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Do All Patients with Childhood-Onset Growth Hormone Deficiency (GHD) and Ectopic Neurohypophysis Have Persistent GHD in Adulthood?

Pediatric Endocrinology and Diabetes Unit, Institut National de la Santé et de la Recherche Médicale, Unité 457 (J.L., S.D., D.S., P.C.), and Radiology Department (C.G.), Hôpital Robert Debré, 75019 Paris, France

Address all correspondence and requests for reprints to: Dr. Juliane Léger, Pediatric Endocrinology and Diabetes Unit, Institut National de la Santé et de la Recherche Médicale, Unité 457, Hopital Robert Debré, 48 boulevard Sérurier, 75019 Paris, France. E-mail: juliane.leger{at}rdb.ap-hop-paris.fr.

	Abstract

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Cerebral magnetic resonance imaging findings are of great value for the diagnosis of nonacquired GH deficiency (GHD), and ectopic posterior pituitary hyperintense signal (EPPHS) is a sensitive and specific indicator of hypopituitarism. It has been suggested that patients with childhood-onset GHD and EPPHS do not require additional investigation of GH secretion and should not be retested when adult height is achieved. This recommendation has never been validated through a systematic study. This study aimed to characterize the anterior pituitary function status of patients with EPPHS treated for GHD during childhood after completion of GH therapy when adult height had been achieved. Patients (n = 18; 15 males and three females) with childhood-onset GHD associated with ectopic neurohypophysis were treated with hGH (0.20 ± 0.05 mg/kg·wk) for 9.9 ± 4.0 yr (from 6.8 ± 4.7 to 17.7 ± 1.3 yr of age) with a mean height gain of 2.6 ± 1.4 SD score. GH secretion was reevaluated by arginine insulin (n = 15) or propanolol glucagon (n = 3) test after 0.5 ± 0.6 yr of GH withdrawal. At reevaluation, peak GH was more than 10 µg/liter in four patients (22%; range, 11.7–19.5 µg/liter; group I), between 5 and 10 µg/liter in three patients (17%; range, 7.3–9 µg/liter; group II), and less than 5 µg/liter in 11 patients (61%; range, 0–4.7 µg/liter; group III). A positive correlation was found between serum IGF-I and peak GH levels after attainment of adult height (P = 0.007). Only one of the seven patients who showed increased GH secretion ability in adulthood (groups I and II) demonstrated other hormonal deficiencies (gonadotropin and adrenal insufficiencies). Among the 11 patients with persistent severe GHD (group III), 10 (91%) of the 11 subjects were shown to have multiple pituitary hormone deficits after attainment of adult height. The structure of the hypothalamo-pituitary axis differs among groups [i.e. patients who showed increased GH secretion ability in adulthood (groups I and II) vs. those who remained severely GHD (group III)]. The location of the EPPHS was significantly different among groups (P < 0.003). The EPPHS was found at the median eminence in all but one of group III patients and along the pituitary stalk (proximal stalk) in all but one of group I and II patients. The pituitary stalk was visible and described as normal (n = 1) or thin (n = 6) in all group I and II patients, whereas the pituitary stalk was not visible even after enhancement in seven of the 11 group III patients (P < 0.02). The prevalence of anterior pituitary hypoplasia and the mean height gain SD score were similar in each group. In conclusion, only 61% of patients with childhood-onset GHD and EPPHS remained severely GHD, and thus suitable for GH therapy, in adulthood. Although the pathogenesis of anterior pituitary dysfunction remains unclear in patients with ectopic neurohypophysis, isolated GHD, location of EPPHS along the stalk, and visibility of the pituitary stalk on magnetic resonance imaging findings clearly represent important markers to predict a less severe form of the disease.

	Introduction

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THE DIAGNOSIS OF GH deficiency (GHD) during childhood requires clinical and auxological assessment and biochemical tests of the GH-IGF axis (1). Cerebral magnetic resonance imaging (MRI) findings are also of great value for the diagnosis of nonacquired GHD by giving a precise description of the hypothalamic-pituitary region and the possibly associated midline abnormalities. They bring important insight to the etiology of GHD. Ectopic neurohypophysis with normal, thin, or absent pituitary stalk is a sensitive and specific indicator of hypopituitarism (2), whereas the finding of an isolated small anterior pituitary gland is not reliable, because pituitary volume can normalize a few years later (3).

We have previously shown that the anatomical anomalies of the hypothalamo-pituitary axis have great prognosis value in patients with ectopic neurohypophysis. Patients with no visible pituitary stalk on MRI present a more severe form of the disease associated with an ectopic neurohypophysis always located at the median eminence and with multiple anterior pituitary hormone deficiency (MPHD), whereas visibility of the pituitary stalk is more probably related to an ectopic neurohypophysis located at different levels of the pituitary stalk and isolated GHD (4). However, the natural history of the disease has never been established until adulthood.

Determination of GH status when final height (FH) is achieved is important to identify patients diagnosed in childhood as GHD who might benefit from continued GH therapy in adulthood (1). Nevertheless, consensus guidelines for the management of GHD in childhood and adolescence did not recommend GH retesting in cases of severe organic GHD and/or multiple pituitary hormone deficits (1). Moreover, it has been suggested that patients with GHD and congenital hypothalamic pituitary abnormalities with either isolated GHD or MPHD do not require additional investigation of GH secretion and need not be retested when adult height is achieved (3).

To describe in more detail the natural history of anterior pituitary dysfunction in patients with ectopic neurohypophysis treated for GHD during childhood, we analyzed the auxological and biochemical data before and after childhood GH replacement therapy once FH had been achieved.

	Subjects and Methods

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The study population consisted of 18 patients with childhood-onset GHD (15 males and three females) associated with ectopic neurohypophysis, retested for GH secretion when FH had been achieved and after GH treatment had been discontinued.

At the time of diagnosis of GHD, their mean chronological age was 6.8 ± 4.7 yr (from 0.02 to 15.2 yr) with a mean height of –2.7 ± 1.3 SD score (SDS) and a mean height velocity of –2.5 ± 1.8 SDS. Nine patients had isolated GHD, and nine patients had MPHD (Table 1). The mean duration of GH treatment was 9.9 ± 4.0 yr, and treatment was stopped at a mean age of 17.7 ± 1.3 yr. Recombinant human GH (hGH) was given sc at a dose of 0.20 ± 0.05 mg/kg·wk in six or seven injections per week, which was the current dose used in France during the study period. Additional replacement, including L-T₄, hydrocortisone, and/or sex steroid therapy, was given when TSH, ACTH, and/or gonadotropin (FSH and LH) deficiencies were diagnosed.

In all patients, GH treatment was discontinued when growth velocity during the previous 6 months was less than 1 cm. GH secretion was reevaluated by arginine insulin tolerance test (n = 15) or propanolol glucagon test (n = 3), and IGF-I levels were determined 0.5 ± 0.6 yr after GH withdrawal.

Informed consent for therapy and for the evaluations was obtained from the children’s parents and the patients.

Height, height velocity (5), and body mass index [weight (kilograms)/height (meters)²] (6) were expressed as the SDS for sex and chronological age. Bone age determinations were made under blinded conditions by one investigator (J.L.) according to the method of Greulich and Pyle (7). Target height was calculated from midparental height (8).

Serum GH (micrograms per liter) was measured on a single sample by a solid phase, two-site immunoradiometric assay, and serum IGF-1 (micrograms per liter) was determined by an immunoradiometric assay using two monoclonal antibodies directed against two different epitopes of the IGF-I molecule (HGH-RIACT, IGF-1-RIACT, Schering, Gif sur Yvette, France).

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 (4). The height of the anterior pituitary was measured on a sagittal T1-weighted image and was judged to be either normal or hypoplastic according to normative data in children. The anterior pituitary was considered to be hypoplastic when the gland height was less than –2 SD for age (9). The presence or absence of the pituitary stalk was recorded before and after gadolinium administration as normal, absent, or thin (4). The precise localization of the ectopic posterior pituitary hyperintense signal (EPPHS) was also established by MRI.

	Statistical analysis

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Results were expressed as the mean ± SD. The Mann-Whitney U test was performed for comparison between groups. The percentages within groups were compared by the ² test (Fisher tests). Correlations among serum IGF-I and peak GH levels were analyzed with the Spearman r coefficient.

	Results

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Hormonal status after completion of treatment

As shown in Table 1, by definition all patients had clinical and biological characteristics (with low serum IGF-I levels when assessed) of GHD at the time of initial evaluation. However, this was not the case at reevaluation when FH had been achieved. Patients were classified into three groups according to the results of the GH test at reassessment. Group I had peak GH greater than 10 µg/liter; group II had peak GH of 5–10 µg/liter; group III had peak GH less than 5 µg/liter. The characteristics of the 18 patients at the time of diagnosis of GHD and after attainment of adult height according to their GH status at reassessment are indicated in Tables 1 and 2.

Isolated GHD was significantly more frequent in patients who showed increased GH secretion ability in adulthood (groups I and II) than in those who remained severely GHD (group III; 86% vs. 9%, respectively; P < 0.003). Only one (patient 6) of the seven patients (groups I and II) who showed increased GH secretion in adulthood demonstrated other hormonal deficiencies (gonadotropin and adrenal insufficiencies) that had been diagnosed during the course of treatment, whereas among group III patients, 10 (91%) of the 11 subjects were shown to have MPHD after attainment of adult height. Only one patient in this group (no. 17) still had isolated GHD at the time of the last evaluation. One patient (no. 15) who initially showed isolated GHD had developed MPHD with thyroid deficiency during follow-up.

A positive correlation was found between serum IGF-I and peak GH levels after attainment of adult height (r = 0.70; P = 0.007). However, the mean serum IGF-I values after attainment of adult height was not significantly different between patients who showed increased GH secretion ability in adulthood (groups I and II) and those who remained severely GHD (group III; 250 ± 95 vs. 144 ± 132 µg/liter, respectively; P = 0.06). Nevertheless, among group III patients, five patients (no. 9, 13, 14, 16, and 18) demonstrated very low serum IGF-I values (Table 2). No correlation was found between the time off therapy and serum IGF-I values (neither in patients who showed increased GH secretion ability in adulthood nor in those who remained severely GHD).

Cerebral MRI findings

As shown in Table 3, the structure of the hypothalamo-pituitary axis differs among groups (i.e. patients who showed increased GH secretion ability in adulthood groups I and II vs. those who remained severely GHD group III). The location of the EPPHS was significantly different among groups (P < 0.003). The EPPHS was found at the median eminence in all but one of group III patients (91% of cases) and along the pituitary stalk (proximal stalk) in all but one of group I and II patients (86% of cases; Fig. 1). Moreover, a difference in the visibility of the pituitary stalk was found between groups (P < 0.02). The pituitary stalk was visible and described as normal (n = 1) or thin (n = 6) in all group I and II patients, whereas the pituitary stalk was not visible, even after enhancement in seven of the 11 group III patients (64% of cases). However, the height of the adenohypophysis did not differ between groups, and the prevalence of anterior pituitary hypoplasia was similar among groups (29% vs. 45% in groups I and II vs. group III).

View larger version (113K): [in this window] [in a new window]   FIG. 1. Cerebral MRI (T1-weighted images). A, Sagittal slice; B, coronal slice; normal morphology of anterior pituitary and pituitary stalk is seen. The hyperintense signal of the posterior pituitary is in the normal location. C, Sagittal slice; D, coronal slice; a normal anterior pituitary with a thin pituitary stalk is seen. The ectopic posterior pituitary hyperintense signal is located along the stalk (at a proximal level of the pituitary stalk; arrow). E, Sagittal slice; F, coronal slice; hypoplastic anterior pituitary with no visible pituitary stalk after gadolinium injection. The ectopic pituitary hyperintense signal is at the median eminence (arrow).

FH and height gain

As shown in Fig. 2, the growth response to hGH therapy was similar among groups. The mean height gain SDS values were 2.3 ± 1.0 and 2.8 ± 1.6 SDS for patients who showed increased GH secretion ability (groups I and II) compared with those showing persistent GHD in adulthood (group III), respectively. The mean adult height was also similar among groups (–0.5 ± 0.9 vs. 0.2 ± 1.2 SD, for groups I and II vs. group III, respectively) and was not different from their target height (0.3 ± 1.1 vs. 0.4 ± 0.7 SDS for groups I and II vs. group III, respectively). Moreover, the mean difference between adult height and target height was similar for groups I and II vs. group III patients (–0.8 ± 1.3 vs. 0.1 ± 1.1 SDS, respectively).

View larger version (15K): [in this window] [in a new window]   FIG. 2. Changes in height SDS from the beginning of treatment until adult height in patients with increased GH secretion ability (groups I and II) compared with those with persistent severe GHD in adulthood (group III).

	Discussion

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During previous years, several studies have pointed out that a high proportion of patients with childhood-onset GHD are no longer GHD when retested at the attainment of FH. The frequency of reported normalization of GH secretion among idiopathic GHD patients varies from 25–75% and was found to be higher in patients with partial GHD than in those with severe GHD during childhood (3, 11, 12, 13, 14, 15, 16, 17). Moreover, although normalization of GH secretion was common in patients with isolated GHD and uncommon in those with MPHD, it did not occur in the patients with congenital hypothalamic-pituitary abnormalities, i.e. ectopic neurohypophysis (3). This finding was not confirmed in our study, suggesting that the diagnosis of GHD in childhood related to anatomical abnormality of the hypothalamic-pituitary area should not be taken as irrefutable evidence of permanent severe GHD. Two previous studies have demonstrated partial GHD in three young adults with ectopic neurohypophysis with (18) and without (19) visibility of the pituitary stalk as shown on MRI. To our knowledge, normal GH secretion at reassessment has never previously been reported among patients with childhood GHD and ectopic neurohypophysis.

The concept of increased GH secretion ability after attainment of adult height may not necessarily represent the end of a transient secretory defect. It has recently been shown that 48% of GHD patients related to radiation therapy during childhood were not severely GHD at reassessment (20). The mechanism of change in GH secretion is of considerable interest. Spontaneous GH secretion increases during pubertal development and is much higher in a teenager than an older adult, possibly as the result of exposure to sex steroids during puberty and/or maturation of the hypothalamic control of GH secretion (14, 21, 22, 23). Therefore, patients with a likelihood of impaired GH secretion, such as congenital hypothalamic pituitary abnormalities or acquired organic GHD after radiotherapy in childhood, might show a change in peak GH response over time and require long-term reassessment of GH secretion.

One of the major problems in assessment of GH secretion is its poor reproducibility and the great number of false negative responses observed (and also seen in normal children) (24). Although biochemical tests for GH secretion clearly distinguish children with severe GHD, recognition of more subtle forms of GH insufficiency still represents a diagnostic dilemma (25). Whether GH secretion returns to normal in these patients or whether this phenomenon is the result of unreliable testing and/or a possible age effect on GH secretion is still under investigation. The insulin tolerance test has been considered the test of choice for the assessment of GH reserve in young adults (26). GH responses less than 3 ng/ml are considered to be diagnostic of severe GHD with almost complete accuracy (10, 26). Although the concordance rates in hypopituitary adult men were very good, the reproducibility of the peak GH response to insulin tolerance test in normal men is highly variable. Nevertheless, this did not lead to the misclassification of any cases as being borderline GH deficient (27). However, it is not clear from this or any other study whether the same degree of variability would be observed in adults with partial GHD, which may lead to their misclassification if based on a single test. Caution is therefore required in the interpretation of borderline results from a single test (28).

The lack of a statistically significant difference between serum IGF-I levels among groups at reassessment is probably due to the small number of investigated patients. However, it has been reported that about one third of patients with adult GHD diagnosed by stimulated GH levels have serum IGF-I levels in the normal range (13, 26, 29). It is also interesting to note that five of eight group III patients with severe GHD demonstrated very low serum IGF-I levels, which should therefore be considered as showing high predictive value for the diagnosis of adult GHD (13, 30, 31).

It also seems impossible to predict the persistence of severe GHD in patients with ectopic neurohypophysis on the basis of either hormonal findings at the initial evaluation or auxological criteria. We found no relationship between the results of GH status at reassessment and height gain after GH treatment. GH treatment was beneficial in all patient groups, and only one group III patient showed a FH below –2 SDS. None of the previous studies had analyzed the possibility of retesting after FH achievement as a means of explaining the response to GH treatment. In two previous studies, an attempt was made to analyze the first year growth response to hGH, and no relationship was found between growth response and the results of retesting either after 1 yr of hGH treatment or after FH achievement (11, 18).

In conclusion, although the pathogenesis of anterior pituitary dysfunction remains unclear in patients with ectopic neurohypophysis, the location of the EPPHS along the pituitary stalk and the visibility of the pituitary stalk on MRI clearly represent important markers to predict a less severe form of the disease. In cases of ectopic neurohypophysis, a careful description of MRI findings is important, including the precise location of the EPPHS and pituitary stalk visibility after gadolinium injection. Retesting for diagnosis of GHD in adulthood after pediatric hGH treatment is a critical step in the management of these childhood-onset GHD patients, because confirmation of the diagnosis has important implications for the patients, as life-long hGH replacement is required in cases of severe GHD (10). Our data suggest that it is not necessary to reconfirm GH deficiency by GH provocative testing once FH had been achieved in those patients who have a location of EPPHS at the median eminence associated with MPHD. However, all other patients, including isolated GHD patients and those with isolated GHD who demonstrate another anterior pituitary hormone deficiency later during the follow-up, regardless of the location of the EPPHS should be retested. We also believe that patients with ectopic neurohypophysis regardless of their GH status in adulthood require regular assessment of pituitary function, because they might develop other pituitary hormone deficiencies. It has recently been demonstrated that adults previously treated for idiopathic childhood-onset GHD who were no longer GH deficient were at risk of developing adrenal insufficiency (32). The concept of partial GHD in adolescent and adult patients requiring long-term follow-up of body composition has also recently been well documented (33, 34). These findings justify a careful follow-up of these patients.

	Footnotes

 
First Published Online November 16, 2004

Abbreviations: EPPHS, Ectopic posterior pituitary hyperintense signal; FH, final height; GHD, GH deficiency; h, human; MPHD, multiple anterior pituitary hormone deficiency; MRI, magnetic resonance imaging; SDS, SD score.

Received July 1, 2004.

Accepted November 3, 2004.

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