Arch. Derm. Res. 253, 53--61 (1975) © by Springer-Verlag 1975
Photodermatoses Induced by Oral Contraceptives Irene Horkay, P. Tam£si, A. Pr6kopa, and L. Dalmy Department of Dermatology (Director: Prof. Dr. L. Szodoray) and Internal Medicine (Director: Prof. S. D£n) University of Dehrecen (Hungary) l~eceived March 11, 1974
Summary. The pathogenetic role of liver damage in photodermatoses induced by oral contraceptives was investigated. From among 121 cases with photodermatosis, it was in 4 eases of polymorphie light eruption-like dermatosis and in 2 cases of porphyria cutanea tarda that a longterm use of antibaby pills preceded the development of skin disease. Physical and biochemical studies of the liver of the patients suggested that the hepatotoxicity of the estrogen component of oral contraceptives can play a role not only in the pathomechanism of porphyric cases, but also in that of cases occurring with the clinical picture of polymorphic light eruption. Zusammen/assuug. Die pathogenetische Rolle der Lebersch~digung wurde in F~llen yon durch orale Kontrazeptiva induzierten Lichtdermatosen untersucht. In einem Krankengut yon 121 Lichtdermatosen ging eine langfristige Einnahme der oralen Kontrazeptiva der Manifestation der Hautkrankheit in 4 F~llen yon chronisch-polymorphen Lichtausschl~gen und in 2 F~llen yon Porphyria cutanea tarda voraus. Die Ergebnisse der biochemischen Untersuchungen der Leberfunktion wiesen darauf bin, dal~ die Hepatotoxicit~t der Oestrogenkomponente der oralen Kontrazeptiva nicht nur im Pathomechanismus der Porphyria cutanea tarda, sondern auch im Pathomechanismus yon denen, die im klinischen Bilde der chroniseh-polymorphen Lichtausschl~ge erscheinen, eine l%ollespielen kann. Introduction R e c e n t l y p h o t o d e r m a t o s e s have been r e p o r t e d more f r e q u e n t l y in which a l o n g t e r m use of oral contraceptives (OC) preceded the d e v e l o p m e n t of light sensit i v i t y . The s y m p t o m s m a n i f e s t e d themselves as hepatic p o r p h y r i a s [4,8,25,31] a n d p o l y m o r p h i c light eruption-like dermatoses [10,11]. Consequently, the cases of p h o t o d e r m a t o s e s i n d u c e d b y estrogens consisted of elderly males with p r o s t a t e carcinoma t r e a t e d b y m e a n s of n a t u r a l or s y n t h e t i c estrones, were increased b y cases of y o u n g females with a history i n v o l v i n g the use of OC. Since oral contraception has been spreading in our c o u n t r y , too, similar cases have been observed more f r e q u e n t l y a t our clinic as well. According to observations, a high significance can be a t t r i b u t e d to the estrogenic c o m p o n e n t well-known b y its h e p a t o t o x i c i t y [3, 5, 20, 27]. The purpose of our paper is to deal with the p a t h o g e n e t i c role of liver damage on the basis of our material.
Material and Methods 121 cases with photodermatoses have been recorded at our clinic during the last 10 years [63 cases of polymorphie light eruption (PLE), 58 cases of porphyria cutanea tarda (PCT), and erythropoietic protoporphyria respectively]. Of these 6 cases were considered to be induced by the longterm use of antibaby pills. All these patients were young, otherwise healthy females whose skin disease manifested as PLE-like dermatosis (PLELD) and PCT following oral contraception for half a year to two. In the history of the patients no other liver-damaging factor (chronic alcoholism, syphilis, hepatitis, etc.) could be revealed.
54
I. Horkay et al.
Fig. 1. E r y t h e m a t o u s maculopapules of pinhead-lentil size on the extensor surface of the upper extremity. Case 1
Case R e p o r t s Case 1. J.E. aged 29. First erupticn en her face, neck and the extensor surface of the upper extremities appeared after sun-exposition, using Infecundimpills (consisting of 2.5 mg norethynodrel a n d 0.1 mg methoxyaethinyloeStradiol) for one year and a half. E r y t h e m a t e u s maculopapules a n d seropapules of pinhead-lentil size reappeared two summers running during continuous use of the pills (Fig. 1), a n d cured spontaneously without leaving any sign in autumn. Next year the patient began to take Bisecurin-pills (consisting of 1 mg aethynodiolum diaceticum and 0.05 mg aethinyloestradiolum) instead of Infecundin on advice of her gynecologist b u t her symptoms returned as before. Case 2. K.A. aged 39. Erythematous, slightly squamous plaques of lentil size, or larger on her face, chest a n d back developed in the second year of Infeeundin-administration. The eruptions showed a butterfly-like arrangement with a n edematous border on the face, a n d cured only with a mild hyperpigmentation without a n y scar or atrophy. Histological picture of the florid lesions was as follows: epidermis grew thin, in the upper p a r t of the corium a lymphocytic infiltration could be seen around the dilated capillaries a n d the follicles, elastic fibers were broken. Case 3. Sz.G. aged 21. The skin on the hands and fingers, later on on the face became fragile in the first year of Infecundin usage, t h e n serous blisters appeared on the same areas cured slowly with a scar. Simultaneously hypertrichosis occurred on the temporal and glabellar regions a n d around the upper lip. Her urine was often dark a n d wine-red showing a characteristic red fluorescence in the light of a Wood-lamp. Case 4. H.Gy. aged 27. The patient noticed reddish macules on her face following every s u n b a t h within half a year of Infecundin administration. A t admission edematous-erythematous maculopapules could be seen on the cheeks, nose a n d under the lower eyelids. These lesions regressed within a few days due avoiding sunshine as well as they did in her former experiences. Case 5. M.V. aged 32. After the use of Infeeundin for 2 years a hypertrichosis a n d hyperpigmentation developed on her face accompanied b y blisterformation on the hands a n d fingers in spring (Fig.2). Urine became d a r k e r a n d wine-red. After admission blistering could be
Photodermatoses Induced by Oral Contraceptives
55
Fig. 2. Hyperpigmentation and hypertrichosis on the face after the use of Infecundinfor 2 years. Case 5 stopped by discontinuation of pill-administration. For 2 years her only symptoms were hyperpigmentation and hypertrichosis, but she often excreted darker urine without any skin lesion. Then she began to take Bisecurin despite our previous warning. Within 2 months new blisters occurred on her face and hands. Case 6. V.I. aged 26. After every sun-exposition itchy eruptions appeared on the exposed areas in the second year of Infecundin-use. At admission erythema exsudativum multiforme like lesions on the extremities and confluent erythematous maculopapules on the uncovered parts of the skin could be seen.
Laboratory Tests/or Porphyrin Metabolism 1. P o r p h y r i n excretion i n u r i n e : P o r p h o b i l i n o g e n : n o r m a l values in every case U r o p o r p h y r i n : 1 , 2., 4. a n d 6. case: < 3 0 g a m m a / l ; 3. a n d 5. case: 168, respect i v e l y 658 gamma/1 C o p r o p o r p h y r i n : 1 , 2 , 4. a n d 6. case: < 1 7 0 g a m m a / 1 ; 3. a n d 5. case: 221, respectively 431 gamma/1 (N.B. : in the sera of b o t h l a t t e r p a t i e n t s a high ser u m iron level characteristic of P C T could also be detected: 198, respectively 192 g a m m a - °/0.)
56
I. Horkay et al.
2. Fecal porphyrins : Normal values in every case. 3. Porphyrins in the red blood cells: Copro- and protoporphyrin : normal values in every case. Considering that one of the components of the antibaby pills : the estrogen is well-known for its hepatotoxicity, the patients had to undergo a thorough internal examination. Its main results are as follows : the liver was found to be quite normal by means of physical examination in all cases with PLE-like dermatosis and in one with PCT. Whereas in the other porphyria ease it was palpable 2 fingers' breadth below the right costal margin on inspiration, and its palpation was somewhat compact. As regards the biochemical tests, the condition of liver parenchyma was estimated by means of enzymatic assays and BSP retention test. The results are shown in Table 1. The activity of the mitochondrial liver-specific glutamatedehydrogenase (GLDtt) must be emphasized first of all. I t was found to be abnormally high in the serum of all patients except one with PLE-like dermatosis, whereas the less specific SGOT activity was found to be above normal only in 1 porphyric case. The results of the quantitative estimation of immunoglobulins (according to Fahey's method: [12]) indicating among others, the rate of the mesenchymal reaction of the liver, can be seen in Table 2. An undoubted increase of the IgG level was demonstrated in the serum of all porphyric patients and in 1 case with PLE-like dermatosis. The level was possibly increased in the serum of another patient with the latter disease. At the same time the IgA level was found unequivocally normal in the serum of all patients. This contradicts the alcoholic origin of liver damage biochemically too. Finally an undoubted or possible increase of IgM level could be demonstrated only in the serum of 1 porphyric and in that of 2 of the PLE-like cases respectively. Patients reacted in different ways when discontinuing the use of the antibaby pills. Symptoms of PLE-like cases regressed gradually (in 3--6 weeks) and did not exacerbate in the following years. The hepatic function tests became normalized within some months according to the biochemical examinations suggesting a transient, reversible liver damage. Porphyric patients got active treatment (Ippen's cure: [16]), because they became only partially symptomfrce after discontinuing the pills and their porphyrinuria remained unchanged for months.
Table 1 Patient
Age
J.E. 29 K.A. 39 Sz.G. 21 I-I.R. 27 M.V. 32 V.I. 26 Normal values
Dg. PLE PLE PCT PLE PCT PLE
GLDH-activity in IU 0.64 2.36 3.44 2.50 1.93 1.73 ~ 1.67
SGOT-activity in U 36 14 14 28 45 12 ~ 40
BSP ret. in °/o 3 0 0 0 2 0
Photodermatoses Induced by Oral Contraceptives Irene Horkay, P. Tam£si, A. Pr6kopa, and L. Dalmy Department of Dermatology (Director: Prof. Dr. L. Szodoray) and Internal Medicine (Director: Prof. S. D£n) University of Dehrecen (Hungary) l~eceived March 11, 1974
Summary. The pathogenetic role of liver damage in photodermatoses induced by oral contraceptives was investigated. From among 121 cases with photodermatosis, it was in 4 eases of polymorphie light eruption-like dermatosis and in 2 cases of porphyria cutanea tarda that a longterm use of antibaby pills preceded the development of skin disease. Physical and biochemical studies of the liver of the patients suggested that the hepatotoxicity of the estrogen component of oral contraceptives can play a role not only in the pathomechanism of porphyric cases, but also in that of cases occurring with the clinical picture of polymorphic light eruption. Zusammen/assuug. Die pathogenetische Rolle der Lebersch~digung wurde in F~llen yon durch orale Kontrazeptiva induzierten Lichtdermatosen untersucht. In einem Krankengut yon 121 Lichtdermatosen ging eine langfristige Einnahme der oralen Kontrazeptiva der Manifestation der Hautkrankheit in 4 F~llen yon chronisch-polymorphen Lichtausschl~gen und in 2 F~llen yon Porphyria cutanea tarda voraus. Die Ergebnisse der biochemischen Untersuchungen der Leberfunktion wiesen darauf bin, dal~ die Hepatotoxicit~t der Oestrogenkomponente der oralen Kontrazeptiva nicht nur im Pathomechanismus der Porphyria cutanea tarda, sondern auch im Pathomechanismus yon denen, die im klinischen Bilde der chroniseh-polymorphen Lichtausschl~ge erscheinen, eine l%ollespielen kann. Introduction R e c e n t l y p h o t o d e r m a t o s e s have been r e p o r t e d more f r e q u e n t l y in which a l o n g t e r m use of oral contraceptives (OC) preceded the d e v e l o p m e n t of light sensit i v i t y . The s y m p t o m s m a n i f e s t e d themselves as hepatic p o r p h y r i a s [4,8,25,31] a n d p o l y m o r p h i c light eruption-like dermatoses [10,11]. Consequently, the cases of p h o t o d e r m a t o s e s i n d u c e d b y estrogens consisted of elderly males with p r o s t a t e carcinoma t r e a t e d b y m e a n s of n a t u r a l or s y n t h e t i c estrones, were increased b y cases of y o u n g females with a history i n v o l v i n g the use of OC. Since oral contraception has been spreading in our c o u n t r y , too, similar cases have been observed more f r e q u e n t l y a t our clinic as well. According to observations, a high significance can be a t t r i b u t e d to the estrogenic c o m p o n e n t well-known b y its h e p a t o t o x i c i t y [3, 5, 20, 27]. The purpose of our paper is to deal with the p a t h o g e n e t i c role of liver damage on the basis of our material.
Material and Methods 121 cases with photodermatoses have been recorded at our clinic during the last 10 years [63 cases of polymorphie light eruption (PLE), 58 cases of porphyria cutanea tarda (PCT), and erythropoietic protoporphyria respectively]. Of these 6 cases were considered to be induced by the longterm use of antibaby pills. All these patients were young, otherwise healthy females whose skin disease manifested as PLE-like dermatosis (PLELD) and PCT following oral contraception for half a year to two. In the history of the patients no other liver-damaging factor (chronic alcoholism, syphilis, hepatitis, etc.) could be revealed.
54
I. Horkay et al.
Fig. 1. E r y t h e m a t o u s maculopapules of pinhead-lentil size on the extensor surface of the upper extremity. Case 1
Case R e p o r t s Case 1. J.E. aged 29. First erupticn en her face, neck and the extensor surface of the upper extremities appeared after sun-exposition, using Infecundimpills (consisting of 2.5 mg norethynodrel a n d 0.1 mg methoxyaethinyloeStradiol) for one year and a half. E r y t h e m a t e u s maculopapules a n d seropapules of pinhead-lentil size reappeared two summers running during continuous use of the pills (Fig. 1), a n d cured spontaneously without leaving any sign in autumn. Next year the patient began to take Bisecurin-pills (consisting of 1 mg aethynodiolum diaceticum and 0.05 mg aethinyloestradiolum) instead of Infecundin on advice of her gynecologist b u t her symptoms returned as before. Case 2. K.A. aged 39. Erythematous, slightly squamous plaques of lentil size, or larger on her face, chest a n d back developed in the second year of Infeeundin-administration. The eruptions showed a butterfly-like arrangement with a n edematous border on the face, a n d cured only with a mild hyperpigmentation without a n y scar or atrophy. Histological picture of the florid lesions was as follows: epidermis grew thin, in the upper p a r t of the corium a lymphocytic infiltration could be seen around the dilated capillaries a n d the follicles, elastic fibers were broken. Case 3. Sz.G. aged 21. The skin on the hands and fingers, later on on the face became fragile in the first year of Infecundin usage, t h e n serous blisters appeared on the same areas cured slowly with a scar. Simultaneously hypertrichosis occurred on the temporal and glabellar regions a n d around the upper lip. Her urine was often dark a n d wine-red showing a characteristic red fluorescence in the light of a Wood-lamp. Case 4. H.Gy. aged 27. The patient noticed reddish macules on her face following every s u n b a t h within half a year of Infecundin administration. A t admission edematous-erythematous maculopapules could be seen on the cheeks, nose a n d under the lower eyelids. These lesions regressed within a few days due avoiding sunshine as well as they did in her former experiences. Case 5. M.V. aged 32. After the use of Infeeundin for 2 years a hypertrichosis a n d hyperpigmentation developed on her face accompanied b y blisterformation on the hands a n d fingers in spring (Fig.2). Urine became d a r k e r a n d wine-red. After admission blistering could be
Photodermatoses Induced by Oral Contraceptives
55
Fig. 2. Hyperpigmentation and hypertrichosis on the face after the use of Infecundinfor 2 years. Case 5 stopped by discontinuation of pill-administration. For 2 years her only symptoms were hyperpigmentation and hypertrichosis, but she often excreted darker urine without any skin lesion. Then she began to take Bisecurin despite our previous warning. Within 2 months new blisters occurred on her face and hands. Case 6. V.I. aged 26. After every sun-exposition itchy eruptions appeared on the exposed areas in the second year of Infecundin-use. At admission erythema exsudativum multiforme like lesions on the extremities and confluent erythematous maculopapules on the uncovered parts of the skin could be seen.
Laboratory Tests/or Porphyrin Metabolism 1. P o r p h y r i n excretion i n u r i n e : P o r p h o b i l i n o g e n : n o r m a l values in every case U r o p o r p h y r i n : 1 , 2., 4. a n d 6. case: < 3 0 g a m m a / l ; 3. a n d 5. case: 168, respect i v e l y 658 gamma/1 C o p r o p o r p h y r i n : 1 , 2 , 4. a n d 6. case: < 1 7 0 g a m m a / 1 ; 3. a n d 5. case: 221, respectively 431 gamma/1 (N.B. : in the sera of b o t h l a t t e r p a t i e n t s a high ser u m iron level characteristic of P C T could also be detected: 198, respectively 192 g a m m a - °/0.)
56
I. Horkay et al.
2. Fecal porphyrins : Normal values in every case. 3. Porphyrins in the red blood cells: Copro- and protoporphyrin : normal values in every case. Considering that one of the components of the antibaby pills : the estrogen is well-known for its hepatotoxicity, the patients had to undergo a thorough internal examination. Its main results are as follows : the liver was found to be quite normal by means of physical examination in all cases with PLE-like dermatosis and in one with PCT. Whereas in the other porphyria ease it was palpable 2 fingers' breadth below the right costal margin on inspiration, and its palpation was somewhat compact. As regards the biochemical tests, the condition of liver parenchyma was estimated by means of enzymatic assays and BSP retention test. The results are shown in Table 1. The activity of the mitochondrial liver-specific glutamatedehydrogenase (GLDtt) must be emphasized first of all. I t was found to be abnormally high in the serum of all patients except one with PLE-like dermatosis, whereas the less specific SGOT activity was found to be above normal only in 1 porphyric case. The results of the quantitative estimation of immunoglobulins (according to Fahey's method: [12]) indicating among others, the rate of the mesenchymal reaction of the liver, can be seen in Table 2. An undoubted increase of the IgG level was demonstrated in the serum of all porphyric patients and in 1 case with PLE-like dermatosis. The level was possibly increased in the serum of another patient with the latter disease. At the same time the IgA level was found unequivocally normal in the serum of all patients. This contradicts the alcoholic origin of liver damage biochemically too. Finally an undoubted or possible increase of IgM level could be demonstrated only in the serum of 1 porphyric and in that of 2 of the PLE-like cases respectively. Patients reacted in different ways when discontinuing the use of the antibaby pills. Symptoms of PLE-like cases regressed gradually (in 3--6 weeks) and did not exacerbate in the following years. The hepatic function tests became normalized within some months according to the biochemical examinations suggesting a transient, reversible liver damage. Porphyric patients got active treatment (Ippen's cure: [16]), because they became only partially symptomfrce after discontinuing the pills and their porphyrinuria remained unchanged for months.
Table 1 Patient
Age
J.E. 29 K.A. 39 Sz.G. 21 I-I.R. 27 M.V. 32 V.I. 26 Normal values
Dg. PLE PLE PCT PLE PCT PLE
GLDH-activity in IU 0.64 2.36 3.44 2.50 1.93 1.73 ~ 1.67
SGOT-activity in U 36 14 14 28 45 12 ~ 40
BSP ret. in °/o 3 0 0 0 2 0
