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Plasma testosterone in narcotic addiction
Plasma Testosterone in Narcotic Addiction
PAUL CUSHMAN,
Jr., M.D.
New York, New’York
From the Department of Medicine, St. Luke’s Hospital Center, and Columbia University College of Physicians and Surgeons. This study was supported by Grant MH 18408 from the National Institutes of Mental Health. Requests for reprints should be addressed to Dr. Paul Cushman, Jr., St. Luke’s Hospital, 113 Street and Amsterdam Avenue, New York, New York 10025. Manuscript accepted April 8, 1973.
452
October 1973
Mean plasma testosterone levels in male heroin addicts, methadone-maintained, former methadone-maintained and abstinent addicts did not differ significantly from that of normal controls. A prospective study before and during 1 year of methadone maintenance treatment showed no change in the mean plasma testosterone levels during treatment: no correlation was observed between plasma testosterone levels and symptoms of sexual disturbances. Some untreated heroin addicts and some methadone-maintained patients had plasma testosterone values below the lower limits of normal. In the methadone-treated group there was no direct methadone dose-testosterone level relationship, although patients receiving 40 mg of methadone or less had significantly higher mean testosterone levels than those receiving more than 40 mg of methadone daily. There was no relationship between serum glutamic oxaloacetic transaminase (SGOT), presence or absence of illicit drug use, or plasma luteinizing hormone level and plasma testosterone. A significant relationship between low testosterone levels and recognized alcoholism was evident. The effect of narcotic addiction on human hormonal and sexual physiology is incompletely understood. There is some clinical evidence suggesting an inhibition of some parameters of sexual function in addicts [1,2], most notably impaired libido, impotency and delayed ejaculation times. Although usually considered to be psychologic in origin, possibly these sexual disturbances may relate directly to narcotic use, since they are reported to be most prevalent when the patients are “high” and to abate rapidly during enforced abstinence [3]. The plasma levels of luteinizing hormone (LH) were normal in both methadone-maintained and active heroin addicts, regardless of the presence or absence of sexual disturbances, implying that their disturbances may not be attributable to a pituitary failure of LH. However, in addiction there is little information about testosterone [4], a widely recognized influence on sexual behavior [5]. Because of the widespread use of methadone as maintenance treatment in chronic narcotic addiction, it is important to ascertain what effects, if any, methadone maintenance may have on testosterone. PATIENTS AND METHODS Prospective Study.
Since the testosterone levels in addiction may be influenced by a number of variables other than heroin or methadone, it was elected to study unselected male patients serially, initially while they were addicted to heroin and subsequently throughout
The American Journal of Medicine
Volume 55
PLASMA
their first year of methadone treatment at St. Luke’s Hospital methadone clinic [6]. Plasma testosterone levels were determined in 19 consecutive men, 34 f 7 years of age, 36 per cent black, every 3 months for 1 year. Simultaneously, histories of current drug abuse, alcohol use and sexual functions were obtained. Physical examinations were also performed, emphasizing liver disease and changes in secondary sex characteristic or testicular consistency and size. Urine samples were obtained weekly and analyzed for morphine, quinine, methadone, barbiturate and amphetamine content by thin layer chromatography [7]. Three patients failed to complete the year’s study: one was jailed after 3 months of study, and 2 others absconded after 9 months of treatment and were lost to follow up. When admitted into the study morphine was found in the urine of all 19 patients, quinine was found in 17, methadone in 2 and barbiturates in only 1. Cross Sectional Study. Five populations of males were studied in order to examine all phases of addiction: normal controls, heroin addicts, methadonemaintained addicts, ex-addicts in an abstinence treatment program and methadone-maintained addicts now detoxified. A detailed medical history and physical examination was obtained on all patients. No evidence of gynecomastia or reduction in testicular size was found. (1) The normal controls consisted of 16 hospital personnel, 31 f 8 years of age (range 25 to 43 years), 25 per cent black, who denied drug use, alcohol, alcoholism and homosexuality, and appeared to be in good health. (2) The 23 male heroin addicts were 33 f 7 years old (range 22 to 37 years), 32 per cent black, addicted to heroin for 11 f 6 years, and applicants for methadone-maintenance treatment. Aside from their addiction, they appeared to be in good health. They denied recent use of drugs other than narcotics. which was substantiated by the results of the urine examinations on their entrance into the study; morphine was identified in all, quinine in 20, methadone in 3 and barbiturates In 1. (3) The 12 abstinent addicts 29 f 9 years old (range 26 to 47 years), 25 per cent black, had been addicted to heroin for 11 f 3 years before their entry into the Exodus House, a residential therapeutic community. They were considered to be drug free on the basis of their behavior and the fact that their weekly urine examination had been negative for at least 1 year. (4) The 54 methadone-maintained patients were 35 f 7 years old (range 22 to 52 years), 27 per cent black and had used heroin for 13 f 7 years before their entry into the methadone treatment program. They had been maintained on daily doses of 91 f 25 mg (range 10 to 130 mg) for 22 f 8 months (range 2 to 62 months). All but four appeared to be taking methadone only on the basis of their history and the results of weekly urine examinations during the months of the study. These urines showed methadone in all, quinine in three, mopphine in one and barbiturates in one. (5) The 15 former methadone-maintained patients, 35 f 8 years old (range 28 to 52 years), addicted to heroin for 11 f 6 years before methadone maintenance which had been
TESTOSTERONE
IN NARCOTIC
ADDICTION
CUSIIMAN
carried out for 30 f 16 months before complete de-toxification occurred 9 f 7 months (range 2 to 28 months) previous to the study. Their current drug-free status was substantiated by failure to detect dangerous drugs in their spot urines obtained at the time of their interview. Significant alcoholism was diagnosed if the patient admitted to daily consumption of and dependence on at least 8 oz of whiskey or equivalent. Since ejaculation times were reported to be between 3 and 12 minutes in the controls, delayed ejaculation was diagnosed if the patient reported that it took more than 15 minutes to accomplish orgasm in at least 50 per cent of attempts at sexual intercourse. Potency was defined as the capability of maintaining an erection until orgasm or 15 minutes; potency difficulties included mainly erectional insufficiency, but occasionally premature ejaculation was reported. Libido was defined operationally in each physician-patient interview as the degree to which the patient’s sexual desire was aroused by the appropriate stimuli. Impaired libido was considered present if the doctor and patient agreed that reduced sexual desires were present. after having taken into consideration the patient’s age, marital status, history of sexual activities during detoxification, and prior to addiction, sexual opportunities. and the like. Blood was taken for testosterone determlnatlons between 11 AM and 3 PM. The plasma was immediately separated and its testosterone content deterrnlned by competitive protein binding [8]. LH was measured by radioimmunoassay [9]. Liver functions were measured utilizing the Autoanalyzer@. Urines, obtained from all patients at the time of the interview, were analyzed for qualitative presence of dangerous drugs 17). RESULTS
The results of the testosterStudy. one determinations in the prospective study are listed in Table I. No change in the mean testosterone levels was observed during methadone maintenance treatment. Normal LH levels were observed before and during methadone maintenance treatment. Comparison of mean testosterone levels in those patients reporting sexual disturbances, i.e., decreased libido, potency or delayed ejaculation time, with those patients claiming these sexual functions to be normal showed no significant relationship either before or during methadone maintenance treatment. There were significant differences in the incidence of patients claiming normal ejaculation times (chi square = 31, p
was diagnosed group, whose
October 1973
in three of the mean testosterone
The American Journal of Medicine
prospective study levels were 240
Volume 55
453
PLASMA
TABLE
TESTOSTERONE
I
IN NARCOTIC
Plasma Testosterone
ADDICTION-CUSHMAN
Levels Prospectively
Before and During Methadone
Treatment
Months of Methadone Treatment 0 All patients Patients with normal libido Impaired libido Normal potency Impaired potency Normal ejaculation time Delayed ejaculation time Impaired libido potency and delayed ejaculation time * ng/dl
f
SD. Figures
in parentheses
488 491 469 452 479 319 489 510
f -f zt =!I + zt z!z f
3
277(19)* 272(7) 292(12) 251(9) 298(10) 163(4) 288(15) 323(7)
represent
494 429 478 408 532 508 441 505
the number
I 0
454
October 1973
observations
451 527 547 527 547 527 547 547
f i zt f +z xt f f
283(17) 224(11) 351(6) 224(U) 351(6) 224(11) 351(6) 351(6)
in each
I
I
I
6
12
0F METHADONE
TREATMENT
before and during methadone
The American Journal of Medicine
f f f It zk + zk f
335(17) 344(14) 41(3) 344(14) 41(3) 337(15) 49(2) 49(2)
urea nitrogen levels to be normal in all groups. The single exception was the total protelns which were slightly but significantly high in all groups of patients (p <0.05 for all groups compared to the normal controls). There were no significant differences in the mean testosterone level in all the other pairings with the exception of the methadone-maintained patients in whom it was significantly lower than in the patients formerly maintained on methadone. Therefore, the question was raised whether there was a dose related relationship between methadone and testosterone. In Figure 2 are plotted 105 observations of plasma testosterone levels in 54 patients grouped according to dose of methadone being administered. Although the values scattered widely, no dose relationship was established (regression coefficient r:0.03). When these data are
3
Sexual tunctions
530 570 356 570 356 554 368 369
category.
TIME
MONTHS
Figure 1.
249(17) 220(7) 258(10) 183(8) 284(9) 269(8) 194(9) 237(6)
of individual
f 140 mg, or less than half of the mean of the entire prospective study group on admission. During the treatment year four patients were diagnosed as alcoholics, although two patients who were alcoholics on admission had markedly reduced their alcohol intake during treatment. Cross Sectional Study. The results of the testosterone determinations in the five groups studied are presented in Table II. There were no significant differences in mean testosterone levels of the controls in any of the four patient groups studied. Similarly, the mean LH levels were normal in all four patient groups. There were the expected abnormalities in the SGOT and alkaline phosphatase values in the addicted groups including those considered to be drug-free [lo-131. The remainder of the Autoanalyzer measurements showed the mean bilirubin, calcium, cholesterol and blood
EJACULATION
f zt zt zt z!z zt It i
12
6
Volume 55
maintenance.
PLASMA
TABLE
II
Cross Sectional
Study of Testosterone
in Treated
TESTOSTERONE
and Untreated
Testosterone Patient Category
Number
Normal Untreated heroin addicts Abstinent addicts in therapeutic community Methadone-maintained addicts Abstinent former methadonemaintained addicts * p
(ml:ml)
(rig/W
16 23 12
589 + 246 523 f 279 737 t 301
9.4z 10.0 i 9.1+
54 15
577 & 284 781 f 300
11.5 * 5.0 13.5 = 5.0
with the mean of the normal with the mean of the normal
3.1 3.2 3.3
IN NARCOTIC
Male Narcotic
ADDICTION-
CUSHMAN
Addicts and Normal
Controls
SGOT (mlU/ml)
Albumm (g/W
Alkaline Phosphatase (mlU/ml)
26 k 6 61 zt 50* 68 t 30*
4.6 -IL 0.5 4.5 -i 0.4 4.9 -4: 0.4
61 ; 4 84 i- 39-l 64 -* 21
65 i 66 i
4.5 3: 0.5 4.8 + 0.4
76 t- 35’ 91_! 24*
40* 57*
controls. controls.
plotted as the mean testosterone level at 0, 10 to 40, 50 to 80 and 90 to 130 mg of methadone/day, it appears that the significant change in the mean testosterone level occurred in those patients whose methadone dose was above 40 mg/day, but there was no direct dose related effect on testosterone. There was no correlation between duration of methadone maintenance and plasma testosterone in the patients, most of whom had been stabilized on methadone for many months prior to study. The role of liver disease in the plasma testosterone levels was examined by classifying the methadone-treated patients into four groups based on their SGOT values. Those 30 patients whose
SGOT was between 0 and 40 mlU/ml had a mean testosterone level of 497 f 201 ng/lOO ml. Those 36 whose SGOT was between 40 and 80‘mlU had a mean testosterone level of 565 f 210 ng/lOO ml. The 16 with SGOT between 80 and 150 mlU/ml had a mean testosterone level of 497 f 280 and the 7 whose SGOT exceeded 150 mlU/ml had a mean testosterone level of 360 f 310 ng/lOO ml. Although the patients with the higher SGOT levels tended to have lower testosterone levels, the differences were not significant (p <0.20), and no correlation was found (r:0.06). The effect of alcoholism was examined in the nine methadone-maintained patients whose histories indicated a daily alcohol consumption of at
. 0
NORMAL
. 4
0
l
. .
!
~______
.
. .
l
. :
_ _---_1_-___
LOWER LIMIT OF NORMAL
RANGE .
,+t
P
0
40
20 DAILY
60
80
s
100
DOSE OF METHADONE
120
140
(MG/DAY)
values (ng/lOO ml) in methadone-mainFigure 2. Plasma testosterone tained narcotic addicts plotted against dose of methadone (closed circles). Open circles are the normal controls. The crosses are methadonemaintained patients after detoxification. The closed circles with superimposed crosses are values of alcoholic methadone-maintained patients. October 1973
The American Journal of Medicine
Volume 55
455
PLASMA
TESTOSTERONE
IN NARCOTIC
ADDICTION-CUSHMAN
least 8 oz of whiskey. Their mean testosterone level was 287 f 230 ng/lOO ml (11 determinations) which was significantly lower than that in the methadone-maintained group as a whole (p <0.05) and in the controls (p
456
October 1973
The American Journal of Medicine
and time of day was ruled out by experimental design. Disordered thyroid function was not evident clinically in the methadone-maintained patients, which was confirmed by the finding of serum thyroxine levels of 4.7 f 3 by column chromatography 1251 in 24 patients. Severe stress, a negative influence on plasma testosterone [21], was absent. LH was not an influence since it was normal in all groups of patients. It is possible that some patients had unrecognized hypogonadism (Klinefilters’ syndrome) despite the absence of gynecomastia and testicular changes on physical examination. No patients were known homosexuals. No measurement was made of the binding capacities of testosterone-binding globulin. Since the frequency of low testosterone levels was high in heroin addicts and methadone-maintained patients, a search for some clinical characteristics of the low testosterone subgroup was made. In view of their prolonged and close contact with the clinic, particular attention was paid to the methadone-treated patients. There was no correlation between testosterone levels and known drug abuse; both patients in the methadone-maintained group who had morphine detected in their urine during the month of study had normal testosterone levels, and no patients studied had amphetamines, cocaine or barbiturates identified in their urine during the period of study. There was no effect of doses above 40 mg/day and no relationship between the duration of methadone treatment and the level of testosterone measured. Neither did the magnitude of liver disease as reflected by the SGOT level correlate with the testosterone level. The alcoholic methadone-maintained patients did have significantly lower testosterone values than either the untreated heroin addicts or the methadone-maintained patients. Besides lower testosterone levels, the alcoholic patients also tended to have greater abnormalities in liver functions than the entire series of methadone-maintained patients, since their mean SGOT was 165 f 51 mg (p
Volume 55
PLASMA TESTOSTERONE IN NARCOTIC ADDICTION ~-CUSHMAN
became aware of a similar study of testosterone in narcotic addicts. Using a radioimmunoassay procedure, the Boston City Hospital investigators (JH Mendelsohn, personal communication) have found low testosterone levels in heroin addicts and high dose methadone-maintained addicts. The difference between these findings and the present study are unexplained. Since heroin addicts commonly report disturbances of their sexual functions, and since mechanisms underlying these disturbances are not well understood, it was of interest to compare testosterone levels in patients who reported sexual symptoms of dysfunctions with those who did not. There were no significant correlations between those reporting impaired libido, potency and delayed ejaculation time, and low testosterone values. The mean testosterone of those reporting impairment of these parameters of sexual functions did not differ from the means of those claiming these sexual functions to be normal. There may be some factors in heroin addiction which are associated with low plasma testosterone levels. Alcohol abuse appeared to be one fac-
tor in the methadone-maintained patients. It is possible that narcotics themselves may have a direct effect. A direct methadone effect appears unlikely in view of the large number of methadone-maintained patients with normal plasma testosterone values. Although a linear methadone dose-testosterone relationship was not established, it appeared that patients receiving doses of 0 to 40 mg/day had higher plasma testosterone levels than patients receiving larger doses. Perhaps, there was a negative influence, as yet undefined, on plasma testosterone, which may have been operative in some methadone-maintained patients and may have abated as the patients underwent detoxification. ACKNOWLEDGMENT The assistance of the director and staff of the Exodus House and the Harlem Hospital Methadone Clinic No. 4 was invaluable in permitting their patients to be studied. The staff of St. Luke’s Hospital methadone clinic was most helpful. The testosterone and LH levels were determined by the Bioscience Laboratories, Van Nuys, California.
REFERENCES
5.
6.
7.
a.
9.
10.
11.
Wieland WF, Yunger M: Proceedings Third National Conference on Methadone Treatment, PHS Publication No. 2172, p 50, 1971. Willis L: Drug dependence: some demographic and psychiatric aspects in UK and US subjects. Brit J Addict 64: 135, 1969. Cushman P Jr: Sexual behavior in heroin addiction and methadone maintenance. NY State J Med 72: 1261, 1972. Cushman P Jr: Some endocrinological aspects of heroin addiction and methadone maintenance therapy, Proceedings Third National Conference on Methadone PHS Publication No. 2172, p 144, Treatment, 1971. Cooper AJ: Androgen function in “psychogenic” and “constitutional types of impotence.” Brit Med J 3: 17, 1970. Cushman P Jr: Methadone maintenance in hard-core criminal addicts: economic effects. NY State J Med 71: 1768, 1971. Dole VP, Kim WK, Eglitis I: Detection of narcotic drugs, tranquilizers, amphetamines and barbiturates in the urine. JAMA 198: 349, 1960. Demetriou JA, Austin B: Quantitation of plasma testosterone by improved competitive protein binding technique. Clin Chem 16: 111, 1970. Schalch DS, Parlow AF, Boo RC, Reichlin S: Measurement of human luteinizing hormone in plasma by radio immunoassay. J Clin Invest 47: 665, 1966. Kreek MJ, Dodes L, Kane S, Knobler J, Martin R: Longterm methadone maintenance therapy: effects on liver function. Ann Intern Med 77: 596, 1972. Cherubin CE, Rosenthal WS, Stenger RE, Prince AM, Baden M, Strauss R, McGinn T: Chronic liver disease in asymptomatic narcotic addicts. Ann Intern Med 76: 391, 1972.
October
12.
13.
Cherubin CE, Kane S, Weinberger DR, Wolfe E, McGinn T: Persistence of transaminas abnormalities in former drug addicts. Ann Intern Med 76: 365. 1972. Stimmel BH, Vernace S, Tobias H: Hepatic dysfunction in heroin addicts. The role of alcohol. JAMA 222:
ail, 14.
15.
16.
17.
ia.
19. 20.
21
1973
1972.
Mayes D, Nugent CA: Determination of plasma testosterone by the use of competitive protein binding. J Clin Endocr 26: 1169, 1966. Rosenfield RL, Eberlein WR, Bongiovanni AM: Measurement of plasma testosterone by means of competitive protein binding. J Clin Endocrinol Metab 130: 854, 1969. August GP. Tkachuk M, Grumbach MM: Plasma-testosterone binding affinity and testosterone in umbilical cord plasma, late pregnancy, prepubertal children and adults. J Clin Endocrinol Metab 29: 691, 1969. Vermeulen A, Rubens R, Verdonck L: Testosterone secretion and metabolism in male senescence. J Clin Endocrinol Metab 34: 730, 1972. Vermeulen A, Verdonck. Van der Straeten L, Orie N: Capacity of the testosterone-binding-globulin in human plasma and influence of specific binding of testosterone on its metabolic clearance rate. J Clin Endocrinol Metab 29: 891, 1969. Coppage WS, Cooner AE: Testosterone in human plasma. New Eng J Med 273: 902, 1965. Olivo J, Southren AL, Gordon GG, Tochimoto S: Studies of protein binding of testosterone in plasma in disorders of thyroid function: effect of therapy. J Clin Endocrinol Metab 31: 539, 1970. Matsumoto K, Takeyasu K, Mizutani S, Hamanaka Y, and Uozumi T: Plasma testosterone levels following surgical stress in male patients. Acta Endocrinol (Kbn) 65: 11, 1970.
The American
Journal
of Medicine
Volume
55
457
PLASMA TESTOSTERONE IN NARCOTIC ADDICTION-CUSHMAN
22.
23. 24.
458
Aono T, Kurachi K, Mizutani S. Hamanaka Y, Uozumi T, Nakasima A, Koshiyama K. Matsumoto K: Influence of major surgical stress on plasma levels of testosterone, luteinizing hormone and follicle stimulating hormone in male patients. J Clin Endocrinol Metab 35: 535, 1972. Kolodny RC, Masters WH, Hendryx J, Toro G: New Eng J Med 285: 1170,197l. Resko JA, Eik-Nes KB: Diurnal variation of testosterone in peripheral plasma of male human subjects. J Clin Endocrinol Metab 26: 573, 1966.
October
1973
The American
Journal
of Medicine
Volume
25.
26.
27.
55
Pileggi VL. Lee ND, Golub OJ, Henry RJ: Determination of iodine compounds in serum. J Clin Endocrinol Metab 21: 1272, 1961. Admirand WI-t, Cronholm T, Sjovall J: Reduction of dehydroepiandrosterone sulfate in the liver during ethanol metabolism. Biochim Biophys Acta 202: 343, 1970. Mendelsohn JH. Mello N: Alcohol, androgens and aggression, Proceedings Association for Research in Mental Diseases: Aggression (Shavert F, ed), Baltimore, Williams & Wilkins, 1973. (In press.)
PAUL CUSHMAN,
Jr., M.D.
New York, New’York
From the Department of Medicine, St. Luke’s Hospital Center, and Columbia University College of Physicians and Surgeons. This study was supported by Grant MH 18408 from the National Institutes of Mental Health. Requests for reprints should be addressed to Dr. Paul Cushman, Jr., St. Luke’s Hospital, 113 Street and Amsterdam Avenue, New York, New York 10025. Manuscript accepted April 8, 1973.
452
October 1973
Mean plasma testosterone levels in male heroin addicts, methadone-maintained, former methadone-maintained and abstinent addicts did not differ significantly from that of normal controls. A prospective study before and during 1 year of methadone maintenance treatment showed no change in the mean plasma testosterone levels during treatment: no correlation was observed between plasma testosterone levels and symptoms of sexual disturbances. Some untreated heroin addicts and some methadone-maintained patients had plasma testosterone values below the lower limits of normal. In the methadone-treated group there was no direct methadone dose-testosterone level relationship, although patients receiving 40 mg of methadone or less had significantly higher mean testosterone levels than those receiving more than 40 mg of methadone daily. There was no relationship between serum glutamic oxaloacetic transaminase (SGOT), presence or absence of illicit drug use, or plasma luteinizing hormone level and plasma testosterone. A significant relationship between low testosterone levels and recognized alcoholism was evident. The effect of narcotic addiction on human hormonal and sexual physiology is incompletely understood. There is some clinical evidence suggesting an inhibition of some parameters of sexual function in addicts [1,2], most notably impaired libido, impotency and delayed ejaculation times. Although usually considered to be psychologic in origin, possibly these sexual disturbances may relate directly to narcotic use, since they are reported to be most prevalent when the patients are “high” and to abate rapidly during enforced abstinence [3]. The plasma levels of luteinizing hormone (LH) were normal in both methadone-maintained and active heroin addicts, regardless of the presence or absence of sexual disturbances, implying that their disturbances may not be attributable to a pituitary failure of LH. However, in addiction there is little information about testosterone [4], a widely recognized influence on sexual behavior [5]. Because of the widespread use of methadone as maintenance treatment in chronic narcotic addiction, it is important to ascertain what effects, if any, methadone maintenance may have on testosterone. PATIENTS AND METHODS Prospective Study.
Since the testosterone levels in addiction may be influenced by a number of variables other than heroin or methadone, it was elected to study unselected male patients serially, initially while they were addicted to heroin and subsequently throughout
The American Journal of Medicine
Volume 55
PLASMA
their first year of methadone treatment at St. Luke’s Hospital methadone clinic [6]. Plasma testosterone levels were determined in 19 consecutive men, 34 f 7 years of age, 36 per cent black, every 3 months for 1 year. Simultaneously, histories of current drug abuse, alcohol use and sexual functions were obtained. Physical examinations were also performed, emphasizing liver disease and changes in secondary sex characteristic or testicular consistency and size. Urine samples were obtained weekly and analyzed for morphine, quinine, methadone, barbiturate and amphetamine content by thin layer chromatography [7]. Three patients failed to complete the year’s study: one was jailed after 3 months of study, and 2 others absconded after 9 months of treatment and were lost to follow up. When admitted into the study morphine was found in the urine of all 19 patients, quinine was found in 17, methadone in 2 and barbiturates in only 1. Cross Sectional Study. Five populations of males were studied in order to examine all phases of addiction: normal controls, heroin addicts, methadonemaintained addicts, ex-addicts in an abstinence treatment program and methadone-maintained addicts now detoxified. A detailed medical history and physical examination was obtained on all patients. No evidence of gynecomastia or reduction in testicular size was found. (1) The normal controls consisted of 16 hospital personnel, 31 f 8 years of age (range 25 to 43 years), 25 per cent black, who denied drug use, alcohol, alcoholism and homosexuality, and appeared to be in good health. (2) The 23 male heroin addicts were 33 f 7 years old (range 22 to 37 years), 32 per cent black, addicted to heroin for 11 f 6 years, and applicants for methadone-maintenance treatment. Aside from their addiction, they appeared to be in good health. They denied recent use of drugs other than narcotics. which was substantiated by the results of the urine examinations on their entrance into the study; morphine was identified in all, quinine in 20, methadone in 3 and barbiturates In 1. (3) The 12 abstinent addicts 29 f 9 years old (range 26 to 47 years), 25 per cent black, had been addicted to heroin for 11 f 3 years before their entry into the Exodus House, a residential therapeutic community. They were considered to be drug free on the basis of their behavior and the fact that their weekly urine examination had been negative for at least 1 year. (4) The 54 methadone-maintained patients were 35 f 7 years old (range 22 to 52 years), 27 per cent black and had used heroin for 13 f 7 years before their entry into the methadone treatment program. They had been maintained on daily doses of 91 f 25 mg (range 10 to 130 mg) for 22 f 8 months (range 2 to 62 months). All but four appeared to be taking methadone only on the basis of their history and the results of weekly urine examinations during the months of the study. These urines showed methadone in all, quinine in three, mopphine in one and barbiturates in one. (5) The 15 former methadone-maintained patients, 35 f 8 years old (range 28 to 52 years), addicted to heroin for 11 f 6 years before methadone maintenance which had been
TESTOSTERONE
IN NARCOTIC
ADDICTION
CUSIIMAN
carried out for 30 f 16 months before complete de-toxification occurred 9 f 7 months (range 2 to 28 months) previous to the study. Their current drug-free status was substantiated by failure to detect dangerous drugs in their spot urines obtained at the time of their interview. Significant alcoholism was diagnosed if the patient admitted to daily consumption of and dependence on at least 8 oz of whiskey or equivalent. Since ejaculation times were reported to be between 3 and 12 minutes in the controls, delayed ejaculation was diagnosed if the patient reported that it took more than 15 minutes to accomplish orgasm in at least 50 per cent of attempts at sexual intercourse. Potency was defined as the capability of maintaining an erection until orgasm or 15 minutes; potency difficulties included mainly erectional insufficiency, but occasionally premature ejaculation was reported. Libido was defined operationally in each physician-patient interview as the degree to which the patient’s sexual desire was aroused by the appropriate stimuli. Impaired libido was considered present if the doctor and patient agreed that reduced sexual desires were present. after having taken into consideration the patient’s age, marital status, history of sexual activities during detoxification, and prior to addiction, sexual opportunities. and the like. Blood was taken for testosterone determlnatlons between 11 AM and 3 PM. The plasma was immediately separated and its testosterone content deterrnlned by competitive protein binding [8]. LH was measured by radioimmunoassay [9]. Liver functions were measured utilizing the Autoanalyzer@. Urines, obtained from all patients at the time of the interview, were analyzed for qualitative presence of dangerous drugs 17). RESULTS
The results of the testosterStudy. one determinations in the prospective study are listed in Table I. No change in the mean testosterone levels was observed during methadone maintenance treatment. Normal LH levels were observed before and during methadone maintenance treatment. Comparison of mean testosterone levels in those patients reporting sexual disturbances, i.e., decreased libido, potency or delayed ejaculation time, with those patients claiming these sexual functions to be normal showed no significant relationship either before or during methadone maintenance treatment. There were significant differences in the incidence of patients claiming normal ejaculation times (chi square = 31, p
was diagnosed group, whose
October 1973
in three of the mean testosterone
The American Journal of Medicine
prospective study levels were 240
Volume 55
453
PLASMA
TABLE
TESTOSTERONE
I
IN NARCOTIC
Plasma Testosterone
ADDICTION-CUSHMAN
Levels Prospectively
Before and During Methadone
Treatment
Months of Methadone Treatment 0 All patients Patients with normal libido Impaired libido Normal potency Impaired potency Normal ejaculation time Delayed ejaculation time Impaired libido potency and delayed ejaculation time * ng/dl
f
SD. Figures
in parentheses
488 491 469 452 479 319 489 510
f -f zt =!I + zt z!z f
3
277(19)* 272(7) 292(12) 251(9) 298(10) 163(4) 288(15) 323(7)
represent
494 429 478 408 532 508 441 505
the number
I 0
454
October 1973
observations
451 527 547 527 547 527 547 547
f i zt f +z xt f f
283(17) 224(11) 351(6) 224(U) 351(6) 224(11) 351(6) 351(6)
in each
I
I
I
6
12
0F METHADONE
TREATMENT
before and during methadone
The American Journal of Medicine
f f f It zk + zk f
335(17) 344(14) 41(3) 344(14) 41(3) 337(15) 49(2) 49(2)
urea nitrogen levels to be normal in all groups. The single exception was the total protelns which were slightly but significantly high in all groups of patients (p <0.05 for all groups compared to the normal controls). There were no significant differences in the mean testosterone level in all the other pairings with the exception of the methadone-maintained patients in whom it was significantly lower than in the patients formerly maintained on methadone. Therefore, the question was raised whether there was a dose related relationship between methadone and testosterone. In Figure 2 are plotted 105 observations of plasma testosterone levels in 54 patients grouped according to dose of methadone being administered. Although the values scattered widely, no dose relationship was established (regression coefficient r:0.03). When these data are
3
Sexual tunctions
530 570 356 570 356 554 368 369
category.
TIME
MONTHS
Figure 1.
249(17) 220(7) 258(10) 183(8) 284(9) 269(8) 194(9) 237(6)
of individual
f 140 mg, or less than half of the mean of the entire prospective study group on admission. During the treatment year four patients were diagnosed as alcoholics, although two patients who were alcoholics on admission had markedly reduced their alcohol intake during treatment. Cross Sectional Study. The results of the testosterone determinations in the five groups studied are presented in Table II. There were no significant differences in mean testosterone levels of the controls in any of the four patient groups studied. Similarly, the mean LH levels were normal in all four patient groups. There were the expected abnormalities in the SGOT and alkaline phosphatase values in the addicted groups including those considered to be drug-free [lo-131. The remainder of the Autoanalyzer measurements showed the mean bilirubin, calcium, cholesterol and blood
EJACULATION
f zt zt zt z!z zt It i
12
6
Volume 55
maintenance.
PLASMA
TABLE
II
Cross Sectional
Study of Testosterone
in Treated
TESTOSTERONE
and Untreated
Testosterone Patient Category
Number
Normal Untreated heroin addicts Abstinent addicts in therapeutic community Methadone-maintained addicts Abstinent former methadonemaintained addicts * p
(ml:ml)
(rig/W
16 23 12
589 + 246 523 f 279 737 t 301
9.4z 10.0 i 9.1+
54 15
577 & 284 781 f 300
11.5 * 5.0 13.5 = 5.0
with the mean of the normal with the mean of the normal
3.1 3.2 3.3
IN NARCOTIC
Male Narcotic
ADDICTION-
CUSHMAN
Addicts and Normal
Controls
SGOT (mlU/ml)
Albumm (g/W
Alkaline Phosphatase (mlU/ml)
26 k 6 61 zt 50* 68 t 30*
4.6 -IL 0.5 4.5 -i 0.4 4.9 -4: 0.4
61 ; 4 84 i- 39-l 64 -* 21
65 i 66 i
4.5 3: 0.5 4.8 + 0.4
76 t- 35’ 91_! 24*
40* 57*
controls. controls.
plotted as the mean testosterone level at 0, 10 to 40, 50 to 80 and 90 to 130 mg of methadone/day, it appears that the significant change in the mean testosterone level occurred in those patients whose methadone dose was above 40 mg/day, but there was no direct dose related effect on testosterone. There was no correlation between duration of methadone maintenance and plasma testosterone in the patients, most of whom had been stabilized on methadone for many months prior to study. The role of liver disease in the plasma testosterone levels was examined by classifying the methadone-treated patients into four groups based on their SGOT values. Those 30 patients whose
SGOT was between 0 and 40 mlU/ml had a mean testosterone level of 497 f 201 ng/lOO ml. Those 36 whose SGOT was between 40 and 80‘mlU had a mean testosterone level of 565 f 210 ng/lOO ml. The 16 with SGOT between 80 and 150 mlU/ml had a mean testosterone level of 497 f 280 and the 7 whose SGOT exceeded 150 mlU/ml had a mean testosterone level of 360 f 310 ng/lOO ml. Although the patients with the higher SGOT levels tended to have lower testosterone levels, the differences were not significant (p <0.20), and no correlation was found (r:0.06). The effect of alcoholism was examined in the nine methadone-maintained patients whose histories indicated a daily alcohol consumption of at
. 0
NORMAL
. 4
0
l
. .
!
~______
.
. .
l
. :
_ _---_1_-___
LOWER LIMIT OF NORMAL
RANGE .
,+t
P
0
40
20 DAILY
60
80
s
100
DOSE OF METHADONE
120
140
(MG/DAY)
values (ng/lOO ml) in methadone-mainFigure 2. Plasma testosterone tained narcotic addicts plotted against dose of methadone (closed circles). Open circles are the normal controls. The crosses are methadonemaintained patients after detoxification. The closed circles with superimposed crosses are values of alcoholic methadone-maintained patients. October 1973
The American Journal of Medicine
Volume 55
455
PLASMA
TESTOSTERONE
IN NARCOTIC
ADDICTION-CUSHMAN
least 8 oz of whiskey. Their mean testosterone level was 287 f 230 ng/lOO ml (11 determinations) which was significantly lower than that in the methadone-maintained group as a whole (p <0.05) and in the controls (p
456
October 1973
The American Journal of Medicine
and time of day was ruled out by experimental design. Disordered thyroid function was not evident clinically in the methadone-maintained patients, which was confirmed by the finding of serum thyroxine levels of 4.7 f 3 by column chromatography 1251 in 24 patients. Severe stress, a negative influence on plasma testosterone [21], was absent. LH was not an influence since it was normal in all groups of patients. It is possible that some patients had unrecognized hypogonadism (Klinefilters’ syndrome) despite the absence of gynecomastia and testicular changes on physical examination. No patients were known homosexuals. No measurement was made of the binding capacities of testosterone-binding globulin. Since the frequency of low testosterone levels was high in heroin addicts and methadone-maintained patients, a search for some clinical characteristics of the low testosterone subgroup was made. In view of their prolonged and close contact with the clinic, particular attention was paid to the methadone-treated patients. There was no correlation between testosterone levels and known drug abuse; both patients in the methadone-maintained group who had morphine detected in their urine during the month of study had normal testosterone levels, and no patients studied had amphetamines, cocaine or barbiturates identified in their urine during the period of study. There was no effect of doses above 40 mg/day and no relationship between the duration of methadone treatment and the level of testosterone measured. Neither did the magnitude of liver disease as reflected by the SGOT level correlate with the testosterone level. The alcoholic methadone-maintained patients did have significantly lower testosterone values than either the untreated heroin addicts or the methadone-maintained patients. Besides lower testosterone levels, the alcoholic patients also tended to have greater abnormalities in liver functions than the entire series of methadone-maintained patients, since their mean SGOT was 165 f 51 mg (p
Volume 55
PLASMA TESTOSTERONE IN NARCOTIC ADDICTION ~-CUSHMAN
became aware of a similar study of testosterone in narcotic addicts. Using a radioimmunoassay procedure, the Boston City Hospital investigators (JH Mendelsohn, personal communication) have found low testosterone levels in heroin addicts and high dose methadone-maintained addicts. The difference between these findings and the present study are unexplained. Since heroin addicts commonly report disturbances of their sexual functions, and since mechanisms underlying these disturbances are not well understood, it was of interest to compare testosterone levels in patients who reported sexual symptoms of dysfunctions with those who did not. There were no significant correlations between those reporting impaired libido, potency and delayed ejaculation time, and low testosterone values. The mean testosterone of those reporting impairment of these parameters of sexual functions did not differ from the means of those claiming these sexual functions to be normal. There may be some factors in heroin addiction which are associated with low plasma testosterone levels. Alcohol abuse appeared to be one fac-
tor in the methadone-maintained patients. It is possible that narcotics themselves may have a direct effect. A direct methadone effect appears unlikely in view of the large number of methadone-maintained patients with normal plasma testosterone values. Although a linear methadone dose-testosterone relationship was not established, it appeared that patients receiving doses of 0 to 40 mg/day had higher plasma testosterone levels than patients receiving larger doses. Perhaps, there was a negative influence, as yet undefined, on plasma testosterone, which may have been operative in some methadone-maintained patients and may have abated as the patients underwent detoxification. ACKNOWLEDGMENT The assistance of the director and staff of the Exodus House and the Harlem Hospital Methadone Clinic No. 4 was invaluable in permitting their patients to be studied. The staff of St. Luke’s Hospital methadone clinic was most helpful. The testosterone and LH levels were determined by the Bioscience Laboratories, Van Nuys, California.
REFERENCES
5.
6.
7.
a.
9.
10.
11.
Wieland WF, Yunger M: Proceedings Third National Conference on Methadone Treatment, PHS Publication No. 2172, p 50, 1971. Willis L: Drug dependence: some demographic and psychiatric aspects in UK and US subjects. Brit J Addict 64: 135, 1969. Cushman P Jr: Sexual behavior in heroin addiction and methadone maintenance. NY State J Med 72: 1261, 1972. Cushman P Jr: Some endocrinological aspects of heroin addiction and methadone maintenance therapy, Proceedings Third National Conference on Methadone PHS Publication No. 2172, p 144, Treatment, 1971. Cooper AJ: Androgen function in “psychogenic” and “constitutional types of impotence.” Brit Med J 3: 17, 1970. Cushman P Jr: Methadone maintenance in hard-core criminal addicts: economic effects. NY State J Med 71: 1768, 1971. Dole VP, Kim WK, Eglitis I: Detection of narcotic drugs, tranquilizers, amphetamines and barbiturates in the urine. JAMA 198: 349, 1960. Demetriou JA, Austin B: Quantitation of plasma testosterone by improved competitive protein binding technique. Clin Chem 16: 111, 1970. Schalch DS, Parlow AF, Boo RC, Reichlin S: Measurement of human luteinizing hormone in plasma by radio immunoassay. J Clin Invest 47: 665, 1966. Kreek MJ, Dodes L, Kane S, Knobler J, Martin R: Longterm methadone maintenance therapy: effects on liver function. Ann Intern Med 77: 596, 1972. Cherubin CE, Rosenthal WS, Stenger RE, Prince AM, Baden M, Strauss R, McGinn T: Chronic liver disease in asymptomatic narcotic addicts. Ann Intern Med 76: 391, 1972.
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12.
13.
Cherubin CE, Kane S, Weinberger DR, Wolfe E, McGinn T: Persistence of transaminas abnormalities in former drug addicts. Ann Intern Med 76: 365. 1972. Stimmel BH, Vernace S, Tobias H: Hepatic dysfunction in heroin addicts. The role of alcohol. JAMA 222:
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Mayes D, Nugent CA: Determination of plasma testosterone by the use of competitive protein binding. J Clin Endocr 26: 1169, 1966. Rosenfield RL, Eberlein WR, Bongiovanni AM: Measurement of plasma testosterone by means of competitive protein binding. J Clin Endocrinol Metab 130: 854, 1969. August GP. Tkachuk M, Grumbach MM: Plasma-testosterone binding affinity and testosterone in umbilical cord plasma, late pregnancy, prepubertal children and adults. J Clin Endocrinol Metab 29: 691, 1969. Vermeulen A, Rubens R, Verdonck L: Testosterone secretion and metabolism in male senescence. J Clin Endocrinol Metab 34: 730, 1972. Vermeulen A, Verdonck. Van der Straeten L, Orie N: Capacity of the testosterone-binding-globulin in human plasma and influence of specific binding of testosterone on its metabolic clearance rate. J Clin Endocrinol Metab 29: 891, 1969. Coppage WS, Cooner AE: Testosterone in human plasma. New Eng J Med 273: 902, 1965. Olivo J, Southren AL, Gordon GG, Tochimoto S: Studies of protein binding of testosterone in plasma in disorders of thyroid function: effect of therapy. J Clin Endocrinol Metab 31: 539, 1970. Matsumoto K, Takeyasu K, Mizutani S, Hamanaka Y, and Uozumi T: Plasma testosterone levels following surgical stress in male patients. Acta Endocrinol (Kbn) 65: 11, 1970.
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Journal
of Medicine
Volume
55
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PLASMA TESTOSTERONE IN NARCOTIC ADDICTION-CUSHMAN
22.
23. 24.
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Aono T, Kurachi K, Mizutani S. Hamanaka Y, Uozumi T, Nakasima A, Koshiyama K. Matsumoto K: Influence of major surgical stress on plasma levels of testosterone, luteinizing hormone and follicle stimulating hormone in male patients. J Clin Endocrinol Metab 35: 535, 1972. Kolodny RC, Masters WH, Hendryx J, Toro G: New Eng J Med 285: 1170,197l. Resko JA, Eik-Nes KB: Diurnal variation of testosterone in peripheral plasma of male human subjects. J Clin Endocrinol Metab 26: 573, 1966.
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Pileggi VL. Lee ND, Golub OJ, Henry RJ: Determination of iodine compounds in serum. J Clin Endocrinol Metab 21: 1272, 1961. Admirand WI-t, Cronholm T, Sjovall J: Reduction of dehydroepiandrosterone sulfate in the liver during ethanol metabolism. Biochim Biophys Acta 202: 343, 1970. Mendelsohn JH. Mello N: Alcohol, androgens and aggression, Proceedings Association for Research in Mental Diseases: Aggression (Shavert F, ed), Baltimore, Williams & Wilkins, 1973. (In press.)