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Journal of Clinical Endocrinology & Metabolism , doi:10.1210/jc.2007-1081
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Right arrow Neuroendocrinology and Pituitary
The Journal of Clinical Endocrinology & Metabolism Vol. 92, No. 10 3875-3884
Copyright © 2007 by The Endocrine Society

Deterioration of Growth Hormone (GH) Response and Anterior Pituitary Function in Young Adults with Childhood-Onset GH Deficiency and Ectopic Posterior Pituitary: A Two-Year Prospective Follow-Up Study

Natascia di Iorgi, Andrea Secco, Flavia Napoli, Carmine Tinelli, Annalisa Calcagno, Nadia Fratangeli, Linda Ambrosini, Andrea Rossi, Renata Lorini and Mohamad Maghnie

Departments of Pediatrics (N.d.I., A.S., F.N., A.C., N.F., L.A., R.L., M.M.) and Neuroradiology (A.R.), Istituto di Ricovero e Cura a Carattere Scientifico G. Gaslini Institute, University of Genova, Genova 16147, Italy; and Division of Biometry-Scientific Direction (C.T.), Istituto di Ricovero e Cura a Carattere Scientifico Policlinico San Matteo, Pavia, Pavia 27100, Italy

Address all correspondence and requests for reprints to: Mohamad Maghnie, M.D., Ph.D., Associate Professor of Pediatrics, Department of Pediatrics Istituto di Ricovero e Cura a Carattere Scientifico G. Gaslini, University of Genova, Largo Gerolamo Gaslini, 5, 16147 Genova, Italy. E-mail: mohamadmaghnie{at}ospedale-gaslini.ge.it.


   Abstract
Top
 Abstract
Introduction
 Patients and Methods
 Results
 Discussion
 References
 
Context: The current criteria for definition of partial GHD in young adults are still a subject of debate.

Objectives: The objective of the study was to reinvestigate anterior pituitary function in young adults with congenital childhood-onset GHD associated with structural hypothalamic-pituitary abnormalities and normal GH response at the time of first reassessment of GH secretion.

Design and Setting: This was a prospective explorative study conducted in a university research hospital.

Patients and Methods: Thirteen subjects with a mean age of 17.2 ± 0.7 yr and a peak GH after insulin tolerance test (ITT) higher than 5 µg/liter were recruited from a cohort of 42 patients with childhood-onset GHD and ectopic posterior pituitary at magnetic resonance imaging. GH secretion after ITT and GHRH plus arginine, IGF-I concentration, and body mass index, waist circumference, blood pressure, total cholesterol, and fibrinogen were evaluated at baseline and at 2-yr follow-up.

Results: At mean age of 19.2 ± 0.7 yr, the mean peak GH response decreased significantly after ITT (P = 0.00001) and GHRH plus arginine (P = 0.0001). GH peak values after ITT and GHRH plus arginine were less than 5 and 9 µg/liter in 10 and eight patients, respectively. Additional pituitary defects were documented in eight patients. Significant changes were found in the values of IGF-I SD score (P = 0.0026), waist circumference (P = 0.00001), serum total cholesterol (P = 0.00001), and serum fibrinogen (P = 0.0004).

Conclusions: The results of this study underline the importance of further reassessment of pituitary function in young adults with GHD of childhood-onset and poststimulation GH responses suggestive of partial GHD.


   Introduction
Top
 Abstract
 Introduction
Patients and Methods
 Results
 Discussion
 References
 
THE SYNDROME OF GH deficiency (GHD) in adults has recently been characterized as a specific clinical entity (1). It is well known that GHD in adults is associated with metabolic consequences such as increased adiposity, abnormal serum lipid profiles, reduced exercise capacity, reduced bone mineral density, reduced insulin sensitivity, decreased psychological well-being, and premature mortality for cardiovascular diseases (2, 3). GH replacement therapy induces favorable changes in metabolic indices and improves body composition, bone density and remodeling, physical and cardiac performance, and overall quality of life, although there is, however, a lack of evidence of improvement in mortality rates (4, 5).

Patients with childhood-onset GHD may need to continue GH replacement after the attainment of adult height. Yet several studies have shown that many subjects are no longer GH deficient when retested at adolescence (6, 7, 8, 9). Indeed, a diagnosis of GHD in young adults relies on GH stimulation tests and is, in essence, a diagnosis based on the likelihood of disease presence including severe GHD, multiple pituitary hormone deficiency (MPHD), and magnetic resonance imaging (MRI) features of anterior pituitary hypoplasia, pituitary stalk agenesis, and ectopic posterior pituitary (EPP) at the level of the median eminence (9). However, young subjects with childhood-onset GHD and structural hypothalamic-pituitary abnormalities may have cutoff values of peak GH response to insulin tolerance test (ITT) up to 6.1 µg/liter (10), indicating that cutoff values of peak GH of less than 3 µg/liter (11) or less than 5 µg/liter could be too restrictive for the diagnosis of permanent GH deficiency in early adulthood. This is in partial agreement with the consensus statement from the European Society for Pediatric Endocrinology that suggests a GH level of less than 5 µg/liter for defining GH status in view of more exuberant physiologic GH secretion during puberty (12).

The reassessment of GH status in young adults with childhood-onset GHD associated with structural hypothalamic-pituitary abnormalities demonstrated that the predictive criteria for permanent severe GHD characterized a subset of patients with EPP at the level of the median eminence and pituitary stalk agenesis (9). Conversely, in a recent study, only 61% of the subjects with structural pituitary abnormalities were diagnosed as severely GHD, whereas the remaining 39% who had a posterior pituitary gland along the pituitary stalk were considered as having an uncertain diagnosis with a probable normal GH response after stimulation tests (13). These controversial findings have important clinical implications for the diagnosis and prognosis of GHD after adult height achievement (14, 15).

Taking all of this into consideration, we sought to evaluate in this prospective study the GH status and anterior pituitary function, as well as metabolic parameters, both after final height achievement and 2 yr after recombinant human GH (rhGH) treatment withdrawal in young adult subjects with childhood-onset GHD who did not fit the biochemical criteria for the diagnosis of severe GHD.


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

The study comprised 96 patients with childhood-onset GHD who reached adult height after a mean duration of 8.7 ± 4.3 yr of rhGH treatment. The diagnosis of GHD during childhood was based on clinical criteria and biochemical findings, i.e. GH responses of less than 10 µg/liter to at least two pharmacological provocative tests and MRI features of normal or abnormal pituitary morphology.

All 96 patients underwent GH reevaluation by means of an ITT; MRI scan was performed within 3 months after rhGH discontinuation. Fifty-four of the 96 subjects (56%) had a peak GH response to ITT higher than 10 µg/liter and normal pituitary morphology at MRI, whereas the remaining 42 (44%) had anterior pituitary hypoplasia, pituitary stalk anomalies, and EPP. Twenty-nine of the 96 (30%) showed GH peak responses to ITT of less than 5 µg/liter and started rhGH treatment, whereas the remaining 13 subjects (14%) with peak GH responses of between 5 and 10 µg/liter were considered eligible for the study. Twenty (12 males and eight females) of the 54 subjects with normal GH response after ITT and normal pituitary gland at MRI were recruited as the control group (Fig. 1Go). Subjects with MPHD were receiving conventional replacement therapy for pituitary deficits


Figure 1
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  		FIG. 1. Flow chart showing the cohort of patients with childhood-onset GHD subdivided according to the peakGH response cutoff point and MRI features at the time of adult height achievement. VPS, Visible pituitary stalk, APS, agenesis of pituitary stalk.

 
Study design

This was a prospective study of 2 yr duration carried out after appropriate approval by the Ethical Committee Board. Signed informed consent was obtained at a mean age of 17.2 ± 0.7 yr from all 13 untreated subjects with a peak GH response of between 5 and 10 µg/liter after ITT and at a mean age of 16.8 ± 0.4 yr from the 20 controls with normal GH response at the time of rhGH withdrawal. Nine of the 13 subjects have isolated GHD, whereas four have MPHD. Their main characteristics are summarized in Table 1Go. The study design consisted of: 1) assessment of GH status by means of ITT and GHRH plus arginine at baseline and after 24 months; 2) the evaluation of thyroid, gonad, and adrenal functions at baseline and after 12 and 24 months; and 3) measurements of body mass index (BMI), waist circumference, systolic blood pressure, diastolic blood pressure, serum IGF-I concentration, serum total cholesterol, and serum fibrinogen at baseline and after 24 months.


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  		TABLE 1. Clinical characteristics and anterior pituitary function at the time of first reassessment of GH status in 13 patients with childhood-onset GHD and GH peak response to ITT > 5 µg/liter

 
Reevaluation of anterior pituitary function

The ITT was administered between 0800 and 0900 h after overnight fasting. A heparin-lock cannula was placed in a forearm vein for blood sampling. Soluble insulin (0.1 U/kg) was given iv at time 0, and venous blood samples for GH and blood glucose determinations were obtained at 0, 30, 60, 90, and 120 min. After another overnight fast, all subjects underwent both total IGF-I measurement and GHRH plus arginine test (GHRH1–29; GEREF, Serono, Italy; 1 µg/kg iv at 0 min; arginine hydrochloride, 0.5 g/kg iv over 30 min from 0 to +30 min, up to a maximum of 30 g). Blood samples for GH evaluation were taken every 15 min from 0 to +90 min. In healthy controls the third percentile limit and the first percentile of the peak GH response after GHRH plus arginine were defined based on normative published data of 16.5 and 9.0 µg/liter, respectively (16).

Hypothyroidism was defined as low or low-normal serum TSH concentration and low serum free T4 (FT4) levels. Serum cortisol values were measured in the morning in all patients; ACTH deficiency was suspected in the presence of a morning serum cortisol concentration of less than 3.6 µg/dl (100 nmol/liter) and confirmed after an impaired cortisol serum concentration increase, i.e. less than 20 µg/dl (550 nmol/liter) during ITT; this diagnosis of adrenal insufficiency was supplemented by dynamic tests including the low-dose ACTH and the standard ACTH tests (data not shown). Hypogonadism was confirmed in both sexes by clinical manifestation (secondary amenorrhea or decreased libido and erections) and low serum estrogen/testosterone levels.

Imaging studies

MRI scans were performed for all patients using a spin-echo technique with a 1.5-T superconductive system. Sagittal and coronal T1-weighted images with 3-mm sections were obtained. Detailed MRI scans were performed before and after contrast medium using gadolinium. The MRI of the hypothalamic-pituitary area that was performed during childhood showed either normal anterior pituitary morphology (Fig. 2Go) or anterior pituitary hypoplasia associated with EPP and visible pituitary stalk or complete pituitary stalk agenesis (Table 1Go).


Figure 2
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  		FIG. 2. A, Normal pituitary gland appearance on sagittal T1-weighted images. The posterior pituitary hyperintensity (arrowhead), anterior pituitary lobe (AP, thick arrow), pituitary stalk (thin arrow), and median eminence (ME) are clearly visible. B (case 11 with MPHD), Small pituitary sella, anterior pituitary hypoplasia (arrow), absent pituitary stalk, and ectopic posterior lobe at the level of the median eminence (arrowhead). C (case 6 with isolated GHD), Small pituitary sella, anterior pituitary hypoplasia (arrow), and ectopic posterior lobe within the middle third (arrowhead) of pituitary stalk (arrow). D (case 7 with evolving pituitary hormone deficiency), Small pituitary sella, anterior pituitary hypoplasia (thick arrow), and ectopic posterior lobe extended (arrowhead) within the pituitary stalk (thin arrow).

 
Assay

Serum GH was measured by chemiluminescent immunometric assay (Immulite 2000, GH; Diagnostic Products Corp., Los Angeles, CA). The sensitivity of the method was 0.01 ng/ml. The inter- and intraassay coefficients of variation (CVs) were 4.2–6.6% and 2.9–4.6%, respectively, at GH levels of 2.6–17 ng/ml, respectively. The international standard was 98/574, 1 µg/liter = 2.4 mIU/liter. All samples from each individual subject were analyzed together at the same time. Serum IGF-I was measured with immunoradiometric assay (Immulite 2000; Diagnostic Products Corp.). The intra- and interassay CVs were 3.4 and 7.1%, respectively, and the sensitivity of the method was 2.6 nmol/liter. IGF-I SD score (SDS) was calculated using the normative data for this analytical method as previously described (17). Serum FT4, TSH, cortisol, FSH/LH, total cholesterol, and fibrinogen were measured using commercial kits.

Statistical analysis

The Shapiro-Wilk’s test was used to verify the normal distribution of quantitative variables. Because all quantitative data were distributed normally, we used mean and SD to summarize them, and parametric tests (Student t test for paired and unpaired data) were used to compare mean values between times or groups. Simple linear correlations were analyzed with the Poisson r coefficient. Differences over time and between groups for GH peak, IGF-I SDS, and metabolic parameters were evaluated with linear regression models for repeated measures; results are expressed as correlation coefficients with their 95% confidence intervals (CIs).

The optimal cutoff points between groups of GH peak after ITT, GHRH plus arginine, and IGF-I SDS were calculated by means of receiver operating characteristic (ROC) curves (18) with the computation of the area under the curve (and its 95% CIs). P < 0.05 was assumed to indicate statistical significance. All tests were two tailed. Analyses were executed with the software packages Statistica 6.0 for Windows (2002; StatSoft Inc., Tulsa, OK) and MedCalc (19).


   Results
Top
 Abstract
 Introduction
 Patients and Methods
 Results
Discussion
 References
 
GH status and anterior pituitary function

At the time of first reevaluation, all 20 control subjects showed GH responses after ITT and GHRH plus arginine that were higher than 10 and 20 µg/liter, respectively. There was a significant difference in the mean peak GH responses at baseline between the controls and the 13 untreated subjects after ITT (17.4 ± 4.0 vs. 7.1 ± 1.3 µg/liter; P = 0.00001) and GHRH plus arginine tests (31.3 ± 6.8 vs. 13.1 ± 3.8 µg/liter; P = 0.00001) (Fig. 3Go).


Figure 3
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  		FIG. 3. Peak GH response to ITT and GHRH plus arginine and IGF-I SDS represented as mean ± SD in the 13 patients at baseline and after 2-yr follow-up, compared with the control group of 20 unaffected subjects.

 
At the 2-yr follow-up, small changes in mean peak GH responses after ITT and GHRH plus arginine were found in the 20 controls (Table 2Go). The 13 untreated subjects with a mean age of 19.2 ± 0.7 yr showed a significant decrease in the mean peak GH response to ITT (7.1 ± 1.3 vs. 4.1 ± 1.6 µg/liter; P = 0.00001) and GHRH plus arginine (13.1 ± 3.8 vs. 7.8 ± 2.5 µg/liter; P = 0.0001). There was a significant difference in the mean peak GH responses between the controls and the 13 untreated subjects after ITT (18.8 ± 3.3 vs. 4.1 ± 1.6 µg/liter; P = 0.00001) and GHRH plus arginine tests (34.6 ± 8.0 vs. 7.8.0 ± 2.5 µg/liter; P = 0.00001) (Fig. 3Go). Specifically, GH peak values after ITT and GHRH plus arginine were less than 5 and 9 µg/liter in 10 (76%) and eight patients (61%), respectively. When applying the cutoff of 6.1 µg/liter after ITT (10), only one patient with isolated GHD showed a peak GH of 7.0 µg/liter after 2 yr (Table 3Go).


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  		TABLE 2. Clinical characteristics, peak GH responses to ITT and GHRH plus arginine, and metabolic parameters at the time of first reassessment of GH secretion (time 0) and after 2-yr follow-up in 20 subjects (12 males and eight females) with childhood-onset GHD and normal GH status

 

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  		TABLE 3. Clinical characteristics and anterior pituitary function after 2-yr follow-up in 13 patients with childhood-onset GHD and GH peak response to ITT greater than 5 µg/liter at the time of re-reassessment

 
Mean IGF-I SDS at baseline evaluation (0.28 ± 0.74 vs. –1.3 ± 0.6; P = 0.0001) and at 2-yr follow-up (0.33 ± 0.68 vs. –1.8 ± 0.4; P = 0.0012) were significantly higher in the control group, compared with the 13 subjects with EPP. It further decreased after 2 yr in the patient group (–1.3 ± 0.6 vs. –1.8 ± 0.4; P = 0.0026) but remained unchanged in the control group (Fig. 3Go).

Additional anterior pituitary defects were documented during follow-up in eight patients (three after 12 months and nine after 24 months) (Table 3Go). Adrenal dysfunction was found in five patients, central hypothyroidism was diagnosed in four, and hypogonadotropic hypogonadism in one. In one patient who showed a serum morning cortisol level of less than 3.6 µg/dl (100 nmol/liter) at 12-month follow-up, adrenal function evaluated by means of ITT test, low-dose ACTH, and standard ACTH stimulation tests (data not shown) was suggestive of ACTH deficiency as previously described (20); hydrocortisone was started at 14 months in this patient and at 26 months in the remaining four. FT4 levels were within the normal range in the eight patients at time 0; two of them showed low FT4 levels after 12 months and two of them after 24 months. Low FT4 levels were confirmed three times within 3 months and T4 treatment was then started. The data of thyroid and adrenal function are reported in Table 4Go.


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  		TABLE 4. Biochemical data of thyroid and adrenal function in 13 patients with childhood-onset GHD at baseline and during follow-up

 
The ROC analysis shows that the optimal threshold for GH peak after ITT, GHRH plus arginine, and IGF-I SDS that is capable of clearly predicting the severity of GHD in subjects with childhood-onset GHD and partial GHD at the time of re-reassessment of GHD are 7 µg/liter, 13.4 µg/liter, and –1.21 SDS, respectively. In all cases the area under the ROC curve was 1.0 with 95% CI 0.89–1.0 and sensitivity and specificity were 100%.

Linear regressions for repeated measures showed that peak GH responses as compared between the 13 subjects with EPP and the control group after ITT [coefficient = –10.3, 95% CI –12.4 to –8.1%; P = 0.0001), GHRH plus arginine (coefficient = –18.2, 95% CI –22.6 to –13.8%; P = 0.0001), IGF-I SDS (coefficient = –1.6, 95%CI-2.7 to –0.4%; P = 0.006), and fibrinogen (coefficient = 18.2, 95% CI 8.2–28.4%; P = 0.001) were statistically significant. There was a significant interaction between time and group for the responses of peak GH responses to ITT (coefficient = –4.5, 95% CI –7.5 to –1.5%; P = 0.004), GHRH plus arginine (coefficient = –8.8 95% CI –15.0 to –2.5%; P = 0.007), serum cholesterol (coefficient = –20.9, 95% CI 8.0 to 33.8%; P = 0.002), and serum fibrinogen (coefficient = 16.1, 95% CI 1.9–30.4%; P = 0.027).

Metabolic parameters

At the time of the first reevaluation, the mean values of BMI (22.1 ± 1.9 vs. 22.1 ± 1.1 kg/m2; P = 0.96), waist circumference (73.6 ± 8.2 vs. 73.5 ± 5.5 cm; P = 0.95), systolic blood pressure (113.0 ± 7.8 vs. 115.8 ± 6.7 mm Hg; P = 0.3), diastolic blood pressure (70.9 ± 5.2 vs. 70.7 ± 4.8 mm Hg; P = 0.9), and serum total cholesterol (154.7 ± 12.0 vs. 153.3 ± 15.1 mg/dl; P = 0.77) were not dissimilar between the control group and the 13 subjects with structural hypothalamic-pituitary abnormalities (Table 2Go). The mean serum fibrinogen, however, was significantly lower in the controls, compared with the 13 patients (226.4 ± 15.0 vs. 244.7 ± 14.6 mg/dl; P = 0.0016) (Fig. 4Go).


Figure 4
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  		FIG. 4. Waist circumference, serum total cholesterol, and serum fibrinogen represented as mean ± SD in the 13 patients at baseline and after 2-yr follow-up, compared with the control group of 20 unaffected subjects.

 
At the 2-yr follow-up, no significant changes from baseline were found in the mean values of BMI (22.0 ± 1.8 vs. 22.9 ± 0.8 kg/m2;P = 0.13), systolic blood pressure (114.6 ± 6.6 vs. 116.8 ± 5.2 mm Hg; P = 0.33), or diastolic blood pressure (70.6 ± 4.5 vs. 70.5 ± 5.6 mm Hg; P = 0.97) between the control group and the 13 subjects (Table 2Go). The mean values of waist circumference (73.5 ± 5.5 vs. 80.7 ± 6.5 cm; P = 0.00001), serum total cholesterol (153.3 ± 15.1 vs. 172.8 ± 16.4 mg/dl; P = 0.00001), and serum fibrinogen (244.7 ± 14.6 vs. 260.2 ± 10.1 mg/dl; P = 0.0004) were significantly higher in the 13 subjects with EPP (Fig. 4Go). In these subjects, there was also a significant increase in waist circumference (80.7 ± 6.5 vs. 73.9 ± 8.3 cm; P = 0.0189), serum total cholesterol (153.3 ± 15.1 vs. 172.8 ± 16.4 mg/dl; P = 0.0001), and serum fibrinogen (260.2 ± 10.01 vs. 225.8 ± 15.1 mg/dl; P = 0.00001), compared with the control group (Fig. 4Go). The metabolic parameters were adjusted for sex and BMI without evidence for statistical differences.

MRI findings and pituitary function

The detailed analysis of MRI findings showed anterior pituitary hypoplasia in all subjects with variable pituitary stalk abnormalities and EPP (Tables 1Go and 3Go). In particular, six subjects of the nine with isolated GHD showed a visible pituitary stalk, whereas no evidence of pituitary stalk structure was found in the remaining three. In these latter patients, the EPP was recognized at the level of the median eminence, whereas in the former the EPP was found downward along the pituitary stalk in three patients, within the pituitary stalk in one, and at the level of the median eminence in two. Three among those subjects with MPHD showed a visible pituitary stalk with EPP along the pituitary stalk in two and at the level of median eminence in one; one patient had pituitary stalk agenesis and EPP at the level of the median eminence. There was a significant difference in mean GH peak response to ITT at 2-yr follow-up between subjects with visible pituitary stalk and those with pituitary stalk agenesis (4.7 ± 1.3 vs. 2.7 ± 1.3 µg/liter; P = 0.031).

Correlations

Significant negative correlations between IGF-I SDS and mean serum total cholesterol were found at the 2-yr follow-up (r = –0.76, P = 0.003 (Fig. 5Go); this same trend was also confirmed between mean GH response to ITT and mean serum total cholesterol (r = –0.53, P = 0.063).


Figure 5
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  		FIG. 5. Correlations between IGF-I SDS values and peak GH responses to ITT with serum cholesterol at 2-yr follow-up in the 13 studied patients.

 
No significant correlations were found at baseline and at 2-yr follow-up between peak GH response to ITT and GHRH plus arginine and BMI, waist circumference, serum total cholesterol, serum fibrinogen, systolic blood pressure, or diastolic blood pressure.

No significant correlations were found at baseline and at 2-yr follow-up between IGF-I SDS and BMI, waist circumference, serum fibrinogen, systolic blood pressure, or diastolic blood pressure. No correlation was found between IGF-I SDS and serum cholesterol at baseline.


   Discussion
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
References
 
This is the first observational prospective study to investigate the outcome of subjects with childhood-onset GHD and structural hypothalamic-pituitary abnormalities with normal GH response after GH stimulation tests based on the current criteria for the diagnosis of permanent GHD in young adults (12). Among our large reevaluated cohort of subjects with childhood-onset GHD, 56% showed normalization of GH response after stimulation test, whereas 30% were confirmed as severe GHD. Moreover, approximately one third of subjects with EPP showed a GH response to ITT suggestive of partial GHD, a condition that has been reported to occur in 16–38% of adult patients with hypopituitarism (21, 22, 23, 24, 25).

The reassessment of GH secretory capacity after the attainment of adult height and completion of growth is the most appropriate means of identifying those GHD subjects who might benefit from further rhGH treatment. Whereas some patients remain GHD into adulthood, various reports have suggested that many of them appear to recover from childhood GHD (6, 7, 8, 9, 26). In particular, our subjects with idiopathic isolated GH deficiency and normal pituitary gland at MRI had a normal GH response after stimulation tests, confirming our previous findings in young adults (9) as well as in prepubertal children with normal pituitary gland morphology who showed normalization of GH responses when retested within 6 months after first evaluation (27).

Our study provides evidence that subjects with EPP have a complex disease, the natural history and etiology of which are still unclear. In particular, patients with such characteristics may have a GH level after puberty that is higher than expected, as shown by a previous study (13), but they are also prone to reconfirm their GH deficits during follow-up, regardless of the location of EPP, i.e. between the median eminence and the proximal part of the pituitary stalk. In the study by Leger et al. (13), 61% of subjects with EPP were diagnosed with severe GHD, whereas the remaining 39% who had a posterior pituitary gland along the pituitary stalk had an uncertain diagnosis or a likelihood of a normal GH response to combined arginine plus insulin or propanolol plus glucagon stimulation tests. It is worth pointing out that the diagnostic cutoff value of peak GH to be adopted after these tests in young adults has not yet been established, strengthening the hypothesis that GH response after stimulation test is related to several factors, e.g. BMI, the particular type of secretagogue, age, time of evaluation, number of pituitary hormone deficits, and type of pituitary stalk-posterior pituitary abnormalities (10, 28, 29, 30, 31). Likewise, the role of puberty and sex steroids in modulating/resetting GH response in these patients remains largely unknown. Although one third of GHD subjects diagnosed before puberty presented a normal secretion at puberty in a recent study (26), normalization of GH response to stimulation occurred irrespective of the time interval from first evaluation, and it was not related to puberty in another study (27). In our opinion, the position of EPP downward the median eminence and along the pituitary stalk cannot simply be considered a normal variant of posterior pituitary gland anatomy, but rather it is an abnormal condition that must not be disregarded.

The impact of GHD on biological end points including reduction of IGF-I concentrations and abnormalities of metabolic parameters such as waist circumference, serum cholesterol, and fibrinogen were clearly suggestive of a GH cause-effect relationship. These findings are, in fact, indicative of long-lasting severe GHD in agreement with our recent report showing that several GHD subjects who have EPP, low IGF-I concentrations, and normal GH response after ITT have low 12-h nocturnal GH secretion (32). Indeed, in a previous study by Tauber et al. (33), untreated adolescents with partial GHD exhibited alterations in body composition but not serum total cholesterol after 1 yr of rhGH withdrawal, compared with adolescents who showed normal GH response at reevaluation. Moreover, Murray et al. (34) showed that the degree of change in body composition was less evident in partial GHD than severe GHD after ITT but still well discriminated from healthy controls. In a recent study by Colao et al. (21), untreated partial-GHD patients had higher glucose and insulin concentrations, worse insulin resistance, and higher intima-media thickness than controls and a trend toward an increase in total cholesterol levels; serum fibrinogen levels were also higher in untreated GHD subjects, compared with normal controls (35) as in our study. In our cohort, significant changes in metabolic parameters including increased waist circumference and serum total cholesterol are also in agreement with those of another study by Vahl et al. (36), in which discontinuation of GH treatment in young adults for 2 yr induced significant and unfavorable modifications in IGF-I, waist circumference, and body composition but not serum cholesterol levels.

Our findings raise several key questions. Can GH response higher than 5 µg/liter in subjects with structural hypothalamic-pituitary abnormalities be defined as partial GHD? Is there any cutoff point of ITT or GHRH plus arginine predictive of deterioration of GH function over time? Should these patients be closely monitored and re-reassessed for severe GHD over time and for how long? Or, to the contrary, should patients with structural-hypothalamic-pituitary abnormalities be treated with rhGH regardless of GH threshold? Are specific metabolic parameters helpful in decision making for subjects with partial GHD? Finally, are changes in GH possibly due to variations of the GH inter- and intraassay CVs used?

We believe that evidence of a decline in both GH responses after stimulation tests and of IGF-I concentrations, together with changes of metabolic parameters in subjects with EPP, on the one hand, and confirmation of normal GH responses and absence of variations of metabolic parameters in the control group, on the other, support the hypothesis of a dynamic involvement of anterior pituitary function rather than of a chance occurrence or unsatisfactory test reproducibility. The magnitude of GH response both after ITT and GHRH plus arginine as well as the development of additional anterior pituitary hormone defects during follow-up are suggestive of a progressive deterioration of pituitary function. It is our opinion that disruption of the vascular portal system in patients with pituitary stalk abnormalities may have a role in pituitary failure and evolving pituitary hormone deficits.

Our data confirm that structural hypothalamic-pituitary abnormalities represent the gold standard because they are highly predictive of future severe GHD development and worsening of GH function, regardless of cutoff peak levels after ITT or GHRH plus arginine. Although the GHRH plus arginine test can give a falsely normal GH response in patients with either congenital or acquired hypothalamic-pituitary disorders (29, 30, 37, 38), re-retesting shows that most of our subjects have a GH peak response compatible with severe GHD. In particular, eight of our subjects showed a decline of peak GH response after GHRH plus arginine to less than 9 µg/liter at the second reevaluation, and all subjects showed a significant reduction of GH response to less than 13.5 µg/liter during follow-up. Although the following cutoff levels have been validated for GHRH plus arginine in adults [for those with a BMI < 25 kg/m2, a peak GH < 11 µg/liter; BMI 25–30 kg/m2, a peak GH < 8 µg/liter; BMI > 30 kg/m2, a peak GH less than 4 µg/liter (26) or < 4.1 µg/liter] (39), our subjects have a BMI of less than 25 kg/m2 and several of them have a peak GH response higher than 11 µg/liter after repeated testing in an appropriate clinical context, suggesting that the cutoff for diagnosis of GHD in young adults (between 16 and 25 yr) has not yet been entirely validated.

In conclusion, our data highlight the importance of selecting subjects at high risk of developing severe GHD and additional pituitary hormone deficits after adult height achievement. Numerous patients with childhood-onset GHD may display partial GHD in adulthood, the diagnosis of which can be challenging and the treatment of which is proving an emerging practice (40). Withdrawal of GH treatment in young adults with childhood-onset GHD, partial GHD, and structural hypothalamic-pituitary abnormalities can lead to severe GHD, derangement of metabolic parameters, and evolving pituitary hormone deficiencies. A second reinvestigation should be considered in young adults with partial GHD or a suspected clinical diagnosis and unsatisfactory or discordant biochemical GH response (where ITT is contraindicated and validated cutoffs for other tests are absent) before the patient’s discharge or before making a commitment to lifelong GH replacement.


   Footnotes
 
Disclosure Statement: The authors have nothing to declare. The authors warrant that they have seen and approved this manuscript and that their contributions meet the requirements criteria for authorship.

First Published Online July 31, 2007

Abbreviations: BMI, Body mass index; CI, confidence interval; CV, coefficient of variation; EPP, ectopic posterior pituitary; FT4, free T4; GHD, GH deficiency; ITT, insulin tolerance test; MPHD, multiple pituitary hormone deficiency; MRI, magnetic resonance imaging; rhGH, recombinant human GH; ROC, receiver-operating characteristic; SDS, SD score.

Received May 15, 2007.

Accepted July 23, 2007.


   References
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
 References
 

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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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