Amitriptyline-induced suppression of growth hormone in acromegaly

Psychoneuroendocrtnology,Vol.

0306-453018010101--0081502.0010

5, pp. 81 to 86.

Pergamon Press Ltd. 1980. Printed in Great Britain.

AMITRIPTYLINE-INDUCED SUPPRESSION OF GROWTH HORMONE IN ACROMEGALY*t ALLAN R. GLASS, MARCUS SCHAAF a n d RICHARD C. DIMOND Kyle Metabolic Unit, Walter Reed Army Medical Center, Washington, D.C. 20012, U.S.A.

(Received 6 July 1979) SUMMARY (1) Amitriptyline (100 mg p.o. daily at bedtime) for 1 month s'~gnificantlyreduced 24 hr mean serum growth hormone in 3 of 5 acromegalic subjects studied (44, 22 and 18 % reductions). (2) Amitriptyline-inducedsuppression of growth hormone occurred primarily in the late afternoon and evening. (3) Amitriptyline delayed the nocturnal rise in serum growth hormone. (4) The clinical usefulness of amitriptyline in treating acromegaly would probably be very limited because of the modest nature of the reductions in serum growth hormone.

Key Words---Amitriptyline; acromegaly; growth hormone. INTRODUCTION IN PATIENTS with a c r o m e g a l y , g r o w t h h o r m o n e p r o d u c t i o n b y the associated p i t u i t a r y t u m o r is often n o t c o m p l e t e l y a u t o n o m o u s . F o r e x a m p l e , c h e m i c a l agents which are t h o u g h t to m o d i f y central n e r v o u s system levels o f n e u r o t r a n s m i t t e r s are often able to alter serum levels o f g r o w t h h o r m o n e in a c r o m e g a l y ( F r o h m a n & S t a c h u r a , 1975). This p h e n o m e n o n has led to the clinical use o f drugs, such as the d o p a m i n e agonist, b r o m o c r i p t i n e , to reduce g r o w t h h o r m o n e o u t p u t in a c r o m e g a l i c p a t i e n t s (Wass, T h o r n e r , M o r r i s , Rees, M a s o n , Jones & Besser, 1977). I n the s t u d y d e s c r i b e d below, a n o t h e r drug, amitriptyline, was f o u n d to suppress g r o w t h h o r m o n e m o d e s t l y , b u t significantly, in 3 o u t o f 5 a c r o m e g a l i c p a t i e n t s w h o h a d persistent elevations o f g r o w t h h o r m o n e despite p r i o r surgery a n d r a d i o t h e r a p y . MATERIALS AND METHODS Five males with acromegaly (failure of serum growth hormone to suppress below 5 ng/ml after oral glucose) agreed to participate in the study and provided written, informed consent. All 5 had had prior pituitary surgery in an attempt to cure the acromegaly, and 4 had also received radiotherapy (conventional X-ray in 3, proton beam in one). Three were on replacement hydrocortisone (20 mg at 08:00 hr, 10 mg at 16:00 hr) and 2 were on replacement thyroid hormone. To obtain 24 hr growth hormone profiles, blood was withdrawn via an indwelling catheter every 2 hr for 24 hr, during which time the patients were on a regular diet (meals at 08:00, 12:00 and 17:00 hr) and were ambulatory in regular ward activities. Blood samples for growth hormone determination were also obtained prior to and after 100 grams of oral glucose. After completion of these baseline studies, subjects were begun on amitriptyline, 50 mg p.o. at bedtime (between 22:00 and 24:00 hr). The dose of amitriptyline was increased over the next few days to 100 mg p.o. at bedtime and continued for 4 weeks. At that time 24 hr growth hormone profile and growth hormone response to oral glucose were reassessed. In patient V, 24 hr growth hormone profiles were obtained on several occasions in * Reprint requests:Dr Allan Glass, Kyle Metabolic Unit, Walter Reed Army Medical Center, Washington, D.C. 20012, U.S.A. * The opinions and assertions contained herein are the private views of the authors and are not to be .~onstrued as official or reflecting the views of the D e l ~ m e n t of the Army or the Department of Defense. 81

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ALLANR. GLASS,MARCUSSCHAAFand RICRARDC. DIMONI)

the following order: baseline, after 4 weeks on amitriptyline (Trial 1), after 12 weeks on amitriptyline, 5 days after discontinuation of amitriptyline, 5 weeks after discontinuation of amitriptyline and 5 weeks after amitriptyline had been restarted (Trial 2). During the latter 4 studies, blood samples were obtained at hourly intervals. Serum samples were stored at -20°C until assayed and all samples from a single patient were measured in the same assay. Growth hormone was measured by double antibody radioimmunoassay as previously described (Dimond, 1976). Limit of detectability was 1.25 ng/ml and intra-assay variation was less than 10 70. Statistical analysis was done by Student's t-test for paired data, comparing, in each subject, serum growth hormone at each time point before and after amitriptyline. This study was approved by the Human Use Committees of Walter Reed Army Medical Center and the Department of the Army, with no infringement of human rights and adherence to the Code of Ethics of the World Medical Association. RESULTS Patients I, III and V showed significant reduction in 24 hr mean serum growth hormone levels after 4 weeks on amitriptyline (Table I). Patients I and III were asympotmatic prior TABLE I.

Patient I II III IV V

2 4 H R MEAN SERUM GROWTH HORMONE BEFORE A N D AFTER AMITRnrrYLINE

Trial 1 Trial 2

Control 23.3 :k 2.6* 17.1 ± 2.0 25.9 :]: 1.9 10.2 ± 1.1 37.4 ± 4.8 25.3 :k 2.0

Amitriptyline 19.0 4- 2.6t 19.9 ± 2.5 20.1 ± 2.4t 10.0 ± 0.8 21.1 ± 2.7t 19.8 4- 1.31"

* Serum growth hormone in ng/ml (mean ± S.E.) (tP <0.05 by paired t-test). to the trial, but patient V had daily diffuse headache and pain in the left shoulder and neck which decreased while he was taking amitriptyline. Patient V showed growth hormone suppression by amitriptyline during 2 separate trials of the drug (Table I; Fig. 1.). His 24 hr mean serum growth hormone level remained suppressed during a 3 month trial of amitriptyline [22.2 -/- 1.4 (S.E.) ng/ml] at the same level as after a one month trial (21.2 -k 2.7 ng/ml), but rose significantly within 5 days of discontinuation of the drug (27.2 ~ 2.3; p <0.01 ; Fig. l, middle). Five weeks after discontinuation of amitriptyline his 24 hr mean growth hormone level remained lower than baseline (25.3 :k 2.0 ng/ml vs 37.4 i 4.8; p<0.05). Nevertheless, reinstitution of amitriptyline at this time (Trial 2) caused a further significant reduction in 24 hr mean growth hormone level (Table I). Examination of the 24 hr growth hormone profiles of the 3 responders showed that much of the growth hormone suppression produced by amitriptyline occurred in the late afternoon and evening (Figs. 1, 2). The acromegalics showed a diurnal variation in serum growth hormone which persisted during the trial of amitriptyline (Fig. 3), though the timing of the nocturnal peak was delayed while on the drug. Amitriptyline did not consistently change the growth hormone response to oral glucose. DISCUSSION A number of drugs, including somatostatin (Christensen, Nerup, Hansen & Lundbaek, 1976), bromocriptine (Wass et al., 1977) and metergoline (Delitala, Masala, Alagna,

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Amitriptyline was administered between22:00 and 24:00 hr. Devilla & Lotti, 1976), has been reported to lower growth hormone levels in subjects with acromegaly. In the current study, 3 of 5 acromegalic subjects who had persistently elevated growth hormone levels despite previous surgery and radiotherapy showed a modest, but significant, reduction in 24 hr mean growth hormone level during a one month trial of amitriptyline. Furthermore, the only responder who was symptomatic prior to the drug trial had substantial improvement in headache and neuromuscular symptoms while on the drug, though this change may have been due to the antidepressant or other effect of amitriptyline rather than the reduction in serum growth hormone. In this subject, mean serum growth hormone remained lower than baseline 5 weeks after amitriptyline had been discontinued. This finding suggests that amitriptyline may have a prolonged effect on suppression of growth hormone, though a spontaneous reduction in growth hormone output cannot be excluded. Thus, amitriptyline might be useful as an adjunctive treatment for selected patients with acromegaly, particularly in patients who have persistent growth hormone elevations following pituitary surgery or irradiation. Our data do not permit us to determine whether the modest reduction in growth hormone produced by amitriptyline will be of clinical benefit. Baseline 24 hr serum growth hormone profiles in our acromegalic patients showed a broad, sustained nocturnal rise in serum growth hormone. A similar pattern has been previously observed in 2/2 untreated and 1/4 radiation-treated acromegalie subjects (Carlson

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ALLAN R. GLASS, MARCUSSCHAAFand RICHARD C. DIIOND

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Gillin, Gorden & Snyder, 1972). Though we were unable to obtain electroencephalographic records of sleep stages to correlate with nocturnal growth hormone levels, previous work indicates there is no change in serum growth hormone with sleep stage acromegaly (Carlson et aL, 1972). Amitriptyline administration at bedtime in our acromegalic subjects seemed to suppress growth hormone primarily in the afternoon and evening, and it delayed the nocturnal rise in serum growth hormone. This property of amitriptyline might make it particularly suitable for use in conjunction with bromocriptine, which produces less suppression of nocturnal growth hormone secretion than of daytime growth hormone secretion (Chihara, Kato, Abe, Furumoto, Maeda & Imura, 1977). The mechanism by which amitriptyline lowers growth hormone in acromegaly is unclear. In normal subjects, other tricyclic anti-depressants produce diverse results, with imipramine suppressing nocturnal growth hormone secretion (Takahashi, Kipnis & Daughaday, 1968) and desimipramine stimulating growth hormone release (Laakman, Schumacher, Benkert & Werder, 1977). Amitriptyline is thought to inhibit the re-uptake of serotonin into nerve endings after its release into the synaptic cleft (Maas, 1975), and amitriptyline might thus be expected to activate serotoninergic pathways. However, the effect of activation of serotonin pathways on serum growth hormone in acromegaly has not been definitively established. Some investigators feel that bromocriptine and L-DOPA, which stimulate growth hormone in normals but suppress growth homone in acromegaly, are exerting these actions by stimulating serotonin pathways in the central nervous system (Smythe, Compton &

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FIo. 3. Diurnal variation in growth hormone in patients I-V while off amitriptyline (e~-Q) or on amitriptyline ( A - A ) . Growth hormone values at each time point for each subject were expressed as a percentage of that subject's 24 hr mean value. Amitriptyline was administered between 22:00 and 24:00 hr.

Lazarus, 1976). On the other hand, administration of cyproheptadine and metergoline, which block serotonin action, cause suppression of growth hormone in acromegaly (Delitala et al., 1976; Feldman, Plonk & Bivens, 1976). Amitriptyline also has anticholinergic actions and anticholinergics have been reported to reduce nocturnal growth hormone secretion in normal subjects (Mendelson, Sitaram, Wyatt, Gillin & Jacobs, 1978). Finally, amitriptyline might be exerting its effects through interaction with noradrenergic or other neurotransmitter pathways. The ability of amitriptyline to suppress afternoon and evening growth hormone output in acromegaly, in contrast to the greater suppression of daytime growth hormone secretion by bromocriptine, suggests that amitriptyline is not working by the same mechanism as bromoeriptine. Moreover, one of the patients who responded to amitriptyline showed no reduction in serum growth hormone during a two-week trial of the dopamine agonist lergotrile mesylate (6 mg/day; data not shown). Further studies will be necessary to clarify the mechanism by which amitriptyline affects growth hormone secretion. We would like to thank Ms Nancy Whorton and Ms Kathy Ward for expert technical assistance and Ms Denise Legere for secretarial help. We are indebted to the nurses of the Kyle Metabolic Unit for their invaluable role in making these studies possible. Dr Prentice Thompson provided valuable assistance. REFERENCES

C A ~ N , H. E., GILLIN, J. C., GORDEN, P. & SNYDER,F. (1972) Absence of sleep related growth hormone peaks in aged normal subjects and in acromegaly. J. Clin. Endocr. Metab. 34, 1102-1105.

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CHIHARA, K., KATO, Y., ABE, H., FURUMOTO,M., MAEDA,K. & 1MURA,H. (1977) Sleep-related growth hormone release following 2-bromo-~t-ergocriptine treatment in acromegalic patients. J. din. Endocr. Metab. 44, 78-84. CHRLq'I~NSEN,S. E., NERUP, J., HANSEN,A. P. & LUNDBAEK,K. (1976) Effects of somatostatin on basal levels of plasma growth hormone and insulin in acromegalics: dose-response studies and attempted total growth hormone suppression. J. elin. Endocr. Metab. 42, 839-845. DELITALA,G., MASALA,A., ALAGNA,S., DEVILLA,L. & LOT'n, G. (1976) Growth hormone and prolactin release in acromegalic patients following metergoline administration. J. clin. Endocr. Metab. 43, 1382-1386. DIMOND, R. C. (1976) Radioimmunoassay of human growth hormone. In Manual of Clinical Immunology, pp. 197-205, American Society for Microbiology, Washington. FELDMAN,J. M., PLONK,J. W. ~k BIVENS,C. H. (1976) Inhibitory effects of serotonin antagonists on growth hormone release in acromegalic patients. Clin. Endocr. 5, 71-78. FROHMAN, L. A. &; STACHURA,M. E. (1975) Neuropharmacologic control of neuroendocrine function in man. Metabolism 24, 211-234. LAAKMAN,G., SCHUMACHER,G., BENKERT,O. & WERDER,K. V. (1977). Stimulation of growth hormone secretion by desimipramin and chlorimipramin in man. J. clin. Endocr. Metab. 44, 1010-1013. MAAS,J. W. (1975) Biogenic amines and depression. Archs gen. Psychiat. 32, 1357-1361. MENDE~N, W. B., SITARAM,N., WYATT,R. J., GILLIN, J. C. • JACOBS,L. S. (1978) Methscopolamine inhibition of sleep-related growth hormone secretion. J. clin Invest. 61, 1683-1690. SMYTHE, G. A., COMPTON,P. J. & LAZARUS,L. (1976) Serotoninergic control of human growth hormone secretion: the actions of L-DOPA and 2-bromo