatively, oral GnRH antagonists, such as elagolix and relugolix, which block the receptor, may also be options. Use of these agents should be supervised by a gynecologist or endocrinologist. Adverse effects are discussed below. (See 'Women who have completed childbearing' below.)

DIAGNOSIS — The diagnosis of PH is primarily based upon clinical history and physical examination. Confirmation of the presence of cutaneous or systemic symptoms that appear during the luteal phase of the menstrual cycle or symptoms that correlate with exposure to exogenous progestogens would be the minimal requirement for diagnosis.

●Depending on the symptom complex, positive immediate skin testing results support the diagnosis, but negative results do not conclusively exclude it, since other mechanisms may be involved. In addition, because the prevalence of positive skin testing to progesterone among asymptomatic women has not been determined, a positive skin test, in the absence of suggestive symptoms is not sufficient to diagnose PH.

●Resolution of symptoms with a gonadotropin-releasing hormone (GnRH) agonist challenge can also be considered diagnostic.

●Other disorders that can mimic aspects of PH should be excluded. (See 'Differential diagnosis' below.)

DIFFERENTIAL DIAGNOSIS — The differential of PH affecting the skin includes dermatoses that fluctuate with the menstrual cycle. In patients with anaphylaxis, the differential includes other triggers of anaphylaxis that occur in association with menses or pregnancy, such as catamenial anaphylaxis or breastfeeding anaphylaxis [57].

NSAID hypersensitivity — Nonsteroidal anti-inflammatory drugs (NSAIDs), which are commonly used in the premenstrual period and the first few days of menses, can cause both urticaria/angioedema or systemic symptoms, including asthma and anaphylaxis [40,58-60]. Patients can refrain from use of NSAIDs in order to determine if symptoms occur in their absence. Alternatively, an NSAID challenge could be performed to conclusively diagnose NSAID hypersensitivity. (See "NSAIDs (including aspirin): Allergic and pseudoallergic reactions" and "Diagnostic challenge and desensitization protocols for NSAID reactions".)

Chronic idiopathic urticaria — Chronic idiopathic (or spontaneous) urticaria (CIU) is defined as the presence of urticaria with or without angioedema on most days of the week for a period of six weeks or longer. Patients with CIU would be expected to have symptoms outside of the luteal phase of the menstrual cycle, although symptoms might worsen perimenstrually or with NSAID use.

Premenstrual exacerbation of a pre-existing dermatosis — Patients may have pre-existing atopic dermatitis, contact dermatitis, acne, psoriasis, or any number of other skin conditions that worsen in temporal relation to menses [61,62].

Estrogen hypersensitivity — Hypersensitivity to endogenous and exogenous estrogens has also been described and appears to be even rarer than PH [63-67]. Estrogen hypersensitivity characteristically presents as a premenstrual flare of urticaria or a delayed-type dermatitis [63]. However, estrogen levels peak earlier in the menstrual cycle (ie, days 6 to 14), compared with progesterone, although there is a secondary rise during the luteal phase that mirrors the rise in progesterone. The diagnosis is supported by a positive immediate or delayed intracutaneous estrogen test [63,64] or an estrogen challenge [65]. Treatments for patients reacting to endogenous estrogens are similar to those for PH and include suppression of estrogen with tamoxifen, leuprolide acetate, progestin-only contraceptives, or oophorectomy [63-67].

Catamenial dermatoses and anaphylaxis — "Catamenial" (of or relating to menstruation) dermatoses and anaphylaxis are also temporally associated with the menstrual cycle, but symptoms correlate with the onset of menses, whereas PH correlates with the period of peak progesterone concentrations prior to the onset of menses [31]. However, the term "catamenial anaphylaxis" has been used loosely in the literature and has been applied to premenstrual reactions to progesterone [68,69].

Progesterone and estrogen both decline significantly prior to the onset of menses (figure 1). It has been proposed that symptoms beginning with the onset of menses are triggered by endometrial release of prostaglandins, which peak on the first day of menses [70,71]. The endometrium synthesizes prostaglandin F₂ (PGF₂) [72] and has been implicated in mediator release by uterine mast cells [73].

In a case report of recurrent anaphylaxis occurring in the first 24 hours of menses, indomethacin, which inhibits prostaglandins, was beneficial. Complete resolution of the patient's symptoms occurred following hysterectomy and salpingo-oophorectomy [70].

Breastfeeding anaphylaxis — There are rare case reports of anaphylaxis associated with breastfeeding [58-60,74]. Symptoms most commonly begin in the first few days after delivery and are associated with the act of breastfeeding or the manual expression of breast milk. Elevations in serum tryptase have been documented [60]. The pathophysiology of lactation-associated anaphylaxis is not well-understood, but one theory is that a rapid decrease in progesterone leads to an exaggerated histamine response [60]. Hypersensitivity to prolactin and oxytocin has also been explored, but skin testing to these hormones was negative [59,60]. In some patients, the symptoms resolve after several days of breastfeeding, although they may occur with subsequent pregnancies [59,74]. (See "Anaphylaxis during pregnancy and delivery".)

TREATMENT — Treatment for PH varies widely based on symptoms and preferences regarding fertility but generally focuses on controlling specific symptoms or inducing anovulation in women who do not wish to conceive in the near future. Coordination between the allergist/immunologist or dermatologist and the gynecologist and/or reproductive endocrinologist may be needed, depending upon the individual patient's goals.

Antiallergy medications — The simplest approach to management of PH is avoidance (if exogenous progestogens are the cause of the symptoms) and/or suppression of symptoms if progesterone is endogenous or necessary. Antihistamines are used to treat pruritus, urticaria, and angioedema, with variable reports of success [9,17,32,75]. A step-wise approach to management, similar to that used for chronic idiopathic (spontaneous) urticaria, is appropriate [76]. Second-generation H1 antihistamines, such as cetirizine, levocetirizine, loratadine, desloratadine, and fexofenadine, are minimally sedating and preferred over first-generation agents, such as diphenhydramine and hydroxyzine. Some patients require higher than standard doses for control of symptoms. Use of H1 antihistamines at higher than standard doses is discussed elsewhere. (See "Chronic spontaneous urticaria: Standard management and patient education", section on 'H1 antihistamines'.)

Topical and oral glucocorticoids have both shown to have efficacy in some studies [11,51], although they are not a viable long-term option for many patients due to the potential for adverse systemic side effects.

Oral contraceptive with a constant progesterone dose — A simple early intervention that is variably successful is treatment with an oral contraceptive (OC) that contains a constant progesterone dose, which should be administered continuously. This would not be appropriate in patients with anaphylaxis or blistering of the skin or mucous membranes, as these patients should not be purposefully exposed to exogenous progestogens. (See "Combined estrogen-progestin oral contraceptives: Patient selection, counseling, and use", section on 'Dosing regimens'.)

Progesterone desensitization — Various types of desensitization protocols have been used to alleviate symptoms of progesterone hypersensitivity in small numbers of patients [2,15,17]. The exact mechanisms underlying desensitization are incompletely understood. Desensitization does not "cure" a drug hypersensitivity but rather is a means of preventing symptoms for as long as the patient remains continually exposed to the drug. Therefore, it is appropriate for patients who will either remain on continual progesterone (eg, OCs) or for those who require exposure for a limited period of time (eg, during fertility treatments).

Indications — Indications for desensitization include:

●Patients with nonanaphylactic symptoms who have failed initiation of an OCP without desensitization. (See 'Oral contraceptive with a constant progesterone dose' above.)

And

●Severe symptoms not controlled with standard medications, such as antihistamines or glucocorticoids, or the desire to avoid long-term use of these medications [2].

And/or

●The need for high-dose progesterone for in vitro fertilization (IVF) [15,17]. (See "In vitro fertilization: Procedure", section on 'Luteal phase support'.)

Safety — For patients with urticaria, asthma, or anaphylaxis to progesterone, desensitization protocols should be performed by allergists or clinicians with specific training in allergy procedures. Because these symptoms are indicative of a possible immunoglobulin E (IgE)-mediated mechanism, patients should be desensitized in a setting equipped with the staff and medications necessary to manage anaphylaxis. Successful completion of a desensitization protocol may require temporarily suspending the procedure if symptoms develop, treatment, and adjustments to the subsequent steps, all of which require some experience in desensitization techniques.

For patients with mild, nonurticarial cutaneous reactions, desensitization has been found to be well-tolerated and carry little risk, although experience with desensitization techniques is recommended.

Specific protocols

●Rapid drug desensitization protocols are appropriate for immediate reactions (eg, urticaria, angioedema, asthma, and/or anaphylaxis) [77-79]. These protocols typically take a few hours to complete. Examples are provided (table 2 and table 3 and table 4), each of which has been successfully applied to three or fewer patients whose skin test sensitivities were not specified. A detailed discussion of rapid drug desensitization for immediate-type reactions is found separately. (See "Rapid drug desensitization for immediate hypersensitivity reactions".)

●There are also gradual dose escalation protocols that are typically applied to delayed forms of drug reactions in the absence of positive skin tests, which includes most of the cutaneous forms of PH (eg, various forms of dermatitis). These protocols usually take a few days to complete. An OC containing both estrogen and progestin is usually preferred. An example is provided (table 5). This protocol was successful in six of seven patients in which it was employed.

●We have also seen patients in whom OCs were initiated without a desensitization protocol and continued without interruption with good results. However, this is not consistently effective.

We typically administer diphenhydramine (50 mg orally) and prednisone (40 mg orally for three days) as premedications prior to desensitizations that take place over a few hours. During the procedure, if patients develop symptoms, we sometimes adjust the protocol by backing up to the last tolerated dose and progressing more gradually through the steps that elicited symptoms.

Omalizumab — Omalizumab, a monoclonal antibody to IgE, has been used successfully in a young woman with urticaria and anaphylaxis due to PH [34]. Omalizumab is well-tolerated and has few adverse effects, although it is effective only as long as it is administered. (See "Anti-IgE therapy".)

Omalizumab can also be administered to facilitate desensitization. For patients who failed an initial attempt at desensitization due to breakthrough symptoms during the procedure, a dose of omalizumab can also be given prior to a second attempt at desensitization.

Therapies with significant limitations — There are several other therapies for PH that have either significant adverse effects or permanently impair fertility, such that they have limited utility. These include gonadotropin-releasing hormone (GnRH) agonists, tamoxifen, and oophorectomy. (See 'Women who have completed childbearing' below.)

Approach for different patient groups — The optimal approach to management depends upon whether the patient is hoping only to relieve symptoms, is also undergoing fertility therapies, or has completed childbearing.

Women not desiring pregnancy in the near future — OCs that contain both estrogen and progestins can eliminate the progesterone peaks that trigger symptoms. However, if just initiated normally, OCs may not be well-tolerated by all patients with PH [38]. In patients who do not tolerate OCs initiated normally, OCs can be introduced using a slow oral protocol (table 5) [2,12]. Preparations containing estrogen combined with a constant dose of progestin throughout the cycle are usually chosen, and these are given continuously without stopping to allow for menstruation, as this could permit resensitization. The steady level of progesterone usually results in improvement in symptoms. (See "Combined estrogen-progestin oral contraceptives: Patient selection, counseling, and use", section on 'Dosing regimens'.)

Women wishing to conceive — For women with PH who wish to conceive, options include the following:

●Manage symptoms with antihistamines and glucocorticoids and conceive naturally with the hope that autodesensitization will occur as a result of pregnancy. There are no data to suggest that PH directly causes infertility.

●Initiate omalizumab (anti-IgE therapy). This would be appropriate for PH presenting as urticaria, asthma, or anaphylaxis and is considered safe to continue during pregnancy (if needed) [34].

Women undergoing fertility treatments — Women undergoing fertility treatments who have developed PH usually need to be desensitized to tolerate the high doses of progesterone required for successful implantation. There are several reports of rapid-dose escalation ("desensitization") to high-dose progesterone that was required for IVF [15,17]. Varied protocols that require several hours to complete have been designed using oral, intravaginal, or intramuscular progesterone [2,14,15]. Desensitization is timed to coordinate with fertility treatment, such as immediately prior to embryo transfer (table 3 and table 4) [2,12,15]. Close coordination with the fertility specialist is essential. It is noteworthy that some of the reported cases of "desensitization" included premedication with steroids and other drugs, and no patients have been re-skin tested after tolerance to demonstrate cellular desensitization, so the mechanism underlying this clinical tolerance is not proven.

Women who have completed childbearing — For women who have completed childbearing, treatment options include rapid-dose escalation ("desensitization") to and continuous use of an estrogen- and progesterone-containing OC until menopause. Alternatively, there are other options with significant drawbacks, including GnRH agonists, tamoxifen, and oophorectomy:

●GnRH agonists, such as leuprolide acetate, have been used to treat PH in patients with severe symptoms refractory to other medical therapies [16,32,33,38,80,81]. At doses used to suppress ovulation, GnRH agonists inhibit pituitary gonadotropin release, thus inhibiting ovulation and suppressing luteal progesterone [82]. In a double-blind crossover study in four women with history of recurrent anaphylaxis corresponding to the luteal phase, all received either GnRH agonists or placebo [81]. Two of the four patients improved on the GnRH agonist, while the other two had no response. The two who improved had positive skin tests to medroxyprogesterone acetate and anaphylaxis to intravenous challenge with luteinizing hormone-releasing hormone, consistent with PH [81]. One of the authors (JB) has successfully used an intranasal GnRH agonist (nafarelin) to control symptoms (unpublished). GnRH agonists have significant adverse effects, including hot flashes, amenorrhea, urogenital atrophy, and bone loss [83-85]. (See "Endometriosis: Long-term treatment with gonadotropin-releasing hormone agonists", section on 'Side effects'.)

●Tamoxifen is a selective estrogen receptor modulator that has been reported to be useful in treating PH, although the authors have not used it in their own practices [26,27,42]. In premenopausal women, tamoxifen induces ovulation, but if given daily over time, women can become oligo- or amenorrheic. Adverse effects include hot flashes, increased risk of thromboembolic events, abnormal uterine bleeding, and other uterine pathology. (See "Abnormal uterine bleeding and uterine pathology in patients on tamoxifen therapy".)

●Oophorectomy has been employed as a definitive treatment for patients with severe PH that cannot otherwise be managed medically [1,25,30,52,86]. A trial of a GnRH agonist beforehand would be helpful to confirm that symptoms improve when endogenous progesterone is suppressed.

PROGNOSIS — We have not observed spontaneous resolution of PH in the absence of either some therapeutic intervention or natural menopause. Patients respond in varying degrees to the interventions described above, but in most cases, symptoms can be managed to the patient's satisfaction.

SUMMARY AND RECOMMENDATIONS

●Progestogen hypersensitivity (PH) is a form of cyclic hypersensitivity that may be more common than reported that can develop in women of reproductive age beginning any time from menarche to menopause, although it is more common in younger women. It can present with a spectrum of cutaneous and/or systemic allergic signs and symptoms, correlating temporally with relative peaks in serum progesterone levels. (See 'Terminology' above and 'Epidemiology' above.)

●In the normal menstrual cycle, progesterone is released from the corpus luteum during the luteal phase (ie, days 14 to 28 of a 28-day cycle) (figure 1). (See 'Progesterone biology' above.)

●PH may present with a broad array of cutaneous and systemic signs and symptoms. Most patients either have cutaneous presentations (dermatitis, urticaria, papular or vesicular eruptions) or asthma/anaphylaxis. For women reacting to endogenous progesterone, the cyclical nature of the reactions relative to the menstrual cycle is a key diagnostic clue. Symptoms typically begin 3 to 10 days before the onset of menses and resolve after the first few days of menstruation. For women reacting to exogenous progestogens, the symptoms follow exposure. During pregnancy, PH can begin intrapartum and may or may not resolve following childbirth. (See 'Clinical manifestations' above.)

●The heterogeneity of clinical presentations suggests that multiple mechanisms may be involved and that mechanisms may differ among patients. Types I, III, and IV reactions have all been implicated (table 1). Women may have a history of exposure to exogenous progestogens, particularly during fertility treatment, but some patients have no such history, and risk factors have not been identified. (See 'Theories of pathogenesis' above.)

●Evaluation includes progesterone-specific IgE testing. Skin testing to progesterone is unreliable and can result in false positive or negative results, so we perform it rarely and usually for cases of immediate-type allergic symptoms. Progesterone challenge has also been used but is infrequently performed. Suppression of the menstrual cycle with a gonadotropin-releasing hormone (GnRH) agonist resulting in resolution of symptoms is also diagnostic. The minimal criteria for diagnosis of PH are suggestive signs and symptoms that appear during the luteal phase of the menstrual cycle or symptoms that correlate with exposure to exogenous progestogens. (See 'Evaluation' above and 'Diagnosis' above.)

●The differential diagnosis includes other causes of cyclic hypersensitivity, reactions to nonsteroidal anti-inflammatory drugs (NSAIDs) taken in the perimenstrual period, chronic idiopathic (or spontaneous) urticaria (CIU), premenstrual exacerbations of other skin disorders, and several other rare conditions. (See 'Differential diagnosis' above.)

●Management options include suppression of symptoms with antiallergy medications, progesterone desensitization, omalizumab, therapies to suppress ovulation (eg, leuprolide acetate), use of a selective estrogen receptor modulator like tamoxifen, and oophorectomy. Different approaches are used for women wishing to suppress symptoms but preserve future fertility, those actively undergoing fertility treatments, and those who have completed childbearing. (See 'Treatment' above.)