Introduction

The menstrual cycle is associated with various systemic diseases. It also may induce a spectrum of cyclic dermatologic conditions referred to as autoimmune sex-hormone dermatitis, including eczema, erythema multiforme, fixed drug eruptions, and folliculitis [1–7]. Although progesterone sensitivity has been the most well-studied cause, estrogens [8–12] and gonadotropins [13] also have been cited as possible etiologies for these cyclic allergic reactions.

The expression “sex hormone hypersensitivity” (SHH) applies to an immunologic sensitivity to the high levels of sex hormones found in various phases of a woman’s menstrual cycle. As progesterone sensitivity has been the most commonly identified cause, dermatologic diseases associated with the menstrual cycle have been labeled alloimmune or autoimmune progesterone dermatitis (APD) [4]. The first documented case of APD was published in 1921 [14] describing acute urticarial lesions caused by administration of patient’s premenstrual serum. In addition, it was shown that the patient's premenstrual serum could be used to desensitize and improve her symptoms [15]. Since 1921, approximately 60 cases of APD have been published in the medical literature. This review will discuss the pathogenesis, clinical presentation, dermatologic manifestations, diagnosis, and treatment of this unfamiliar phenomenon. We are using the term SHH for the discussion of the general phenomenon and APD when the studies focused on progesterone.

Female Sex Hormones Throughout the Menstrual Cycle and Life

The hormonal status of women is controlled by the hypothalamic-hypophyseal-ovarian axis and involves the release of gonadotrophins and ovarian hormones, estrogen and progesterone. The variations in the levels of these hormones regulate the menstrual cycle, pregnancy, puerperium, and menopause.

The menstrual cycle is a monthly cycle that averages 28 days. It can be divided into three phases: the follicular phase (days 1-9), ovulation (days 10–14), and the luteal phase (days 15–28). The first day of menstruation is considered the beginning of follicular phase, during which stimulation of ovarian follicles occurs and estrogen is the predominate hormone. It is followed by the ovulatory phase, when the oocyte is released from the ovary and the estrogen levels peak. The luteal phase begins just after ovulation, and the follicle, now termed a corpus luteum, secretes large amounts of progesterone. These changes are orchestrated by the pituitary hormones, follicular stimulating hormone (FSH) and luteinizing hormone (LH). The oocyte is only viable for approximately 24 hours without fertilization. If fertilization or implantation of the fertilized oocyte does not occur within 2 weeks, the corpus luteum will degenerate, resulting in a sharp drop in progesterone and estrogen levels. This drop causes the lining of the uterus to shed, resulting in menstruation. Hemodynamic changes [16], migraines [17], and mood disorders [18] have been associated with the hormonal fluctuations occurring in the menstrual cycle.

The first menstruation is termed menarche, typically occurring around age 12-13 years. The end of a woman's reproductive phase is called menopause, commonly occurring between the ages of 45–55 years.

In pregnancy, human chorionic gonadotropin (hCG) is released, allowing the corpus luteum to continue the production of estrogen and progesterone until the formation of the placenta. The placenta, once formed, produces the majority of estrogen and progesterone necessary to support the pregnancy. Serum levels of estradiol and progesterone gradually increase to their highest levels during the third trimester. At term, estradiol levels are 30–40 times higher compared with nonpregnant women and progesterone levels are 10 to 5,000 times those of nonpregnant women [19]. During the puerperium period, following delivery until a few weeks postdelivery, the hormone levels drop sharply to the prepregnancy state.

Pathogenesis

The mechanism of hormone hypersensitivity has not been fully explained. It is possible that there are various causes for APD, as there are different manifestations, differences in laboratory results cited in the literature, and a variety of reactions noted on intradermal/intramuscular testing.

Several factors have been proposed to explain the phenomena, such as stimulation of T-2 helper cells by progesterone, immunoglobulin [Ig]E synthesis, direct effects of progesterone on mast cells and basophils, or progesterone serving as an autoantigen and inducing antibody responses. The resulting reaction between the antibodies to the hormone can induce immune response in susceptible individuals.

It was suggested that sensitization could occur through previous use of exogenous progesterone [9]. This hypothesis may be true in some but not all cases; some effected women have never been exposed to exogenous progesterone [20–22]. An alternative mechanism for sensitization might be steroid cross-sensitivity [23]. A third possibility is that the woman might tolerate low levels of her own hormones, but as levels of progesterone rise, the inflammatory system reacts to her endogenous progesterone [9]. There are reports of APD presenting at the onset of menarche [24] or during pregnancy [25], when progesterone levels rise 20-fold compared with prepregnancy levels.

Some women note an improvement of symptoms during pregnancy. A number of theories have emerged, including that the slow rise of progesterone during pregnancy caused desensitization, there is a decrease in maternal immune response during pregnancy, or that the improvement is due to an increased production of anti-inflammatory glucocorticoids [24, 26]. Another proposed mechanism suggests that pregnancy may cause sensitization to progesterone or its metabolites, as pregnancy itself alters the immune response.

To further delineate the pathogenesis, antibodies against progesterone have been investigated. Using immunofluorescent techniques, basophil degranulation tests and purification of different IgG antibodies, studies have found that antibodies against progesterone exist in certain patients with APD [1, 24, 27]. However, the absence of these antibodies also has been reported in affected patients [28]. In addition, skin testing for progesterone allergy have shown immediate reactions (within 30 minutes), delayed reactions (24–48 hours later), and mixed reactions [24, 29–31]. This may indicate both type I and type IV hypersensitivity reactions.

Progesterone also may has a direct histamine releasing effect on mast cells, yet very little research has been done to support this hypothesis [32]. Additionally, one study found an in vitro increase of an interferon-γ release, possibly implying a role for TH1-type cytokines in APD [33]. Eosinophils also may be involved in the pathogenesis of APD; eosinophilia has been correlated with cutaneous symptoms in some cases, and studies have found a decrease in total eosinophil count after therapy [24, 27, 34]. Whether increased eosinophils represent a response to lymphocytes` derived cytokines or play a primary mechanistic role in APD remains to be determined.

With hypersensitivity to sex hormones, the skin appears to show the most prominent clinical presentation compared with other organs. This may result from the presence of an immune response against foreign antigens and an inflammatory reaction [35].

It was found that the cutaneous immune response to estradiol valerate, a synthetic estrogen, resembles a classic response to a lipid antigen [33, 34]. It is therefore possible that xenoestrogens commonly found in food, medications, and industrial compounds may be processed by the skin as a foreign antigen and presented to immunocompetent cells, possibly leading to a cross-reactive autoimmune response to endogenous estrogen [27].

Clinical Presentation

Intolerance to sex steroid hormones may include hypersensitivity to estrogen, progesterone, or both and can manifest in various clinical presentations. Usually there is a history of cyclical, hormone-dependent symptoms as the symptoms typically appear in correlation to maximal sex hormone production; in progesterone hypersensitivity, for example, symptoms begin 3 to 10 days before menstruation, and end 1 to 2 days into the menstrual flow. In some cases of SHH, symptoms persist throughout the entire menstrual cycle or occur at apparently random times of the cycle. Symptoms may appear with the usage of oral contraceptives [36], following hormone administration for infertility treatment [37], or when given to prevent preterm birth [38]. SHH also can present during pregnancy or the postpartum period [25].

Most descriptions of SHH in the literature apply to dermatological manifestations (see below), but other clinical presentations may be attributed to SHH, including premenstrual syndrome, mastalgia, headaches, dysmenorrhea, arthralgia, infertility, recurrent miscarriages, hyperemesis gravidarum, and anaphylactic reactions.

Premenstrual syndrome (PMS) is the cyclic occurrence of psychological and somatic symptoms that cause a negative influence on daily functioning and levels of distress, beginning sometime after ovulation and ending by the end of the menstrual flow, with a symptom-free interval before the next ovulation [39]. PMS may affect as many as 20 % of ovulatory women. Symptoms include joint, muscle and back pain, breast tenderness, abdominal swelling or bloating, headaches, skin disorders, swelling of extremities, mood swings, depression, anxiety, changes in appetite, food cravings, sleep disturbances, and more [39].

In a study evaluating a possible association between SHH and PMS, both immediate and delayed hypersensitivity reactions to sex hormones were observed in patients with PMS, but were not detected in patients without it. PMS symptoms included mood swings, tension, irritability, breast tenderness, headaches, and craving for sweets or salt, as well as dermatologic disorders [40]. Desensitization treatment resulted in a marked decrease in PMS symptoms and improvement of symptoms in 50–87 % of patients [36, 40, 41].

SHH was described as a cause for anaphylactic reactions presenting with urticaria, flushing, laryngeal edema, bronchospasm, hypotension, and shock [32, 42–44]. SHH also may have a role in various infertility and obstetrics disorders. In a recent study, hormonal desensitization for APD presenting with cyclic rashes or anaphylaxis was associated with successful in vitro fertilization [45•]. In another study, women with recurrent pregnancy loss, concurrent PMS, and SHH on skin testing underwent desensitization with sex hormones. In addition to amelioration of PMS symptoms, 16 of 26 women (61 %) had subsequent live births, without obstetric complications. The authors concluded that correction of sex hormone hypersensitivity may have a positive effect on the chances of a successful pregnancy in women with recurrent pregnancy loss [46•]. Mabray et al. [41], utilizing a desensitization regimen for progesterone, treated hyperemesis gravidarum and dysmenorrhea, with success rates of 100 % and 84 %, respectively.

In addition to the above-mentioned disorders, many other disorders have been associated with changes in the menstrual cycle, including asthma, hereditary angioedema, porphyria, epilepsy, myasthenia gravis, allergic rhinitis, and migraines. It is possible that at least in a number of patients some of these disorders result from SHH. Using appropriate diagnostic tests (see below) may allow for determination of the role of SHH in the pathogenesis of these disorders and may offer new therapeutic options.

Dermatological Presentation

In a small group of women, the menstrual cycle has been associated with a spectrum of dermatologic diseases, including eczema, prurigo, erythema multiforme, fixed drug eruption, papulopustular lesions, folliculitis, annular erythema, bullous or vesicopustular eruption, angioedema, urticaria, and oral erosions (stomatitis and aphthous ulcers) [1–7, 47, 48] (Table 1).

Table 1 Dermatologic manifestations of autoimmune progesterone dermatitis
Full size table

The common dermatological presentation is urticaria or erythema multiforme-like lesions and it is usually pruritic. Anaphylactic reactions with urticaria, flushing, laryngeal edema, hypotension, bronchospasm, and shock have been described but are generally rare [32, 43, 44]. The skin rash may involve all skin surfaces, including extremities, genitals, and the oral cavity. The clinical presentation may be variable and include: erosions and crusted lesions in the oral mucosa, lips, vulva, and perineal area, mimicking bullous disease; target lesions on the extremities mimicking erythema multiforme skin lesion [49]; exacerbation of hereditary angioedema type I or type III; idiopathic angioedema symptoms [47]; and petechiae and purpura on the chest not induced by scratching [50].

The symptoms of APD correlate with progesterone levels during the luteal phase of the menstrual cycle. Progesterone begins to rise 14 days before the onset of menses, peaks 7 days before menses, and returns to a low baseline level 1–2 days after menses begins. The clinical symptoms of APD (eczema, urticaria, angioedema, etc.) usually begin 3–10 days before the onset of menstrual flow and end 1–2 days into menses. Severity of symptoms can vary from nearly undetectable to anaphylactic and can progress in severity over time [44, 51••].

The histological findings are extremely variable and normally reflect the clinical picture [52]. A dermal perivascular infiltrate composed of mixed lymphocytes and eosinophils is a common pattern [53]. Immunofluorescence studies are usually negative.

Diagnosis

Unfortunately, there is no definitive, diagnostic laboratory test for APD. As the skin is the most commonly involved organ in APD, various forms of skin testing have been used [1, 2, 28]. The diagnosis of APD requires an appropriate clinical history accompanied by a positive progesterone intradermal injection test.

An aqueous suspension or aqueous alcohol solution of progesterone is the recommended vehicle of testing, as progesterone in oil can cause a local irritant reaction [12]. Nevertheless, many published case reports have used progesterone in oil preparation for testing. Various authors have advocated different amounts of progesterone or medroxyprogesterone to be used for testing [33, 52, 53].

As mentioned earlier, APD may be due to an immediate or delayed hypersensitivity reaction. Therefore, intradermal testing may not become positive until 24–48 hours after the injection [28, 30]. In addition, some authors have used patch testing with progesterone to further evaluate for a hypersensitivity reaction [33]. Of note, there are reports of a negative intradermal testing in patients with typical clinical symptoms of APD who subsequently improved after treatment [3, 6, 28]. Some authors have recommended additional tests to confirm the immunologic component in APD, including measuring circulating antibodies to progesterone, basophil granulation tests, direct and indirect immunofluorescent staining of luteinizing cells in the corpus luteum, in vitro interferon-γ release assay, and circulating antibodies to 17-α-hydroxyprogesterone [1, 7, 24, 27, 33, 53].

However, in most case reports, routine testing for serologic evidence in APD is not performed, and when tested, these markers have not always been found to be reliable. This is most likely due to the fact that, as mentioned above, the pathogenesis of APD is not completely understood.

Our diagnostic testing includes a 0.02-mL test dose of both estradiol (estradiol valerate 10 mg/mL) and progesterone, (progesterone BP 50 mg/mL in aqueous solution) intradermally into the forearm during the luteal phase of the cycle. A negative control is provided by saline solution injection and a positive control by histamine. Ethyl oleate (ethyl oleate BP in 10 % benzyl alcohol), the vehicle in which the hormones are dissolved in, also is used as control. Immediate and delayed reactions are then assessed, at 20 minutes and after 1 and 5 days after the injection. Intradermal testing is considered positive when erythema and infiltration >5 mm are observed at the site of injection after 20 minutes. Persistence of a papule for >24 hours from the injection, at the injection site is required for a positive test. Readings are done separately for estradiol and progesterone. The delayed hypersensitivity reaction is confirmed by persistence of the papule after 48 hours. The patient is asked to report daily changes at the injection sites for 1 month following the procedure [40].

Some authors suggest that the clinical diagnosis requires in addition to recurrent cutaneous eruptions, two of the four main criteria: 1) a positive intradermal skin test with progesterone; 2) prevention of the premenstrual flare by inhibiting ovulation; 3) demonstration of circulating antibodies to progesterone; and 4) reproduction of symptoms with an intramuscular hormonal challenge [52, 54].

Treatment

Various therapeutic modalities were described for the treatment of APD. Due to the rarity of the phenomena, most publications are case reports, thus comparison between treatments is not available and there is no preferable treatment. APD is usually resistant to conventional antiallergic therapy, such as antihistamines. The use of systemic glucocorticoids, usually in high doses, has been reported to control the cutaneous lesions of APD in some studies but not in all [3, 51••, 55].

Some therapeutic modalities are designed to inhibit endogenous progesterone secretion by preventing ovulation. Hormonal contraceptives often are used as initial therapy but have had limited success, possibly due to the fact that virtually all hormonal contraceptives contain progesterone. Conjugated estrogens also have been used for the treatment of APD, but often high doses are required [6, 20, 56]. However, due to the increased risk of endometrial carcinoma with unopposed estrogens, this treatment is not commonly used [57].

GnRH agonists have been used to induce ovarian suppression [7, 22, 44], but side effects of estrogen deficiency (hot flashes, vaginal dryness, decreased bone mineral density) may require estrogen supplementation [58]. Alkylated steroids, such as stanozolol and danazol, have been used to suppress ovulation, occasionally in combination with low dose corticosteroids [55]. The side effects of alkylated steroids—the growth of abnormal facial or body hair, hepatic dysfunction, and mood disorders—may limit their use. To decrease the risk of these side effects, alkylated steroids may be used only in the perimenstrual period [55]. Another therapeutic option for the treatment of APD is tamoxifen, an antiestrogen, which suppresses ovulation [2, 3]. As with GnRH agonists, patients on tamoxifen may experience symptoms of estrogen withdrawal. For patients with severe and refractory disease bilateral oophorectomy has been required for the successful, definitive treatment [22, 28, 51••].

Another treatment of APD is desensitization towards the involved hormone. This treatment was described in the early reports of APD, and various methods of desensitization have been described since, including a rapid desensitization protocol with increasing doses of progesterone administered vaginally [45•].

We use a three-step procedure of desensitization until a negative skin test is obtained.

Desensitization treatment consists of monthly estrogen and/or progesterone interdermal injections according to the immediate and delayed skin test reactions. In each subsequent month, the volume of intradermal injection is doubled, with 0.04 mL used in the first month, 0.08 mL in the second month, and 0.16 mL in the third [40].

Desensitization should be used with caution, because latent autoimmunity may be aggravated in genetically predisposed women. Preliminary reports suggest that desensitization is not deleterious for the normal tolerance of pregnancy and actually improves the prognosis in selected patients.

Conclusions

APD is a rare disorder that primarily affects women as a reaction to progesterone in the luteal phase. Patients with APD may present with a number of different unusual manifestations, resulting in a delayed diagnosis. The autoimmune dermatologic disorders may range from a cyclic, monthly eruption associated with the luteal phase to a continuous cutaneous reaction, and rarely, recurrent systemic anaphylactic reactions. The pathogenesis of APD is poorly understood, and more studies are required to understand it.

Management includes a variety of options involving suppression of ovarian function or desensitization towards the involved hormone. Using appropriate diagnostic tests may allow determining the role of sex hormone hypersensitivity in various cyclic disorders.