Adrenocorticotrophin and Cortisol secretion in children after low dose cranial irradiation

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<ul><li><p>Clinical Endocrinology (1993) 39, 297-305 </p><p>Adrenocorticotrophin and cortisol secretion in children after low dose cranial irradiation </p><p>E. C. Crowne, W. H. B. Wallace, S. Gibson, C. M. Moore, A. White and S. M. Shalet Department of Endocrinology, Christie Hospital, Manchester, UK </p><p>(Received 2 July 1992; returned for revision 6 Ocfober 1992; finally revised 5 February 1993; accepted 23 February 1993) </p><p>Summary </p><p>OBJECTIVE We investigated the effect of low dose cranial irradiation (18-24 Gy) on spontaneous ACTH and cortisol secretion in children. DESIGN We analysed 24-hour plasma ACTH and cortisol profiles sampled at 20-minute intervals. PATIENTS Twenty long-term survivors of acute lympho- blastic leukaemia were studied and results compared with those in 14 normal children. MEASUREMENTS ACTH and cortisol profiles were ana- lysed by Fourier transformation and spectral analysis of stationarired data, autocorrelation and coherency analy- sis. RESULTS The normal circadian rhythms of ACTH and cortisol were preserved in the children after cranial irradiation. The median 0900 h and midnight values were 1.50 (0.8-6.4)pmolll and 1 ~O(0~6-3~7)pmolll respectively for ACTH and 282(48-1913) nmol/l and 575(44-637)nmol/l respectively for cortisol, and were not significantly differ- entfrom those in the normal group. Fourier transformation revealed dominant periodicities for ACTH at 0.7-1.1 h, equivalent to 22-34 ACTH secretory bursts per 24 hours, and for cortisol at 0.7-1.1 h and 2-4.8 h. Similar results were found in the normal group. </p><p>Coherency analysis indicated a significant shared per- iodicity of 0.7-1.2 h in nine children, corresponding to 20- 34 related secretory bursts in 24 hours for ACTH and cortisol. After pooling the coherency spectra in the cranially irradiated group, comparison with the pooled data from the normal group revealed no significant difference between the two groups in the relationship between the two hormones. CONCLUSION No significant disruption of spontaneous ACTH or cortisol secretion, either in the amount or pattern </p><p>Correspondence: S.M. Shalct, Department of Endocrinology, Christie Hospital, Wilmslow Road, Withington, Manchester M20 9BX. UK. </p><p>of hormones secreted, was found in children after low dose cranial irradiation (18-24 Gy) </p><p>Abnormalities of the hypothalamic-pituitary axis following cranial irradiation are well established (Littley et a/., 1989a; Shalet, 1989) and can range from isolated G H deficiency to panhypopituitarism. The extent of pituitary hormone defi- ciency has been shown to be affected by irradiation dose, fractionation schedule and time elapsed since treatment (Shalct et ul., 1976; Rappaport &amp; Brauner, 1989; Clayton &amp; Shalet, 1991). There is an orderly sequence of hormone deficits following external pituitary irradiation; G H defi- ciency is followed by gonadotrophin deficiency in two-thirds of patients and by ACTH deficiency in the remaining third of adult patients who havc multiple deficits (Littley er a/., 1989a). In children, Sanders et al. (1 986) reported 24% of 78 children who received total body irradiation (dose 9.2- 15.75 Gy) in preparation for a bone marrow transplant showed abnormalities of the pituitary-adrenal axis 1-8 years later. </p><p>Recognition of ACTH and cortisol deficiency may be difficult as clinical signs are non-specific and the diagnosis may therefore be delayed. Furthermore, ACTH deficiency may not always be detected by conventional dynamic tests (Tsatsoulis et ul., 1988). The availability of a n immunoradio- metric assay for ACTH requiring only small sample volumes and with good precision at low concentrations (White et al., 1987) has allowed a re-evaluation of spontaneous ACTH secretion in both normal adults (Horrocks et al., 1990; Veldhuis et a/., 1990) and normal children (Wallace et al., 1991). </p><p>The aim of the present study is to assess the impact of low dose cranial irradiation (18-24 Gy) on physiological ACTH and cortisol secretion in children who have been treated for acute lymphoblastic leukaemia (ALL). </p><p>Patients and methods </p><p>The children were divided into two groups. </p><p>Group I: Post cranial irradiation children </p><p>This group consisted of 20 children ( 1 1 boys, 9 girls; aged 6.9-18.2 years), who were in first remission after treatment of ALL 3.6-10 years prior to study. Their ALL had been treated according t o standard UK protocols which had </p><p>297 </p></li><li><p>298 . C. Crowne et a / . Clinical Endocrinology (1993) 39 </p><p>included prophylactic cranial irradiation (18 Gy in 10 fractions over 14 days, n = 17; 24 Gy in 12 fractions over 21 days, I I = 3). </p><p>Group 2: Normal children </p><p>Details of these 14 children (9 boys, 5 girls; aged 3.0-15.5 years) have previously been reported (Wallace et a/ . , 1991). In brief, eight were normal siblings of Group 1 and six were children with familial short stature but normal growth velocities and normal G H responses to standard provocation tests. They were undergoing hormone investigations as part of on-going studies of G H secretion. </p><p>The children were admitted the night before sampling to acclimatize to the hospital. None of the children showed any cvidcncc of chronic disease or wcrc taking any medication. Pubertal staging was performed according to Tanner (1 962). </p><p>Samples were taken every 20 minutes for 24 hours (0900- 0900 h). Thc children rcmained ambulant and ate meals a t appropriate times. Extension tubing was attached at night to avoid disturbance of sleep. Samples were collected into heparinized containers, centrifuged and separated every hour, and then stored at -70C until assayed. Care was taken to ensure that the total volume of blood taken was always less than 8% of the subject's estimated blood volume. </p><p>The study was approved by the local ethical committee and written informed consent given by a parent for cach child. </p><p>Assays </p><p>All samples from one individual were measured in duplicate in the same assay. ACTH was measured in unextracted plasma using a two-site immunoradiometric assay (White et a/., 1987) which detects intact ACTH but not ACTH fragments (detection limit 1 pmol/l). Two monoclonal antibodies were employed; radiolabelled antibody IA12 binds to ACTH 10-18, and antibody 2A3 coupled to Sephacryl for the solid phase of the assay binds to ACTH 24- 39. </p><p>Cortisol was measured in unextracted plasma at low pH to eliminate binding by corticosteroid binding proteins. Corti- sol antiserum was preincubated with donkey anti-sheep antiserum and normal sheep serum (Scottish Antibody Production Unit) diluted in 0.13 M sodium chloride/phos- phate buffer, pH 4.0. This was then incubated with cortisol- 3-carbo~ymethyloxime~~~1 histamine and either standard or sample for 90 rninutcs at 37"C, centrifuged, separated and the supernatant counted in a multigamma counter. </p><p>Anafysis </p><p>The regularly sampled ACTH and cortisol profiles each form classical time series and are therefore amenable to spectral analysis. The profiles wcre examined to look at the impact of cranial irradiation on both the underlying patterns of secretion of ACTH and cortisol considcred separately, and the shared pulsatile features of the paired hormones. These techniques of hormone profile analysis have bccn uscd previously by Follenius et ul. (1987) for ACTH and cortisol, Veldhuis and Johnson (1988) for prolactin and LH, and Wallace et a/. (1991) also for ACTH and cortisol. The basic approach is an extension of cross-spectral analysis into coherency, where It is the shared spectral propcrtics that are of primary interest. The coherency spectrum has some advantages over the cross spectrum itself. Spectral analysis and coherency are discussed in the appendix. </p><p>Statistics </p><p>The areas under the curve (AUC) were calculated by the Gill-Miller Quadrature method (Gill &amp; Millcr, 1972). Diffcr- ences between groups of individual factors were analysed using the Mann-Whitney U-test initially. In addition, allow- ance for possible interactions between the three factors, namely treatment group, sex and pubertal status, were investigated using a rcgression approach to the analysis of unbalanced data. The hormone data were clearly not normally distributed on thc original scale of measurement and suitablc lransformations were required, namely the square root of the ACTH data and logarithmic transforma- tion of the cortisol data. The necessary assumptions for the analysis were satisfied with the transformed scales. Results are expressed as median(range). </p><p>Results </p><p>A normal circadian rhythm of ACTH and cortisol secretion was preserved in the children who had received cranial irradiation. The median 0900 h and midnight ACTH values were 1.5 (0.8-6.4)pmol/l and 1 .O (0.6-3.7)pmol/l respect- ively. The midnight value was below the level of detection of the ACTH assay in nine subjects. For cortisol the 0900 h and midnight values were 282 (48-1913)nmol/l and 57.5 (44- 637)nmo1/1 respectively. </p><p>The median AUC for ACTH and cortisol for Groups 1 and 2 sub-divided according to pubertal status are shown in Table 1. There was no significant difTerence within Group 1 between the prepubertal and pubertal children, or thc males and females, for either ACTH or cortisol AUC, mean 0900 or midnight value. Analysis of variance was used to look for any interactions of irradiation, pubertal status or sex on the </p></li><li><p>Clinical Endocrinology (1993) 39 </p><p>Table 1 Comparison of ACTH and cortisol profiles (median (range)) in children after low dose cranial irradiation (Group 1) with those in normal children (Group 2) </p><p>Table 2 Fourier transform of autocovariance data for ACTH and cortisol in children after cranial irradiation </p><p>ACTH and cortisol secretion after cranial irradiation 299 </p><p>Group 1 </p><p>ACTH (AUC) Cortisol (AUC) n (pmol/l h) (nmolil h) n </p><p>Total 20 32 (3-90) 4931 (3154-7242) 14 Prepubertal 7 25 (8-54) 4512 (3154-5842) 9 Pubertal 13 36 (3-90) 4936 (3778-7242) 5 </p><p>Group 2 </p><p>ACTH (AUC) Cortisol (AUC) (pmoI/l h) (nmol/l h) </p><p>30 (9-54) 5114 (3562-8631) 29 (9-54) 5223 (4627-863 I ) 30 (12-47) 4290 (3562-4833) </p><p>~~ ~ ~~ </p><p>ACTH dominant </p><p>Subject frequencies </p><p>Prepubertal I 0.8' 2 0.8* 0.9* 1.5 3 0.7* 0.9* 4 0.9* 1.0 2.0t 5 0.9* 1.3 6 0,8* 1.0 7 I.1* </p><p>8 0.8* 2.4 9 0.8* </p><p>10 0.7* 11 0.7* 0.9* 12 0.7* 13 0.7* 14 0.9* 15 0,7* 1.4t 3.0 16 0,8* 17 1.0* 18 0.9* 1.1' 19 NIL 20 0.7* </p><p>Pubertal </p><p>Cortisol dominant </p><p>frequencies </p><p>Coherency significantly shared </p><p>periodicities </p><p>0.8* 1.2 3.7 0.8* 0.9* 1.7 0.7* 0.9* 3.7 0,8* 2.17 I . l * 1.8 3.7 0.7* 1.3 2.7 1.0* 1,2* 2.0 </p><p>0.8* 1.3 3.2 0.7* 1.4 2.3 4.4 0.7* 0.8* 2.5 0,7* 0.9* 1.6 2.3 1.6 0.8* 1.2 2.3 0.7* 0,9* 1.8 0.7* 0.9* 4.8 0.8* 1.4t 2.5 0.8* 1.2 4.8/1 0.7 0.9* 1.5 0,8* 1.1* 2.5 1.0 1.2 2.5 0.8* 1.2 2.3 </p><p>0.7* 0.9' 1.3 0,7* 0.9* 1.7 3.4 0.8* 1.9t 2.7 5.3 0.7 4.0 1.4 2.2 0.8 0.9* 2-1 </p><p>2.7 Nil Nil (near 1.0) (Near 1.0) 3.4 Nil 0.7* 0,8* 3.2 I.O* 2.3 0.8* 1.9 2.7 5.3 1.2* 1.5 2.3 I.O* 2.5 Nil (near 1.1) 0.9* 2.5 </p><p>Values are in hours. *and 7, Related periodicities. </p><p>amount (i.e. AUC or mean level) of hormone secreted. There was no significant effect of these factors on ACTH secretion. Cortisol secretion did not show any effect of sex, either alone or combined with the other factors. Analysis of variance did however show a significant interaction of pubertal status and treatment group on cortisol secretion (P=0.01). It can be seen in Table 1 that cortisol AUC is lower in the pubertal normal group when compared with the prepubertal group. There is no significant difference in the irradiated group and the trend is in the opposite direction. </p><p>The dominant periodicities revealed by Fourier transfor- mation of the autocovariance data of both ACTH and cortisol in Group 1 are shown in Table 2. Univariate spectra </p><p>(the first two columns) show individual characteristic perio- dicities but say nothing about how closely related are ACTH and cortisol. The coherency data in the third column identify what is effectively the square of the linear correlation between ACTH and cortisol at each periodicity. The closer the coherency to unity, the more closely related are ACTH and cortisol secretory processes during a given period. </p><p>The results arc very similar to those found in the normal children (Wallace et al., 1991). Cortisol shows two significant periodicies, at 0.7-1 ' 1 h and 2-4.8 h (cf.O.7-1.0 h and 2-3.2 h in Group 2). ACTH has dominant periodicities at 0.7-1.1 h, equivalent to 22-34 ACTH secretory bursts per 24 hours (cf. 0.7-1.0 h in Group 2). </p></li><li><p>300 E. C. Crowne e ta / . Clinical Endocrinology (1993) 39 </p><p>2 1.0 V </p><p>0.6 </p><p>0 . 2 </p><p>1.0 </p><p>0.6 </p><p>0 - 2 </p><p>4.8 1.6 0.96 0-68 4.8 1-6 0.960.68 4.8 1.6 0.96 0.68 4.8 1.6 0-46 0.68 4.8 1.6 0.96 0.66 </p><p>Periodicity ( h ) </p><p>Table 2 also shows the significant shared periodicities between ACTH and cortisol (i.e. those that have achieved a 9S'X confidence levcl) for Group 1 . The coherency spectrum for each child in Group 1 is shown in Fig. 1. There is a significant shared periodicity of 0.7-1.2 h in nine childrcn, corresponding lo 20-34 related secretory bursts in 24 hours for ACTH and cortisol. I t is interesting to note in the pubertal group, although there are significant periodicities for both ACTH and cortisol a t 0.8 1.0 h in most of the individual profiles, Lhese do not achieve significance in the coherency data because the longer periodicities of 1.6-3.4 h are the more dominant for cortisol. </p><p>Figure 2 presents the pooled coherency spectra for Group 1 and Group 2, and it can be seen that both normal and irradiated children show pooled cohcrcncics that have peaks at the same periodicities. </p><p>Fig. 1 The coherency spectrum for each of the 20 children who had received cranial irradiation is displayed and significant shared periodicities indicated with an arrow. The dashed line shown on each coherency spectrum represents the 95% confidence interval above which significance is achieved </p><p>Discussion </p><p>Low dose prophylactic cranial irradiation (18-24 Gy) has succesfully reduced the incidence of CNS relapse in ALL (Nesbit et al., 1981) but has been shown to cause damage to the hypothalamic-pituitary axis. Of the pituitary hormones, G H appears to bc the most sensitive to radiahn-induced damage (Shalet, 1989). Reported abnormalities following cranial irradiation with 24 Gy include blunted G H responses to pharmacological stimuli in both prepubertal and pubertal children (Kirk et al., 1987; Shalet et al., 1979), a normal G H response to pharmacological stimulus but subnormal spon- tancous GH secretion (Blatt et al., 1984), and reduced spontaneous GH secretion in prepubertal and pubertal girls with a failurc of the expected increase of GH secretion at puberty (Moell et ul., 1989). We havc shown that the lower </p></li><li><p>Clinical Endocrinology (1993) 39 </p><p>0.45 </p><p>0.40 </p><p>I / d </p><p>L a </p><p>0 5 0.55 </p><p>0.45 </p><p>0.40 </p><p>0.35 I 1 </p><p>0.30 </p><p>0.25 </p><p>P i </p><p>0.9 loo 2 </p><p>Periodicity ( h ) </p><p>I </p><p>I_-/ 3 4 </p><p>Fig. 2 The pooled coherency spectra for the ACTH and cortisol profiles of a, Group 2 and b, Group 1 are shown. Both groups show pooled coherencies that have peaks at the same periodicities. </p><p>prop...</p></li></ul>

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