CED
Clinical dermatology • Review article
Clinical and Experimental Dermatology
CPD
The menstrual cycle and the skin R. S. Raghunath, Z. C. Venables and G. W. M. Millington Department of Dermatology, Norfolk and Norwich University Hospital, Norwich, UK doi:10.1111/ced.12588
Summary
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.
Introduction The fluctuations in oestrogen and progesterone that define menstruation are associated with numerous physiological and psychosocial changes. Despite vast improvements in our understanding of reproductive endocrinology, we have limited understanding of the effect of these hormonal changes on the skin; nevertheless, it is clear that several skin diseases are influenced by them (Table 1).1,2 In this article, we explore the clinical manifestations and mechanisms of the menstrual cycle and its effect on the skin. A better understanding of these mechanisms may improve the management of perimenstrual dermatoses in the future.
Physiology of the menstrual cycle and its effect on skin Much of our understanding of the effects of oestrogen on the skin is based upon observations of the effects of its Correspondence: Dr Rakhi Singh Raghunath, Norfolk and Norwich University Hospital, Norwich, UK E-mail: [email protected] Conflict of interest: RSR and ZV declare that they have no conflicts of interest. GWMM is the current editor of Clinical and Experimental Dermatology. Accepted for publication 10 September 2014
ª 2015 British Association of Dermatologists
reduced levels in postmenopausal women and from in vitro and animal studies.3 The production of hormones during the menstrual cycle is shown in Fig. 1, with associated dermatoses shown in Fig. 2.4 Oestrogen is important for the normal functioning of many structures in the epidermis and dermis, including the vasculature, hair follicles, sebaceous/apocrine glands, eccrine glands and melanocytes.5,6 In cultured human cells, oestrogen receptor (ER)b, progesterone and androgen receptors are expressed in keratinocytes, fibroblasts and macrophages in the skin. ERa receptors are found in skin fibroblasts and macrophages, but not keratinocytes.7,8 ERa and b receptors are also found on melanocytes.6 Oestrogen is associated with collagen synthesis, increased skin thickness and dermal water content (through hyaluronic acid production), and improved barrier function and wound healing.3 In postmenopausal women, low levels of oestrogen cause collagen atrophy and reduced water content.3 Oestrogen also stimulates melanogenesis, along with thyroxine and melanocytestimulating hormone, and this can result in premenstrual hyperpigmentation.1,6,9 The effects of oestrogen on pigmentation were first inferred from changes in pigmentation observed during pregnancy, including patches of increased pigmentation on the face, and darkening of the skin of the areolae, the perineum, and the skin over the linea alba, which fades shortly after delivery.1 Hyperpig-
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The menstrual cycle and the skin R. S. Raghunath et al.
Table 1 Dermatoses exacerbated during the menstrual cycle. References
Acne vulgaris Aphthous ulceration Atopic eczema Autoimmune progesterone dermatitis Autoimmune oestrogen dermatitis Dermatitis Herpetiformis Erythema multiforme Herpes simplex Hyperpigmentation Lichen Planus Lupus erythematosus Pompholyx Pruritus vulvae Psoriasis Rosacea Solitary Fibrous tumor Urticaria
4,10 4,10 4,23 13,14,16,18 12 4 4 10 10 4 4 4 4 4 4,10
Day
1
5
9
13
Phase Menstrual Follicular APD OD Acne AD
17
21
25
Luteal
Postmenopausal
30 4,10
Figure 2 Timescale showing when different perimenstrual dermatoses commonly occur during the menstrual cycle, e.g. APD occurs 3– 10 days before and 5–10 days after menstruation. AD, atopic dermatitis, OD, oestrogen dermatitis.
Oestrogen Progesterone Ovulation
Production
Oestrogen Progesterone Ovulation
Production
Dermatosis
mones (perimenstruation) are associated with heightened patch test reactivity, which account for exacerbations in atopic patients.10 This suggests that oestrogen and progesterone may inhibit cellular immunity.10
Autoimmune progesterone dermatitis and oestrogen dermatitis Day
1
5
9
13
Phase Menstrual Follicular
17
21 Luteal
25 Postmenopausal
Figure 1 The menstrual cycle begins with onset of menstruation on day 1, and the thickened endometrium is shed over 4–6 days (menstrual phase).4 Days 7–14 represent the follicular phase, which culminates in ovulation. The ovary is the main source of oestrogen in premenopausal women; it produces several types of oestrogen, of which oestradiol is the most potent. Oestradiol production steadily increases during the week prior to ovulation, and peaks 1 day prior to ovulation. This is followed by the luteal phase from day 14 to day 28. Ovulation results in the formation of the corpus luteum, which produces progesterone in the week following ovulation. Oestradiol rises again in the luteal phase, and has a second peak 5 days after ovulation. In the later stages of the luteal phase, oestrogen and progesterone levels decline, resulting in menstruation and the cycle restarts.3
mentation is also observed in some women using oral contraceptives.1 Oestrogens induce salt and water retention, causing oedema of the hands and feet, which is a feature of premenstrual syndrome.5 The effects of progesterone are less clear. During the second phase of menstruation, there is increased vascularity and increased sebum production, which has been attributed to the effect of progesterone.4 Studies show that elevated levels of oestrogen and progesterone in the periovulatory period inhibit delayed-type hypersensitivity reactions, while lower levels of both hor-
112
Clinical and Experimental Dermatology (2015) 40, pp111–115
Autoimmune progesterone dermatitis (APD) is a rare mucocutaneous disease characterized by cyclical skin changes, as a result of progesterone produced during the luteal phase of the menstrual cycle, hence it does not occur in post-menopausal women.11,12 The skin manifestations can vary from eczema, erythema multiforme (EM), purpura and petechiae, dermatitis herpetiformis, fixed drug eruption and stomatitis to urticaria, angio-oedema and anaphylaxis2,11–14,16 (Fig. 3a, Table 2). The symptoms usually start 3–10 days prior to the onset of menses, and can last up to 5–10 days after this onset.11,12 In women with irregular periods, the correlation might not be as obvious, and thus the patient might have the symptoms for several years prior to diagnosis.11,12 A similar entity related to sensitivity to oestrogens in the premenstrual period, known as oestrogen dermatitis (OD), has also been described.11,12 The pathogenesis of APD is not entirely clear. Intradermal test results to progesterone can produce both type 1 and type 4 hypersensitivity reactions.13,14 Oestrogen is processed by the skin as a foreign antigen and presented to immunocompetent cells, leading to an autoimmune response to endogenous oestrogen.15 Similar mechanisms have been proposed for progesterone autoimmunity.16 Previous exposure to progesterone in oral contraceptives or during pregnancy in predisposed individuals leads to hypersensitivity to endogenous hormones
ª 2015 British Association of Dermatologists
The menstrual cycle and the skin R. S. Raghunath et al.
(a)
cycle.21 Patients have been successfully treated with conjugated oestrogens,21 gonadotrophin hormone-releasing analogues,19 tamoxifen,16 danazol22 and bilateral oophorectomy.18 OD has also been shown to respond to the anti-oestrogen agent tamoxifen.12,23 Hormone desensitization has been tried as a potential treatment, although this is not used routinely in clinical practice.15
Other dermatoses exacerbated by menstruation (b)
Figure 3 (a) Macular rash in autoimmune progesterone dermatitis; (b) papular and scarring acne in a menstruating woman.
and APD in later life.12,15 However, APD resolves during pregnancy.17 It is suggested that the gradual rise of progesterone during pregnancy acts as a desensitizing agent, ultimately reducing symptoms. Owing to increased production of anti-inflammatory glucocorticoids during pregnancy, the decrease in maternal immune response also plays a role in improving symptoms.17 Diagnosis of APD is based on the appearance of recurrent skin lesions in relation to the menstrual cycle and demonstrating progesterone sensitivity by intradermal, intramuscular or vaginal administration of progesterone.16,18,19 There are no specific histological findings for the disorder, although there may be perivascular lymphocytic inflammation, with eosinophils.20 Direct immunofluorescence is negative.20 The main aim of therapy in APD is to suppress the progesterone surge during the luteal phase of the menstrual
ª 2015 British Association of Dermatologists
Dermatoses such as atopic and contact dermatitis, psoriasis, acne and even EM and solitary fibrous tumour may be exacerbated premenstrually or perimenstrually.2,10,23– 30 Nearly half of all patients with atopic eczema experience deterioration in their condition in the week prior to the menstruation, with the exacerbation rapidly settling after the onset of menstrual flow.23 Skin barrier permeability is greater just prior to menstruation.10 This increases the susceptibility of skin to the effects of both environmental allergens and general irritants, which partially explains the premenopausal flares of eczema in some women.13,26 Psoriasis has many aggravating and alleviating factors, hormonal influences being one of them.24 The perimenopausal worsening of symptoms of psoriasis has been shown to be blocked by coincidental long-term antioestrogen therapy, such as tamoxifen, thus supporting the influence of oestrogens on symptoms of psoriasis.24 The influence of oestrogen on immunity is complex.25 T helper cells show a dose-dependent effect to oestrogens, and oestrogen also stimulates the production of regulatory T cells through ERa. The B-cell response to oestrogen is via ERb, causing increased antibody production.25 As psoriasis is now considered to be an immunological disease,26 these complex influences of oestrogen on the immune system explain the menstrual variation of psoriasis.25–27 Premenstrual exacerbation of acne is multifactorial (Fig. 3b).28 Higher levels of androgens and oestrogens during the follicular phase and periovulation causes increased sebum production, resulting in higher level of skin lipids and subsequent increase in skin microflora.28 The use of combined oestrogen/progesterone contraceptives cause improvement in acne by suppressing the androgens secreted from the ovary, and increasing the levels of sex hormone-binding globulin, thus decreasing the amount of free, biologically active androgens.29 In addition, progesterone blocks the androgen receptors, inhibiting the action of circulating androgens. Hence, the premenstrual exacerbation of acne can be explained by the low levels of progesterone in the latter stage of the menstrual cycle. A perimenstrual EM-like eruption has also recently been reported, with prostaglandins being implicated in its aetiology.2
Clinical and Experimental Dermatology (2015) 40, pp111–115
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Table 2 Clinical features of autoimmune progesterone dermatitis. Clinical feature
References
Angio-oedema Anaphylaxis Aphthous ulceration/stomatitis Dermatitis Eczema Erythema multiforme Fixed drug eruption Macules Palmoplantar dyshidrosis Papules Pompholyx Pruritus Stomatitis Urticaria Vesicles
12 2,12 2,12,16 4 2,11,13 2,11,13,14 2,16 12 12 11,13,14 4 14 4 2,11–14 2,12,13
Conclusion The dynamic effects of the cyclical changes in oestrogen and progesterone in women of reproductive age affect the severity of a range of inflammatory dermatoses, including some of the most common conditions seen in dermatology clinics and general practice. In addition, there are a number of rare perimenstrual disorders, of which APD is the best characterized.
Learning points ● Perimenstrual exacerbations of dermatoses are common and often overlooked. ● Hormonal variations and their action on the skin during various phases of the menstrual cycle explain the causes of perimenstrual exacerbations of dermatoses. ● APD and OD, although rare, are underdiagnosed, and treatment can be targeted to improve management and symptom control. ● Our article highlights the importance of recognizing perimenstrual dermatoses in order to provide patient-centred care.
References 1 Farage M, Neill S, MacLean AB. Physiological changes associated with the menstrual cycle: a review. Obstet Gynecol Surv 2009; 64: 58–72. 2 Verdolini R, Atkar R, Clayton N et al. Catamenial dermatoses: has anyone ever considered prostaglandins? Clin Exp Dermatol 2014; 39: 509–12. 3 Shah MG, Maibach HI. Estrogen and skin. Am J Clin Dermatol 2001; 2: 143–50.
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4 Stephens CJM. Perimenstrual eruptions. Clin Dermatol 1997; 15: 31–4. 5 Thornton MJ. The biological actions of estrogens on skin. Exp Dermatol 2002; 11: 487–502. 6 Videira IF, Moura DF, Magina S. Mechanisms regulating melanogenesis. An Bras Dermatol 2013; 88: 76–83. 7 Conrad F, Paus R. Estrogens and the hair follicle. J Dtsch Dermatol Ges 2004; 2: 412–23. 8 Kanda N, Watanabe S. Regulatory roles of sex hormones in cutaneous biology and immunology. J Dermatol Sci 2005; 38: 1–7. 9 Millington GWM. Proopiomelanocortin (POMC): the cutaneous roles of its melanocortin products and receptors. Clin Exp Dermatol 2006; 31: 407–12. 10 Farage M, Berardesca E, Maibach H. The possible relevance of sex hormones on irritant and allergic responses: their importance for skin testing. Contact Dermatitis 2010; 62: 67– 74. 11 Kumar A, Georgouras KE. Oestrogen dermatitis. Australas J Dermatol 1999; 40: 96–8. 12 Shelley WB, Shelley ED, Talanin NY et al. Estrogen dermatitis. J Am Acad Dermatol 1995; 32: 25–31. 13 Georgouras K. Autoimmune progesterone dermatitis. Australas J Dermatol 1981; 12: 109–12. 14 Poffet F, Abraham S, Taramarcaz P et al. Autoimmune progesterone dermatitis: potential role of cutaneous angiogenin expression. Dermatology 2011; 223: 32–5. 15 Itsekson A, Seidman DS, Zolti M et al. Steroid hormone hypersensitivity: clinical presentation and management. Fertil Steril 2011; 95: 2571–73. 16 Moghadam BK, Hersini S, Barker BF. Autoimmune progesterone dermatitis and stomatitis. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1998; 85: 537–41. 17 George R, Badawy SZA.Autoimmune progesterone dermatitis: a case report. Case Rep Obstet Gynecol 2012; 2012: 757854. 18 Rodenas H. Tercedor. Autoimmune progesterone dermatitis: treatment with oophorectomy. Br J Dermatol 1998; 139: 508–11. 19 Nemeth H, Kov acs E, G€ odeny S et al. Autoimmune progesterone dermatitis diagnosed by intravaginal progesterone provocation in a hysterectomised woman. Gynecol Endocrinol 2009; 25: 410–12. 20 Toms-Whittle LM, John LH, Griffiths DJ, Buckley DA. Autoimmune progesterone dermatitis: a diagnosis easily missed. Clin Exp Dermatol 2011; 36: 378–80. 21 Oskay T, Lale Kutluay L, Asli Kaptanocglu A et al. Autoimmune progesterone dermatitis. Eur J Dermatol 2002; 12: 589–91. 22 Shahar E, Bergman R, Pollack S. Autoimmune progesteron.e dermatitis: effective prophylactic treatment with danazol. Int J Dermatol 1997; 36: 708–711. 23 Kiriyama K, Sugiura H, Uehara M. Premenstrual deterioration of skin symptoms in female patients with atopic dermatitis. Dermatology 2003; 206: 110–112. 24 Boyd AS, King LE. Tamoxifen-induced remission of psoriasis. J Am Acad Dermatol 1999; 41: 887–89. 25 Cunningham M, Gilkeson G. Estrogen receptors in immunity and autoimmunity. Clin Rev Allergy Immunol 2011; 40: 66– 73.
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The menstrual cycle and the skin R. S. Raghunath et al.
26 Rivas Bejarano JJ, Valdecantos WC. Psoriasis as an autoinflammatory disease. Dermatol Clin 2013; 31: 445–60. 27 Millington GWM, Buckingham JC. Thymic peptides and neuroendocrine-immune communication. J Endocrinol 1992; 133: 163–68. 28 Steventon K. Expert opinion and review article: the timing of comedone extraction in the treatment of premenstrual acne
– a proposed therapeutic approach. Int J Cosmet Sci 2011; 33: 99–104. 29 Schindler AE. Non-contraceptive benefits of oral hormonal contraceptives. Int J Endocrinol Metab 2013; 11: 41–7. 30 Hata H, Natsuga K, Aoyagi S et al. Solitary fibrous tumor fluctuating in size with menstrual period. Clin Exp Dermatol 2014; 39: 753–5.
CPD questions
(e) Oestrogen is associated with reduced barrier function. Question 4
Learning objective
To review the menstrual cycle changes and treatment of various dermatoses.
and diagnosis
Question 1
Regarding the menstrual cycle, which of the following is correct? (a) The menstrual cycle begins on day 1 after menstrual bleeding is complete. (b) The menstrual phase of the cycle is associated with the highest production of oestrogen. (c) The follicular phase is the day 14 in the 28-day menstrual cycle. (d) The luteal phase begins after ovulation. (e) The duration of the cycle is always 28 days. Question 2
Which of the following dermatoses have been shown to have associated premenstrual exacerbations? (a) Acne. (b) Bowen disease. (c) Erythema nodosum. (d) Granuloma annulare. (e) Solar keratosis. Question 3
The effect of oestrogen on the skin is multifactorial; which of the following is correct? (a) Oestrogen receptor (ER)b receptors are expressed in keratinocytes, fibroblasts and macrophages in the skin. (b) Oestrogen reduces skin thickness. (c) Oestrogen causes a decrease in dermal water content. (d) Oestrogen has no effect on wound healing and collagen synthesis.
ª 2015 British Association of Dermatologists
Which of the following is the most important investigation for diagnosing autoimmune progesterone dermatitis? (a) Blood test for autoantibodies. (b) Punch biopsy. (c) Skin prick testing. (d) Progesterone levels in blood. (e) Trial of topical progesterone. Question 5
Treatment options for autoimmune progesterone dermatitis (APD) include which of the following? (a) Conjugated progesterone. (b) Gonadotrophin hormone releasing analogues. (c) Hysterectomy when all medical options have been exhausted. (d) Prednisolone. (e) Venesection.
Instructions for answering questions
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Clinical and Experimental Dermatology (2015) 40, pp111–115
115
Clinical dermatology • Review article
Clinical and Experimental Dermatology
CPD
The menstrual cycle and the skin R. S. Raghunath, Z. C. Venables and G. W. M. Millington Department of Dermatology, Norfolk and Norwich University Hospital, Norwich, UK doi:10.1111/ced.12588
Summary
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.
Introduction The fluctuations in oestrogen and progesterone that define menstruation are associated with numerous physiological and psychosocial changes. Despite vast improvements in our understanding of reproductive endocrinology, we have limited understanding of the effect of these hormonal changes on the skin; nevertheless, it is clear that several skin diseases are influenced by them (Table 1).1,2 In this article, we explore the clinical manifestations and mechanisms of the menstrual cycle and its effect on the skin. A better understanding of these mechanisms may improve the management of perimenstrual dermatoses in the future.
Physiology of the menstrual cycle and its effect on skin Much of our understanding of the effects of oestrogen on the skin is based upon observations of the effects of its Correspondence: Dr Rakhi Singh Raghunath, Norfolk and Norwich University Hospital, Norwich, UK E-mail: [email protected] Conflict of interest: RSR and ZV declare that they have no conflicts of interest. GWMM is the current editor of Clinical and Experimental Dermatology. Accepted for publication 10 September 2014
ª 2015 British Association of Dermatologists
reduced levels in postmenopausal women and from in vitro and animal studies.3 The production of hormones during the menstrual cycle is shown in Fig. 1, with associated dermatoses shown in Fig. 2.4 Oestrogen is important for the normal functioning of many structures in the epidermis and dermis, including the vasculature, hair follicles, sebaceous/apocrine glands, eccrine glands and melanocytes.5,6 In cultured human cells, oestrogen receptor (ER)b, progesterone and androgen receptors are expressed in keratinocytes, fibroblasts and macrophages in the skin. ERa receptors are found in skin fibroblasts and macrophages, but not keratinocytes.7,8 ERa and b receptors are also found on melanocytes.6 Oestrogen is associated with collagen synthesis, increased skin thickness and dermal water content (through hyaluronic acid production), and improved barrier function and wound healing.3 In postmenopausal women, low levels of oestrogen cause collagen atrophy and reduced water content.3 Oestrogen also stimulates melanogenesis, along with thyroxine and melanocytestimulating hormone, and this can result in premenstrual hyperpigmentation.1,6,9 The effects of oestrogen on pigmentation were first inferred from changes in pigmentation observed during pregnancy, including patches of increased pigmentation on the face, and darkening of the skin of the areolae, the perineum, and the skin over the linea alba, which fades shortly after delivery.1 Hyperpig-
Clinical and Experimental Dermatology (2015) 40, pp111–115
111
The menstrual cycle and the skin R. S. Raghunath et al.
Table 1 Dermatoses exacerbated during the menstrual cycle. References
Acne vulgaris Aphthous ulceration Atopic eczema Autoimmune progesterone dermatitis Autoimmune oestrogen dermatitis Dermatitis Herpetiformis Erythema multiforme Herpes simplex Hyperpigmentation Lichen Planus Lupus erythematosus Pompholyx Pruritus vulvae Psoriasis Rosacea Solitary Fibrous tumor Urticaria
4,10 4,10 4,23 13,14,16,18 12 4 4 10 10 4 4 4 4 4 4,10
Day
1
5
9
13
Phase Menstrual Follicular APD OD Acne AD
17
21
25
Luteal
Postmenopausal
30 4,10
Figure 2 Timescale showing when different perimenstrual dermatoses commonly occur during the menstrual cycle, e.g. APD occurs 3– 10 days before and 5–10 days after menstruation. AD, atopic dermatitis, OD, oestrogen dermatitis.
Oestrogen Progesterone Ovulation
Production
Oestrogen Progesterone Ovulation
Production
Dermatosis
mones (perimenstruation) are associated with heightened patch test reactivity, which account for exacerbations in atopic patients.10 This suggests that oestrogen and progesterone may inhibit cellular immunity.10
Autoimmune progesterone dermatitis and oestrogen dermatitis Day
1
5
9
13
Phase Menstrual Follicular
17
21 Luteal
25 Postmenopausal
Figure 1 The menstrual cycle begins with onset of menstruation on day 1, and the thickened endometrium is shed over 4–6 days (menstrual phase).4 Days 7–14 represent the follicular phase, which culminates in ovulation. The ovary is the main source of oestrogen in premenopausal women; it produces several types of oestrogen, of which oestradiol is the most potent. Oestradiol production steadily increases during the week prior to ovulation, and peaks 1 day prior to ovulation. This is followed by the luteal phase from day 14 to day 28. Ovulation results in the formation of the corpus luteum, which produces progesterone in the week following ovulation. Oestradiol rises again in the luteal phase, and has a second peak 5 days after ovulation. In the later stages of the luteal phase, oestrogen and progesterone levels decline, resulting in menstruation and the cycle restarts.3
mentation is also observed in some women using oral contraceptives.1 Oestrogens induce salt and water retention, causing oedema of the hands and feet, which is a feature of premenstrual syndrome.5 The effects of progesterone are less clear. During the second phase of menstruation, there is increased vascularity and increased sebum production, which has been attributed to the effect of progesterone.4 Studies show that elevated levels of oestrogen and progesterone in the periovulatory period inhibit delayed-type hypersensitivity reactions, while lower levels of both hor-
112
Clinical and Experimental Dermatology (2015) 40, pp111–115
Autoimmune progesterone dermatitis (APD) is a rare mucocutaneous disease characterized by cyclical skin changes, as a result of progesterone produced during the luteal phase of the menstrual cycle, hence it does not occur in post-menopausal women.11,12 The skin manifestations can vary from eczema, erythema multiforme (EM), purpura and petechiae, dermatitis herpetiformis, fixed drug eruption and stomatitis to urticaria, angio-oedema and anaphylaxis2,11–14,16 (Fig. 3a, Table 2). The symptoms usually start 3–10 days prior to the onset of menses, and can last up to 5–10 days after this onset.11,12 In women with irregular periods, the correlation might not be as obvious, and thus the patient might have the symptoms for several years prior to diagnosis.11,12 A similar entity related to sensitivity to oestrogens in the premenstrual period, known as oestrogen dermatitis (OD), has also been described.11,12 The pathogenesis of APD is not entirely clear. Intradermal test results to progesterone can produce both type 1 and type 4 hypersensitivity reactions.13,14 Oestrogen is processed by the skin as a foreign antigen and presented to immunocompetent cells, leading to an autoimmune response to endogenous oestrogen.15 Similar mechanisms have been proposed for progesterone autoimmunity.16 Previous exposure to progesterone in oral contraceptives or during pregnancy in predisposed individuals leads to hypersensitivity to endogenous hormones
ª 2015 British Association of Dermatologists
The menstrual cycle and the skin R. S. Raghunath et al.
(a)
cycle.21 Patients have been successfully treated with conjugated oestrogens,21 gonadotrophin hormone-releasing analogues,19 tamoxifen,16 danazol22 and bilateral oophorectomy.18 OD has also been shown to respond to the anti-oestrogen agent tamoxifen.12,23 Hormone desensitization has been tried as a potential treatment, although this is not used routinely in clinical practice.15
Other dermatoses exacerbated by menstruation (b)
Figure 3 (a) Macular rash in autoimmune progesterone dermatitis; (b) papular and scarring acne in a menstruating woman.
and APD in later life.12,15 However, APD resolves during pregnancy.17 It is suggested that the gradual rise of progesterone during pregnancy acts as a desensitizing agent, ultimately reducing symptoms. Owing to increased production of anti-inflammatory glucocorticoids during pregnancy, the decrease in maternal immune response also plays a role in improving symptoms.17 Diagnosis of APD is based on the appearance of recurrent skin lesions in relation to the menstrual cycle and demonstrating progesterone sensitivity by intradermal, intramuscular or vaginal administration of progesterone.16,18,19 There are no specific histological findings for the disorder, although there may be perivascular lymphocytic inflammation, with eosinophils.20 Direct immunofluorescence is negative.20 The main aim of therapy in APD is to suppress the progesterone surge during the luteal phase of the menstrual
ª 2015 British Association of Dermatologists
Dermatoses such as atopic and contact dermatitis, psoriasis, acne and even EM and solitary fibrous tumour may be exacerbated premenstrually or perimenstrually.2,10,23– 30 Nearly half of all patients with atopic eczema experience deterioration in their condition in the week prior to the menstruation, with the exacerbation rapidly settling after the onset of menstrual flow.23 Skin barrier permeability is greater just prior to menstruation.10 This increases the susceptibility of skin to the effects of both environmental allergens and general irritants, which partially explains the premenopausal flares of eczema in some women.13,26 Psoriasis has many aggravating and alleviating factors, hormonal influences being one of them.24 The perimenopausal worsening of symptoms of psoriasis has been shown to be blocked by coincidental long-term antioestrogen therapy, such as tamoxifen, thus supporting the influence of oestrogens on symptoms of psoriasis.24 The influence of oestrogen on immunity is complex.25 T helper cells show a dose-dependent effect to oestrogens, and oestrogen also stimulates the production of regulatory T cells through ERa. The B-cell response to oestrogen is via ERb, causing increased antibody production.25 As psoriasis is now considered to be an immunological disease,26 these complex influences of oestrogen on the immune system explain the menstrual variation of psoriasis.25–27 Premenstrual exacerbation of acne is multifactorial (Fig. 3b).28 Higher levels of androgens and oestrogens during the follicular phase and periovulation causes increased sebum production, resulting in higher level of skin lipids and subsequent increase in skin microflora.28 The use of combined oestrogen/progesterone contraceptives cause improvement in acne by suppressing the androgens secreted from the ovary, and increasing the levels of sex hormone-binding globulin, thus decreasing the amount of free, biologically active androgens.29 In addition, progesterone blocks the androgen receptors, inhibiting the action of circulating androgens. Hence, the premenstrual exacerbation of acne can be explained by the low levels of progesterone in the latter stage of the menstrual cycle. A perimenstrual EM-like eruption has also recently been reported, with prostaglandins being implicated in its aetiology.2
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Table 2 Clinical features of autoimmune progesterone dermatitis. Clinical feature
References
Angio-oedema Anaphylaxis Aphthous ulceration/stomatitis Dermatitis Eczema Erythema multiforme Fixed drug eruption Macules Palmoplantar dyshidrosis Papules Pompholyx Pruritus Stomatitis Urticaria Vesicles
12 2,12 2,12,16 4 2,11,13 2,11,13,14 2,16 12 12 11,13,14 4 14 4 2,11–14 2,12,13
Conclusion The dynamic effects of the cyclical changes in oestrogen and progesterone in women of reproductive age affect the severity of a range of inflammatory dermatoses, including some of the most common conditions seen in dermatology clinics and general practice. In addition, there are a number of rare perimenstrual disorders, of which APD is the best characterized.
Learning points ● Perimenstrual exacerbations of dermatoses are common and often overlooked. ● Hormonal variations and their action on the skin during various phases of the menstrual cycle explain the causes of perimenstrual exacerbations of dermatoses. ● APD and OD, although rare, are underdiagnosed, and treatment can be targeted to improve management and symptom control. ● Our article highlights the importance of recognizing perimenstrual dermatoses in order to provide patient-centred care.
References 1 Farage M, Neill S, MacLean AB. Physiological changes associated with the menstrual cycle: a review. Obstet Gynecol Surv 2009; 64: 58–72. 2 Verdolini R, Atkar R, Clayton N et al. Catamenial dermatoses: has anyone ever considered prostaglandins? Clin Exp Dermatol 2014; 39: 509–12. 3 Shah MG, Maibach HI. Estrogen and skin. Am J Clin Dermatol 2001; 2: 143–50.
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4 Stephens CJM. Perimenstrual eruptions. Clin Dermatol 1997; 15: 31–4. 5 Thornton MJ. The biological actions of estrogens on skin. Exp Dermatol 2002; 11: 487–502. 6 Videira IF, Moura DF, Magina S. Mechanisms regulating melanogenesis. An Bras Dermatol 2013; 88: 76–83. 7 Conrad F, Paus R. Estrogens and the hair follicle. J Dtsch Dermatol Ges 2004; 2: 412–23. 8 Kanda N, Watanabe S. Regulatory roles of sex hormones in cutaneous biology and immunology. J Dermatol Sci 2005; 38: 1–7. 9 Millington GWM. Proopiomelanocortin (POMC): the cutaneous roles of its melanocortin products and receptors. Clin Exp Dermatol 2006; 31: 407–12. 10 Farage M, Berardesca E, Maibach H. The possible relevance of sex hormones on irritant and allergic responses: their importance for skin testing. Contact Dermatitis 2010; 62: 67– 74. 11 Kumar A, Georgouras KE. Oestrogen dermatitis. Australas J Dermatol 1999; 40: 96–8. 12 Shelley WB, Shelley ED, Talanin NY et al. Estrogen dermatitis. J Am Acad Dermatol 1995; 32: 25–31. 13 Georgouras K. Autoimmune progesterone dermatitis. Australas J Dermatol 1981; 12: 109–12. 14 Poffet F, Abraham S, Taramarcaz P et al. Autoimmune progesterone dermatitis: potential role of cutaneous angiogenin expression. Dermatology 2011; 223: 32–5. 15 Itsekson A, Seidman DS, Zolti M et al. Steroid hormone hypersensitivity: clinical presentation and management. Fertil Steril 2011; 95: 2571–73. 16 Moghadam BK, Hersini S, Barker BF. Autoimmune progesterone dermatitis and stomatitis. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1998; 85: 537–41. 17 George R, Badawy SZA.Autoimmune progesterone dermatitis: a case report. Case Rep Obstet Gynecol 2012; 2012: 757854. 18 Rodenas H. Tercedor. Autoimmune progesterone dermatitis: treatment with oophorectomy. Br J Dermatol 1998; 139: 508–11. 19 Nemeth H, Kov acs E, G€ odeny S et al. Autoimmune progesterone dermatitis diagnosed by intravaginal progesterone provocation in a hysterectomised woman. Gynecol Endocrinol 2009; 25: 410–12. 20 Toms-Whittle LM, John LH, Griffiths DJ, Buckley DA. Autoimmune progesterone dermatitis: a diagnosis easily missed. Clin Exp Dermatol 2011; 36: 378–80. 21 Oskay T, Lale Kutluay L, Asli Kaptanocglu A et al. Autoimmune progesterone dermatitis. Eur J Dermatol 2002; 12: 589–91. 22 Shahar E, Bergman R, Pollack S. Autoimmune progesteron.e dermatitis: effective prophylactic treatment with danazol. Int J Dermatol 1997; 36: 708–711. 23 Kiriyama K, Sugiura H, Uehara M. Premenstrual deterioration of skin symptoms in female patients with atopic dermatitis. Dermatology 2003; 206: 110–112. 24 Boyd AS, King LE. Tamoxifen-induced remission of psoriasis. J Am Acad Dermatol 1999; 41: 887–89. 25 Cunningham M, Gilkeson G. Estrogen receptors in immunity and autoimmunity. Clin Rev Allergy Immunol 2011; 40: 66– 73.
ª 2015 British Association of Dermatologists
The menstrual cycle and the skin R. S. Raghunath et al.
26 Rivas Bejarano JJ, Valdecantos WC. Psoriasis as an autoinflammatory disease. Dermatol Clin 2013; 31: 445–60. 27 Millington GWM, Buckingham JC. Thymic peptides and neuroendocrine-immune communication. J Endocrinol 1992; 133: 163–68. 28 Steventon K. Expert opinion and review article: the timing of comedone extraction in the treatment of premenstrual acne
– a proposed therapeutic approach. Int J Cosmet Sci 2011; 33: 99–104. 29 Schindler AE. Non-contraceptive benefits of oral hormonal contraceptives. Int J Endocrinol Metab 2013; 11: 41–7. 30 Hata H, Natsuga K, Aoyagi S et al. Solitary fibrous tumor fluctuating in size with menstrual period. Clin Exp Dermatol 2014; 39: 753–5.
CPD questions
(e) Oestrogen is associated with reduced barrier function. Question 4
Learning objective
To review the menstrual cycle changes and treatment of various dermatoses.
and diagnosis
Question 1
Regarding the menstrual cycle, which of the following is correct? (a) The menstrual cycle begins on day 1 after menstrual bleeding is complete. (b) The menstrual phase of the cycle is associated with the highest production of oestrogen. (c) The follicular phase is the day 14 in the 28-day menstrual cycle. (d) The luteal phase begins after ovulation. (e) The duration of the cycle is always 28 days. Question 2
Which of the following dermatoses have been shown to have associated premenstrual exacerbations? (a) Acne. (b) Bowen disease. (c) Erythema nodosum. (d) Granuloma annulare. (e) Solar keratosis. Question 3
The effect of oestrogen on the skin is multifactorial; which of the following is correct? (a) Oestrogen receptor (ER)b receptors are expressed in keratinocytes, fibroblasts and macrophages in the skin. (b) Oestrogen reduces skin thickness. (c) Oestrogen causes a decrease in dermal water content. (d) Oestrogen has no effect on wound healing and collagen synthesis.
ª 2015 British Association of Dermatologists
Which of the following is the most important investigation for diagnosing autoimmune progesterone dermatitis? (a) Blood test for autoantibodies. (b) Punch biopsy. (c) Skin prick testing. (d) Progesterone levels in blood. (e) Trial of topical progesterone. Question 5
Treatment options for autoimmune progesterone dermatitis (APD) include which of the following? (a) Conjugated progesterone. (b) Gonadotrophin hormone releasing analogues. (c) Hysterectomy when all medical options have been exhausted. (d) Prednisolone. (e) Venesection.
Instructions for answering questions
This learning activity is freely available online at http:// www.wileyhealthlearning.com/ced. Users are encouraged to Read the article in print or online, paying particular attention to the learning points and any author conflict of interest disclosures Reflect on the article Register or login online at www.wileyhealthlearning. com/ced and answer the CPD questions Complete the required evaluation component of the activity Once the test is passed, you will receive a certificate and the learning activity can be added to your RCP CPD diary as a self-certified entry
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