and adults with growth hormone deficiency

Transcription

1 Postgrd Med J (1993) 69, D The Fellowship of Postgrdute Medicine, 1993 New mrkers of one nd collgen turnover in children nd dults with growth hormone deficiency A. Srtorio, A. Conti nd M. Monzni Itlin Auxologicl Center, Miln nd Institute ofendocrine Sciences, University ofmiln, Miln, Itly Summry: Serum one Gl protein (BGP), mrker of osteolstic function, serum croxyterminl cross-linked telopeptide of type I collgen (ICTP), mrker of one resorption, nd serum minoterminl propeptide of type III procollgen (PIIINP) levels, n index of collgen synthesis, were determined in seven children nd eight dults with congenitl growth hormone deficiency (). In children with, serum BGP (men ± s.e.: 12.9 ±.7 ng/ml), ICTP (8.3 ± 1.3 ng/ml) nd PIIINP (3.5 ±.5 ng/ml) levels were significntly lower (P <.1) thn those recorded in norml children (BGP 18.9 ±.8 ng/ml, ICTP 14.4 ±.5 ng/ml nd PIIINP 6.7 ±.7 ng/ml). Totl lkline phosphtse (184.7 ± 13.4 IU/l) nd one lkline phosphtse (77.8 ± 4.1 IU/I) levels were lso significntly lower (P <.1) thn in controls (338.1 ± 14.9 IU/I nd 181. ± 7.8 IU/1, respectively). Serum BGP, ICTP nd PIIINP levels were not significntly correlted with height velocity vlues. In dults with, men BGP levels (3.8 ±.3 ng/ml) were significntly lower (P <.1) thn those recorded in normls (5.4 ±.1 ng/ml). On the contrry, serum ICTP levels were similr to those found in controls (ptients: 4.7 ±.8 ng/ml vs normls: 4.1 ±.3 ng/ml), suggesting the presence of norml resorption ctivity ssocited with reduced osteolstic function. This finding ws lso confirmed y the presence of reduced one lkline phosphtse levels (: 44.9 ± 6.9 IU/I vs controls: 58.3 ± 2. IU/I; P<.2), while the less specific totl lkline phosphtse levels (119.5 ± 14.8 IU/I) were similr to those recorded in norml sujects (122.3 ± 4. IU/I). Serum PIIINP levels (3.7 ±.6 ng/ ml) were similr to those recorded in normls (3.2 ±.2 ng/ml), suggesting tht in dulthood the collgen turnover is not negtively influenced y the chronic. No significnt correltions were found etween BGP/ICTP/PIIINP nd IGF-I levels. In conclusion, our dt show tht in children with the lck of GH insulin-like growth fctor-i (IGF-I) effects on one nd collgen turnover is ssocited with significnt reduction of one turnover (low one formtion plus low one resorption) nd collgen synthesis. On the contrry, dult seems to exert less relevnt effects on one nd collgen turnover, proly due to the fct tht in dult life further hormones or locl fctors might prtilly counterct the negtive consequences of chronic GH-IGF-I deficiency. Introduction It is well known tht growth hormone (GH) plys relevnt role in one nd collgen turnover, its effects eing medited t lest in prt y insulin-like growth fctor I (IGF-I).'-5 The negtive effects of GH deficiency () on one (tht is, osteopeni, low one remodelling) nd collgen turnover (tht is, reduced totl skin collgen content, reduced skin thickness) hve een prtilly evluted in children with,3'6- " while the importnce of the metolic effects of GH hs een pprecited only recently in dults with.'-'4 Correspondence: Alessndro Srtorio, M.D., Lortorio Sperimentle di Ricerche Endocrinologiche, Centro Auxologico Itlino, IRCCS, Vi Ariosto Milno, Itly. This study ws prtilly supported y Progetti di Ricerc Corrente, Centro Auxologico Itlino, IRCCS, Miln, Itly. Accepted: 7 July Up to now, the iochemicl evlution of oth one formtion/resorption nd collgen synthesis hs een prevented y the lck of specific nd relile mrkers, since the use of clssicl prmeters (tht is, totl lkline phosphtse, urinry hydroxyproline, urinry clcium/cretinine rtio) is frequently unle to clerly detect the finest modifictions occurring in one nd collgen turnover. In the lst few yers, new specific nd relile iochemicl mrkers of one formtion/resorption nd of collgen synthesis hve een discovered nd usefully employed for monitoring the course of severl metolic nd endocrine disorders In this study we determined serum one Gl protein (BGP), mrker of osteolstic function, serum croxyterminl cross-linked telopeptide of type I collgen (ICTP), mrker of one resorption, nd serum minoterminl propeptide of type

2 III procollgen (PIIINP) levels, n index of collgen synthesis, in children nd in dults with congenitl. Mterils nd methods Seven children (6M/lF, men ge ± s.e.: 12.1 ±.9 yers) nd eight dults (8M, men ge: 29.6 ± 1.2 yers) with idiopthic were dmitted to the study fter giving informed consent. Children with (criterifor dmission to the study) The dignosis of ws sed on the following criteri: (1) yerly growth velocity less thn 3rd centile for ge; (2) dely of one ge greter thn 2 yers for their chronologicl ge; nd (3) filure of plsm GH to respond (pek < 5 ng/ml) to insulin hypoglycemi nd L-dop plus proprnolol tests. Men height, mesured with Hrpenden stdiometer, ws 134. ± 3.9 cm (rnge: cm); men ody weight ws 35. ± 2. kg (rnge kg). Body mss index (BMI, kg/m2) ws 19.6 ±.6 (rnge: 17..5). Men height velocity ws 2.7 ±.4 cm/yer (rnge: cm/yer); one ge (BA), estimted y single oserver using the method of Tnner- Whitehouse (TW2), ws 1.6 ±.9 yer (rnge: 8-14 yer). Adults with The dignosis of ws confirmed in ech suject y mens of two GH stimultion tests. All ptients hd erlier received GH sustitution therpy during childhood; the men durtion of erlier GH tretment ws 5.2 ± 3.9 months; previous GH therpy hd een interrupted t lest 7 yers (men: 11.4 ± 1.1 yers) efore the entry into the present study. Five ptients hd in ddition multiple hormone deficiencies nd therefore received stndrd sustitution therpy of hydrocortisone, thyroxine nd/or testosterone. The men ctul height ws ± 3.6 cm (rnge: cm); men weight ws 45.9 ± 3.7 kg (rnge: kg); men BMI vlue ws 21.6 ± 1.5 (rnge: ). Lortory ssys Dt otined were compred with those recorded in two ge- nd sex-mtched control groups ( norml children nd 28 norml dults). Serum BGP, ICTP nd PIIINP levels nd plsm IGF-I levels were determined using commercil RIA kits (CIS Dignostics, Itly; Orion Dignostic, Finlnd; Frmos, Finlnd; nd BONE AND COLLAGEN TURNOVER IN GH DEFICIENCY 847.u = - ) c o I- - 1 E 8 z CL 4 EO Children P <.1 _ cp <.1 8 co LIpP<.1 Figure 1 Serum BGP (), ICTP () nd PIIINP (c) levels in seven children with GH deficiency nd in controls (gend sex-mtched control group, ). Nichols Institute, USA; respectively). The intrnd inter-ssy coefficients of vrition of BGP, ICTP nd PIIINP RIA methods were lower thn 6%; the sensitivity ws.5 ng/ml (for BGP),.5 ng/ml (for ICTP) nd.2 ng/ml (for PIIINP). Totl lkline phosphtse ctivity ws mesured spectrophotometriclly using p-nitrophenylphosphte s sustrte. Serum one isoenzyme (lectin-precipitted) lkline phosphtse ctivity ws determined y the method descried y Roslky nd Foo.'9 I

3 848 A. SARTORIO et l. 5 4 v 3 FL v 3 m 1 u Children Figure 2 Serum totl lkline phosphtse (T-AP; ) nd one lkline phosphtse (B-AP; ) levels in seven children with GH deficiency nd in controls (ge- nd sex-mtched control group, ). Serum clcium nd phosphte were nlysed ccording to stndrd lortory methods. Sttisticl nlysis Student's t pired nd unpired t-tests were clculted s pproprite; P vlues less thn.5 were considered significnt. All dt re expressed s men ± stndrd error (s.e.). Results., I_ P <.1 P <.1 9D In children with, serum BGP, ICTP nd PIIINP levels (BGP: 12.9 ±.7 ng/ml; ICTP: 8.3 ± 1.3 ng/ml; PIIINP: 3.5 ±.5 ng/ml) were significntly lower (P <.1) thn those recorded in norml children (BGP: 18.9 ±.8 ng/ml; ICTP: 14.4 ±.5 ng/ml; PIIINP: 6.7 ±.7 ng/ml), s shown in Figure 1 (pnels -c). Totl lkline phosphtse nd one lkline phosphtse levels were lso significntly lower E ccm I- - z Q- 1 5 _3 Adults P < YJ E ~ Figure 3 Serum BGP (), ICTP () nd PIIINP (c) levels in eight dults with GH deficiency nd in controls (gend sex-mtched control group, 28). (P<.1) thn in controls (totl lkline phosphtse: ± 13.4 vs ± 14.9 IU/l; one lkline phosphtse: 77.8 ± 4.1 vs 181. ± 7.8 IU/ 1), s shown in Figure 2 (pnels nd ). In children with, serum BGP, ICTP nd PIIINP levels were not significntly correlted with the vlues of height velocity (r =.29, r =. nd r =.23, respectively). In dults with, men BGP levels (3.8 ±.3 ng/ml) were significntly lower (P<.1) thn those recorded in normls (5.4 ±.1 ng/ml). On

4 ( x 151 < 1 D Adults BONE AND COLLAGEN TURNOVER IN GH DEFICIENCY 849 NS Dl W X 1 io4~ o. P<. P <.2 Figure 4 Serum totl lkline phosphtse (T-AP; ) nd one lkline phosphtse (B-AP; ) levels in eight dults with GH deficiency nd in controls (ge- nd sex-mtched control group, 28). the contrry, serum ICTP levels were similr to those found in controls (ptients: 4.7 ±.8 ng/ml vs normls: 4.1 ±.3 ng/ml), suggesting the presence of norml resorption ctivity ssocited with reduced osteolstic function (Figure 3, pnels nd ). Serum PIIINP levels (3.7 ±.6 ng/ ml) were similr to those recorded in normls (3.2 ±.2 ng/ml), suggesting tht in dulthood the collgen turnover is not negtively influenced y the chronic (Figure 3c). Totl lkline phosphtse (119.5 ± 14.8 IU/1) levels were similr to those found in controls (122.3 ± 4. IU/1); on the contrry, one lkline phosphtse levels (44.9 ± 6.9 IU/1) were significntly lower (P <.2) thn those recorded in norml sujects (58.3 ± 2. IU/1), s shown in Figure 4 (pnels nd ). In dults with, no significnt correltions were found etween BGP/ ICTP/PIIINP nd IGF-I levels (r =.6, r =.4 nd r =.39, respectively). Men serum clcium nd phosphte levels were similr to those recorded in controls. i Discussion Our dt show tht in children with the effects of the lck of GH/IGF-I on one turnover re ssocited with significnt reduction of BGP, totl nd one lkline phosphtse, nd ICTP levels. These findings suggest the presence of reduced one turnover (low one formtion ssocited with low one resorption) nd support previous oservtions, which showed reltive osteopeni in children with untreted GH deficiency, oth isolted nd s component of pnhypopituitrism.6'7 Furthermore, GH deficiency seems to e le to cuse negtive effects on collgen turnover, s documented y the significnt reduction of serum PIIINP levels. The presence of low collgen synthesis might contriute to explin the skin thickness (due to reduced skin collgen content) nd the chrcteristic crow's foot sign of fcil wrinkling of ptients with hypopituitrism. In dults with, the chronic sence of GH seems to exert less relevnt effects on one nd collgen turnover, s demonstrted y the presence of norml one resorption ctivity nd of norml collgen synthesis, in the presence of reduced one formtion. Our finding of reduced BGP levels disgrees with those previously reported y Johnsen et l.,'2 who hd found norml BGP levels in dults with. However, in our study the presence of reduced osteolstic citivity ws lso confirmed y the finding of significnt reduction of one lkline phosphtse levels. The discrepncy etween our dt nd those recorded y Johnsen et l. might e proly due to their shorter withdrwl of GH tretment efore the ptients' entry into the study, which might hve positively influenced their osteolstic ctivity. In fct, it is well known tht GH tretment is le to exert prolonged effects on one formtion, which might e long-lsting event.2' In our dults with, the negtive equilirium etween one formtion nd resorption might contriute to explin the finding tht dults with hve low one mss, in prticulr t the forerm site.22 This spect might ecome relevnt in the view of future therpeuticl trils with recominnt GH in dults with GH deficiency. Although the ville dt cn still e considered preliminry, it seems tht GH tretment might increse one turnover, stimulting oth one formtion nd one resorption (our unpulished dt). However, t the moment the finl mening of this 'sustitutive' tretment on one mss cnnot e definitely predicted. In dulthood, the effects of chronic GH deficiency on collgen turnover pper to e less relevnt thn in childhood. In this respect, the finding of norml PIIINP levels might suggest tht

5 85 A. SARTORIO et l. in dult life further hormones nd/or locl fctors prtilly counterct the negtive consequences of chronic GH-IGF-I deficiency on collgen synthesis. In conclusion, our study shows tht GH deficiency exerts relevnt negtive effects on one nd collgen turnover in childhood, while in dults it References 1. Ernst, M. & Froesch, E.R. Growth hormone dependent stimultion of osteolst-like cells in serum-free cultures vi locl synthesis of insulin-like growth fctor I. Biochem Biophys Res Commun 1988, 151: Hock, J.M., Centrell, M. & Cnlis, E. Insulin-like growth fctor I hs independent effects on one mtrix formtion nd cell repliction. Endocrinology 1988, 122: Johnsen, J.S., Giwercmn, A., Hrtwell, D. et l. Serum one-gla protein s mrker of one growth in children nd dolescents: correltion with ge, height, serum insulinlike growth fctor I, nd serum testosterone. J Clin Endocrinol Met 1988, 67: Risz, L.G. Locl nd systemic fctors in the pthogenesis of osteoporosis. N Engl J Med 1988, 328: Bouillon, R. Growth hormone nd one. Horm Res 1991, 36 (Suppl 1): Ferrndez, A., Zchmnn, M., Prder, A. & Illig, R. Isolted growth hormone deficiency in prepuertl children: influence of humn growth hormone on longitudinl growth, dipose tissue, one mss nd one mturtion. Helv Peditr Act 197, 6: Shore, R.M., Chesney, R.W., Mzess, R.B., Rose, P.G. & Brgmn, G.J. Bone minerl sttus in growth hormone deficiency. J Peditr 198, 96: Johnsen, J.S., Jensen, S.B., Riis, B.J., Rsmussen, L., Zchmnn, M. & Christinsen, C. Serum one Gl protein: potentil mrker of growth hormone (GH) deficiency nd the response to GH therpy. J Clin Endocrinol Met 199, 71: Prfitt, A.M. Growth hormone nd dult one remodeling. Clin Endocrinol 1991, 35: Srtorio, A., Conti, A., Guzzloni, G. & Fgli, G. Serum osteoclcin levels in ptients with GH deficiency efore nd during GH tretment. Act Peditr Scnd 1991, 8: Srtorio, A., Conti, A., Morito, F., Monzni, M. & Fgli, G. Serum one Gl protein nd minoterminl propeptide of type III procollgen level in ptients with GH deficiency efore nd fter met-gh tretment. In: Cvllo, L., Jo, J.C. & New, M.I. (eds) Growth Disorders: The Stte of the Art. Rven Press, New York, 1991, pp seems to cuse minor consequences. However, lthough the metolic effects of GH on one nd collgen turnover pper to e limited, t present it cnnot e ruled out tht dults with GH deficiency might hve in ny cse enefit from recominnt GH tretment. 12. Johnsen, J.S., Pedersen, S.A., Jorgensen, J.O.L. et l. Effects of growth hormone (GH) on plsm one Gl protein in GH-deficient dults. J Clin Endocrinol Met 199, 7: Cuneo, R.C., Slomon, F., McGuley, G.A. & Sonksen, P.H. The growth hormone deficiency syndrome in dults. Clin Endocrinol 1992, 37: Whitehed, H.M., Borem, C., McIlrth, E.M. et l. Growth hormone tretment of dults with growth hormone deficiency: results of 13-month plceo controlled cross-over study. Clin Endocrinol 1992, 36: Epstein, S. Serum nd urinry mrker of one remodeling: ssessment of one turnover. Endocr Rev 1988, 9: Price, P.A., Prthemore, J.G. & Deftos, L.J. New iochemicl mrker for one metolism. J Clin Invest 1988,66: Delms, P.D. Biochemicl mrkers of one metolism. Presse Medicle 1993, 22: Eriksen, E.F., Chrles, P., Melsen, F., Mosekilde, L., Risteli, L. & Risteli, J. Serum mrkers of type I collgen formtion nd degrdtion in metolic one disese. Correltion with one histomorphometry. J Bone Min Res 1993, 8: Roslky, S.B. & Foo, A.Y. Two new methods for seprting nd quntifying one nd liver lkline phosphtse isoenzyme in plsm. Clin Chem 1984, 3: Blck, M.M., Shuster, S. & Bottoms, E. Skin collgen nd thickness in cromegly nd hypopituitrism. Clin Endocrinol 1972, 1: Brixen, K., Nielsen, H.K., Mosekilde, L. & Flyvjerg, A. A short course of recominnt humn growth hormone tretment stimultes osteolst nd ctivtes one remodelling in norml humn volunteers. JBone Min Res 199, 5: Kufmn, J.M., Telmn, P., Vermeulen, A. & Vndeweghe, M. Bone minerl sttus in growth hormone-deficient mles with isolted nd multiple pituitry deficiencies of childhood onset. J Clin Endocrinol Met 1992, 74: Postgrd Med J: first pulished s /pgmj on 1 Novemer Downloded from on 2 April 19 y guest. Protected y