Effect of sustained-release theophylline administration on pituitary-thyroid axis

Effect of sustained-release theophylline administration on pituitary-thyroid axis Michio Hiratani, M.D., Kazuhiko Muto, M.D., Yoshihiro Oshida, M.D., Shigeru lto, M.D., Masaharu Kasei, M.D., Satoko Ueda, M.D., and Tamotsu Sato, M.D., Kanazawa, Japan

The efiec~ of therapeutic doses of theof&vfline on the pituitary-thyroid uxis was studied in .fixtt normal adults and in 1.5 asthmatic children on theophylline treatment. In the Jour normal adult.c, sustained-release theophylline was administered every 12 hr for 60 hr, and serial determinations of‘ serum theophylline, thyroxine (T4), triiodothyronine (Tsl. reverse triiodothyronine (VT, ), thprotropin (TSH). and cyclic AMP (CAMP) were done. In all four cnws. serum T4 increased .signiJcantly (134% + 4% vs basal level) with significant correlation to plasma (-AMP fe\-el Ir = 0.67. p < 0.05). Changes in T3 and rT3 showed a marked individuality: an incretrsc in T,, occurretf in a subject with severe side effects, while the increase in rTS was observed in a .subject with mild side effects. Of the IS children on theophyfline treatment, u higher 7; level was,found in I2 und a lower T3 level in nine at I wk, but these valtces returned to the previous le\~l Ltfter 4 \vk. These results indicate that the therapeutic doses of theophylline significantly bat rransientfy increased the serum T4 level. In most cases, T4 is metabolized to rT,, an irzrrc,ti\tc’ metabofite of T4, but in a few cases it is metabolized to T:%.which might double the side cf@ I.~ qftheophyiline. (J ALLERGY CLINIMMUNOL 70:48/. 1982.)

Theophylline is thought to improve asthma by increasing CAMP levels through its inhibition of cyclic nucleotide phosphodiesterase. This results in the inhibition of bronchial smooth muscle contraction and the inhibition of mediator release in asthmatic subjects. The role of the cyclic nucleotide, CAMP, as an intracellular second messenger has gained wide acceptance in explaining the mechanisms of action of many hormones and drugs.‘, 2 Although oral theophylline therapy might have some effects on various endocrine hormone secretions, there are few studies that demonstrate the in vivo3-’ and in vitros, g effects of theophylline on endocrine hormones. For example, there is evidence that aminophylline given intravenously elicits a greater elevation in the plasma thyrotropin (TSH) response to the TSH-releasing factor in man7 or blunts the growth hormone response to insulin-induced hypoglycemia.” In isolated anterior pituitary tissue from rats or humans9 it was observed that theophylline sig-

nificantly stimulated growth hormone secretion. Recently Tulin-Silver et al.” reported that therapeutic doses of theophylline given orally to humatn subjects caused a significant but transient increase in cortisol secretion. All these effects of theophyliine are thought to be mediated by increased intracellular CAMP levels. In the thyroid gland, CAMP, acting as the second intracellular mediator of TSH, appears to be able to reproduce the important actions of the hormone.” But there are no published studies concerning the effects of therapeutic doses of theophylline on thyroid hormone secretion. In addition, both the states of hyperthyroidism and theophylline toxicity have a common character, which includes the increased activity of the sympathetic nervous system.“’ I2 It is well known that hyperthyroidism has been noted to increase the severity of asthma attacks.‘:’

Abbreviations From the Department of Pediatrics, School of Medicine, Kanazawa University, Kanazawa, Japan. Supported in part by a grant from the Ministry of Education, Japan. Received for publication March 9, 1982. Accepted for publication July 19, 1982. Reprint requests to: Dr. Michio Hiratani, Department of Pediatrics, School of Medicine. Kanazawa University, Kanazawa-920. Japan. 0091-6749/82/120481+06$00.60/0

0 1982 The C. V. Mosby Co.

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In the present study we have demonstrated that therapeutic doses of theophylline brought about a significant but transient rise in the plasma T4 levels. MATERIALS

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Four normal healthy adults who had no significant past or current history of allergic or other systemic diseases received five doses of 300 mg of sustained-release theophylline (Theo-Dur, Mitsubishi Kasei Kogyo, Inc., Tokyo, Japan). Serial plasma samples were collected 12 hr before and 0, 2, 4, 8, 12, 20, 24, 36, 40, 44, 48, 56, and 60 hr after theophylline administration for measurement of theophylline, Tq, T,, rT,, TSH, and CAMP levels. The mean of the first two samples (12 hr before and just before theophylline) was used as a baseline level. Urine samples were collected every 12 hr for 24 hr before and 60 hr during theophylline administration for measurement of urinary CAMP excretion. The mean of the first two samples collected for 24 hr before theophylline administration was used as a baseline of 12 hr CAMP excretion. In the second experiment, 15 children who were receiving theophylline prophylaxis for chronic asthma were examined. All were from the Pediatric Allergic Service at the Kanazawa University Hospital. The study group included 11 girls and four boys whose ages ranged from 5 to 14 yr. None was receiving corticosteroids or other bronchodilating drugs. Plasma samples were collected before and 1 and 4 wk after receiving theophylline for measurement of theophylline, Tq, T,, and rT, levels. Plasma theophylline concentration was assayed by a homogeneous Enzyme Immunoassay (Syva Semiautomatic for Emit Assayi4). The thyroid hormone concentrations were measured by commercially available kits, T4 by Gamma Coat radioimmunoassay (RIA) kit (Clinical Assay, Division of Travenol Laboratories, Inc., Deerfield, Ill.), T, and rT, by RIA kits (Dainabot Radioisotope Laboratories, Tokyo), TSH by RIA kit (Daiichi RI Co., Tokyo), and CAMP by RIA kit (Yamasa Shoyu Inc., Tokyo). The study

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FIG. 2. Percent increase in plasma T, (top), T, (middle), rT, (bottom) levels of four normal subjects receiving 300 mg of theophylline every 12 hr for 60 hr. Arrows indicate the time of administration. One subject (0) stopped receiving theophylline at 46 hr because of severe side effects. Basal levels of T,, T, and rT, of the four subjects are given. Shaded areas, Basal levels and below.

of Orgiazzi et al.” indicated that the presence of theophylline in the serum would not interfere with the measurement of CAMP, and it was confirmed by our preliminary study (data not shown) that the presence of theophylline did not affect measurement of T4 and T,.

RESULTS Short-term challenge with theophylline in the four normal subjects Serum theophylline concentration (Fig. 1). Serum theophylline concentration reached its plateau level by 40 hr. Peak concentrations (mean + 1 SD) were 11.9 t 4.3 pg/ml. One subject stopped receiving theophylline at the final treatment (48 hr) because of severe side effects, including tachycardia, restlessness, nausea, and sleep disturbance. Serum T4, Tt, rT3, and TSH levels (Fig. 2). In all four cases, serum T4 levels increased in parallel with theophylline concentrations, and all concentrations significantly exceeded the normal range at their peak levels (12.1 to 15.0 pg/ml). There were no significant differences in the percent increase levels between the

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t’our subjects ( 134% t 4% vs basal level). Changes in serum Ts and rT3 varied individually. A significant

increase in T, (250% vs basal level) with no change in rT, was observed in one subject who had to stop receiving theophylline because of severe side effects. A significant increase in rT, (233% and 222% vs basal levels) with no change in T, level was observed in two subjects who showed only mild side effects. In another subject, no remarkable change in T3 and rT3 was observed. Baseline TSH levels of each individual were 3.2, 1.7, 2.4, and 2.0 (@J/ml), respectively, and the means (L 1 SD) of the TSH level of the four subjects at 0. 12, 24. 36, and 48 hr were 2.3 t 0.65, 2.4 t 0.39, 2.3 + 0.38, 2.3 + 0.25, and 1.72 + 0.60 ~IUlml, respectively. These results showed that TSH had no significant correlation with the plasma T, levels. Plasmaie~~els und urinary excretion of CAMP (Fig,

3). Plasma CAMP levels and urinary excretion of CAMP reached peak levels in 24 hr but gradually decreased after 48 hr. Correlation betweenplasma theophylline, T,, and CAMP levels (Fig. 4). Because of the following rea-

sons we compared only the plasma T, and CAMP levels from 8 hr to 36 hr after theophylline treatment. First, plasma half-time of T, (6 to 7 days) is much longer than that of plasma CAMP (<30 min),16 and plasma CAMP levels decreased after 40 hr, whereas T, levels were unchanged until 60 hr. In Fig. 4 (left panel) we compared the percent increase in CAMP levels and plasma theophylline concentrations. A wide variation of CAMP levels was observed in certain concentrations of theophylline. For example, one subject (L.) showed high plasma CAMP levels but low theophylline concentrations; on. the other hand, another subject (J) showed low CAMP levels and high theophylline levels. But there seems to exist a positive correlation between CAMP and theophylline concentrations in the four subjects. In the right panel of Fig. 4 we compared the percent increase rate in plasma T, and CAMP levels. There was a significant correlation between them (Y = 0.24x k 10.4, r = 0.67, p < 0.05). Changes in thyroid asthmatic children treatment

hormone levels in 15 on daily theophylline

Changes in T4, T,, and rT3 levels (Fig. 5). Mean (2 1 SD) plasma levels of each hormone before and after 1 and 4 wk of theophylline therapy were as follows: T,, 9.4? 2.1, 10.7 t 1.3, and 9.8 2 1.6 pug/ml; T,, 144 r 22, 131 + 18, and 142 t 23 ng/dl; rT,, 337 2 115, 395 ? 155, and 322 + 61 ng!dl. After 1 wk of theophylline therapy a slight increase in T,, a decrease in T,, and an increase in rT,

FIG. 3. Percent increase in plasma cAfvlP (top) and 12 hr urinary excretion (b@k&. Arrows indicate the time of administration of theophylline. One subject (~4 stopped receiving theophylline at 48 hr because of severe side effects. Basal levels of plasma CAMP concentrations (pmollml) and 12 hr urinary excretion (ctmoU12 hr) of the four subjects are as follows: C, 28.7, 10.3; e, 31.5, 8.3; c, 19.4, 9.5; A, 20.6, 3.96.

were observed. Although these changes are not significant, after 1 wk of therapy 12 of the 15 subjects had higher T4 (p < 0.05 by sign test) and nine had lower T3 levels in comparison with their basal levels. After 4 wk, in the seven subjects examined, these hormone levels returned to their basal levels. Mean (+ 1 SD) plasma theophylline level of these children was 7.9 ? 2.1 kg/ml at 1 wk. DISCUSSION The data from this study showed that the therapeutic range of theophylline caused a significant increase in T, excretion. Similar results showed that fheophylline in therapeutic quantities produced a small increase in cortisol secretion, and a clearance that dissipated within 3 days during theophylline administration was reported by Tulin-Silver et ai.s It is well known that in the thyroid gland, CAMP acting as the intracellular mediator of TSH appears to reproduce the important action of TSH. It was also demonstrated that betaadrenergic agonists activate thyroid adenykyclase and thus stimulate the thyroid function.1° Our results show that there is a significant correlation between the percent increase of T, and CAMP levels and no parallel change between TSH and T, levels. These results indicate that heightened T, production was mediated by in-

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FIG. 4. Correlation between plasma theophylline, T,, and cAMP levels. Only the results from 8 hr to 36 hr were compared. Left, Regression coefficient of each subject between CAMP and theophylline are as follows: (all of them are not significant) (0, Y = 3.9x - 5.6, r = 0.79; l , Y = 9.9x - 42.3, r = 0.36; A, Y = 13.4x + 21.9, r = 0.45; A, Y = 8.8x - 12.2, r = 0.80. Right,There was a significant correlation between percent increase in plasma CAMP and T, levels.

creased intracellular CAMP concentration induced by theophylline. But it is conceivable that the increase in total T4 may reflect alteration of binding of thyroid hormone to binding globulin or could result from displacement of storage sites of Tq, perhaps in the liver. These possibilities remain to be clarified in a future study. In our experiment, T, was at a peak level even at 60 hr, and the 15 children under the prophylactic treatment with sustained-release theophylline showed high T4 levels at 1 wk, which returned to the basal level after 4 wk. Although we did not assay the intracellular CAMP level, the gradual decrease in the serum levels and urinary excretion of CAMP during 48 hr showed that the enhancing effect of theophylline on CAMP levels is a transient one. From the above-mentioned results we can confirm that the effects of theophylline on T., excretion are also transient, dissipating between 1 and 4 wk. Compared with the results of Tulin-Silver et al.,fi this longer duration probably comes from the longer half-time of T, (6 to 7 days)” as opposed to that of cortisol (about 1.5 hr).i7 The concentration of theophylline that inhibits the CAMP phosphodiesterase activity in vivoi8 and in vitro1H-2n is higher than can be achieved therapeutically in humans,rs so we cannot conclude that this action of theophylline to elevate T, secretion is by its direct effect on phosphodiesterase activity. Although there might exist some other mechanisms between theophylline treatment and the increase in CAMP levels,‘**” we can conclude that the therapeutic range of theophylline actually elevated the CAMP levels and stimulated the T4 secretion. It is well known that one of the important routes of metabolism of T4 is the peripheral conversion of T, and rT3,24 and because thyroid secretion may account

for about 23.8% of serum T, and only about 2.5% of rTQ level,*j we assayed the plasma T, and rT3 levels. One subject who showed several signs of side effects from the theophylline treatment had a higher level of theophylline (17.3 pg/ml). It is interesting to note that this subject had a remarkable increase in T,, with no change in the rT, level. In contrast, the other two subjects with significant increase in rT3 and no change in T, showed only slight side effects. It was also reported that when T, was given to euthyroid subjects, some of them first showed high T, levels and high rT, levels thereafter, but others responded with high rT, levels with stable T, levels.26 T, is metabolically four times more potent than T4, but rT, is inactive or rather inhibits T, activities. l l We found that in most of the asthmatic children taking daily administration of theophylline, higher T4, lower T,, and higher rT, levels were observed after 7 days of treatment. These results suggested that although T4 levels were elevated by theophylline administration, in a majority of these cases T, is converted to rT,, the inactive metabolite of T4, thus bringing about no hyperthyroidic state. It is also well known that hyperthyroidism has been noted to increase the severity of asthma, and control of it might relieve asthma.13 But the state of hyperthyroidism induced by theophylline is very mild and probably a subclinical one, and we can find no report showing that theophylline treatment worsened the severity of asthma. We can therefore confirm that an elevated T4 or T, level has no effect on the asthmatic state. In conclusion, therapeutic doses of theophylline produced a small increase in plasma T4 level, and in a majority of these cases, elevated T4 is converted to rT,, an inactive metabolite of T4, thus bringing about

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FIG. 5. Changes in plasma T,, T,, and rT, levels of asthmatic children during prophylactic treatment with theophylline. Twelve had higher T, levels (p < 0.05 by sign test) and nine had lower T3 levels (not significant) after 1 wk, which dissipated after 4 wk.

no hyperthyroid state. In a few cases, however, it is metabolized to T,, which might double the side effects of theophylline, but this effect would be a transient one. Therefore long-term administration of theophylline to control asthma in children is a safe method with regard to the thyroid function. We are deeply grateful to professor N. Taniguchi (Department of Pediatrics, School of Medicine, Kanazawa University) for his valuable suggestions and criticism.

REFERENCES I. Greengard P, Robison GA: Advances in cyclic nucleotide research. New York, 1972-1977, Raven Press, vols. l-8. 2. Robison GA, Butcher RW, Sutherland EW: Cyclic AMP. New York. 1971, Academic Press, Inc. 3. Peracchi M, Cavagnani F, Pontiroli AE, Raggi IJ, Malinnvemi A, Pinto M: Effect of aminophylline on growth hormone secretion in man. Acta Endocrinol 76:488, 1974. 4. Amman K. Carlstrom S. Thorell JI: The effect of norepinephrine and theophylline on blood glucose, plasma FFA, plasma glycerol and plasma insulin in normal subjects. Acta Med Stand 197:271, 1975. 5. Ensick JW, Stall RW, Gale CC, Santen RJ, Touber JL, Williams RH: Effect of aminophylline on the secretion of insulin. glucagon, luteinizing hormone and growth hormone in human. J Clin Endocrinol 31: 153, 1970. 6. Tulin-Silver J, Schteingart DE, Mathews KP: Effect of theophylline on cortisol secretion. J ALLERGY CLIN IMMUNOL 67:45. 1981. 7. Faglia G, Ambrosi B, Beck-Peccoz P, Travaglini P, Ferrari C: rhe effect of theophylline on plasma thyrotropin (HTSH) response to thyrotropin releasing factor (TRF) in man. J Clin Endocrinol Metab 34~906, 1972. 8. Lockhart Ewart RB, Taylor KW: The regulation of growth hormone secretion from the isolated rat anterior pituitary in vitro. The role of adenosine 3’ : 5’-cyclic monophosphate. Biochem J 124:815. 1971.

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9. Adams EF. Brajkovich IE, Mashiter Ki: Hormt~nz ;ccrt’~l,‘n h) dispersed cell culture of human pituitary aden+lmss: eflect ot theophylline, thyrotropin-releasmg hormcrnc. somato\tatln. and 2-bromo-tr-ergocr)ptine. J Clin Fntirrcrrt li Mrr;th 4% 120. 1979 10. Dumont JE, Boeynaems JM. Decoster C’, Ernt~iix i L~rn) F. Lecocq R. Moeckel J. Unger .I. Sandr J\. Hi~r~:hen:ical mechanism in the control of thyroid function and :i:)~..lh Adi Cvclic Nucleotide Res 9:723, 1978. Il. Hayneh RC Jr. Murad F: Thyroid and dnt@hcrord drugs. l,t Gilman AG, Goodman LS, Gilman A . edItor\: T‘hc pharmacological haais of therapeutic\. cd 6 ‘le\~ \iork !Y80. Macmillan Publishing Co., Inc.. p. 1 ic)?. ttx tanthmes. (II 12. Rail TW: Central nervous system stunulant\: Gilman AG. Goodman LS. Gilman 4. rcditor” The pharmacological baslc of therapeutics. cd b Net>- ?nrl, 1980. Macmillan Puhlishmg Co.. Inc.. p. 592 13. Bush RK, Ehrlich EN, Reed CE: Thyroid diie;tse and asthma J ALLERGY CLIN IMMIJNOL 59:398, 1077 14 Gushaw JB. Hu MW. Singh P. Miller JG. Schneider RS: Homogenous enzyme immunoassay for theophylline in serum. Clin Chem 23: 1144. 1977. 15 Orgiazzi J, Williams DE, Chopra IJ, Suiomton DH: Human thyroid adenyl cyclase-stimulating activity in immunoglobulin G of patients with Graves’s disease I Clin Endocrinol Metab 42:341, 1976. 16 Broadus AE, Kaminsky NI, Hardman JG, Sutherland EW, Liddle GW: Kinetic parameters and renal clearances of plasma adenosine 3’,5’-monophosphate and guanosine 3’.5’monophosphate. J Clin Invest 492222. 1970. 17 Haynes RC Jr, Murad F: Adrenocorticotropic hormone: adrenocorticosteroids and their synthetic analogs; inbibttors of adrenocortical steroid biosynthesis, in Gilman AG. Goodman LS, Gilman A. editors: The pharmacological basis 01 therapeutics, ed. 6 New York. 1980. Macmillan Publishing Co.. Inc.. p. 1466. 18 Vemikos DJ, Haris CG III: The effect 01 in vitro and III vtvo caffein and hydrocortisone on the phosphodiesterase activity of the pituitary. median eminence, heart and cerebral uxtex of the rat. Proc Sot Exp Biol Med 128~1016. 1968. 19 Kolbeck RC. Speir WA Jr, Carrier GO. Bransom ED Jr: Apparent irrelevance of cyclic nucleotides to the relaxation of tracheal smooth muscle induced by theophyltine. Lung 156:173, 1979. 20 Horrobin DF, Manku MS, Franks DJ. Iiamet P: Methyl xanthine phosphodiesterase inhibitors behave as prostaglandin antagonists in a perfused rat mesenteric artery preparation. Prostaglandins 13:33, 1979. aminophylline. Lancet 3: 1056, 1974. 21 Atuk NO: Intravenous 22 Aunis D, Mandel P, Miras-Portugal MT. Coquillat G. Rohmer F. Warter JM: Changes of human plasma dopamine-/3hydroxylase activity after intravenous administration of theophyliine. Br J Pharmacol 53:425. 1975. 23 Atuck NO, Cary Brayders MC, Westervelt FB Jr, Wood JE Jr: Effect of aminophylline on urinary excretion of epinephrine and norepinephrine in man. Circulation 35745. I%7 S, Burger A. Tibblin 24 Westgren U, Melander A, Ingemansson S, Wahlin E: Secretion of thyroxine , 3.5.3’~triiodothyronine and 3,3’,5’-triiodothyronine in euthyroid man. Acta Endocrinol 84:281, 1977. 25 Chopra IJ: An assessment of daily production and signtlicance of thyroidal secretion of 3.3’S’-triiodothyronine (reverse T,) in man. J Clin Invest 58~32, 1976. 26 Masuyama T: The study of anterior pitmury hormones in childhood. J Juzen Med Sot 87:387, 197X