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Comparison of cyproterone acetate (CPA) and leuprolide acetate (LHRH agonist) in a chronic pedophile: A clinical case study
I
mll
II
III
Comparison of Cyproterone Acetate (CPA) and Leuprolide Acetate (LHRH Agonist) in a Chronic Pedophile: A Clinical Case Study Alan J. Cooper and Zack Z. Cernovsky Key W o r d s :
Cyproterone acetate, leuprolide acetate, pedophile, L H R H agonist
Introduction The anfiandrogen drugs, medroxyprogesterone acetate (MPA) and cyproterone acetate (CPA) have been available as part of a treatment package for sexual transgressors for almost 30 years. Uncontrolled and controlled studies on approximately !,000 sexual offenders (e.g., pedophiles, rapists; exhibitionists) indicate the agents to be equipotent and approximately equivalent in decreasing sexual tensions, fantasies, preoccupation, and "sexual actingout" and in cases studied longitudinally over several years, recidivism has been reduced (Cooper 1986). MPA and CPA are not effective in every case, however, (Dickey |992; Rousseau et al 1990) and paradoxical effects have been reported in which sexual arousal has increased despite the expected marked reduction in testosterone levels (Cooper 1987). Additionally, CPA and MPA are steroids and may be associated with a number of adverse consequences, including: fatigue, depression, hypoglycemia, gynecomastia, weight gain, breast nodules, possible thromboemboiic p~enomena, and adrenal suppression. MPA is believed to be possibly carcinogenic in beagle dogs. (Rosenfield et al 1983). The recent development of LHRH (luteinizing hormone-releasing hormone) agonists and experience gained during their use in the treatment of prostatic carcinoma, have suggested that they might be helpful in reducing libido in some sexual offenders. Moreover, synthetic LHRH agonists, like native LHRH are peptides, therefore, they are inherently safer than steroids, and are to be preferred for this reason. Moreover, a few case studies (Dickey 1992; Rousseau et al 1990) have pointed to superior efficacy in From the Department of Psychiauy. St. Thomas Psychiatric Hospital, St. Thomas Ontario. Canada (AJC, ZZC). and the University of Western Ontario. London. Ontario, Canada (AJC). Address reprint requests to Dr. A. J. Cooper, St. Thomas Psychiatric Hospital, P.O. Box 7004, St. Thomas, ON. N5P3V9, Canada. Received September 20,1993, revised January 27, 1994.
© 1994 Society of BiologicalPsychiatry
offenders who have not responded satisfactorily to either CPA or MPA. We report the extension of a previously p u b l i ~ study (Cooper et al 1992) (a 38-month placebo and "no ueam~nt" coml:aison of the antilibidinal effects of CPA up to 200 mg daily), in a heterosexual pedophile who, because of "apparent" weakening of the antilibidinal effects of CPA, requested @.attreatment be continued with leuprolide acetate. At the time, it could not be anticipated how long it might take for the patient to be brought to trial, or the precise nature of any sentence imposed (e.g., incarceration versus nonincarceration). Therefore, a flexible methodology (but one that required a minimum of 4 weeks for each phase; it being generally befieved that the clinical and endocrine effects of CPA take 2-3 weeks to be fully developed), which could be changed according to circumstances, was favored. As it tamed out, the sequence of treatment was as follows: I. 2. 3. 4. 5. 6. 7. 8. 9. 10.
placeboron-in---16 weeks; CPA IDomgperdayml6weeks; "no treatment"--16 weeks (e.g. no pills were given); CPA lDOnag pe~"dayml6 weeks; placebo--16 weeks; "no treatment"--16 weeks, CPA 1DOnag per daym36 weeks; CPA 200 mgper day--42 weeks; "no treatment"~10 weeks; leuprolide acetate 7.5 mg IM per month--24 weeks (maximal effect takes 2-4 weeks to develop and persists for as long as the drug is taken); 1I. "no treatment"--I0 weeks. Details for stages "1-8" have been published elsewhere (Cooper et al 1992) but are summarized in the present results (Figure 1) for comparison. 0006-3223/94/$07.00
2~
BIOLPSYCHIATRY t9~1;36:~271
CaseR¢lX)llS
Testosterone and Phallometric Data Teetosterone nmol/I
Phellometry: 9. ot full erec~loa
" lrm
t" 86
16
SO
10
20
S
10
o
Plecebo
32 wks
--
No Treatment CPA 100rag
62 was
CPA ~O0mg Leuprollde
88 wka
tutoetsrone
~
42 wk8
~
24 wk8
phidlometry
Self-Reporfs of Sexual Arousal Ratings from 1 to S
°'i
Placebo 32 wks
No Troalmenl CPA lOOmg 52 wks 68 wks Arousal: 5 variables
Figure 1. Measures of sexual arousal.
CPA 200m9 42 wks ~l
Erection
LeupraUde 24 wk$
Case Repens
Measures o f Sexual Arousal Frequencies of sexual thoughts, fantasies, self-masturbation and morning erections on awakening were recorded weekly by the patient in a specially provided sexual diary, on a 5-point l i k e n scale. The degree of pleasure associated with masturbation and sexual frustration was recorded weekly on a 4-point Liken scale. The 4-point m e a s u r e s were subsequently convened mathematically to 5-point equivalents for the purpose of graphing all measures on the same scale. The scores for the final week of each month were used in computing the results. Phallometric evaluations were made in a standard sexual laboratory during the final week of each phase. The patient was tested with balanced audio and video sets. each appmxirnately 2 rain in length. Stimuli included: audio and video depictions of a variety of consensual sexual activities between adult men and women, and between adult men and girls aged 4-to-9 years. Increases in penile circumference were expressed as a percentage of full erection.
E n d o c r i n e Assays Throughout the 54 months, blood was drawn monthly at approximately IO:00AM for endocrinological evaluation, Serum testosterone, lutenizing hormone, follicle-stimulating hormone and prolactin were measured in the same laboratory with standard radioimmune assay techniques.
Results The data from the ! 1 stages of treatment were collapsed into five categories: placebo (32 weeks), "no treatment" (52 weeks), CPA 100 mg per day (68 weeks), CPA 200 mg per day (42 weeks), and leuprolide acetate 7.5 mg per month (24 weeks). The scores for the morning erections were considered separately. The scores for the other five sexual variables were pooled and a single arousal mean was calculated. The main results are displayed in Figure 1, which shows the mean phallometric and testosterone values and the mean sexual arousal self-report scores (e.g., early morning erections on awakening and the five other arousal variables combined).
Discussion Circumstances made it possible to study our patient in a continuous fashion over 54 months. As can be seen (Figure 1), leuprolide almost totally suppressed both self-report and phallometric measures of sexual arousal, and reduced testosterone levels to near 0. Our patient reported no side effects, although it should be remembered that he only received the drug for 24 weeks. Prolonged use (longer than 6 months) calls for scrupulous physical and biochemical monitoring, especially calcium metabolism. It is known that extended use of LHRH agonists can cause osteoporosis (Casper 1991). That the antilibidinal effects were specific to leuprolide, rather than secondary to other factors (e.g., [a] declining sex drive with increasing age--the patient was almost 4 years older than when he started CPA (Cooper et al 1992); [b] his sex drive had already been significantly and permanently suppressed by the prior chronic
m o t PSYCmA~y
adminislralion ofCPA)(Davis 1974~ Lascbet a n d ~
almostcertain.Thus,the 24-week~
271
1969)is
phasewas
by and followed by a I O-week "no treatment" phase, when within approximately 3 weeks, in each case, om patient's sexual behaviors and testosterone i ~ to levels as high as anything pt'eviously noted throughout the entire ~ inv--. Leupmlide, like other synthetic LHRH agonists, is considerably more active biologically than the ~ hem',one (e.g., 60150 times more potent Casper 1991)~ Contirttmus admiK~suati~ of leupmlide induces an initial increase in LH and FSH section, followed by a paradoxical decrease due to g~mdotrophinreleasing hormone receptor downregulation in the anxerior pituitary. Ultimately LH and FSH cease to be released and temlx~ary inhibition of gonadal function ensues, with, in the male, a resultant dramatic decrease in serum testosterone and ~ydrolestosterone to casuation levels. Clinical experience with leuprolide as an antilibidinai agent for the treatment of sexual offenders is limited. To date, the drug has been used in a few cases, in whom CPA or MPA have failed to produce the desired clinical effects (Dickey I992, Rousseau et al 1990). The actions of leuprolide (e.g., downregulaton of gon~,~trophin releasing hormone receptors) are more circumscribed than CPA, which, in addition to ~ b i t i n g the synthesis of testosterone, also blocks androgen-sensitive receptors wherever they occur in the body. Yet, LHRH agonists have succeeded where antiandrogen has failed. Possibly the fact that leuprolide generally reduces testosterone levels below those achieved with recommended doses of CPA and MPA, may be the critical factor. The drug may be a superior alternative to currently available antiandrogens (MPA/CPA), but m~i'e h-ials are necessary.
References Cooper AJ (1986): Progestogens in the treatment of male sex off~aders: A review. Can J Psychiatry 31:73-79. Dickey R (1992): The management of a case of treatment-resistant paraphilia with a long-acting LHRH agonist. Can J Psychiatry 37:567-569. Rousseau L, Couture M, Dupout A, Labrie F, Couture N (1990): Effect of combined androgen blockade with an LHRH agnnist and flutamide in one severe case of male exhibitionism. Can J Psychiatry 35:338-34t. Cooper AJ (1987): Sadistic homosexual pedophilia treatment with cyproterone acetate. Can J Psychiatry 32:738-740. Rosenfield A, Maine D, Rochat R, Shelton J, Hatcher R (1983): The Food and Drug Administration and medroxyprogesterone acetate. JAMA 249:(2 i):2922-2928. Cooper AJ, Cernovsky Z, Magnus RV (I 992): The Long-term use of cyproterone acetate in pedophilia: A case study. J Sex & Marital Therapy 18(4):292-302. Casper R (i 991 ): Clinical Uses of Gonadotrophin-releasing Hormone Analogues. Can MedAssoc J 144:(2): 153-158. Davis TS (1974): Cyproterone acetate for male hyposexuality. J Int Med Res 159-153. Laschet V, Laschet L (1969): Three years' clinical research with cyproterone acetate in the inhibiting of male sexuality. Acta Endocrinolo 138(suppl) 232.
mll
II
III
Comparison of Cyproterone Acetate (CPA) and Leuprolide Acetate (LHRH Agonist) in a Chronic Pedophile: A Clinical Case Study Alan J. Cooper and Zack Z. Cernovsky Key W o r d s :
Cyproterone acetate, leuprolide acetate, pedophile, L H R H agonist
Introduction The anfiandrogen drugs, medroxyprogesterone acetate (MPA) and cyproterone acetate (CPA) have been available as part of a treatment package for sexual transgressors for almost 30 years. Uncontrolled and controlled studies on approximately !,000 sexual offenders (e.g., pedophiles, rapists; exhibitionists) indicate the agents to be equipotent and approximately equivalent in decreasing sexual tensions, fantasies, preoccupation, and "sexual actingout" and in cases studied longitudinally over several years, recidivism has been reduced (Cooper 1986). MPA and CPA are not effective in every case, however, (Dickey |992; Rousseau et al 1990) and paradoxical effects have been reported in which sexual arousal has increased despite the expected marked reduction in testosterone levels (Cooper 1987). Additionally, CPA and MPA are steroids and may be associated with a number of adverse consequences, including: fatigue, depression, hypoglycemia, gynecomastia, weight gain, breast nodules, possible thromboemboiic p~enomena, and adrenal suppression. MPA is believed to be possibly carcinogenic in beagle dogs. (Rosenfield et al 1983). The recent development of LHRH (luteinizing hormone-releasing hormone) agonists and experience gained during their use in the treatment of prostatic carcinoma, have suggested that they might be helpful in reducing libido in some sexual offenders. Moreover, synthetic LHRH agonists, like native LHRH are peptides, therefore, they are inherently safer than steroids, and are to be preferred for this reason. Moreover, a few case studies (Dickey 1992; Rousseau et al 1990) have pointed to superior efficacy in From the Department of Psychiauy. St. Thomas Psychiatric Hospital, St. Thomas Ontario. Canada (AJC, ZZC). and the University of Western Ontario. London. Ontario, Canada (AJC). Address reprint requests to Dr. A. J. Cooper, St. Thomas Psychiatric Hospital, P.O. Box 7004, St. Thomas, ON. N5P3V9, Canada. Received September 20,1993, revised January 27, 1994.
© 1994 Society of BiologicalPsychiatry
offenders who have not responded satisfactorily to either CPA or MPA. We report the extension of a previously p u b l i ~ study (Cooper et al 1992) (a 38-month placebo and "no ueam~nt" coml:aison of the antilibidinal effects of CPA up to 200 mg daily), in a heterosexual pedophile who, because of "apparent" weakening of the antilibidinal effects of CPA, requested @.attreatment be continued with leuprolide acetate. At the time, it could not be anticipated how long it might take for the patient to be brought to trial, or the precise nature of any sentence imposed (e.g., incarceration versus nonincarceration). Therefore, a flexible methodology (but one that required a minimum of 4 weeks for each phase; it being generally befieved that the clinical and endocrine effects of CPA take 2-3 weeks to be fully developed), which could be changed according to circumstances, was favored. As it tamed out, the sequence of treatment was as follows: I. 2. 3. 4. 5. 6. 7. 8. 9. 10.
placeboron-in---16 weeks; CPA IDomgperdayml6weeks; "no treatment"--16 weeks (e.g. no pills were given); CPA lDOnag pe~"dayml6 weeks; placebo--16 weeks; "no treatment"--16 weeks, CPA 1DOnag per daym36 weeks; CPA 200 mgper day--42 weeks; "no treatment"~10 weeks; leuprolide acetate 7.5 mg IM per month--24 weeks (maximal effect takes 2-4 weeks to develop and persists for as long as the drug is taken); 1I. "no treatment"--I0 weeks. Details for stages "1-8" have been published elsewhere (Cooper et al 1992) but are summarized in the present results (Figure 1) for comparison. 0006-3223/94/$07.00
2~
BIOLPSYCHIATRY t9~1;36:~271
CaseR¢lX)llS
Testosterone and Phallometric Data Teetosterone nmol/I
Phellometry: 9. ot full erec~loa
" lrm
t" 86
16
SO
10
20
S
10
o
Plecebo
32 wks
--
No Treatment CPA 100rag
62 was
CPA ~O0mg Leuprollde
88 wka
tutoetsrone
~
42 wk8
~
24 wk8
phidlometry
Self-Reporfs of Sexual Arousal Ratings from 1 to S
°'i
Placebo 32 wks
No Troalmenl CPA lOOmg 52 wks 68 wks Arousal: 5 variables
Figure 1. Measures of sexual arousal.
CPA 200m9 42 wks ~l
Erection
LeupraUde 24 wk$
Case Repens
Measures o f Sexual Arousal Frequencies of sexual thoughts, fantasies, self-masturbation and morning erections on awakening were recorded weekly by the patient in a specially provided sexual diary, on a 5-point l i k e n scale. The degree of pleasure associated with masturbation and sexual frustration was recorded weekly on a 4-point Liken scale. The 4-point m e a s u r e s were subsequently convened mathematically to 5-point equivalents for the purpose of graphing all measures on the same scale. The scores for the final week of each month were used in computing the results. Phallometric evaluations were made in a standard sexual laboratory during the final week of each phase. The patient was tested with balanced audio and video sets. each appmxirnately 2 rain in length. Stimuli included: audio and video depictions of a variety of consensual sexual activities between adult men and women, and between adult men and girls aged 4-to-9 years. Increases in penile circumference were expressed as a percentage of full erection.
E n d o c r i n e Assays Throughout the 54 months, blood was drawn monthly at approximately IO:00AM for endocrinological evaluation, Serum testosterone, lutenizing hormone, follicle-stimulating hormone and prolactin were measured in the same laboratory with standard radioimmune assay techniques.
Results The data from the ! 1 stages of treatment were collapsed into five categories: placebo (32 weeks), "no treatment" (52 weeks), CPA 100 mg per day (68 weeks), CPA 200 mg per day (42 weeks), and leuprolide acetate 7.5 mg per month (24 weeks). The scores for the morning erections were considered separately. The scores for the other five sexual variables were pooled and a single arousal mean was calculated. The main results are displayed in Figure 1, which shows the mean phallometric and testosterone values and the mean sexual arousal self-report scores (e.g., early morning erections on awakening and the five other arousal variables combined).
Discussion Circumstances made it possible to study our patient in a continuous fashion over 54 months. As can be seen (Figure 1), leuprolide almost totally suppressed both self-report and phallometric measures of sexual arousal, and reduced testosterone levels to near 0. Our patient reported no side effects, although it should be remembered that he only received the drug for 24 weeks. Prolonged use (longer than 6 months) calls for scrupulous physical and biochemical monitoring, especially calcium metabolism. It is known that extended use of LHRH agonists can cause osteoporosis (Casper 1991). That the antilibidinal effects were specific to leuprolide, rather than secondary to other factors (e.g., [a] declining sex drive with increasing age--the patient was almost 4 years older than when he started CPA (Cooper et al 1992); [b] his sex drive had already been significantly and permanently suppressed by the prior chronic
m o t PSYCmA~y
adminislralion ofCPA)(Davis 1974~ Lascbet a n d ~
almostcertain.Thus,the 24-week~
271
1969)is
phasewas
by and followed by a I O-week "no treatment" phase, when within approximately 3 weeks, in each case, om patient's sexual behaviors and testosterone i ~ to levels as high as anything pt'eviously noted throughout the entire ~ inv--. Leupmlide, like other synthetic LHRH agonists, is considerably more active biologically than the ~ hem',one (e.g., 60150 times more potent Casper 1991)~ Contirttmus admiK~suati~ of leupmlide induces an initial increase in LH and FSH section, followed by a paradoxical decrease due to g~mdotrophinreleasing hormone receptor downregulation in the anxerior pituitary. Ultimately LH and FSH cease to be released and temlx~ary inhibition of gonadal function ensues, with, in the male, a resultant dramatic decrease in serum testosterone and ~ydrolestosterone to casuation levels. Clinical experience with leuprolide as an antilibidinai agent for the treatment of sexual offenders is limited. To date, the drug has been used in a few cases, in whom CPA or MPA have failed to produce the desired clinical effects (Dickey I992, Rousseau et al 1990). The actions of leuprolide (e.g., downregulaton of gon~,~trophin releasing hormone receptors) are more circumscribed than CPA, which, in addition to ~ b i t i n g the synthesis of testosterone, also blocks androgen-sensitive receptors wherever they occur in the body. Yet, LHRH agonists have succeeded where antiandrogen has failed. Possibly the fact that leuprolide generally reduces testosterone levels below those achieved with recommended doses of CPA and MPA, may be the critical factor. The drug may be a superior alternative to currently available antiandrogens (MPA/CPA), but m~i'e h-ials are necessary.
References Cooper AJ (1986): Progestogens in the treatment of male sex off~aders: A review. Can J Psychiatry 31:73-79. Dickey R (1992): The management of a case of treatment-resistant paraphilia with a long-acting LHRH agonist. Can J Psychiatry 37:567-569. Rousseau L, Couture M, Dupout A, Labrie F, Couture N (1990): Effect of combined androgen blockade with an LHRH agnnist and flutamide in one severe case of male exhibitionism. Can J Psychiatry 35:338-34t. Cooper AJ (1987): Sadistic homosexual pedophilia treatment with cyproterone acetate. Can J Psychiatry 32:738-740. Rosenfield A, Maine D, Rochat R, Shelton J, Hatcher R (1983): The Food and Drug Administration and medroxyprogesterone acetate. JAMA 249:(2 i):2922-2928. Cooper AJ, Cernovsky Z, Magnus RV (I 992): The Long-term use of cyproterone acetate in pedophilia: A case study. J Sex & Marital Therapy 18(4):292-302. Casper R (i 991 ): Clinical Uses of Gonadotrophin-releasing Hormone Analogues. Can MedAssoc J 144:(2): 153-158. Davis TS (1974): Cyproterone acetate for male hyposexuality. J Int Med Res 159-153. Laschet V, Laschet L (1969): Three years' clinical research with cyproterone acetate in the inhibiting of male sexuality. Acta Endocrinolo 138(suppl) 232.