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.     

Hypopituitarism and stalk agenesis: a congenital syndrome worsened by breech delivery?

Thirty-seven patients with idiopathic hypopituitarism, of whom 12 had multiple pituitary hormone deficiencies (MPHD) and 25 isolated growth hormone deficiency (IGHD), were evaluated by magnetic resonance imaging (MRI). Twenty-two of the 37 showed congenital anterior pituitary hypoplasia, stalk agenesis and ectopic posterior pituitary gland at the infundibular recess (group A), while the remaining 15 presented isolated anterior pituitary hypoplasia (group B). Perinatal histories obtained from all patients demonstrated that 18/22 children of group A (81.81%) had histories of adverse perinatal events, with breech presentation in 15 (68.18%). Twelve of 12 children of group A born by breech delivery developed MPHD; 3 born by cesarean section for breech presentation had only IGHD. Patients of group B had also a high incidence of perinatal insults (12/15, 80%), but breech delivery was markedly less frequent (13.33 vs. 68.18% of group A) and responsible for only IGHD. Group B had also higher percentages of maternal spontaneous abortion and low birth weight. Our study suggests that several factors may play a role in the development of growth hormone deficiency. Some patients had severe perinatal insults apparently leading to hypopituitarism. We were able to define by MRI a group of patients with congenital abnormalities, such as anterior pituitary hypoplasia, stalk agenesis and posterior pituitary ectopia, among whom breech presentation was very common. In this group, breech delivery was always followed by MPHD while cesarean or normal delivery in such patients was followed by IGHD only.     

Isolated growth hormone deficiency and the GH-1 gene: update 2002

This short review will focus on the mechanisms which are thought to be directly involved in GH expression and particularly on the monogenetic disorders which were shown to cause isolated growth hormone deficiency (IGHD) due to insufficient expression of GH. The overwhelming majority of genetic defects detected in isolated growth hormone deficiency (IGHD) are mutations of the coding region of the GH-1 gene which belongs to a five genes containing gene cluster located on 17q22-24. Depending on the type of the GH-1 gene mutation, the mode of inheritance is recessive or dominant. The promotor region of the GH-1 gene which encompasses the 300 bp of the 5' flanking region is highly polymorphic, but the functionally important cis-acting elements are conserved. This sequence is sufficient to control GH expression in cultured cells, but not in transgenic mice: the human GH locus control region, an enhancer region of the GH-1 gene located approximately 15-32 kB upstream of the GH-1 coding region was shown to direct pituitary-specific, high-level GH expression in vivo. Promotion of the GH expression needs the coordinate binding of pituitary-specific (i.e., POU1F1) and ubiquitous trans-acting factors to the cis-acting elements. The mutational analysis of trans-acting factors and cis-acting elements of the GH-1 gene has so far not established any defect outside the coding region as the genetic basis of IGHD except for POU1F1 mutations which cause multiple pituitary hormone deficiency including GHD. Several mutations of the GHRH-receptor gene were shown to result in severe IGHD. In the future, the discovery of new defects of the GH expression machinery will add to our understanding of how GH is sufficiently supplied to the organism and will hopefully simplify and improve the diagnostic approach in a subset of children with IGHD.     

Aged PROP1 deficient dwarf mice maintain ACTH production

Humans with PROP1 mutations have multiple pituitary hormone deficiencies (MPHD) that typically advance from growth insufficiency diagnosed in infancy to include more severe growth hormone (GH) deficiency and progressive reduction in other anterior pituitary hormones, eventually including adrenocorticotropic hormone (ACTH) deficiency and hypocortisolism. Congenital deficiencies of GH, prolactin, and thyroid stimulating hormone have been reported in the Prop1(null) (Prop1(-/-)) and the Ames dwarf (Prop1(df/df)) mouse models, but corticotroph and pituitary adrenal axis function have not been thoroughly investigated. Here we report that the C57BL6 background sensitizes mutants to a wasting phenotype that causes approximately one third to die precipitously between weaning and adulthood, while remaining homozygotes live with no signs of illness. The wasting phenotype is associated with severe hypoglycemia. Circulating ACTH and corticosterone levels are elevated in juvenile and aged Prop1 mutants, indicating activation of the pituitary-adrenal axis. Despite this, young adult Prop1 deficient mice are capable of responding to restraint stress with further elevation of ACTH and corticosterone. Low blood glucose, an expected side effect of GH deficiency, is likely responsible for the elevated corticosterone level. These studies suggest that the mouse model differs from the human patients who display progressive hormone loss and hypocortisolism.     

Plasma growth hormone response to synthetic GH-RH1-44 in 52 children and adults with growth hormone deficiency of various etiologies

52 patients (42 children and 10 adults) with growth hormone deficiency (GHD), grouped into four diagnostic categories, and 6 children with constitutional short stature who served as controls were tested for plasma GH response to synthetic GH-RH1-44 given in an intravenous bolus. The response was classified into three degrees according to the magnitude of the maximal rise: Good, greater than 9 ng/ml; Partial, 3.1-9.0 ng/ml; None, less than or equal to 3 ng/ml. Among the GHD patients the highest response was observed in patients with partial growth hormone deficiency (PGHD), and 60% of the children with isolated GH deficiency (IGHD) showed an increase in plasma GH levels. Nevertheless, the response of the GHD patients was lower than that in the control group. In the children and adolescents with PGHD and IGHD the response was not age related. Among those with multiple pituitary hormone deficiencies-idiopathic (MPHD-ID) there was no response in the adolescents although a hypothalamic disorder had been documented by other tests. Among those with MPHD-organic (MPHD-ORG) the GH-RH stimulated GH secretion in the patients with glioma, who had received only irradiation treatment, and in the youngest of the patients with craniopharyngioma. Of the 10 young adults tested none showed a good response. It is concluded that GH-RH is useful in differentiating between GH deficiency of hypothalamic origin and that of pituitary origin, and in selecting those patients who might benefit from long-term treatment with GH-RH in the future.     

Extended Haplotypes in the Growth Hormone Releasing Hormone Receptor Gene (GHRHR) Are Associated with Normal Variation in Height

Mutations in the gene for growth hormone releasing hormone receptor (GHRHR) cause isolated growth hormone deficiency (IGHD) but this gene has not been found to affect normal variation in height. We performed a whole genome linkage analysis for height in a population from northern Sweden and identified a region on chromosome 7 with a lod-score of 4.7. The GHRHR gene is located in this region and typing of tagSNPs identified a haplotype that is associated with height (p = 0.00077) in the original study population. Analysis of a sample from an independent population from the most northern part of Sweden also showed an association with height (p = 0.0039) but with another haplotype in the GHRHR gene. Both haplotypes span the 3′ part of the GHRHR gene, including the region in which most of the mutations in IGHD have been located. The effect size of these haplotypes are larger than that of any gene previously associated with height, which indicates that GHRHR might be one of the most important genes so far identified affecting normal variation in human height.     

Eventos adversos perinatales y anomalías neuroanatómicas en pacientes con hipopituitarismo idiopático

ObjectiveTo analyze the possible causes of growth hormone (GH) deficiency, whether isolated (GHD) or in combination with other pituitary deficiencies classified as idiopathic.Patients and methodsWe studied patients with idiopathic GHD included in a protocol of recombinant GH treatment in adults attending the outpatient clinic of the Endocrinology and Nutrition Service of the San Cecilio University Hospital. Perinatal history, findings on magnetic resonance imaging (MRI) of the hypothalamic-pituitary axis and diagnosis of GHD and other deficiencies were retrospectively evaluated.ResultsA total of 17 patients were included: 14 men and 3 women with a mean age at diagnosis of 8.4±7.3 years. Perinatal adverse events occurred in 12 patients (69.2%). MRI showed empty sella (2 patients), pituitary hypoplasia or absence of the pituitary stalk (7 patients) and pituitary hypoplasia with ectopic posterior pituitary gland (6 patients); in the remaining 2 patients these data were not available. All had an established diagnosis of GHD: 15 with (88.2%) gonadotropin deficiency, 9 (52.9%) with adrenocorticotropic hormone (ACTH) deficiency and 8 (47.1%) with thyroid-stimulating hormone (TSH) deficiency.ConclusionsIn our patients, adverse events during pregnancy or the perinatal period and the presence of anatomical abnormalities identified by MRI are a marker of pituitary dysfunction and may be important in the pathogenesis of this entity. The clinical spectrum of disease varies from isolated GH deficiency to multiple pituitary hormone deficiencies.     

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

Objective: 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® Studies: 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.Methods: Data were evaluated for GH stimulation test (GHST) usage and Norditropin® doses over 4 years.Results: 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.Conclusion: 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.Abbreviations:AACE = American Association of Clinical EndocrinologistsAGHD = adult growth hormone deficiencyANSWER = American Norditropin® Studies: Web-Enabled-ResearchBMI = body mass indexGH = growth hormoneGHD = growth hormone deficiencyGHRH = growth hormone-releasing hormoneGHST = growth hormone stimulation testIGF-1 = insulin-like growth factor-1IGHD = isolated growth hormone deficiencyITT = insulin tolerance testKIMS = Pfizer International Metabolic DatabaseMPHD = multiple pituitary hormone deficiencyTES = The Endocrine Society     

Factors influencing the growth hormone response to growth hormone-releasing hormone in children with idiopathic growth hormone deficiency

OBJECTIVE: To evaluate the factors influencing the growth hormone (GH) response to GH-releasing hormone (GHRH) test in idiopathic GH deficiency. METHODS: 28 patients aged 4.9 +/- 0.7 years with certain GH deficiency were given GHRH (2 microg/kg). RESULTS: The GH peak after GHRH was correlated negatively with age at evaluation (r = -0.37, p < 0.05) and body mass index (r = -0.44, p = 0.02), and positively with anterior pituitary height (r = 0.47, p = 0.02), GH peak after non-GHRH stimulation (r = 0.78, p < 0.0001) and spontaneous GH peak (r = 0.82, p = 0.007). It was lower in the patients aged >5 years than in the youngest (p = 0.04), but it was similar in the patients with and without features suggesting a hypothalamic origin. CONCLUSION: The GH response to GHRH test cannot be used to differentiate between hypothalamic and pituitary forms of idiopathic GH deficiency, probably because the GH response decreases after the first 5 years of life, whatever the origin of the deficiency.     

Normal progression of testicular size in boys with idiopathic short stature and isolated growth hormone deficiency treated with growth hormone: experience from the KIGS

BACKGROUND: The aim of this retrospective analysis was to evaluate the effects of growth hormone (GH) treatment on testicular development in boys with idiopathic short stature (ISS) and isolated GH deficiency (IGHD) followed in the KIGS (Pharmacia International Growth Database). METHODS: For inclusion in the study, the patients had to have received more than 1 year of prepubertal GH treatment, at least 4 consecutive years of GH treatment in total, and to have attained their final height, defined as a height velocity of less than 2 cm/year. Data on 107 boys in the KIGS database have been analyzed. RESULTS: No significant differences in duration of GH treatment and testicular volume at the start of treatment or at final height were found between the boys with ISS and those with IGHD. The progression of testicular volume in boys with ISS or IGHD during GH treatment did not differ from the reference population. CONCLUSIONS: This analysis shows that GH treatment does not alter testicular growth in boys with ISS or IGHD. However, prospective controlled studies are needed to rule out moderate attenuating or stimulating effects.     

Novel insights into the aetiology and pathogenesis of hypopituitarism

Recent advances in our knowledge of pituitary development, acquired mainly from animal models, have enhanced our understanding of the aetiology of isolated growth hormone deficiency (IGHD) and combined pituitary hormone deficiency (CPHD), as well as several syndromic forms of growth hormone deficiency (GHD). A number of developmental genes known to be important for organ commitment and cell differentiation and proliferation (HESX1, LHX3, LHX4, PROP1 and PIT1) have been implicated in CPHD with or without other syndromic features. Phenotypes associated with these genetic mutations and their inheritance may be highly variable. Functional analyses of these mutations reveal valuable insights into the function of the proteins and hence into the effect of these mutations on phenotype. Novel insights have been gained into the mechanisms whereby these genes are associated with particular phenotypes as a result of murine transgenesis, e.g. type II autosomal dominant GHD. Mutations within known genes account for a small proportion of cases of IGHD and CPHD, suggesting the role of other as yet unidentified genetic and environmental factors. Hence, genetic testing will in the future have a greater role to play in understanding the mechanisms leading to particular hypopituitary phenotypes and also in predicting the evolution of these disorders. There is, however, no substitute for careful delineation of the phenotype prior to undertaking genetic studies.     

Cutting edge: Requirement for growth hormone-releasing hormone in the development of experimental autoimmune encephalomyelitis

Growth hormone (GH)-releasing hormone (GHRH) is a neuropeptide that stimulates secretion of GH from the pituitary gland. Although GHRH and its receptor (GHRHR) are expressed in leukocytes, physiological function of GHRH in the immune system remains unclear. To study the influence of GHRH in autoimmunity, susceptibility to experimental autoimmune encephalomyelitis (EAE) was examined in C57BL/6J-Ghrhr(lit/lit) (lit/lit), mice deficient in the GHRHR gene. We found that lit/lit mice were resistant to myelin oligodendrocyte glycoprotein (MOG)-induced EAE. Splenocytes from MOG-immunized lit/lit mice proliferated normally in response to MOG peptide, suggesting that activation of MOG-specific T cells in GHRHR-deficient mice is not impaired. Our data strongly suggest that GHRH plays a crucial role in the development of EAE and may provide the basis for a novel therapeutic approach protecting from autoimmune diseases.