Multiple Pituitary Hormone Deficiencies Patients Research Articles

Adding T2-Weighted Images to FAST1 Protocol to Evaluate the Anatomy of the Hypothalamic-Pituitary Region

Introduction: Ectopic posterior pituitary (EPP) is a malformation of the hypothalamic-pituitary region presented as a spectrum from isolated growth hormone deficiency (GHD) to multiple pituitary hormone deficiencies (MPHDs). Our goal was to establish whether the FAST1.2 protocol, which combines the FAST1 protocol with 3D-T2 DRIVE images, could identify the pituitary stalk (PS) and the regional anatomy more accurately. Methods: A retrospective study of 36 individuals with EPP and hypopituitarism and a control group of 78 individuals with eutopic posterior pituitary was conducted. All individuals were submitted to FAST1.2. The position and size of the pituitary lobes were described, and the presence/absence of the PS was confirmed. Results: FAST1 identified the PS in 19% of individuals with EPP, while FAST1.2 identified the PS in 67% (p < 0.001). In the FAST1.2 protocol, the PS was visible in all control individuals. All EPP patients with isolated GHD had visible PS in FAST1.2, while only 58.6% of MPHD cases had visible PS. The size of the anterior lobe and the anteroposterior length of the posterior pituitary were smaller in the EPP group versus controls (p < 0.001). We noticed a reduced anterior pituitary lobe in both diameters in MPHD patients (p < 0.05). Six patients acquired new pituitary hormone deficiencies not recognized at the time of MRI; in this group, only 1 patient had a PS not visible in FAST1.2. Discussion/Conclusion: The FAST1.2 protocol could prevent the misdiagnosis of idiopathic GHD in patients with short stature and could also be important in the progression to MPHD. The PS could be considered a predictor of hypopituitarism, but its use as an isolated indicator for the progression to MPHD is not recommended. Our results reinforce the use of the size of the anterior lobe as a predictor of hypopituitarism and a possible predictor of the degree of pituitary insufficiency. The FAST1.2 protocol could be used as an alternative to gadolinium administration, as a cheaper and faster method, while eliminating the potential risks associated with the administration of contrast media.

Immune checkpoint inhibitors and adrenal insufficiency: a large-sample case series study.

BackgroundAdrenal insufficiency (AI) represents a rare, yet potentially life-threatening immune checkpoint inhibitor (ICI)-related adverse event. The clinical characteristics of ICI-induced AI are still poorly defined due to its low incidence but need to be comprehensively understood.MethodsWe systematically retrieved and screened the PubMed/Medline, Embase, Web of Science, and Cochrane Library databases for all articles published on AI related to anti-cytotoxic T-lymphocyte antigen 4 (CTLA-4), anti-programmed cell death protein-1 (PD-1) receptor or its ligand (PD-L1), or combination ICI therapy. The retrieved articles were reviewed and selected in accordance with the exclusion criteria. The detailed data of individual cases were then collected and analyzed.ResultsWe identified 206 ICI-induced AI patients, comprising 11 (5.3%) primary AI patients, 191 (92.7%) secondary AI patients, and 4 (1.9%) mixed-type AI patients. The subclassification of the secondary AI patients, comprising 108 isolated adrenocorticotropic hormone (ACTH) insufficiency (IAD) and 83 multiple pituitary hormone deficiency (MPHD) patients, revealed that 56.5% of secondary AIs were related to IAD. Fatigue, anorexia/loss of appetite, headache, and nausea/vomiting were the most prevalent symptoms, and MPHD patients had a significantly higher rate of headache than primary AI patients and IAD patients (67.2% vs. 9.1% vs. 10.2%; P=0.000). Further, anti-PD-1-induced AI patients showed more complex and poorer clinical manifestations than anti-CTLA-4-induced patients, including a higher rate of emergency admission (28.7% vs. 4.9%; P=0.003), tachycardia (30.4% vs. 0; P=0.014), hypotension (50.0% vs. 8.6%; P=0.000), hypoglycemia (19.5% vs. 2.6%; P=0.014), hyponatremia (64.2% vs. 33.3%; P=0.002), and a prolonged median duration from ICI initiation to symptom onset (26 vs. 9 weeks; P=0.000).DiscussionThe ICI-induced AI events could be primary, secondary, or mixed-type, and IAD was the most common reason for such events. The symptoms were usually unspecific and could be complex. AI should be excluded in a timely manner, and the patients should be followed-up with and receive extra attention for AI events even after the discontinuation of ICI treatment. Additionally, the discrepancy in relation to clinical characteristics between anti-PD-1- and anti-CTLA4-induced AI events warrants further exploration.

Cognitive outcome in congenital central hypothyroidism: a systematic review with meta-analysis of individual patient data.

To provide an overview of cognitive and motor outcome, and quality of life (QoL) in patients with congenital central hypothyroidism (CH-C). Systematic review with individual patient data (IPD) meta-analysis. OVID MEDLINE, EMBASE and PsycInfo were searched from inception to June 11th, 2019. Studies in patients with CH-C, either isolated or with multiple pituitary hormone deficiency (MPHD), were included if CH-C patients could be separated from any additional patient groups. Primary outcomes were full-scale intelligence quotient (FSIQ) and motor outcome; secondary outcome was QoL. Following data-extraction, one-stage IPD meta-analysis was performed, fitting a linear mixed model with FSIQ as dependent variable. Random intercepts were fitted for each study. Six studies measuring FSIQ were eligible for meta-analysis, comprising 30 CH-C patients (20 males; 27 MPHD patients). FSIQ range was wide (64-123). Mean weighted FSIQ was 97 (95% CI: 88-105). Twenty-seven percent had an FSIQ below 85 (≥1 s.d. below norm score), and 10% below 70 (≥2 s.d. below norm score). There was no significant association between FSIQ and sex or age. Age at treatment initiation was available from three studies only, thus impeding a reliable analysis of this parameter. Motor outcome and QoL were each studied in one study; no quantitative analyses could be performed for these outcomes. A wide range in FSIQ scores was observed in CH-C patients. Results should be interpreted with caution, because included patients mainly had MPHD and age at treatment initiation was unknown for the majority of patients.

Long-Term Outcomes, Genetics, and Pituitary Morphology in Patients with Isolated Growth Hormone Deficiency and Multiple Pituitary Hormone Deficiencies: A Single-Centre Experience of Four Decades of Growth Hormone Replacement

Background: Growth hormone (GH) has been used to treat children with GH deficiency (GHD) since 1966. Aims: Using a combined retrospective and cross-sectional approach, we explored the long-term outcomes of patients with GHD, analysed factors influencing therapeutic response, determined persistence into adulthood, investigated pituitary morphology, and screened for mutations in causative genes. Methods: The files of 96 GH-deficient children were reviewed. In a subset of 50 patients, re-assessment in adulthood was performed, including GHRH-arginine testing, pituitary magnetic resonance imaging (MRI), and mutational screening for the growth hormone-1 gene (GH1) and the GHRH receptor gene (GHRHR) in isolated GHD (IGHD), and HESX1, PROP1, POU1F1, LHX3, LHX4, and GLI2 in multiple pituitary hormone deficiency (MPHD) patients. Results: GH was started at a height SDS of -3.2 ± 1.4 in IGHD patients and of -4.1 ± 2.1 in MPHD patients. Relative height gain was 0.3 SDS/year, absolute gain 1.6 SDS, and 1.2/2.6 SDS in IGHD/MPHD, respectively. Mid-parental target height was reached in 77%. Initial height SDS, bone age retardation and duration of GH replacement were correlated with height SDS gain. GHD persisted into adulthood in 19 and 89% of subjects with IGHD and MPHD, respectively. In 1/42 IGHD patients a GH1 mutation was detected; PROP1 mutations were found in 3/7 MPHD subjects. Anterior pituitary hypoplasia, combined with posterior pituitary ectopy and pituitary stalk invisibility on MRI, was an exclusive finding in MPHD patients. Conclusions: GH replacement successfully corrects the growth deficit in children with GHD. While the genetic aetiology remains undefined in most cases of IGHD, PROP1 mutations constitute a major cause for MPHD. Persistence of GHD into adulthood is related to abnormal pituitary morphology.

Trends In Growth Hormone Stimulation Testing And Growth Hormone Dosing In Adult Growth Hormone Deficiency Patients: Results From The Answer Program

Adult growth hormone deficiency (AGHD) results in physiologic impairments that may reduce quality of life and negatively impact body composition. AGHD can be treated with recombinant human growth hormone (GH). This study analyzes AGHD patients enrolled in the American Norditropin(®) Web-Enabled-Research (ANSWER) Program/NovoNet, a U.S. observational noninterventional study of patients treated with Norditropin(®) (somatropin [recombinant DNA origin] injection) at the discretion of their physicians. Data were evaluated for GH stimulation test (GHST) usage and Norditropin(®) doses over 4 years. Adults (N = 468) with isolated GHD (IGHD) or multiple pituitary hormone deficiency (MPHD) were evaluated. The most commonly used GHSTs were arginine + L-dopa (27%; mostly a single center) and glucagon (25%; most frequent test after 2009). The percent of patients meeting recommended test-specific cut points varied from 32 to 100%, depending on the GHST used. Mean baseline GH doses were higher for MPHD patients and for younger patients in both IGHD and MPHD groups. MPHD was more common than IGHD. Mean GH doses were higher in younger patients, consistent with a transition from higher pediatric to lower adult dosing. Over time, glucagon became the most popular GHST. The use, in some patients, of other GHSTs with cut points, as well as starting doses not consistent with current recommendations, highlights the need for continued education regarding treatment guidelines for AGHD.

High Prevalence ofPROP1Defects in Lithuania: Phenotypic Findings in an Ethnically Homogenous Cohort of Patients With Multiple Pituitary Hormone Deficiency

PROP1 gene mutations cause multiple pituitary hormone deficiency (MPHD). We sought to expand experience with PROP1 mutation carriers by studying a large cohort of Lithuanian patients. Sixty-seven MPHD patients were tested for PROP1 defects. Perinatal and postnatal data were obtained from medical records. Hormonal investigations, pituitary imaging, and GH therapy were provided in a single center in Kaunas, Lithuania. A biallelic PROP1 gene mutation was found in 47 subjects (70.1%), of which 46 were homozygous for 296delGA. Positive finding rate among MPHD and population prevalence of PROP1 defects in Lithuania (15.8 per million) were the highest reported to date. Patients' birth lengths/weights were normal. Testicular retention was noted in 31% of boys. Median height SD scores declined over years 1-5: -1.56, -2.34, -3.43, -3.52, and -3.70. Mid-parental height predicted severity of growth retardation at diagnosis (r2=0.30; P=.0001). Deficiencies of GH, TSH, ACTH, and FSH/LH were diagnosed in 44/44, 44/44, 19/44, and 22/44 subjects at median age of 5.5, 5.6, 13.1, and 15.0 years, respectively. Pituitary height ranged from 16.6 mm (+20.2 SD) to 1.4 mm (-15.5 SD) and declined with age (r2=0.27, P=.001). GH replacement (dose 0.027 mg/kg/d) led to height velocities 12.2; 9.1; 6.9; 6.8; 6.7; 5.6; and 5.7 cm/y (medians) at years 1-7 and final height SD scores (17 patients) -0.98±1.77 (-1.04±1.41 below target height; P=.008 vs 0). High prevalence of PROP1 defects in Lithuania is due to 296delGA mutation, suggesting a founder effect.

Functional Characterization of a Heterozygous GLI2 Missense Mutation in Patients With Multiple Pituitary Hormone Deficiency

The GLI2 transcription factor is a major effector protein of the sonic hedgehog pathway and suggested to play a key role in pituitary development. Genomic GLI2 aberrations that mainly result in truncated proteins have been reported to cause holoprosencephaly or holoprosencephaly-like features, sometimes associated with hypopituitarism. Our objective was to determine the frequency of GLI2 mutations in patients with multiple pituitary hormone deficiency (MPHD). Patients were selected from participants in the Genetics and Neuroendocrinology of Short Stature International Study (GeNeSIS) program. Patients with mutations within established candidate genes were excluded. A total of 165 patients with MPHD defined as GH deficiency and at least 1 additional pituitary hormone deficiency were studied regardless of the presence of extrapituitary clinical manifestations. Prevalence of GLI2 variations in MPHD patients was assessed and detailed phenotypic characterization is given. Transcriptional activity of identified GLI2 variants was evaluated by functional reporter assays. In 5 subjects, 4 heterozygous missense variants were identified, of which 2 are unpublished so far. One variant, p.R516P, results in vitro in a complete loss of protein function. In addition to GH deficiency, the carrier of the mutation demonstrates deficiency of thyrotrope and gonadotrope function, a maldescended posterior pituitary lobe, and polydactyly, but no midline defects. For the first time, we show that heterozygous amino acid substitutions within GLI2 may lead to MPHD with mild extrapituitary findings. The phenotype of GLI2 mutations is variable, and penetrance is incomplete. GLI2 mutations are associated with anterior pituitary hypoplasia, and frequently, ectopy of the posterior lobe occurs.

The use of neuroimaging for assessing disorders of pituitary development

Magnetic resonance imaging (MRI) is the radiological examination method of choice for evaluating hypothalamo-pituitary-related endocrine disease and is considered essential in the assessment of patients with suspected hypothalamo-pituitary pathology. Physicians involved in the care of such patients have, in MRI, a valuable tool that can aid them in determining the pathogenesis of their patients' underlying pituitary conditions. Indeed, the use of MRI has led to an enormous increase in our knowledge of pituitary morphology, improving, in particular, the differential diagnosis of hypopituitarism. Specifically, MRI allows detailed and precise anatomical study of the pituitary gland by differentiating between the anterior and posterior pituitary lobes. MRI recognition of pituitary hyperintensity in the posterior part of the sella, now considered a marker of neurohypophyseal functional integrity, has been the most striking finding in the diagnosis and understanding of certain forms of 'idiopathic' and permanent growth hormone deficiency (GHD). Published data show a number of correlations between pituitary abnormalities as observed on MRI and a patient's endocrine profile. Indeed, several trends have emerged and have been confirmed: (i) a normal MRI or anterior pituitary hypoplasia generally indicates isolated growth hormone deficiency that is mostly transient and resolves upon adult height achievement; (ii) patients with multiple pituitary hormone deficiencies (MPHD) seldom show a normal pituitary gland; and (iii) the classic triad of ectopic posterior pituitary, pituitary stalk hypoplasia/agenesis and anterior pituitary hypoplasia is more frequently reported in MPHD patients and is generally associated with permanent GHD. Pituitary abnormalities have also been reported in patients with hypopituitarism carrying mutations in several genes encoding transcription factors. Establishing endocrine and MRI phenotypes is extremely useful for the selection and management of patients with hypopituitarism, both in terms of possible genetic counselling and in the early diagnosis of evolving anterior pituitary hormone deficiencies. Going forward, neuroimaging techniques are expected to progressively expand and improve our knowledge and understanding of pituitary diseases.

Early Changes in Body Composition After Cessation of Growth Hormone Therapy in Childhood-Onset Growth Hormone Deficiency

At final height, somatic maturity has not been reached yet. We investigated bone and body composition in patients, who completed pediatric growth hormone (GH) treatment at final height. After a mean period of 0.55 ± 0.17 yr off GH treatment 90 (66 m/24 f) childhood-onset growth hormone deficiency (GHD) patients were reinvestigated for GHD by insulin tolerance testing at a mean age of 17.52 ± 1.50 yr. Thirty-seven (25 m/12 f) patients remained GH deficient (persistent GHD). Bone and body composition were measured using peripheral quantitative computed tomography of the nondominant forearm. Bone mineral density (BMD) was within normal limits. Total cross-sectional bone area Z-score (0.64 ± 1.3) was significantly higher as a result of an enlarged medullary cavity Z-score (1.12 ± 1.2) leading to reduction of cortical thickness Z-score (−1.21 ± 1.0). Patients with persistent GHD had a significantly higher fat mass (13.3 ± 8.7 and 6.8 ± 4.6 cm 2, p < 0.05), which was more pronounced in multiple pituitary hormone deficiency patients. Shortly after cessation of GH treatment in patients treated for childhood-onset GHD age adequate normal BMD and enlarged diaphysis was detectable. Patients with persistent GHD status had a significant higher fat mass.

From isolated GH deficiency to multiple pituitary hormone deficiency: an evolving continuum – a KIMS analysis

To describe baseline clinical presentation, treatment effects and evolution of isolated GH deficiency (IGHD) to multiple pituitary hormone deficiency (MPHD) in adult-onset (AO) GHD. Observational prospective study. Baseline characteristics were recorded in 4110 patients with organic AO-GHD, who were GH naïve prior to entry into the Pfizer International Metabolic Database (KIMS; 283 (7%) IGHD, 3827 MPHD). The effect of GH replacement after 2 years was assessed in those with available follow-up data (133 IGHD, 2207 MPHD), and development of new deficiencies in those with available data on concomitant medication (165 IGHD, 3006 MPHD). IGHD and MPHD patients had similar baseline clinical presentation, and both groups responded similarly to 2 years of GH therapy, with favourable changes in lipid profile and improved quality of life. New deficiencies were observed in 35% of IGHD patients, which was similar to MPHD patients with one additional deficit other than GH. New deficiencies most often presented within the first year but were observed up to 6 years after GH commencement. Conversion of IGHD into MPHD was not predicted by aetiology, baseline characteristics, surgery or radiotherapy, whereas in MPHD additional deficits were predicted by age (P<0.001) and pituitary disease duration (P<0.01). Both AO-IGHD and -MPHD patients have similar baseline clinical presentation and respond equally well to 2 years of GH replacement. Hypopituitarism in adults seems to be a dynamic condition where new deficiencies can appear years after the initial diagnosis, and careful endocrine follow-up of all hypopituitary patients, including those with IGHD, is warranted.

Antipituitary Antibodies in Dutch Patients with Idiopathic Hypopituitarism

Background: Despite extensive research, in the majority of patients with isolated growth hormone deficiency (IGHD) and multiple pituitary hormone deficiency (MPHD), the cause of their clinical picture remains unknown. Recent articles suggest that some cases of idiopathic growth hormone deficiency might be explained by a silent form of autoimmune hypophysitis based on the presence of antipituitary antibodies (APA) at high titers (>1:8). Methods: We collected clinical data and serum from 71 patients participating in the Dutch HYPOPIT study. APA screening in 40 IGHD patients and 31 MPHD patients was performed by an indirect immunofluorescence method. APA, when present, were related to clinical and morphological pituitary findings. Results: APA were present at high titers in 7 of 31 MPHD patients (23%) and 1 of 40 IGHD patients (2.5%). Among APA-positive MPHD patients, apart from growth hormone deficiency, all patients of pubertal age had gonadotroph defi- ciency, all had thyroid hormone deficiency and 50% had ACTH deficiency. Conclusion: The high frequency of APA in our idiopathic MPHD population indicates that, in 23% of the patients diagnosed with idiopathic MPHD, the hormone deficiencies might actually be caused by a silent form of autoimmune hypophysitis. Screening for APA should therefore be considered in all patients with ‘idiopathic’ MPHD.

Evaluation of Permanent Growth Hormone Deficiency (GHD) in Young Adults with Childhood Onset GHD: A multicenter study

Background: Reconfirming the diagnosis of childhood onset growth hormone deficiency (GHD) in young adults is necessary to demonstrate the need for continuation of GH therapy.Objective: This nationally−based study was planned to establish GH status during adulthood in childhood−onset GH deficient patients and to evaluate factors that would predict persistency of the GHD.Methods: In this multicenter study, 70 GH deficient patients who had reached final height were evaluated after completion of GH treatment. Fifty−two patients (74%) had isolated GHD and 18 patients (26%) had multiple pituitary hormone deficiency (MPHD). Patients who had reached final height and the pubertal Tanner stage 5 were reevaluated for GH status. After at least 6 weeks of cessation of GH treatment, patients were retested with insulin induced hypoglycemia.Results: GHD was found to be transient in 64.3% of all patients. Of the isolated GH deficient patients 82.7% had transient GHD, whereas 88.9% of the MPHD patients showed persistent GHD. Comparison of isolated GH deficient and multiple hormone deficient patients indicated higher peak GH, IGF−I and IGFBP−3 levels in isolated GH deficient patients. No parameter was significantly different in the transiently and persistently GH deficient patients with respect to gender. Although specificity of IGF−I value of less than −2 SD showing persistency of GHD was lower than the specificity of IGFBP−3 value of less than −2 SD (65.7% vs 84%), negative predictive values were similar for the two parameters (85.2% and 84%, respectively).Conclusion: Most of the cases of childhood onset GHD are idiopathic and the GHD is transient. In patients with MPHD, GHD is generally permanent. Low IGF−I and IGFBP−3 levels are supporting findings to show persistency of the GHD.Conflict of interest:None declared.

Adult Height in Patients with Permanent Growth Hormone Deficiency with and without Multiple Pituitary Hormone Deficiencies

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. 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. This was a retrospective multicenter study conducted in university research hospitals and a tertiary referral endocrine unit. 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. 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. Adult height in patients with permanent IGHD and spontaneous puberty is similar to adult height in patients with MPHD and induced puberty.

Congenital adenohypophysis aplasia: Clinical features and analysis of the transcriptional factors for embryonic pituitary development

Anterior pituitary agenesis (APA) has very rarely been reported. Therefore, its phenotypical and genotypical features are not well known. The aim of this study was to ascertain whether the clinical picture in 4 subjects with APA and multiple pituitary hormone deficiencies (MPHD) was different compared to the one observed in a selected control group consisting of 7 MPHD individuals with hypoplastic (and not aplastic) adenohypophysis and pituitary stalk interruption syndrome. Another goal was to investigate genetic basis of APA by analyzing for the first time in this condition many of the transcriptional factors which are required for both structural development and cellular differentiation of hypophysis. Age at diagnosis was significantly lower in APA children than in controls (1.5+/-2.3 vs 11.1+/-7.6 yr, p<0.0005). Microphallus and neonatal cholestasis were observed only in APA subjects (chi-squared=4.3, p<0.05) and also neonatal hypoglycemia was more frequent in APA patients than in controls (X2=4.05, p<0.05). Molecular analyses of the genes of the transcriptional factors POU1F1, PROP1, LHX3, LHX4, ISL1 and HESX1 detected no mutations in APA patients. a) if compared with a selected cohort of MPHD patients with both adenohypophysis hypoplasia and pituitary stalk interruption syndrome, the ones with APA show an earlier and more severe picture of hypopituitarism; b) mutations in several transcription factors that are known to be essential for the development of Rathke's pouch are not necessarily found in humans with APA.

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.

Craniocerebral imaging in children with short stature

To analyse the type and frequency of cranial CT and NMR imaging anomalies in children of short stature. We studied 57 children of short stature with a mean age (+/-SD) of 10.1 +/- 3.8 years, 34 boys and 23 girls, all of them with auxometric criteria of GH deficiency. After studying the pituitary function and determination of karyotype in the girls, the children were classified in to five groups:-Isolated GHD (IGHD) (n = 32), multiple pituitary hormone deficiency (MPHD) (n = 6), neurosecretory dysfunction (NSD) (n = 8), Turner syndrome (n = 7) and idiopathic short stature (ISS) (n = 4). The imaging methods used were cranial CT or NMR. Of the 57 children studied the CT/NMR was abnormal in 37(64.9%) children. We found anomalies in 65.6% of IGHD patients, 62.5% of NSD patients, 100% of MPHD patients and 57.1% and 25% in the Turner s. patients and ISS patients respectively. The most frequent anomaly was hypoplastic pituitary found in 50% of IGHD patients, 37.5% of NSD patients and 33.3% of MPHD patients. None of the cases of Turner s. or ISS had hypoplastic pituitary. An empty sella was the second most frequent anomaly found in 7 patients (IGHD-3, MPHD-3, DNS-1). Of the 25 children in which NMR was performed, 8 had hypoplastic pituitary and stalk and 2 had interruption of the pituitary stalk and ectopic neurohypophysis. These results strengthen the necessity for CT/NMR imaging in children of short stature which, besides allowing identification of tumors, also permits the diagnosis of idiopathic GHD because of its frequent association with cranial imaging anomalies, mainly hypoplastic pituitary.

Growth hormone response to growth hormone-releasing hormone varies with the hypothalamic-pituitary abnormalities

We determined growth hormone (GH) and insulin-like growth factor I (IGF-I) levels after a 3 h infusion of escalating doses of growth hormone-releasing hormone (GHRH(1-29)) followed by a bolus injection in hypopituitary patients with marked differences in pituitary features at magnetic resonance imaging (MRI) in order to evaluate further the contribution of MRI in the definition of pituitary GH reserve in GH-deficient patients. Twenty-nine patients (mean age 14.5 +/- 4.0 years) were studied. Group I comprised 13 patients: seven with isolated GH deficiency (IGHD) (group Ia) and six with multiple pituitary hormone deficiency (MPHD) (group Ib) who had anterior pituitary hypoplasia, unidentified pituitary stalk and ectopic posterior pituitary at MRI, Group II consisted of eight patients with IGHD and small anterior pituitary/empty sella, while in group III eight had IGHD and normal morphology of the pituitary gland. Growth hormone and IGF-I levels were measured during saline infusion at 08.30-09.00 h, as well as after infusion of GHRH (1-29) at escalating doses for 3h: 0.2 micrograms/kg at 09.00-10.00 h, 0.4 micrograms/kg at 10.00-11.00 h, 0.6 micrograms/kg at 11.00-12.00 h and an intravenous bolus of 2 micrograms/ kg at 12.00 h. In the group I patients, the peak GH response to GHRH(1-29) was delayed (135-180 min) and extremely low (median 2mU/l). In group II it was delayed (135-180 min), high (median 34.8 mU/l) and persistent (median 37.4 mU/l at 185-210 min). In group III the peak response was high (median 30.8 mU/l) and relatively early (75-120 min) but it declined rapidly (median 14.4 mU/l at 185-210 min). In one group I patient, GH response increased to 34.6 mU/l. The mean basal value of IGF-I levels was significantly lower in group I (0.23 +/- 0.05 U/ml) than in groups II (0.39 +/- 0.13U/ ml, p < 0.01) and III (1.54 +/- 0.46 U/ml, p < 0.001) and did not vary significantly during the GHRH(1-29) infusion. The present study demonstrates that the impaired GH response to 3 h of continuous infusion of escalating doses of GHRH(1-29) was strikingly indicative for pituitary stalk abnormality, strengthening the case for use of GHRH in the differential diagnosis of GH deficiency. The low GH response, more severe in MPHD patients, might be dependent on the residual somatotrope cells, while the better response (34.6 mU/l) in the group Ia patients might suggest that prolonged GHRH infusion could help in evaluating the amount of residual GH pituitary tissue. Pituitary GH reserve, given the GH response to GHRH infusion in GH-deficient patients with small anterior pituitary/empty sella, seems to be maintained.

Body composition in adult growth hormone-deficient men, assessed by anthropometry and bioimpedance analysis.

Anthropometry and bioimpedance analysis (BIA) were used to assess body composition in 42 GH-deficient (GHD) adult males (mean age, 27.2 +/- 4.7 yr). During childhood, all patients had received GH treatment for a mean period of 8.4 +/- 3.8 yr. At the start of this study, GH therapy had been discontinued for a mean period of 7.5 +/- 4.5 yr. Eighteen patients had isolated GH deficiency (I-GHD). Twenty-four patients had multiple pituitary hormone deficiencies (M-PHD), substituted adequately. Compared to age- and sex-matched controls, the sum of skinfolds measured at 7 different sites was significantly higher in I-GHD and M-PHD patients [controls, 73.1 +/- 25.4 mm; I-GHD patients, 102.1 +/- 37.7 mm (P less than 0.001); M-PHD patients, 126.8 +/- 35.4 mm (P less than 0.001)]. The increase in sc fat deposition was most pronounced on the trunk, particularly in the breast and abdominal area. Total body muscle mass was significantly lower in GHD patients (P less than 0.001). In patients, body muscle mass and plasma somatomedin-C level were positively correlated (r = 0.43; P less than 0.005). Total body resistance measured by whole body BIA was significantly higher in the patient group and was negatively correlated with plasma somatomedin-C (r = -0.53; P less than 0.001). The high resistance values observed in GHD patients could only in part be explained by their lower lean body mass. The most important cause, however, was an increase in specific electrical resistance of the lean body mass (LBM), reflecting relative dehydration. We conclude that GH deficiency in adult males is associated with an increase in sc fat and a decrease in body muscle mass. In addition, there is a qualitative change in LBM. The BIA data indicate that in these patients, the hydration state of the LBM is lower than normal, due to a decrease in extracellular water.

Evidence of Morphological and Functional Abnormalities in the Hypothalamus of Growth-Hormone-Deficient Children: A Combined Magnetic Resonance Imaging and Endocrine Study

Fifty-seven children with growth hormone deficiency and 15 healthy age-matched controls were studied by magnetic resonance imaging (MRI). Of the patients, 36 (63%) had isolated GH deficiency (IGHD) and 21 (37%) multiple pituitary hormone deficiency (MPHD). MRI studies showed a marked reduction in pituitary volume in all patients in comparison with normal controls. Moreover, a striking morphological abnormality with the apparent absence of the pituitary stalk and an ectopic posterior pituitary lobe was detected in 34 of the patients (59%). This pituitary stalk abnormality was detected in 95% of the MPHD patients and in 39% of the IGHD patients. All but one of the patients with a normal pituitary stalk had IGHD. Endocrine evaluation showed no correlation with MRI data: in particular patients with an apparent anatomical interruption of the hypothalamic-pituitary axis showed a variety of patterns of hormonal responses. In conclusion, our study shows a high frequency of hypothalamic-pituitary anomalies in patients with GH deficiency, particularly related with MPHD. However, further studies are needed to improve our understanding of the relationship between MRI and endocrine data.

The impact of long-term therapy by a multidisciplinary team on the education, occupation and marital status of growth hormone deficient patients after termination of therapy.

Forty-two GH deficient patients (14 isolated GH deficiency (IGHD), 28 multiple pituitary hormone deficiencies (MPHD), 23 males and 19 females) were evaluated after termination of hGH therapy and achievement of final height. IGHD patients were found to score higher in intelligence quotients (IQ) than the MPHD patients. The educational and occupational achievements of all patients positively correlated with their IQ level. Three patients achieved only elementary education, 26 completed high school and 13 had higher education. Thirty patients who had completed their education were employed, whereas 12 continued to study. Seventeen of the male patients and five females served in the Army. Eight patients were married and half of the single patients reported having a stable relationship with the opposite sex. The hypopituitary patients did not differ in five out of seven subscales of the human services rehabilitation scale when compared to a normal control group. These results which vary from those previously reported demonstrate the importance of long-term psychosocial counselling initiated at the time of diagnosis as part of the therapeutic approach in hypopituitary patients.