Case of autoimmune progesterone dermatitis presenting as fixed drug eruption

Autoimmune progesterone dermatitis is a rare disorder that presents as a cyclical cutaneous eruption during the luteal phase of the menstrual cycle. It typically occurs in women due to an autoimmune phenomenon to endogenous progesterone production. We describe a 34‐year‐old woman with an erythematous round plaque with blistering, which recurred a few days before her menstrual cycle, at the identical site on the left arm. The diagnosis of autoimmune progesterone dermatitis is made with i.d. skin testing on the affected lesion with progesterone. After the beginning of oral prednisolone (40 mg daily) therapy during menstruation, although slight recurrence appeared, the severity was significantly improved.     

Case of autoimmune progesterone dermatitis presenting as necrotic migratory erythema successfully controlled by danazol

Autoimmune progesterone dermatitis (APD) is a rare cutaneous disorder with cyclic skin eruptions during the luteal phase of the menstrual cycle. Patients can present with various clinical manifestations, including urticaria and angioedema, erythema multiforme, eczema, fixed drug eruption and centrifugal erythema annulare. In our case, however, the patient’s skin lesions mimic necrotic migratory erythema (NME) which is most commonly associated with glucagonoma and rarely with liver disease, inflammatory bowel disease, malnutrition and other tumors. To our knowledge, this is the first case of NME-like APD and is successfully controlled by danazol. This also sheds lights on the etiologic diversity of NME.     

Autoimmune progesterone dermatitis: Case report of an unexpected treatment reaction

Autoimmune progesterone dermatitis (APD) is a rare skin condition with a varying morphology, which appears on a monthly basis during the luteal phase of the menstrual cycle and resolves spontaneously with the endogenous decrease in progesterone during menses. We present the case of 39‐year‐old multiparous Caucasian woman with generalised, self‐limited urticaria in her perimenstrual period. APD was diagnosed in light of the cyclical nature of the symptoms. An intradermal test with the administration of 0.5 mg/mL of medroxyprogesterone acetate showed a positive result. She started using vaginal hormonal contraceptive that paradoxically exacerbate the symptoms, which ceased after the removal of the device. An oral combined contraceptive was initiated instead, with complete resolution of the symptoms. We share the case because of the rarity of the situation, emphasising the importance of a multidisciplinary team for differential diagnosis and patient follow up.     

The menstrual cycle and the skin

Perimenstrual exacerbations of dermatoses are commonly recognized, yet our knowledge of the underlying pathophysiological mechanisms remains imperfect. Research into the effects of oestrogen on the skin has provided evidence to suggest that oestrogen is associated with increases in skin thickness and dermal water content, improved barrier function, and enhanced wound healing. Research into the effects of progesterone suggests that the presence of various dermatoses correlates with peak levels of progesterone. Dermatoses that are exacerbated perimenstrually include acne, psoriasis, atopic eczema and irritant dermatitis, and possibly also erythema multiforme. Exacerbations occur at the peak levels of progesterone in the menstrual cycle. Underlying mechanisms include reduced immune and barrier functions as a result of cyclical fluctuations in oestrogen and/or progesterone. Autoimmune progesterone and oestrogen dermatitis are the best‐characterized examples of perimenstrual cutaneous reactions to hormones produced during the menstrual cycle. In this review, we describe the current understanding of the menstrual cycle, and its effect on the skin and cutaneous disorders.     

Estrogen dermatitis that appeared twice in each menstrual period

A 23-year-old woman presented with millet-sized red papules that were scattered over her chest and abdomen. She stated that since the age of 20, she had recurrently suffered from pruritic eruptions that coincided with ovulation and the time prior to menstruation, and that they persisted for a few days before vanishing spontaneously leaving some pigmentation. A skin biopsy specimen revealed spongiotic bullae in the epidermis and marked infiltration of lymphocytes accompanied by some histiocytes and eosinophils in the upper dermis. An intradermal test for conjugated estrogen showed an urticarial reaction that faded in about four hours. Although the test did not strictly meet the criterion (erythema to remain for more than 24 hours for papulovesicular eruptions), it was concluded that the timing of the episodes along with the result of the test suggested that a diagnosis of estrogen dermatitis was highly probable. There have been several reports of this condition since it was first reported as a distinct entity in 1995; but whatever the reasons, the flares were observed only before menstruation in these cases, despite the fact that the serum estrogen levels showed a double-peaked pattern during each menstrual period. This is considered to be a rare case of estrogen dermatitis that flared twice in each menstrual period. Limited improvement was noted in the symptoms even without treatment.     

Nickel contact allergy and menstrual cycle

According to some reports in the literature, the hormonal fluctuations which occur during the menstrual cycle may affect the clinical expression of contact allergy to a greater or lesser degree. In clinical practice, too, patient history often shows exacerbation of the contact dermatitis during the days immediately preceding menstruation. On the contrary, the follicular phase of the cycle seems to have a temporary protective role in inhibiting the eliciting phase of allergic contact dermatitis. One possible explanation for this phenomenon is of immunological type: it has been demonstrated that oestradiol induces inhibition of delayed hypersensitivity type reactions, probably by acting indirectly on cells having a regulatory function in cell-mediated immunity. To investigate any inhibitory effect of the ovulatory phase of the menstrual cycle on contact sensitization, 30 selected fertile women, allergic to nickel sulfate and with a regular menstrual cycle lasting between 25 and 32 days, were enrolled. Patch tests were performed with a series of 10 serial aqueous dilutions of nickel sulfate, from 5% to 0.0013%. The 30 women were tested at 2 different times, in the ovulatory phase (demonstrated by transvaginal ultrasound) and the progestinic phase; they were subdivided into 2 groups of 15 women: in one group, the tests were made first in the ovulatory phase, and in the other, first in the progestinic phase of the menstrual cycle. There was a minimum interval of 5 weeks between the 2 test phases. The study shows that during ovulation the patch tests elicited significantly less intense responses than in the progestinic phase. These data therefore suggest that the ovulatory phase of the cycle has a significant inhibitory role on delayed hypersensitivity type reactions. For this reason, negative responses to patch tests executed in this phase could likely be false-negatives, and after careful evaluation of the phenomenon and of the clinical condition and patient history, it may be considered advisable to repeat the tests during the progestinic phase of the menstrual cycle.     

Progesterone-induced urticaria—need it be autoimmune?

Summary A patient with persistent urticaria related to the premenstrual phase of the menstrual cycle is presented. Although systemic administration of progesterone provoked the eruption, we were unable to confirm that there was an immunological reaction to endogenous progesterone or oestrogen. Mechanisms whereby progesterone can augment subclinical types I and IV hypersensitivity reactions are discussed.     

The influence of female sex hormones on skin thickness: evaluation using 20 MHz sonography

Changes in skin thickness and echodensity during the spontaneous menstrual cycle, in women taking hormonal contraceptives and pregnant women were investigated by high-frequency (20 MHz) ultrasound. Women with a spontaneous ovulatory menstrual cycle (group I), women taking one-phase contraceptives (group II), women taking three-phase contraceptives (group III) and pregnant women (group IV) were measured at the following locations: proximal and distal forearm and lower leg on both sides. The skin was investigated during three phases of the menstrual cycle: days 2–4 (phase A), days 12–14 (phase B) and days 20–22 (phase C). Oestradiol and progesterone levels were determined at each phase. The pregnant women were investigated 2 weeks prepartal and 6 weeks after delivery. Group I showed a statistically significant increase in the skin thickness from phase A to phase B, but not from phase B to phase C. Group II showed no significant changes in skin thickness, whereas the skin thickness increased from phase A to phase B in group III. In group IV, the skin was significantly thicker prepartal than after delivery. The measured echodensity showed a negative correlation with skin thickness in group III and in pregnant women. We were able to demonstrate that the status of female sex hormones influences the thickness of the skin. These results can be explained by hormone-induced water retention in the skin. Sonography at 20 MHz is able to quantify these effects, which should be considered when performing ultrasound measurement in women.     

A premenstrual urticarial eruption treated with bilateral oophorectomy and hysterectomy

Recurrent episodes of urticaria and erythema multiforme which occur in the luteal phase of each menstrual cycle are well recognized, albeit rare. This clinical entity was described by Hart (1977)¹ and attributed to a hypersensitivity to endogenous progesterone. We report a patient with a cyclical urticarial eruption which commenced during pregnancy and recurred pre-menstrually over a period of 11 years. Her symptoms were controlled by suppressing ovulation and finally by bilateral oophorectomy and hysterectomy. Post-operative challenge with an oral oestrogen resulted in a prompt recurrence of the eruption, whereas the administration of a progesterone had no effect. We suggest that this premenstrual eruption was oestrogen-rattier than progesterone-dependent.     

Autoimmune progesterone dermatitis.

A 35-year-old woman had recurrent urticarial erythemas on her trunk and extremities for 3 years. The eruptions appeared regularly 3 to 5 days prior to menstruation and persisted for several days. The patient showed a positive skin test response to progesterone and had circulating antiprogesterone IgG antibodies. A speculative concept of the possible autoimmune damage to the ovary, the major organ producing progesterone, is discussed.     

Cyclical psoriatic arthritis responding to anti-oestrogen therapy

We report a patient with severe psoriatic arthritis in whom the severity of both the arthritis and psoriasis fluctuated with the menstrual cycle. These features failed to improve with standard therapy, but there was a prompt response to treatment which suppressed oestrogen secretion. Such treatment should be considered in patients with disabling cyclical changes in psoriatic arthritis.     

Estrogen dermatitis: Case report and examination of estrogen receptor‐β in the skin

Many women experience some skin reaction or trouble in their monthly menstrual cycle, including the exacerbation of pre‐existing diseases and skin eruptions directly associated with sex hormones. We herein report a Japanese woman who experienced repeated systemic urticaria in her premenstrual period, and was diagnosed as having estrogen dermatitis based on a positive result of intradermal estrogen skin test. Of note, the expression of estrogen receptor‐β was increased in small dermal vessels of this case as well as in those of patients with other inflammatory skin diseases. These results suggest that inflammation may induce estrogen receptor‐β expression in small dermal vessels, which potentially modifies the pathological skin inflammation during the menstrual period, leading to the development of estrogen dermatitis.     

Autoimmune progesterone dermatitis

Autoimmune progesterone dermatitis (APD) is an uncommon cutaneous disorder characterized by exacerbations during the luteal phase of the menstrual cycle. We describe a 27-year-old woman with a recurrent skin eruption for 3 years. She had no history of exposure to synthetic progesterones. At each menses, the patient developed scaly, erythematous maculopapular lesions over the face. Intradermal skin test reaction to progesterone was positive. Progesterone sensitivity was also demonstrated by challenge test with intramuscular progesterone acetate. These features were consistent with the diagnosis of APD. Our patient was treated successfully with conjugated estrogen for 6 months. At one year follow-up, the patient had had no recurrence of facial eruption.     

A case of autoimmune progesterone dermatitis diagnosed by progesterone pessary

Autoimmune progesterone dermatitis is a rare, cyclical eruption that occurs in the luteal phase of the menstrual cycle and during pregnancy. Many manifestations have been reported including cyclical eczema, urticaria, erythema multiforme, stomatitis and even anaphylaxis. The condition spontaneously resolves after menopause. As histopathology is non-specific, the diagnosis rests on history with precipitation of the eruption by a progesterone challenge, usually by the intradermal, intramuscular or oral route. We present the case of a 34-year-old woman with a premenstrual papular and eczematous eruption that was exacerbated after pregnancy. Biopsy showed subacute spongiotic dermatitis. To confirm the diagnosis, we used an intravaginal progesterone pessary as a provocation challenge. There was recurrence of the rash 12 h after insertion of the pessary with spontaneous resolution thereafter. We propose that use of a progesterone pessary is an effective tool in the diagnosis of autoimmune progesterone dermatitis.     

Comparison of nickel patch test reactivity in phases of the menstrual cycle

BACKGROUND: In earlier studies, it has been shown that severity of some diseases varies with menstrual cycle. Severity of skin diseases such as atopic dermatitis, lupus erythematosus, infections due to herpes virus, urticaria and acne were also reported to increase in the premenstrual phase. Effect of estradiol on the cellular immune system was investigated and it was found to depress the cellular immune response. In our study, we investigated whether nickel patch test reactivity was different during phases of the menstrual cycle and whether there was an increase in sensitivity to nickel during the premenstrual cycle in nickel-sensitive women. METHODS: The study consisted of 30 women who had a history of nickel sensitivity. Finn Chamber nickel patch test was applied to all 30 women by dividing them into two groups of 15 and applying the test first on days 7-10 and then on days 20-24 of the menstrual cycle or vice versa. RESULTS: The reactions of both the groups on days 20-24 were more severe than those on days 7-10 even though the results were not statistically significant. CONCLUSIONS: Estrogens not only impair the skin barrier but also have a negative impact on the immune system. Estradiol has been proved to suppress cellular immunity. In a few studies conducted to date, the relationship between phases of the menstrual cycle and the severity of patch test reactivity has been examined with equivocal results. In our study, we observed that the presence of reactions due to nickel sensitivity was independent of the phases of the menstrual cycle. Nevertheless, we would like to point out the fact that the reactions seen in the second phase of the menstrual cycle were more severe than those seen in the first phase.     

Unilateral naevoid telangiectatic syndrome—a study of two cases

Two cases of Unilateral Naevoid Telangiectatic Syndrome (UNTS) are described; in one of them the early follicular phase oestrogen level was elevated. The oestrogen receptor concentration was estimated in skin samples taken from involved and uninvolved sites in both patients. In one patient, receptors were undetectable (< 2 fmol/mg protein) in either involved or uninvolved skin; in the second patient, receptors were again undetectable in uninvolved skin but a trace of receptor activity (6 fmol mg protein) was detected in the involved skin sample.     

Skin extensibility time in women. Changes in relation to sex hormones

The influence of female sex hormones on mechanical properties of the skin has been assessed in an in vivo extensometric study. Twenty young (20 +/- 4 years) and 12 middle-aged healthy women (42 +/- 3 years) entered the study. Measurements were carried out on the volar surface of the left forearm on the 10th and 25th day of the menstrual cycle. A significantly decreased skin extensibility time in the pre-menstrual phase was found (25th day) when compared with the 10th day in the young group, while the older one did not reveal significant changes. The data are compatible with an increased water content of the skin noticeable in the pre-menstrual phase and more relevant in young women. In studies on mechanical properties of the skin, changes relative to sex hormones and menstrual cycle need to be taken into account.     

Menstrual cycle and skin reactivity

The hypothesis was tested that a cyclic variation exists in skin reactivity to irritant stimuli. Twenty-nine healthy women with regular menstrual cycles were challenged with sodium lauryl sulfate as an irritant patch test at day 1 and at days 9 through 11 of the menstrual cycle. The skin response to the applied irritant stimulus was evaluated by visual scoring and also quantified by measurements of transepidermal water loss, edema formation, and blood flow in the skin. The skin response to challenge with sodium lauryl sulfate was found to be significantly stronger at day 1 than at days 9 through 11 in the menstrual cycle as evaluated by visual scoring (p less than 0.05) as well as by measurement of transepidermal water loss (p less than 0.05) and edema formation (p less than 0.005).     

Autoimmune progesterone dermatitis: absence of contact sensitivity to glucocorticoids, oestrogen and 17-α-OH-progesterone

Autoimmune progesterone dermatitis is a rare condition, characterized by recurrent premenstrual exacerbations of a dermatosis, in which sensitivity to progesterone can be demonstrated. The sensitizing mechanism is unknown. The aim of this study was to test the hypothesis that cross-sensitivity between steroid groups could induce allergy to endogenous progesterone in these patients. 5 patients with autoimmune progesterone dermatitis and 1 with oestrogen-sensitive dermatitis have been patch tested with a corticosteroid series, conjugated oestrogen 1% in petrolatum (pet.), and 17-α-OH-progesterone 2% pet. There were no immediate or delayed reactions at 2 and 4 days to any steroid group. We have therefore been unable to demonstrate steroid cross-sensitivity, or a use for 17-α-OH-progesterone in the investigation of oestrogen - and progesterone-sensitive dermatoses.     

Treatment of severe atopic dermatitis with extracorporeal photopheresis

Extracorporeal photopheresis using UVA irradiation of enriched lymphocytes in the presence of 8-methoxypsoralen (8-MOP) as a photoactivatable substrate has been employed for the treatment of several immunologically mediated disorders. We report on the first three patients subjected to extracorporeal photopheresis for severe atopic dermatitis. All patients had a lifelong history of atopic skin inflammation, and their disease had finally become resistant to well-established therapeutic regimes. Extracorporeal photopheresis resulted in a marked clinical improvement in the skin lesions of all patients. The decrease in cutaneous inflammatory activity became evident by the end of the second photopheresis cycle. In two patients skin lesions had virtually disappeared after the fifth treatment cycle, while in the third patient a lasting and substantial improvement in pruritus and erythema was achieved. Clinical remission was stable under maintenance therapy with prolonged intervals between photopheresis sessions. Therapeutic efficacy was reflected by a marked reduction in IgE serum levels in all three patients, while serum concentration of IgG, IgM and IgA as well as the profile of circulating lymphocytes remained essentially unchanged. No clinical signs of immunosuppression or other severe adverse events became evident. Collectively, our preliminary results indicate that extracorporeal photopheresis may interfere with the pathomechanisms leading to atopic dermatitis and therefore should be considered as a treatment modality for severe forms of this recalcitrant disorder.