Exp. Clin. Endocrinol. Vol. 98, No. 2, 1991, pp. 71-80
J. A. Barth, Leipzig
Department of Clinical Research, Schering AG Berlin/Germany
Cyproterone Acetate in the Treatment of Sexual Disorders: Pharmacological Base and Clinical Experience F. NEUMANN and J. KALMUS
Summary: Cyproterone acetate (CPA) has been discovered more than 25 years ago and it was the first antiandrogen suitable for clinical use. CPA inhibits the action of endogenous and exogenous androgens at all androgen target organs; these include the prostate, seminal vesicles, testes, and the vas deferens. However, this antiandrogen also antagonizes less sex-specific effects of androgens, for example ossification of the epiphyseal cartilage, sebaceous gland function and skin thickness. Indications for CPA: Prostate cancer, androgen induced disorders of the skin (acne, seborrhoea, hirsutism, alopecia), precocious puberty and sexual disorders in men. Concerning sexual deviations clinical trials started in 1966. CPA leads to loss of libido and the ability to achieve erection, followed by the inability to achieve orgasm, alter about 14 days of treatment (100-200 mg daily orally or 300 mg weekly i.m.). These effects are reversed in the same order as the onset. About 75 to 80% of patients respond to this therapy. CPA is generally well tolerated. Tiredness, lack of drive, listlessness and depressive moods have been reported as non-specific side-effects. Slight gynecomastia occurs in about 20% of patients. There are no good alternatives in this indication. Pure antiandrogens are unsuitable, because these are unable to inhibit libido sufficiently. Tranquilizers are not very effective, high doses of estrogens are associated with severe (cardiovascular) side effects. Orchidectomy is an irreversible intervention, LHRH analogues are associated with hot flushes and the initial increase in testosterone (flare phenomenon).
Key words: Cyproterone acetate - Sexual deviation - Pharmacology - Clinical application
Introduction
When we discovered Cyproterone acetate (CPA), more than 25 years ago, we were advancing completely unknown territory because CPA was the first antiandrogen which seemed to be suitable for clinical use. The first indication we were thinking about was carcinoma of the prostate. And indeed, this is the most important indication today. We also thought CPA might be usefull to treat women with symptoms of androgenisation like acne, seborrhoea, hirsutism and alopecia. And again this is another important indication for CPA today.
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With 10 Figures
72
Exp. Clin. Endocrinol. 98 (1991) 2 CH3
CH2
CH,
¿lOAc
CH3
NHCOCH
NO2
¿H3 CF3
Cyproterone Acetate
Flutamide
CI O»
,CNH
CH3
N
NO2
'CCCH
CH2 CF3
S02
Casodex
CF3
O
CH3
Nilutamide
Fig. 1 Chemical structure of some important antiandrogens
But surprisingly to us, the first established indication was suppression of drive in sexually deviant behaviour. CPA was introduced into the market in 1973, for this indication only. Why have we been surprised? Until the mid sixties it was firmly believed that the higher a particular species stood on the evolutionary ladder the less the libido of the male individual depended on androgens. That means it should be possible to
inhibit the libido of the male rat with an antiandrogen to a greater extent than that of the human male. The opposite is the case. In the usual laboratory animals like rats, mice, guinea pigs, and hamsters CPA was not able or only partially able to inhibit libido and potency, whereas it has been shown to be highly effective in men. We will not discuss the reasons or misunderstandings why CPA was developed first for this indication only. This has been published elsewhere (Neumann und Wichert, 1984). Chemistry and Mechanism of Action Today besides CPA, which is a steroidal antiandrogen, there are some nonsteroidal antiandrogens available for clinical use. Fig. 1 shows the chemical structure of the most important compounds. Antiandrogens compete with androgens for receptor sites. Because the mechanism of action of all known compounds with antiandrogenic activities is the same, one would expect identical in vivo effects. However, as will be shown, this is not the case.
A distinction is made between pure antiandrogens which have antiandrogenic properties only and those which also have other endocrine properties such as progestational and antigonadotrophic partial effects. Because these two different types of compounds, steroidal antiandrogens like CPA and nonsteroidal antiandrogens, behave quite differently in vivo, there must be implications for clinical use. Generally speaking pure antiandrogens are not suitable for monotherapy in men, also not suitable for treatment of sexual deviant patients. This will be explained in a little more detail in the following.
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NHCOCOH
NC
73
F. NEUMAN and J. KALMUS, CPA Treatment of Sexual Disorders
e
Hypothalamus
Hypothalamus
$LHRH
j LHIRH Testosterone )neg. teedback)
Pituitary
Pituitary
LH
LH
Adrenal gland
Adrenal gland
Adrenal androgens
Adrenal"
Testosterone (T)
Synthesis ot proteins, enzymes, etc.
andro5ens\
estosterone (T)
Synthesis of proteins, enzymes, etc,
Target cell for androgens
Target cell for androgens
Fig. 2 Regulation of androgen biosynthesis
Fig. 3 Inhibition of androgen action by pure antiandrogens
under physiological conditions
Fig. 2 shows the regulation of androgen biosynthesis under physiological conditions. .LHRH (luteinising hormone releasing hormone) stimulates the biosynthesis and secretion of pituitary FSH (follicle stimulating hormone) and LH (luteinizing hormone). LH maintains the biosynthesis of testosterone in the Leydig cells. Androgens of adrenal origin account for about 10% of the total amount of androgens (mainly androstendione and dehydroepiandrosterone). The adrenal production of androgens is governed by the adreno-corticotrophic hormone (ACTH). Pure antiandrogens compete with androgens for receptor sites not only in androgen sensitive target organs (e g. in the prostate) but also within the hypothalamus where androgens exert their negative feedback effect. An androgen deficiency is simulated centrally and consequently more LHRH is released, LH synthesis is stimulated and so is testosterone biosynthesis. The interference of pure antiandrogens with the negative feedback is illustrated in Fig. 3. The stimulating effect of pure antiandrogens on the hypothalamo-pituitary axis can be seen in Fig. 4 and 5 which illustrate the effect of flutamide on the secretion of LH and testosterone in adult male rats. A dramatic increase in LH and testosterone is already evident after one single dose Animal experiments revealed that this counter regulatory effect of pure antiandrogens even influences the morphology of the hypothalamus, the pituitary, and the testes. Within the hypothalamus there is an increase in LHRH containing neurones. In the pituitary the gonado-
Downloaded by: Universite Laval. Copyrighted material.
Testis
74 V
Exp. Clin. Endocrinol. 98 (1991) 2 V
LH (ng/ml serum)
Testosterone (nmol/l serum)
-
100-
280 -
90 -
260
240 -
80 -
220 70 -
200 -
180 -
60
160
140 -
120 100 -
40 20 24 hours
D
6 weeks
2 weeks
Control Cyproterone acetate
Flutamide
I Mean ± SEM, Number of animals: 12 tor each parameter
Fig. 4 Serum concentrations of LH in adult rats
treated with cyproterone acetate (20 mg/day/ animal, s.c.) or flutamide (10 mg/day/animal, s.c.) after 1 day, 2 or 6 weeks of treatment
24 hours
D
6 weeks
2 weeks
Control Cyproterone acetate
Elutamide
I Mean ± S.E.M. Number of animals: 12 tor each parameter
Fig. 5 Serum concentrations of testosterone in adult rats treated with cyproterone acetate (20 mg/day/animal, s.c.) or flutamide (10 mg/day/ animal, s.c.) after 1 day, 2 or 6 weeks of treatment
trophin producing cells are increased in number and size. These morphological changes within the hypothalamus and the pituitary in animals given pure antiandrogens can be estimated quantitatively (see Fig. 6). In this case rats have been treated for six weeks with 10 mg/day/animal flutamide or 20 mg/day/animal CPA. The area in the hypothalamus containing LHRH neurons is increased by about 30% under treatment with flutamide. Within the pituitary the area covered by LH and FSH producing cells is increased by two times as compared with controls. The consequence of increased LH secretion is a marked Leydig cell hyperplasia in the testes. All these morphological changes were not seen when the steroidal antiandrogen CPA was administered to the animals. As a result of the interference of pure antiandrogens with the hypothalamo-pituitary-gonadal axis, spermatogenesis is not or only partially inhibited. As it is well known from prostatic carcinoma patients, where pure antiandrogens are given as monotherapy libido which in males is androgen dependent is maintained at least to a certain degree (Stegmayr et al., 1988). In contrast to the pure antiandrogens the steroidal antiandrogen CPA decreases LH and testosterone serum levels (see Fig. 4 and 5). These findings have been confirmed in humans as is shown in Fig. 7. In this study healthy volunteers were treated with flutamide or CPA once, for one or two weeks respectively. After 14 days of treatment with flutamide, LH rises and is consecutively followed by an
Downloaded by: Universite Laval. Copyrighted material.
80 60 -
F. NEUMAN and J. KALMUS, CPA Treatment of Sexual Disorders
75
V
25
15
FSH-area
LH-area
LiControl
CPA
(F
Fig. 6 Influence of flutamide (F) and cyproterone acetate (CPA) on LH and FSH producing cells and LHR}{ containing neurons in male rats. Area covered by LH and FSH producing cells or LHRH containing neurons, respectively. Total area measured: 0,76 10_2 mm2
LHRH-area
Imean±SD,n6
Duration of treatment: 6 weeks 10mg/day/animal Dose F: Dose CPA: 20mg/day/animal
increase in testosterone and estradiol. The elevation of estradiol results from augmented aromatisation of testosterone and causes gynecomastia. In contrast to pure antiandrogens which have no other endocrine activities, CPA as a nonpure antiandrogen has in addition progestogenic and antigonadotrophic properties. The
inhibition of androgen dependent organs and functions is based on a twofold LH ng/ml
10-
-
Serum conc. (mean ± SEM) 1=d1
T
2=d8
Control (Placebo)
3= CPA: 100 mg/d
flfl 123 123 CPA
FL
FL
Estradiol pmolfl
Testosterone nmol/l
200150-
302520 -
_I_
Control
Control (Placebo)
(Placebo) 100_
15
10-
-I-
ftri 123 123 CPA
FL
flfl 123 123 CPA
FL
Fig. 7 Influence of cyproterone acetate (CPA) and flutamide (FL) on serum concentrations of LH, testosterone and estradiol in healthy males (Adapted from Knuth et al., 1984)
Downloaded by: Universite Laval. Copyrighted material.
10
76
Exp. Clin. Endocrino!. 98 (1991) 2
Hypothalamus
LHRH
f Pituitary
LH
Adrenal gland
Testis
Adrenal androgena
Testosterone (T)
Target cell for androgens
Fig. 8 Inhibition of androgen action by steroidal antiandrogens
mechanism of action, first inhibition of androgen biosyntheses and second inhibition of androgn action within the target tissue or target cell. This dual mechanism of action of CPA is illustrated in Fig. 8. Based on this mechanism of action antiandrogens like CPA are able to inhibit androgen dependent organs and functions complete1y when given in doses high enough. And indeed, it has been shown in a large number of pharmacological studies that the effect of CPA is comparable with the effect of surgical castration or surgical hypophysectomy. One example, the histology of the prostate in normal, castrated or CPA treated rats, is shown in Fig. 9. Clinical Experience
Reduction of sexual drive is required when abnormal sexual tendencies and behaviour cause distress and place the person concerned at risk of becoming dissociai or punishable by law. Androgens are an important factor for the maintenance of sexual drive in men. CPA as a highly effective antiandrogen is able to reduce male sexual drive. Some important prerequisites have to be taken into account before starting CPA therapy in this indication:
Downloaded by: Universite Laval. Copyrighted material.
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F. NEUMAN and J. KALMUS, CPA Treatment of Sexual Disorders
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The patient has to agree to be treated; Treatment should always be combined with psychotherapy; The indication should be restricted to those who came or might come into conflict with existing laws and long for treatment; those who suffer as a consequence of an uncontrollable sexual drive from severe psychic pressure. Medication should always be supplemented by psychotherapeutic and sociother-
apeutic measures. The period of reduced drive can be used for the personal and social reorientation of the patient. During the last 25 years approximately 60 to loo papers have been published dealing with the CPA treatment of patients suffering from sexual deviant behaviour.
First clinical trials with cyproterone acetate were started in 1966 (Laschet and Laschet, 1971) in which 110 men suffering from sexual deviant behaviour were treated. CPA was shown to be highly effective in sexual deviant patients (exhibitionism, homosexual and heterosexual pedophilia, sexual aggression, incest, fetishism, excessive masturbation, hypersexuality, sexual murder, masochism). The competitive blocking effect was reported to reduce male sexuality in the order
libido - erection - orgasm. It has to be stressed that not any kind of sexual deviation is from today's point of view in need of treatment. Accurate diagnosis with regard to above mentioned criteria is imperative.
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,.
-
78
Exp. Clin. Endocrinol. 98 (1991) 2
In 80% of cases it was possible to inhibit sexuality to the desired degree with 100 mg CPA per day. 20% of the patients required 200 mg per day. With the admin-
istration of 100 mg/day the patients report a reduction of libido and erectional ability at the end of the first week. Regardless of the dosage administered the maximum effect is attained between the 20th and 25th day of treatment. The effects of the antiandrogenic action are reversed in the same order as the onset of action: sexual drive returns first followed by erectile potency and lastly spermatogenesis. CPA is described to be less effective in geriatric patients (cerebral sclerosis) and in patients with posttraumatic damage, dilation of the third ventricle or alcoholism.
increase, slight gynecomastia (20%), and decrease in sebaceous gland function. Head hair in baldness patients increase, body hair decrease. In further clinical investigations the effective ability to influence the intensity of sexual drive of the male, including psychosexual criteria, and numerous psychopathological parameters was demonstrated by progress observations (Mothes et al., 1971). After the first year of treatment the clinical investigators of this multicenter study graded 43.7% of the cases as "considerably improved" and 31% as "very considerably improved" (n = 352). Global improvement after 2 and 3 years of treatment vas, according to the impression of investigators, n more than 90% of the cases "good" or "very good". Fluctuations of body weight, transient gynecomastia (20%), and pain in the genital region have occurred as side effects of cyproterone acetate treatment. The analyses of a recently performed double blind study from Canada showed the effectiveness of cyproterone acetate as compared to placebo (Bradford et al., 1988). P-values for sexual arousal, sexual activity, sexual interest, degree of psychopathology (brief psychiatric rating scale) were all below 0.001. Positive side-effects were reduction .of anxiety, irritability and restlessness.
A review published by Ortmann (1980) is based on studies performed in New Zealand, Switzerland, Wales and Germany. Sexual relapse rate of male sexual offenders is shown to be very low during treatment with cyproterone acetate as compared with the values prior to treatment. As mentioned before, cyproterone acetate inhibits LHRH secretion and consequently testosterone biosynthesis. The effect of the low levels of remaining androgens is abolished by the direct antagonistic effect within the target organs, including androgen sensitive brain areas being responsible for sexual drive in man. Change
in serum testosterone of sexual offenders before, during and after cyproterone acetate treatment is shown in Fig. 10. Besides libido and potency all typical androgen dependent organs like the prostate or seminal vesicles are affected by CPA treatment. It has been shown in patients under CPA treatment that even though they were able to achieve an orgasm they
experienced a so called dry orgasm. The function of the accessory glands was completely inhibited. Spermatogenesis is also androgen dependent and is inhibited by CPA. That means that patients treated with high doses of CPA are sterile. All the effects of CPA are fully reversible.
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Side effects, mainly during first weeks, were fatiguability, depressive mood, weight
F. NEUMAN and J. KALMUS, CPA Treatment of Sexual Disorders
79
3. 30
I
s'' ''" '' 20
.'' '
'\
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Fig. 10 Serum testosterone in eight subjects
-s-
o
I
0 Mean basal
I
20
Days of treatment
400
25
50
before, during and after treatment with cyproterone acetate. Normal adult male
Days after
range 11 44 nmol/1 (3-11 ng/mg). (From
treatment
Jeffcoate et al., 1980)
Until now there are no good alternatives to CPA in the treatment of patients suffering from sexual deviant behaviour. Tranquilizers are not very effective in that indication. Surgical castration is irreversible and there are some other disadvantages like the psychological impact, the occurrence of hot flushes comparable with the hot flushes during the menopause in women, and the risk due to surgery. Estrogens have also been used, but they have several disadvantages. Even though
the psychological impact is not as severe as after castration, they have serious side-effects in the high doses. Cardiovascular side-effects should be mentioned in the first place, but also gastrointestinal problems and the high incidence of gynecomastia. The whole body is undergoing changes in the direction of feminization.
Since recently LHRH analogues are also used for androgen deprivation. There are only few cases described where such analogues were used in sexual deviant patients (Allolio et al., 1985, Dyer, 1988). But there are some disadvantages. First of all, an initial increase in testosterone is seen lasting for about 14 days. This period might be quite dangerous for the patient with regard to sexual relapse. As a second disadvantage the occurrence of hot flushes should be mentioned. Cyproterone acetate is not associated with the occurrence of hot flushes. Taking all aspects into account it can be stated that cyproterone acetate is the most suitable therapeutical method to reduce sexual drive in man. Cyproterone acetate stands out for marked decrease of testosterone, efficient blockade of all androgenic stimuli at the receptor level, general good tolerance and long term experience demonstrating the efficacy and safety. Social and professional rehabilitation is possible in a high percentage of patients given a combined psychotherapy
and CPA treatment.
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\
80
Exp. Clin. Endocrinol. 98 (1991) 2
References ALL0LI0, B. et al. 1985: Behandlung sexueller Verhaltensstörungen mit LH-RH Superagonisten. Dtsch. Med. Wschr. 110 (1985) 1952. A. Amsterdam: Elsevier Science Publishers B. V., vol. 6, 1988, pp. 526-536. DYER, C.: Mental Health Commission defeated over paedophile. Brit. Med. J. 296 (1988) 1660-1661. JEFFCOATE, W. J. et al.: The effect of cyproterone acetate on serum testosterone, LH, FSH, and prolactin in male sexual offenders. Clin. Endocnnol. 13 (1980) 189-195. KNUTH, U. A. et al.: Effect of flutamide or cyproterone acetate on pituitary and testicular hormones in normal men. J. Clin. Endocrinol. Metab. 59 (1984) 963 969. LASCHET, U. et al.: Psychopharmakotherapy of sex offenders with cyproterone acetate. Pharmakopsychiat. Neuro. Psychopharmakol. 4 (1971) 99-104. MOTHES, B. et al.: Klinische Prüfung von Cyproteron-acetat bei Sexualdeviationen Gesamtauswertung. In: Schering Symposium über Sexualdeviationen und ihre medikamentöse Behandlung, Berlin 17. 18. Mai 1971. Hrsg. Raspé G, Oxford-Edingburgh-New York: Pergamon Press Vieweg, Life Sciences Monographs 2, 1971, pp. 65-84. NEUMANN, F. et al.: Die Geschichte von Cyproteronacetat. MPS, Med-Pharmazeut. Studienges. e. V., Mainz: Verlag Kirchheim + Co. GmbH, 1984, pp. 1-52. ORTMANN, J.: The treatment of sexual offenders. mt. J. Law Psychiat. 3 (1980) 443 451. STEGMAYR, B. et al.: Flutamide - an antiandrogen inhibiting prostatic cancer and prostatic secretion with retention of potency. Med. Oncol. Tumor Pharmakother. 5 (1988) 61 65. Author's address: Prof. F. NEUMANN, Dept. of Clinical Research, Schering AG, PF 65 0311, W1000 Berlin, Germany
Downloaded by: Universite Laval. Copyrighted material.
BRADFORD, J. M. W.: Treatment of sexual offenders with cyproterone acetate. In: Handbook of Sexology. The Pharmacology and Endocrinology of Sexual Function. Ed. SITSEN, J. M.
J. A. Barth, Leipzig
Department of Clinical Research, Schering AG Berlin/Germany
Cyproterone Acetate in the Treatment of Sexual Disorders: Pharmacological Base and Clinical Experience F. NEUMANN and J. KALMUS
Summary: Cyproterone acetate (CPA) has been discovered more than 25 years ago and it was the first antiandrogen suitable for clinical use. CPA inhibits the action of endogenous and exogenous androgens at all androgen target organs; these include the prostate, seminal vesicles, testes, and the vas deferens. However, this antiandrogen also antagonizes less sex-specific effects of androgens, for example ossification of the epiphyseal cartilage, sebaceous gland function and skin thickness. Indications for CPA: Prostate cancer, androgen induced disorders of the skin (acne, seborrhoea, hirsutism, alopecia), precocious puberty and sexual disorders in men. Concerning sexual deviations clinical trials started in 1966. CPA leads to loss of libido and the ability to achieve erection, followed by the inability to achieve orgasm, alter about 14 days of treatment (100-200 mg daily orally or 300 mg weekly i.m.). These effects are reversed in the same order as the onset. About 75 to 80% of patients respond to this therapy. CPA is generally well tolerated. Tiredness, lack of drive, listlessness and depressive moods have been reported as non-specific side-effects. Slight gynecomastia occurs in about 20% of patients. There are no good alternatives in this indication. Pure antiandrogens are unsuitable, because these are unable to inhibit libido sufficiently. Tranquilizers are not very effective, high doses of estrogens are associated with severe (cardiovascular) side effects. Orchidectomy is an irreversible intervention, LHRH analogues are associated with hot flushes and the initial increase in testosterone (flare phenomenon).
Key words: Cyproterone acetate - Sexual deviation - Pharmacology - Clinical application
Introduction
When we discovered Cyproterone acetate (CPA), more than 25 years ago, we were advancing completely unknown territory because CPA was the first antiandrogen which seemed to be suitable for clinical use. The first indication we were thinking about was carcinoma of the prostate. And indeed, this is the most important indication today. We also thought CPA might be usefull to treat women with symptoms of androgenisation like acne, seborrhoea, hirsutism and alopecia. And again this is another important indication for CPA today.
Downloaded by: Universite Laval. Copyrighted material.
With 10 Figures
72
Exp. Clin. Endocrinol. 98 (1991) 2 CH3
CH2
CH,
¿lOAc
CH3
NHCOCH
NO2
¿H3 CF3
Cyproterone Acetate
Flutamide
CI O»
,CNH
CH3
N
NO2
'CCCH
CH2 CF3
S02
Casodex
CF3
O
CH3
Nilutamide
Fig. 1 Chemical structure of some important antiandrogens
But surprisingly to us, the first established indication was suppression of drive in sexually deviant behaviour. CPA was introduced into the market in 1973, for this indication only. Why have we been surprised? Until the mid sixties it was firmly believed that the higher a particular species stood on the evolutionary ladder the less the libido of the male individual depended on androgens. That means it should be possible to
inhibit the libido of the male rat with an antiandrogen to a greater extent than that of the human male. The opposite is the case. In the usual laboratory animals like rats, mice, guinea pigs, and hamsters CPA was not able or only partially able to inhibit libido and potency, whereas it has been shown to be highly effective in men. We will not discuss the reasons or misunderstandings why CPA was developed first for this indication only. This has been published elsewhere (Neumann und Wichert, 1984). Chemistry and Mechanism of Action Today besides CPA, which is a steroidal antiandrogen, there are some nonsteroidal antiandrogens available for clinical use. Fig. 1 shows the chemical structure of the most important compounds. Antiandrogens compete with androgens for receptor sites. Because the mechanism of action of all known compounds with antiandrogenic activities is the same, one would expect identical in vivo effects. However, as will be shown, this is not the case.
A distinction is made between pure antiandrogens which have antiandrogenic properties only and those which also have other endocrine properties such as progestational and antigonadotrophic partial effects. Because these two different types of compounds, steroidal antiandrogens like CPA and nonsteroidal antiandrogens, behave quite differently in vivo, there must be implications for clinical use. Generally speaking pure antiandrogens are not suitable for monotherapy in men, also not suitable for treatment of sexual deviant patients. This will be explained in a little more detail in the following.
Downloaded by: Universite Laval. Copyrighted material.
NHCOCOH
NC
73
F. NEUMAN and J. KALMUS, CPA Treatment of Sexual Disorders
e
Hypothalamus
Hypothalamus
$LHRH
j LHIRH Testosterone )neg. teedback)
Pituitary
Pituitary
LH
LH
Adrenal gland
Adrenal gland
Adrenal androgens
Adrenal"
Testosterone (T)
Synthesis ot proteins, enzymes, etc.
andro5ens\
estosterone (T)
Synthesis of proteins, enzymes, etc,
Target cell for androgens
Target cell for androgens
Fig. 2 Regulation of androgen biosynthesis
Fig. 3 Inhibition of androgen action by pure antiandrogens
under physiological conditions
Fig. 2 shows the regulation of androgen biosynthesis under physiological conditions. .LHRH (luteinising hormone releasing hormone) stimulates the biosynthesis and secretion of pituitary FSH (follicle stimulating hormone) and LH (luteinizing hormone). LH maintains the biosynthesis of testosterone in the Leydig cells. Androgens of adrenal origin account for about 10% of the total amount of androgens (mainly androstendione and dehydroepiandrosterone). The adrenal production of androgens is governed by the adreno-corticotrophic hormone (ACTH). Pure antiandrogens compete with androgens for receptor sites not only in androgen sensitive target organs (e g. in the prostate) but also within the hypothalamus where androgens exert their negative feedback effect. An androgen deficiency is simulated centrally and consequently more LHRH is released, LH synthesis is stimulated and so is testosterone biosynthesis. The interference of pure antiandrogens with the negative feedback is illustrated in Fig. 3. The stimulating effect of pure antiandrogens on the hypothalamo-pituitary axis can be seen in Fig. 4 and 5 which illustrate the effect of flutamide on the secretion of LH and testosterone in adult male rats. A dramatic increase in LH and testosterone is already evident after one single dose Animal experiments revealed that this counter regulatory effect of pure antiandrogens even influences the morphology of the hypothalamus, the pituitary, and the testes. Within the hypothalamus there is an increase in LHRH containing neurones. In the pituitary the gonado-
Downloaded by: Universite Laval. Copyrighted material.
Testis
74 V
Exp. Clin. Endocrinol. 98 (1991) 2 V
LH (ng/ml serum)
Testosterone (nmol/l serum)
-
100-
280 -
90 -
260
240 -
80 -
220 70 -
200 -
180 -
60
160
140 -
120 100 -
40 20 24 hours
D
6 weeks
2 weeks
Control Cyproterone acetate
Flutamide
I Mean ± SEM, Number of animals: 12 tor each parameter
Fig. 4 Serum concentrations of LH in adult rats
treated with cyproterone acetate (20 mg/day/ animal, s.c.) or flutamide (10 mg/day/animal, s.c.) after 1 day, 2 or 6 weeks of treatment
24 hours
D
6 weeks
2 weeks
Control Cyproterone acetate
Elutamide
I Mean ± S.E.M. Number of animals: 12 tor each parameter
Fig. 5 Serum concentrations of testosterone in adult rats treated with cyproterone acetate (20 mg/day/animal, s.c.) or flutamide (10 mg/day/ animal, s.c.) after 1 day, 2 or 6 weeks of treatment
trophin producing cells are increased in number and size. These morphological changes within the hypothalamus and the pituitary in animals given pure antiandrogens can be estimated quantitatively (see Fig. 6). In this case rats have been treated for six weeks with 10 mg/day/animal flutamide or 20 mg/day/animal CPA. The area in the hypothalamus containing LHRH neurons is increased by about 30% under treatment with flutamide. Within the pituitary the area covered by LH and FSH producing cells is increased by two times as compared with controls. The consequence of increased LH secretion is a marked Leydig cell hyperplasia in the testes. All these morphological changes were not seen when the steroidal antiandrogen CPA was administered to the animals. As a result of the interference of pure antiandrogens with the hypothalamo-pituitary-gonadal axis, spermatogenesis is not or only partially inhibited. As it is well known from prostatic carcinoma patients, where pure antiandrogens are given as monotherapy libido which in males is androgen dependent is maintained at least to a certain degree (Stegmayr et al., 1988). In contrast to the pure antiandrogens the steroidal antiandrogen CPA decreases LH and testosterone serum levels (see Fig. 4 and 5). These findings have been confirmed in humans as is shown in Fig. 7. In this study healthy volunteers were treated with flutamide or CPA once, for one or two weeks respectively. After 14 days of treatment with flutamide, LH rises and is consecutively followed by an
Downloaded by: Universite Laval. Copyrighted material.
80 60 -
F. NEUMAN and J. KALMUS, CPA Treatment of Sexual Disorders
75
V
25
15
FSH-area
LH-area
LiControl
CPA
(F
Fig. 6 Influence of flutamide (F) and cyproterone acetate (CPA) on LH and FSH producing cells and LHR}{ containing neurons in male rats. Area covered by LH and FSH producing cells or LHRH containing neurons, respectively. Total area measured: 0,76 10_2 mm2
LHRH-area
Imean±SD,n6
Duration of treatment: 6 weeks 10mg/day/animal Dose F: Dose CPA: 20mg/day/animal
increase in testosterone and estradiol. The elevation of estradiol results from augmented aromatisation of testosterone and causes gynecomastia. In contrast to pure antiandrogens which have no other endocrine activities, CPA as a nonpure antiandrogen has in addition progestogenic and antigonadotrophic properties. The
inhibition of androgen dependent organs and functions is based on a twofold LH ng/ml
10-
-
Serum conc. (mean ± SEM) 1=d1
T
2=d8
Control (Placebo)
3= CPA: 100 mg/d
flfl 123 123 CPA
FL
FL
Estradiol pmolfl
Testosterone nmol/l
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Fig. 7 Influence of cyproterone acetate (CPA) and flutamide (FL) on serum concentrations of LH, testosterone and estradiol in healthy males (Adapted from Knuth et al., 1984)
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Exp. Clin. Endocrino!. 98 (1991) 2
Hypothalamus
LHRH
f Pituitary
LH
Adrenal gland
Testis
Adrenal androgena
Testosterone (T)
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Fig. 8 Inhibition of androgen action by steroidal antiandrogens
mechanism of action, first inhibition of androgen biosyntheses and second inhibition of androgn action within the target tissue or target cell. This dual mechanism of action of CPA is illustrated in Fig. 8. Based on this mechanism of action antiandrogens like CPA are able to inhibit androgen dependent organs and functions complete1y when given in doses high enough. And indeed, it has been shown in a large number of pharmacological studies that the effect of CPA is comparable with the effect of surgical castration or surgical hypophysectomy. One example, the histology of the prostate in normal, castrated or CPA treated rats, is shown in Fig. 9. Clinical Experience
Reduction of sexual drive is required when abnormal sexual tendencies and behaviour cause distress and place the person concerned at risk of becoming dissociai or punishable by law. Androgens are an important factor for the maintenance of sexual drive in men. CPA as a highly effective antiandrogen is able to reduce male sexual drive. Some important prerequisites have to be taken into account before starting CPA therapy in this indication:
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F. NEUMAN and J. KALMUS, CPA Treatment of Sexual Disorders
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The patient has to agree to be treated; Treatment should always be combined with psychotherapy; The indication should be restricted to those who came or might come into conflict with existing laws and long for treatment; those who suffer as a consequence of an uncontrollable sexual drive from severe psychic pressure. Medication should always be supplemented by psychotherapeutic and sociother-
apeutic measures. The period of reduced drive can be used for the personal and social reorientation of the patient. During the last 25 years approximately 60 to loo papers have been published dealing with the CPA treatment of patients suffering from sexual deviant behaviour.
First clinical trials with cyproterone acetate were started in 1966 (Laschet and Laschet, 1971) in which 110 men suffering from sexual deviant behaviour were treated. CPA was shown to be highly effective in sexual deviant patients (exhibitionism, homosexual and heterosexual pedophilia, sexual aggression, incest, fetishism, excessive masturbation, hypersexuality, sexual murder, masochism). The competitive blocking effect was reported to reduce male sexuality in the order
libido - erection - orgasm. It has to be stressed that not any kind of sexual deviation is from today's point of view in need of treatment. Accurate diagnosis with regard to above mentioned criteria is imperative.
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Exp. Clin. Endocrinol. 98 (1991) 2
In 80% of cases it was possible to inhibit sexuality to the desired degree with 100 mg CPA per day. 20% of the patients required 200 mg per day. With the admin-
istration of 100 mg/day the patients report a reduction of libido and erectional ability at the end of the first week. Regardless of the dosage administered the maximum effect is attained between the 20th and 25th day of treatment. The effects of the antiandrogenic action are reversed in the same order as the onset of action: sexual drive returns first followed by erectile potency and lastly spermatogenesis. CPA is described to be less effective in geriatric patients (cerebral sclerosis) and in patients with posttraumatic damage, dilation of the third ventricle or alcoholism.
increase, slight gynecomastia (20%), and decrease in sebaceous gland function. Head hair in baldness patients increase, body hair decrease. In further clinical investigations the effective ability to influence the intensity of sexual drive of the male, including psychosexual criteria, and numerous psychopathological parameters was demonstrated by progress observations (Mothes et al., 1971). After the first year of treatment the clinical investigators of this multicenter study graded 43.7% of the cases as "considerably improved" and 31% as "very considerably improved" (n = 352). Global improvement after 2 and 3 years of treatment vas, according to the impression of investigators, n more than 90% of the cases "good" or "very good". Fluctuations of body weight, transient gynecomastia (20%), and pain in the genital region have occurred as side effects of cyproterone acetate treatment. The analyses of a recently performed double blind study from Canada showed the effectiveness of cyproterone acetate as compared to placebo (Bradford et al., 1988). P-values for sexual arousal, sexual activity, sexual interest, degree of psychopathology (brief psychiatric rating scale) were all below 0.001. Positive side-effects were reduction .of anxiety, irritability and restlessness.
A review published by Ortmann (1980) is based on studies performed in New Zealand, Switzerland, Wales and Germany. Sexual relapse rate of male sexual offenders is shown to be very low during treatment with cyproterone acetate as compared with the values prior to treatment. As mentioned before, cyproterone acetate inhibits LHRH secretion and consequently testosterone biosynthesis. The effect of the low levels of remaining androgens is abolished by the direct antagonistic effect within the target organs, including androgen sensitive brain areas being responsible for sexual drive in man. Change
in serum testosterone of sexual offenders before, during and after cyproterone acetate treatment is shown in Fig. 10. Besides libido and potency all typical androgen dependent organs like the prostate or seminal vesicles are affected by CPA treatment. It has been shown in patients under CPA treatment that even though they were able to achieve an orgasm they
experienced a so called dry orgasm. The function of the accessory glands was completely inhibited. Spermatogenesis is also androgen dependent and is inhibited by CPA. That means that patients treated with high doses of CPA are sterile. All the effects of CPA are fully reversible.
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Side effects, mainly during first weeks, were fatiguability, depressive mood, weight
F. NEUMAN and J. KALMUS, CPA Treatment of Sexual Disorders
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Until now there are no good alternatives to CPA in the treatment of patients suffering from sexual deviant behaviour. Tranquilizers are not very effective in that indication. Surgical castration is irreversible and there are some other disadvantages like the psychological impact, the occurrence of hot flushes comparable with the hot flushes during the menopause in women, and the risk due to surgery. Estrogens have also been used, but they have several disadvantages. Even though
the psychological impact is not as severe as after castration, they have serious side-effects in the high doses. Cardiovascular side-effects should be mentioned in the first place, but also gastrointestinal problems and the high incidence of gynecomastia. The whole body is undergoing changes in the direction of feminization.
Since recently LHRH analogues are also used for androgen deprivation. There are only few cases described where such analogues were used in sexual deviant patients (Allolio et al., 1985, Dyer, 1988). But there are some disadvantages. First of all, an initial increase in testosterone is seen lasting for about 14 days. This period might be quite dangerous for the patient with regard to sexual relapse. As a second disadvantage the occurrence of hot flushes should be mentioned. Cyproterone acetate is not associated with the occurrence of hot flushes. Taking all aspects into account it can be stated that cyproterone acetate is the most suitable therapeutical method to reduce sexual drive in man. Cyproterone acetate stands out for marked decrease of testosterone, efficient blockade of all androgenic stimuli at the receptor level, general good tolerance and long term experience demonstrating the efficacy and safety. Social and professional rehabilitation is possible in a high percentage of patients given a combined psychotherapy
and CPA treatment.
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References ALL0LI0, B. et al. 1985: Behandlung sexueller Verhaltensstörungen mit LH-RH Superagonisten. Dtsch. Med. Wschr. 110 (1985) 1952. A. Amsterdam: Elsevier Science Publishers B. V., vol. 6, 1988, pp. 526-536. DYER, C.: Mental Health Commission defeated over paedophile. Brit. Med. J. 296 (1988) 1660-1661. JEFFCOATE, W. J. et al.: The effect of cyproterone acetate on serum testosterone, LH, FSH, and prolactin in male sexual offenders. Clin. Endocnnol. 13 (1980) 189-195. KNUTH, U. A. et al.: Effect of flutamide or cyproterone acetate on pituitary and testicular hormones in normal men. J. Clin. Endocrinol. Metab. 59 (1984) 963 969. LASCHET, U. et al.: Psychopharmakotherapy of sex offenders with cyproterone acetate. Pharmakopsychiat. Neuro. Psychopharmakol. 4 (1971) 99-104. MOTHES, B. et al.: Klinische Prüfung von Cyproteron-acetat bei Sexualdeviationen Gesamtauswertung. In: Schering Symposium über Sexualdeviationen und ihre medikamentöse Behandlung, Berlin 17. 18. Mai 1971. Hrsg. Raspé G, Oxford-Edingburgh-New York: Pergamon Press Vieweg, Life Sciences Monographs 2, 1971, pp. 65-84. NEUMANN, F. et al.: Die Geschichte von Cyproteronacetat. MPS, Med-Pharmazeut. Studienges. e. V., Mainz: Verlag Kirchheim + Co. GmbH, 1984, pp. 1-52. ORTMANN, J.: The treatment of sexual offenders. mt. J. Law Psychiat. 3 (1980) 443 451. STEGMAYR, B. et al.: Flutamide - an antiandrogen inhibiting prostatic cancer and prostatic secretion with retention of potency. Med. Oncol. Tumor Pharmakother. 5 (1988) 61 65. Author's address: Prof. F. NEUMANN, Dept. of Clinical Research, Schering AG, PF 65 0311, W1000 Berlin, Germany
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BRADFORD, J. M. W.: Treatment of sexual offenders with cyproterone acetate. In: Handbook of Sexology. The Pharmacology and Endocrinology of Sexual Function. Ed. SITSEN, J. M.
