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Endocrine studies in heroin addicts
Psychoneuroendocrinology. Vol. 4, pp. 145 to 153.
0306-4530]7910401-0145502.00/0
© Pergamon Press Ltd. 1979. Printed in Great Britain.
E N D O C R I N E STUDIES IN HEROIN ADDICTS M. ALI AFRASIABI, MICHAEL FLOMM,* HERBERT FRIEDLANDERand LUBOMIRJ. VALENTA University of California, Irvine Medical Center, Departments of Medicine and Psychiatry, Orange, California 92668, U.S.A. *Endocrine Sciences, Tarzana, California, U.S.A. (Received 11 September 1978; in revisedform 2 February 1979)
SUMMARY In 10 heroin addicts actively taking the drug, 5 males, 5 females, a number of endocrine abnormalities were identified. These included especially: (1) Increased thyroid function manifested by high total T4 (and occasionally T3) and T3 resin uptake, and by blunted TSH response to TRH. (2) Changes in sex hormones, LH and FSH, and LH/FSH responsivenessto GnRH compatible with either primary gonadal failure or disturbance of the hypothalamopituitary regulations of the reproductive functions. (3) Abnormal increase in growth hormone in response to TRH/GnRH. (4) Occasionally increased baseline prolactin; blunted response or slightly increased responsiveness of PRL to TRH/GnRH. (5) No apparent change in the adrenocortical function. The results are best explained by multiglandular abnormalities due possibly to multiple effects of heroin on the endocrine system and its regulations. INTRODUCTION A NUMBER of endocrine abnormalities has been recognized in heroin addicts. Regarding thyroid function, the observed abnormalities included an increase in total serum thyroxine (T4), tri-iodothyronine (T3) and thyroxine binding globulin (TBG) (Azizi, Vagenakis & Portnay, 1974; Webster, Coupal & Cushman, 1973). Normal TSH response to T R H was obtained in heroin addicts on the chronic methadone program (Shenkman, Massie & Mitsuma, 1972). Regarding gonadal function, the most consistent abnormality was impotence and a decrease in plasma testosterone (T) in males (Mendelson, Mendelson & Patch, 1975a; Azizi, Vagenakis, Longcope, Ingbar & Braverman, 1973), although no change in plasma testosterone was obtained in another study (Cushman, 1973). Decrease in plasma testosterone in males has been observed under controlled research ward conditions (Mendelson, Meyer, Ellinboe, Mirin & McDougle, 1975b). Heroin addiction also caused reduction of seminal vesicular and prostatic secretions, and sperm motility (Cicero, Bell, Wiest, Allison, Polakoski & Robins, 1975). In females, the amenorrhea-galactorrhea syndrome has been associated with the abuse of heroin (Pelosi, Saran, Caterini & Kaminetzki, 1974). Controversial findings have been reported regarding the pituitary-adrenal axis. While subnormal production rates of cortisol (and estradiol) were observed in 2 male heroin addicts in one study with a several-fold increase upon withdrawal of the drug (Hellman, Fukushima, Roffwarg & Fishman, 1975), no change in plasma cortisol was observed in another study (Mendelson et al., 1975b). In still another report, the only abnormality was a disturbance of the diurnal rhythm of cortisol (Cushman, Bordier & Hilton, 1970). 145
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T h u s far, it has n o t b e e n r e s o l v e d w h e t h e r the e n d o c r i n e a b n o r m a l i t i e s are d u e to f u n c t i o n al i m p a i r m e n t o f the h y p o t h a l a m o - p i t u i t a r y axis o r o f the p e r i p h e r a l e n d o c r i n e organs. D a t a o n r e s p o n s i v e n e s s to g o n a d o t r o p i n releasing h o r m o n e ( G n R H ) are n o t a v a i l a b l e a n d t h e T R H test was p e r f o r m e d o n l y o n p a t i e n t s in t h e c h r o n i c m e t h a d o n e p r o g r a m . T h e p r e s e n t w o r k was d e s i g n e d to study the r e g u l a t o r y e n d o c r i n e m e c h a n i s m s in m o r e detail. MATERIALS A N D METHODS Subjects Ten individuals were studied, 5 males, 5 females, ages 18-43, average: 29 yr. Twelve normal, healthy individuals, age and sex matched, were used as controls. Nine of the patients were admitted to the psychiatric ward less than 24 hr prior to the testing. The reason for admission was heroin overdose. However, none of the patients was critically ill and none had severe disturbance of consciousness. All patients received nalorphin immediately after admission. The tenth patient examined was admitted for early signs of heroin withdrawal. The patients admitted drug abuse for 3-15 yr, average 5-5 yr, except for one male who had not been taking heroin for more than 6 months. They denied abuse of any drug other than heroin during at least a month prior to admission. Past medical history included hysterectomy for fibroid uterine tumors in one girl while another suffered from amenorrhea and noticed galactorrhea 9 months prior to admission. The remaining 3 females suffered from oligomenorrhea. Three out of five males complained of loss of libido and decreased potency. In one male, a diagnosis of chronic active hepatitis was established, with acute arthropathy. Two patients had hepatitis in the past but were asymptomatic on this admission. At the time of laboratory testing, all patients were alert and afebrile with stable vital signs and in no acute distress. They were not taking any medication. Their last dose of heroin was taken no more than 24 hr prior to examination, and they received narcane 6-12 hr prior to the test. All were fasting overnight and the test was performed in the morning hours (between 8 and 10 a.m.). Physical examination revealed obesity in one girl. The patient with chronic active hepatitis had two large joints swollen and tender, and enlarged tender liver. In this individual, the liver function tests were abnormal. They were normal in all remaining patients. Two males had decreased size of the testicles. There were no other clinical signs of endocrine disease in any of the individuals. One of the patients was hypertensive with blood pressure of 160/100 mm Hg, and 3 had tachycardia with the pulse rate between 100 and ll0/min.
Pituitary reserve test The response of pituitary hormones to simultaneous i.v. administration of TRH and G n R H was studied. TRH (Abbott) 500 i~g and GnRH (Ayerst) 100 ~tg mixed together were injected i.v. over 10 sec. Serum hormone levels were obtained at time 0, 20, 30 and 60 min. The range of responses was compared with those obtained in 12 sex and age matched healthy individuals. In these controls, normal responsiveness of the pituitary functions was the same as in our large series of more than 50 healthy euthyroid and eugonadal individuals of both sexes, ages 20--55. At the time of study, all our female patients were in the follicular phase of the menstrual cycle. This was established by the history and by obtaining serum progesterone levels which were low in all of them. Hormone assays All hormones were measured by specific radioimrnunoassays. The double antibody technique was used for separation of free and bound hormone in all assays except for serum T4 where ammonium sulphate precipitation was used. WHO standards were used for calibration of all peptide and protein hormone assays. Normal values have been established in a series of more than 50 healthy individuals.
RESULTS
Thyroid function tests N o r m a l r a n g e f o r s e r u m T4 was 4.5-12.5 ~g/100 m l a n d for T3 6 0 - 1 7 0 ng/100 ml. In 5 o u t o f 10 patients, t h e s e r u m T4 v a l u e s w e r e clearly e l e v a t e d , b e t w e e n 12.8 a n d 18.5 ~g/100 ml, a n d t h e y w e r e in the u p p e r n o r m a l r a n g e in the r e m a i n i n g patients. A v e r a g e s e r u m t o t a l T4 was 12.1 IJg/100 ml. T h e a v e r a g e s e r u m T3 in the p a t i e n t s was 146.5 ng/100 ml, w i t h t h e
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FIG. 1. TSH response to TRH in 10 heroin addicts. TRH, 500 lag, and GnRH, 100 lag, were administered i.v. over 10 sec at time 0. Serum TSH was measured before TRH administration and 20, 30 and 60 min later. The shaded area represents the range of TSH response to TRH in 12 healthy age and sex matched individuals. The TSH response in most of the patients of the present series is blunted. Total serum T4 in patients No. 1, 3, 6, 9 and 10 was above normal range. range between 110 and 160 ng/100 ml, which is normal. However, in one patient who had the highest serum T4 concentration of 18.5 lag/100 ml, the T3 was also elevated, to 225 ng/100 ml. The T3 resin uptake (T3RU) (normal 35-45 %) varied between 31 and 45, average 37.6 %, T R H test The results of the T R H test are illustrated in Fig. 1. The baseline TSH concentration was low to unmeasurable in most of the patients, and the TSH response to T R H was blunted. Suppressed TSH responsiveness to T R H was observed especially in the individual with both serum T4 and T3 elevated (No. 6) and in others with elevated serum T4 concentration (Nos. 3 and 9). Only 4/10 individuals showed TSH response which could be classified as normal and even these were in the low normal range. Sex hormone studies In males, serum testosterone varied between 265 and 738 ng/100 ml, average 563 ng/ml (normal 400-1000). In only one case the result was below normal, 265 ng/100 ml. In females, plasma estradiol (E2) concentration was decreased in a single case. In the remaining females, plasma estradiol was normal for the follicular phase. In all females, plasma progesterone was within normal range for the follicular phase.
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FIG. 2. LH response to G n R H in 10 heroin addicts. GnRH, I00 lag, and TRH, 500 pg, were administered over 10 sec i.v. at time 0. LH was measured prior to G n R H and 20, 30 and 60 min later. Shaded area represents LH response to G n R H in 12 age and sex matched healthy individuals. Two kinds of response in the patients are observed, a blunted or an exaggerated LH response. In patients with clinical hypogonadism, these responses would be compatible with secondary or primary gonadal failure respectively. However, only patients No. 5 and 8 demonstrated hypogonadism with a decrease of serum sex steroids. In these two cases, exaggerated LH response confirms the presence of primary gonadal failure.
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FIG. 3. FSH response to G n R H in 10 heroin addicts. Conditions same as described in Fig. 2. Blunted FSH response with delayed peak is observed in most of the cases but may be a variant of normal response. Case No. I with an exaggerated FSH response exhibited also exaggerated LH response (Fig. 2).
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GnRH test The response of LH and FSH to G n R H is apparent from Figs. 2 and 3. Exaggerated LH response as compatible with primary hypogonadism was observed in at least 4/10 patients (Nos. 1, 4, 5, 8 and possibly 10). In the remaining patients, the responsiveness was low normal or slightly suppressed. Patient No. 1 also demonstrated exaggerated response of FSH with delayed maximum, while FSH response in the remaining patients was normal. It should be remembered that patients No. 8 and 5, who demonstrated exaggerated LH response, showed low serum testosterone and estradiol respectively.
Serum prolactin Basal and T R H stimulated values of prolactin (PRL) are apparent from Fig. 4. In 2 males (Nos. 7 and 9), basal P R L was elevated and there was a blunted response to TRH. In 2 other males (Nos. 8 and 10) who complained of impotence and both of whom showed increased LH responsiveness to G n R H , the response of P R L to T R H was exaggerated. Exaggerated reaction of P R L to T R H was also obtained in the females Nos. 1 and 2, the latter suffering from the amenorrhea-galactorrhea syndrome, and the former showing grossly abnormal increase of LH and FSH following G n R H injection. /~\x 50
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FIG. 4. Prolactin (PRL) response to TRH in 10 heroin addicts. Conditions were the same as described in Fig. 1. Total shaded area represents PRL response to TRH in 7 healthy females of age comparable to the heroin addicts studied, in the early follicular phase of their menstrual cycle. The lower shaded area is for 5 healthy male controls. Two male heroin addicts (Nos. 7 and 9) showed basal hyperprolactinemia and blunted response to TRH. Females No. 1 (with exaggerated response of LH and FSH to GnRH, Figs. 2 and 3), and No. 2 (with amenorrhea-galactorrhea syndrome) demonstrate exaggerated PRL response according to our criteria, and so does the male No. I0, who complained of impotence.
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Serum growth hormone Baseline growth hormone (GH) was low to unmeasurable in all of our patients. Changes following T R H / G n R H administration are illustrated in Fig. 5. In 6/10 patients there was a significant increase in serum G H within 60 min after T R H / G n R H administration which was as high as 35 ng/ml. There was no appreciable change in serum glucose and immunoreactive insulin during that time period. 40
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FI~. 5. GH response to TRH/GnRH in 10 heroin addicts. TRH 500 i~gplus GnRH 100 I~gwere injected i.v. at time 0. Serum GH was measured before, and 20, 30 and 60 min after TRH/GnRH administration. In 6/10 patients, significant increase in GH occurred, mostly at time 60 rain. At the same time, there was no appreciable change in serum glucose or immunoreactive insulin.
Adrenocortical function Serum cortisol (a.m.) was, and remained within the normal range (10-20 I~g/100 ml) during the whole observation period. Plasma A C T H was normal on admission in all patients (between 10 and 80 pg/ml). In two, there was an increase in plasma A C T H within 20 min of T R H / G n R H administration, to 2000 and 5000 pg/ml respectively. This was classified as a stress reaction in susceptible individuals. DISCUSSION Our data obtained in the 10 heroin addicts can be summarized as follows: (1) There was an increase in total T, and occasionally T3 and normal T3 resin uptake. This differs slightly from previously reported data which were compatible with increased binding capacity of TBG, i.e. increased total T4 and decreased T3RU (Azizi et al., 1974, Webster et aL, 1973). Our T R H studies also differ from previously reported normal TSH responsiveness to T R H
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(Shenkman et al., 1972). The differences may be due to the fact that in the previous studies the heroin addicts were in the chronic methadone program, whereas our patients were taking the drug both chronically and acutely. Although low TSH response to TRH may represent a variation of normal reaction (Sawin & Hershman, 1976), in our sex and age matched controls peak TSH values lower than 8 FU/ml, 20 or 30 min after TRH administration, were not reported. In addition, all our female heroin addicts were examined during the follicular phase of their menstrual cycle when TSH responsiveness to TRH was shown to be highest (Boyd & Sanchez-Franco, 1977). Thus, our conclusion is that, the data should be interpreted as a suppressed TSH response. Together with the other thyroid function tests, this is compatible with the presence of borderline hyperthyroidism. It can be argued that factors other than heroin caused abnormal thyroid function tests, e.g. one patient with high T4 suffered from chronic active hepatitis. Hepatitis is known to increase total T4 by increasing TBG. However, our patient demonstrated elevated T4 and blunted response of TSH to TRH in the presence of normal TBG binding capacity, which is compatible with hyperthyroidism. It may also be argued that our patients were acutely ill and this influenced their thyroid function studies. However, at the time of the hormonal studies the patients were stable, in no distress, and acute illness does not usually produce thyroid function tests characteristic of hyperthyroidism. Therefore, we conclude that acute abuse of heroin itself may result in borderline hyperthyroidism. (2) A number of abnormalities of gonadal function existed in our patients. They were manifested by decreased potency in males and, in females, by menstrual abnormalities or occasionally, galactorrhea. Male hypogonadism with decreased serum testosterone is one of the most consistent hormonal abnormalities observed in heroin addicts (Mendelson et al., 1975a). The decrease in plasma testosterone was shown to be reversible upon withdrawal of the drug (Mendelson & Mello, 1975). In the study of Cushman (1973) plasma testosterone was normal. 111 our study, low plasma testosterone concentration was observed in one patient only, in the remaining 4 males it was normal. However, 3/5 males complained of some degree of impotance. Although plasma testosterone was not necessarily below normal range, a relative decrease in individual patients may be present and may become symptomatic. Such a relative decrease in plasma testosterone was demonstrated in addicts taking heroin under controlled research ward conditions (Mendelson et al., 1975b). Similarly, only one of our female heroin addicts demonstrated low plasma estradiol, although 3/5 females complained of oligomenorrhea and one suffered from the amenorrhea-galactorrhea syndrome. The latter syndrome was previously described to be associated with heroin addiction (Pelosi et al., 1974), but no detailed study of the hormonal abnormalities has been reported In our patient, basal PRL concentration was normal. However, prolactin responsiveness to TRH was exaggerated and the response of gonadotropins to GnRH was blunted. Amenorrhea and hypogonadism in hyperprolactinemic states are most likely to be due to a decrease in basal or stimulated gonadotropins, or both (Child, Nader, Mashiter, Kjeld, Banks & Russell-Fraser, 1975). Morphine has been shown to increase prolactin release (Tolls, Hickey & Guyda, 1975) and hyperprolactinemia may in turn cause hypogonadism. However, in most of our patients, basal serum prolactin concentration was normal. The nature of hypogonadism in heroin addicts has not been elucidated. Detailed studies of gonadotropin concentration are missing. In a study of Martin, Jasinski, Haertzen, Kay,
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Jones, Mansky & Carpenter (1973), serum gonadotropins were decreased. No data are available on LH and FSH responsiveness to GnRH in heroin addicts. In the present study, basal FSH was normal in all and LH was within normal range in 7 patients and elevated in 3. According to the LH responsiveness to the gonadotropin releasing hormone, the patients could be classified into a group with exaggerated response and those with normal or blunted response (Fig. 2). Noticeably, the patients with clearly abnormal plasma testosterone or estradiol and clinical hypogonadism had an exaggerated response of LH to GnRH. These data are compatible with primary hypogonadism in at least some of the heroin addicts. In others, the blunted response of LH and FSH suggests a decreased pituitary reserve for gonadotropins. Thus both primary and secondary gonadal failure may be responsible in different individuals for clinical hypogonadism. (3) As mentioned above, serum prolactin was normal in most of our patients, the basal value being elevated only in 2 males. During TRH stimulation, PRL was clearly abnormal only in one male patient who showed a blunted response. According to our criteria, the response was slightly exaggerated in a number of other patients; the significance of this finding is not clear. (4) In at least 6/10 of our patients, TRH/GnRH administration provoked a significant release of growth hormone. In our experience as well as that of others, this does not occur in normal healthy individuals. However, an abnormal increase of GH in response to TRH or GnRH is not specific for heroin abuse, and has been observed in a number of conditions such as acromegaly, chronic renal failure, severe depression or anorexia nervosa (Irie & Tsushima, 1972; Gonzalez-Barcena, Kastin, Schalch, Torres-Zamora, Perez-Tasten, Kato & Schally, 1973; Takahashi, Kondo & Yoshimura, 1975; Maeda, Kato, Yamaguchi, Chihara, Ohgo, Iwasaki & Yoshimoto, 1976). (5) In the present study, no abnormality was identified in the ACTH--cortisol axis, and grossly elevated plasma ACTH during the pituitary reserve test in two patients was due probably to a stress reaction. In previous studies, plasma cortisol was found to be mostly normal (Cushman et al., 1970; Mendelson et aL, 1975b), and the only abnormality consisted of the absence of the diurnal rhythm of cortisol (Cushman et al., 1970). However, serial sampling in another study demonstrated low normal or subnormal values of serum cortisol during narcotic maintenance, and a steep increase upon withdrawal (Hellman et al., 1975). A similar effect of narcotic withdrawal was demonstrated by George, Reier, Lanese & Rower (1974). (6) Factors other than heroin might have influenced the results of the present study; such as simultaneous abuse of drugs different from heroin, early withdrawal from heroin abuse or the use of narcane upon admission. However, all our patients denied abuse of drugs other than heroin, they were examined within 24 hr after the last heroin dose, and received a single dose of narcane 6 or more hr prior to the test. Thus the contribution of factors other than chronic and acute heroin abuse should be negligible. In summary, the present results illustrate a number of hormonal abnormalities in heroin addicts which are best explained by a multiglandular involvement. Synthetic G n R H (Factrel) was a gift of Ayerst. The able secretarial help of Mrs. V. L. Porter is appreciated.
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REFERENCES AzIzI, F., VAGENAKIS,A. G. • PORTNAY,G. I. (1974) Thyroxine transport and metabolism in methadone and heroin addicts. Ann. intern Med. g0, 194-199. AZIZI, F., VAGENAKIS,A. G., LONGCOPE,C., INGBAR,S. H. & BRAVERMAN,L. E. (1973) Decreased serum testosterone concentration in male heroin and methadone addicts. Steroids 22, 467-472. BOYD, R. E. & SANCHEZ-FRANCO, V. (1977) Changes in the prolactin response to thyrotropin-releasing hormone (TRH) during the menstrual cycle of normal woman. J. clin. Endocr. Metab. 44, 985-988. CHILD, D. F., NADER, S., MASHITER,K., KJELD, M., BANKS, L. & RUSSELL-FRASER,T. (1975) Prolactin studies in "functionless" pituitary tumors. Br. reed. J. 1, 604-606. CICERO, T. J., BELL, R. D., WIEST,W. G., ALLISON,J. H., POLAKOSKI,K. & ROBINS,E. (1975) Function of the male sex organs in heroin and methadone users. New Engl. J. Med. 292, 882-886. CUSHMAN,P. JR. (1973) Plasma testosterone in narcotic addiction. Am J. Med. 55, 452-457. CUSHMAN,P. JR., BORDIER,B. & HILTON)J. G. (1970) Hypothalamic-pituitary-adrenal axis in methadonetreated heroin addicts. J. clin. Endocr. Metab. 30, 24-29. GEORGE,J. M., REIrR, C. E., LANESE,R. R. & ROWER,J. M. (1974) Morphine anesthesia blocks cortisol and growth hormone response to surgical stress in humans. J. clin. Endocr. Metab. 38, 736-741. GONZALEZ-BARCENA,D., KASTIN,A. J., SCHALCH,D. S., TORRES-ZAMORA,M., PEREz-TASTEN,E., KATO, A. t~ SCHALLY,A. V. (1973) Responses to thyrotropin-releasing hormone in patients with renal failure and after infusion in normal men. J. clin. Endocr. Metab. 36, 117-120. HELLMAN, L., FUKUSHIMA,D. K., ROFFWARG,H. & FISHMAN,J. (1975) Changes in estradiol and cortisol production rates in men under the influence of narcotics. J. din. Endocr. Metab. 41, 1014-1019. IRIE, M. & TSUSHIMA,T. (1972) Increase of serum growth hormone concentration following thyrotropinreleasing hormone injection in patients with acromegaly or gigantism. J. clin. Endocr. Metab. 35, 97-100. MAEDA, K., KATO, Y., YAMAGUCHI,N., CHIHARA,K., OHGO, S., IWASAKI,Y. & YOSHIMOTO,Y. (1976) Growth hormone release following thyrotropin-releasing hormone injection into patients with anorexia nervosa. Acta Endocr. 81, 1-8. MARTIN,W. R., JASINSKI,D. R., HAERTZEN,C. A., KAY, D. C., JONES,B. E., MANSKY,P. A. & CARPENTER, R. W. (1973) Methadone--a re-evaluation. Archs gen. Psychiat. 28, 286-295. MENDELSON,J. H. & MELLO, N. K. (1975) Plasma testosterone levels during chronic heroin use and protracted abstinence. Cli~. Pharmac. Ther. 17, 529-533. MENDELSON,J. H., MENDELSON,J. E. & PATCH,V. D. (1975a) Plasma testosterone levels in heroin addiction and during methadone maintenance. J. Pharmac. exp. Ther. 192, 211-217. MENDELSON,J. H., MEYER,R. E., ELLINGBOE,J., MIRIN, S. M. & McDOUGLE, M. (1975b) Effects of heroin and methadone on plasma cortisol and testosterone. J. Pharrnac. exp. Ther. 195, 296-302. PELOSI, M. A., SAMA,J. C., CATEmNI,H. & KAMINETZKY,H. A. (1974) Galactorrhea-amenorrhea syndrome associated with heroin addiction. Am. J. Obstet. Gynecol. 118, 966-969. SAWIN, C. T. & HERSHMAN,J. M. (1976) The TSH response to thyrotropin-releasing hormone (TRH) in young adult men: intraindividual variation and relation to basal serum TSH and thyroid hormones. J. clin. Endocr. Metab. 42, 809-816. SHENKMAN, L., MASSIE, B. & MITSUMA,T. (1972) Effects of chronic methadone administration on the hypothalamic-pituitary-thyroid axis. J. clin. Endocr. Metab. 35, 169-170. TAKAHASHI,S., KONDO,H. & YOSHIMURA,M. (1975) Enhanced growth hormone responses to TRH injection in bipolar depressed patients. Folia psychiat, neurol, jap. 29, 215-220. TOLLS,G., HICKEY,J. & GUYDA,H. (1975) Effects of morphine on serum growth hormone, cortisol, prolactin and thyroid stimulating hormone in man. J. clin. Endocr. Metab. 41, 797-800. WEBSTER, J. B., COUPAL,J. J. t~ CUSHMAN,P., JR. (1973) Increased serum thyroxine levels in euthyroid narcotic addicts. J. clin. Endocr. Metab. 37, 928-933.
0306-4530]7910401-0145502.00/0
© Pergamon Press Ltd. 1979. Printed in Great Britain.
E N D O C R I N E STUDIES IN HEROIN ADDICTS M. ALI AFRASIABI, MICHAEL FLOMM,* HERBERT FRIEDLANDERand LUBOMIRJ. VALENTA University of California, Irvine Medical Center, Departments of Medicine and Psychiatry, Orange, California 92668, U.S.A. *Endocrine Sciences, Tarzana, California, U.S.A. (Received 11 September 1978; in revisedform 2 February 1979)
SUMMARY In 10 heroin addicts actively taking the drug, 5 males, 5 females, a number of endocrine abnormalities were identified. These included especially: (1) Increased thyroid function manifested by high total T4 (and occasionally T3) and T3 resin uptake, and by blunted TSH response to TRH. (2) Changes in sex hormones, LH and FSH, and LH/FSH responsivenessto GnRH compatible with either primary gonadal failure or disturbance of the hypothalamopituitary regulations of the reproductive functions. (3) Abnormal increase in growth hormone in response to TRH/GnRH. (4) Occasionally increased baseline prolactin; blunted response or slightly increased responsiveness of PRL to TRH/GnRH. (5) No apparent change in the adrenocortical function. The results are best explained by multiglandular abnormalities due possibly to multiple effects of heroin on the endocrine system and its regulations. INTRODUCTION A NUMBER of endocrine abnormalities has been recognized in heroin addicts. Regarding thyroid function, the observed abnormalities included an increase in total serum thyroxine (T4), tri-iodothyronine (T3) and thyroxine binding globulin (TBG) (Azizi, Vagenakis & Portnay, 1974; Webster, Coupal & Cushman, 1973). Normal TSH response to T R H was obtained in heroin addicts on the chronic methadone program (Shenkman, Massie & Mitsuma, 1972). Regarding gonadal function, the most consistent abnormality was impotence and a decrease in plasma testosterone (T) in males (Mendelson, Mendelson & Patch, 1975a; Azizi, Vagenakis, Longcope, Ingbar & Braverman, 1973), although no change in plasma testosterone was obtained in another study (Cushman, 1973). Decrease in plasma testosterone in males has been observed under controlled research ward conditions (Mendelson, Meyer, Ellinboe, Mirin & McDougle, 1975b). Heroin addiction also caused reduction of seminal vesicular and prostatic secretions, and sperm motility (Cicero, Bell, Wiest, Allison, Polakoski & Robins, 1975). In females, the amenorrhea-galactorrhea syndrome has been associated with the abuse of heroin (Pelosi, Saran, Caterini & Kaminetzki, 1974). Controversial findings have been reported regarding the pituitary-adrenal axis. While subnormal production rates of cortisol (and estradiol) were observed in 2 male heroin addicts in one study with a several-fold increase upon withdrawal of the drug (Hellman, Fukushima, Roffwarg & Fishman, 1975), no change in plasma cortisol was observed in another study (Mendelson et al., 1975b). In still another report, the only abnormality was a disturbance of the diurnal rhythm of cortisol (Cushman, Bordier & Hilton, 1970). 145
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M. A u AFRASIABI,MICHAELFLOMM, HERBERTFRIEDLANDERand LUBOMIRJ. VALENTA
T h u s far, it has n o t b e e n r e s o l v e d w h e t h e r the e n d o c r i n e a b n o r m a l i t i e s are d u e to f u n c t i o n al i m p a i r m e n t o f the h y p o t h a l a m o - p i t u i t a r y axis o r o f the p e r i p h e r a l e n d o c r i n e organs. D a t a o n r e s p o n s i v e n e s s to g o n a d o t r o p i n releasing h o r m o n e ( G n R H ) are n o t a v a i l a b l e a n d t h e T R H test was p e r f o r m e d o n l y o n p a t i e n t s in t h e c h r o n i c m e t h a d o n e p r o g r a m . T h e p r e s e n t w o r k was d e s i g n e d to study the r e g u l a t o r y e n d o c r i n e m e c h a n i s m s in m o r e detail. MATERIALS A N D METHODS Subjects Ten individuals were studied, 5 males, 5 females, ages 18-43, average: 29 yr. Twelve normal, healthy individuals, age and sex matched, were used as controls. Nine of the patients were admitted to the psychiatric ward less than 24 hr prior to the testing. The reason for admission was heroin overdose. However, none of the patients was critically ill and none had severe disturbance of consciousness. All patients received nalorphin immediately after admission. The tenth patient examined was admitted for early signs of heroin withdrawal. The patients admitted drug abuse for 3-15 yr, average 5-5 yr, except for one male who had not been taking heroin for more than 6 months. They denied abuse of any drug other than heroin during at least a month prior to admission. Past medical history included hysterectomy for fibroid uterine tumors in one girl while another suffered from amenorrhea and noticed galactorrhea 9 months prior to admission. The remaining 3 females suffered from oligomenorrhea. Three out of five males complained of loss of libido and decreased potency. In one male, a diagnosis of chronic active hepatitis was established, with acute arthropathy. Two patients had hepatitis in the past but were asymptomatic on this admission. At the time of laboratory testing, all patients were alert and afebrile with stable vital signs and in no acute distress. They were not taking any medication. Their last dose of heroin was taken no more than 24 hr prior to examination, and they received narcane 6-12 hr prior to the test. All were fasting overnight and the test was performed in the morning hours (between 8 and 10 a.m.). Physical examination revealed obesity in one girl. The patient with chronic active hepatitis had two large joints swollen and tender, and enlarged tender liver. In this individual, the liver function tests were abnormal. They were normal in all remaining patients. Two males had decreased size of the testicles. There were no other clinical signs of endocrine disease in any of the individuals. One of the patients was hypertensive with blood pressure of 160/100 mm Hg, and 3 had tachycardia with the pulse rate between 100 and ll0/min.
Pituitary reserve test The response of pituitary hormones to simultaneous i.v. administration of TRH and G n R H was studied. TRH (Abbott) 500 i~g and GnRH (Ayerst) 100 ~tg mixed together were injected i.v. over 10 sec. Serum hormone levels were obtained at time 0, 20, 30 and 60 min. The range of responses was compared with those obtained in 12 sex and age matched healthy individuals. In these controls, normal responsiveness of the pituitary functions was the same as in our large series of more than 50 healthy euthyroid and eugonadal individuals of both sexes, ages 20--55. At the time of study, all our female patients were in the follicular phase of the menstrual cycle. This was established by the history and by obtaining serum progesterone levels which were low in all of them. Hormone assays All hormones were measured by specific radioimrnunoassays. The double antibody technique was used for separation of free and bound hormone in all assays except for serum T4 where ammonium sulphate precipitation was used. WHO standards were used for calibration of all peptide and protein hormone assays. Normal values have been established in a series of more than 50 healthy individuals.
RESULTS
Thyroid function tests N o r m a l r a n g e f o r s e r u m T4 was 4.5-12.5 ~g/100 m l a n d for T3 6 0 - 1 7 0 ng/100 ml. In 5 o u t o f 10 patients, t h e s e r u m T4 v a l u e s w e r e clearly e l e v a t e d , b e t w e e n 12.8 a n d 18.5 ~g/100 ml, a n d t h e y w e r e in the u p p e r n o r m a l r a n g e in the r e m a i n i n g patients. A v e r a g e s e r u m t o t a l T4 was 12.1 IJg/100 ml. T h e a v e r a g e s e r u m T3 in the p a t i e n t s was 146.5 ng/100 ml, w i t h t h e
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FIG. 1. TSH response to TRH in 10 heroin addicts. TRH, 500 lag, and GnRH, 100 lag, were administered i.v. over 10 sec at time 0. Serum TSH was measured before TRH administration and 20, 30 and 60 min later. The shaded area represents the range of TSH response to TRH in 12 healthy age and sex matched individuals. The TSH response in most of the patients of the present series is blunted. Total serum T4 in patients No. 1, 3, 6, 9 and 10 was above normal range. range between 110 and 160 ng/100 ml, which is normal. However, in one patient who had the highest serum T4 concentration of 18.5 lag/100 ml, the T3 was also elevated, to 225 ng/100 ml. The T3 resin uptake (T3RU) (normal 35-45 %) varied between 31 and 45, average 37.6 %, T R H test The results of the T R H test are illustrated in Fig. 1. The baseline TSH concentration was low to unmeasurable in most of the patients, and the TSH response to T R H was blunted. Suppressed TSH responsiveness to T R H was observed especially in the individual with both serum T4 and T3 elevated (No. 6) and in others with elevated serum T4 concentration (Nos. 3 and 9). Only 4/10 individuals showed TSH response which could be classified as normal and even these were in the low normal range. Sex hormone studies In males, serum testosterone varied between 265 and 738 ng/100 ml, average 563 ng/ml (normal 400-1000). In only one case the result was below normal, 265 ng/100 ml. In females, plasma estradiol (E2) concentration was decreased in a single case. In the remaining females, plasma estradiol was normal for the follicular phase. In all females, plasma progesterone was within normal range for the follicular phase.
148
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FIG. 2. LH response to G n R H in 10 heroin addicts. GnRH, I00 lag, and TRH, 500 pg, were administered over 10 sec i.v. at time 0. LH was measured prior to G n R H and 20, 30 and 60 min later. Shaded area represents LH response to G n R H in 12 age and sex matched healthy individuals. Two kinds of response in the patients are observed, a blunted or an exaggerated LH response. In patients with clinical hypogonadism, these responses would be compatible with secondary or primary gonadal failure respectively. However, only patients No. 5 and 8 demonstrated hypogonadism with a decrease of serum sex steroids. In these two cases, exaggerated LH response confirms the presence of primary gonadal failure.
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FIG. 3. FSH response to G n R H in 10 heroin addicts. Conditions same as described in Fig. 2. Blunted FSH response with delayed peak is observed in most of the cases but may be a variant of normal response. Case No. I with an exaggerated FSH response exhibited also exaggerated LH response (Fig. 2).
ENDOCRINE STUDIES IN HEROIN ADDICTS
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GnRH test The response of LH and FSH to G n R H is apparent from Figs. 2 and 3. Exaggerated LH response as compatible with primary hypogonadism was observed in at least 4/10 patients (Nos. 1, 4, 5, 8 and possibly 10). In the remaining patients, the responsiveness was low normal or slightly suppressed. Patient No. 1 also demonstrated exaggerated response of FSH with delayed maximum, while FSH response in the remaining patients was normal. It should be remembered that patients No. 8 and 5, who demonstrated exaggerated LH response, showed low serum testosterone and estradiol respectively.
Serum prolactin Basal and T R H stimulated values of prolactin (PRL) are apparent from Fig. 4. In 2 males (Nos. 7 and 9), basal P R L was elevated and there was a blunted response to TRH. In 2 other males (Nos. 8 and 10) who complained of impotence and both of whom showed increased LH responsiveness to G n R H , the response of P R L to T R H was exaggerated. Exaggerated reaction of P R L to T R H was also obtained in the females Nos. 1 and 2, the latter suffering from the amenorrhea-galactorrhea syndrome, and the former showing grossly abnormal increase of LH and FSH following G n R H injection. /~\x 50
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FIG. 4. Prolactin (PRL) response to TRH in 10 heroin addicts. Conditions were the same as described in Fig. 1. Total shaded area represents PRL response to TRH in 7 healthy females of age comparable to the heroin addicts studied, in the early follicular phase of their menstrual cycle. The lower shaded area is for 5 healthy male controls. Two male heroin addicts (Nos. 7 and 9) showed basal hyperprolactinemia and blunted response to TRH. Females No. 1 (with exaggerated response of LH and FSH to GnRH, Figs. 2 and 3), and No. 2 (with amenorrhea-galactorrhea syndrome) demonstrate exaggerated PRL response according to our criteria, and so does the male No. I0, who complained of impotence.
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M. ALl AFRhaSIABI, MICHAEL FLOMM, HERBERT FRIEDLANDER a n d LUBOMIR J. VALENTA
Serum growth hormone Baseline growth hormone (GH) was low to unmeasurable in all of our patients. Changes following T R H / G n R H administration are illustrated in Fig. 5. In 6/10 patients there was a significant increase in serum G H within 60 min after T R H / G n R H administration which was as high as 35 ng/ml. There was no appreciable change in serum glucose and immunoreactive insulin during that time period. 40
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FI~. 5. GH response to TRH/GnRH in 10 heroin addicts. TRH 500 i~gplus GnRH 100 I~gwere injected i.v. at time 0. Serum GH was measured before, and 20, 30 and 60 min after TRH/GnRH administration. In 6/10 patients, significant increase in GH occurred, mostly at time 60 rain. At the same time, there was no appreciable change in serum glucose or immunoreactive insulin.
Adrenocortical function Serum cortisol (a.m.) was, and remained within the normal range (10-20 I~g/100 ml) during the whole observation period. Plasma A C T H was normal on admission in all patients (between 10 and 80 pg/ml). In two, there was an increase in plasma A C T H within 20 min of T R H / G n R H administration, to 2000 and 5000 pg/ml respectively. This was classified as a stress reaction in susceptible individuals. DISCUSSION Our data obtained in the 10 heroin addicts can be summarized as follows: (1) There was an increase in total T, and occasionally T3 and normal T3 resin uptake. This differs slightly from previously reported data which were compatible with increased binding capacity of TBG, i.e. increased total T4 and decreased T3RU (Azizi et al., 1974, Webster et aL, 1973). Our T R H studies also differ from previously reported normal TSH responsiveness to T R H
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(Shenkman et al., 1972). The differences may be due to the fact that in the previous studies the heroin addicts were in the chronic methadone program, whereas our patients were taking the drug both chronically and acutely. Although low TSH response to TRH may represent a variation of normal reaction (Sawin & Hershman, 1976), in our sex and age matched controls peak TSH values lower than 8 FU/ml, 20 or 30 min after TRH administration, were not reported. In addition, all our female heroin addicts were examined during the follicular phase of their menstrual cycle when TSH responsiveness to TRH was shown to be highest (Boyd & Sanchez-Franco, 1977). Thus, our conclusion is that, the data should be interpreted as a suppressed TSH response. Together with the other thyroid function tests, this is compatible with the presence of borderline hyperthyroidism. It can be argued that factors other than heroin caused abnormal thyroid function tests, e.g. one patient with high T4 suffered from chronic active hepatitis. Hepatitis is known to increase total T4 by increasing TBG. However, our patient demonstrated elevated T4 and blunted response of TSH to TRH in the presence of normal TBG binding capacity, which is compatible with hyperthyroidism. It may also be argued that our patients were acutely ill and this influenced their thyroid function studies. However, at the time of the hormonal studies the patients were stable, in no distress, and acute illness does not usually produce thyroid function tests characteristic of hyperthyroidism. Therefore, we conclude that acute abuse of heroin itself may result in borderline hyperthyroidism. (2) A number of abnormalities of gonadal function existed in our patients. They were manifested by decreased potency in males and, in females, by menstrual abnormalities or occasionally, galactorrhea. Male hypogonadism with decreased serum testosterone is one of the most consistent hormonal abnormalities observed in heroin addicts (Mendelson et al., 1975a). The decrease in plasma testosterone was shown to be reversible upon withdrawal of the drug (Mendelson & Mello, 1975). In the study of Cushman (1973) plasma testosterone was normal. 111 our study, low plasma testosterone concentration was observed in one patient only, in the remaining 4 males it was normal. However, 3/5 males complained of some degree of impotance. Although plasma testosterone was not necessarily below normal range, a relative decrease in individual patients may be present and may become symptomatic. Such a relative decrease in plasma testosterone was demonstrated in addicts taking heroin under controlled research ward conditions (Mendelson et al., 1975b). Similarly, only one of our female heroin addicts demonstrated low plasma estradiol, although 3/5 females complained of oligomenorrhea and one suffered from the amenorrhea-galactorrhea syndrome. The latter syndrome was previously described to be associated with heroin addiction (Pelosi et al., 1974), but no detailed study of the hormonal abnormalities has been reported In our patient, basal PRL concentration was normal. However, prolactin responsiveness to TRH was exaggerated and the response of gonadotropins to GnRH was blunted. Amenorrhea and hypogonadism in hyperprolactinemic states are most likely to be due to a decrease in basal or stimulated gonadotropins, or both (Child, Nader, Mashiter, Kjeld, Banks & Russell-Fraser, 1975). Morphine has been shown to increase prolactin release (Tolls, Hickey & Guyda, 1975) and hyperprolactinemia may in turn cause hypogonadism. However, in most of our patients, basal serum prolactin concentration was normal. The nature of hypogonadism in heroin addicts has not been elucidated. Detailed studies of gonadotropin concentration are missing. In a study of Martin, Jasinski, Haertzen, Kay,
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Jones, Mansky & Carpenter (1973), serum gonadotropins were decreased. No data are available on LH and FSH responsiveness to GnRH in heroin addicts. In the present study, basal FSH was normal in all and LH was within normal range in 7 patients and elevated in 3. According to the LH responsiveness to the gonadotropin releasing hormone, the patients could be classified into a group with exaggerated response and those with normal or blunted response (Fig. 2). Noticeably, the patients with clearly abnormal plasma testosterone or estradiol and clinical hypogonadism had an exaggerated response of LH to GnRH. These data are compatible with primary hypogonadism in at least some of the heroin addicts. In others, the blunted response of LH and FSH suggests a decreased pituitary reserve for gonadotropins. Thus both primary and secondary gonadal failure may be responsible in different individuals for clinical hypogonadism. (3) As mentioned above, serum prolactin was normal in most of our patients, the basal value being elevated only in 2 males. During TRH stimulation, PRL was clearly abnormal only in one male patient who showed a blunted response. According to our criteria, the response was slightly exaggerated in a number of other patients; the significance of this finding is not clear. (4) In at least 6/10 of our patients, TRH/GnRH administration provoked a significant release of growth hormone. In our experience as well as that of others, this does not occur in normal healthy individuals. However, an abnormal increase of GH in response to TRH or GnRH is not specific for heroin abuse, and has been observed in a number of conditions such as acromegaly, chronic renal failure, severe depression or anorexia nervosa (Irie & Tsushima, 1972; Gonzalez-Barcena, Kastin, Schalch, Torres-Zamora, Perez-Tasten, Kato & Schally, 1973; Takahashi, Kondo & Yoshimura, 1975; Maeda, Kato, Yamaguchi, Chihara, Ohgo, Iwasaki & Yoshimoto, 1976). (5) In the present study, no abnormality was identified in the ACTH--cortisol axis, and grossly elevated plasma ACTH during the pituitary reserve test in two patients was due probably to a stress reaction. In previous studies, plasma cortisol was found to be mostly normal (Cushman et al., 1970; Mendelson et aL, 1975b), and the only abnormality consisted of the absence of the diurnal rhythm of cortisol (Cushman et al., 1970). However, serial sampling in another study demonstrated low normal or subnormal values of serum cortisol during narcotic maintenance, and a steep increase upon withdrawal (Hellman et al., 1975). A similar effect of narcotic withdrawal was demonstrated by George, Reier, Lanese & Rower (1974). (6) Factors other than heroin might have influenced the results of the present study; such as simultaneous abuse of drugs different from heroin, early withdrawal from heroin abuse or the use of narcane upon admission. However, all our patients denied abuse of drugs other than heroin, they were examined within 24 hr after the last heroin dose, and received a single dose of narcane 6 or more hr prior to the test. Thus the contribution of factors other than chronic and acute heroin abuse should be negligible. In summary, the present results illustrate a number of hormonal abnormalities in heroin addicts which are best explained by a multiglandular involvement. Synthetic G n R H (Factrel) was a gift of Ayerst. The able secretarial help of Mrs. V. L. Porter is appreciated.
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REFERENCES AzIzI, F., VAGENAKIS,A. G. • PORTNAY,G. I. (1974) Thyroxine transport and metabolism in methadone and heroin addicts. Ann. intern Med. g0, 194-199. AZIZI, F., VAGENAKIS,A. G., LONGCOPE,C., INGBAR,S. H. & BRAVERMAN,L. E. (1973) Decreased serum testosterone concentration in male heroin and methadone addicts. Steroids 22, 467-472. BOYD, R. E. & SANCHEZ-FRANCO, V. (1977) Changes in the prolactin response to thyrotropin-releasing hormone (TRH) during the menstrual cycle of normal woman. J. clin. Endocr. Metab. 44, 985-988. CHILD, D. F., NADER, S., MASHITER,K., KJELD, M., BANKS, L. & RUSSELL-FRASER,T. (1975) Prolactin studies in "functionless" pituitary tumors. Br. reed. J. 1, 604-606. CICERO, T. J., BELL, R. D., WIEST,W. G., ALLISON,J. H., POLAKOSKI,K. & ROBINS,E. (1975) Function of the male sex organs in heroin and methadone users. New Engl. J. Med. 292, 882-886. CUSHMAN,P. JR. (1973) Plasma testosterone in narcotic addiction. Am J. Med. 55, 452-457. CUSHMAN,P. JR., BORDIER,B. & HILTON)J. G. (1970) Hypothalamic-pituitary-adrenal axis in methadonetreated heroin addicts. J. clin. Endocr. Metab. 30, 24-29. GEORGE,J. M., REIrR, C. E., LANESE,R. R. & ROWER,J. M. (1974) Morphine anesthesia blocks cortisol and growth hormone response to surgical stress in humans. J. clin. Endocr. Metab. 38, 736-741. GONZALEZ-BARCENA,D., KASTIN,A. J., SCHALCH,D. S., TORRES-ZAMORA,M., PEREz-TASTEN,E., KATO, A. t~ SCHALLY,A. V. (1973) Responses to thyrotropin-releasing hormone in patients with renal failure and after infusion in normal men. J. clin. Endocr. Metab. 36, 117-120. HELLMAN, L., FUKUSHIMA,D. K., ROFFWARG,H. & FISHMAN,J. (1975) Changes in estradiol and cortisol production rates in men under the influence of narcotics. J. din. Endocr. Metab. 41, 1014-1019. IRIE, M. & TSUSHIMA,T. (1972) Increase of serum growth hormone concentration following thyrotropinreleasing hormone injection in patients with acromegaly or gigantism. J. clin. Endocr. Metab. 35, 97-100. MAEDA, K., KATO, Y., YAMAGUCHI,N., CHIHARA,K., OHGO, S., IWASAKI,Y. & YOSHIMOTO,Y. (1976) Growth hormone release following thyrotropin-releasing hormone injection into patients with anorexia nervosa. Acta Endocr. 81, 1-8. MARTIN,W. R., JASINSKI,D. R., HAERTZEN,C. A., KAY, D. C., JONES,B. E., MANSKY,P. A. & CARPENTER, R. W. (1973) Methadone--a re-evaluation. Archs gen. Psychiat. 28, 286-295. MENDELSON,J. H. & MELLO, N. K. (1975) Plasma testosterone levels during chronic heroin use and protracted abstinence. Cli~. Pharmac. Ther. 17, 529-533. MENDELSON,J. H., MENDELSON,J. E. & PATCH,V. D. (1975a) Plasma testosterone levels in heroin addiction and during methadone maintenance. J. Pharmac. exp. Ther. 192, 211-217. MENDELSON,J. H., MEYER,R. E., ELLINGBOE,J., MIRIN, S. M. & McDOUGLE, M. (1975b) Effects of heroin and methadone on plasma cortisol and testosterone. J. Pharrnac. exp. Ther. 195, 296-302. PELOSI, M. A., SAMA,J. C., CATEmNI,H. & KAMINETZKY,H. A. (1974) Galactorrhea-amenorrhea syndrome associated with heroin addiction. Am. J. Obstet. Gynecol. 118, 966-969. SAWIN, C. T. & HERSHMAN,J. M. (1976) The TSH response to thyrotropin-releasing hormone (TRH) in young adult men: intraindividual variation and relation to basal serum TSH and thyroid hormones. J. clin. Endocr. Metab. 42, 809-816. SHENKMAN, L., MASSIE, B. & MITSUMA,T. (1972) Effects of chronic methadone administration on the hypothalamic-pituitary-thyroid axis. J. clin. Endocr. Metab. 35, 169-170. TAKAHASHI,S., KONDO,H. & YOSHIMURA,M. (1975) Enhanced growth hormone responses to TRH injection in bipolar depressed patients. Folia psychiat, neurol, jap. 29, 215-220. TOLLS,G., HICKEY,J. & GUYDA,H. (1975) Effects of morphine on serum growth hormone, cortisol, prolactin and thyroid stimulating hormone in man. J. clin. Endocr. Metab. 41, 797-800. WEBSTER, J. B., COUPAL,J. J. t~ CUSHMAN,P., JR. (1973) Increased serum thyroxine levels in euthyroid narcotic addicts. J. clin. Endocr. Metab. 37, 928-933.