0021-972X/90/7003-0642$02.00/0 Journal of Clinical Endocrinology and Metabolism Copyright© 1990 by The Endocrine Society
Vol. 70, No. 3 Printed in U.S.A.
Cyproterone Acetate Versus Hydrocortisone Treatment in Late-Onset Adrenal Hyperplasia POLI SPRITZER, LINE BILLAUD, JEAN-CHRISTOPHE THALABARD, PASCAL BIRMAN, IRENE MOWSZOWICZ, MARIE-CHARLES RAUX-DEMAY, FRANQOIS CLAIR, FREDERIQUE KUTTENN, AND PIERRE MAUVAIS-JARVIS Departement d'Endocrinologie et Medecine de la Reproduction and Laboratoire de Biochimie B (I.M.), Hopital Necker, 75015 Paris; and Laboratoire d'Explorations Fonctionnelles Endocriniennes, Hdpital Trousseau (m.-C.R.-D.), 75012 Paris, France; and Departamento de Fisiologia, Instituto de Biociencias, Uniuersidade Federal do Rio Grande do Sul. R. Sarmento Leite 500 (P.S.), Porto Alegre 90049, Brazil
ABSTRACT. Thirty late-onset adrenal hyperplasia patients consulting for isolated hirsutism were randomly divided into two groups; group 1 (n = 16) was treated with hydrocortisone in order to suppress androgen adrenal secretion, and group 2 (n = 14) received cyproterone acetate (CPA) antiandrogen therapy to inhibit peripheral androgen activity. The clinical and hormonal effects of each type of treatment were evaluated. Before treatment, the clinical and hormonal profiles of the two patient groups did not differ significantly. Excellent clinical evolution in terms of the regression of hirsutism was observed in the CPA-treated patients (54% decrease in the clinical score in 1 yr), in contrast with the slight decrease in hirsutism (26%) after hydrocortisone treatment. In hydrocortisone-treated patients, plasma androgen decreased to normal levels: testosterone
from 3.05 ± 1.45 to 1.46 ± 0.42 nmol/L and A4-androstenedione from 13.6 ± 4.1 to 6.33 ± 1.47 nmol/L. Conversely, in CPAtreated patients, only a slight decrease in testosterone from 2.98 ± 1.98 to 2.29 ± 0.64 nmol/L and in A4-androstenedione from 12.9 ± 5.9 to 9.86 ± 2.23 nmol/L was observed. This slight decrease in plasma androgens contrasts with the rapid clinical improvement after CPA. These results emphasize the importance of peripheral receptivity to androgens in the clinical expression of hyperandrogenism. Moreover, they indicate that peripheral antiandrogen therapy may be more appropriate in late-onset adrenal hyperplasia patients than conventional adrenal inhibition using cortisone therapy. (J Clin Endocrinol Metab 70: 642, 1990)
T
compared with those obtained in 16 other LAH patients who received hydrocortisone treatment.
HE CONVENTIONAL treatment for late-onset adrenal hyperplasia (LAH) due to a partial defect in 21-hydroxylase (1-6) is glucocorticoid therapy, as used for the classical form of congenital adrenal hyperplasia resulting from a major enzyme defect. Indeed, glucocorticoid therapy corrects the cortisol deficiency and inhibits ACTH secretion, thereby decreasing adrenal androgen secretion (7-11). However, in LAH, clinical symptoms of cortisol deficiency are infrequent and are limited to periods of stress. The majority of LAH patients consult for isolated hirsutism and/or acne (5,12-14). Moreover, the results of glucocorticoid therapy in hirsutism due to LAH are very often disappointing in contrast with the dramatic improvement observed with antiandrogen therapy in hirsutism of other origins (15-17). Antiandrogen treatment consisting of cyproterone acetate (CPA) combined with percutaneous estradiol, as previously described (16,17), was, therefore, proposed to 14 LAH patients. The clinical and hormonal results were
Materials and Methods Patients Thirty-two LAH patients who consulted for hirsutism over the past 5 yr and who did not plan to become pregnant were included in the study. Thirty, whose ages ranged from 15-38 yr (mean, 24.3 ± 5.8), were retained for the study. The other 2 dropped out of the follow-up. All 30 patients had had a normal puberty, after which moderate to severe hirsutism developed, but without major signs of virilization, such as clitoromegaly or muscle hypertrophy. There was no clinical history of salt loss syndrome at birth and no family history of salt loss or hirsutism. Menstrual cycles were regular and ovulatory in 22 patients, and irregular and dysovulatory in the other 8. Fourteen patients had had normal pregnancies before diagnosis. Gynecological examination of all patients was normal. Hormonal determinations
Received May 19, 1989. Address all correspondence and requests for reprints to: Dr. F. Kuttenn, Department of Endocrinology and Reproductive Medicine, Hopital Necker, 149 rue de Sevres, 75743 Paris Cedex 15, France.
The following routine etiological investigation for hirsutism was carried out in all patients: basal plasma testosterone (T) and A4-androstenedione (A) assays; and plasma cortisol (F) 642
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ANTIANDROGEN TREATMENT IN LAH and 17-hydroxyprogesterone (17-OHP) measured before and 1 h after im administration of 0.250 mg synthetic ACTH-(l-24) (Synacthen, Ciba). Blood samples were collected at 0800 h during the follicular phase of the menstrual cycle. Plasma levels were determined by RIAs, as previously described (5, 12, 1719). Treatments Patients were randomly separated into two groups. Group 1 (n = 16) received conventional hydrocortisone treatment (20 mg/day; 10 mg twice daily). Group 2 (n = 14) was treated with the antiandrogen CPA (50 mg/day) from the 5th to the 25th day of the menstrual cycle combined with percutaneous estradiol (3 mg/day) over the last 10 days of CPA administration (16). To evaluate the therapeutic effects on hirsutism, the Ferriman clinical score (20) was determined before and during treatment in both groups. Plasma T and A were checked every 3 or 6 months. Statistical analysis and calculations Data are expressed as the mean ± SD. Statistical analysis was carried out using Student's t test.
Results The clinical profile of patients before treatment is summarized in Table 1 and did not differ significantly between the two groups. The clinical score for hirsutism was 22 ± 7 in group 1 and 23 ± 9 in group 2. Plasma androgen levels (T and A) were higher than normal in the two groups (T, 3.05 ± 1.45 and 2.98 ± 1.98 nmol/L; A, 13.6 ± 4.1 and 12.9 ± 5.9 nmol/L in groups 1 and 2, respectively). The basal level of 17-OHP was high (24.4 ± 10.5 and 26.1 ± 11.8 nmol/L in groups 1 and 2, respectively) and increased dramatically after ACTH stimulation in all patients (144.7 ± 87.8 nmol/L in group 1; 127.8 ± 49.7 nmol/L in group 2; Table 1), establishing the diagnosis of LAH due to partial 21-hydroxylase deficiency (4, 5, 19, 21). Basal plasma F concentrations were normal in both groups (Table 1); however, the response of F to ACTH was subnormal in both groups (414 ± 1 1 3 and 419 ± 69 nmol/L in groups 1 and 2, respectively; normal values, 654 ± 116 nmol/L; Table 1). In patients from group 1, who received the 20 mg
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hydrocortisone treatment, hirsutism regressed slowly. The clinical scores were 21.3 ± 6.5, 19.5 ± 5.6, and 16.5 ± 5.2 after 3, 6, and 12 months of treatment (i.e. 32% decrease after 1 yr; Fig. 1). In contrast, there was a striking fall in the clinical score among the CPA-treated group 2 (17.0 ± 7.03, 12.9 ± 7.2, and 10.0 ± 5.5) after 3, 6, and 12 months (i.e. 54% decrease; Fig. 2). The difference in the clinical score between the two groups was already significant after 3 months of treatment (P < 0.05) and even more so after 6 and 12 months of treatment (P< 0.005). In group 1, plasma T and A decreased to 2.15 ± 0.63 and 10.42 ± 1.80 nmol/L, respectively, after 3 months and to 1.74 ± 0.45 and 7.45 ± 1.42, 1.46 ± 0.42, and 6.33 ± 1.47 nmol/L after 6 and 12 months of hydrocortisone treatment. In contrast, in CPA-treated group 2, plasma T and A decreased only slightly and remained significantly higher than values in group 1 (2.57 ± 0.62 and 11.54 ± 4.14 nmol/L after 3 months, 2.43 ± 0.53 and 10.42 ± 2.11, 2.29 ± 0.64 and 9.86 ± 2.23 nmol/L after 6 and 12 months of CPA treatment; Fig. 3). The difference in androgen levels between the two groups was significant after 3 months of treatment (P < 0.05) for T and A. The difference was even more significant after 6 and 12 months (P < 0.005). The slight decrease in plasma androgens with CPA contrasts with the rapid clinical improvement observed. Both treatment were well tolerated. No patients reported any side-effects.
Discussion The effects on hirsutism of 2 different types of treatment, glucocorticoid and antiandrogen, were compared in 30 LAH patients. Sixteen patients received the classical daily 20-mg hydrocortisone treatment to suppress adrenal androgen oversecretion, and 14 patients received antiandrogen CPA therapy. Whereas hydrocortisone produced only a mild reduction in hirsutism, CPA yielded far better clinical results. This excellent improvement was similar to that observed with CPA on hirsutism of other origins (polycystic ovaries, idiopathic hirsutism, etc.) (16,17,22,23).
TABLE 1. Clinical and hormonal data before treatment in the two groups of LAH patients: (patients were randomly assigned to either group 1, treated with hydrocortisone, or group 2, treated with CPA) F (nmol/L) Age (yr) Group 1 (n = 16) Group 2 (n = 14) Normal women (n = 20)
24.9 ± 5.6 23.6 ± 6.2 22.3 ± 5.9
17-OHP (nmol/L)
Clinical score for hirsutism
T (nmol/L)
A (nmol/L)
Basal
After ACTH
Basal
After ACTH
22 ± 7 23 ± 9 6 (2-10)"
3.05 ± 1.45 2.98 ± 1.98 1.14 ± 0.10
13.6 ± 4.1 12.9 ± 5.9 4.65 ± 0.24
284 ± 124 273 ± 124 248 ± 99
414 ± 113 419 ± 69 654 ± 116
24.4 ± 10.5 26.1 ± 11.8 2.1 (0.6-7.26)a
144.7 ± 87.8 127.8 ± 49.7 4.2 (1.5-11.2)"
Values are expressed as the mean ± SD, except for normal values of the clinical score and 17-OHP (°), expressed as mean and extreme values. No statistical difference was observed between the two groups in any of the parameters.
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644
SPRITZER ET AL. HYDROCORTISONE
TREATMENT
II I
100 30
%
20 50--
II
0
3
6
" 12 MONTHS
12 MONTHS
FIG. 1. Evolution of the clinical scores of 16 LAH hirsute women treated with hydrocortisone. Left panel, Individual values. Right panel, The mean of the original scores is referred to as 100%. The percentages shown at 3, 6, and 12 months of treatment represent the mean percentage of each individual score.
CPA TREATMENT
100 30
%
I!I
20 50--
10
12
"
MONTHS
12
MONTHS
FlG. 2. Evolution of the clinical scores of 14 LAH hirsute women treated with oral CPA and percutaneous estradiol. See Fig. 1 for details.
ng/ml nmol/L 1
ng/ml 4
nmol/L
H
0.5
J MONTHS OF TREATMENT
FIG. 3. Evolution of plasma T (left panel) and A [right panel) in the 16 LAH patients treated with hydrocortisone (group 1; • ) and the 14 LAH patients treated with CPA (group 2; M). Values are expressed as the mean ± SD.
JCE & M • 1990 Vol 70 • No 3
Corticosteroid therapy is the classical treatment for adrenal hyperplasia (7-11). It derives from the observation of cortisol deficiency in the precocious congenital form of adrenal hyperplasia. Cortisol deficiency causes excess ACTH secretion, resulting in adrenal hyperplasia and androgen overproduction. However, in LAH patients, the enzymatic defect is only partial, and at the expense of adrenal hyperplasia, the plasma F level is normal and may be sufficient, at least under basal conditions, since most patients consulted for isolated hirsutism (5,12,13, 24). Moreover, the clinical result of hydrocortisone therapy is poor (15). A possible explanation for this poor result is that a standard hydrocortisone dose cannot accurately replace adrenal secretion, which is essentially designed to respond to stress. Patients receiving a standard dose of hydrocortisone are, therefore, subjected to alternate periods of under- and overtreatment, depending on the level of stress. Therefore, peripheral antiandrogen therapy may be more appropriate in LAH patients who have no actual cortisol deficiency, at least under basal conditions, and who consult for cosmetic reasons. In both groups the clinical results were in contrast with the changes observed in plasma androgen levels. In group 1, treated with hydrocortisone, a consistent reduction of A and T levels was observed, due to inhibition of ACTH secretion. Plasma androgen decreased continuously over several months of treatment, probably reflecting a progressive reduction in adrenal hyperplasia. Contrasting with the fall of plasma androgen levels in group 1, there was only a slight decrease in plasma T and A levels in the CPA-treated group 2. This slight decrease was apparent at the beginning of treatment and may correspond to the suppression of ovarian androgen secretion through the antigonadotropic effect of CPA (16, 17, 25). In patients with hirsutism due to polycystic ovaries, CPA acts through two mechanisms: 1) suppression of ovarian androgen secretion excess, and 2) competitive inhibition of residual androgens at the target cell level. However, in LAH patients treated with CPA, plasma androgen levels remain above normal, and CPA may only act peripherally, inhibiting androgen binding to the androgen receptor (16, 17, 26). The excellent clinical results with CPA, despite higher than normal T and A levels, stress the importance of peripheral receptivity to androgens in the clinical expression of hyperandrogenism. The role of target cell sensitivity to androgens in the clinical expression of biological hyperandrogenism is now well documented. The most striking evidence is provided by the androgen insensitivity syndrome, also designated in its complete form as the testicular feminization syndrome due to an androgen receptor defect in XY patients with normal testicular secretion (27). Deficiency in 5a-
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ANTIANDROGEN TREATMENT IN LAH reductase can also be responsible for male pseudohermaphroditism (28, 29). In women, the importance of skin sensitivity to androgens has also been emphasized. Lobo et al. (30) have shown that patients with the polycystic ovary syndrome and high plasma androgen levels could be hirsute or nonhirsute. These researchers also observed that in these patients, 3a-androstanediol glucuronide, the terminal androgen metabolite in the active 5a-reductase pathway, was the best biological marker for hirsutism (30). In LAH families, we have observed wide variations in the clinical expression of biological hyperandrogenism between the propositi and their HLA-identical siblings considered to be homozygotes for LAH (5). The 17-OHP response to the Synacthen test and plasma androgen levels were similar in the homozygotes of a given family, but the clinical expression differed and the level of urinary 3«-androstanediol glucuronide excretion was especially high in the patients presenting hirsutism, reflecting peripheral utilization of elevated plasma androgens (5, 15). On the other hand, high 5a-reductase activity in the skin has been held responsible for the so-called idiopathic hirsutism in a group of hirsute patients without any sign of ovarian or adrenal dysfunction and with normal plasma androgen levels (18, 31). High skin 5a-reductase activity measured in vitro (18) and high 3a-androstanediol glucuronide levels contrasting with the normal plasma androgen levels (18,32), suggest excess peripheral androgen utilization (33). These observations emphasize the importance of peripheral androgen utilization in hirsutism. Moreover, the good clinical results observed in CPA-treated compared with hydrocortisone-treated LAH patients confirm the importance of acting primarily at the target level. 3«-Androstanediol glucuronide was not systematically studied, since we have previously shown that CPA was a partial liver enzymatic inducer, increasing 3a-androstanediol glucuronide levels (26). This metabolite can, therefore, be used as a marker of androgen peripheral utilization only in the absence of any therapy interfering with liver metabolism. An inhibitory effect of CPA on adrenal steroidogenesis has been reported in animals (34-36) and also in children and men receiving high doses of CPA (36, 37). This has been ascribed to an inhibitory effect of CPA on ACTH secretion due to a partial glucocorticoid-like effect of CPA. However, these results were observed in studies using high doses of CPA (200 mg/day). No sign of adrenal insufficiency was observed by researchers using 100 mg CPA/day in hirsute patients (22, 23, 25, 26). In our experience, hirsute women treated with 50 mg CPA/day for 20 days/cycle for periods ranging from 6 months to 3 yr showed no sign of cortisol deficiency; moreover,
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plasma and urinary free F and responses to Synacthen and metyrapone tests were not altered (16, 17, 38). In the present study, patients were informed of the potential risk of F deficiency during intercurrent stress, and all received a card bearing instructions for hydrocortisone administration in case of stress. However, none of them showed signs of adrenal insufficiency or received additional glucocorticoid therapy. Percutaneous estradiol (3 mg/day) combined with CPA has no antigonadotropic effect, but ensures substitutive estrogen input. It permits regular bleeding and maintains target organ eutrophy (16). As previously reported, natural estradiol administered by the percutaneous route does not have the deleterious hepatic, metabolic, or vascular effects observed with orally administered synthetic estrogens (16, 17). This study is, to our knowledge, the first report on CPA treatment in LAH. It indicates that in LAH patients characterized by isolated hirsutism without actual F deficiency under basal conditions, peripheral antiandrogen therapy may be more appropriate than conventional adrenal inhibition using cortisone therapy. Conversely, hydrocortisone replacement therapy should be reserved 1) for patients with more severe forms of enzymatic deficiency, as evidenced by lower plasma F levels, 2) for patients planning a pregnancy, or 3) for all LAH patients in situations of stress. References 1. Decourt J, Jayle MF, Baulieu E. Virilisme cliniquement tardif avec
2.
3. 4. 5. 6. 7.
8.
9.
10. 11.
excretion de pregnanetriol et insuffisance de production de cortisol. Ann Endocrinol (Paris). 1957;18:416-22. Migeon CJ, Rosenwaks Z, Lee PA, Urban MD, Bias WB. The attenuated form of congenital adrenal hyperplasia an allelic form of the 21-hydroxylase deficiency. J Clin Endocrinol Metab. 1980;51:647-9. Kohn B, Levine LS, Pollack MS, et al. Late-onset steroid 21hydroxylase deficiency: a variant of classical congenital adrenal hyperplasia. J Clin Endocrinol Metab. 1982;55:817-27. Lee PA, Rosenwaks Z, Urban MD, Migeon CJ, Bias WD. Attenuated forms of congenital adrenal hyperplasia due to 21-hydroxylase deficiency. J Endocrinol Metab. 1982;55:866-71. Kuttenn F, Couillin Ph, Girard F, et al. Late-onset adrenal hyperplasia in hirsutism. N Engl J Med. 1985;313:224-31. White PC, New MI, Dupont B. Congenital adrenal hyperplasia (I). N Engl J Med. 1987;316:1519-24. Klingensmith GJ, Garcia CG, Jones HW, Migeon CJ, Blizzard RM. Glucocorticoid treatment of girls with congenital adrenal hyperplasia : Effects on height, sexual maturation and fertility. J Pediatr. 1977;90:996-1004. Korth-Schutz S, Virdis R, Saenger P, Chow DM, Levine LS, New MI. Serum androgens as a continuing index of adequacy of treatment of congenital adrenal hyperplasia. J Clin Endocrinol Metab. 1978;46:452-8. Smith R, Donald RA, Espiner EA, Glathaar C, Abbott G, Scandrett M. The effect of different treatment regimens on hormonal profiles in congenital adrenal hyperplasia. J Clin Endocrinol Metab. 1980;51:230-6. Antony G. Management of congenital adrenal hyperplasia. Lancet. 1984;l:1073. Winterer J, Chrousos GP, Loriaux DL, Cutler BG. Effect of hydrocortisone dose schedule on adrenal steroid secretion in congenital
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adrenal hyperplasia. J Pediatr. 1985;106:137-42. 12. Bouchard P, Kuttenn F, Mowszowicz I, Schaison G, Raux-Eutorin MC, Mauvais-Jarvis P. Congenital adrenal hyperplasia due to 21hydroxylase deficiency : a study of five cases. Acta Endocrinol (Copenh). 1981;96:107-ll. 13. Chrousos GP, Loriaux DL, Mann DL, Cutler Jr GB. Late-onset 21 -hydroxylase deficiency mimicking idiopathic hirsutism or polycystic ovarian disease: an allelic variant of congenital virilizing adrenal hyperplasia with a milder enzymatic defect. Ann Intern Med. 1982;96:143-8. 14. Chetkowski RJ, De Fazio J, Shamonki I, Judd HL, Chang RJ. The incidence of late-onset congenital adrenal hyperplasia due to 21hydroxylase deficiency among hirsute women. J Clin Endocrinol Metab., 1984;58:595-8. 15. Kuttenn F, Billaud L, Thalabard JC, et al. L'hyperplasie congenitale des surrenales a revelation tardive. Sensibilite peripherique aux androgenes et implications therapeutiques. Ann Endocrinol (Paris). 1987;48:35-7. 16. Kuttenn F, Rigaud C, Wright F, Mauvais-Jarvis P. Treatment of hirsutism by oral cyproterone acetate and percutaneous estradiol. J Clin Endocrinol Metab. 1980;51:1107-ll. 17. Rigaud C, Vincens M, Mowszowicz I, et al. Mecanisme d'action de l'acetate de cyproterone dans le traitement de l'hirsutisme. Ann Endocrinol (Paris). 1983;44:387-92. 18. Kuttenn F, Mowszowicz I, Schaison G, Mauvais-Jarvis P. Androgen production and skin metabolism in hirsutism. J Endocrinol. 1977;75:83-91. 19. Gourmelen M, Pham-Huu-Trung MT, Bredon MG, Girard F. 17Hydroxyprogesterone in the cosyntropin test: results in normal and hirsute women and in mild congenital adrenal hyperplasia. Acta Endocrinol (Copenh). 1970;90:481-9. 20. Ferriman D, Gallwey JD. Clinical assessment of body hair growth in women. J Clin Endocrinol Metab. 1961;21:1440-8. 21. New MI, Lorenzen F, Lerner AJ, et al. Genotyping steroid 21hydroxylase deficiency; hormonal reference data. J Clin Endocrinol Metab. 1983;57:320-6. 22. Ismail AAA, Davidson DW, Sonka AR, et al. The evaluation of the role of androgens in hirsutism and the use of a new anti-androgen "cyproterone acetate" for therapy. J Clin Endocrinol Metab. 1974;39:81-95. 23. Hammerstein J, Meckies J, Leo-Rossberg I, Moltz L, Zielske F. Use of cyproterone acetate (CPA) in the treatment of acne, hirsutism and virilism. J Steroid Biochem. 1975;6:827-36. 24. Lobo RA, Goebelsmann U. Adult manifestation of congenital ad-
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31. 32. 33. 34. 35. 36. 37. 38.
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renal hyperplasia due to incomplete 21-hydroxylase deficiency mimicking polycystic ovarian disease. Am J Obstet Gynecol. 1980;138:720-6. Neumann F, Berswordt-Wallrabe Von R, Eiger W, Steinbeck H, Hahn JD, Kramec M. Aspect of androgen-dependent events as studied by antiandrogens. Recent Prog Horm Res. 1970;26:337405. Mowszowicz I, Wright F, Vincens M, et al. Androgen metabolism in hirsute patients treated with cyproterone acetate. J Steroid Biochem., 1984;20:757-61. Griffin JE, Wilson JD. The syndrome of androgen resistance. N Engl J Med. 1980,302:198-209. Imperato-McGinley J, Peterson RE. Male pseudohermaphroditism: the complexities of male phenotypic development. Am J Med. 1976;61:251-65. Kuttenn F, Mowszowicz I, Wright F, et al. Male pseudohermaphroditism: a comparative study of one patient with 5«-reductase deficiency and three patients with the complete form of testicular feminization. J Clin Endocrinol Metab. 1979;49:861-5. Lobo RA, Goebelsmann U, Horton R. Evidence for the importance of peripheral tissue events in the development of hirsutism in polycystic ovary syndrome. J Clin Endocrinol Metab. 1983;57:3937. Mauvais-Jarvis P, Kuttenn F, Mowszowicz I. Idiopathic hirsutism. In: Monographs on endocrinology. Berlin: Springer-Verlag ed.; 1981;19:74-82. Kirschner MA, Samojlik E, Szmal E. Clinical usefulness of plasma androstanediol glucuronide measurements in women with idiopathic hirsutism. J Clin Endocrinol Metab. 1987;65:597-601. Wright F, Mowszowicz I, Mauvais-Jarvis P. Urinary 5«-androstane-3a,17diol radiommunoassay: a new clinical evaluation. J Clin Endocrinol Metab. 1978;47:850-4. Neri RO, Monahan MD, Meyer JG, Afonso BA, Tabalhnick IA. Biological studies on an antiandrogen. Eur J Pharmacol. 1967;l:438-44. Zieger G, Lux B, Kubatsch B. The effect of cyproterone acetate on the adrenal of the male hamster. Acta Endocrinol (Copenh). 1976;82:127-33. Girard J, Baumann JB, Buchler U, et al. Cyproterone acetate and ACTH adrenal function. J Clin Endocrinol Metab. 1978;101:5816. Jeffcoate WJ, Howards CRW, Rees LH, Besser GM. Cyproterone acetate. Lancet. 1976;2:1140. Kuttenn F, Bricaire C. Traitement de l'hirsutisme. In: Flammarion, ed. L'Hirsutisme. Paris; 1988;217-49.
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Vol. 70, No. 3 Printed in U.S.A.
Cyproterone Acetate Versus Hydrocortisone Treatment in Late-Onset Adrenal Hyperplasia POLI SPRITZER, LINE BILLAUD, JEAN-CHRISTOPHE THALABARD, PASCAL BIRMAN, IRENE MOWSZOWICZ, MARIE-CHARLES RAUX-DEMAY, FRANQOIS CLAIR, FREDERIQUE KUTTENN, AND PIERRE MAUVAIS-JARVIS Departement d'Endocrinologie et Medecine de la Reproduction and Laboratoire de Biochimie B (I.M.), Hopital Necker, 75015 Paris; and Laboratoire d'Explorations Fonctionnelles Endocriniennes, Hdpital Trousseau (m.-C.R.-D.), 75012 Paris, France; and Departamento de Fisiologia, Instituto de Biociencias, Uniuersidade Federal do Rio Grande do Sul. R. Sarmento Leite 500 (P.S.), Porto Alegre 90049, Brazil
ABSTRACT. Thirty late-onset adrenal hyperplasia patients consulting for isolated hirsutism were randomly divided into two groups; group 1 (n = 16) was treated with hydrocortisone in order to suppress androgen adrenal secretion, and group 2 (n = 14) received cyproterone acetate (CPA) antiandrogen therapy to inhibit peripheral androgen activity. The clinical and hormonal effects of each type of treatment were evaluated. Before treatment, the clinical and hormonal profiles of the two patient groups did not differ significantly. Excellent clinical evolution in terms of the regression of hirsutism was observed in the CPA-treated patients (54% decrease in the clinical score in 1 yr), in contrast with the slight decrease in hirsutism (26%) after hydrocortisone treatment. In hydrocortisone-treated patients, plasma androgen decreased to normal levels: testosterone
from 3.05 ± 1.45 to 1.46 ± 0.42 nmol/L and A4-androstenedione from 13.6 ± 4.1 to 6.33 ± 1.47 nmol/L. Conversely, in CPAtreated patients, only a slight decrease in testosterone from 2.98 ± 1.98 to 2.29 ± 0.64 nmol/L and in A4-androstenedione from 12.9 ± 5.9 to 9.86 ± 2.23 nmol/L was observed. This slight decrease in plasma androgens contrasts with the rapid clinical improvement after CPA. These results emphasize the importance of peripheral receptivity to androgens in the clinical expression of hyperandrogenism. Moreover, they indicate that peripheral antiandrogen therapy may be more appropriate in late-onset adrenal hyperplasia patients than conventional adrenal inhibition using cortisone therapy. (J Clin Endocrinol Metab 70: 642, 1990)
T
compared with those obtained in 16 other LAH patients who received hydrocortisone treatment.
HE CONVENTIONAL treatment for late-onset adrenal hyperplasia (LAH) due to a partial defect in 21-hydroxylase (1-6) is glucocorticoid therapy, as used for the classical form of congenital adrenal hyperplasia resulting from a major enzyme defect. Indeed, glucocorticoid therapy corrects the cortisol deficiency and inhibits ACTH secretion, thereby decreasing adrenal androgen secretion (7-11). However, in LAH, clinical symptoms of cortisol deficiency are infrequent and are limited to periods of stress. The majority of LAH patients consult for isolated hirsutism and/or acne (5,12-14). Moreover, the results of glucocorticoid therapy in hirsutism due to LAH are very often disappointing in contrast with the dramatic improvement observed with antiandrogen therapy in hirsutism of other origins (15-17). Antiandrogen treatment consisting of cyproterone acetate (CPA) combined with percutaneous estradiol, as previously described (16,17), was, therefore, proposed to 14 LAH patients. The clinical and hormonal results were
Materials and Methods Patients Thirty-two LAH patients who consulted for hirsutism over the past 5 yr and who did not plan to become pregnant were included in the study. Thirty, whose ages ranged from 15-38 yr (mean, 24.3 ± 5.8), were retained for the study. The other 2 dropped out of the follow-up. All 30 patients had had a normal puberty, after which moderate to severe hirsutism developed, but without major signs of virilization, such as clitoromegaly or muscle hypertrophy. There was no clinical history of salt loss syndrome at birth and no family history of salt loss or hirsutism. Menstrual cycles were regular and ovulatory in 22 patients, and irregular and dysovulatory in the other 8. Fourteen patients had had normal pregnancies before diagnosis. Gynecological examination of all patients was normal. Hormonal determinations
Received May 19, 1989. Address all correspondence and requests for reprints to: Dr. F. Kuttenn, Department of Endocrinology and Reproductive Medicine, Hopital Necker, 149 rue de Sevres, 75743 Paris Cedex 15, France.
The following routine etiological investigation for hirsutism was carried out in all patients: basal plasma testosterone (T) and A4-androstenedione (A) assays; and plasma cortisol (F) 642
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ANTIANDROGEN TREATMENT IN LAH and 17-hydroxyprogesterone (17-OHP) measured before and 1 h after im administration of 0.250 mg synthetic ACTH-(l-24) (Synacthen, Ciba). Blood samples were collected at 0800 h during the follicular phase of the menstrual cycle. Plasma levels were determined by RIAs, as previously described (5, 12, 1719). Treatments Patients were randomly separated into two groups. Group 1 (n = 16) received conventional hydrocortisone treatment (20 mg/day; 10 mg twice daily). Group 2 (n = 14) was treated with the antiandrogen CPA (50 mg/day) from the 5th to the 25th day of the menstrual cycle combined with percutaneous estradiol (3 mg/day) over the last 10 days of CPA administration (16). To evaluate the therapeutic effects on hirsutism, the Ferriman clinical score (20) was determined before and during treatment in both groups. Plasma T and A were checked every 3 or 6 months. Statistical analysis and calculations Data are expressed as the mean ± SD. Statistical analysis was carried out using Student's t test.
Results The clinical profile of patients before treatment is summarized in Table 1 and did not differ significantly between the two groups. The clinical score for hirsutism was 22 ± 7 in group 1 and 23 ± 9 in group 2. Plasma androgen levels (T and A) were higher than normal in the two groups (T, 3.05 ± 1.45 and 2.98 ± 1.98 nmol/L; A, 13.6 ± 4.1 and 12.9 ± 5.9 nmol/L in groups 1 and 2, respectively). The basal level of 17-OHP was high (24.4 ± 10.5 and 26.1 ± 11.8 nmol/L in groups 1 and 2, respectively) and increased dramatically after ACTH stimulation in all patients (144.7 ± 87.8 nmol/L in group 1; 127.8 ± 49.7 nmol/L in group 2; Table 1), establishing the diagnosis of LAH due to partial 21-hydroxylase deficiency (4, 5, 19, 21). Basal plasma F concentrations were normal in both groups (Table 1); however, the response of F to ACTH was subnormal in both groups (414 ± 1 1 3 and 419 ± 69 nmol/L in groups 1 and 2, respectively; normal values, 654 ± 116 nmol/L; Table 1). In patients from group 1, who received the 20 mg
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hydrocortisone treatment, hirsutism regressed slowly. The clinical scores were 21.3 ± 6.5, 19.5 ± 5.6, and 16.5 ± 5.2 after 3, 6, and 12 months of treatment (i.e. 32% decrease after 1 yr; Fig. 1). In contrast, there was a striking fall in the clinical score among the CPA-treated group 2 (17.0 ± 7.03, 12.9 ± 7.2, and 10.0 ± 5.5) after 3, 6, and 12 months (i.e. 54% decrease; Fig. 2). The difference in the clinical score between the two groups was already significant after 3 months of treatment (P < 0.05) and even more so after 6 and 12 months of treatment (P< 0.005). In group 1, plasma T and A decreased to 2.15 ± 0.63 and 10.42 ± 1.80 nmol/L, respectively, after 3 months and to 1.74 ± 0.45 and 7.45 ± 1.42, 1.46 ± 0.42, and 6.33 ± 1.47 nmol/L after 6 and 12 months of hydrocortisone treatment. In contrast, in CPA-treated group 2, plasma T and A decreased only slightly and remained significantly higher than values in group 1 (2.57 ± 0.62 and 11.54 ± 4.14 nmol/L after 3 months, 2.43 ± 0.53 and 10.42 ± 2.11, 2.29 ± 0.64 and 9.86 ± 2.23 nmol/L after 6 and 12 months of CPA treatment; Fig. 3). The difference in androgen levels between the two groups was significant after 3 months of treatment (P < 0.05) for T and A. The difference was even more significant after 6 and 12 months (P < 0.005). The slight decrease in plasma androgens with CPA contrasts with the rapid clinical improvement observed. Both treatment were well tolerated. No patients reported any side-effects.
Discussion The effects on hirsutism of 2 different types of treatment, glucocorticoid and antiandrogen, were compared in 30 LAH patients. Sixteen patients received the classical daily 20-mg hydrocortisone treatment to suppress adrenal androgen oversecretion, and 14 patients received antiandrogen CPA therapy. Whereas hydrocortisone produced only a mild reduction in hirsutism, CPA yielded far better clinical results. This excellent improvement was similar to that observed with CPA on hirsutism of other origins (polycystic ovaries, idiopathic hirsutism, etc.) (16,17,22,23).
TABLE 1. Clinical and hormonal data before treatment in the two groups of LAH patients: (patients were randomly assigned to either group 1, treated with hydrocortisone, or group 2, treated with CPA) F (nmol/L) Age (yr) Group 1 (n = 16) Group 2 (n = 14) Normal women (n = 20)
24.9 ± 5.6 23.6 ± 6.2 22.3 ± 5.9
17-OHP (nmol/L)
Clinical score for hirsutism
T (nmol/L)
A (nmol/L)
Basal
After ACTH
Basal
After ACTH
22 ± 7 23 ± 9 6 (2-10)"
3.05 ± 1.45 2.98 ± 1.98 1.14 ± 0.10
13.6 ± 4.1 12.9 ± 5.9 4.65 ± 0.24
284 ± 124 273 ± 124 248 ± 99
414 ± 113 419 ± 69 654 ± 116
24.4 ± 10.5 26.1 ± 11.8 2.1 (0.6-7.26)a
144.7 ± 87.8 127.8 ± 49.7 4.2 (1.5-11.2)"
Values are expressed as the mean ± SD, except for normal values of the clinical score and 17-OHP (°), expressed as mean and extreme values. No statistical difference was observed between the two groups in any of the parameters.
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SPRITZER ET AL. HYDROCORTISONE
TREATMENT
II I
100 30
%
20 50--
II
0
3
6
" 12 MONTHS
12 MONTHS
FIG. 1. Evolution of the clinical scores of 16 LAH hirsute women treated with hydrocortisone. Left panel, Individual values. Right panel, The mean of the original scores is referred to as 100%. The percentages shown at 3, 6, and 12 months of treatment represent the mean percentage of each individual score.
CPA TREATMENT
100 30
%
I!I
20 50--
10
12
"
MONTHS
12
MONTHS
FlG. 2. Evolution of the clinical scores of 14 LAH hirsute women treated with oral CPA and percutaneous estradiol. See Fig. 1 for details.
ng/ml nmol/L 1
ng/ml 4
nmol/L
H
0.5
J MONTHS OF TREATMENT
FIG. 3. Evolution of plasma T (left panel) and A [right panel) in the 16 LAH patients treated with hydrocortisone (group 1; • ) and the 14 LAH patients treated with CPA (group 2; M). Values are expressed as the mean ± SD.
JCE & M • 1990 Vol 70 • No 3
Corticosteroid therapy is the classical treatment for adrenal hyperplasia (7-11). It derives from the observation of cortisol deficiency in the precocious congenital form of adrenal hyperplasia. Cortisol deficiency causes excess ACTH secretion, resulting in adrenal hyperplasia and androgen overproduction. However, in LAH patients, the enzymatic defect is only partial, and at the expense of adrenal hyperplasia, the plasma F level is normal and may be sufficient, at least under basal conditions, since most patients consulted for isolated hirsutism (5,12,13, 24). Moreover, the clinical result of hydrocortisone therapy is poor (15). A possible explanation for this poor result is that a standard hydrocortisone dose cannot accurately replace adrenal secretion, which is essentially designed to respond to stress. Patients receiving a standard dose of hydrocortisone are, therefore, subjected to alternate periods of under- and overtreatment, depending on the level of stress. Therefore, peripheral antiandrogen therapy may be more appropriate in LAH patients who have no actual cortisol deficiency, at least under basal conditions, and who consult for cosmetic reasons. In both groups the clinical results were in contrast with the changes observed in plasma androgen levels. In group 1, treated with hydrocortisone, a consistent reduction of A and T levels was observed, due to inhibition of ACTH secretion. Plasma androgen decreased continuously over several months of treatment, probably reflecting a progressive reduction in adrenal hyperplasia. Contrasting with the fall of plasma androgen levels in group 1, there was only a slight decrease in plasma T and A levels in the CPA-treated group 2. This slight decrease was apparent at the beginning of treatment and may correspond to the suppression of ovarian androgen secretion through the antigonadotropic effect of CPA (16, 17, 25). In patients with hirsutism due to polycystic ovaries, CPA acts through two mechanisms: 1) suppression of ovarian androgen secretion excess, and 2) competitive inhibition of residual androgens at the target cell level. However, in LAH patients treated with CPA, plasma androgen levels remain above normal, and CPA may only act peripherally, inhibiting androgen binding to the androgen receptor (16, 17, 26). The excellent clinical results with CPA, despite higher than normal T and A levels, stress the importance of peripheral receptivity to androgens in the clinical expression of hyperandrogenism. The role of target cell sensitivity to androgens in the clinical expression of biological hyperandrogenism is now well documented. The most striking evidence is provided by the androgen insensitivity syndrome, also designated in its complete form as the testicular feminization syndrome due to an androgen receptor defect in XY patients with normal testicular secretion (27). Deficiency in 5a-
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ANTIANDROGEN TREATMENT IN LAH reductase can also be responsible for male pseudohermaphroditism (28, 29). In women, the importance of skin sensitivity to androgens has also been emphasized. Lobo et al. (30) have shown that patients with the polycystic ovary syndrome and high plasma androgen levels could be hirsute or nonhirsute. These researchers also observed that in these patients, 3a-androstanediol glucuronide, the terminal androgen metabolite in the active 5a-reductase pathway, was the best biological marker for hirsutism (30). In LAH families, we have observed wide variations in the clinical expression of biological hyperandrogenism between the propositi and their HLA-identical siblings considered to be homozygotes for LAH (5). The 17-OHP response to the Synacthen test and plasma androgen levels were similar in the homozygotes of a given family, but the clinical expression differed and the level of urinary 3«-androstanediol glucuronide excretion was especially high in the patients presenting hirsutism, reflecting peripheral utilization of elevated plasma androgens (5, 15). On the other hand, high 5a-reductase activity in the skin has been held responsible for the so-called idiopathic hirsutism in a group of hirsute patients without any sign of ovarian or adrenal dysfunction and with normal plasma androgen levels (18, 31). High skin 5a-reductase activity measured in vitro (18) and high 3a-androstanediol glucuronide levels contrasting with the normal plasma androgen levels (18,32), suggest excess peripheral androgen utilization (33). These observations emphasize the importance of peripheral androgen utilization in hirsutism. Moreover, the good clinical results observed in CPA-treated compared with hydrocortisone-treated LAH patients confirm the importance of acting primarily at the target level. 3«-Androstanediol glucuronide was not systematically studied, since we have previously shown that CPA was a partial liver enzymatic inducer, increasing 3a-androstanediol glucuronide levels (26). This metabolite can, therefore, be used as a marker of androgen peripheral utilization only in the absence of any therapy interfering with liver metabolism. An inhibitory effect of CPA on adrenal steroidogenesis has been reported in animals (34-36) and also in children and men receiving high doses of CPA (36, 37). This has been ascribed to an inhibitory effect of CPA on ACTH secretion due to a partial glucocorticoid-like effect of CPA. However, these results were observed in studies using high doses of CPA (200 mg/day). No sign of adrenal insufficiency was observed by researchers using 100 mg CPA/day in hirsute patients (22, 23, 25, 26). In our experience, hirsute women treated with 50 mg CPA/day for 20 days/cycle for periods ranging from 6 months to 3 yr showed no sign of cortisol deficiency; moreover,
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plasma and urinary free F and responses to Synacthen and metyrapone tests were not altered (16, 17, 38). In the present study, patients were informed of the potential risk of F deficiency during intercurrent stress, and all received a card bearing instructions for hydrocortisone administration in case of stress. However, none of them showed signs of adrenal insufficiency or received additional glucocorticoid therapy. Percutaneous estradiol (3 mg/day) combined with CPA has no antigonadotropic effect, but ensures substitutive estrogen input. It permits regular bleeding and maintains target organ eutrophy (16). As previously reported, natural estradiol administered by the percutaneous route does not have the deleterious hepatic, metabolic, or vascular effects observed with orally administered synthetic estrogens (16, 17). This study is, to our knowledge, the first report on CPA treatment in LAH. It indicates that in LAH patients characterized by isolated hirsutism without actual F deficiency under basal conditions, peripheral antiandrogen therapy may be more appropriate than conventional adrenal inhibition using cortisone therapy. Conversely, hydrocortisone replacement therapy should be reserved 1) for patients with more severe forms of enzymatic deficiency, as evidenced by lower plasma F levels, 2) for patients planning a pregnancy, or 3) for all LAH patients in situations of stress. References 1. Decourt J, Jayle MF, Baulieu E. Virilisme cliniquement tardif avec
2.
3. 4. 5. 6. 7.
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10. 11.
excretion de pregnanetriol et insuffisance de production de cortisol. Ann Endocrinol (Paris). 1957;18:416-22. Migeon CJ, Rosenwaks Z, Lee PA, Urban MD, Bias WB. The attenuated form of congenital adrenal hyperplasia an allelic form of the 21-hydroxylase deficiency. J Clin Endocrinol Metab. 1980;51:647-9. Kohn B, Levine LS, Pollack MS, et al. Late-onset steroid 21hydroxylase deficiency: a variant of classical congenital adrenal hyperplasia. J Clin Endocrinol Metab. 1982;55:817-27. Lee PA, Rosenwaks Z, Urban MD, Migeon CJ, Bias WD. Attenuated forms of congenital adrenal hyperplasia due to 21-hydroxylase deficiency. J Endocrinol Metab. 1982;55:866-71. Kuttenn F, Couillin Ph, Girard F, et al. Late-onset adrenal hyperplasia in hirsutism. N Engl J Med. 1985;313:224-31. White PC, New MI, Dupont B. Congenital adrenal hyperplasia (I). N Engl J Med. 1987;316:1519-24. Klingensmith GJ, Garcia CG, Jones HW, Migeon CJ, Blizzard RM. Glucocorticoid treatment of girls with congenital adrenal hyperplasia : Effects on height, sexual maturation and fertility. J Pediatr. 1977;90:996-1004. Korth-Schutz S, Virdis R, Saenger P, Chow DM, Levine LS, New MI. Serum androgens as a continuing index of adequacy of treatment of congenital adrenal hyperplasia. J Clin Endocrinol Metab. 1978;46:452-8. Smith R, Donald RA, Espiner EA, Glathaar C, Abbott G, Scandrett M. The effect of different treatment regimens on hormonal profiles in congenital adrenal hyperplasia. J Clin Endocrinol Metab. 1980;51:230-6. Antony G. Management of congenital adrenal hyperplasia. Lancet. 1984;l:1073. Winterer J, Chrousos GP, Loriaux DL, Cutler BG. Effect of hydrocortisone dose schedule on adrenal steroid secretion in congenital
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adrenal hyperplasia. J Pediatr. 1985;106:137-42. 12. Bouchard P, Kuttenn F, Mowszowicz I, Schaison G, Raux-Eutorin MC, Mauvais-Jarvis P. Congenital adrenal hyperplasia due to 21hydroxylase deficiency : a study of five cases. Acta Endocrinol (Copenh). 1981;96:107-ll. 13. Chrousos GP, Loriaux DL, Mann DL, Cutler Jr GB. Late-onset 21 -hydroxylase deficiency mimicking idiopathic hirsutism or polycystic ovarian disease: an allelic variant of congenital virilizing adrenal hyperplasia with a milder enzymatic defect. Ann Intern Med. 1982;96:143-8. 14. Chetkowski RJ, De Fazio J, Shamonki I, Judd HL, Chang RJ. The incidence of late-onset congenital adrenal hyperplasia due to 21hydroxylase deficiency among hirsute women. J Clin Endocrinol Metab., 1984;58:595-8. 15. Kuttenn F, Billaud L, Thalabard JC, et al. L'hyperplasie congenitale des surrenales a revelation tardive. Sensibilite peripherique aux androgenes et implications therapeutiques. Ann Endocrinol (Paris). 1987;48:35-7. 16. Kuttenn F, Rigaud C, Wright F, Mauvais-Jarvis P. Treatment of hirsutism by oral cyproterone acetate and percutaneous estradiol. J Clin Endocrinol Metab. 1980;51:1107-ll. 17. Rigaud C, Vincens M, Mowszowicz I, et al. Mecanisme d'action de l'acetate de cyproterone dans le traitement de l'hirsutisme. Ann Endocrinol (Paris). 1983;44:387-92. 18. Kuttenn F, Mowszowicz I, Schaison G, Mauvais-Jarvis P. Androgen production and skin metabolism in hirsutism. J Endocrinol. 1977;75:83-91. 19. Gourmelen M, Pham-Huu-Trung MT, Bredon MG, Girard F. 17Hydroxyprogesterone in the cosyntropin test: results in normal and hirsute women and in mild congenital adrenal hyperplasia. Acta Endocrinol (Copenh). 1970;90:481-9. 20. Ferriman D, Gallwey JD. Clinical assessment of body hair growth in women. J Clin Endocrinol Metab. 1961;21:1440-8. 21. New MI, Lorenzen F, Lerner AJ, et al. Genotyping steroid 21hydroxylase deficiency; hormonal reference data. J Clin Endocrinol Metab. 1983;57:320-6. 22. Ismail AAA, Davidson DW, Sonka AR, et al. The evaluation of the role of androgens in hirsutism and the use of a new anti-androgen "cyproterone acetate" for therapy. J Clin Endocrinol Metab. 1974;39:81-95. 23. Hammerstein J, Meckies J, Leo-Rossberg I, Moltz L, Zielske F. Use of cyproterone acetate (CPA) in the treatment of acne, hirsutism and virilism. J Steroid Biochem. 1975;6:827-36. 24. Lobo RA, Goebelsmann U. Adult manifestation of congenital ad-
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renal hyperplasia due to incomplete 21-hydroxylase deficiency mimicking polycystic ovarian disease. Am J Obstet Gynecol. 1980;138:720-6. Neumann F, Berswordt-Wallrabe Von R, Eiger W, Steinbeck H, Hahn JD, Kramec M. Aspect of androgen-dependent events as studied by antiandrogens. Recent Prog Horm Res. 1970;26:337405. Mowszowicz I, Wright F, Vincens M, et al. Androgen metabolism in hirsute patients treated with cyproterone acetate. J Steroid Biochem., 1984;20:757-61. Griffin JE, Wilson JD. The syndrome of androgen resistance. N Engl J Med. 1980,302:198-209. Imperato-McGinley J, Peterson RE. Male pseudohermaphroditism: the complexities of male phenotypic development. Am J Med. 1976;61:251-65. Kuttenn F, Mowszowicz I, Wright F, et al. Male pseudohermaphroditism: a comparative study of one patient with 5«-reductase deficiency and three patients with the complete form of testicular feminization. J Clin Endocrinol Metab. 1979;49:861-5. Lobo RA, Goebelsmann U, Horton R. Evidence for the importance of peripheral tissue events in the development of hirsutism in polycystic ovary syndrome. J Clin Endocrinol Metab. 1983;57:3937. Mauvais-Jarvis P, Kuttenn F, Mowszowicz I. Idiopathic hirsutism. In: Monographs on endocrinology. Berlin: Springer-Verlag ed.; 1981;19:74-82. Kirschner MA, Samojlik E, Szmal E. Clinical usefulness of plasma androstanediol glucuronide measurements in women with idiopathic hirsutism. J Clin Endocrinol Metab. 1987;65:597-601. Wright F, Mowszowicz I, Mauvais-Jarvis P. Urinary 5«-androstane-3a,17diol radiommunoassay: a new clinical evaluation. J Clin Endocrinol Metab. 1978;47:850-4. Neri RO, Monahan MD, Meyer JG, Afonso BA, Tabalhnick IA. Biological studies on an antiandrogen. Eur J Pharmacol. 1967;l:438-44. Zieger G, Lux B, Kubatsch B. The effect of cyproterone acetate on the adrenal of the male hamster. Acta Endocrinol (Copenh). 1976;82:127-33. Girard J, Baumann JB, Buchler U, et al. Cyproterone acetate and ACTH adrenal function. J Clin Endocrinol Metab. 1978;101:5816. Jeffcoate WJ, Howards CRW, Rees LH, Besser GM. Cyproterone acetate. Lancet. 1976;2:1140. Kuttenn F, Bricaire C. Traitement de l'hirsutisme. In: Flammarion, ed. L'Hirsutisme. Paris; 1988;217-49.
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