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Topical testosterone for lichen sclerosus
253
Int. J. Gynecol. Obstet., 1989, 30: 253-255 International Federation of Gynecology and Obstetrics
Topical testosterone for lichen sclerosus A. Ayhan”, B. Urmana, K. Yiice”, A. Ayhanb and A. Giik6zb %zpartment of Obstetrics and Gynecology, Division of Gynecologic Oncology and bDepartment of Pathology, School of Medicine Hacettepe University, Ankara (Turkey) (Received June 9th, 1988) (Revised and accepted November 22nd. 1988)
Abstract Twenty- three patients diagnosed as lichen sclerosus with colposcopic directed biopsy were given topical testosterone as a first line therapy. The overall remission rate was found to be 87.7%; 8.7% of the patients experienced undesirable androgenic side effects. Of the three patients who did not respond satisfactorily to testosterone treatment, two had alcohol injection to the vulva and one had vulvar denervation.
established by adequate biopsy usually requiring tissue from several affected areas in order to exclude the presence of an associated dysplasia or carcinoma. Both surgery and laser therapy have a high failure rate [6]. Medical therapy such as topical testosterone, topical progesterone and a short course of corticosteroids when indicated, are the current treatments of choice [4,7,13]. The purpose of this study is to evaluate the results of topical testosterone in patients with LS. Material and methods
Keywords: Vulvar dystrophy; Lichen sclerosus; Topical testosterone; Topical progesterone; Topical corticosteroids; Vulvar atypia. Introduction Lichen sclerosus (LS) occurs predominantly in postmenopausal women [ 11,141. The most common symptom is pruritus [ 181. There is a progressive loss of tissue elasticity. The etiology of LS is obscure but there is a causual relationship between LS and autoimmune disease, genetic factors and abnormal 5-alpha-reductase activity [ 1,810]. Approximately 5% of the cases are associated with vulvar carcinoma at the time of diagnosis [16]. The diagnosis of LS is 0020-7292/89/$03.50 0 1989 International Federation of Gynecology and Obstetrics Published and Printed in Ireland
Twenty-three patients were diagnosed as LS in our institution between January 1978 and January 1988. Data were obtained from the patient files, follow-up forms and pathology reports. The mean age was 54.4 f 5.5 (range 38-70). Of these patients 20 presented with vulvar pruritus, 6 had vulvar atrophy, 2 had excoriations and ecchymosis and 3 were asymptomatic. Two patients had insulindependent diabetes mellitus, one patient had autoimmune thyroiditis and one patient had treated hyperthyroidism. All patients were subjected to colposcopic examination. Six patients (26%) who had normal colposcopic findings were also subjected to 1% toluidine blue dye test to detect any suspicious areas. Biopsy was performed from all suspicious areas detected either by Clinical and Clinical Research
254
Ayhan et al.
colposcopy or dye test. All specimens were evaluated by a co-author pathologist. After tissue diagnosis, in 21 patients topical testosterone was applied to all affected areas twice daily for a period of at least 6 weeks (2% testosterone propionate in petrolatum is not commercially available in Turkey, but it can be compounded by mixing 3 ml of 100 mg/ml of testosterone propionate in sesame oil with 12 g petrolatum to obtain a 2% ointment) [4]. In two patients fluorinated corticosteroids (Locacortone-viaformeR 0.02% flumethasone + 3% iodochlorhydroxy quinolone) were applied before testosterone for severe pruritus, traumatic excoriations and ecchymosis. Following this, topical testosterone was applied as outlined above. Each patient was re-evaluated clinically after 6 weeks of therapy. The follow-up time for all patients ranged from 6 to 10 months with a mean follow-up time of 3 years. Results The overall remission rate following topical testosterone was found to be 87.7% (20/ 23). Only two patients experienced androgenie side effects (8.7%) with enhanced libido and minimal clitoral enlargement. Three patients did not respond satisfactorily to testosterone treatment at the end of 6 weeks. Of these three patients, two had alcohol injection to the vulva and one had a Mering procedure for denervation of the vulvar nerves [ 151. These three patients with a minimum followup of 3 years are found to be free of symptoms. All of the patients were symptom and lesion free at the follow-up times ranging from 6 months to 10 years. Testosterone therapy had to be continued in 8 patients intermittently for 2-6 months until the symptoms completely resolved. Control biopsies were taken from these patients upon completion of their treatment programs. All of the biopsies revealed marked histologic improvement. Of the 23 patients in our study group none demonstrated atypia on biopsy. Int J Gynecol Obstet 30
Discussion The treatment of choice for LS is topical testosterone propionate [4,7,18]. Testosterone therapy when used diligently is reported to be highly effective in controlling symptoms of LS. The success rate of the therapy varies from 80% to 100% [2,3,5,8]. The therapeutic success rates as reported by several authors are shown in Table I. The topical effects of androgens on the skin have been extensively investigated. Testosterone penetrates the intact skin rapidly and also is associated with an increased perfusion of the surface capillaries and has a direct stimulatory action upon axillary and pubic hair [5]. The effects of various topical steroids on the aged human axilla, have shown rete development and fibroblastic proliferation with stimulation of the hair follicles and sebaceous glands after testosterone application and to a more limited extent, with progesterone as well [19]. Strauss and Pochi point out that the human skin has significant potential to metabolize androgens [17]. The formation rate of dihydrotestosterone in vitro in vulvar skin was found to be four to five times higher than that in perineal skin [20]. All of these studies point to the vital role of androgens in skin metabolism generally and in vulvar skin particularly. The topical ‘application of androgens, therefore, constitute a logical approach to the treatment of LS. Topical testosterone produced good results in the relief of pruritus. Gross appear-
Table I.
Results of testosterone
in lichen sclerosus.
Reference
No. patients/ treatment failures
-. Remission rate (%)
PI
14/o 612 184/1P 121/6 IO/2 23/3
100 67 93 95 80 88
[51 [41 [31
PI Present study “8 reports.
____
Lichen sclerosus
ante improved in many cases and histologic change toward a more normal skin structure could be identified. Topical testosterone has some side effects which are increased pubic and facial hair, clitoral enlargement, enhanced libido, acne formation, hoarsness, local burning and ulcerations [5,16]. An alternative to topical testosterone propionate is topical progesterone in oil [ 121. Progesterone is especially suitable to treat the child with symptomatic LS, since the side effects of testosterone are undesirable in children. In this study none of the patients recieved topical progesterone. In the occasional patient with severe traumatic excoriations and pruritus, ecchymosis, therapy is begun with a fluorinated corticosteroid applied topically. The ointment can be applied as frequently as desired in order to bring pruritus under control [ 161. This therapy is continued for at least 2 weeks. After all superficial traumatic lesions have healed, topical testosterone is prescribed as outlined above. In the event of testosterone, progesterone and corticosteroid failure, other treatment regimens such as alcohol injection or the Mering procedure can be used [IS]. In this study only three patients required this form of treatment. Skinning vulvectomy and laser therapy are much more radical procedures for the treatment of LS and are also prone to recurrences. They should be considered in patients exhibiting severe atypia on control biopsies and are resistant to medical therapy [16,18]. Watchful1 waiting is a good alternative option in the presence of minimal atypia, but requires the patient to be rebiopsied at appropriate intervals.
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9 10
11
12
13 14
15
16
17
18 19
20
255
DiPaola GR: The problem of the so called precancerous lesions of the vulva: ten years of prospective experience. Eur J Gynaecol Gncol I: 20,198O. Friedrich EG Jr: Lichen sclerosus. J Reprod Med 17: 147, 1976. Friedrich EC: Topical testosterone for benign vulvar dystrophy. Obstet Gynecol37: 677, 1971. Friedrich EG: Treating vulvar dystrophy. Contemp Obstet Gynecol JO: 19,1973. Friedrich EG: Vulvar dystropy. Clin Obstet Gynecol 28: 198, 1985. Friedrich EG Jr, Kalra PS. Serum levels of sex hormones in vulvar lichen sclerosus et atrophicus and the effect of topical testosterone. N Engl Med 310: 488, 1984. Friedrich EG Jr, Mclaren NK; Genetic aspects of lichen sclerosus. Am Obstet Gynecol150: 161, 1984. Harrington CA, Dunsmore IR: An investigation into the autoimmune disorders in patients with lichen sclerosus et atrophicus. Br J DermatolZO4: 563, 1981. Hart WR, Norris HJ, Helwig EB: Relation of lichen sclerosus et atrophicus of the vulva to development of carcinoma. Obstet Gynecol45: 369,1975. Jasionowski EA, Jasionowski PA: Further observations on the effect of topical progesterone on vulvar disease. Am J Obstet Gynecol134: 565, 1979. Kaufman RH, Gardner HC: Vulvar dystrophias. Clin Obstet Gynecol21: 1081,1978. Kaufman RH, Gardner HC, Brown D Jr, Beyth Y: Vulvar dystrophias: an evaluation. Am J Obstet Gynecol 120: 363,1974. Mering JH: Some observations on wide skin undercutting for intractible pruritus vulvae. Am Obstet Gynecol 71: 386, 1956. Morrow CP; Advances in the treatment of preinvasive and invasive carcinoma of the vulva. In Recent Advances in Obstetrics and Gynecology (ed J Bonnar, N Rifteen) p 157. Churchill Livingstone, London 1987. Strauss JS, Pochi PE: Recent advances in androgen metabolism and their relation to the skin. Arch Dermatol 100: 621, 1969. Soperj T, Creasman WT: Vulvar dystrophias. Clin Obstet Gynecol29: 43 1, 1986. Rony HR, Zakon SJ: Effect of androgen on the sebaceous glands of human skin. Arch Belg Dermatol Syph 48: 601.1943. Wilson JD, Walker JD: The conversion of testosterone to 5-alpha-androstan-7-beta-ol-3-one (dihydrotestosterone) by skin slices of man. J Clin Invest 48: 371, 1969.
References Address for reprints:
1
2
Bewsher PD, Stanklar L: Direct evidence of localized immunological damage in vulvar lichen sclerosus et atrophicus. J Clin Path01 35: 1395, 1982. Cinberg BL: Postmenapousal pruritus vulvae. Am J Obstet Gynecol49: 647, 1945.
A. Ayhan Kadin Hastaiiklari ve Dojum Ann BiIim Dali Hncettepe hiversitesi Tip Fakttltesi Ankara, Ttirkiye
Clinical and Clinical Research
Int. J. Gynecol. Obstet., 1989, 30: 253-255 International Federation of Gynecology and Obstetrics
Topical testosterone for lichen sclerosus A. Ayhan”, B. Urmana, K. Yiice”, A. Ayhanb and A. Giik6zb %zpartment of Obstetrics and Gynecology, Division of Gynecologic Oncology and bDepartment of Pathology, School of Medicine Hacettepe University, Ankara (Turkey) (Received June 9th, 1988) (Revised and accepted November 22nd. 1988)
Abstract Twenty- three patients diagnosed as lichen sclerosus with colposcopic directed biopsy were given topical testosterone as a first line therapy. The overall remission rate was found to be 87.7%; 8.7% of the patients experienced undesirable androgenic side effects. Of the three patients who did not respond satisfactorily to testosterone treatment, two had alcohol injection to the vulva and one had vulvar denervation.
established by adequate biopsy usually requiring tissue from several affected areas in order to exclude the presence of an associated dysplasia or carcinoma. Both surgery and laser therapy have a high failure rate [6]. Medical therapy such as topical testosterone, topical progesterone and a short course of corticosteroids when indicated, are the current treatments of choice [4,7,13]. The purpose of this study is to evaluate the results of topical testosterone in patients with LS. Material and methods
Keywords: Vulvar dystrophy; Lichen sclerosus; Topical testosterone; Topical progesterone; Topical corticosteroids; Vulvar atypia. Introduction Lichen sclerosus (LS) occurs predominantly in postmenopausal women [ 11,141. The most common symptom is pruritus [ 181. There is a progressive loss of tissue elasticity. The etiology of LS is obscure but there is a causual relationship between LS and autoimmune disease, genetic factors and abnormal 5-alpha-reductase activity [ 1,810]. Approximately 5% of the cases are associated with vulvar carcinoma at the time of diagnosis [16]. The diagnosis of LS is 0020-7292/89/$03.50 0 1989 International Federation of Gynecology and Obstetrics Published and Printed in Ireland
Twenty-three patients were diagnosed as LS in our institution between January 1978 and January 1988. Data were obtained from the patient files, follow-up forms and pathology reports. The mean age was 54.4 f 5.5 (range 38-70). Of these patients 20 presented with vulvar pruritus, 6 had vulvar atrophy, 2 had excoriations and ecchymosis and 3 were asymptomatic. Two patients had insulindependent diabetes mellitus, one patient had autoimmune thyroiditis and one patient had treated hyperthyroidism. All patients were subjected to colposcopic examination. Six patients (26%) who had normal colposcopic findings were also subjected to 1% toluidine blue dye test to detect any suspicious areas. Biopsy was performed from all suspicious areas detected either by Clinical and Clinical Research
254
Ayhan et al.
colposcopy or dye test. All specimens were evaluated by a co-author pathologist. After tissue diagnosis, in 21 patients topical testosterone was applied to all affected areas twice daily for a period of at least 6 weeks (2% testosterone propionate in petrolatum is not commercially available in Turkey, but it can be compounded by mixing 3 ml of 100 mg/ml of testosterone propionate in sesame oil with 12 g petrolatum to obtain a 2% ointment) [4]. In two patients fluorinated corticosteroids (Locacortone-viaformeR 0.02% flumethasone + 3% iodochlorhydroxy quinolone) were applied before testosterone for severe pruritus, traumatic excoriations and ecchymosis. Following this, topical testosterone was applied as outlined above. Each patient was re-evaluated clinically after 6 weeks of therapy. The follow-up time for all patients ranged from 6 to 10 months with a mean follow-up time of 3 years. Results The overall remission rate following topical testosterone was found to be 87.7% (20/ 23). Only two patients experienced androgenie side effects (8.7%) with enhanced libido and minimal clitoral enlargement. Three patients did not respond satisfactorily to testosterone treatment at the end of 6 weeks. Of these three patients, two had alcohol injection to the vulva and one had a Mering procedure for denervation of the vulvar nerves [ 151. These three patients with a minimum followup of 3 years are found to be free of symptoms. All of the patients were symptom and lesion free at the follow-up times ranging from 6 months to 10 years. Testosterone therapy had to be continued in 8 patients intermittently for 2-6 months until the symptoms completely resolved. Control biopsies were taken from these patients upon completion of their treatment programs. All of the biopsies revealed marked histologic improvement. Of the 23 patients in our study group none demonstrated atypia on biopsy. Int J Gynecol Obstet 30
Discussion The treatment of choice for LS is topical testosterone propionate [4,7,18]. Testosterone therapy when used diligently is reported to be highly effective in controlling symptoms of LS. The success rate of the therapy varies from 80% to 100% [2,3,5,8]. The therapeutic success rates as reported by several authors are shown in Table I. The topical effects of androgens on the skin have been extensively investigated. Testosterone penetrates the intact skin rapidly and also is associated with an increased perfusion of the surface capillaries and has a direct stimulatory action upon axillary and pubic hair [5]. The effects of various topical steroids on the aged human axilla, have shown rete development and fibroblastic proliferation with stimulation of the hair follicles and sebaceous glands after testosterone application and to a more limited extent, with progesterone as well [19]. Strauss and Pochi point out that the human skin has significant potential to metabolize androgens [17]. The formation rate of dihydrotestosterone in vitro in vulvar skin was found to be four to five times higher than that in perineal skin [20]. All of these studies point to the vital role of androgens in skin metabolism generally and in vulvar skin particularly. The topical ‘application of androgens, therefore, constitute a logical approach to the treatment of LS. Topical testosterone produced good results in the relief of pruritus. Gross appear-
Table I.
Results of testosterone
in lichen sclerosus.
Reference
No. patients/ treatment failures
-. Remission rate (%)
PI
14/o 612 184/1P 121/6 IO/2 23/3
100 67 93 95 80 88
[51 [41 [31
PI Present study “8 reports.
____
Lichen sclerosus
ante improved in many cases and histologic change toward a more normal skin structure could be identified. Topical testosterone has some side effects which are increased pubic and facial hair, clitoral enlargement, enhanced libido, acne formation, hoarsness, local burning and ulcerations [5,16]. An alternative to topical testosterone propionate is topical progesterone in oil [ 121. Progesterone is especially suitable to treat the child with symptomatic LS, since the side effects of testosterone are undesirable in children. In this study none of the patients recieved topical progesterone. In the occasional patient with severe traumatic excoriations and pruritus, ecchymosis, therapy is begun with a fluorinated corticosteroid applied topically. The ointment can be applied as frequently as desired in order to bring pruritus under control [ 161. This therapy is continued for at least 2 weeks. After all superficial traumatic lesions have healed, topical testosterone is prescribed as outlined above. In the event of testosterone, progesterone and corticosteroid failure, other treatment regimens such as alcohol injection or the Mering procedure can be used [IS]. In this study only three patients required this form of treatment. Skinning vulvectomy and laser therapy are much more radical procedures for the treatment of LS and are also prone to recurrences. They should be considered in patients exhibiting severe atypia on control biopsies and are resistant to medical therapy [16,18]. Watchful1 waiting is a good alternative option in the presence of minimal atypia, but requires the patient to be rebiopsied at appropriate intervals.
3
4 5 6 7 8
9 10
11
12
13 14
15
16
17
18 19
20
255
DiPaola GR: The problem of the so called precancerous lesions of the vulva: ten years of prospective experience. Eur J Gynaecol Gncol I: 20,198O. Friedrich EG Jr: Lichen sclerosus. J Reprod Med 17: 147, 1976. Friedrich EC: Topical testosterone for benign vulvar dystrophy. Obstet Gynecol37: 677, 1971. Friedrich EG: Treating vulvar dystrophy. Contemp Obstet Gynecol JO: 19,1973. Friedrich EG: Vulvar dystropy. Clin Obstet Gynecol 28: 198, 1985. Friedrich EG Jr, Kalra PS. Serum levels of sex hormones in vulvar lichen sclerosus et atrophicus and the effect of topical testosterone. N Engl Med 310: 488, 1984. Friedrich EG Jr, Mclaren NK; Genetic aspects of lichen sclerosus. Am Obstet Gynecol150: 161, 1984. Harrington CA, Dunsmore IR: An investigation into the autoimmune disorders in patients with lichen sclerosus et atrophicus. Br J DermatolZO4: 563, 1981. Hart WR, Norris HJ, Helwig EB: Relation of lichen sclerosus et atrophicus of the vulva to development of carcinoma. Obstet Gynecol45: 369,1975. Jasionowski EA, Jasionowski PA: Further observations on the effect of topical progesterone on vulvar disease. Am J Obstet Gynecol134: 565, 1979. Kaufman RH, Gardner HC: Vulvar dystrophias. Clin Obstet Gynecol21: 1081,1978. Kaufman RH, Gardner HC, Brown D Jr, Beyth Y: Vulvar dystrophias: an evaluation. Am J Obstet Gynecol 120: 363,1974. Mering JH: Some observations on wide skin undercutting for intractible pruritus vulvae. Am Obstet Gynecol 71: 386, 1956. Morrow CP; Advances in the treatment of preinvasive and invasive carcinoma of the vulva. In Recent Advances in Obstetrics and Gynecology (ed J Bonnar, N Rifteen) p 157. Churchill Livingstone, London 1987. Strauss JS, Pochi PE: Recent advances in androgen metabolism and their relation to the skin. Arch Dermatol 100: 621, 1969. Soperj T, Creasman WT: Vulvar dystrophias. Clin Obstet Gynecol29: 43 1, 1986. Rony HR, Zakon SJ: Effect of androgen on the sebaceous glands of human skin. Arch Belg Dermatol Syph 48: 601.1943. Wilson JD, Walker JD: The conversion of testosterone to 5-alpha-androstan-7-beta-ol-3-one (dihydrotestosterone) by skin slices of man. J Clin Invest 48: 371, 1969.
References Address for reprints:
1
2
Bewsher PD, Stanklar L: Direct evidence of localized immunological damage in vulvar lichen sclerosus et atrophicus. J Clin Path01 35: 1395, 1982. Cinberg BL: Postmenapousal pruritus vulvae. Am J Obstet Gynecol49: 647, 1945.
A. Ayhan Kadin Hastaiiklari ve Dojum Ann BiIim Dali Hncettepe hiversitesi Tip Fakttltesi Ankara, Ttirkiye
Clinical and Clinical Research