Abstract
Cutaneous manifestations of hyperandrogenic disorders (acne, seborrhea, hirsutism and androgenetic alopecia) can be caused by elevated levels of free testosterone or androgen precursors. In women with normal serum levels of testosterone or androgen precursors, enhanced local conversion to testosterone, or to the more potent androgen dihydrotestosterone, may lead to increased androgen activity in the pilosebaceous unit. Large individual variations in the response to normal or elevated androgens suggests considerable differences in local androgen metabolism and androgen receptor-mediated activities, which may partly be related to genetic disposition. Androgens cause opposite effects on hair follicles in the scalp compared with the face and body, and there are large differences in the length of anagen phase. Androgens enhance sebum production and keratinization, prolong the growth phase of face and body hair, stimulate the transformation of vellus to terminal hair, and shorten the anagen phase of scalp hair. Estrogens may antagonize the androgen-induced actions on sebaceous glands and hair follicles.
Treatment with oral contraceptives (OCs) reduces the production of androgens and androgen precursors and increases sex hormone-binding globulin, resulting in a decrease of free testosterone levels. According to type and dose, the estrogen and progestogen components of OCs may directly reduce the effect of androgens within sebaceous glands and hair follicles. Therefore, OCs with a predominant estrogen effect may improve mild to moderate forms of acne and seborrhea, hirsutism and androgenetic alopecia, in a time-dependent manner.
In women who do not respond satisfactorily, treatment with OCs containing a progestogen with antiandrogenic activity is recommended. In many women with severe acne or hirsutism, a considerable increase in the local concentration of the antiandrogenic progestogen is required to reduce the androgenic interaction with the androgen receptor. For this therapy, an OC containing cyproterone acetate can be used. If necessary, the dose of cyproterone acetate can be increased in a stepwise manner. While androgenetic alopecia is best treated with a low-dose OC containing cyproterone acetate (optimal effect occurs after at least 12 months of therapy), severe acne and hirsutism are significantly improved after 6–12 months of regimens containing high doses of cyproterone acetate (25–100 mg/day). After termination of treatment the disorders may reappear, therefore treatment with suitable low-dose formulations is recommended to maintain the therapeutic effect.
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References
Randall VA. Androgens and human hair growth. Clin Endocrinol 1994; 40: 439–57
Azziz R, Carmina E, Sawaya ME. Idiopathic hirsutism. Endocr Rev 2000; 21: 347–62
Deplewski D, Rosenfield RL. Role of hormones in pilosebaceous unit development. Endocr Rev 2000; 21: 363–92
Bergfeld WF. Androgenetic alopecia: an autosomal dominant disorder. Am J Med 1995; 98 Suppl. 1A: 95S–8S
Serafini P, Lobo RA. Increased 5α-reductase activity in idiopathic hirsutism. Fertil Steril 1985; 43: 74–8
Jenkins JS, Ash S. The metabolism of testosterone by human skin in disorders of hair growth.J Endocrinol 1973; 59: 345–51
Cassidenti DL, Paulson RJ, Serafini P, et al. Effects of sex steroids on skin 5α-redictase activity in vitro. Obstet Gynecol 1991; 78: 102–7
Voigt W, Hsia SL. Further studies on testosterone 5α-reductase of human skin. J Biol Chem 1973; 248: 4280–5
Rabe T, Kowald A, Ortmann J, et al. Inhibition of skin 5 alpha-reductase by oral contraceptive progestins in vitro. Gynecol Endocrinol 2000; 14: 223–30
Giacomini M, Wright F. The effects of progesterone and pregnanedione on the reductive metabolism of dihydrotestosterone in human skin. J Steroid Biochem Molec Biol 1980; 13:645–51
Thiboutot D, Harris G, Iles V, et al. Activity of the type I 5-reductase exhibits regional differences in isolated sebaceous glands and whole skin. J Invest Dermatol 1995; 105: 209–14
Guy R, Ridden C, Kealey T. The improved organ maintenance of the human sebaceous gland: modeling in vitro the effects of epidermal growth factor, androgens, estrogens, 13-cis retinoic acid, and phenol red. J Invest Dermatol 1996 Mar; 106(3): 454–60
Castello R, Tosi F, Perrone F, et al. Outcome of long-term treatment with the 5α-reductase inhibitor finasteride in idiopathic hirsutism: clinical and hormonal effects during a 1-year course of therapy and 1-year follow-up. Fertil Steril 1996; 66: 734–40
Moltz L, Haase F, Schwartz U, Hammerstein J. Treatment of virilized women with intramuscular administration of cyproterone acetate [in German]. Geburtshilfe Frauenheilkd 1983 May; 43(5): 281–7
vanWayjen RGA, van denEnde A. Experience in the long-term treatment of patients with hirsutism and/or acne with cyproterone acetate-containing preparations: efficacy, metabolic and endocrine effects. Exp Clin Endocrinol 1995; 103: 241–51
Marcondes JAM, Wajchenberg BL, Abujamra AC, et al. Monthly cyproterone acetate in the treatment of hirsute women: clinical and laboratory effects. Fertil Steril 1990; 53: 40–4
Sawaya ME, Price VH. Different levels of 5α-reductase type I and II, aromatase, and androgen receptor in hair follicles of women and men with anrogenetic alopecia. J Invest Dermatol 1997; 109: 296–300
Rittmaster RS. Medical treatment of androgen-dependent hirsutism. J Clin Endocrinol Metab 1995; 80: 2559–63
Bergfeld WF. Hirsutism in women. Postgrad Med 2000; 107: 93–104
Rittmaster RS. Androgen conjugates: physiology and clinical significance. Endocr Rev 1993; 14: 121–32
Gompel A, Wright F, Kuttenn F, et al. Contribution of plasma androstenedione to 5α-androstanediol glucuronide in women with idiopathic hirsutism. J Clin Endocrinol Metab 1986; 62: 441–4
Gruschke A, Kuhl H. Validity of radioimmunological methods for determining free testosterone in serum. Fertil Steril 2001; 76: 576–82
Barbieri RL. Hyperandrogenism. In: Wallach EE, Zacur HA, editors. Reproductive medicine and surgery. St Louis (MO): Mosby, 1995: 209–29
Kelly CJG, Gordon D. The effect of metformin on hirsutism in polycystic ovary syndrome. Eur J Endocrinol 2002; 147: 217–21
Wiegratz I, Jung-Hoffmann C, Kuhl H. Effect of two oral contraceptives containing ethinylestradiol and gestodene or norgestimate upon androgen parameters and serum binding proteins. Contraception 1995; 51: 341–6
Jung-Hoffmann C, Heidt F, Kuhl H. Effect of two oral contraceptives containing 30 μg ethinylestradiol and 75 μg gestodene or 150 μg desogestrel upon various hormonal parameters. Contraception 1988; 38: 593–603
Kuhl H, Gahn G, Romberg G, et al. A randomized cross-over comparison of two low dose oral contraceptives upon hormonal and metabolic parameters: I. effects upon sexual hormone levels. Contraception 1985; 31: 583–93
New MI. Steroid 21-hydroxylase deficiency (congenital adrenal hyperplasia).Am J Med 1885; 98 Suppl 1A: 2S–8S
Moran C, Downing Potter H, Reyna R, et al. Prevalence of 3ß-hydroxysteroid dehydrogenase-deficient nonclassic adrenal hyperplasia in hyperandrogenic women with adrenal androgen excess. Am J Obstet Gynecol 1999; 181: 596–600
Oettel M, Elger W, Ernst M, et al. Experimentelle Endokrinpharmakologie. In: Teichmann AT, editor. Dienogest —Präklinik und Klinik eines Oestagens. Berlin: de Gruyter, 1995: 11–21
Muhn P, Krattenmacher R, Beier S, et al. Drospirenone: a novel progestogen with antimineralocorticoid and antiandrogenic activity: pharmacological characterization in animal models. Contraception 1995 Feb; 51(2): 99–110
Jasonni VM, Bulletti C, Naldi S, et al. Treatment of hirsutism by an association of oral cyproterone acetate and transdermal 17ß-estradiol. Fertil Steril 1991; 55: 742–5
Fern M, Rose DP, Fern EB. Effect of oral contraceptives on plasma androgenic steroids and their precursors. Obstet Gynecol 1978; 51: 541–4
Palatsi R, Hirvensalo E, Liukko P, et al. Serum total and unbound testosterone and sex hormone binding globulin (SHBG) in female acne patients treated with two different oral contraceptives. Acta Derm Venereol 1984; 64: 517–23
Kaiser E. Wirkung eines neuen hormonalen Kontrazeptivums (Neo-Eunomin) bei Frauen mit Androgenisierungserscheinungen. Geburtsh Frauenheilk 1984; 44: 651–5
Carlborg L. Cyproterone acetate versus levonorgestrel combined with ethinyl estradiol in the treatment of acne. Acta Obstet Gynecol Scand Suppl 1986; 134: 29–32
Worret I, Arp W, Zahradnik HP, et al. Acne resolution rates: results of a single-blind, randomized, controlled, parallel phase III trial with EE/CMA (Belara) and EE/LNG (Microgynon). Dermatology 2001; 203: 38–44
Lemay A, Dewailly SD, Grenier R, et al. Attenuation of mild hyperandrogenic activity in postpuberal acne by a triphasic oral contraceptive containing low doses of ethynyl estradiol and d,l-norgestrel. J Clin Endocrinol Metab 1990; 71: 8–14
Jung-Hoffmann C, Kuhl H. Divergent effects of two low-dose oral contraceptives on sex hormone-binding globulin and free testosterone. Am J Obstet Gynecol 1987; 156: 199–203
Refn H, Kjaer A, Lebech AM, et al. Clinical and hormonal effects of two oral contraceptives: correlations to serum concentrations of levonorgestrel and gestodene. Contraception 1990; 41: 259–68
van der Vange N, Blankenstein MA, Kloosterboer HJ, et al. Effects of seven low-dose combined oral contraceptives on sex hormone binding globulin, cortico-steroid binding globulin, total and free testosterone. Contraception 1990; 41: 345–51
Coenen CMH, Thomas CMG, Borm GF, et al. Changes in androgens during treatment with four low-dose contraceptives. Contraception 1996; 53: 171–6
Gaspard UJ, Romus MA, Gillain D, et al. Plasma hormone levels in women receiving new oral contraceptives containing ethinylestradiol plus levonorgestrel and desogestrel. Contraception 1983; 27: 577–90
Gaspard UJ, Dubois M, Gillain D, et al. Ovarian function is effectively inhibited by a low-dose triphasic oral contraceptive containing ethinylestradiol and levonorgestrel. Contraception 1984; 29: 305–18
Kuhnz W, Baumann A, Staks T, et al. Pharmacokinetics of gestodene and ethinylestradiol in 14 women in three months of treatment with a new tri-step combination oral contraceptive: serum protein binding of gestodene and influence of treatment on free and total testosterone levels in the serum. Contraception 1993; 48: 303–22
Lucky AW, Henderson TA, Olson WH, et al. Effectiveness of norgestimate and ethinylestradiol in treating moderate acne vulgaris. J Am Acad Dermatol 1997; 37: 746–54
Redmond GP, Olson WH, Lippman JS, et al. Norgestimate and ethinyl estradiol in the treatment of acne vulgaris: a randomized, placebo-controlled trial. Obstet Gynecol 1997; 89: 615–22
Thiboutot D, Archer DF, Lemay A, et al. A randomized, controlled trial of a low-dose contraceptive contaning 20 μg of ethinyl estradiol and 100 μg of levonorgestrel for acne treatment. Fertil Steril 2001; 76: 461–8
Thorneycroft ICH, Stanczyk FZ, Bradshaw KD, et al. Effect of low-dose oral contraceptives on androgenic markers and acne. Contraception 1999; 60:255–62
Dieben TOM, Vromans L, Theeuwes A, et al. The effects of CTR-24, a biphasic oral contraceptive combination, compared to Diane-35 in women with acne. Contraception 1994; 50: 373–82
Mango D, Ricci S, Manna P, et al. Clinical and hormonal effects of ethinylestradiol combined with gestodene and desogestrel in young women with acne vulgaris. Contraception 1996; 53: 163–70
Luderschmidt C, Schreiber G, Moltz L. The significance of antiandrogenic properties of oral contraceptives in androgen influenced skin disorders: a double blind study using two different OCs containing 30 μg EE and 2mg dienogest and 35 μg EE and 2mg cyproterone acetate. In: Kuhl H, Nikolov R, editors. Re-evaluation of contraceptive steroids. Bad Blankenburg: Harfe Verlag, 1998: 37–43
Zahradnik HP, Goldberg J, Andreas JO. Efficacy and safety of the new antiandrogenic oral contraceptive Belara. Contraception 1998; 57: 103–9
Falsetti L, Gambera A, Tisi G. Efficacy of the combination ethinyl oestradiol and cyproterone acetate on endocrine, clinical and ultrasonographic profile in polycystic ovarian syndrome. Hum Reprod2001; 16: 36–42
Venturoli S, Marescalchi O, Colombo FM, et al. A prospective randomized trial comparing low dose flutamide, finasteride, ketoconazole, and cyproterone acetate-estrogen regimens in the treatment of hirsutism. J Clin Endocrinol Metab 1999; 84: 1304–10
Fruzzetti F, Bersi C, Parrini D, et al. Treatment of hirsutism: comparisons between different antiandrogens with central and peripheral effects. Fertil Steril 1999; 71: 445–51
Barth JH, Cherry CA, Wojnarowska F, et al. Cyproterone acetate for severe hirsutism: results of a double-blind dose-ranging study. Clin Endocrinol 1991; 35: 5–10
O’Brien RC, Cooper ME, Murray RML, et al. Comparison of sequential cypoterone acetate/estrogen vs Spironolactone / oral contraceptive in the treatment of hirsutism. J Clin Endocrinol Metab 1991; 72: 1008–13
Erenus M, Yücelten D, Gürbüz O, et al. Comparison of spironolactone-oral contraceptive vs Cyproterone acetate-estrogen regimens in the treatment of hirsutism. Fertil Steril 1996; 66: 216–9
Hammerstein J, Meckies J, Leo-Rossberg I, et al. Use of cyproterone acetate (CPA) in the treatment of acne, hirsutism and virilism. J Steroid Biochem 1975 Jun; 6(6): 827–36
Moltz L, Schwartz U, Hamerstein J. Die klinische Andwendung von Anti-androgenen bei der Frau. Gynäkologe 1980; 13: 1–17
Moltz L. Differenzierter Einsatz von Cyproteronacetat bei verschiedenen androgenbedingten Krankheitsbildern der Frau. In: Breckwoldt M, editor. Diagnostik und Therapie von Androgenisierungserscheinungen bei der Frau. Berlin: Diesbach Verlag, 1992: 154–161
Carmina E, Lobo RA. A comparison of the relative efficacy of antiandrogens for the treatment of acne in hyperandrogenic women. Clin Endocrinol 2002; 57: 231–4
Hammerstein J, Moltz L, Schwartz U. Antiandrogens in the treatment of acne and hirsutism. J Steroid Biochem 1983; 19: 591–7
Holdaway IM, Croxson MS, Evans MC, et al. Effect of cyproterone acetate on glucocorticoid secretion in patients treated for hirsutism. Acta Endocrinol (Copenh) 1983; 104: 222–6
Schützel H, Neumann F. Potential risk of intrauterine feminization in man from the antiandrogen cyproterone acetate (CPA) in recommended dose regimens [abstract]. XII World Congress on Gynecology and Obstetrics; 1988 Oct; Rio de Janeiro. 703
Kokaly W, McKenna TJ. Relapse of hirsutism following long-term successful treatment with oestrogen-progestogen combination. Clin Endocrinol 2000; 52: 379–82
Porcile A, Gallardo E. Oral contraceptives containing desogestrel in the maintenance of the remission of hirsutism: monthly versus bimonthly treatment. Contraception 1991; 44: 533–40
Ibanez L, Potau N, Marcos MV, et al. Treatment of hirsutism, hyperandrogenism, oligomenorrhea, dyslipidemia, and hyperinsulinism in nonobese, adolescent girls: effect of flutamide. J Clin Endocrinol Metab 2000; 85: 3251–5
Venturoli S, Paradisi R, Bagnoli A, et al. Low-dose flutamide (125 mg/day) as maintenance therapy in the treatment of hirsutism. Horm Res 2001; 56: 25–31
Erenus M, Yücelten D, Durmusoglu F, et al. Comparison of finasteride versus spironolactone in the treatment of idiopathic hirsutism. Fertil Steril 1997; 68: 1000–3
Müderris II, Bayram F, Güven M. A prospective, randomized trial comparing flutamide (250 mg/d) and finasteride (5 mg/d) in the treatment of hirsutism. Fertil Steril 2000; 73: 984–7
Sahin Y, Dilber S, Kelestimur F. Comparison of Diane 35 and Diane 35 plus finasteride in the treatment of hirsutism. Fertil Steril 2001; 75: 496–500
Castelo-Branco C, Martinez de Osaba MJ, Pons F, et al. Gonadotropin-releasing hormone analog plus an oral contraceptive containing desogestrel in women with severe hirsutism: effects on hair, bone, and hormone profile after 1-year use. Metabolism 1997; 46: 437–40
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Wiegratz, I., Kuhl, H. Managing Cutaneous Manifestations of Hyperandrogenic Disorders. Treat Endocrinol 1, 373–386 (2002). https://doi.org/10.2165/00024677-200201060-00003
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DOI: https://doi.org/10.2165/00024677-200201060-00003