Growth hormone (GH) deficiency (GHD) of childhood onset: reassessment of GH status and evaluation of the predictive criteria for permanent GHD in young adults

GH secretion was reevaluated after completion of GH treatment at a mean age of 19.2 +/- 3.2 yr in 35 young adults with childhood-onset GH deficiency (GHD). The patients were subdivided into 4 groups according to their first pituitary magnetic resonance imaging (MRI) findings: group I, 11 patients with isolated GHD (IGHD) and normal pituitary volume (280 +/- 59.4 mm3); group II, 7 patients with IGHD and small pituitary gland (163.1 +/- 24.4 mm3; P = 0.0009 vs. group I); group III, 13 patients (5 with IGHD and 8 with multiple pituitary hormone deficiency) with congenital hypothalamic-pituitary abnormalities such as pituitary hypoplasia (95.8 +/- 39.3 mm3; P < 0.00001 vs. group I and P = 0.003 vs. group II), pituitary stalk agenesis, and posterior pituitary ectopia; and group IV, 4 patients with multiple pituitary hormone deficiency secondary to craniopharyngioma. Pituitary MRI and GH secretory status were reevaluated after GH withdrawal using arginine, insulin induced-hypoglycemia, and sequential arginine-insulin tests. Serum insulin-like growth factor I (IGF-I) and IGF-binding protein-3 (IGFBP-3) were determined at the time of retesting and 6, 12, and 24 months after discontinuation of treatment in the patients with permanent GHD and after 6 months in those with normal GH responses to stimulation. The patients in groups I and II showed a normal response to stimulation after completion of GH treatment regardless of pituitary size, whereas all patients in groups III and IV still had a GH response of less than 3 microg/L to any of the tests. Pituitary volume normalized in 6 of 7 patients in group II, whereas in all patients in group III MRI studies confirmed the initial findings. Mean IGF-I and IGFBP-3 concentrations at the time of retesting were significantly higher in groups I and II than in groups III and IV. In patients of groups III and IV, mean IGF-I was significantly decreased after 6 and 12 months, whereas IGFBP-3 was significantly decreased 12 months after treatment withdrawal. Our results confirm that a high proportion of children with IGHD and normal or small pituitary show normalization of GH secretion at the completion of GH treatment, whereas GHD is permanent in all patients with pituitary hypoplasia, pituitary stalk agenesis, and posterior pituitary ectopia. IGF-I and IGFBP-3 determinations shortly after GH withdrawal had limited value in the diagnosis of GHD of childhood onset associated with congenital hypothalamic-pituitary abnormalities, but became accurate after 6-12 months. We suggest that patients with GHD and congenital hypothalamic-pituitary abnormalities do not require further investigation of GH secretion, whereas patients with IGHD and normal or small pituitary gland should be retested well before the attainment of adult height.     

Long-term follow-up evaluation of magnetic resonance imaging in the prognosis of permanent GH deficiency

OBJECTIVE: In patients with GH deficiency (GHD), magnetic resonance imaging (MRI) has revealed morphological abnormalities such as pituitary hypoplasia, pituitary stalk agenesis (PSA) and ectopia of the posterior pituitary (PPE). The MRI anomalies have been more frequently reported in patients with multiple pituitary hormone deficiency (MPHD) than in subjects with isolated GH deficiency (IGHD). The aim of this work was to define which MRI anatomical abnormalities of the hypothalamo-pituitary area can be considered as a prognostic marker of permanent GHD. DESIGN: To investigate the relationship between the neuroradiological images and endocrine findings, we clinically re-evaluated 93 out of the 121 GHD patients with IGHD and MPHD previously studied. RESULTS: No additional hormone deficiencies were observed in 55 out of 60 patients initially classified as having IGHD with a normal (15 cases) or reduced (40 cases) pituitary gland size, without other MRI abnormalities. The remaining five children, who had initially shown an apparently IGHD in spite of PSA and PPE, developed a MPHD over time. In 33 MPHD patients with (25 cases) or without (8 cases) MRI abnormalities, the associated hormone deficiencies were confirmed during follow-up. CONCLUSIONS: The IGHD patients showing PSA and PPE inevitably develop additional hormone deficiencies, while IGHD subjects having no MRI abnormalities maintain IGHD. Moreover, the anatomical abnormalities of the hypothalamo-pituitary area can be considered as a prognostic marker of permanent GHD.     

Role of magnetic resonance imaging in the diagnosis and prognosis of growth hormone deficiency

OBJECTIVE In patients with congenital GH deficiency (GHD), magnetic resonance Imaging (MRI) has revealed morphological abnormalities such as pituitary hypoplasia, absence of the stalk and ectopia of the posterior pituitary (PPE). Our study was aimed at investigating the possible relationship between neuroradioiogical Images and the presence of Isolated GH or multiple pituitary hormone deficiency. DESIGN We studied 121 patients, aged 0.3–25 years, with Isolated GHD (IGHD, 81 cases) or multiple pituitary hormone deficiency (MPHD, 40 cases). Of 81 IGHD patients, 50 were at prepubertal and 22 at pubertal age, while 9 had a delayed onset of puberty. Out of 40 MPHD patients, 25 were at prepubertal age and 15 at the age of puberty. RESULTS Pituitary hypoplasia, defined as a gland with a height of less than ?2 SD for age, was observed more frequently in prepubertal (66%) than pubertal (18%) IGHD patients. It was also found in the majority of MPHD patients of prepubertal (76%) and pubertal age (80%), and of IGHD patients with delayed onset of puberty (100%). Mean ± SEM pituitary height was significantly lower (P < 0.001) In both prepubertal IGHD (?2.70 ± 0.20 SD) and MPHD children (?3.10 ± 0.39 SD) than in IGHD patients with normal onset of puberty (?1.55 ± 0.2 SD). A significantly greater pituitary height was observed in IGHD patients with normal onset of puberty (?1.55 ± 0.20 SD) than In MPHD patients at the age of puberty (?4.38 ± 0.61 SD, P < 0.001) and in IGHD subjects with delayed onset of puberty (?4.06 ± 0.41 SD, P < 0.001). An Important Increase (P < 0.02) in the height of the pituitary gland was found in 6 of the 9 patients with delayed puberty when they were re-evaluated after completing their spontaneous pubertal development. The frequency of other MRI abnormalities (PPE, stalk transection) was significantly higher in MPHD patients than In IGHD patients (P < 0.001). CONCLUSION Our results confirm the usefulness of MRI In the evaluation of children affected by GH deficiency. The association of gland hypoplasia with other MR abnormalities could suggest the presence of multiple anterior pituitary deficiencies. Finally, puberty seems to play an important role in the increase of pituitary size in multiple pituitary hormone deficiency and isolated GH deficiency patients.     

Isolated growth hormone (GH) deficiency in adult patients: baseline clinical characteristics and responses to GH replacement in comparison with hypopituitary patients. A sub-analysis of the KIMS database.

BACKGROUND: Isolated growth hormone deficiency (IGHD) provides the ideal model to characterize GHD without interference from other pituitary deficiencies or their treatment. No study has addressed the question whether adult patients with IGHD differ in clinical presentation or in responsiveness to GH replacement from adult patients with multiple pituitary hormone deficiencies (MPHD) receiving conventional replacement therapy. PATIENTS AND METHODS: Data were retrieved from the outcomes research database KIMS (Pfizer international metabolic database). Patients with IGHD accounted for 9.6% (274/2868) of all GHD patients. Patients were separated according to the timing of onset. In the adult-onset (AO) group, 167 patients with IGHD were compared to 1992 patients with MPHD. In the childhood-onset (CO) group, 107 patients with IGHD were compared to 602 patients with MPHD. To assess the effect of GH replacement after one year, a longitudinal sub-analysis in the AO group was performed comparing 89 IGHD patients to 1234 MPHD patients. The same study was done in the CO group comparing 66 IGHD patients to 386 MPHD patients. Because IGHD patients were significantly younger than MPHD patients, data analysis was also performed after adjustment for gender and age. RESULTS: In the AO group, non-functioning and secreting pituitary adenomas were the most common primary diagnoses in both IGHD and MPHD. Medical history revealed a high prevalence of hypertension and fractures in both subgroups, but also of non-insulin dependent diabetes mellitus. The prevalence of obesity was high and the waist circumference was elevated. The lipid profile was unfavourable in both IGHD and MPHD. IGF-I concentration and SDS were comparable in both subgroup. Quality of life assessed by QoL-AGHDA was equally poor in both IGHD and MPHD. GH replacement therapy induced favourable changes without distinction. In the CO group, the most common cause in both subgroups was idiopathic. Fracture rate was similarly prevalent in both IGHD and MPHD. Obesity was prominent in both subgroups, but BMI and waist circumference were lower in IGHD. Adverse lipid changes were similarly found in both IGHD and MPHD. IGF-I concentration and SDS were significantly higher in the IGHD subgroup compared to the MPHD subgroup. The QoL-AGHDA score was equally abnormal in both IGHD and MPHD. GH replacement achieved similar significant improvement in both subgroups. CONCLUSIONS: GHD patients with AO-IGHD and AO-MPHD present with a similar clinical expression and respond similarly to GH replacement. Patients with CO-IGHD are less severely affected by GHD than CO-MPHD patients, but, nevertheless, both groups show a comparable adverse lipid profile and poor quality of life and respond favourably to GH replacement. These findings support the concept that GH alone is responsible for most if not all metabolic aspects of hypopituitary patients receiving conventional replacement therapy, regardless of age of onset or aetiology. As a consequence, GH replacement therapy not only has potential benefit in GHD patients with additional hormonal deficits, but also the indication of treatment must be extended to patients with isolated GHD.     

MRI findings of the pituitary gland in short children born small for gestational age (SGA) in comparison with growth hormone-deficient (GHD) children and children with normal stature

BACKGROUND: Disturbances in the GH/IGF-I axis are reported in 25-60% of short children born small for gestational age (SGA). We hypothesized that these abnormalities might be related to abnormalities in the pituitary region. Therefore, the results of magnetic resonance imaging (MRI) of short SGA children were compared to MRI results of other groups of short children and to normal controls. PATIENTS AND METHODS: MRI was performed in four groups of short children: SGA children without GH deficiency (SGA group; n = 17), SGA children with isolated GH deficiency (SGA + IGHD group; n = 10), non-SGA children with isolated GH deficiency (IGHD group; n = 24) and non-SGA children with multiple pituitary hormone deficiencies (MPHD group; n = 15). MRI was also performed in children with normal stature (control group; n = 13). Pituitary height (PH) and thickness of the pituitary stalk (PS) were measured and their relationship with the maximum GH peak during a GH stimulation test, serum IGF-I and IGFBP-3 levels was evaluated. RESULTS: Short SGA children either with or without IGHD did not show major anatomical abnormalities in the hypothalamic-pituitary region in contrast to 58% of the non-SGA IGHD children and 87% of the MPHD children who had anatomical abnormalities. PH in SGA children without GHD was normal whereas it was significantly lower in SGA children with IGHD. The lowest PHs were measured in non-SGA children with MPHD. A moderate decrease in PH was associated with significantly lower maximum serum GH peaks and lower serum IGF-I and IGFBP-3 levels. CONCLUSION: Measuring PHs in children with less severe GHD, who underwent MRI as part of the diagnostic process, might support the diagnosis of GHD even in the absence of anatomical abnormalities. Our study demonstrates that there is no indication to perform MRI of the pituitary region in short children born SGA without GHD.     

Adult height in patients with permanent growth hormone deficiency with and without multiple pituitary hormone deficiencies

CONTEXT: It has been reported that patients with multiple pituitary hormone deficiencies (MPHDs) achieve a greater final height, compared with patients with isolated GH deficiency (IGHD). However, the outcome of patients with permanent GH deficiency (GHD) has not yet been reported. OBJECTIVES: The objectives of the study were to evaluate and compare adult height data and the effect of spontaneous or induced puberty after long-term treatment with GH in young adults with either permanent IGHD or MPHD. DESIGN AND SETTING: This was a retrospective multicenter study conducted in university research hospitals and a tertiary referral endocrine unit. PATIENTS AND METHODS: Thirty-nine patients with IGHD (26 males, 13 females) and 49 with MPHD (31 males, 18 females), diagnosed at a median age of 7.7 and 6.9 yr, respectively, were reevaluated for GH secretion after adult height achievement (median age 17.6 and 19.8 yr). The diagnosis of permanent GHD was based on peak GH levels less than 3 microg/liter after an insulin tolerance test or peak GH levels less than 5 microg/liter after two different tests. Fifteen subjects had idiopathic GHD and seventy-three had magnetic resonance imaging evidence of congenital hypothalamic-pituitary abnormalities. Height sd score (SDS) was analyzed at diagnosis, the onset of puberty (either spontaneous or induced), and the time of GH withdrawal. RESULTS: The subjects with IGHD entered puberty at a median age of 12.6 yr (females) and 13.4 yr (males). Puberty was induced at a median age of 13.5 and 14.0 yr, respectively, in males and females with MPHD. Median height SDS at the beginning of puberty was similar in the IGHD and MPHD subjects. Total pubertal height gain was similar between patients with IGHD or MPHD. Median adult height was also not significantly different between IGHD and MPHD patients (males, 168.5 vs. 170.3 cm; females, 160.0 vs. 157.3 cm). The adult height SDS of the IGHD subjects was positively correlated with height at the time of diagnosis and with total pubertal height gain. Conversely, the adult height SDS of the MPHD subjects was positively correlated with both the duration of GH treatment and height SDS at the time of GHD diagnosis. CONCLUSIONS: Adult height in patients with permanent IGHD and spontaneous puberty is similar to adult height in patients with MPHD and induced puberty.     

Relationship between the morphological evaluation of the pituitary and the growth hormone (GH) response to GH-releasing hormone Plus arginine in children and adults with congenital hypopituitarism

The relationship between the hypothalamus-pituitary morphology and the somatotroph responsiveness to maximal provocative tests exploring the GH releasable pool is still unclear. We evaluated the GH-releasing effect of GHRH plus arginine (GHRH plus Arg) in 36 patients with congenital GH deficiency (GHD) according to their pituitary magnetic resonance imaging findings, consisting of anterior pituitary hypoplasia, stalk agenesis (neural and or vascular component), and posterior pituitary ectopia. Seventeen children (12 boys and 5 girls, aged 1--5.2 yr) were evaluated at the time of diagnosis of GHD (mean age, 3.6 +/- 1.4 yr), and 19 adults (13 males and 6 females, aged 15.9-28.6 yr) with childhood-onset GHD were reevaluated after completion of GH treatment (at least 6 months of withdrawal) at a mean age of 20.5 +/- 3.5 yr. Eleven children had isolated GHD, and 6 had multiple pituitary hormone deficiency (MPHD) whereas 7 adults had isolated GHD, and 12 had MPHD. A residual vascular component of the pituitary stalk was visualized in 7 children and 7 adults with isolated GHD, whereas magnetic resonance imaging showed complete pituitary stalk agenesis (both vascular and neural components) in 10 children and 10 adults, including 16 with MPHD (6 children) and 4 children with isolated GHD. In the children, the median peak GH response to GHRH plus Arg (7.6 microg/L; range, 2.4--40.2 microg/L) was significantly higher than that in the adults (1.8 microg/L; range, 0.8--37.4 microg/L; P = 0.0039); it was also significantly higher in the isolated GHD patients (18 microg/L; range, 3.3--40.2 microg/L) than in those with MPHD (1.9 microg/L; range, 0.8--7.6 microg/L; P = 0.00004). In the patients with residual vascular component of the pituitary stalk the median peak GH responses to GHRH plus Arg (19.1 microg/L; range, 1.6--40.2 microg/L) was significantly higher than that in patients with complete pituitary stalk agenesis (2.2 microg/L; range, 0.8--8.8 microg/L; P = 0.00005). There was a trend toward a decrease with age in peak GH response to GHRH plus ARG: Mean serum insulin-like growth factor I (IGF-I) levels were 36 +/- 7.1 microg/L in the children and 63.5 +/- 22.6 microg/L in the adults (P = 0.0001). The mean IGF-I level did not differ between the children with (35.7 +/- 4.8 microg/L) and those without (36.3 +/- 8.7 microg/L) the pituitary stalk; it was much higher in the adults with residual vascular pituitary stalk (81.1 +/- 17.7 microg/L) than in those with complete pituitary stalk agenesis (47.7 +/- 12.5 microg/L; P = 0.0002). The IGF-I level was 36.1 +/- 6.7 microg/L in the isolated GHD children and 36 +/- 8.6 microg/L in those with MPHD; levels were 82.1 +/- 19.4 and 52.7 +/- 16.8 microg/L respectively, in the adults (P = 0.003). In this study we have confirmed that the partial integrity of the hypothalamic pituitary connections is essential for GHRH plus Arg to express its GH-releasing activity and have shown that this provocative test is able to stimulate GH secretion to a greater extent in those patients with GHD, but with a residual vascular component of the pituitary stalk. This test is reliable in the diagnosis of congenital hypopituitarism in both children and adults when associated with complete pituitary stalk agenesis and MPHD. In younger children with congenital GHD but less severe impairment of the pituitary stalk the GH response to GHRH plus Arg may be within the normal range; deterioration of pituitary GH reserve with a GH response of less than 10 microg/L after 20 yr of age makes this test very sensitive in the diagnosis of adult GHD.     

Diagnosis of GH deficiency in the transition period: accuracy of insulin tolerance test and insulin-like growth factor-I measurement

OBJECTIVE: A consensus exists that severe growth hormone deficiency (GHD) in adults is defined by a peak GH response to insulin-induced hypoglycemia (insulin tolerance test, ITT) of less than 3 microg/l based on a cohort of subjects with a mean age of 45 years. DESIGN AND METHODS: By considering one of the following two criteria for the diagnosis of probable permanent GHD, i.e. the severity of GHD (suggested by the presence of multiple pituitary hormone deficiencies (MPHD)) or the magnetic resonance (MR) imaging identification of structural hypothalamic-pituitary abnormalities, 26 patients (17 males, 9 females, mean age 20.8 +/- 2.3 years, range 17-25 years) were selected for re-evaluation of the GH response to ITT and their IGF-I concentration. Eight subjects had isolated GHD (IGHD) and 18 had MPHD. Normative data for peak GH were obtained after ITT in 39 healthy subjects (mean age 21.2 +/- 4.4 years, range 15.1-30.0 years) and the reference range for IGF-I was calculated using normative data from 117 healthy individuals. RESULTS: Mean peak GH response to ITT was significantly lower in the 26 patients (1.8+/-2.0 microg/l, range 0.1-6.1 microg/l) compared with the 39 controls (18.5 +/- 15.5 microg/l, range 6.1-84.0 microg/l; P < 0.0001). One subject with septo-optic dysplasia had a peak GH response of 6.1 microg/l that overlapped the lowest peak GH response obtained in normal subjects. There was an overlap for IGF-I SDS between subjects with IGHD and MPHD, as well as with normal controls. The diagnostic accuracy of a peak GH response of 6.1 microg/l showed a 96% sensitivity with 100% specificity. The maximum diagnostic accuracy with IGF-I SDS was obtained with a cut-off of -1.7 SDS (sensitivity 77%, specificity 100%) while an IGF-I < or = - 2.0 SDS showed a sensitivity of 62%. CONCLUSION: Our data show that the cut-off value of the peak GH response to ITT of less than 3 microg/l or 5 microg/l and of IGF-I of less than -2.0 SDS are too restrictive for the diagnosis of permanent GH deficiency in the transition period. We suggest that permanent GHD could be investigated more accurately by means of an integrated analysis of clinical history, the presence of MPHD, IGF-I concentration and the MR imaging findings of structural hypothalamic-pituitary abnormalities.     

Effect of growth hormone (GH) treatment on the near-final height of 1258 patients with idiopathic GH deficiency: analysis of a large international database

CONTEXT: Treatment with GH has been used to correct the growth deficit in children with GH deficiency (GHD). Although successful in increasing height velocity, such treatment often falls short of helping patients achieve full genetic height potential. OBJECTIVE: This study set out to analyze near-final height (FH) data from a cohort of GH-treated children with idiopathic GHD. DESIGN, SETTING, AND PARTICIPANTS: Of 1258 evaluable patients in the Pfizer International Growth Database (KIGS) with GHD, 980 were of Caucasian origin, and 278 were of Japanese origin; 747 had isolated GHD (IGHD), and 511 had multiple pituitary hormone deficiencies (MPHD). MAIN OUTCOME MEASURES: Near-FH, relation to midparental height, and factors predictive of growth outcomes were the main outcome measures. RESULTS: Median height sd scores (SDS) at the start of treatment were -2.4 (IGHD) and -2.9 (MPHD) for Caucasian males and -2.6 (IGHD) and -3.4 (MPHD) for females, respectively; comparable starting heights were -2.9 (IGHD) and -3.6 (MPHD) for Japanese males and -3.3 (IGHD) and -4.0 (MPHD) for females, respectively. Corresponding near-adult height SDS after GH treatment were -0.8 (IGHD) and -0.7 (MPHD) for Caucasian males and -1.0 (IGHD) and -1.1 (MPHD) for females, respectively; and -1.6 (IGHD) and -1.9 (MPHD) for Japanese males and -2.1 (IGHD) and -1.8 (MPHD) for females, respectively. Differences between near-adult height and midparental height ranged between -0.6 and +0.2 SDS for the various groups, with the closest approximation to MPH occurring in Japanese males with MPHD. The first-year increase in height SDS and prepubertal height gain was highly correlated with total height gain, confirming the importance of treatment before pubertal onset. CONCLUSIONS: It is possible to achieve FH within the midparental height range in patients with idiopathic GHD treated from an early age with GH, but absolute height outcomes remain in the lower part of the normal range. Patients with MPHD generally had a slightly better long-term height outcome.     

Ectopic posterior pituitary and stalk abnormality predicts severity and coexisting hormone deficiencies in patients with congenital growth hormone deficiency

Certain pituitary imaging abnormalities are a specific indicator of hypopituitarism. The objective of this study is to compare phenotypical features with radiological findings in patients with congenital growth hormone deficiency (GHD). Magnetic Resonance imaging (MRI) was performed in 103 patients [72 with Isolated GHD (IGHD) and 31 with Combined Pituitary Hormone Deficiency (CPHD)]. Images were assessed for the following abnormalities: (1) small/absent anterior pituitary, (2) thin or interrupted pituitary stalk (PSA), and (3) Ectopic posterior pituitary (EPP), and (4) others. Radiological findings were correlated with the clinical and biochemical parameters. MRI abnormalities were observed in 48.6% patients with IGHD, 93.5% with CPHD. Jaundice, hypoxia, hypoglycemia and breech deliveries were more common in EPP/PSA group. EPP/PSA was observed in 87.1% patients with severe GHD (peak GH?<?3???g/L) as compared to 12.9% with mild to moderate GHD (peak GH: 3?C10???g/L). Amongst CPHD, EPP/PSA was present in 80% of subjects with associated hypocortisolism?±?hypothyroidism as compared to 18.2% of subjects with hypogonadism. Over a mean follow up period of 4.5?years, 5.4% of subjects with IGHD and abnormal MRI progressed to CPHD while none of those with normal MRI progressed. This study emphasizes a significant clinico-radiological correlation in Asian Indian GHD patients. MRI abnormalities in the hypothalamic pituitary area, especially EPP/PSA are more common in patients with CPHD and severe GHD. Among CPHD, EPP/PSA predicts association with hypothyroidism or hypocortisolism. IGHD with MRI abnormality may evolve into CPHD.     

Dynamic MRI in the congenital agenesis of the neural pituitary stalk syndrome: the role of the vascular pituitary stalk in predicting residual anterior pituitary function

OBJECTIVE Magnetic resonance imaging (MRI) without contrast medium is unable to give detailed information on the hypothalamic-pituitary structures. MRI using gadopentetate dimeglumine (Gd-DTPA), and dynamic MRI, were performed in patients with hypopituitarism previously diagnosed as having anterior pituitary hypoplasia, ectopic posterior pituitary and unidentified pituitary stalk (1) to determine whether Gd-DTPA improves the delineation of hypothalamic-pituitary structures; (2) to verify whether, if so, such improvement can be correlated with residual pituitary function in patients subjected to long-term follow-up; and (3) to identify the hypothalamic-pituitary vascular network in such cases. PATIENTS Eighteen patients (13 males, 5 females) aged 10–26.4 years with unidentified pituitary stalk at first MRI study were evaluated. Eight had isolated GH deficiency (IGHD), and 10 had multiple pituitary hormone defect (MPHD) with the progression to complete anterior pituitary deficits seen by the age of 15 years in 8 patients (1 had GH and FSH–LH deficiency and 1 had GH, TSH and FSH–LH deficiency). RESULTS The MRI revealed a very thin pituitary stalk in 7 patients (38.8%), 6 with IGHD (75%) and 1 (10%) with MPHD (GH and FSH-LH deficiency), after Gd-DTPA administration. Reassessment of anterior pituitary function showed that the thyroid, adrenal and gonadal functions were intact in the 6 patients with IGHD and pituitary stalk identified by Gd-DTPA as well as in one IGHD patient with no evidence of pituitary stalk. In one 10-year-old with IGHD at the time of presentation (6 years) and no pituitary stalk seen after Gd-DTPA, subclinical hypothalamic hypothyroidism and suspected hypogonadotropic hypogonadism were documented. Partial ACTH deficiency was recorded In the patient with TSH and FSH–LH deficiency with no pituitary stalk. After Gd-DTPA, patients with absent pituitary stalk had a risk of developing MPHD 27 times greater than had those with an identified pituitary stalk (relative risk r=27, 95% confidence interval 1.9–368.4, Fisher’s exact test P=0.009). Dynamic MR images obtained every 4.6 s revealed rapid enhancement of hypothalamic-pituitary structures and allowed the determination of the times to initial enhancement of ectopic posterior pituitary and hypoplastic anterior pituitary which ranged between 9.2 and 18.4 s, and that of complete anterior pituitary (32.2–41.4 s). The time to maximum enhancement of anterior pituitary was significantly longer than in controls (35.5±3.8 s vs 25.2±1.6 s, P<0.0001). CONCLUSIONS MRI with Gd-DTPA proved more sensitive in identifying the vascular component of pituitary stalk and added new information about the partial preservation of hypothalamo-hypophyseal portal vessels. The vascular pituitary stalk is easily recognized after Gd-DTPA in most IGHD patients, but exceptionally in MPHD; this sheds light on the possible normal course of affected patients. The neural component of the pituitary stalk is lacking regardless of whether patients have IGHD or MPHD, indicating that the term congenital agenesis of the neural pituitary stalk is more appropriate than pituitary stalk interruption. The times to enhancement of ectopic posterior pituitary and residual anterior pituitary obtained by the fast-framing MRI technique disclose dynamic changes in regional blood supply which appear direct, arterial and mainly independent of the portal system     

Do all patients with childhood-onset growth hormone deficiency (GHD) and ectopic neurohypophysis have persistent GHD in adulthood?

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 mug/liter in four patients (22%; range, 11.7-19.5 microg/liter; group I), between 5 and 10 microg/liter in three patients (17%; range, 7.3-9 mug/liter; group II), and less than 5 microg/liter in 11 patients (61%; range, 0-4.7 microg/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.     

Antipituitary antibodies recognizing growth hormone (GH)-producing cells in children with idiopathic GH deficiency and in children with idiopathic short stature

CONTEXT: Antipituitary antibodies (APA) recognizing GH-secreting cells may indicate an autoimmune pituitary involvement in adults with idiopathic GH deficiency (IGHD). OBJECTIVE: We aimed 1) to investigate the presence of APA in prepubertal children with IGHD or idiopathic short stature (ISS), identifying the pituitary hormone-producing cells targeted by APA; and 2) to verify whether in patients with ISS the presence of APA could predict the development of GHD. DESIGN: We performed a cross-sectional and partially longitudinal cohort study. SETTING: The study was performed at the Endocrinology Unit and Pediatric Unit of the Second University and University Federico II of Naples, respectively. PATIENTS: Twenty-six children with IGHD (group 1), 60 children with ISS (group 2), 33 children with GHD caused by lesions/abnormalities of the hypothalamus or pituitary (group 3), and 40 controls participated in the study. Nineteen children of group 2 were reevaluated after 2 yr. MAIN OUTCOME MEASURES: IGF-I levels, GH secretion, and APA (by indirect immunofluorescence) were evaluated in all participants. RESULTS: At study entry, APA recognizing GH-producing cells were detected in seven of 26 children in group 1 and in 14 of 60 in group 2. Two years later, all eight initially APA-positive and all 11 APA-negative of the 19 reevaluated patients persisted positive and negative, respectively. The reevaluation of GH secretion in these patients revealed the development of GHD in all but one of the APA-positive children but in none of the APA-negative ones. CONCLUSIONS: IGHD in children can be frequently associated with APA targeting GH-secreting cells; thus, the detection of APA in children with ISS could identify those prone to develop GHD.     

儿童原发性生长激素缺乏症远期随访:附80例临床分析

目的 观察原发性儿童生长激素缺乏症(CO-GHD)过渡至成人期终身高(FAH)、脂代谢变化、性发育及生活质量等问题,再评估进入成年期后生长激素(GH)-胰岛素样生长因子I(IGF-I)轴功能.探讨不同类型GHD各时期的有效管理.方法 原发性CO-GHD随访至成人期80例,男62例,年龄均≥18岁;女18例,年龄均≥16岁.其中单纯性GHD(IGHD)22例、多垂体激素缺乏(MPHD)58例.随访身高、体重、血压、生长速率(GV)、性发育及婚育状况;空腹血脂、血糖、胰岛素、IGF-I及胰岛素样生长因子结合蛋白3(IGFBP3);骨龄、B超(肝、盆腔)、学历职业、既往rhGH及其他激素治疗等.结果 rhGH治疗组较未治组FAH有明显改善;两组血脂、血糖和胰岛素水平无统计学差异,血脂异常检出率分别为39.0%、47.4%;脂肪肝检出率26.8%、31.6%,均无统计学差异(P>0.05),尚无代谢综合征发现.IGHD与MPHD患者IGF-I SDS分别为-1.43+0.31、-3.01±0.66,IGFBP3 SDS为-2.10±0.33、-3.17±0.19,差异均有统计学意义(P<0.05).IGHD患者性发育正常,MPHD性功能低下者占79.7%,婚育状况较IGHD者差.结论 CO-GHD经rhGH治疗可改善FAH;转换期后再评估GH-IGF轴是必要的;成年后有血脂代谢异常的风险;IGHD育龄妇女可正常生育,MPHD虽存在垂体低促性腺激素,但亦有程度差异.     

Long-term effects of growth hormone (GH) on bone mineral status and bone turnover markers in patients with isolated GH deficiency and multiple pituitary hormone deficiency

OBJECTIVE: This study was designed to assess the long-term effects of growth hormone (GH) replacement therapy on bone mass and bone turnover markers in children with isolated GH deficiency (IGHD) and multiple pituitary hormone deficiency (MPHD). MATERIALS AND METHODS: Fifty children (35 IGHD, 15 MPHD) receiving GH replacement therapy were enrolled in the study. The patients were followed for 38.6 +/- 15.7 months (1-5 years). Bone mineral density (BMD) of the lumbar region and bone turnover markers [PTH, osteocalcin, bone-specific alkaline phosphatase (boneALP), and the carboxyterminal propeptide of type-1 collagen (CPP-I)] were assessed annually. RESULTS: The height standard deviation score (SDS) of patients with IGHD and MPHD at diagnosis was statistically significant (P = 0.012), and the change in height SDS during 3 years (Deltaheight SDS(3 years)) was statistically similar between these two groups (P = 0.651). The BMD z-scores of the two groups were comparable at the start of GH therapy (P = 0.083), and then increased in both groups similarly during 5 years of GH replacement therapy (F = 0.349, P = 0.567). When the BMD z-scores during 5 years of GH therapy were analysed in the IGHD and MPHD groups separately, it was found that the BMD z-score increased significantly in IGHD (P < 0.001) but the increase was not significant in MPHD (P = 0.140). Multiple regression analysis showed that the change in BMD z-score during 3 years of GH therapy (DeltaBMD z-score(3 years)) was predicted by the BMD z-score and height SDS at the start of GH therapy and by Deltaheight SDS(3 years) in the IGHD group (t = -2.582, P = 0.02; t = 2.322, P = 0.034 and t = 2.908, P = 0.01, respectively). Age and BMD z-score and height SDS at diagnosis were found to have predictive values for the DeltaBMD z-score(3 years) (t = -3.652, P = 0.022; t = -4.073, P = 0.015 and t = 3.389, P = 0.028, respectively) in the MPHD group. The changes in boneALP, osteocalcin, CPP-1 and PTH levels during the therapy were statistically similar between the IGHD and MPHD groups. CONCLUSION: BMD increased during GH therapy in the IGHD and MPHD groups. GH had a positive effect on bone mass in the short as well as the long term. Early diagnosis and treatment could improve peak bone mass in patients with MPHD. The time and dose of sex steroids for pubertal induction and progression, which mimics physiological secretion, might also contribute to bone accretion in patients with MPHD.     

Isolated GH deficiency (IGHD) type II: imaging of the pituitary gland by magnetic resonance reveals characteristic differences in comparison with severe IGHD of unknown origin

OBJECTIVE: To determine the specific morphology of the pituitary gland in children with severe isolated GH deficiency due to GH-1 gene mutations (IGHD type II). DESIGN: The pituitary gland morphology in magnetic resonance imaging (MRI) of children with IGHD type II was analyzed and compared with the findings in a group of children with comparably severe IGHD of unknown origin. In addition, the birth histories of both groups were studied. SUBJECTS: Thirteen children with IGHD type II were diagnosed in seven European children's hospitals and they carried a corresponding GH-1 gene mutation. For comparison, we selected from a group of 66 MRI-studied GH-insufficient subjects diagnosed in our clinic, all children with severe IGHD (all GH peaks <4 microg/l) who had no GH-1 gene mutation, no first-grade relative with IGHD and no septo-optic dysplasia. METHODS: Sagittal and coronal images of the brain were analyzed for the presence of any malformation of the pituitary gland and the intracranium. The height of each adenohypophysis was measured in a strict midline sagittal image for quantification of the gland's size. In addition, patients' files were reviewed for birth trauma or breech delivery. RESULTS: Normal MRI morphology of the pituitary gland was observed in all patients of the familial IGHD type II group (P<0.003) in which, however, five of thirteen patients (38%) exhibited a mild hypoplasia of their gland (mean sagittal adenohypophysial height -1.0+/-0.03 SD score (SDS)). In contrast, the pituitary gland in the idiopathic group showed a definitive malformation with hypoplasia of pituitary stalk and adenohypophysis in all cases, while ectopia of the neurohypophysis was present in nine of the ten cases. The adenohypophysis was significantly smaller in the idiopathic group (mean sagittal adenohypophysial height -3.2+/-0.3 SDS) (P<0.0001). All thirteen birth histories in the familial group (IGHD type II) were unremarkable while, in the idiopathic group, three of eight available birth histories recorded a breech delivery or traumatic birth (37.5%) (P<0.05). CONCLUSIONS: This study shows for the first time that MRI pituitary morphology may correlate with the etiology of severe IGHD: normal morphology suggests the presence of GH-1 gene mutations, while severe hypoplasia with malformation have other causes which might include so far unknown genetic defects as well as traumatic insults.     

GH receptor d3 polymorphism in Dutch patients with MPHD and IGHD born small or appropriate for gestational age

Objective  GH acts through the GH receptor (GHR). The GHR gene contains a genetic polymorphism caused by a deletion of exon 3 ( d3 ), with high frequency in the normal population. There is a continuing controversy whether the presence or absence of the exon 3 deletion ( d3+ vs. d3– ) affects the effect of GH in human growth.
Design, patients and measurements  For 144 patients with idiopathic isolated GH deficiency (IGHD, n  = 72) or multiple pituitary hormone deficiency (MPHD, n  = 72), amplification of the region around exon 3 of the GHR gene was performed. Clinical data and response to GH treatment were compared between GHR d3+ and d3– IGHD and MPHD patients born either small for gestational age (SGA) or appropriate for gestational age (AGA).
Results  IGHD patients born SGA had a significantly higher d3+ frequency (82%) than IGHD patients born AGA (35%, P  = 0·006). Within the group of IGHD patients born SGA, d3 – patients showed a slightly better spontaneous catch up growth before start of GH treatment than d3 + patients (1·1 ± 1·1 SD vs. 0·6 ± 1·1 SDS, P  = 0·040) There was no difference in patients first year's response to GH treatment between GHR d3 + and d3– patients.
Conclusions  In IGHD and MPHD patients, response to GH treatment was independent of GHR genotype. GHR- d3 was significantly more frequent among IGHD patients born SGA. As we are the third to report an association between birth size and GHR d3 status, it is conceivable that the GHR- d3 might affect prenatal growth in IGHD patients by a yet unknown mechanism.     

Bone loss is correlated to the severity of growth hormone deficiency in adult patients with hypopituitarism.

Reduced bone mineral density (BMD) has been reported in patients with isolated GH deficiency (GHD) or with multiple pituitary hormone deficiencies (MPHD). To investigate whether the severity of GHD was correlated with the degree of bone mass and turnover impairment, we evaluated BMD at the lumbar spine and femoral neck; circulating insulin-like growth factor I (IGF-I), IGF-binding protein-3 (IGFBP-3), and osteocalcin levels, and urinary cross-linked N-telopeptides of type I collagen (Ntx) levels in 101 adult hypopituitary patients and 35 sex- and age-matched healthy subjects. On the basis of the GH response to arginine plus GHRH (ARG+/-GHRH), patients were subdivided into 4 groups: group 1 included 41 patients with a GH peak below 3 microg/L (0.9 +/- 0.08 microg/L), defined as very severe GHD; group 2 included 25 patients with a GH peak between 3.1-9 microg/L (4.7 +/- 0.4 microg/L), defined as severe GHD; group 3 included 18 patients with a GH peak between 9.1-16.5 microg/L (11.0 +/- 0.3 microg/L), defined as partial GHD; and group 4 included 17 patients with a GH peak above 16.5 microg/L (28.3 +/- 4.3 microg/L), defined as non-GHD. In all 35 controls (group 5), the GH response after ARG+/-GHRH was above 16.5 microg/L (40.7 +/- 2.2 microg/L). In patients in group 1, circulating IGF-I (P < 0.001), IGFBP-3 (P < 0.05), osteocalcin (P < 0.001), and urinary Ntx levels (P < 0.001) were lower than those in group 3-5, which were not different from each other; the t score at the lumbar spine (-1.99 +/- 0.2) and that at the femoral neck (-1.86 +/- 0.3) were lower than those in groups 3 (-0.5 +/- 0.7, P < 0.01 and -0.3 +/- 0.7, P < 0.01, respectively), 4 (-0.5 +/- 0.2, P < 0.01 and -0.3 +/- 0.7, P < 0.01, respectively), and 5 (-0.5 +/- 0.2, P < 0.001 and 0.0 +/- 0.02, P < 0.001, respectively). In patients in group 2, circulating IGF-I and IGFBP-3 levels were not different from those in group 1, whereas the t scores at the lumbar spine (-1.22 +/- 0.3) and femoral neck (-0.9 +/- 0.3) were significantly higher and lower, respectively, than those in groups 1 and 5 (P < 0.05) but not those in groups 3 and 4, and serum osteocalcin and urinary Ntx levels were significant higher than those in group 1 and lower than those in groups 3-5 (P < 0.001). To evaluate the effect of isolated GHD vs. MPHD, patients were subdivided according to the number of their hormonal deficits, such as panhypopituitarism with (10 patients) or without (31 patients) diabetes insipidus, GHD with 1 or more additional pituitary deficit(s) (36 patients), isolated GHD (7 patients), 1-2 pituitary hormone deficit(s) without GHD (10 patients), and normal anterior pituitary function (7 patients). The t score at the lumbar spine and femoral neck and the biochemical parameters of bone turnover were not significantly different among the different subgroups with similar GH secretions. A significant correlation was found between the GH peak after ARG+GHRH and IGF-I, osteocalcin, urinary Ntx levels, and the t score at the lumbar spine, but not that at the femoral neck level. A significant correlation was also found between plasma IGF-I levels and the t score at the lumbar spine and femoral neck, serum osteocalcin, and urinary Ntx. Multiple correlation analysis revealed that the t score at the lumbar spine, but not that at the femoral neck, was more strongly predicted by plasma IGF-I levels (t = 3.376; P < 0.005) than by the GH peak after ARG+GHRH (t = -0.968; P = 0.338). In conclusion, a significant reduction of BMD associated with abnormalities of bone turnover parameters was found only in patients with very severe or severe GHD, whereas normal BMD values were found in non-GHD hypopituitary patients. These abnormalities were consistently present in all patients with GHD regardless of the presence of additional hormone deficits, suggesting that GHD plays a central role in the development of osteopenia in hypopituitary patients.     

INTERMITTENT TREATMENT WITH HUMAN GROWTH HORMONE (GH) IN ISOLATED GH DEFICIENCY AND IN MULTIPLE PITUITARY HORMONE DEFICIENCIES

The results of intermittent GH treatment of 3-7 1/2 years duration in seven patients with isolated GH deficiency (IGHD) and five patients with multiple pituitary hormone deficiencies (MPHD) are presented. This therapeutic schedule was found to be comparably effective to those using a continuous-administration schedule. In contradistinction to the findings obtained with the latter, there was no progressive decline in growth velocity. The patients with IGHD were found to respond better than the patients with MPHD both in the first course as well as in consequent courses. In the intervals between courses, the growth velocity was less than in the pretreatment period in both groups. It is concluded that optimal results can be obtained by instituting an initial course of continuous treatment of 1 year's duration for the IGHD patients and of 2 years' duration for the MPHD patients, followed by an intermittent therapeutic schedule. This regime not only leads to the same growth achievement obtained with long-term continuous administration of GH but allows conservation of supplies of this very scarce hormone.     

Evolution of gonadotropin deficiency in a patient with type II autosomal dominant GH deficiency

BACKGROUND: Type II isolated GH deficiency (IGHD type II) is caused by dominant negative splicing or point mutations of the GH-1 gene. Studies have suggested that dominant mutant GH forms prevent the secretion of wild-type GH, resulting in eventual cell death; surprisingly, some patients with these GH mutations develop other hormonal deficiencies (ACTH, TSH). Subjects: The proband presented at the age of 2.3 years with IGHD. His father, also known to have been treated for IGHD as a child, had subsequently been lost to follow-up, having remained without treatment during this time. At re-evaluation at the age of 38 years, he complained of lack of stamina and poor libido. Clinical and biochemical assessment confirmed severe GHD, borderline ACTH insufficiency, suboptimal basal and stimulated gonadotropins, and a poor prolactin response to provocation. The basal testosterone concentration was low, and he complained of secondary infertility. Magnetic resonance imaging revealed anterior pituitary hypoplasia in both patients. Genetic testing revealed a heterozygous splicing mutation in GH-1 (intervening sequence-3 + 1G>A) in both patients, known to cause IGHD type II. Interventions: The proband showed an excellent growth response to recombinant human GH (rhGH). His father, also treated with rhGH, showed improved quality of life on rhGH, but testosterone concentrations continued to decline, necessitating treatment with testosterone with symptomatic benefit but no improvement in semen quality. CONCLUSIONS: This case supports recent experimental and clinical observations suggesting that the cytotoxicity associated with accumulation of dominant negative mutant 17.5 kDa GH causes a form of GHD that can evolve into multiple hormone deficiencies. Hence, patients diagnosed initially with IGHD type II require continued long-term clinical follow-up.