CED
Clinical dermatology • Concise report
Clinical and Experimental Dermatology
Catamenial dermatoses: has anyone ever considered prostaglandins? R. Verdolini,1 R. Atkar,1 N.Clayton,2 R. Hasan3 and C. M. Stefanato4 1 Department of Dermatology, Princess Alexandra Hospital, Harlow, Essex, UK; 2Department of Dermatology and 3Institute of Pathology, Royal London Hospital, London, UK; and 4Department of Dermatopathology, St John’s Institute of Dermatology, St Thomas’ Hospital, London, UK
doi:10.1111/ced.12333
Summary
Catamenial dermatoses are unusual, cyclic, perimenstrual reactions to hormones produced during the menstrual cycle. They occur in a variety of clinical presentations, including urticaria, eczema, fixed drug eruptions, erythema multiforme and anaphylaxis. Autoimmune progesterone dermatitis is the most common, and is caused by an autoimmune response to endogenous progesterone in women of reproductive age. We report a case of catamenial dermatosis in a 42-year-old Jamaican woman with a 10-year history of cyclic blistering and ulcerative eruptions of her mouth and limbs. Her symptoms were fully in keeping with a Stevens–Johnson-type reaction, and were associated with production of prostaglandins occurring during her menstrual cycle.
It has long been documented that a variety of skin conditions can become exacerbated during particular phases of the menstrual cycle. The pathogenesis of such diseases is poorly understood. They have been attributed to fluctuations in reproductive hormones, especially progesterone and, less commonly, oestrogens. Catamenial dermatoses are cyclical skin reactions to hormones produced during the menstrual cycle.1,2 The most common of these reactions is autoimmune progesterone dermatitis (APD), which is caused by an autoimmune response to endogenous progesterone in women of reproductive age.3 We present a case of recurrent Stevens–Johnson (SJS)-type reaction associated with the production of prostaglandins (PGs) during the menstrual cycle.
Report A 42-year-old Jamaican woman presented with a clinical history of cyclical blistering eruptions of the Correspondence: Dr Roberto Verdolini, Department of Dermatology, Princess Alexandra Hospital NHS Trust, St Margaret’s Hospital, The Plain, Epping, Essex, CM16 6TN, UK E-mail: [email protected] Conflict of interest: the authors declare that they have no conflicts of interest. Accepted for publication 5 December 2013
ª 2014 British Association of Dermatologists
extremities associated with oral ulceration, spiking temperatures and malaise, which had been present for a period in excess of 10 years. The symptoms consistently appeared a few minutes prior to the onset of her menses, and resolved within 5 days of her menstrual cycle. The patient’s symptoms resolved each time with the administration of prednisolone at a dose of 40 mg daily for 5–6 days, usually started at the onset of the symptoms. Prophylactic courses had also been attempted, with good response, by administering prednisolone 1 day before the presumptive menstrual date, and continuing it for 5 days during the menstrual cycle. However, the patient was happy to have access to the treatment and to be able to start it at the first onset of the symptoms, and this had become her choice of monthly routine. Her only other relevant medical history was a long-standing history of endometriosis. On physical examination, the patient was seen to have aphthous ulceration of the tongue, buccal mucosa and lower lip, as well as erythematous, targetoid plaques over her hands (Fig. 1a, b). Histopathology of a lesion biopsied from the dorsum of one of the fingers showed interface changes with subepidermal clefting, dyskeratotic keratinocytes, and a mild lichenoid lymphocytic infiltrate of the superficial dermis, consistent with bullous erythema multiforme (Fig. 1c).
Clinical and Experimental Dermatology (2014) 39, pp509–512
509
Catamenial dermatoses: association with prostaglandins? R. Verdolini et al.
(a)
(b)
(c)
Figure 1 (a) Aphthous ulceration of the lower lip, tongue and
buccal mucosa. (b) Erythematous, targetoid plaques, with central vesiculation and bullae formation, over the dorsum of the fingers. (c) A biopsy taken from one of the fingers showed interface dermatitis with dermoepidermal separation and mild lymphocytic infiltrate in the papillary dermis. Diffuse confluent epidermal keratinocytic necrosis, consistent with bullous erythema multiforme was also visible. Haematoxylin and eosin, original magnification 9 200.
510
Clinical and Experimental Dermatology (2014) 39, pp509–512
Laboratory investigations including complement level, autoimmune screening and herpes serology all gave negative results. Direct immunofluorescence was also negative. Because of the striking direct correlation between the onset of symptoms and the patient’s menstrual cycle, a provisional diagnosis of APD was considered, and a trial with tamoxifen was commenced;4 however, there was no improvement. A prick test was carried out by intradermally injecting 0.01 mL of a 50 mg/mL progesterone aqueous suspension into the forearm, which gave no reaction.5 This negative result was complemented by a complete lack of reaction to intravaginal application of 8% progesterone gel (Crinone; Merck Serono, Darmstadt, Germany). An alternative trigger, such as oestrogen sensitivity, was therefore considered. Our patient, however, had never reported any reactions to medications containing oestrogen, such as the oral contraceptive pill.6,7 A test carried out by applying oestrogen only content cream, using 0.1% oestriol intravaginal cream (Ovestin; Organon, Oss, the Netherlands) resulted in no reaction, excluding the likelihood of an oestrogenrelated dermatosis. Careful monitoring of possible hormonal triggers produced immediately before and during the menstrual cycle raised the possibility of PGs released from the contracting uterus being a possible aetiological factor. A prick test was performed by subcutaneously injecting 0.01 mL of a PG-F2 analogue (carboprost tromethamine; Hemabate; Pfizer, Zaventem, Belgium) at two different dilutions (250 lg/10 mL and 250 lg/1 mL) resulted in a positive reaction for both concentrations (Fig. 2a). Moreover, 40–50 min after the prick test, there was an onset of new, tiny blisters, similar to the lesions of EM, on the fingers at the same side as the injection. A skin biopsy was taken from the site of the prick test 12–13 min after the injection, and histological1 examination revealed a neutrophilic vasculitis with neutrophils and neutrophilic dust, consistent with urticarial vasculitis (Fig. 2b). Treatment with the gonadotropin-releasing factor analogue buserelin and the PG inhibitor mefenamic acid induced only a limited response. The patient underwent hysterectomy because of complications caused by her endometriosis. Following her surgery, the skin symptoms completely resolved, and she remains symptom-free. Establishing the possible underlying trigger of recurrent EM may represent a difficult challenge.8 In our case, a provisional diagnosis of recurrent EM due to
ª 2014 British Association of Dermatologists
Catamenial dermatoses: association with prostaglandins? R. Verdolini et al.
(a)
(a)
(b)
(b)
Figure 3 Timeline showing release of (a) progesterone and (b)
oestrogen during the menstrual cycle. The arrows indicate the stage of the menstrual cycle when the reactions usually occur; yellow for progesterone-induced and light blue for oestrogeninduced dermatitis. The red arrows indicate the moment of the cycle when the reaction occurred in our patient at the beginning of the cycle, when release of prostaglandins starts.
Figure 2 (a) Clinical image of urticarial reaction after prick test-
ing with a prostaglandin-F2 analogue demonstrates a positive response with an urticarial, erythematous area occurring 10– 15 min after the test. Control prick test with the solvent (water for injection) only remained negative. (b) A punch biopsy taken from the site of the prick test, 25 min after the intradermal inoculation of the prostaglandin-F2 revealed changes in keeping with urticarial vasculitis. Haematoxylin and eosin, original magnification 9100.
herpes simplx virus (HSV), which is recognized as the most common underlying aetiology, was initially considered. However, we had carried out HSV serology
ª 2014 British Association of Dermatologists
testing when the patient initially presented to us; this was negative, and there was no response to aciclovir treatment. When the direct correlation between the patient’s symptoms and her menstrual cycle was recognized, catamenial dermatitis became our working diagnosis. The most common of these conditions, APD, is triggered by the release of progesterone in the luteal phase of the menstrual cycle1–3 (Fig. 3a). In our case, however, tests for progesterone sensitivity completely failed to elicit a reaction. An oestrogen-related dermatosis was subsequently considered, but again confidently excluded. Monitoring of possible hormonal triggers released at the beginning of the menstrual blood loss raised the possibility that PGs played a role. PGs are hormone-like compounds released from the endometrium, which result in contractions of the uterine smooth muscle and sloughing of the degraded endometrial tissue. Together with leucotrienes, they are part of the cascade of molecular events that leads
Clinical and Experimental Dermatology (2014) 39, pp509–512
511
Catamenial dermatoses: association with prostaglandins? R. Verdolini et al.
to erythema and inflammation, and may induce a falsely positive response to both prick and patch tests.9,10 However, the onset of a blistering rash on our patient’s fingers after undergoing a prick test with PG-F2, together with the strong relationship between prostaglandin release and the occurrence or the rash, suggest that this hormone (or other structurally similar PGs) was the primary cause of the dermatitis. Figure 3 compares the timing of progesterone, oestrogen and prostaglandin fluctuations related to the menstrual cycle. APD is apparent 3–10 days prior to menstrual shedding, coinciding with the peak at day 21 of the menstrual cycle, and resolves within 2 days of menses (Fig. 3a). Oestrogens peak at day 14 and day 216,7 (Fig. 3b). PG release occurs at day 1 of the menstrual cycle, which would fit with the clinical presentation in our case (Fig. 3a,b). It is possible that a number of catamenial dermatoses labelled as APD are caused instead by PGs, especially when the timing of the rash is not supportive for progesterone or oestrogen as possible triggers.
Learning points ● Catamenial dermatoses are rare, cyclic, peri-
menstrual reactions to hormones produced during the menstrual cycle. ● The clinical presentations vary from urticaria, eczema, vesiculopustular rashes, fixed drug eruptions, stomatitis, EM, and anaphylaxis. ● The most commonly known triggers are progesterone and oestrogen. ● PGs may represent an additional trigger, and should be included in the list for catamenial dermatoses.
512
Clinical and Experimental Dermatology (2014) 39, pp509–512
References 1 Halevy S, Cohen AD, Lunenfeld E, Grossman N. Autoimmune progesterone dermatitis manifested as erythema annulare centrifugum: confirmation of progesterone sensitivity by in vitro interferon-gamma release. J Am Acad Dermatol 2002; 47: 311–13. 2 Wojnarowska F, Greaves MW, Peachey RD et al. Progesterone-induced erythema multiforme. J R Soc Med 1985; 78: 407–8. 3 Chawla SV, Quirk C, Sondheimer SJ et al. Autoimmune progesterone dermatitis. Arch Dermatol 2009; 145: 341–2. 4 Stephens CJ, Wojnarowska FT, Wilkinson JD. Autoimmune progesterone dermatitis responding to Tamoxifen. Br J Dermatol 1989; 121: 135–7. 5 Stranahan D, Rausch D, Deng A et al. The role of intradermal skin testing and patch testing in the diagnosis of autoimmune progesterone dermatitis. Dermatitis 2006; 17: 39–42. 6 Coustou D, Gautier C, Ducombs G et al. Dermatitis caused by estrogens. Ann Dermatol Venereol 1998; 125: 484–5. 7 Murano K, Koyano T. Estrogen dermatitis that appeared twice in each menstrual period. J Dermatol 2003; 30: 719–22. 8 Wetter DA, Davis MDP. Recurrent erythema multiforme: clinical characteristics, etiologic associations, and treatment in a series of 48 patients at Mayo Clinic, 2000 to 2007. J Am Acad Dermatol 2010; 62: 45–53. 9 Jøorgensen HP, Søondergaard J. Biosynthesis of prostaglandins in human allergic contact dermatitis. Arch Dermatol Res 1976; 257: 143–7. 10 Saarinen JV, Harvima RJ, Horsmanheimo M et al. Modulation of the immediate allergic wheal reaction in the skin by drugs inhibiting the effects of leukotriene C4 and prostaglandin D2. Eur J Clin Pharmacol 2001; 57: 1–4.
ª 2014 British Association of Dermatologists
Clinical dermatology • Concise report
Clinical and Experimental Dermatology
Catamenial dermatoses: has anyone ever considered prostaglandins? R. Verdolini,1 R. Atkar,1 N.Clayton,2 R. Hasan3 and C. M. Stefanato4 1 Department of Dermatology, Princess Alexandra Hospital, Harlow, Essex, UK; 2Department of Dermatology and 3Institute of Pathology, Royal London Hospital, London, UK; and 4Department of Dermatopathology, St John’s Institute of Dermatology, St Thomas’ Hospital, London, UK
doi:10.1111/ced.12333
Summary
Catamenial dermatoses are unusual, cyclic, perimenstrual reactions to hormones produced during the menstrual cycle. They occur in a variety of clinical presentations, including urticaria, eczema, fixed drug eruptions, erythema multiforme and anaphylaxis. Autoimmune progesterone dermatitis is the most common, and is caused by an autoimmune response to endogenous progesterone in women of reproductive age. We report a case of catamenial dermatosis in a 42-year-old Jamaican woman with a 10-year history of cyclic blistering and ulcerative eruptions of her mouth and limbs. Her symptoms were fully in keeping with a Stevens–Johnson-type reaction, and were associated with production of prostaglandins occurring during her menstrual cycle.
It has long been documented that a variety of skin conditions can become exacerbated during particular phases of the menstrual cycle. The pathogenesis of such diseases is poorly understood. They have been attributed to fluctuations in reproductive hormones, especially progesterone and, less commonly, oestrogens. Catamenial dermatoses are cyclical skin reactions to hormones produced during the menstrual cycle.1,2 The most common of these reactions is autoimmune progesterone dermatitis (APD), which is caused by an autoimmune response to endogenous progesterone in women of reproductive age.3 We present a case of recurrent Stevens–Johnson (SJS)-type reaction associated with the production of prostaglandins (PGs) during the menstrual cycle.
Report A 42-year-old Jamaican woman presented with a clinical history of cyclical blistering eruptions of the Correspondence: Dr Roberto Verdolini, Department of Dermatology, Princess Alexandra Hospital NHS Trust, St Margaret’s Hospital, The Plain, Epping, Essex, CM16 6TN, UK E-mail: [email protected] Conflict of interest: the authors declare that they have no conflicts of interest. Accepted for publication 5 December 2013
ª 2014 British Association of Dermatologists
extremities associated with oral ulceration, spiking temperatures and malaise, which had been present for a period in excess of 10 years. The symptoms consistently appeared a few minutes prior to the onset of her menses, and resolved within 5 days of her menstrual cycle. The patient’s symptoms resolved each time with the administration of prednisolone at a dose of 40 mg daily for 5–6 days, usually started at the onset of the symptoms. Prophylactic courses had also been attempted, with good response, by administering prednisolone 1 day before the presumptive menstrual date, and continuing it for 5 days during the menstrual cycle. However, the patient was happy to have access to the treatment and to be able to start it at the first onset of the symptoms, and this had become her choice of monthly routine. Her only other relevant medical history was a long-standing history of endometriosis. On physical examination, the patient was seen to have aphthous ulceration of the tongue, buccal mucosa and lower lip, as well as erythematous, targetoid plaques over her hands (Fig. 1a, b). Histopathology of a lesion biopsied from the dorsum of one of the fingers showed interface changes with subepidermal clefting, dyskeratotic keratinocytes, and a mild lichenoid lymphocytic infiltrate of the superficial dermis, consistent with bullous erythema multiforme (Fig. 1c).
Clinical and Experimental Dermatology (2014) 39, pp509–512
509
Catamenial dermatoses: association with prostaglandins? R. Verdolini et al.
(a)
(b)
(c)
Figure 1 (a) Aphthous ulceration of the lower lip, tongue and
buccal mucosa. (b) Erythematous, targetoid plaques, with central vesiculation and bullae formation, over the dorsum of the fingers. (c) A biopsy taken from one of the fingers showed interface dermatitis with dermoepidermal separation and mild lymphocytic infiltrate in the papillary dermis. Diffuse confluent epidermal keratinocytic necrosis, consistent with bullous erythema multiforme was also visible. Haematoxylin and eosin, original magnification 9 200.
510
Clinical and Experimental Dermatology (2014) 39, pp509–512
Laboratory investigations including complement level, autoimmune screening and herpes serology all gave negative results. Direct immunofluorescence was also negative. Because of the striking direct correlation between the onset of symptoms and the patient’s menstrual cycle, a provisional diagnosis of APD was considered, and a trial with tamoxifen was commenced;4 however, there was no improvement. A prick test was carried out by intradermally injecting 0.01 mL of a 50 mg/mL progesterone aqueous suspension into the forearm, which gave no reaction.5 This negative result was complemented by a complete lack of reaction to intravaginal application of 8% progesterone gel (Crinone; Merck Serono, Darmstadt, Germany). An alternative trigger, such as oestrogen sensitivity, was therefore considered. Our patient, however, had never reported any reactions to medications containing oestrogen, such as the oral contraceptive pill.6,7 A test carried out by applying oestrogen only content cream, using 0.1% oestriol intravaginal cream (Ovestin; Organon, Oss, the Netherlands) resulted in no reaction, excluding the likelihood of an oestrogenrelated dermatosis. Careful monitoring of possible hormonal triggers produced immediately before and during the menstrual cycle raised the possibility of PGs released from the contracting uterus being a possible aetiological factor. A prick test was performed by subcutaneously injecting 0.01 mL of a PG-F2 analogue (carboprost tromethamine; Hemabate; Pfizer, Zaventem, Belgium) at two different dilutions (250 lg/10 mL and 250 lg/1 mL) resulted in a positive reaction for both concentrations (Fig. 2a). Moreover, 40–50 min after the prick test, there was an onset of new, tiny blisters, similar to the lesions of EM, on the fingers at the same side as the injection. A skin biopsy was taken from the site of the prick test 12–13 min after the injection, and histological1 examination revealed a neutrophilic vasculitis with neutrophils and neutrophilic dust, consistent with urticarial vasculitis (Fig. 2b). Treatment with the gonadotropin-releasing factor analogue buserelin and the PG inhibitor mefenamic acid induced only a limited response. The patient underwent hysterectomy because of complications caused by her endometriosis. Following her surgery, the skin symptoms completely resolved, and she remains symptom-free. Establishing the possible underlying trigger of recurrent EM may represent a difficult challenge.8 In our case, a provisional diagnosis of recurrent EM due to
ª 2014 British Association of Dermatologists
Catamenial dermatoses: association with prostaglandins? R. Verdolini et al.
(a)
(a)
(b)
(b)
Figure 3 Timeline showing release of (a) progesterone and (b)
oestrogen during the menstrual cycle. The arrows indicate the stage of the menstrual cycle when the reactions usually occur; yellow for progesterone-induced and light blue for oestrogeninduced dermatitis. The red arrows indicate the moment of the cycle when the reaction occurred in our patient at the beginning of the cycle, when release of prostaglandins starts.
Figure 2 (a) Clinical image of urticarial reaction after prick test-
ing with a prostaglandin-F2 analogue demonstrates a positive response with an urticarial, erythematous area occurring 10– 15 min after the test. Control prick test with the solvent (water for injection) only remained negative. (b) A punch biopsy taken from the site of the prick test, 25 min after the intradermal inoculation of the prostaglandin-F2 revealed changes in keeping with urticarial vasculitis. Haematoxylin and eosin, original magnification 9100.
herpes simplx virus (HSV), which is recognized as the most common underlying aetiology, was initially considered. However, we had carried out HSV serology
ª 2014 British Association of Dermatologists
testing when the patient initially presented to us; this was negative, and there was no response to aciclovir treatment. When the direct correlation between the patient’s symptoms and her menstrual cycle was recognized, catamenial dermatitis became our working diagnosis. The most common of these conditions, APD, is triggered by the release of progesterone in the luteal phase of the menstrual cycle1–3 (Fig. 3a). In our case, however, tests for progesterone sensitivity completely failed to elicit a reaction. An oestrogen-related dermatosis was subsequently considered, but again confidently excluded. Monitoring of possible hormonal triggers released at the beginning of the menstrual blood loss raised the possibility that PGs played a role. PGs are hormone-like compounds released from the endometrium, which result in contractions of the uterine smooth muscle and sloughing of the degraded endometrial tissue. Together with leucotrienes, they are part of the cascade of molecular events that leads
Clinical and Experimental Dermatology (2014) 39, pp509–512
511
Catamenial dermatoses: association with prostaglandins? R. Verdolini et al.
to erythema and inflammation, and may induce a falsely positive response to both prick and patch tests.9,10 However, the onset of a blistering rash on our patient’s fingers after undergoing a prick test with PG-F2, together with the strong relationship between prostaglandin release and the occurrence or the rash, suggest that this hormone (or other structurally similar PGs) was the primary cause of the dermatitis. Figure 3 compares the timing of progesterone, oestrogen and prostaglandin fluctuations related to the menstrual cycle. APD is apparent 3–10 days prior to menstrual shedding, coinciding with the peak at day 21 of the menstrual cycle, and resolves within 2 days of menses (Fig. 3a). Oestrogens peak at day 14 and day 216,7 (Fig. 3b). PG release occurs at day 1 of the menstrual cycle, which would fit with the clinical presentation in our case (Fig. 3a,b). It is possible that a number of catamenial dermatoses labelled as APD are caused instead by PGs, especially when the timing of the rash is not supportive for progesterone or oestrogen as possible triggers.
Learning points ● Catamenial dermatoses are rare, cyclic, peri-
menstrual reactions to hormones produced during the menstrual cycle. ● The clinical presentations vary from urticaria, eczema, vesiculopustular rashes, fixed drug eruptions, stomatitis, EM, and anaphylaxis. ● The most commonly known triggers are progesterone and oestrogen. ● PGs may represent an additional trigger, and should be included in the list for catamenial dermatoses.
512
Clinical and Experimental Dermatology (2014) 39, pp509–512
References 1 Halevy S, Cohen AD, Lunenfeld E, Grossman N. Autoimmune progesterone dermatitis manifested as erythema annulare centrifugum: confirmation of progesterone sensitivity by in vitro interferon-gamma release. J Am Acad Dermatol 2002; 47: 311–13. 2 Wojnarowska F, Greaves MW, Peachey RD et al. Progesterone-induced erythema multiforme. J R Soc Med 1985; 78: 407–8. 3 Chawla SV, Quirk C, Sondheimer SJ et al. Autoimmune progesterone dermatitis. Arch Dermatol 2009; 145: 341–2. 4 Stephens CJ, Wojnarowska FT, Wilkinson JD. Autoimmune progesterone dermatitis responding to Tamoxifen. Br J Dermatol 1989; 121: 135–7. 5 Stranahan D, Rausch D, Deng A et al. The role of intradermal skin testing and patch testing in the diagnosis of autoimmune progesterone dermatitis. Dermatitis 2006; 17: 39–42. 6 Coustou D, Gautier C, Ducombs G et al. Dermatitis caused by estrogens. Ann Dermatol Venereol 1998; 125: 484–5. 7 Murano K, Koyano T. Estrogen dermatitis that appeared twice in each menstrual period. J Dermatol 2003; 30: 719–22. 8 Wetter DA, Davis MDP. Recurrent erythema multiforme: clinical characteristics, etiologic associations, and treatment in a series of 48 patients at Mayo Clinic, 2000 to 2007. J Am Acad Dermatol 2010; 62: 45–53. 9 Jøorgensen HP, Søondergaard J. Biosynthesis of prostaglandins in human allergic contact dermatitis. Arch Dermatol Res 1976; 257: 143–7. 10 Saarinen JV, Harvima RJ, Horsmanheimo M et al. Modulation of the immediate allergic wheal reaction in the skin by drugs inhibiting the effects of leukotriene C4 and prostaglandin D2. Eur J Clin Pharmacol 2001; 57: 1–4.
ª 2014 British Association of Dermatologists
