Pituitary Growth Hormone Deficiency Research Articles

The Treatment of Growth Disorders in Childhood and Adolescence.

3% of all children are unusually short, and 3% are unusually tall. New approaches have broadened the range of therapeutic options in treating growth disorders. This review is based on publications retrieved by a selective review of the literature and on the authors' clinical experience. Pituitary growth hormone deficiency is treated with recombinant growth hormone. Long-acting preparations of this type became available recently, but their long-term safety and efficacy are still unknown. Vosoritide, a CNP analogue, has also been approved for the treatment of achondroplasia, and severe primary deficiency of insulin-like growth factor 1 (IGF-1) can be treated with recombinant IGF-1. In the treatment of excessively tall stature, new information on the safety of growth-attenuating treatment and an altered perception of above-average height in society have led to a change in management. There are new options for the treatment of rare causes of short stature, while new information on the safety of treatment strategies for excessive tallness have led to a reconsideration of surgical intervention. There is insufficient evidence on the benefits and risks of supraphysiological GH therapy and of newer treatment options for which there are as yet no robust data on adult height. Therefore, before any treatment is provided, physicians should give patients and their families detailed information and discuss their expectations from treatment and the goals that treatment can be expected to achieve.

778 A Systematic Review of Surgery for Optic Pathway Glioma

Abstract Aim Optic pathway gliomas (OPG) are a rare group of primary CNS malignancies usually found in children. The contemporary role of surgery in managing OPG is unclear. This review aimed to systematically assess the contemporary role for surgery in managing OPGs with respect to survival and functional outcomes. Method A systematic review was conducted in accordance with the PRISMA guidelines. A broad search strategy was employed in the literature search of the major medical databases. Articles describing OPG patients (stratified by modified Dodge classification (mDC) location) undergoing tumour-directed surgery were included, whilst articles with <10 patients, published before 2000 and describing individual case reports, opinions or secondary research were excluded. Primary outcomes were overall survival (OS), progression-free survival (PFS), visual outcome and endocrine outcome. Results 1221 articles were originally identified, with 21 included in the qualitative synthesis. There were 13 Level II and 8 Level IV articles. 5-year OS and PFS was 94.6% and 57.8% respectively (n = 2139). Total resection of mDC I OPG was curative, with no other surgical strategy being associated with survival benefit. Surgery was not significantly associated with visual or endocrine outcome, aside from preservation of contralateral vision (p < 0.001) in one series and predicting posterior pituitary dysfunction and GH deficiency (both p = 0.05) in one cohort. Conclusions Patients undergoing surgery for OPG have excellent overall survival, but a significant proportion have disease progression and associated endocrinopathy. Although total resection of mDC I OPG appears curative, more robust evidence is required to ascertain the surgical role in OPG.

Effect of recombinant human growth hormone on liver fat content in young adults with nonalcoholic fatty liver disease.

Nonalcoholic fatty liver disease (NAFLD) is highly prevalent in young adults with obesity. Obesity is associated with relative growth hormone (GH) deficiency, and data from animal studies and from humans with pituitary GH deficiency suggest a role for GH deficiency in the pathogenesis of NAFLD. The effects of GH on NAFLD in those with obesity are unknown, however, prompting this pilot study to assess effects of GH administration on measures of NAFLD in young adults. Twenty-four men and women aged 18-29years with BMI≥30kg/m2 , hepatic fat fraction (HFF)≥5% on proton magnetic resonance spectroscopy (1 H-MRS) and insulin-like growth factor 1 (IGF-1) z-score≤0 were randomized to treatment with recombinant human GH (rhGH) versus no treatment for 24weeks. The primary endpoint was change in HFF. Compared to no treatment, the effect size of rhGH on absolute HFF over 24weeks was -3.3% (95% confidence interval: -7.8%, 1.2%; p=.14). At 24weeks, HFF<5% was achieved in 5 of 9 individuals receiving rhGH versus 1 of 9 individuals receiving no treatment (p=.04). rhGH did not significantly reduce ALT, AST or GGT. Serum IGF-1 increased as expected with rhGH treatment, and there were no changes in fasting lipids, C-reactive protein, fasting glucose or 2-h glucose following an oral glucose tolerance test. Data from this pilot study suggest that rhGH treatment in young adults with obesity and NAFLD may have benefits to reduce liver fat content, although larger studies are needed to confirm this effect.

Vitamin D3 and Dental Caries in Children with Growth Hormone Deficiency.

Vitamin D deficiency is a common risk factor for multifactorial diseases, and it seems to be associated with growth hormone deficiency (GHD). Vitamin D could prevent dental caries. The goal of this study was to identify whether there is an association between hormonal therapy with growth hormone (GH), vitamin D3 supplementation, vitamin D3 levels, and the occurrence of caries among children affected by GHD. The study group consisted of patients from the Department of Endocrinology and Diabetology of the University Paediatric Hospital at the Medical University of Lublin treated with recombinant human GH for pituitary GHD. It was conducted between October 2014 and June 2015. The study group included 121 children and adolescents aged 6 to 18 years, with 56 children from rural areas and 65 from urban areas. The study group was stratified by the area of residence. We found the statistically significant impact of vitamin D3 concentration on the average value of the DMFT (decayed, missed, and filled teeth) index and its component—DT (decayed teeth), which was noted in subjects from rural areas. Among patients from urban areas, we found a statistically significant correlation between duration of therapy and the DMFT index. An increase in duration of GH therapy by 10 months leads to a mean increase in DMFT index by 0.70. Based on multiple regression analysis, we developed the following model: value of DT = 3.10 − 0.73∗category of vitamin D3 concentration − 0.07∗duration of supplementation (in months). In this model, variables with a significant impact on the value of DT in the group of patients from rural areas include time of vitamin D3 supplementation and category of vitamin D3 concentration. Greater emphasis should be placed on promoting vitamin D3 as a potentially effective agent reducing the number of dental caries, especially among patients with GHD.

Dental caries and vitamin D3 in children with growth hormone deficiency

Vitamin D may prevent dental caries. To date, no attempts have been made to examine the correlation between the incidence of caries and the concentrations of vitamin D in children with pituitary growth hormone deficiency.The study observed patients of the Department of Endocrinology and Diabetology of the University Paediatric Hospital of the Medical University of Lublin treated with human recombinant growth hormone for pituitary growth hormone deficiency (GHD). The study was conducted between October 2014 and June 2015. The study group consisted of 121 children and adolescents (6–17 years old), including 56 children from rural areas and 65 children from urban areas. The study group was stratified by area of residence.In our study, the increase in vitamin D3 [25(OH)D] levels reduced the D component by 0.66 per each 10 ng/mL of vitamin D3 concentration. The percentage of children with active caries in rural areas is 91.07% (n = 51), which is significantly higher than the percentage of children with active caries in urban areas (81.54%, n = 53).To date, information regarding the potential possibility of reducing the incidence of dental caries by means of increasing the levels of vitamin D was sidelined by paediatricians and dentists alike. Therefore, this aspect of caries prevention should be highlighted.

Growth hormone/IGF-1 axis longitudinal evaluation in clinically isolated syndrome patients on interferon β-1b therapy: stimulation tests and correlations with clinical and radiological conversion to multiple sclerosis.

Growth hormone (GH)/insulin-like growth factor 1 (IGF-1) axis abnormalities in multiple sclerosis (MS) suggest their role in its pathogenesis. Interferon β (IFN-β) efficacy could be mediated also by an increase of IGF-1 levels. A 2-year longitudinal study was performed to estimate the prevalence of GH and/or IGF-1 deficiency in clinically isolated syndrome (CIS) patients and their correlation with conversion to MS in IFN treated patients. Clinical and demographic features of CIS patients were collected before the start of IFN-β-1b. IGF-1 levels and GH response after arginine and GH releasing hormone + arginine stimulation tests were assessed. Clinical and magnetic resonance imaging evaluations were performed at baseline, 1 year and 2 years. Thirty CIS patients (24 female) were enrolled. At baseline, four patients (13%) showed a hypothalamic GH deficiency (GHD), whilst no one had a pituitary GHD. Baseline demographic, clinical and radiological data were not related to GHD, whilst IGF-1 levels were inversely related to age (P < 0.001) and GH levels (P = 0.03). GH and IGF-1 serum mean levels were not significantly modified after 1 and 2 years of treatment in the whole group, although 3/4 GHD patients experienced a normalization of GH levels, whilst one dropped out. After 2 years of treatment 13/28 (46%) patients converted to MS. The presence of GHD and GH and IGF-1 levels were not predictive of relapses, new T2 lesions or conversion occurrence. Growth hormone/IGF-1 axis function was found to be frequently altered in CIS patients, but this was not related to MS conversion. Patients experienced an improvement of GHD during IFN therapy. Longer follow-up is necessary to assess its impact on disease progression.

Growth hormone deficiency and hypopituitarism in adults after complicated mild traumatic brain injury.

Traumatic brain injury is considered the main cause of hypopituitarism in adults, and GH deficiency appears to be the most frequent pituitary deficit. Most of the available studies have included all degrees of severity of trauma. We aimed to assess pituitary function and GH deficiency in adult patients at different time lengths after complicated mild TBI according to Glasgow Coma Scale. We also aimed to evaluate whether mild TBI patients with GH deficiency had developed alterations in the glycolipid profile. Forty-eight patients (34 men and 14 women) with complicated mild TBI were included in the study. Twenty-three patients were evaluated at 1 year (Group A) and 25 patients at 5 years or longer after the injury (Group B). All patients underwent basal hormonal evaluation for pituitary function. GH deficiency was investigated by the combined test (GH releasing hormone + arginine). The glycolipid profile was also evaluated. GH deficiency occurred in 8/23 patients (34.7 %) of Group A and in 12/25 patients (48 %) of Group B. In addition, two patients, one in each group, showed evidence of central hypothyroidism. Patients with GH deficiency, especially in Group A, presented a higher frequency of visceral adiposity and adverse metabolic profile as compared to no-GH deficiency patients. Patients examined at 1 year or several years from complicated mild TBI had a similarly high occurrence of isolated GH deficiency, which was associated with visceral adiposity and metabolic alterations. Our findings suggest that patients undergone complicated mild TBI should be evaluated for GH deficiency even after several years from trauma.

Impact of GH replacement therapy on sleep in adult patients with GH deficiency of pituitary origin

We previously reported that adult patients with GH deficiency (GHD) due to a confirmed or likely pituitary defect, compared with healthy controls individually matched for age, gender, and BMI, have more slow-wave sleep (SWS) and higher delta activity (a marker of SWS intensity). Here, we examined the impact of recombinant human GH (rhGH) therapy, compared with placebo, on objective sleep quality in a subset of patients from the same cohort. Single-blind, randomized, crossover design study. Fourteen patients with untreated GHD of confirmed or likely pituitary origin, aged 22-74 years, participated in the study. Patients with associated hormonal deficiencies were on appropriate replacement therapy. Polygraphic sleep recordings, with bedtimes individually tailored to habitual sleep times, were performed after 4 months on rhGH or placebo. Valid data were obtained in 13 patients. At the end of the rhGH treatment period, patients had a shorter sleep period time than at the end of the placebo period (479±11 vs 431±19 min respectively; P=0.005), primarily due to an earlier wake-up time, and a decrease in the intensity of SWS (delta activity) (559±125 vs 794±219 μV(2) respectively; P=0.048). Four months of rhGH replacement therapy partly reversed sleep disturbances previously observed in untreated patients. The decrease in delta activity associated with rhGH treatment adds further evidence to the hypothesis that the excess of high-intensity SWS observed in untreated pituitary GHD patients is likely to result from overactivity of the hypothalamic GHRH system due to the lack of negative feedback inhibition by GH.

Improving the Concept of Recovery in Endocrine Disease by Consideration of Psychosocial Issues

Stringent criteria have been established to define remission by hormone parameters in several endocrine disorders. An example is provided by the criteria for cure of acromegaly (1). However, it is clear that such criteria are far from being comprehensive of a patient status, and often there is a need for filling a gap between the “hard data” of laboratory results and imaging findings on one hand, and the “soft information” related to the patient presentation and complaints on the other hand. Indeed, long-standing endocrine disorders may imply a degree of irreversibility of the pathological process and induce highly individualized affective responses based on each patient’s psychological assets and liabilities. In recent years, there has been increasing awareness of the unsatisfactory degree of remission that current therapeutic strategies entail in a variety of endocrine disorders. Studies concerned with psychological well-being, functional capacity, and social and interpersonal components of illness have provided new insights in clinical endocrinology (2–4). Psychiatric disturbances and impaired quality of life, which were present in the acute phase of illness, are often found to improve upon normalization of hormonal parameters (2, 3). However, disappearance of psychiatric symptoms and amelioration of quality of life are not always the case. This has been observed in several studies concerned with patients with either pituitary disease (acromegaly, Cushing’s disease, hyperprolactinemia, nonfunctioning pituitary adenomas, hypopituitarism, and GH deficiency) or nonpituitary endocrine disorders (thyroid disturbances, primary hyperparathyroidism, primary aldosteronism, adrenocortical insufficiency, and polycystic ovary syndrome) (2). There may be different reasons for a delayed or impaired process of recovery. Hormonal alterations are frequently associated with affective disturbances, which do not always remit upon normalization of blood parameters. Hormone replacement may not fully restore optimal endocrine balance, and subtle dysfunctions may still exert their influence on psychological states. This has been observed particularly in hypopituitarism ensuing from the treatment of pituitary disease (2–4). When surgery is performed (e.g. pituitary microadenomectomy in Cushing’s disease), the patient is likely to have expectations of a quick recovery toward his/her former normal condition. Unrealistic hopes of “cure” may foster discouragement and apathy. Harvey Cushing himself had acknowledged the difficult recovery of patients suffering from pituitary disease: “It is even more common for a physician or surgeon to eradicate or otherwise treat the obvious focus of disease, with more or less success, and to leave the mushroom of psychic deviations to vex and confuse the patient for long afterwards, if not actually to imbalance him” (5). Currently, however, the average endocrinologist is still unfamiliar with the psychosocial aspects of patient care, both in terms of personal skills and organizational structure, and lacks an adequate background for facilitating the process of recovery. The customary taxonomy does not include patterns of symptoms, severity of illness, effects of comorbid conditions, timing of phenomena, rate of progression of illness, functional capacity, and other clinical features that demarcate major prognostic and therapeutic differences among patients who otherwise seem deceptively similar because they have the same diagnosis and

A mathematical model in the analysis of the response to growth hormone treatment in pediatric patients with diagnosis of growth hormone deficiency

In the literature, few studies analyze the effect of GH therapy on height, preferring a more indirect approach, where factors influencing the total pubertal and pre-pubertal growth in GH-deficient patients are evaluated and subsequently used to estimate the overall effect at the end of the therapy; unfortunately, this approach does not quantify the real growth gain in treated patients. Using a non-parametric Empirical Bayes approach, our study analyzes the growth response to GH treatment in a homogeneous cohort of 317 patients with pituitary GH deficiency who were enrolled during their pre-pubertal stage in the GH Piedmont Registry (Italy), between January 2000-October 2008, and have at least 2 yr of follow-up. To estimate the growth curve for males and females, a non-parametric regression model was fitted, applying Empirical Bayes techniques. A validation of the model was also performed. Improvement was evident in both genders, since both males and females mean growth curve, which started below the 3rd percentile at the beginning of the therapy, reached the 10th percentile of the Tanner curve at the end of observation (17 yr old for males and 14 yr old for females); the estimation procedure achieved a good precision. The methodological approach allows for fitting a model able to evaluate longitudinally the response to GH treatment, by means of estimating the overall growth curve, even in presence of sparse information about children heights.

Sleep Disturbances, Daytime Sleepiness, and Quality of Life in Adults with Growth Hormone Deficiency

Low energy and fatigue are frequent complaints in subjects with GH deficiency (GHD). Because interrelations between sleep and GH regulation are well documented, these complaints could partly reflect alterations of sleep quality. The objective of the study was to determine objective and subjective sleep quality and daytime sleepiness in adult GHD patients. Thirty patients, aged 19-74 yr, with untreated GHD (primary pituitary defects confirmed or likely in 26 patients, hypothalamic origin in four patients), and 30 healthy controls individually matched for gender, age, and body mass index participated in the study. Patients with associated pituitary deficiencies (n = 28) were on hormonal replacement therapy. Polygraphic sleep recordings, assessment of Pittsburgh Sleep Quality Index, and Quality of Life Assessment for GHD in Adults were measured. Irrespective of etiology, GHD patients had a Pittsburgh Sleep Quality Index score above the clinical cutoff for poor sleep and lower Quality of Life Assessment for GHD in Adults scores than controls, with tiredness being the most affected domain. Patients with pituitary GHD spent more time in slow-wave sleep (SWS) and had a higher intensity of SWS than their controls. Among these patients, older individuals obtained less total sleep than controls, and their late sleep was more fragmented. Contrasting with pituitary GHD, the four patients with hypothalamic GHD had lower intensity of SWS than their controls. GHD is associated with sleep disorders that may be caused by specific hormonal alterations as well as with poor subjective sleep quality and daytime sleepiness. Disturbed sleep is likely to be partly responsible for increased tiredness, a major component of quality of life in GHD.

Arginine test is not reliable for diagnosing cerebellar multiple system atrophy

We evaluated the arginine growth hormone (GH) stimulation test for the diagnosis of cerebellar-type multiple system atrophy (MSAc) in patients with ataxia. Fourteen subjects with MSAc, 11 with idiopathic late-onset cerebellar ataxia (ILOCA), 10 with familial ataxia, and 10 healthy controls were tested. After pituitary GH deficiency was excluded, subjects underwent arginine testing. Peak serum GH response was analyzed. No significant differences in peak GH response were found between subject populations. Thirty-three percent of MSAc subjects mounted responses >10 microg/l GH. Thirty-six percent of ILOCA subjects and 40 percent of healthy controls mounted responses <4 microg/l GH. Arginine thus appears to be unreliable for the diagnosis of MSAc.

The effects of recombinant human growth hormone (rhGH) supplementation on adipokines and C-reactive protein in obese subjects

Objective Obese subjects have functional growth hormone deficiency (GHD). Recombinant human GH (rhGH) treatment of pituitary GHD improves serum levels of leptin, adiponectin and C-reactive protein (CRP). This study was undertaken to determine whether these rhGH-induced changes occur in obese subjects during rhGH supplementation. Design Randomized double-blind placebo-controlled trial of low-dose rhGH (200 μg/day for the first month, then 400 μg/day for men and 600 μg/day for women thereafter) or placebo supplementation as an adjuvant to a standard weight loss program. Subjects Forty healthy obese subjects, 28 premenopausal menstruating women (35 ± 7 SD years) and 12 men (37 ± 6 years). Measurements Body weight, BMI, body composition (assessed by dual energy X-ray absorptiometry [DEXA]), and serum levels of glucose, insulin, IGF-I, IGFBP-3, insulin resistance index (homeostasis modal assessment [HOMA]), leptin, CRP and adiponectin were performed at baseline and at 6 months. Results For similar entry BMI values, women when compared with men had higher percent body fat (BF) (43.5 ± 4.6% vs. 29.8 ± 4.0%, p < 0.001), higher leptin levels (16.9 ± 8.4 μg/L vs. 4.2 ± 3.0 μg/L, p < 0.001), and higher CRP levels (13.8 ± 16.8 mg/L vs. 2.4 ± 3.2 mg/L, p = 0.04). Serum levels of leptin and CRP, but not adiponectin, correlated significantly with BF in both sexes. Recombinant human GH treatment increased levels of IGF-I Z-Score between baseline and 6 months (from −0.7 ± 0.9 SD to 0.1 ± 1.1 SD, p = 0.01) and modestly decreased BF (from 38.4 ± 7.8% to 35.6 ± 7.5%, p = 0.046). Despite increased IGF-I, there were no differences between rhGH and placebo with regard to changes in leptin, CRP, or adiponectin. Conclusion It is concluded that in obesity, although rhGH treatment significantly increases IGF-I and modestly reduces body fat, the lack of significant changes in serum leptin, adiponectin or CRP levels suggests that rhGH treatment does not have a significant effect on these serum markers of adiposity.

Pregnancy‐induced changes in insulin‐like growth factor I (IGF‐I), insulin‐like growth factor binding protein 3 (IGFBP‐3), and acid‐labile subunit (ALS) in patients with growth hormone (GH) deficiency and excess

Under most circumstances with altered growth hormone (GH) secretion, the changes of insulin-like growth factor I (IGF-I), insulin-like growth factor binding protein 3 (IGFBP-3), and acid-labile subunit (ALS) are in parallel. The aim of the present study was to compare the effects of pregnancy in a hypopituitary patient with those of pregnancy in an acromegalic patient on IGF-I, IGFBP-3, and ALS. IGF-I and ALS were low before pregnancy in the hypopituitary patient under glucocorticoid and thyroxine treatment. Gonadotropin treatment allowed her to become pregnant; IGF-I and ALS levels rose in the second half of pregnancy and fell again after delivery. IGF-I concentrations were elevated in the patient with persistent acromegaly before and dropped into the normal range during the first half of pregnancy. In the second half of pregnancy and following delivery, IGF-I levels increased again. IGFBP-3 levels (as assessed by immunoblot analysis as well as by 125I-IGF II ligand blotting) decreased markedly during pregnancy in both patients, suggesting that the placenta rather than pituitary GH regulates IGFBP-3 proteolysis in human pregnancy. The increase of IGF-I (and ALS) during the second half of pregnancy in the individual with pituitary GH deficiency may be attributed to placental GH. The fall of IGF-I (and ALS) into the normal range in the acromegalic patient during the first trimester of pregnancy may be related to decreased production or decreased half-life of these proteins. Our data suggest that measures to continuously replace GH or to suppress GH secretion during pregnancy in patients with GH deficiency or excess, respectively, may not be warranted.

Growth hormone expression in the perinatal and postnatal rat lung

It is now established that the lung is a target site for pituitary growth hormone (GH) action, because pathophysiological states of pituitary GH excess and deficiency are associated with impaired pulmonary function. The onset of lung development and differentiation is, however, before the ontogenic differentiation of pituitary somatotrophs. GH may be involved, nevertheless, in lung development, because it is present in extrapituitary tissues of preimplantation mouse embryos and in the lung buds of embryonic chickens. The possibility that GH may be expressed in the rat lung during fetal and neonatal development, therefore, has been assessed. GH mRNA was detected in the lung, and its 693-bp sequence was identical to that in the pituitary gland. By in situ hybridization, this transcript was found to be abundantly expressed in the lungs of embryonic day (ED) 17 rats in mesenchymal, mucosal epithelial, and smooth muscle cells. This transcript was expressed in neonates until at least day 14 postnatally and was localized to type I and II epithelial cells and to pulmonary tissue macrophages and alveolar macrophages. GH immunoreactivity paralleled GH mRNA cellular localization throughout the time course studied. This immunoreactivity was specific and was lost after antibody preabsorption. The perinatal and postnatal lung is, therefore, an extrapituitary site of GH gene expression during development. Given that the GH receptor is present in the lung from early development, lung GH may have autocrine and/or paracrine roles in lung growth or differentiation or in pulmonary function.

Human growth hormone receptor (hGHR) gene: A new single nucleotide polymorphism (SNP) of exon 6 entailing possible amino acid exchange in the extracellular hormon-binding region of the human growth hormone receptor (hGHR) in adult patients with pituitary growth hormone deficiency

Human growth hormone receptor (hGHR) gene: A new single nucleotide polymorphism (SNP) of exon 6 entailing possible amino acid exchange in the extracellular hormon-binding region of the human growth hormone receptor (hGHR) in adult patients with pituitary growth hormone deficiency

Differential Regulation of Insulin-Like Growth Factor-(IGF) I and IGF-Binding Protein (IGFBP) Secretion by Human Peripheral Blood Mononuclear Cells

Background: Recent studies have shown that immunocompetent cells synthesize and express growth hormone (GH), growth hormone receptors (GH-R), insulin-like growth factor I (IGF-I), IGF-I receptors (IGF-I-R) and different insulin-like growth factor binding proteins (IGFBPs). The aim of the current study was to evaluate the regulation of IGFBP and IGF-I secretion from immunocompetent cells by different mitogens. Methods/Results: We studied the in vitro secretion pattern of IGFBPs and IGF-I from human peripheral blood mononuclear cells (PBMC), derived from 10 normal adults and 8 GH-deficient patients with adult onset. In serum-free conditioned medium of unstimulated PBMC, derived from normal adults, Western ligand blotting (1D-WLB) revealed a 24-kD, a 34-kD and a 39/43-kD doublet band to be most prominent. According to their molecular weight and two-dimensional Western ligand blot analysis (2D-WLB), these bands are deglycosylated IGFBP-4, IGFBP-2 and IGFBP-3, respectively. When the cells were treated with the T-cell mitogen phytohemagglutinin (PHA) (10 µg/ml), a differential stimulation of IGFBPs was found with a 2.57 ± 0.48-fold increase of IGFBP-4 (p < 0.01), a 1.55 ± 0.13-fold increase of IGFBP-2 (p < 0.01), and a 1.35 ± 0.19-fold increase of IGFBP-3 (n.s.). In contrast, treatment with the B-cell mitogen pokeweed mitogen (PWM) (10 µg/ml) caused only a modest 1.40 ± 0.07-fold increase of IGFBP-4 (p < 0.01). Treatment with rhGH (100 ng/ml) or rhIGF-I (200 ng/ml) caused no significant induction of any specific band, respectively. In contrast to the secretion pattern of IGFBPs, IGF-I secretion of the PBMC was not stimulated by either PHA or PWM, but showed a significant increase after GH incubation (p < 0.01). A similar differentiated secretion pattern of IGFBPs and IGF-I was also observed in the conditioned medium of PBMC, derived from GH-deficient patients. Conclusion: In summary, at least three different IGFBPs are secreted by human PBMC. Secretion of IGFBPs by PBMC is differentially regulated by different lymphocyte mitogens. Secretion of IGFBPs by PBMC is independent of GH or IGF-I, whereas the secretion of IGF-I is stimulated by GH. PBMC derived from normal adults and GH-deficient patients show similar patterns of IGF-I and IGFBPs secretion, thus indicating that the paracrine/autocrine IGF-I–IGFBPs interactions of the PBMC are not altered by pituitary GH deficiency.

Evaluation of free insulin-like growth factor-I measurement on the diagnosis and follow-up treatment of growth hormone-deficient adult patients.

Insulin-like growth factor (IGF-I) and IGF binding protein-3 (IGFBP-3) are GH-dependent and their concentrations have been used in the diagnosis of GH deficiency. Recently, the free fraction of IGF-I has received more attention. The aim of the study was to assess the role of free IGF-I in the diagnosis of GH deficiency in adults, and in follow-up during treatment with recombinant human GH (rhGH). We studied 24 adult patients with pituitary disease and GH deficiency and 25 matched controls. Nine patients were re-evaluated after 6 months of treatment with rhGH (0.25 U/kg/week). Serum levels of IGF-I, free IGF-I, IGFBP-3 and IGFBP-1 were measured by immunoradiometric assay. Serum free IGF-I levels were significantly lower in the GH deficient group than in the normal group (mean: 0.84 and 1.32 micrograms/l respectively, P = 0.0009). Furthermore, serum IGF-I levels were also lower (mean: 92.24 and 230.47 micrograms/l respectively, P < 0.0001). 63% of patients had serum IGF-I concentration below the normal range. For free IGF-I, 52% of the GH deficient patients showed levels below the lowest value obtained for the normal group. Seventy-five percent of the patients showed at least one of the two determinations below the normal range. The free-total IGF-I ratio was significantly higher (P = 0.025) in GH deficient group (range: 0.19-21.29, mean: 2.53) than in normal controls (range: 0.2-2.15, mean: 0.6). Regarding IGFBP-3 and IGFBP-1 no differences were observed between the two groups. During rhGH treatment the increase in serum total and free IGF-I and IGFBP-3 paralleled the beneficial effects on body composition. Free IGF-I may be another useful method for the diagnosis of GH deficiency, particularly if related to total IGF-I concentration.

Survival Following α Particle Pituitary Irradiation for Diabetic Retinopathy

The purpose of this study was to evaluate the mortality experience of persons with longstanding diabetes who had received pituitary irradiation for diabetic retinopathy compared to a matched group of persons with diabetes who had not had pituitary ablation. The irradiated cohort consisted of 167 patients treated at the Donner Pavilion (Lawrence Berkeley Laboratory, University of California, Berkeley), and the comparison cohort was the population evaluated in the Wisconsin Epidemiologic Study of Diabetic Retinopathy (WESDR). Survival analyses were performed comparing the two cohorts using three different sets of matching criteria, each more restrictive than the previous analyses. The three different strategies were (1) matched only on severity of diabetic retinopathy; (2) matched on severity of retinopathy and age; and (3) matched on severity of retinopathy, age, gender, and hypertension status. Tests of comparison were the log-rank test, the Wilcoxon test, and the likelihood ratio test. For the model matching only on severity of retinopathy, mean survival was 8.3 years for the WESDR group and 9.4 years for the ablated group ( p > 0.05 for all three statistical tests). For the model matched on retinopathy and age, mean survival was 8.9 years for the WESDR group and 9.2 years for the ablated group ( p = 0.05 log–rank test, 0.32 Wilcoxon test, and 0.06 likelihood ratio test). For the model matching on retinopathy, age, gender, and hypertension status, mean survival was 8.9 years for the WESDR group and 11.6 years for the ablated group ( p = 0.72 log–rank test, 0.08 Wilcoxon test, and 0.82 likelihood ratio test). These data are compatible with the notion that pituitary ablation, and therefore induced pituitary growth hormone deficiency, may not decrease survival in those with severe diabetic retinopathy.

The growth hormone response to hexarelin in patients with Prader-Willi syndrome.

Hexarelin (Hex) is a synthetic hexapeptide with potent GH-releasing activity in both animals and men. Aim of this study was to evaluate the GH response to a maximal dose of Hex and GH-releasing hormone (GHRH) in a group of patients with Prader-Willi syndrome (PWS). Seven patients (4 boys and 3 girls, age 2.4-14.2 yr) with PWS, 10 prepubertal obese children (7 boys and 3 girls, age 7.5-12.0 yr), and 24 prepubertal short normal children (11 boys and 13 girls, age 5.9-13 yr) with body weight within +/- 10% of their ideal weight were studied. All subjects were tested on two occasions with GHRH 1-29 at the dose of 1 microgram/Kg i.v., and with Hex at the dose of 2 micrograms/Kg i.v. In the PWS patients the GH response to GHRH (peak = 6.4 +/- 2.0 micrograms/l, p < 0.0001; AUC = 248 +/- 70 micrograms min/l, p < 0.0001) was significantly lower than that observed in the short normal children and similar to that observed in the obese children. In the PWS children the GH response to Hex (peak = 7.5 +/- 1.6 micrograms/l; AUC = 309 +/- 53) was similar to that observed after GHRH and significantly lower than that observed in the obese children (p < 0.05). The results of this study show that PWS patients have a blunted GH response to the administration of a maximal dose of Hex. Whether these findings reflect a more severe pituitary GH deficiency in PWS than in obese children or a deranged hypothalamic regulation of GH secretion need further investigation.