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0021-972X/97/$03.00/0 Journal of Clinical Endocrinology and Metabolism Copyright © 1997 by The Endocrine Society Vol. 82, No. 2 Printed in U.S.A. Growth Hormone (GH) Retesting and Auxological Data in 131 GH-Deficient Patients after Completion of Treatment MAÏTHÉ TAUBER, PIERRE MOULIN, CATHERINE PIENKOWSKI, BÉATRICE JOURET, AND PIERRE ROCHICCIOLI Service de Pédiatrie Endocrinologie, Centre, Hospitalier Universitoine, Purpan, F-31059 Toulouse Cedex, France ABSTRACT GH state and auxological data after completion of GH therapy are reported in 131 patients (79 males, 52 females). They were treated from 1980 –1994 for partial (n ⫽ 98) or complete (n ⫽ 33) GH deficiency (GHD), either idiopathic (n ⫽ 121) or organic (n ⫽ 10). A single stimulation test (clonidine ⫹ betaxolol) was used, and only 50 patients (38%) maintained a blunted response (GH peak below 10 g/L). Although 9 of the 10 patients with organic GHD had an abnormal low GH peak, 67% of patients with idiopathic GHD normalized their GH secretion. This was particularly true of partial GHD patients (71% vs. 36% of complete GH-deficient patients). Based on a retest GH peak below 5 g/L, only 23% of the patients were considered to be GH deficient and therefore candidates for GH treatment during adulthood. We found no significant difference between hormonal state at completion of treatment and initial GH deficiency, pubertal state, or sex, although we did find a significantly lower GH peak value before and after treatment in patients with elevated body mass index. Of the 14 obese children who were treated, 50% had an abnormally low serum insulin-like growth factor-I level, arguing for true GHD, and only two children remained obese at cessation of treatment. Auxological data showed that with a mean duration of treatment of 3.6 ⫾ 2.0 yr, patients classified as having complete GHD before treatment had significantly greater catch-up growth as expressed in SDS for height than patients with partial GHD (0.6 ⫾ 1.1 vs. 1.1 ⫾ 0.7 SDS, P ⬍ 0.05), and that boys grew better than girls (1.4 ⫾ 0.8 vs. 1.6 ⫾ 0.6 SDS) for height, P ⬍ 0.01). That catch-up growth was not correlated with the result of GH peak after cessation of treatment. (J Clin Endocrinol Metab 82: 352–356, 1997) A LMOST 40 yr since GH was first used in therapy (1), there is still no consensus on what is the best means to study GH secretion and diagnose GH deficiency (GHD) (2–5). The use of pharmacological or physiological GH tests and the study of spontaneous GH secretion, urinary GH secretion, or indirect data with evaluation of serum insulinlike growth factor-I (IGF-I) and serum IGF-binding protein 3 (IGFBP-3) has been widely discussed. The results of pharmacological and physiological studies of GH secretion appear widely variable on repeated testing (6). The problem of diagnosing GHD now extends to adulthood, because GHD in adults with childhood or late-onset deficiency has been shown to significantly increase mortality and morbidity (7–11). In the absence of GH, body mass index (BMI) increased, body composition was modified with an elevated waist/hip ratio, metabolic disorders such as syndrome X were reported, and muscle strength, myocardial efficiency, and bone mineral density were altered. All the abnormal parameters are corrected by GH after either shortor long-term treatment (11–15). The incidence and prevalence of adult-onset GHD can be easily evaluated because the majority of cases (about 85%) occur after pituitary surgery. However, the proportion of adults with childhood-onset GHD (those patients who should continue GH treatment after the end of somatic growth) is not known. It thus appears very important to clarify this point. There is little data in the literature on GH state together with auxological data in GHD patients just after completion of GH treatment. For these reasons, we decided to systematically retest patients at the end of GH treatment, and we report here the data of 131 patients treated with GH in our department during the last 14 yr. Subjects and Methods The cohort was composed of 131 patients (79 males and 52 females) who had received GH treatment from 1980 –1994 for complete (n ⫽ 33) or partial (n ⫽ 98) GHD. Treatment was discontinued between 1992 and 1994. Most patients presented with idiopathic GHD (n ⫽ 121) and 10 patients presented with organic GHD caused by neurofibromatosis without glioma (n ⫽ 1), central nervous system irradiation (n ⫽ 2), spina bifida with myelomeningocele (n ⫽ 1), medulloblastoma (n ⫽ 2), astrocytoma (n ⫽ 2), medullar hypoplasia (n ⫽ 1), and so-called empty sella turcica (n ⫽ 1). The mean dose of GH was that given in France by France Hypophyse during the last 15 yr and ranged from 0.4 – 0.6 IU/kg per week. Table 1 summarizes auxological data: mean chronological age was 16.7 ⫾ 1.7 yr (17.6 ⫾ 1.4 yr for boys and 15.3 ⫾ 1.3 yr for girls), mean bone age 14.8 ⫾ 2.0 yr (15.3 ⫾ 2.0 for boys and 14.2 ⫾ 3.0 for girls), mean BMI was 20 ⫾ 2. Mean duration of treatment was 3.7 ⫾ 2.1 yr, and mean sds for height increased from ⫺2.7 ⫾ 1.0 sds before treatment to ⫺1.5 ⫾ 1.0 sds at the end of treatment. Boys started treatment at a mean age of 13.7 ⫾ 2.8 yr, were treated for 3.8 ⫾ 2.2 yr, and had a mean sds for height after completion of GH treatment of ⫺3 ⫾ 1.0 sds. Girls started treatment earlier, at 11.7 ⫾ 2.3 yr, were treated for a shorter period, 3.6 ⫾ 2 yr, and showed less improvement in sds for height at the end of treatment: ⫺1.7 ⫾ 1.0 sds. Before treatment, 33 children (11 girls, 22 boys) were classified as complete GHD because they had two abnormal GH peaks below 5 g/L after two different stimulation tests. Ninety-eight children (41 girls, 57 Received July 23, 1996. Revision received September 17, 1996. Rerevision received October 16, 1996. Accepted October 16, 1996. Address all correspondence and requests for reprints to: Maı̈thé Tauber, Service de Pédiatrie Endocrinologie, CHU Purpan, Place Baylac, F-31059 Toulouse Cedex, France. 352 3.8 ⫾ 2.2 14.7/1.25 3.6 ⫾ 2.0 11.0/1.0 3.7 ⫾ 2.1 14.7/1.0 15.3 ⫾ 2.0 17.0/14.5 14.2 ⫾ 3.0 16.5/14.0 14.8 ⫾ 2.0 17.0/14.0 164.6 ⫾ 6.0 176.0/148.0 150.3 ⫾ 7.0 163.0/142.0 159 ⫾ 9.0 176.0/142.0 17.6 ⫾ 1.4 23.0/14.0 15.3 ⫾ 1.3 17.5/13.9 16.7 ⫾ 1.7 23.0/13.9 Hormonal dosages ⫺2.7 ⫾ 1.2 ⫺1.0/⫺5.0 ⫺2.7 ⫾ 1.0 ⫺1.0/⫺6.0 ⫺2.7 ⫾ 1.0 ⫺1.0/⫺6.0 18 ⫾ 2 27/14 17 ⫾ 2 30/14 18 ⫾ 2 30/14 mean ⫾ SD max/min mean ⫾ SD max/min mean ⫾ SD max/min ⫺1.3 ⫾ 1.0 ⫺0.8/⫺4.8 ⫺1.7 ⫾ 1.0 0/⫺4.2 ⫺1.5 ⫾ 1.0 0.8/⫺4.8 GH dosage. Kits were purchased from Cis Oris (Cis BioInternational, Gif-sur-Yvette, France) throughout the study. The method changed in 1987 from RIA to immunoradiometric assay. The laboratory compared the values obtained with both methods at this time, and the results were satisfactory. With RIA, the intraassay coefficient of variation (CV) ranged from 7.6 –9.2%, and the interassay CV ranged from 11.0 –13.7%. With the immunoradiometric assay, the intraassay CV ranged from 2.3–2.8%, and interassay CV ranged from 3.2– 4.4%. All the GH dosages at retesting were performed with the same method. IGF-I dosage. Kits were purchased from the same manufacturer (Mallinckrodt, Medica, Evry, France), and the same method was used for all sera at retesting. Statistical analysis We used Pearson’s 2 and Yates or Fisher tests for qualitative variables. For quantitative variables, means were compared using covariance analysis to control confounding factors. Results GH peak at retesting after completion of treatment SDS, Total (n ⫽ 131) Girls (n ⫽ 52) Standard deviation score. 139.7 ⫾ 15.0 166.0/80.0 130.6 ⫾ 13.0 146.0/80.0 136.0 ⫾ 15.0 166.0/80.0 11.1 ⫾ 2.8 15.0/2.0 9.8 ⫾ 2.6 13.0/1.0 10.6 ⫾ 2.8 15.0/1.0 13.7 ⫾ 2.8 22.0/3.0 11.7 ⫾ 2.3 15.3/3.2 12.9 ⫾ 2.8 22.0/3.0 Boys (n ⫽ 79) 353 boys) were classified as partial GHD because they had either two low GH peaks between 5 and 10 g/L after stimulation tests (n ⫽ 74) or one abnormal test below 10 g/L and low 24-h GH secretion with an integrated concentration below 2.5 g/L/min (n ⫽ 24). Ten percent of organic GHD patients had partial GHD and 90% had complete GHD. Eighty percent of idiopathic GHD patients had partial GHD and 20% had complete GHD. The ratio between complete and partial GHD did not significantly differ between prepubertal (n ⫽ 58) and pubertal (n ⫽ 73) patients at the start of treatment. Various stimulation tests were performed either with a single stimulus: ornithine (n ⫽ 17), l-dopa (n ⫽ 40, clonidine (n ⫽ 3), arginine (n ⫽ 45), or glucagon (n ⫽ 1) or with combined stimuli: clonidine and betaxolol (n ⫽ 99), insulin and arginine (n ⫽ 13), glucagon and propanolol (n ⫽ 10), or glucagon and betaxolol (n ⫽ 8). Only a small number of patients were primed with sex steroids before therapy. During the first year following the discontinuation of therapy and at least 15 days after the last GH injection, each patient came to the day hospital unit for a single GH stimulation test that used clonidine and betaxolol as pharmacological stimuli. This test was the most commonly used test in our department for practical reasons, and most patients had been tested with it before treatment (n ⫽ 99). 20 ⫾ 2 31/14 19 ⫾ 2 27/15 20 ⫾ 2 31/4 Bone age (yr) Height (cm) Bone age (yr) Age (yr) Before treatment TABLE 1. Auxological data of the patients before and after GH treatment SDS Height Body mass index (kg/m2) After treatment Height SDS Body mass index (kg/m2) Height (cm) Age (yr) Duration GH therapy (yr) GH RETESTING AFTER COMPLETION OF GH Mean value for the group was 14.4 ⫾ 10.0 g/L (range 0.2– 49.5 g/L). Thirty patients had a blunted response below 5 g/L (23%), 19 patients had a partially blunted response between 5 and 10 g/L (15%), and 82 patients had a normal GH peak above 10 g/L (62%). Of the 10 patients with organic GHD, only 1 (10%) had a normal GH peak, and 9 still had a low GH peak below 5 g/L. Conversely, a large majority (67%) of idiopathic GHD patients had a peak above 10 g/L, 16% had a peak between 5 and 10 g/L, and 17% had a peak less than 5 g/L. Data are presented in Fig. 1. Complete and partial GHD patients. Of the 33 patients with complete GHD, 21 (64%) still had an abnormal GH peak, 16 (49%) had a peak below 5 g/L, and 5 (15%) had a peak between 5 and 10 g/L, whereas 12 (36%) had a normal GH peak. Of the 98 patients with partial GHD, 28 (29%) still had an abnormal GH peak, 14 (14%) had a peak below 5 g/L, and 14 (15%) had a peak between 5 and 10 g/L. The majority, 70 (71%), had a normal GH peak. Data are presented in Fig. 2. 354 JCE & M • 1997 Vol 82 • No 2 TAUBER ET AL. TABLE 2. Mean SDS gain for height in patients according to the results of GH test after treatment, type of GHD, complete or partial, before treatment and sex GH ⬍ 10 g/L at retesting GH ⬎10 g/L at retesting Complete GHD Partial GHD Boys Girls Number Mean SDS gain height Duration of GH therapy (yr) 49 1.4 ⫾ 0.8 (NS) 3.9 ⫾ 2.1 82 1.2 ⫾ 1 (NS) 3.6 ⫾ 1.2 33 98 79 52 1.6 ⫾ 1.1a 1.1 ⫾ 0.7a 1.4 ⫾ 0.8b 1.1 ⫾ 0.7b 4.3 ⫾ 3.1 3.6 ⫾ 1.7 3.8 ⫾ 2.2 3.6 ⫾ 2.0 SDS, a b FIG. 1. Results of GH test in percentages of low, intermediate (between 5 and 10 mg/L), and normal values of GH peak a end of treatment in patients with organic and idiopathic GHD. FIG. 2. Results of GH test expressed percentages of low, intermediate (between 5 and 10 mg/L), and normal values of GH peak at end of treatment in patients with complete and partial GHD. Sex ratio. Of the 11 girls with complete GHD, 6 (55%) had a low GH peak and 5 (45%) normalized their test. Of the 41 girls with partial GHD, 12 (28%) had a low GH peak and 29 (72%) a normal test. Therefore 64% of the girls (n ⫽ 33) had a normal GH peak. Of the 22 boys with complete GHD, 15 (68%) had a low GH peak and 7 (32%) had a normal test. In the 57 boys with partial GHD, 16 (28%) had a low GH peak and 41 (72%) had a normal test. Therefore 60% of the boys (n ⫽ 48) had a normal GH peak, which was not statistically different from the results obtained in girls (64%) and in the group as a whole (62%). Pubertal stage. Of the 58 children who were prepubertal when starting treatment, 14 (24%) had complete GHD, of whom 10 (72%) still had a low GH peak. In the 44 partial GHD patients, 12 (27%) still had a low GH peak. Therefore 36 (60%) of the 58 children who were prepubertal before treatment had a normal GH test. Of the 73 children who were pubertal at the start of treatment, 19 (26%) had complete GHD, 11 of whom (58%) still had a low GH peak. In the 54 with partial GHD, 16 (30%) still had a low GH peak. Therefore, 63% of the 73 pubertal children had a normal GH test after treatment, which is not statistically different from the result obtained in the group of prepubertal children. BMI state. When starting treatment, only 14 patients were obese, with a BMI above the 97th percentile, and 8 of those Standard deviation score; NS, Not significant. P ⬍ 0.01. P ⬍ 0.05. (57%) had complete GHD and 6 (75%) had a low GH peak after completion of treatment. Of the 6 patients with partial GHD, 4 (67%) still had a GH-deficient test. Therefore, at the end of treatment 4/14 (29%) normalized their GH test, which was significantly lower than the result of the whole group (P ⬍ 0.001). Only 2/14 remained obese, and these two patients had a GH peak below 5 g/L. Before treatment, GH peak was also significantly lower (P ⬍ 0.001) in the group of obese children than in the nonobese children. Moreover, serum IGF-I levels were obtained in 12 of the 14 patients before treatment and 7 had low values, suggesting that the blunted GH response was not caused by their obesity but related to GHD. IGF-I plasma levels. We measured IGF-I levels in 119 patients at retesting. The mean value was 358 ⫾ 193 ng/mL and ranged from 37–1149 ng/mL. GH peak at retesting was positively correlated with IGF-I levels (P ⬍ 0.02). IGF-I levels were lower in patients with persistent GHD than in those who normalized their GH peak. The difference was more marked in patients with complete GHD (P ⬍ 0.001) than in patients with partial GHD (P ⬍ 0.004). Conversely, there was no significant difference in IGF-I values between patients with persistent complete GHD and those with partial GHD. Auxological data In the 33 patients with complete GHD, mean sds gain for height was ⫹1.6 ⫾ 1.1 sds for a mean duration of therapy of 4.3 ⫾ 3.1 yr. We did not find a significant difference in sds gain between those who normalized their test (n ⫽ 12) and those who did not (n ⫽ 21) (1.6 ⫾ 0.6 vs. 1.7 ⫾ 1.3 sds). In the 98 patients with partial GHD, mean sds gain for height was 1.1 ⫾ 0.7 sds for a mean duration of therapy of 3.6 ⫾ 1.7 yr. Again, we did not find a significant difference in sds gain between those who had a normal test (n ⫽ 70) and those who did not (n ⫽ 28) (1.1 ⫾ 0.8 vs. 1.2 ⫾ 0.9). However, patients with complete GHD grew significantly better (P ⬍ 0.01) than patients with partial GHD. Boys grew significantly better than girls (P ⬍ 0.05): 1.4 ⫾ 0.8 sds for a duration of 3.8 ⫾ 2.2 yr vs. 1.1 ⫾ 0.7 SDS for a duration of 3.6 ⫾ 2.0 yr. Data are summarized in Table 2. Discussion These data show that the great majority (62%) of GHD patients have a normal GH test at the end of GH therapy. GH RETESTING AFTER COMPLETION OF GH Normalization of the GH test was twice as frequent in patients with partial GHD (71%) as in patients with complete GHD (36%) and occurred in 10% of organic vs. 67% of idiopathic GHD. In idiopathic GHD, the main question is: Do the data merely reflect the lack of reproducibility of GH testing, or does transient GHD really exist? Concerning the latter point, we did not find a higher incidence of transient GHD during puberty, as previously has been reported (6). As for the lack of reproducibility of GH tests, a recent report on retesting children with GHD throughout the course of treatment (6) using pharmacological tests and spontaneous GH secretion showed that 58.1% of subjects changed from the initial diagnostic group after the first retesting (1.1 ⫾ 5.0 yr after starting GH therapy) and 48.5% at the second retesting (1.5 ⫾ 0.4 yr after the first retesting). Previous studies also reported the lack of reproducibility of GH testing, with pharmacological tests (16, 17) being significantly more variable than spontaneous secretion studies (18). Moreover, the level of reproducibility varied with the type of test used, and clonidine was reported to be the most reproducible test (19). These studies again point out the difficulty of finding a reliable test to diagnose GHD, probably because of the wide variation of GH secretion in short children. We cannot completely exclude transient GHD in some cases, or the decreased capacity to increase GH secretion in some circumstances, such as puberty. Other criteria of GHD such as plasma IGF-I or IGFBP-3 evaluation could be of interest. It has been documented in adults that serum IGF-I and IGFBP-3 are useful diagnostic tests in identifying young adults with severe GH deficiency if there is a sufficiently large number of age and sex-matched controls (20, 21). The correlation we found between GH peak and IGF-I levels and the significant difference between the patients who had persistent GHD and those who normalized their test is an argument in favor of transient GHD. Unfortunately, we do not have IGF-I values before treatment or any IGFBP-3 data. Nevertheless, our study helps to predict approximately the number of patients who should continue GH treatment in adulthood. In France, it has been decided that patients should continue treatment if the GH peak is lower than 3 g/L at retesting. In our series, 23% had complete GHD with a GH peak below 5 g/L at the end of GH treatment and 14% had a GH peak lower than 3 g/L. Half of the patients with complete GHD when starting treatment would need to continue GH therapy compared with 14% of partial GHD patients. This point has been poorly documented in the literature. In one study of 34 patients (22), 19 patients with postirradiation GHD continued to have complete GHD with a GH peak lower than 3.5 g/L, whereas of 15 idiopathic GH patients, only 26% remained GH deficient. A recent study (23) of 69 adult patients diagnosed as GH deficient in childhood (54 idiopathic GHD, 15 organic), retested by using GHRH ⫹ pyridostigmine, found that 57% had persistent GHD with a GH peak below 10 g/L, of whom 52% had a GH peak below 5 g/L. In most studies, however, the percentage of patients with complete or partial GHD before treatment is not stated, and this could account for the difference observed. Another study (16) of 50 men (17 with isolated GH deficiency, 33 with 355 multiple pituitary hormone deficiencies) 1.0 –15.5 yr after discontinuation of GH therapy for childhood-onset GHD found 100% persistent GHD (GH peak below 7 g/L) using GHRH or the insulin tolerance test (24). The auxological data in our study are also interesting, reflecting our strategy of diagnosis and treatment of GHD during the last 14 yr. The sex ratio was 79 boys/52 girls, age at start of treatment was too high, and the mean duration of treatment was significantly different in boys as compared with girls, probably because of the poorer results obtained in the girls. There was no difference in response to GH therapy related to peak GH response after therapy, except for those with GHD before treatment, who grew significantly better than patients with partial GHD. 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