Clinical Endocrinology (1979) 10,557-565.

EFFECTS O F HEROIN ADDICTION ON THYROTROPHIN, THYROID HORMONES A N D PROLACTIN SECRETION

IN MEN

VIVIAN CHAN, CHRISTINA WANG A N D ROSE T . T. YEUNG

University Department of Medicine, Queen Mary Hospital, Hong Kong

(Received 3 May 1978; revised 29 Seprember 1978; accepted 20 October 1978)

SUMMARY

Pituitary-thyroid function in male heroin addicts and addicts after abstinence (ex- addicts) was studied and compared with that of healthy euthyroid men. In heroin addicts the increases in circulating total thyroxine and triiodothyronine levels were accompanied by an increase in the thyroid hormone uptake test. These changes may reflect a quantitative increase in thyroxine binding globulin. Reverse triiodo- thyronine concentrations in heroin addicts were normal. The thyrotrophin-releasing hormone elicited a diminished thyrotrophin response in heroin addicts which was significantly different from that in control subjects and ex-addicts. An elevation of serum prolactin was noted in heroin addicts, while ex-addicts had normal levels. Gradual recovery of pituitary-thyroid function occurred after heroin withdrawal.

The suppression of the hypothalamic-pituitary-gonadal and adrenal functions in association with narcotic addiction has been well documented (Arimura e t al., 1967; Glass e t al., 1973; Azizi et al., 1973; Cicero et al., 1975; Mendelson & Mello, 1975), but little information is available regarding the effects of opiates on the hypothalamic-pituitary-thyroid function. Results of animal studies showed decreased pituitary thyrotrophin (TSH) content in mor- phine-treated rats (Bakke et al., 1974; Hohlweg e t al., 1961) and inhibition of 1311 release from the thyroid after implantation of morphine into rat hypothalamus (Lomax e t al., 1970). Cushman (1972) observed that in heroin addicts there were subnormal growth hormone and cortisol responses to insulin-induced hypoglycaemia, but found normal levels of serum luteinizing hormone, thyroxine (T4), triiodothyronine (T3) and protein bound iodine (PBI) in both heroin addicts and methadone-maintained patients. He con- cluded that there might be mild hypothalamic-pituitary dysfunction in some, but not all, heroin addicts. Other workers (Azizi et al., 1974) found that in narcotic addicts there were increases in total T4 level and T4 binding to thyroxine binding globulins (TBG) causing decreased clearance and fractional turnover rate of the hormone. Since the liver is the major site of T4 metabolism in man, the mild abnormalities in liver function of heroin addicts

Correspondence: Dr V. Chan, University Department of Medicine, Queen Mary Hospital, Hong Kong. 0300-0164/79/0600-0557$02.00 0 1979 Blackwell Scientific Publications

557

558 Vivian Chan, Christina Wang and Rose T. T. Yeung

might also be the cause of retarded T4 metabolism (Azizi et al., 1974). No data on the peripheral conversion of T4 to reverse T3 (rT3) is as yet available.

Galactorrhoea-amenorrhoea syndrome associated with long term use of heroin had been reported (Pelosi et d., 1974) and although prolactin (PRL) determinations were not per- formed, its presence in elevated amounts was surmised by the presentation of galactorrhoea in all the patients. It was thought that heroin acted at the hypothalamus causing decreased secretion of prolactin-inhibiting factor (PIF).

To clarify the possible effects of heroin addiction on pituitary-thyroid function and on the peripheral metabolism of thyroid hormones, we measured circulating TSH, PRL, total T4, total and free T3, as well as rT3 levels in heroin addicts and ex-addicts, and compared them with those measured in healthy euthyroid men. Furthermore, the integrity of the hypothalamic-pituitary-thyroid axis in the same groups was examined by the thyrotrophin- releasing hormone (TRH) test.

MATERIALS AND METHODS Subjects

Fifty-four male heroin addicts (mean age k SEM, 34.6 k 1.5) and nineteen male heroin addicts after withdrawal (ex-addicts) (28.4 _+ 1.4 years) were examined and compared with forty-three healthy euthyroid men (33.9 ? 1.5 years). The mean duration of addiction of the heroin addicts was 11 years, and the drug was either inhaled or taken intravenously (average three times daily). All the ex-addicts were inpatients at a rehabilitation centre. They were addicted for 9.4 years (mean) and had abstained from heroin and methadone for a period of 1.5-4.5 months (mean 2.5 months) at the time of the study. Apart from heroin addiction, all the subjects were in normal physical health and none admitted to significant alcohol abuse.

Methods The heroin addicts admitted to taking the drug at 07.00 h before coming to the hospital.

A 10 ml blood sample was taken from all the subjects at 09.00 h for the measurement of circulating basal hormone levels, liver function tests and morphine concentration. TRH test (200 pg iv) was performed in ten subjects from each group. Five ml of blood was withdrawn through an indwelling catheter at - 20, 0, 20 ,60 and 240 min in relation to the TRH injec- tion. Blood was allowed to clot at room temperature, the serum was separated and stored at - 20°C until required for assay. A spot urine sample was obtained from all the subjects for the analysis of morphine, codeine, nicotine and methadone ,by thin layer chromatography as described by Dole et al., 1966).

Standard liver function tests were performed on the Technicon auto-analyser (Technicon Handbook No. N-12 b, N-25 b 1/11, AA 11-14, SF 4-0030 FC4; Kind & King, 1954). Serum morphine was measured using a radioimmunoassay (RIA) kit (Abuscreen, Roche Diagnostics).

Serum total T3, total T4, TSH and PRL concentrations were measured by specific RIA as previously described (Chan et al., 1975a; Chan et al., 1975b; Nye et al., 1975; McNeilly & Hagen, 1974). Purified human PRL was used for iodiAation and the MRC 75/504 was used as standard.

Total rT3 concentrations were determined in 50 p1 of serum by a highly specific and sensitive RIA using 8-anilino-1 -napthalene sulphonic acid to inhibit rT3 binding to endo- genous TBG, and charcoal to separate the antibody bound and free hormone fractions (Chan et al., 1978). The rabbit anti-rT3 serum was used at a final dilution of 1 :36000 and

Pituitary-thyroid function in heroin addicts 559

cross-reacted with T4 to the extent of 0.006%. The detection limit of the assay is 61 pmol/l. The coefficients of variation for ten intra-assay measurements of low, normal and high hormone concentrations were 4.5,2.5 and 4.0% respectively, and for ten inter-assay measure- ments, they were 6.5,4.5 and 6.5%.

Serum FT3 was estimated directly by Sephadex equilibration and RIA (Chan et al., 1975~) . The degree of unsaturation of TBG was determined by the thyroid hormone uptake test (THUT), where the radioactivity in the supernatant is measured, values fall below 80% in hyperthyroidism and rise above 100% in hypothyroidism, compared with a control serum.

All results were compared using the analysis of variance and Student’s t test.

RESULTS

Morphine was undetectable in the urine and serum of both euthyroid controls and ex-addicts. Only 80% of the heroin addicts gave positive test for urine morphine but all had serum morphine of greater than 40 yg/l.

Similar levels of bilirubin, alkaline phosphatase and serum glutamate pyruvate trans- aminase (SGPT) were found in heroin addicts and healthy controls (Table 1). In heroin addicts, albumin was significantly lower (P < 0.0 l), while globulin and serum glutamate oxaloacetate transaminase (SGOT) were higher (P < 0.01 for both) than in euthyroid sub- jects. When individual values were considered, 4% of heroin addicts had lower albumin, 17% had higher globulin and 28% had elevated SGOT levels exceeding 95% confidence limits of the mean normal value.

The mean basal hormone concentrations of all three groups of subjects were shown in Table 2 . Circulating levels of total T4 and T3 were significantly increased (P< 0.001 and P < 0.01 respectively) in heroin addicts as compared to euthyroid controls. In ex-addicts, total T4 concentrations were comparable to those of the control group, whilst their total T3 levels were elevated. These increases in the levels of total T4 and T3 were accompanied by increases in THUT. Mean FT3 levels in both heroin addicts and ex-addicts were not

Table 1. Liver function in healthy euthyroid men, heroin addicts and ex-addicts (mean f SEM)

Healthy Heroin Abstinent controls addicts addicts P (n = 43) (n = 54) (n = 19)

A B C A vs B A vs C B vs C

Bilirubin 9.1 2 0.4 9.4 f 0.6 10.8 * 0.7 NS NS NS (mol/l) Alkaline phosphatase 87.0 f 5.5 86.6 f 3.1 104.0 f 6.7 NS NS NS (IU) SGOT 16.3 f 0.7 24.5 * 2.5 20.9 f 1.6 < 0.01 NS NS (IU) SGPT 14.9 f 1.1 23.0 f 3.1 23.1 f 2.6 1 NS NS NS (IU) Albumin 47.3 2 0.5 42.6 2 1.0 49.3 f 1.0 < 0.01 NS < 0.01 &/I) Globulin 29.2 f 0.6 36.2 f 1.0 32.9 f 1.2 < 0.01 NS < 0.05 &/l)

NS = nonsignificant. Statistical analysis by analysis of variance.

Vivian Chan, Christina Wang and Rose T. T, Yeung

significantly different from the mean value of the euthyroid group. rT3 levels were similar in all three groups of subjects.

Serum TSH concentrations were normal in the three groups, and the mean values were not significantly different from each other.

Eighteen out of fifty-four heroin addicts had high basal PRL level (above 25 pg/l) and the mean concentration for the entire group of addicts (19.04 f 3.22 pg/l) was significantly elevated (P < 0.005) when compared to euthyroid controls and ex-addicts.

The integrity of the hypothalamic-pituitary-thyroid axis TRH test Table 3 shows the areas (mean f SEM) under the TSH, T3 and PRL response curves to

Table 2. Basal (mean f SEM) circulating hormone concentrations in healthy euthyroid men, heroin addicts and ex-addicts

Healthy Heroin

(n = 43) (n = 54) (n = 19) euthyroids addicts Ex-addicts P

Hormone A B C A vs B A vs C B vs C

T4 84.57 f 3.09 120.99 f 3.99 93.06 t 4.12 < 0.001 NS NS (nmol/l) T3 1.93 f 0.06 2.23 f 0.07 2.38 f 0.08 < 0.01 < 0.01 NS (nmol/l) FT3 6.85 f 1.77 5.31 f 1.54 3.32 t 0.61 NS NS NS

rT3 0.29 f 0.02 0.31 f 0.02 0.26 ?r 0.02 NS NS NS (nmol/l) THUT 86.53 f 0.97 93.57 +_ 0.75 94.40 f 1.15 < 0.001 < 0.001 NS (%I TSH 1.04 f 0.11 1.56 f 0.18 1.34 f 0.27 NS NS NS (mU/l) PRL 4.73 f 1.71 19.04 t 3.22 6.05 f 2.24 < 0.005 N S < 0.005 o l d )

(pmol/l)

Statistical analysis by Student’s unpaired t test.

Table 3. Area (mean t SEM) under the TSH, T3, and PRL response curves obtained after TRH injection in healthy euthyroid men, heroin addicts and ex-addicts

Area under the response curve

T SH (mU/l-min) T3 (nmol/I-min) PRL

-min)

Healthy Heroin

(n = 10) (n = 10) (n = 10) . eu thyroids addicts (Ex-addicts P

A B C A v s B A v s C B v s C

1016.8 r 116.7 617.6 f 92.5 1051.7 t 183.9 < 0.02 NS < 0.05

657.5 f 50.1 774.1 t 51.3 689.3 f 36.0 NS NS NS

5834.8 f 1772.3 5585.5 t 1568.7 4426.4 f 1135.3 NS NS NS

Statistical analysis by Student’s paired t test.

Fig. 1. TSH SEM of each

10

- - \ 3 - € 0 I v) + E 2 6 . v)

4 .

2

0

Pituitary-thyroid function in heroin addicts

TRH

200 pg i.v.

I 4 r 1 1

I 2 t

I Healthy controls

0 Heroin addicts

A Addicts after withdrawal

I i T T

3.0

rc +- - 2.5 e

+ 0

E 2 m

2 .o

1.5

I Healthy controls

Heroin addicts

A Addicts after wit hdrawa I

561

mean value f

-20 0 20 60 240 Time (min)

Fig. 2. Serum total T3 (mean f SEM) response to TRH injection in the three groups.

5 62 Vivian Chan, Christina Wang and Hose T. T. Yeung

Hea I thy controls Heroin addicts Addicts after withdrawal

TRH TRH TRH 1 3 0 r I I I

-# 0 20 60 240 I+ 0 20 60 240

-+ 0 20 60 240

Time ( m i n l

Fig. 3. Serum PRL response to TRH injection in individual subjects.

TRH. The peak TSH response was diminished in heroin addicts (Fig. l) , and the area under the response curve (calculated by integration) was significantly lower than in the control group (P<O.O2). In contrast, the response in ex-addicts was similar to that of controls. There was no significant difference between the areas under the T3 response curves in the three groups. Heroin addicts exhibited a prompt response, T3 rose to reach a peak at 60 min (3.08 f 0.21 nmol/l) and remained elevated at 240 min (Fig. 2). T3 level at 60 min in ex- addicts (2.61 f 0.12 nmol/l) was not significantly different from the control group (2.35 f 0.20 nmol/l). Heroin addicts had higher basal PRL levels (mean +- SEM, 9.13 +_ 3.55 pg/l vs 2.40 4 1.33 pg/l in euthyroid controls) and variable response to TRH (Fig. 3). In four addicts, the PRL levels were still rising 240 min after TRH stimulation, while at this time in healthy controls, they had returned to base-line values. Ex-addicts had normal PRL res- ponse to TRH.

DISCUSSION

The increase in circulating total T4, T3 and THUT in heroin addicts in the present study may be interpreted as indicating an increase in serum TBG. This is in agreement with the result of Azizi et al. (1974). Increases in TBG result from decreased levels of androgens or increased levels of oestrogen in the blood(Engbring& Engstrom, 1959). Furthermore, studies in these same groups of subjects have demonstrated low testosterone, normal oestradiol and high sex hormone binding globulin capacities in the heroin addicts (Wang et al., 1978). It is reasonable to conclude that the raised total T4, T3 and THUT in heroin addicts are secondary to the effect of decreased androgens on TBG. The major pathway of rT3 production is via peripheral monodeiodination of T4 (Chopra, 1974). The decreased peripheral T4 turnover

Pituitary -th y ro id function in hero in addicts 563

and metabolism in heroin addicts reported by Azizi e t al. (1974) would cause a decrease in rT3 level, and this would be balanced by the increase in TBG-bound rT3. The net result is a normal rT3 concentration as observed in this study. The diminished TSH response to TRH in addicts may be an indication of pituitary suppression, while the enhanced T3 response could be due to increased TBG resulting in sustained concentrations of T3.

Since heroin is rapidly metabolised into morphine, the elevation of serum PRL in heroin addicts was probably morphine-induced. Tolis and his colleagues (1975) have suggested that morphine acts by suppression of PIF, rather than by mediation by TRH. This would seem to be correct, as all except one heroin addict had TSH levels within the normal range, showing that the elevation in PRL was not associated with increases in TRH and TSH. Alternatively, the PRL increase may be due to direct morphine stimulation of the pituitary lactotrophes. Hellman et al. (1975) and Wang et ~ l . (1978) did not observe any significant increases in oestrogen level in heroin addicts, thus it was unlikely that the increase in PRL was secondary t o oestrogen stimulation.

It had been recently observed (Zanoboni & Zanoboni-Muciaccia, 1975; Panerai et ~ l . , 1977) that an exaggerated and sustained PRL rise was present after TRH in patients with liver disease, whose mean basal PRL levels were within the normal range. Decreased de- gradation of PRL in those patients, possibly due to a reduced number of lactogenic receptors in the liver (Friesen et ~ l . , 1973) was thought to be a contributory factor for the persistence of raised PRL levels 120 min or more after TRH stimulation. Abnormal levels of SCOT, albumin and globulins were found in the present group of addicts. The sustained PRL rise after TRH in four heroin addicts seemed more likely ascribable to decreased hepatic de- gradation of the hormone in these individuals.

The high basal PRL levels in active addicts would suggest that heroin addiction exerts its effects at the hypothalamus, while their diminished TSH response to TRH may also be an indication of pituitary suppression. It is however, of interest to note that pituitary-thyroid function recovers after heroin withdrawal as evidence by the normal basal hormone levels and normal responses to TRH in ex-addicts.

ACKNOWLEDGEMENTS

We thank members of the Society for the Aid and Rehabilitation of Drug Addicts for allowing us to study their patients, the National Institute of Biological Standards and Control, Mill Hill, England, and the Hormone Distribution Program of the NIAMD, Bethesda, USA, for gifts of human thyrotrophin, Drs P.J. Lowry and A.S. McNeilly for the generous gift of human prolactin, Henning GMBH, Berlin, for generous supply of reverse triiodothyronine, Mews A. Wong and A. Leung for expert technical assistance, and the Higher Degree and Research Grant Committee of the Hong Kong University for financial support for this project.

This paper was presented in part at a meeting of the Endocrine Society, San Francisco, California, June 1976.

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