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Cyproterone acetate in blood of hirsute women during long-term treatment. The absorption and elimination after oral application
CYPROTERONE ACETATE IN BLOOD OF HIRSUTE WOMEN DURING LONG-TERM TREATMENT. THE ABSORPTION AND ELIMINATION AFTER ORAL APPLICATION MARIJKE FRGLICH*, HUIB L. VADER?, SJOUKJENT. WALMA* and HANS A. M. DE RooYt *Department of Chemical Pathology, University Hospital, Leiden, The Netherlands, and jSt. Joseph’s Hospital, Eindhoven, The Netherlands (Received 4 December 1979)
SUMMARY Twenty-nine women with birsutism, either idiopathic or due to the poiycystic ovary syndrome, were treated with cyproterone acetate (CA) (50 or 100 mg daily) or with a combination of cyproterone acetate (100 mg) and ethinyl oestradiol (50 pg) in a reversed sequential regimen (CA i EE) for 2 years. Liver function was assessed by measurement of alkaline phosphatase, glutamic-oxalacetic transaminase, glutamic-pyruvic transaminase, and lactic dehydrogenase. No changes were perceived. Prolactin, cortisol and thyroxin were measured in the blood of patients who received only CA. Cortisol and thyroxin remained on the pretreatment level, whereas prolactin showed a slight increase. The CA level was measured at intervals of 4 months. In the blood of patients being under reversed sequential treatment, the CA level lay between 279 and 307 @ml on the days when the drug was taken. During the treatment cycle the CA levels dropped to levels between 24 and 36 ngiml after the 12th day. When 50 mg CA was given daily, the level varied between 199 and 228 ng/ml, and when 100 mg was taken the range was between 436 and 520. In the latter group CA levels rose during therapy. Studies on absorption and elimination were performed. The absorption of CA was not dose related. Peak levels of CA were found 2.35 h after oral intake in patients on CA + EE as well as in patients given only CA. The mean half-time of elimination in the first 8 h after oral intake was 3.3 h in the first of these groups and 4.2 h in the other.
evidence concerning ACTH suppression [S-lo] description of prolactin stimulation [ll, 121.
INTRODUCTION Cyproterone acetate (CA) has been used beneficially in the treatment of hirsute women [l, 2-J. This compound has a reducing influence on the concentration of androgen levels in blood [3,4]. Studies on the
absorption and elimination of CA have been performed with either radioactive CA [S] or by measuring blood levels after a low single dose [6]. The blood levels and elimination of CA after a high single dose were measured by Hiimpfe et al. [7J In our investigations on hirsutism, women were treated with CA under different regimens for 2 years. During this treatment we measured the levels of CA in the blood by radioimmunoassay. These results and those obtained in studies on the blood appearance rate of the drug after oral administration and the disappearance rate in the first 8 h after administration are presented here. Liver function was followed for control purposes. In the blood of patients treated with only CA, the serum concentrations of cortisol, prolactin, and thyroxin were followed, because of conflicting
Steroids: Androstenedione, 4-androstene-3,17-dione; cyproterone acetate, 1,2a-methylene-.S-chloro-17p-hydroxy4,6-pregnadiene-3,20-dion-17-acetate; dihydrotestosterone, 17/3-hydroxy-S-androstan-3-one; ethinyl oestradiol, 1,3,5(10)-oestratriene-3,17j%diol-17u-ethyne: testosterone, 17/Lhydroxy-4-androsten-3-one.
and
SUBJECTS
Twenty-nine female patients aged between 19 and 48 years, and suffering from hirsutism, either idiopathic or due to the polycystic ovary syndrome, were divided into two groups on the basis of the need for contraception, as follows. Group I(20 women) was treated with CA and ethinyl oestradiol (EE) under reversed sequential treatment. 1OOmg CA was given in single doses every day for 10 days and also, starting on day 1 of the treatment cycle, 50 pg EE for 21 days, followed by an interval of 7 days without treatment. Group II (9 women) was treated with daily doses of CA. Six women received 50 mg every day in a single dose (Group IIa) and three women (Group Ilb) received 1OOmg every day in 2 doses of 50 mg (at 8 a.m. and 6 p.m.) Blood was collected for the determination of CA over a period of two years at cl-month intervals on various days during the treatment cycle. Liver function was followed in both groups by measurement of the levels of alkaline phosphatase (AP), glutamicoxalacetic transaminase (GOT), glutamic-pyruvic transaminase (GPT), and lactic dehydrogenase (LDH) in serum.
1097
1098
MARUKE FR~~LICHer al.
Serum concentrations of cortisol, prolactin, and thyroxin were determined in Group II. No hormones were measured in Group I, because of the well-known disturbing effects of EE on binding proteins for thyroxin and cortisol as well as on prolactin secretion. Studies on the appearance and the elimination of CA were performed in 12 subjects of group I after at least 4 months of treatment. After the 7-day interval (= 18 days without CA), 50 mg CA and 50 pg EE were given orally and the CA levels in serum were measured at intervals over a period of 8 h. These studies were also done in five subjects of Group Ha, who received 50 mg CA at 8 p.m. after an interval of 24 h without medication. MATERIALS AND METHODS
Cyproterone acetate in 50 mg tablets and in the prescribed combination with ethinyl oestradiol, as well as the CA for the radioimmunoassay standard were obtained from Schering Nederland b.v., Weesp, The Netherlands. [3H]-Acetoxy-cyproterone acetate and anti-serum against a cyproterone acetate-l la-hemisuccinate-BSA conjugate were a generous gift from B. Nieuweboer, Schering A. G., Berlin, FRD. The radioimmunoassay of CA was performed according to Nieuweboer and Liibke [13]. In this assay cross-reactivity of metabolites can be considered negligible [ 143. Prolactin, cortisol, and thyroxin were also measured by radioimmunoassay. In the prolactin determination NIH-F1 was used as standard reference preparation. Liver enzymes were analyzed with a SMAC autoanalyzer (Technicon) according to the manufacturer’s directions. All chemicals used were of analytical grade. Statistical analysis was performed with Student’s t-test for unpaired data. RESULTS
Compared to the pretreatment levels, no changes were found in the AP, GOT, GPT or LDH levels during treatment with 50mg CA daily, 1OOmg CA daily or 100 mg CA + 50 pg EE under reversed sequential treatment. The levels of cortisol and thyroxin also showed no significant changes in the serum of patients not receiving EE (Group IIa and IIb). Prolactin showed a slight increase from 17.7 + 4.8 ng/ml (mean + SE) before treatment to 24.1 + 5.7 ng/ml after two years of treatment in Group IIa and from 16.8 + 5.4 ng/ml to 21.7 t_ 11.3 in Group II\, (not significant). The levels of CA measured in the peripheral blood of women taking 100 mg CA + 50 pg EE, 2-5 h after ingestion, (Group I) are shown in Table I. Between the values found in blood of women who visited the clinic in the first 12 days of the treatment cycle and those who came more than 2 days after cessation of CA administration (day lo), a division is made according to Speck et aI.[5]. The CA levels measured
Table 1. Levels of cyproterone acetate in serum of women taking 1OOmg CA + 5Opg EE in a reversed sequential therapy regimen (Group I) means f SE
Period of medication (months)
Group I (ng/ml serum) Samples taken on Samples taken on days l-12 of the days 13-28 of the treatment cycle treatment cycle
34 668 lo-12 16-18 22-24
289 279 329 306 307
f 39 (n f 37 (n If: 29(n + 37(n i 34 (n
= = = = =
8) 6) 7) 8) 8)
36 + 701 24 i 6(n 30+8(n=l3) 30 f 8(n 31 f 8(n
= 12) = 13) = 12) = 11)
in serum every 4 months
for 2 years during the first 12 days of the cycle ranged between 279 f 37 ngjml (mean SE) and 307 & 34 ng/ml and did not show significant differences. In the second part of the cycle the CA levels were lower, ranging between 24 + 6 ng/ml and 36 k 7 ng/ml, here too with no significant differences. The CA levels in the blood of women taking 50 mg CA daily (Group IIa), measured 2-5 h after ingestion, or 100 mg daily in two doses (Group IIb) are shown in Table 2. In Group IIa these levels lay between 199 f 23 ng/ml and 228 k 25 ng/ml serum, which differs significantly from the levels measured in the peripheral blood of the patients of Group IIb. No differences were found in the CA levels measured at various times after the start of treatment in Group IIa. In Group IIb the levels. measured 2--5 h after the morning dose, range between 436 +- 29 ngjml and 520 _t 31 ng/ml, with a significant increase during the treatment (P < 0.1). Figure 1 shows the mean CA levels in the serum 01 12 patients of Group I, who were given 50 mg CA + 5Opg EE after the 7-day interval. The levels were measured during the 8 h following the medication. Starting at a CA level of 13.2 + 3.3 ng/ml maximum of t = 0, the (mean + SE) at 340 _t 24ng/ml was reached at 2.35 _t 0.06 h (mean & SE) (range 2.1-2.7 h). The half time (tl) of elimination was 3.31 + 0.13 h (range 2.6-4.1 h) estimated according to the calculations of Speck et u1.[5] and Hiimpel et a[.[6]. Figure 2 shows the CA levels in the serum of five patients of Group IIa, who were given 50 mg CA after
Table 2. Levels of cyproterone acetate in serum of women taking
either 50 mg (Group Ha) or 100 mg (Group daily. Means & SE
Period of medication (months) 34 6-8 l&l2 16-18 22-24 * P < 0.1 related
Group 1Ia 50 mg CA daily ng/ml (n = 6) 208 217 199 228 212
+ & + + +
Group IIb 100 mg CA daily ng/ml (n = 3)
21 15 23 25 19
to the 3--l-month
Ilb) CA
436 483 441 520 513 value.
+ + + k &
29 54 32 31* 45*
1099
Cyproterone acetate in blood of hirsute women ng/ml 400 r
4
,P,
200 _
\
80 loo1 20 i
10
I d
Ir -
0 hours
Fig. 1. Course of mean concentration (*SE) of cyproterone acetate in serum of 12 patients after oral administration of 50 mg CA + 50 pg EE in a reversed sequential therapy regimen.
an interval of 24 h without medication. These levels were also measured during the 8 h following the oral administration. Starting from a CA level of 125 f 24 ng/ml at t = 0, the maximum level reached was 426 + 38 ng/ml 2.35 &- 0.04 h (range 2.25-2.45 h) after the gift. The mean increment of the CA concentration (301 ng/ml) does not differe from the mean increase of the CA levels in Group I (327 ng/ml). The calculation of the t+ of elimination is more complex in Group IIa, because of the higher starting level and the amounting to several second t+ of elimination days [S, 61. Estimations of t+ based on measurements of CA levels at t = 4 h and t = 8 h after oral intake, gave 4.2 k 1.6 h (range 2.26.4 h). The CA levels in the blood of women who stopped taking the medication for more than 3 months were undetectable (not shown).
with more frequent sampling, taking the circadian rhythm and the pulsatile release of prolactin into account are needed to ‘elucidate this increase. In our study the reversed sequential treatment did not lead to changes in liver functions either. The CA levels found in Group I (Table 1) during the first 12 days of the treatment cycle gave no indication of accumulation of the drug, which is in accordance with the t+ of elimination amounting to 3.31 h (Fig. 1). Hiimpel et a/.[63 reported a tt of 3 h for CA elimination during the first 24 h after administration. When 1OOmg CA was given daily in two doses (Group IIb), the steady-state level reached was more than two times higher than the level in Group IIa. When the tt of elimination of several hours is taken into account, this higher level might be an indication that it is more profitable to give the daily dose of CA in portions. We noticed a slight increase in the CA levels in Group IIb during the two years of the investigation. We think this might be a warning that accumulation can occur when a high daily dose has been prescribed. The t+ of elimination found in Group I (Fig. 1) is in accordance with the findings of others [S, 61. The increase of CA in Group IIa (301 ng/ml) which started from a much higher basal level, is not different from the increase seen in Group I. Since it has been found [S] that EE does not influence CA absorption, we may conclude that the absorption of CA is independent of the starting level in the blood. The levels of CA measured in our investigations lay in the range of 20&6OOng/ml serum when the drug was taken every day. This level is a hundred times higher than the androstenedione level and even 2oo-400 times higher than the testosterone (T) or dihydrotestosterone (DHT) level. It was shown [15] that this large amount of CA can lead to a slight displacement of T and DHT from sex hormonebinding globulin (SHBG). Vermeulen et a/.[163 found that such displacement will elevate the metabolic ng/ml
DISCUSSION
Cyproterone acetate, even given in rather high doses of 50 mg or 100 mg daily for a long time, did not affect the investigated liver function. Thyroxin and cortisol levels in the blood were also unaffected. Panesar et aI.[8] and Girard et aI.[9] strongly warned against long treatment with CA in their publications on the ACTH suppressive effects of CA. This was contested by Smals et al.[lO], who did not find cortisol suppression in patients who were treated with CA during three months. Our results are in agreement with the findings of the latter. The increase we found of prolactin levels is also mentioned by Bartsch et al.[ll] for male patients with prostatic carcinoma, and by Fonzo et a1.[12], who treated idiopathic precocious puberty in girls with CA. But time studies
500
200
100
1
1
v
8 hours
Fig. 2. Course of mean concentration (+ SE) of cyproterone acetate in serum of five patients after oral administration of 50 mg CA in a daily regimen.
1100
MARIJKEFR~LICHet
clearance rate of T and DHT. Apart from the reducing influence of CA on the blood production rate of androgens [4], this displacement will contribute to the reduction of the androgen levels in the blood of hirsute women, especially when the SHBG levels are not raised by the simultaneous administration of EE.
al.
tion of 2.0 mg cyproterone acetate in combination with 50 ng ethinyl oestradiol to 6 young women. Contruception 15 (1977) 579-588. 7, Hiimpel M., Dogs H., Wendt H. and Speck U.: Plasmaspiegel und Pharmakokinetik von Cyproteronacetat nach oraler Applikation als 50-mg-Tablette bei 5 Mannern. Arzneim.-Forsch./Drug Res. 28 (1978) 319.-322.
Acknowledgements-AP, GOT, GPT, and LDH were measured by Dr J. H. Souverijn in the Laboratory for Clinical Chemistry (Head: Dr W. van der Slik), and cortisol and thyroxin in the Laboratory for Chemical Pathology (Head: Dr A. J. Moolenaar), both in the Leiden University Hospital.
8. Panesar N. S., Herries D. G. and Stitch S. R.: Effects of cyproterone acetate on the andrenal gland in the rat: studies in riuo and in tlitro. /. Endocr. 80 (1979) 229-238.
9, Girard J., Baumann J. B., Biihler U., Zuppinger K.. Haas H. G., Staub J. J. and Wyss H. I.: Cyproterone acetate and ACTH adrenal function. J. c/in. Endocr. Metab.
REFERENCES 1. Hammerstein J. and Cupceancu B.: Behandlung des Hirsutismus mit Cyproteronacetat. Deutsche Med. W&r. 94 (1969) 8299834. 2. Ismail A. A. A., Davidson D. W., Souka A. R., Barnes E. W., Irvine W. J., Kilimnik, H. and Vanderbeeken Y.: The evaluation of the role of androgens in hirsutism and the use of a new anti-androgen “cyproterone acetate” for therapy. J. c/in. Endocr. Metab. 39 (1974) 81-95. 3. Friilich M., Lachinsky N. and Moolenaar A. J.: The influence of combined cyproterone acetate-ethinyl oestradiol therapy on serum levels of dehydroepiandrosterone, androstenedione and testosterone in hirsute women. Acta endocr., Copenh. 84 (1977) 3333342. 4. Frolich M., Vader H. L., Walma S. T. and Rooy H. A. M. de: The influence of long-term treatment with cyproterone acetate or a cyproterone acetate-ethinyl oestradiol combination on androgen levels in blood of hirsute women. J. steroid Biochem. 12 (1980) 499-502. 5. Speck U., Wendt H., Schulze P. E. and Jentsch D.: Bio-availability and pharmacokinetics of cyproterone acetate-14C and ethinyl oestradiol-[3H] after oral administration as a coated tablet (SH B 209 AB). Contraception 14 (1976) 151-163. 6. Hiimpel M., Wendt H., Schulze P. E., Dogs G., Wiess Chr. and Speck U.: Bio-availability and pharmacokinetics of cyproterone acetate after oral administra-
47 (1978) 581-586.
10. Smals A. G. H., Kloppenborg P. W. C., Goverde H. J. M. and Benraad Th. J.: The effect of cyproterone acetate on the pituitary-adrenal axis in hirsute women. Acta endocr.,
Copenh. 87 (1978) 352-358.
11. Bartsch W., Horst H.-J., Becker H. and Nehse, G.: Sex hormone binding globulin binding capacity. testosterone, 5x_dihydrotestosterone, oestradiol and prolactin in plasma of patients with prostatic carcinoma under various types of hormonal treatment. Actu endocr..
Covenh. 85 (1977) 65&664.
12. Fonzo D., kngeli A.: Sivieri R., Andriolo S., Frajria R. and Ceresa F.: Hyperprolactinemia in girls with idiopathic precocious puberty under prolonged treatment with cyproterone acetate. J. c/in. Endocr. Metah. 45 (1977) 164168. 13. Nieuweboer B. and Ltibke K.: Radioimmunological determination of cyproterone acetate. Hormone Rex 8 (1977) 21@218. 14. Bhargava A. S., Seeger A. and Giinzel P.: Isolation and identification of 15-P-hydroxy cyproterone acetate as a new metabolite of cyproterone acetate in dog, monkey and man. Steroids 30 (1977) 407418. 15 Frijlich M., Schie M. G. van and Brand E. C.: Sex hormone binding globulin binding capacity and studies on the binding of cyproterone acetate and other steroids. C/in. chim. Acta 87 (1978) 239-244. 16 Vermeulen A.. Verdonck L., Straeten M. van der and Orie N.: Capacity of the testosterone-binding globulin in human plasma and influence of specific binding of testosterone on its metabolic clearance rate. J. c/in. Endocr. Metah. 29 (1969) 1470-1480.
SUMMARY Twenty-nine women with birsutism, either idiopathic or due to the poiycystic ovary syndrome, were treated with cyproterone acetate (CA) (50 or 100 mg daily) or with a combination of cyproterone acetate (100 mg) and ethinyl oestradiol (50 pg) in a reversed sequential regimen (CA i EE) for 2 years. Liver function was assessed by measurement of alkaline phosphatase, glutamic-oxalacetic transaminase, glutamic-pyruvic transaminase, and lactic dehydrogenase. No changes were perceived. Prolactin, cortisol and thyroxin were measured in the blood of patients who received only CA. Cortisol and thyroxin remained on the pretreatment level, whereas prolactin showed a slight increase. The CA level was measured at intervals of 4 months. In the blood of patients being under reversed sequential treatment, the CA level lay between 279 and 307 @ml on the days when the drug was taken. During the treatment cycle the CA levels dropped to levels between 24 and 36 ngiml after the 12th day. When 50 mg CA was given daily, the level varied between 199 and 228 ng/ml, and when 100 mg was taken the range was between 436 and 520. In the latter group CA levels rose during therapy. Studies on absorption and elimination were performed. The absorption of CA was not dose related. Peak levels of CA were found 2.35 h after oral intake in patients on CA + EE as well as in patients given only CA. The mean half-time of elimination in the first 8 h after oral intake was 3.3 h in the first of these groups and 4.2 h in the other.
evidence concerning ACTH suppression [S-lo] description of prolactin stimulation [ll, 121.
INTRODUCTION Cyproterone acetate (CA) has been used beneficially in the treatment of hirsute women [l, 2-J. This compound has a reducing influence on the concentration of androgen levels in blood [3,4]. Studies on the
absorption and elimination of CA have been performed with either radioactive CA [S] or by measuring blood levels after a low single dose [6]. The blood levels and elimination of CA after a high single dose were measured by Hiimpfe et al. [7J In our investigations on hirsutism, women were treated with CA under different regimens for 2 years. During this treatment we measured the levels of CA in the blood by radioimmunoassay. These results and those obtained in studies on the blood appearance rate of the drug after oral administration and the disappearance rate in the first 8 h after administration are presented here. Liver function was followed for control purposes. In the blood of patients treated with only CA, the serum concentrations of cortisol, prolactin, and thyroxin were followed, because of conflicting
Steroids: Androstenedione, 4-androstene-3,17-dione; cyproterone acetate, 1,2a-methylene-.S-chloro-17p-hydroxy4,6-pregnadiene-3,20-dion-17-acetate; dihydrotestosterone, 17/3-hydroxy-S-androstan-3-one; ethinyl oestradiol, 1,3,5(10)-oestratriene-3,17j%diol-17u-ethyne: testosterone, 17/Lhydroxy-4-androsten-3-one.
and
SUBJECTS
Twenty-nine female patients aged between 19 and 48 years, and suffering from hirsutism, either idiopathic or due to the polycystic ovary syndrome, were divided into two groups on the basis of the need for contraception, as follows. Group I(20 women) was treated with CA and ethinyl oestradiol (EE) under reversed sequential treatment. 1OOmg CA was given in single doses every day for 10 days and also, starting on day 1 of the treatment cycle, 50 pg EE for 21 days, followed by an interval of 7 days without treatment. Group II (9 women) was treated with daily doses of CA. Six women received 50 mg every day in a single dose (Group IIa) and three women (Group Ilb) received 1OOmg every day in 2 doses of 50 mg (at 8 a.m. and 6 p.m.) Blood was collected for the determination of CA over a period of two years at cl-month intervals on various days during the treatment cycle. Liver function was followed in both groups by measurement of the levels of alkaline phosphatase (AP), glutamicoxalacetic transaminase (GOT), glutamic-pyruvic transaminase (GPT), and lactic dehydrogenase (LDH) in serum.
1097
1098
MARUKE FR~~LICHer al.
Serum concentrations of cortisol, prolactin, and thyroxin were determined in Group II. No hormones were measured in Group I, because of the well-known disturbing effects of EE on binding proteins for thyroxin and cortisol as well as on prolactin secretion. Studies on the appearance and the elimination of CA were performed in 12 subjects of group I after at least 4 months of treatment. After the 7-day interval (= 18 days without CA), 50 mg CA and 50 pg EE were given orally and the CA levels in serum were measured at intervals over a period of 8 h. These studies were also done in five subjects of Group Ha, who received 50 mg CA at 8 p.m. after an interval of 24 h without medication. MATERIALS AND METHODS
Cyproterone acetate in 50 mg tablets and in the prescribed combination with ethinyl oestradiol, as well as the CA for the radioimmunoassay standard were obtained from Schering Nederland b.v., Weesp, The Netherlands. [3H]-Acetoxy-cyproterone acetate and anti-serum against a cyproterone acetate-l la-hemisuccinate-BSA conjugate were a generous gift from B. Nieuweboer, Schering A. G., Berlin, FRD. The radioimmunoassay of CA was performed according to Nieuweboer and Liibke [13]. In this assay cross-reactivity of metabolites can be considered negligible [ 143. Prolactin, cortisol, and thyroxin were also measured by radioimmunoassay. In the prolactin determination NIH-F1 was used as standard reference preparation. Liver enzymes were analyzed with a SMAC autoanalyzer (Technicon) according to the manufacturer’s directions. All chemicals used were of analytical grade. Statistical analysis was performed with Student’s t-test for unpaired data. RESULTS
Compared to the pretreatment levels, no changes were found in the AP, GOT, GPT or LDH levels during treatment with 50mg CA daily, 1OOmg CA daily or 100 mg CA + 50 pg EE under reversed sequential treatment. The levels of cortisol and thyroxin also showed no significant changes in the serum of patients not receiving EE (Group IIa and IIb). Prolactin showed a slight increase from 17.7 + 4.8 ng/ml (mean + SE) before treatment to 24.1 + 5.7 ng/ml after two years of treatment in Group IIa and from 16.8 + 5.4 ng/ml to 21.7 t_ 11.3 in Group II\, (not significant). The levels of CA measured in the peripheral blood of women taking 100 mg CA + 50 pg EE, 2-5 h after ingestion, (Group I) are shown in Table I. Between the values found in blood of women who visited the clinic in the first 12 days of the treatment cycle and those who came more than 2 days after cessation of CA administration (day lo), a division is made according to Speck et aI.[5]. The CA levels measured
Table 1. Levels of cyproterone acetate in serum of women taking 1OOmg CA + 5Opg EE in a reversed sequential therapy regimen (Group I) means f SE
Period of medication (months)
Group I (ng/ml serum) Samples taken on Samples taken on days l-12 of the days 13-28 of the treatment cycle treatment cycle
34 668 lo-12 16-18 22-24
289 279 329 306 307
f 39 (n f 37 (n If: 29(n + 37(n i 34 (n
= = = = =
8) 6) 7) 8) 8)
36 + 701 24 i 6(n 30+8(n=l3) 30 f 8(n 31 f 8(n
= 12) = 13) = 12) = 11)
in serum every 4 months
for 2 years during the first 12 days of the cycle ranged between 279 f 37 ngjml (mean SE) and 307 & 34 ng/ml and did not show significant differences. In the second part of the cycle the CA levels were lower, ranging between 24 + 6 ng/ml and 36 k 7 ng/ml, here too with no significant differences. The CA levels in the blood of women taking 50 mg CA daily (Group IIa), measured 2-5 h after ingestion, or 100 mg daily in two doses (Group IIb) are shown in Table 2. In Group IIa these levels lay between 199 f 23 ng/ml and 228 k 25 ng/ml serum, which differs significantly from the levels measured in the peripheral blood of the patients of Group IIb. No differences were found in the CA levels measured at various times after the start of treatment in Group IIa. In Group IIb the levels. measured 2--5 h after the morning dose, range between 436 +- 29 ngjml and 520 _t 31 ng/ml, with a significant increase during the treatment (P < 0.1). Figure 1 shows the mean CA levels in the serum 01 12 patients of Group I, who were given 50 mg CA + 5Opg EE after the 7-day interval. The levels were measured during the 8 h following the medication. Starting at a CA level of 13.2 + 3.3 ng/ml maximum of t = 0, the (mean + SE) at 340 _t 24ng/ml was reached at 2.35 _t 0.06 h (mean & SE) (range 2.1-2.7 h). The half time (tl) of elimination was 3.31 + 0.13 h (range 2.6-4.1 h) estimated according to the calculations of Speck et u1.[5] and Hiimpel et a[.[6]. Figure 2 shows the CA levels in the serum of five patients of Group IIa, who were given 50 mg CA after
Table 2. Levels of cyproterone acetate in serum of women taking
either 50 mg (Group Ha) or 100 mg (Group daily. Means & SE
Period of medication (months) 34 6-8 l&l2 16-18 22-24 * P < 0.1 related
Group 1Ia 50 mg CA daily ng/ml (n = 6) 208 217 199 228 212
+ & + + +
Group IIb 100 mg CA daily ng/ml (n = 3)
21 15 23 25 19
to the 3--l-month
Ilb) CA
436 483 441 520 513 value.
+ + + k &
29 54 32 31* 45*
1099
Cyproterone acetate in blood of hirsute women ng/ml 400 r
4
,P,
200 _
\
80 loo1 20 i
10
I d
Ir -
0 hours
Fig. 1. Course of mean concentration (*SE) of cyproterone acetate in serum of 12 patients after oral administration of 50 mg CA + 50 pg EE in a reversed sequential therapy regimen.
an interval of 24 h without medication. These levels were also measured during the 8 h following the oral administration. Starting from a CA level of 125 f 24 ng/ml at t = 0, the maximum level reached was 426 + 38 ng/ml 2.35 &- 0.04 h (range 2.25-2.45 h) after the gift. The mean increment of the CA concentration (301 ng/ml) does not differe from the mean increase of the CA levels in Group I (327 ng/ml). The calculation of the t+ of elimination is more complex in Group IIa, because of the higher starting level and the amounting to several second t+ of elimination days [S, 61. Estimations of t+ based on measurements of CA levels at t = 4 h and t = 8 h after oral intake, gave 4.2 k 1.6 h (range 2.26.4 h). The CA levels in the blood of women who stopped taking the medication for more than 3 months were undetectable (not shown).
with more frequent sampling, taking the circadian rhythm and the pulsatile release of prolactin into account are needed to ‘elucidate this increase. In our study the reversed sequential treatment did not lead to changes in liver functions either. The CA levels found in Group I (Table 1) during the first 12 days of the treatment cycle gave no indication of accumulation of the drug, which is in accordance with the t+ of elimination amounting to 3.31 h (Fig. 1). Hiimpel et a/.[63 reported a tt of 3 h for CA elimination during the first 24 h after administration. When 1OOmg CA was given daily in two doses (Group IIb), the steady-state level reached was more than two times higher than the level in Group IIa. When the tt of elimination of several hours is taken into account, this higher level might be an indication that it is more profitable to give the daily dose of CA in portions. We noticed a slight increase in the CA levels in Group IIb during the two years of the investigation. We think this might be a warning that accumulation can occur when a high daily dose has been prescribed. The t+ of elimination found in Group I (Fig. 1) is in accordance with the findings of others [S, 61. The increase of CA in Group IIa (301 ng/ml) which started from a much higher basal level, is not different from the increase seen in Group I. Since it has been found [S] that EE does not influence CA absorption, we may conclude that the absorption of CA is independent of the starting level in the blood. The levels of CA measured in our investigations lay in the range of 20&6OOng/ml serum when the drug was taken every day. This level is a hundred times higher than the androstenedione level and even 2oo-400 times higher than the testosterone (T) or dihydrotestosterone (DHT) level. It was shown [15] that this large amount of CA can lead to a slight displacement of T and DHT from sex hormonebinding globulin (SHBG). Vermeulen et a/.[163 found that such displacement will elevate the metabolic ng/ml
DISCUSSION
Cyproterone acetate, even given in rather high doses of 50 mg or 100 mg daily for a long time, did not affect the investigated liver function. Thyroxin and cortisol levels in the blood were also unaffected. Panesar et aI.[8] and Girard et aI.[9] strongly warned against long treatment with CA in their publications on the ACTH suppressive effects of CA. This was contested by Smals et al.[lO], who did not find cortisol suppression in patients who were treated with CA during three months. Our results are in agreement with the findings of the latter. The increase we found of prolactin levels is also mentioned by Bartsch et al.[ll] for male patients with prostatic carcinoma, and by Fonzo et a1.[12], who treated idiopathic precocious puberty in girls with CA. But time studies
500
200
100
1
1
v
8 hours
Fig. 2. Course of mean concentration (+ SE) of cyproterone acetate in serum of five patients after oral administration of 50 mg CA in a daily regimen.
1100
MARIJKEFR~LICHet
clearance rate of T and DHT. Apart from the reducing influence of CA on the blood production rate of androgens [4], this displacement will contribute to the reduction of the androgen levels in the blood of hirsute women, especially when the SHBG levels are not raised by the simultaneous administration of EE.
al.
tion of 2.0 mg cyproterone acetate in combination with 50 ng ethinyl oestradiol to 6 young women. Contruception 15 (1977) 579-588. 7, Hiimpel M., Dogs H., Wendt H. and Speck U.: Plasmaspiegel und Pharmakokinetik von Cyproteronacetat nach oraler Applikation als 50-mg-Tablette bei 5 Mannern. Arzneim.-Forsch./Drug Res. 28 (1978) 319.-322.
Acknowledgements-AP, GOT, GPT, and LDH were measured by Dr J. H. Souverijn in the Laboratory for Clinical Chemistry (Head: Dr W. van der Slik), and cortisol and thyroxin in the Laboratory for Chemical Pathology (Head: Dr A. J. Moolenaar), both in the Leiden University Hospital.
8. Panesar N. S., Herries D. G. and Stitch S. R.: Effects of cyproterone acetate on the andrenal gland in the rat: studies in riuo and in tlitro. /. Endocr. 80 (1979) 229-238.
9, Girard J., Baumann J. B., Biihler U., Zuppinger K.. Haas H. G., Staub J. J. and Wyss H. I.: Cyproterone acetate and ACTH adrenal function. J. c/in. Endocr. Metab.
REFERENCES 1. Hammerstein J. and Cupceancu B.: Behandlung des Hirsutismus mit Cyproteronacetat. Deutsche Med. W&r. 94 (1969) 8299834. 2. Ismail A. A. A., Davidson D. W., Souka A. R., Barnes E. W., Irvine W. J., Kilimnik, H. and Vanderbeeken Y.: The evaluation of the role of androgens in hirsutism and the use of a new anti-androgen “cyproterone acetate” for therapy. J. c/in. Endocr. Metab. 39 (1974) 81-95. 3. Friilich M., Lachinsky N. and Moolenaar A. J.: The influence of combined cyproterone acetate-ethinyl oestradiol therapy on serum levels of dehydroepiandrosterone, androstenedione and testosterone in hirsute women. Acta endocr., Copenh. 84 (1977) 3333342. 4. Frolich M., Vader H. L., Walma S. T. and Rooy H. A. M. de: The influence of long-term treatment with cyproterone acetate or a cyproterone acetate-ethinyl oestradiol combination on androgen levels in blood of hirsute women. J. steroid Biochem. 12 (1980) 499-502. 5. Speck U., Wendt H., Schulze P. E. and Jentsch D.: Bio-availability and pharmacokinetics of cyproterone acetate-14C and ethinyl oestradiol-[3H] after oral administration as a coated tablet (SH B 209 AB). Contraception 14 (1976) 151-163. 6. Hiimpel M., Wendt H., Schulze P. E., Dogs G., Wiess Chr. and Speck U.: Bio-availability and pharmacokinetics of cyproterone acetate after oral administra-
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10. Smals A. G. H., Kloppenborg P. W. C., Goverde H. J. M. and Benraad Th. J.: The effect of cyproterone acetate on the pituitary-adrenal axis in hirsute women. Acta endocr.,
Copenh. 87 (1978) 352-358.
11. Bartsch W., Horst H.-J., Becker H. and Nehse, G.: Sex hormone binding globulin binding capacity. testosterone, 5x_dihydrotestosterone, oestradiol and prolactin in plasma of patients with prostatic carcinoma under various types of hormonal treatment. Actu endocr..
Covenh. 85 (1977) 65&664.
12. Fonzo D., kngeli A.: Sivieri R., Andriolo S., Frajria R. and Ceresa F.: Hyperprolactinemia in girls with idiopathic precocious puberty under prolonged treatment with cyproterone acetate. J. c/in. Endocr. Metah. 45 (1977) 164168. 13. Nieuweboer B. and Ltibke K.: Radioimmunological determination of cyproterone acetate. Hormone Rex 8 (1977) 21@218. 14. Bhargava A. S., Seeger A. and Giinzel P.: Isolation and identification of 15-P-hydroxy cyproterone acetate as a new metabolite of cyproterone acetate in dog, monkey and man. Steroids 30 (1977) 407418. 15 Frijlich M., Schie M. G. van and Brand E. C.: Sex hormone binding globulin binding capacity and studies on the binding of cyproterone acetate and other steroids. C/in. chim. Acta 87 (1978) 239-244. 16 Vermeulen A.. Verdonck L., Straeten M. van der and Orie N.: Capacity of the testosterone-binding globulin in human plasma and influence of specific binding of testosterone on its metabolic clearance rate. J. c/in. Endocr. Metah. 29 (1969) 1470-1480.