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Journal of Clinical Endocrinology & Metabolism , doi:10.1210/jc.2007-1003
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The Journal of Clinical Endocrinology & Metabolism Vol. 92, No. 10 3788-3795
Copyright © 2007 by The Endocrine Society

Subnormal Serum Insulin-Like Growth Factor-I Levels in Young Adults with Childhood-Onset Nonacquired Growth Hormone (GH) Deficiency Who Recover Normal GH Secretion May Indicate Less Severe but Persistent Pituitary Failure

Georges Gelwane, Catherine Garel, Didier Chevenne, Priscilla Armoogum, Dominique Simon, Paul Czernichow and Juliane Léger

Pediatric Endocrinology Department, Centre de Référence Maladies Endocriniennes de la Croissance and Institut National de la Santé et de la Recherche Médicale (INSERM) Unit 690 (G.G., D.S., P.C., J.L.), Radiology (C.G.), and Biochemistry (D.C.) Departments, and Unit of Clinical Epidemiology INSERM CIE5 (P.A.), Assistance Publique-Hôpitaux de Paris, Robert Debré Hospital, Université Paris VII, 75019 Paris, France

Address all correspondence and requests for reprints to: Juliane Léger, M.D., Pediatric Endocrinology Unit and INSERM U 690, Reference Center for Rare Endocrine Growth Disease, Hopital Robert Debré, 48 Boulevard Sérurier, 75019 Paris, France. E-mail: juliane.leger{at}rdb.aphp.fr.


   Abstract
Top
 Abstract
Introduction
 Patients and Methods
 Results
 Discussion
 References
 
Context: The unexpected observation of a normal GH peak in 22% of young adults with childhood-onset GH deficiency (GHD) and ectopic neurohypophysis has raised questions about the criteria defining GHD in young adults and whether patients with subsequent increases in GH secretion nonetheless have a subtle form of GHD.

Objective: Our objective was to determine the characteristics of patients with childhood-onset nonacquired GHD who recover normal peak GH secretion when adult height has been achieved.

Design and Setting: We conducted a university hospital-based observational follow-up study.

Participants: Sixty-two patients with ectopic neurohypophysis (n = 24), isolated hypoplastic anterior pituitary (n = 14), or normal hypothalamic pituitary area (n = 24) on magnetic resonance imaging (MRI) at the time of GHD diagnosis underwent reevaluation of the GH-IGF-I axis at a mean age of 16.8 ± 1.6 yr.

Main Outcome Measures: Outcome measures included clinical and MRI findings and serum IGF-I and peak GH levels.

Results: On retesting, peak GH exceeded 10 µg/liter in 31 patients (50%): six (20%) patients with ectopic neurohypophysis, 10 (32%) patients with initially isolated hypoplastic anterior pituitary, and 15 (48%) patients with normal MRI findings. Among these patients, serum IGF-I levels were significantly lower in patients with ectopic neurohypophysis than in those without structural abnormalities of the hypothalamic pituitary axis (n = 25), but patients without structural abnormalities also had significantly lower serum IGF-I levels than control subjects, after controlling for age, sex, and body mass index (mean serum IGF-I levels of 374 ± 83 vs. 446 ± 108 µg/liter; ß-coefficient = –72; P = 0.003).

Conclusions: The severity of the disease seems to have decreased over time in these patients, who may nonetheless present persistent pituitary failure. The natural history and clinical implications of these findings remain to be clarified. The possibility of a deterioration in the secretion of GH and other pituitary hormones later in life in a subset of these patients warrants the careful long-term follow-up of this population.


   Introduction
Top
 Abstract
 Introduction
Patients and Methods
 Results
 Discussion
 References
 
THE DIAGNOSIS OF GH deficiency (GHD) in childhood is confirmed by retesting in young adults for only a fraction of patients, using an arbitrary cutoff of 10, 5, or 3 µg/liter for the GH peak in pharmacological tests (1, 2, 3, 4, 5, 6, 7, 8). These patients may have nonacquired or acquired GHD, as in patients treated by cerebral irradiation (9). It is therefore unclear whether these patients were misdiagnosed with GHD during childhood or whether the deficiency was truly transient (1, 2, 3, 4, 5, 6, 7, 8, 10, 11, 12), and these findings highlight the possible influence of sex steroid hormones on the endogenous rate of GH production (13). Even patients with structural hypothalamic-pituitary abnormalities, such as ectopic neurohypophysis, may display an increase in GH secretion, as we recently showed in 22% of such patients treated with GH until adult height was reached and displaying an increase in GH secretion and a normal GH peak, exceeding 10 µg/liter, in the transition period between late puberty and adulthood (14). These results raise questions about whether these patients had persistent but subtle forms of GH insufficiency at that time, the methods and cutoff values of peak GH response in stimulation tests that should be used for the diagnosis of childhood-onset GHD after adult height has been obtained, the role of serum IGF-I concentration, and whether other patients with no structural hypothalamic pituitary abnormalities also have persistent subtle forms of GH insufficiency despite the normal GH peak observed after stimulation.

This issue is difficult to resolve but has a number of important implications, because these patients should be investigated during adulthood for GH insufficiency and for other pituitary deficiencies, such as hypothyroidism, hypogonadism, and adrenal insufficiency, all of which are associated with a high lifetime risk of morbidity (15, 16). Patients with ectopic neurohypophysis constitute a useful model for studying this issue. In this study, we aimed to determine the characteristics of patients with childhood-onset nonacquired GHD with and without structural hypothalamic-pituitary abnormalities, recovering a normal GH secretion peak after pharmacological stimulation once adult height has been achieved, and to compare these patients with others with persistent GHD and a healthy control group.


   Patients and Methods
Top
 Abstract
 Introduction
 Patients and Methods
Results
 Discussion
 References
 
Patients

All patients with nonacquired childhood-onset GHD who had achieved adult height and had been followed up in our department between 1988 and 2006 were studied. The inclusion criteria for the study were treatment with GH until adult height and retesting for GH secretion once adult height had been achieved and GH treatment stopped.

In total, 98 patients with nonacquired childhood-onset GHD had achieved adult height at the time of the study. Of these, 31 patients were lost to follow-up or stopped GH treatment before achieving adult height, and five were not reevaluated for GH secretion after the end of GH treatment [n = 2 with multiple anterior pituitary hormone deficiency (MPHD), n = 3 with isolated GHD; these patients having a normal hypothalamo-pituitary area (n = 1), isolated anterior pituitary hypoplasia (n = 3), or ectopic neurohypophysis (n = 1) assessed on magnetic resonance imaging (MRI) findings].

The characteristics at the time of GHD diagnosis of the participants (n = 62) and nonparticipants (n = 36) are shown Table 1Go. The study population was representative of the entire population treated for GHD during childhood, as shown by mean age at diagnosis, the severity of GHD assessed on the basis of height, growth velocity, height deficit with respect to target height at diagnosis [height SD score (SDS) minus target height SDS), GH peak, and whether GHD was isolated or associated with MPHD. However, the participants were more likely to have an ectopic neurohypophysis on MRI than the nonparticipants. MRI of the 62 participating patients revealed a normal hypothalamo-pituitary area in 24 subjects, isolated anterior pituitary hypoplasia in 14 subjects, and an ectopic neurohypophysis in 24 subjects. The clinical characteristics at the time of GHD diagnosis of the patients studied, as a function of MRI findings, are indicated in Table 2Go. By definition, patients had clinical [growth retardation and/or low growth velocity (n = 57) and/or neonatal hypoglycemia (n = 3) and/or micropenis with or without cryptorchidism (n = 6)] and biological (low GH and IGF-I levels) characteristics of GHD at the time of initial evaluation. At that time, patients with ectopic neurohypophysis were younger and had a significantly greater height deficit with respect to target height and a lower serum GH peak in pharmacological tests than those with isolated anterior pituitary hypoplasia or with normal MRI findings.


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  		TABLE 1. Initial characteristics of participants and nonparticipants at the time of GHD diagnosis

 

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  		TABLE 2. Initial characteristics of the patients with nonacquired childhood-onset GHD, according to MRI findings at diagnosis

 
Recombinant human GH (hGH) was administered sc at a dose of 0.21 ± 0.04 mg/kg·wk, as six or seven injections per week, corresponding to the standard dose used in France during the study period. Additional replacement therapy, including L-T4, hydrocortisone, and/or sex steroid therapy, was administered if deficiencies in TSH (n = 12), ACTH (n = 10), and/or gonadotropin (FSH and LH, n = 9) were diagnosed [MPHD, n = 13 patients diagnosed either at the initial evaluation (n = 10) or during follow-up (n = 3)].

Controls

The control population consisted of a large group of healthy Caucasian subjects (n = 411) who had achieved adult height. All were under the age of 20 yr, with no history of chronic disease and no current illness or drug treatment, and all underwent auxological and serum IGF-I determinations, as previously described (17).

The study protocol was approved by the faculty ethics committee. Written informed consent was obtained from the subjects or their parents.

Methods

Childhood-onset GHD was diagnosed based on a GH peak of less than 10 µg/liter in two pharmacological tests, one of which was the arginine insulin tolerance test (arginine, 0.5 g/kg given iv over a period of 30 min, and insulin, 0.1 IU/kg body weight given iv as a bolus) in 55 of the 62 patients (Table 2Go).

A complete evaluation of other anterior pituitary functions was carried out in all patients at diagnosis and was repeated during follow-up if deemed necessary based on clinical examination and serum free T4 and morning cortisol measurements. TSH deficiency was diagnosed as a plasma T4 concentration less than 10 pmol/liter and/or abnormal TSH stimulation after TRH administration (normal values for TSH were 0.5–6, 14 ± 7, and <8 mU/liter for basal, peak, and 120-min post-TRH administration levels, respectively). ACTH deficiency was diagnosed as a morning basal plasma cortisol concentration less than 165 nmol/liter and less than 415 nmol/liter during insulin-induced hypoglycemia. We did not systematically evaluate corticotropin reserves if morning cortisol concentration exceeded 275 nmol/liter. Evaluations of the pituitary-gonadal axis were mainly clinical. Patients were considered not to have a deficiency if spontaneous pubertal development occurred. Gonadotropin deficiency was suspected in patients showing no pubertal development at a normal pubertal age, as assessed by measuring plasma sex steroid levels and FSH and LH levels after GnRH treatment or after induced puberty. Diabetes insipidus was excluded in all patients, by means of a 12-h water deprivation test. MPHD was defined as GHD associated with abnormal levels of at least one of the other anterior pituitary hormones.

GH treatment was stopped, in all patients, when growth velocity during the previous 6 months was less than 1 cm. GH secretion was reevaluated 0.7 ± 1.1 yr after the cessation of GH treatment, by means of an insulin tolerance test (n = 48), propranolol glucagon test (n = 13), or ornithine test (n = 1), with simultaneous determination of IGF-I levels. Severe persistent GHD was defined as a peak GH response of less than 5 µg/liter, using the currently recommended criterion of a peak GH value less than 5 µg/liter for GHD in adulthood (18).

MRI was initially carried out either at the time of GHD diagnosis or shortly after the initiation of hGH treatment. A second MRI was carried out when the patient had reached adult height [n = 34 (55%) of the 62 patients] in patients with ectopic neurohypophysis (in 14 of the 24 patients), isolated anterior pituitary hypoplasia (in 10 of the 14 subjects), or normal hypothalamo-pituitary area (in 10 of the 24 patients).

All cerebral MRI readings (0.5 Tesla Magnet, Gyrex; Elscint, Haifa, Israel) were reviewed by the same investigator (C.G.), who was not aware of the endocrinological data, according to the method previously described (14, 19). The anterior pituitary was considered to be hypoplastic if its height was below –2 SDS for age (20). The presence or absence of the pituitary stalk was recorded before and after gadolinium injection, as present or absent. The precise location of the ectopic posterior pituitary hyperintense signal (EPPHS) was also established by MRI (19).

Height, height velocity (21), and body mass index (BMI) (weight in kilograms divided by height in meters squared) (22) were expressed as the SDS for sex and chronological age. Bone age was determined blind, by the same investigator in each case (J.L.) according to the method of Greulich and Pyle (23). Target height was calculated from midparental height (24).

For all subjects (patients and controls), blood samples were collected in fasting condition during the early morning. Serum GH concentration (micrograms per liter) was measured on a single sample, by solid-phase two-site immunoradiometric assay, and serum IGF-I concentrations were determined by fully automated two-site chemiluminescence immunoassays (Nichols Advantage; Nichols Institute Diagnostics, Paris, France), with an interassay coefficient of variation of less than 5.8%. Serum values are expressed as SDS, according to our normative data (17).

Statistical analysis

Data are presented as means ± SD for quantitative variables and as absolute numbers for qualitative variables. We assessed the significance of differences in clinical characteristics between controls and patients, using nonparametric tests; {chi}2 or Fisher’s exact test for categorical variables, Wilcoxon’s test for continuous variables (when comparing two groups), or the Kruskal-Wallis ANOVA (when comparing more than two groups) were used as appropriate. Correlations were tested using Spearman’s nonparametric method. Variables were log-transformed when appropriate. We checked the normality of residuals and the absence of heteroskedasticity for regression analyses. All tests were two-tailed. Statistical analyses were performed with the SAS version 9.1 (SAS Inc., Cary, NC) software package for PC.


   Results
Top
 Abstract
 Introduction
 Patients and Methods
 Results
Discussion
 References
 
Clinical characteristics of the subjects with nonacquired childhood-onset GHD and the control subjects at the time of the study

The characteristics of the 62 patients at the time of the study are indicated in Table 3Go. As expected, mean adult height and the difference between adult height and target height (SDS) were significantly lower for patients with nonacquired childhood-onset GHD than for the control subjects (adult height = –0.2 ± 1.1 vs. 0.8 ± 1.1 SDS, and adult height – target height = 0.1 ± 1.1 vs. 0.7 ± 0.9 SDS for patients and control subjects, respectively; P < 0.0001).


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  		TABLE 3. Characteristics of the patients once adult height had been reached, as a function of MRI findings at diagnosis and the results of GH status reevaluation

 
MRI findings and hormonal status after the completion of GH treatment

The characteristics of the patients are given as a function of MRI findings at diagnosis and according to the results of the reevaluation of GH status after attainment of adult height in Table 3Go.

MRI findings. MRI findings at reevaluation were similar to those for the initial MRI for patients with ectopic neurohypophysis (only one patient showed an increase in anterior pituitary height, with conversion from hypoplastic to normal) and patients with a normal hypothalamo-pituitary area. However, all patients with initial anterior pituitary hypoplasia (n = 10 evaluated) showed an increase in anterior pituitary size, with normalization by the time of reevaluation (Figs. 1Go and 2Go).


Figure 1
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  		FIG. 1. Cerebral MRI (T1-weighted images) of a 2.3-yr-old patient (A) with reevaluation at the age of 15.5 yr (B). A, Sagittal slice. A hypoplastic anterior pituitary is seen (pituitary height of 2.5 mm) (arrow). The hyperintense signal of the posterior pituitary is in the normal location (arrowhead), with a normal pituitary stalk. B, Sagittal slice. The anterior pituitary of this patient increased between childhood and early adulthood and appeared normal when adult height was achieved (pituitary height at 5 mm) (arrow). C, Sagittal slice; D, coronal slice. The ectopic posterior pituitary is located in the middle of the pituitary stalk (arrow). Associated abnormalities included the presence of a persistent craniopharyngeal canal (arrowhead). E, Sagittal slice; F, coronal slice. The ectopic posterior pituitary is located at the median eminence (arrow). The pituitary stalk is not visible even after gadolinium injection. The anterior pituitary is hypoplastic. Associated abnormalities included the presence of a persistent craniopharyngeal canal (arrowhead).

 

Figure 2
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  		FIG. 2. Anterior pituitary height in patients with isolated anterior pituitary hypoplasia at the time of GHD diagnosis during childhood and at reevaluation after GH treatment had been stopped and adult height attained. Patients with persistent severe GHD (peak GH < 5 µg/liter) at reassessment are indicated with a small arrow. None of these patients presented a hormonal deficiency other than GHD, either at diagnosis or at reevaluation. Data on normal values are from Argyropoulou et al. (20 ). M, Mean.

 
Peak GH after stimulation. On retesting in adulthood, the GH peak exceeded 10 µg/liter in 31 patients (50%): six patients (20%) with ectopic neurohypophysis, 10 patients (32%) with initially isolated hypoplastic anterior pituitary, and 15 patients (48%) with normal MRI findings. The GH peak was 5–10 µg/liter in 11 patients (18%) and less than 5 µg/liter in 20 patients (32%). Only 14 (58%) of the 24 patients with GHD associated with ectopic neurohypophysis; four (29%) of the 14 patients with initial anterior pituitary hypoplasia and two (8%) of the 24 patients with normal MRI findings were found to have severe GHD (peak GH < 5 µg/liter) when retested in adulthood (Table 3Go). All 13 MPHD patients had ectopic neurohypophysis, with a GH peak of less than 5 µg/liter in 12 patients and between 5 and 10 µg/liter in one patient.

In patients with ectopic neurohypophysis (Table 4Go), the location of the EPPHS differed significantly between patients with and without persistent severe GHD (GH peak < 5 µg/liter). It was found at the median eminence in all but one patient (93% of cases) with persistent severe GHD and along the stalk in eight of the 10 patients (80%) with a GH peak of at least 5 µg/liter at reassessment (P = 0.0004). The visibility of the pituitary stalk also depended on GH status at reassessment. The pituitary stalk was visible in nine of the 10 patients (90% of patients) with a GH peak of at least 5 µg/liter at reassessment, whereas it was not visible, even after enhancement, in nine of the 14 patients (64%) with a GH peak of less than 5 µg/liter (P < 0.01).


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  		TABLE 4. MRI findings in patients with ectopic neurohypophysis, according to GH status reevaluation after attainment of adult height

 
Serum IGF-I levels. As expected, serum IGF-I levels after adjustment for age, sex, and BMI (SDS) were significantly lower in patients with persistent severe GHD (GH peak < 5 µg/liter) than in patients with a GH peak between 5 and 10 µg/liter (ß-coefficient = 197; P = 0.0005) and in patients with a GH peak of more than 10 µg/liter (ß-coefficient = 213; P < 0.0001) (Table 3Go). However, in the 31 patients with a normal GH peak at reassessment (>10 µg/liter), serum IGF-I levels at reassessment, after controlling for age, sex, and BMI (SDS), although higher than at diagnosis (if expressed as SDS), remained significantly lower than those in the control population (ß-coefficient = –90; P < 0.0001). Among patients with a normal GH peak at reassessment, serum IGF-I levels were lower in patients with ectopic neurohypophysis (n = 6) than in those with normal MRI findings at reevaluation (n = 25, including patients with initial isolated anterior pituitary hypoplasia), but patients with normal MRI findings at reevaluation also had significantly lower serum IGF-I levels than control subjects (ß-coefficient = –72; P = 0.003) (mean serum IGF-I levels of 374 ± 83 vs. 446 ± 108 ng/ml, i.e.–0.7 ± 1.0 vs. 0.1 ± 1 SDS, respectively) (Fig. 3Go). Serum IGF-I levels remained significantly lower than control levels (ß-coefficient = –58; P = 0.05) if we considered only the 15 patients with normal MRI findings at diagnosis and at reevaluation (excluding patients with initial hypoplastic anterior pituitary).


Figure 3
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  		FIG. 3. Serum IGF-I levels at diagnosis and reevaluation in patients with ectopic neurohypophysis and patients with normal structure of the hypothalamic pituitary area, according to MRI findings and the GH peak at the time of reevaluation of GH status after attainment of adult height, in 42 patients with childhood-onset GHD who showed an increase in GH secretion when reevaluated (GH peak > 5 µg/liter). The data have been adjusted for age, sex, and BMI (SDS). All subjects were at Tanner pubertal stage 5. *, P = 0.003 and ß-coefficient = –72 for patients with a normal hypothalamic pituitary area on MRI and GH peak of more than 10 µg/liter at the time of reassessment vs. controls.

 
After correction for BMI (SDS), serum IGF-I (SDS) levels were found to be correlated with the GH peak after stimulation test ({rho} = 0.67; P < 0.0001; Fig. 4Go). No correlation was found between serum IGF-I (SDS) levels and time between the end of GH treatment and retesting ({rho} = 0.01; P = 0.95).


Figure 4
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  		FIG. 4. Correlation between serum IGF-I levels (SDS) and peak GH levels after adult height had been achieved, a mean of 0.7 yr after the end of GH treatment, in 62 patients with childhood-onset GHD [Spearman’s rank correlation, adjusted for BMI (SDS)]. The dotted lines indicate the two cutoff values for peak GH currently used for GHD diagnosis: 5 µg/liter for adults and 10 µg/liter for children. MRI findings at diagnosis for these patients demonstrated ectopic neurohypophysis (located at the median eminence or along the pituitary stalk), anterior pituitary hypoplasia, or a normal hypothalamic pituitary area.

 
Auxological outcome. As shown Table 3Go, mean adult height and height gain (SDS) were significantly higher in patients with ectopic neurohypophysis (n = 24) than in patients with normal MRI findings at reevaluation (n = 38) [for adult height, –0.10 ± 1.2 vs. –1.0 ± 1.1 SDS (P = 0.002), and for height gain, 2.4 ± 1.3 vs. 1.2 ± 1.1 SDS (P = 0.0002)]. As expected, mean adult height and height gain (SDS) were significantly higher in patients with severe persistent GHD (GH peak < 5 µg/liter; n = 20) than in those displaying an increase in GH secretion (n = 42) [adult height, 0.1 ± 1.1 vs. –1.0 ± 1.1 SDS (P = 0.001), and height gain, 2.4 ± 1.4 vs. 1.3 ± 1.2 SDS (P = 0.002)].


   Discussion
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
References
 
The results of this study extend our knowledge of somatotrophic axis function in young adults with childhood-onset GHD by providing evidence not only of an increase in the ability to secrete GH but also of an increase in IGF-I levels (expressed as SDS) in most patients with isolated GHD with or without ectopic neurohypophysis and intact pituitary stalk. Furthermore, despite increasing significantly from childhood to adulthood in these patients, with no evidence of nutritional status change, serum IGF-I levels remained significantly lower than those of a carefully selected healthy control group at pubertal stage 5 controlled for age, sex, and BMI. Subnormal serum IGF-I levels were found in patients with ectopic neurohypophysis, in whom values were particularly low for some patients, and in patients with normal hypothalamic pituitary area structure on MRI, suggesting less severe but persistent failure of the somatotrophic axis in these patients. The extent to which GH secretion was truly normal, given the moderately low serum IGF-I levels observed, remains unclear. Conflicting data, with normal or subnormal serum IGF-I levels, have been reported for young adults with childhood-onset GHD who recover normal GH secretion (3, 6, 7, 15, 25, 26), but not all previous studies have reported MRI findings (1, 2, 3, 4, 5, 6, 15, 25, 26, 27). None of these previous studies analyzed the possibility that moderately low serum IGF-I levels may indicate less severe but persistent pituitary failure. Ectopic neurohypophysis, located in the median eminence or along the pituitary stalk, has been shown to be a marker of congenital abnormal developmental processes and cannot be considered a normal variant of the posterior pituitary gland (28). During childhood, a less severe form of anterior pituitary function deficiency has been described in patients in whom the EPPHS is located along a normal visible pituitary stalk than in those in whom it is located in the median eminence with a nonvisible pituitary stalk (29). GH dysfunction would be expected to persist into adult life in all patients with ectopic neurohypophysis. This persistence is not consistent with the GH secretion peak obtained after pharmacological stimulation in our patients but was strongly suggested by serum IGF-I levels. MRI findings at reevaluation were similar to those for the initial MRI in the studied patients with ectopic neurohypophysis or normal hypothalamic pituitary area on MRI, whereas all with initial hypoplastic anterior pituitary studied displayed an increase in pituitary volume to within the normal range at reevaluation, as previously reported in a few patients (7). Our data, showing that 32 (84%) of the 38 patients with no structural abnormality of the hypothalamic pituitary area on MRI had a peak GH concentration exceeding 5 µg/liter and that 25 (66%) of these patients had a peak GH concentration exceeding 10 µg/liter, are consistent with previous reports concerning patients with idiopathic GHD (1, 2, 3, 4, 5, 6, 7, 8, 30). Moreover, as expected, severe persistent GHD with peak GH values less than 5 µg/liter was found in all but one patient with MPHD (all had ectopic neurohypophysis), confirming that multiple hormone deficiency is associated with severe GHD (8, 31).

The insulin-induced hypoglycemia test remains the GH stimulation test of choice, but the arginine and glucagon tests are also widely considered to be the most reliable of the classical stimulation tests (18). However, the known limitations of GH tests must be taken into account, i.e. difference in GH response according to the stimulus used, poor reproducibility, and the impact of puberty on GH response (27, 32, 33, 34). Moreover, it remains unclear whether the GH peak obtained in these tests is fully representative of GH secretion status. The choice of an arbitrary cutoff of 5 µg/liter (or even of 10 µg/liter, at least in some cases) for defining GHD in adolescents or in young adults, therefore, remains debatable. It should also be borne in mind that, despite the poor reproducibility of the peak GH response to the insulin tolerance test in normal young adults, none of the normal subjects was classified as borderline GH deficient, because GH responses exceeding 20 µg/liter were obtained in three separate tests in all cases (33). We also found that, for our subjects with a GH peak of more than 20 µg/liter, there was concordance between peak GH and normal serum IGF-I levels. In our patients with peak GH values between 5 and 20 µg/liter at reassessment, patients with moderately low serum IGF-I levels may have retained a certain degree of hypothalamic pituitary axis damage, insufficient to reduce stimulated responses to levels below the threshold for GHD diagnosis but probably severe enough to impair the normal physiological increase in GH secretion during the transition period at the end of puberty (13, 35), thereby accounting for the slightly low serum IGF-I levels. Thus, subjects with borderline insufficient pituitary GH production are probably unable to generate appropriate serum IGF-I levels. In healthy subjects, physiological pituitary hypertrophy is observed during puberty, coinciding with the increase in sex steroid and GH levels (13, 19). Possible hyperreactivity of the residual functioning of GHRH neurons and somatotrophic cells may account for the increases in GH secretion and anterior pituitary volume observed in some of our patients with a normal pituitary stalk. Thus, a partially compensatory mechanism, probably depending at least partly on the dynamic physiological relationships between sex steroid hormones and the GH axis, may be responsible for the partial recovery of pituitary function in at least some cases. More investigations are required to clarify the pathophysiological relevance of GH-regulating neuropeptides, the neurotransmitter pathway, and metabolic substrates in regulation of the GH axis (35) throughout this critical period of life and to determine the cellular and biological changes occurring in our patients at that time, taking into account the central role of puberty. It has never previously been determined whether the residual pituitary function found at that time remains stable, deteriorates, or normalizes later in adulthood in childhood-onset GHD patients. Long-term follow-up of this population is required to resolve this issue. In patients with adult-onset partial GHD, the use of two GH stimulation tests has been recommended for the assessment of GH secretion (36). Changes in GH secretion over time have also recently been shown, with partial GHD progressing to severe GHD or normal GH secretion, with equal probabilities, in one third of patients after pituitary surgery (37). Thus, partial damage to the hypothalamic pituitary axis, as shown anatomically by the conservation of a visible pituitary stalk on MRI in our patients with ectopic neurohypophysis located along the stalk, may not strongly affect GH levels during this critical period of life in young adult patients. Such damage probably also has little effect on GH levels in some patients diagnosed with and treated for isolated idiopathic GHD in childhood with a normal pituitary stalk, EPPHS normally located in the sella turcica, and persistently subnormal serum IGF-I levels. It is also interesting to note that in adults with partial GHD, the degree of body composition abnormality (intermediate between that of severe GHD patients and healthy subjects) is more closely correlated with serum IGF-I levels than with peak GH levels (38).

However, as in other studies (3, 25, 26, 30, 39), normal serum IGF-I levels were also found in some of our patients with severe GHD, diagnosed on the basis of GH peak levels of less than 5 µg/liter. Excess weight and hyperinsulinism in some patients with GHD might account for the known limitations of serum IGF-I and, to a greater extent, of serum IGF-binding protein-3 concentrations in terms of sensitivity for GHD diagnosis in some such patients (39, 40, 41, 42).

In this study, we were able to follow to adult height 66% of a well defined population of patients with childhood-onset GHD treated with GH. One of the limitations of our study was the observational nature of data collection. Treatment with hGH successfully increased adult height in all patients, and despite our relatively small study sample, severe GHD and anatomical abnormalities of the hypothalamic pituitary axis were also found to be associated with a better auxological outcome, as previously reported (43, 44, 45).

In conclusion, we report here the first population-based study to provide evidence of subnormal serum IGF-I levels in young adults with childhood-onset GHD who have recovered normal GH secretion, with and without structural abnormalities of the hypothalamic pituitary on MRI. Our data suggest a decrease in the severity of disease in these patients, most of whom may nonetheless present persistent pituitary failure during this critical period of transition from childhood to adulthood. These patients are not currently eligible for hGH treatment. The natural history and clinical implications of these findings for these patients remain to be clarified. The possibility of deterioration in the secretion of GH and other pituitary hormones over time in a subset of patients warrants the careful long-term follow-up of this population.


   Footnotes
 
Disclosure Statement: G.G., C.G., D.C., P.A., D.S., P.C., and J.L. have nothing to declare.

First Published Online July 31, 2007

Abbreviations: BMI, Body mass index; EPPHS, ectopic posterior pituitary hyperintense signal; GHD, GH deficiency; hGH, human GH; MPHD, multiple anterior pituitary hormone deficiency; MRI, magnetic resonance imaging; SDS, SD score.

Received May 4, 2007.

Accepted July 24, 2007.


   References
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
 References
 

  1. Clayton PE, Price DA, Shalet SM 1987 Growth hormone state after completion of treatment with growth hormone. Arch Dis Child 62:222–226[Abstract/Free Full Text]
  2. Longobardi S, Merola B, Pivonello R, Di Rella F, Di Somma C, Colao AM, Ghigo E, Camanni F, Lombardi G 1996 Reevaluation of growth hormone (GH) secretion in 69 adults diagnosed as GH deficient patients during childhood. J Clin Endocrinol Metab 81:1244–1247[Abstract]
  3. Juul A, Kastrup KW, Pedersen SA, Skakkebaek NE 1997 Growth hormone provocative retesting of 108 young adults with childhood-onset GH deficiency and the diagnostic value of insulin-like growth factor I (IGF) and IGF-binding protein 3. J Clin Endocrinol Metab 82:1195–1201[Abstract/Free Full Text]
  4. Tauber M, Moulin P, Pienkowski C, Jouret B, Rochiccioli P 1997 Growth hormone retesting and auxological data in 131 GH-deficient patients after completion of treatment. J Clin Endocrinol Metab 82:352–356[Abstract/Free Full Text]
  5. Wacharasindhu S, Cotterill AM, Camacho-Hübner C, Besser GM, Savage MO 1996 Normal growth hormone secretion in growth hormone insufficient children retested after completion of linear growth. Clin Endocrinol (Oxf) 45:553–556[CrossRef][Medline]
  6. Nicolson A, Toogood AA, Rahim A, Shalet SM 1996 The prevalence of severe growth hormone deficiency in adults who received growth hormone replacement in childhood. Clin Endocrinol (Oxf) 44:311–316[CrossRef][Medline]
  7. Maghnie M, Strigazzi C, Tinelli C, Autelli M, Cisternino M, Loche S, Severi F 1999 Growth hormone (GH) deficiency (GHD) of childhood onset: reassessment of GH status and evaluation of the predictive criteria for permanent GHD in young adults. J Clin Endocrinol Metab 84:1324–1328[Abstract/Free Full Text]
  8. Thomas M, Massa G, Maes M, Beckers D, Craen M, François I, Heinrichs C, Bourguignon JP, Belgian Study Group for Paediatric Endocrinology 2003 Growth hormone secretion in patients with childhood-onset GH deficiency: retesting after one year of therapy and at final height. Horm Res 59:7–15[CrossRef][Medline]
  9. Gleeson HK, Gattamaneni HRG, Smethurst L, Brennen BM, Shalet SM 2004 Reassessment of growth status is required at final height in children treated with growth hormone replacement after radiation therapy. J Clin Endocrinol Metab 89:662–666[Abstract/Free Full Text]
  10. Cacciari E, Tassoni P, Parisi G, Pirazzoli P, Zucchini S, Mandini M, Cicognani A, Balsamo A 1992 Pitfalls in diagnosing impaired growth hormone secretion: retesting after replacement therapy of 63 patients defined as GH deficient. J Clin Endocrinol Metab 74:1284–1289[Abstract]
  11. Shalet SM, Toogood A, Rahim A, Brennan BM 1998 The diagnosis of growth hormone deficiency in children and adults. Endocr Rev 19:203–223[Abstract/Free Full Text]
  12. Rosenfeld RG, Albertsson-Wikland K, Cassorla F, Frasier SD, Hasegawa Y, Hintz RL, Lafranchi S, Lippe B, Loriaux L, Melmed S, Preece MA, Ranke MB, Reiter EO, Rogol AD, Unerwood LE, Werther GA 1995 Diagnostic controversy: the diagnosis of childhood growth hormone deficiency revisited. J Clin Endocrinol Metab 80:1532–1540[Free Full Text]
  13. Kerrigan JR, Rogol AD 1992 The impact of gonadal steroid hormone action on growth hormone secretion during childhood and adolescence. Endocr Rev 13:281–298[Abstract/Free Full Text]
  14. Léger J, Danner S, Simon D, Garel C, Czernichow P 2005 Do all patients with childhood onset growth hormone deficiency and ectopic neurohypophysis have persistent GHD in adulthood. J Clin Endocrinol Metab 90:650–656[Abstract/Free Full Text]
  15. Lange M, Feldt-Rasmussen U, Svendsen OL, Kastrup KW, Juul A, Müller J 2003 High risk of adrenal insufficiency in adults previously treated for idiopathic childhood onset growth hormone deficiency. J Clin Endocrinol Metab 88:5784–5789[Abstract/Free Full Text]
  16. Vance ML1994. Hypopituitarism. N Engl J Med 330:1651–1662
  17. Léger J, Mercat I, Alberti C, Chevenne D, Armoogum P, Tichet J, Czernichow P 2006 The relationship between the GH/IGF1 axis and serum markers of bone turnover metabolism in healthy children. Horm Res 65:177
  18. Clayton PE, Cuneo RC, Juul A, Monson JP, Shalet SM, Tauber M 2005 Consensus statement on the management of the GH-treated adolescent in the transition to adult care. Eur J Endocrinol 152:165–170[Abstract/Free Full Text]
  19. Garel C, Léger J 2007 Contribution of magnetic resonance imaging in non-tumoral hypopituitarism in children. Horm Res 67:194–202[CrossRef][Medline]
  20. Argyropoulou M, Pérignon F, Brunelle F, Brauner R, Rappaport R 1991 Height of normal pituitary gland as a function of age evaluated by magnetic resonance imaging in children. Pediatr Radiol 21:247–249[CrossRef][Medline]
  21. Sempé M, Pedron G, Roy-Pernot MP 1970 Auxologie, méthodes et séquences. Paris: Theraplix
  22. Rolland-Cachera MF, Cole TJ, Sempe M, Tichet J, Rossignol C, Charraud A 1991 Body mass index variations: centiles from birth to 87 years. Eur J Clin Nutrition 45:13–21[Medline]
  23. Greulich WW, Pyle S 1959 Radiographic atlas of skeletal development of the hand and the wrist. 2nd ed. Stanford, CA: Stanford University Press
  24. Tanner JM, Goldstein H, Whitehouse RH 1970 Standards for children’s height at ages 2–9 years allowing for heights of parents. Arch Dis Child 45:755–762[Abstract/Free Full Text]
  25. Tauber M, Jouret B, Cartault A, Lounis N, Gayrard M, Marcouyeux C, Pienkowski C, Oliver I, Moulin P, Otal P, Joffre F, Arnaud C, Rochiccioli P 2003 Adolescent with partial growth hormone deficiency develop alterations of body composition after GH discontinuation and require follow-up. J Clin Endocrinol Metab 88:5101–5106[Abstract/Free Full Text]
  26. Attanasio AF, Howell S, Bates PC, Blum WF, Frewer P, Quigley C, Shalet SM 2002 Confirmation of severe GH deficiency after final height in patients diagnosed as GH deficient during childhood. Clin Endocrinol (Oxf) 56:503–507[CrossRef][Medline]
  27. Lissett CA, Thompson EGE, Brennan BM, Shalet SM 1999 How many tests are required to diagnose growth hormone deficiency in adults? Clin Endocrinol (Oxf) 51:551–557[CrossRef][Medline]
  28. Simon D, Hadjiathanasiou CG, Garel C, Czernichow P, Léger J 2006 Phenotypic variability in children with growth hormone deficiency associated with posterior pituitary ectopia. Clin Endocrinol (Oxf) 64:416–422[Medline]
  29. Chen S, Léger J, Garel C, Hassan M, Czernichow P 1999 Growth hormone deficiency with ectopic neurohypophysis: anatomical variations and relationship between the visibility of the pituitary stalk asserted by magnetic resonance imaging and anterior pituitary function. J Clin Endocrinol Metab 84:2408–2413[Abstract/Free Full Text]
  30. Zucchini S, Pirazzoli P, Baronio F, Gennari M, Bal MO, Balsamo A, Gualandi S, Cicognani A 2006 Effect on adult height of pubertal growth hormone retesting and withdrawal of therapy in patients with previously diagnosed growth hormone deficiency. J Clin Endocrinol Metab 91:4271–4276[Abstract/Free Full Text]
  31. Toogood AA, Beardwell CG, Shalet SM 1994 The severity of growth hormone deficiency in adults with pituitary disease is related to the degree of hypopituitarism. Clin Endocrinol (Oxf) 41:511–516[Medline]
  32. Ghigo E, Bellone J, Aimaretti G, Bellone S, Loche S, Cappa M, Bartolotta E, Dammaco F, Camanni F 1996 Reliability of provocative tests to assess growth hormone secretory status: study in 472 normally growing children. J Clin Endocrinol Metab 81:3323–3327[Abstract]
  33. Pfeifer M, Kanc K, Verhovec R, Kocijancic A 2001 Reproducibility of the insulin tolerance test for assessment of growth hormone and cortisol secretion in normal and hypopituitary adult men. Clin Endocrinol (Oxf) 54:17–22[CrossRef][Medline]
  34. Molitch ME 2002 Diagnosis of GH deficiency in adults: how good do the criteria need to be? J Clin Endocrinol Metab 87:473–476[Free Full Text]
  35. Giustina A, Veldhuis JD 1998 Pathophysiology of the neuroregulation of GH secretion in experimental animals and the human. Endocr Rev 19:717–797[Abstract/Free Full Text]
  36. Murray RD, Bidlingmaier M, Strasburger CJ, Shalet SM 2007 The diagnosis of partial GH deficiency in adults with a putative insult to the hypothalamo-pituitary axis. J Clin Endocrinol Metab 92:1705–1709[Abstract/Free Full Text]
  37. Colao A, Di Somma C, Spiezia S, Rota F, Pivonello R, Savastano S, Lombardi G 2006 The natural history of partial growth hormone deficiency in adults: a prospective study on the cardiovascular risk and atherosclerosis. J Clin Endocrinol Metab 91:2191–2200[Abstract/Free Full Text]
  38. Murray RD, Adams JE, Shalet S 2004 Adults with partial growth hormone deficiency have an adverse body composition. J Clin Endocrinol Metab 89:1586–1591[Abstract/Free Full Text]
  39. Maghnie M, Aimaretti G, Bellone S, Bona G, Bellone J, Baldelli R, De Sanctis C, Gargantini L, Gastaldi R, Ghizzoni L, Secco A, Tinelli C, Ghigo E 2005 Diagnosis of GH deficiency in the transition period: accuracy of insulin tolerance test and insulin-like growth factor-I. Eur J Endocrinol 152:589–596[Abstract/Free Full Text]
  40. Boquette HR, Sobrado PGV, Fideleff HL, Sequera AM, Giaccio AV, Suarez MG, Ruibal GF, Miras M 2003 Evaluation of diagnostic accuracy of insulin-like growth factor (IGF) I and IGF-binding protein-3 in growth hormone deficient children and adults using ROC Plot analysis. J Clin Endocrinol Metab 88:4702–4708[Abstract/Free Full Text]
  41. Cianfarani S, Liguori A, Boemi S, Maghnie M, Iughetti L, Wasniewska M, Street ME, Zucchini S, Aimaretti G, Germani D 2005 Inaccuracy of insulin-like growth factor (IGF) binding protein (IGFBP)-3 assessment in the diagnosis of growth hormone (GH) deficiency from childhood to young adulthood: association to low GH dependency of IGF-II and presence of circulating IGFBP-3 18-kilodalton fragment. J Clin Endocrinol Metab 90:6028–6034[Abstract/Free Full Text]
  42. Hilding A, Hall K, Wivall-Helleryd IL, Saaf M, Melin AL, Thoren M 1999 Serum levels of insulin-like growth factor I in 152 patients with growth hormone deficiency, aged 19–82 years, in relation to those in healthy subjects. J Clin Endocrinol Metab 84:2013–2019[Abstract/Free Full Text]
  43. Carel JC, Ecosse E, Nicolino M, Tauber M, Léger J, Cabrol S, Bastié-Sigeac I, Chaussain JL, Coste J 2002 Adult height after long term treatment with recombinant growth hormone for idiopathic isolated growth hormone deficiency: observational follow up study of the French population based registry. BMJ 325:70–73[Abstract/Free Full Text]
  44. Reiter EO, Price DA, Wilton P, Albertsson-Wikland K, Ranke MB 2006 Effect of growth hormone treatment on the final height of 1258 patients with idiopathic GH deficiency: analysis of a large international database. J Clin Endocrinol Metab 91:2047–2054[Abstract/Free Full Text]
  45. Zenaty D, Garel C, Limoni C, Czernichow P, Léger J 2003 Presence of magnetic resonance imaging abnormalities of the hypothalamic-pituitary axis is a significant determinant of the first 3 years growth response to human growth hormone treatment in prepubertal children with nonacquired growth hormone deficiency. Clin Endocrinol (Oxf) 58:647–652[Medline]



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A. Secco, N. di Iorgi, F. Napoli, E. Calandra, A. Calcagno, M. Ghezzi, C. Frassinetti, N. Fratangeli, S. Parodi, M. Benassai, et al.
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The Diagnosis of GHD in Young Adults With Recovery of GH Testing and Subnormal IGF-I Values
Mohamad Maghnie, et al.
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