Meta-analysis of mortality in adults with growth hormone deficiency: Does growth hormone replacement therapy really improve mortality rates?

Growth hormone (GH) deficiency (GHD) is one of the most prevalent deficiencies in patients with hypopituitarism and several cohort studies have demonstrated an increased mortality risk in hypopituitary patients with a presumed GHD. The cause of the excess mortality is most likely multifactorial, including the etiology of the hypopituitarism, non-physiological replacement therapies (mostly glucocorticoid), tumor treatment and its side effects as well as untreated GHD. Several years later, other cohort studies that investigated life expectancy in patients with hypopituitarism on GH replacement therapy (GHRT) that showed a normalized mortality. By comparison of the distribution of characteristics of interest between cohorts, we discuss the existing literature to answer the following question: does growth hormone replacement really improve mortality rates in adult patients with hypopituitarism and GHD? We also conducted a meta-analysis of these studies. Since the literature suffers from selection and time bias (improvement of tumor management and other pituitary hormone replacement therapies), there is no high-quality evidence that replacement therapy for GHD really improves mortality. However, the available data does suggest that GHRT plays a significant part in the normalization of the mortality in patients with hypopituitarism.

Decreased Activity of the Ghrhr and Gh Promoters Causes Dominantly Inherited GH Deficiency in Humanized GH1 Mouse Models.

Isolated growth hormone deficiency type II (IGHD2) is mainly caused by heterozygous splice-site mutations in intron 3 of the GH1 gene. A dominant-negative effect of the mutant GH lacking exon 3 on wild-type GH secretion has been proposed; however, the molecular mechanisms involved are elusive. To uncover the molecular systems underlying GH deficiency in IGHD2, we established IGHD2 model mice, which carry both wild-type and mutant copies of the human GH1 gene, replacing each of the endogenous mouse Gh loci. Our IGHD2 model mice exhibited growth retardation along with intact cellular architecture and mildly activated endoplasmic reticulum stress in the pituitary gland, caused by decreased GH-releasing hormone receptor (Ghrhr) and Gh gene promoter activities. Decreased Ghrhr and Gh promoter activities were likely caused by reduced levels of nuclear CREB3L2, which was demonstrated to stimulate Ghrhr and Gh promoter activity. To our knowledge, this is the first in vivo study to reveal a novel molecular mechanism of GH deficiency in IGHD2, representing a new paradigm that differs from widely accepted models.

Prevalence of growth hormone (GH) deficiency in previously GH-treated young adults with Prader-Willi syndrome.

OBJECTIVE: Some features of subjects with Prader-Willi syndrome (PWS) resemble those seen in growth hormone deficiency (GHD). Children with PWS are treated with growth hormone (GH), which has substantially changed their phenotype. Currently, young adults with PWS must discontinue GH after attainment of adult height when they do not fulfil the criteria of adult GHD. Limited information is available about the prevalence of GHD in adults with PWS. This study aimed to investigate the GH/insulin-like growth factor (IGF-I) axis and the prevalence of GHD in previously GH-treated young adults with PWS. DESIGN: Cross-sectional study in 60 young adults with PWS. MEASUREMENTS: Serum IGF-I and IGFBP-3 levels, GH peak during combined growth hormone-releasing hormone (GHRH)-arginine stimulation test. RESULTS: Serum IGF-I was <-2 standard deviation scores (SDS) in 2 (3%) patients, and IGFBP-3 was within the normal range in all but one patient. Median (IQR) GH peak was 17.8 µg/L (12.2; 29.7) [~53.4 mU/L] and below 9 µg/L in 9 (15%) patients. Not one patient fulfilled the criteria for adult GHD (GH peak < 9 µg/L and IGF-I < -2 SDS), also when BMI-dependent criteria were used. A higher BMI and a higher fat mass percentage were significantly associated with a lower GH peak. There was no significant difference in GH peak between patients with a deletion or a maternal uniparental disomy (mUPD). CONCLUSIONS: In a large group of previously GH-treated young adults with PWS, approximately 1 in 7 exhibited a GH peak <9 µg/L during a GHRH-arginine test. However, none of the patients fulfilled the consensus criteria for adult GHD.

Incidence and Outcomes of Pituitary Microadenomas in Children with Short Stature/Growth Hormone Deficiency.

BACKGROUND/AIMS: Patients with short stature (SS)/growth hormone deficiency (GHD) and precocious puberty (PP) undergo brain MRI to evaluate for structural brain abnormalities or pituitary lesions, and pituitary microadenomas are a common finding. Theoretically, a mass effect from these lesions could cause GHD and growth hormone treatment could cause them to enlarge, but they should not cause PP, at least in females. METHODS: We investigated if pituitary microadenomas cause GHD by comparing their incidence in patients with SS/GHD to that in females with PP. We performed a retrospective chart review of patients with these disorders who had a brain MRI between 2000 and 2013. RESULTS: The incidence of microadenoma was high in both groups, 18.5% for SS (n = 346) and 21.1% for PP females (n = 194), but did not differ between groups (p = 0.46). In patients with microadenomas, repeat imaging showed resolution in 58% (SS, n = 33) and 67% (PP females, n = 21). Importantly, none of the lesions grew, even in patients treated with growth hormone. CONCLUSIONS: Pituitary microadenomas are common in children with GHD/SS and PP, but it does not appear that they are a cause of GHD. They appear to be of limited clinical significance and should not be considered a contraindication to growth hormone therapy.

Hypothalamic abnormalities: Growth failure due to defects of the GHRH receptor.

Several acquired or congenital hypothalamic abnormalities may cause growth failure (GF). We described two of these congenital abnormalities. First, a case of CHARGE syndrome, an epigenetic disorder mostly caused by heterozygous mutations in the gene encoding CHD7, a chromatin remodeling protein, causing several malformations, some life-threatening, with additional secondary hypothalamus-hypophyseal dysfunction, including GF. Second, a cohort of individuals with genetic isolated severe GH deficiency (IGHD), due to a homozygous mutation in the GH-releasing hormone (GHRH) receptor gene described in Itabaianinha County, in northeast Brazil. In this IGHD, with marked reduction of serum concentrations of IGF-I, and an up regulation of IGF-II, GF is the principal finding in otherwise normal subjects, with normal quality of life and longevity. This IGHD may unveil the effects of GHRH, pituitary GH and IGF-I, IGF-II and local GH and growth factor on the size and function of body and several systems. For instance, anterior pituitary hypoplasia, and impairment of the non-REM sleep may be due to GHRH resistance. Proportionate short stature, doll facies, high-pitched pre-pubertal voice, and reduced muscle mass reflect the lack of the synergistic effect of pituitary GH and IGF-I in bones and muscles. Central adiposity may be due to a direct effect of the lack of GH. Brain, eyes and immune system may also involve IGF-II and local GH or growth factors. A concept of physiological hierarchy controlling body size and function by each component of the GH system may be drawn from this model.

Growth Hormone Treatment in Children With Prader-Willi Syndrome: Three Years of Longitudinal Data in Prepubertal Children and Adult Height Data From the KIGS Database.

Context: Longitudinal data of children with Prader-Willi syndrome (PWS) treated with genotropin were registered in the Pfizer International Growth Database (KIGS). Objective: To evaluate efficacy and safety of growth hormone (GH) treatment in a large group of children with PWS. Design: Data registered in KIGS from 1987 to 2012. Setting: Worldwide retrospective cohort study. Patients: Patients included 522 prepubertal children treated with GH for three years and 173 children who had reached adult height. Safety analysis included 2332 children. Intervention involved GH treatment. Main outcome measure: Height standard deviation score (SDS), body mass index (BMI) SDS, occurrence of serious adverse events, and deaths reported in KIGS. Results: In prepubertal children, mean (standard deviation) height SDS improved to -0.31 (1.34) (P < 0.05) during three years of GH treatment. In the adolescent group, height SDS improved until the start of puberty to -0.22 (1.31) (P < 0.05) but had a loss of -0.77 (0.81) during puberty, resulting in a mean adult height SDS of -1.19 (1.37). Total height gain was 0.95 (1.32) SDS. BMI SDS increased in the prepubertal group from 1.11 (2.09) to 1.53 (1.43) (P < 0.05) and did not significantly change in the adolescent group, who had a BMI SDS at an adult height of 1.78 (1.26). KIGS contained 12 death reports. Conclusions: GH treatment in children with PWS significantly improves linear growth. BMI remains on average below +2 SDS, in contrast to the natural course of increasing obesity in PWS. Safety should be closely monitored in children with PWS, with and without GH treatment.

GH deficiency in adult survivors of childhood cancer.

Childhood cancer survivors (CCS) are a fast growing population, but late adverse effects of cancer therapies are not rare. In CCS treated with cranial radiotherapy, growth hormone deficiency (GHD) is a well-known occurrence and the potential impact of GH replacement therapy on the global outcome of CCS is under continuous evaluation. In the present review, we discuss advantages and disadvantages of GH replacement therapy in survivors of pediatric malignancies, taking into consideration the different reasons for treating GHD during childhood or adult life. It is doubtless that GH treatment is advisable to obtain a normal growth in pediatric patients. As far as the beginning/continuation of the replacement therapy in adult age is concerned, contrasting results have been reported in literature. The suggestion is that the decision to treat adult CCS should be taken after careful evaluation of each patient's clinical history and of the potential side effects, in agreement with the patients.

Effects of aerobic exercise on ectopic lipids in patients with growth hormone deficiency before and after growth hormone replacement therapy.

Growth hormone replacement therapy (GHRT) increases exercise capacity and insulin resistance while it decreases fat mass in growth hormone-deficient patients (GHD). Ectopic lipids (intramyocellular (IMCL) and intrahepatocellular lipids (IHCL) are related to insulin resistance. The effect of GHRT on ectopic lipids is unknown. It is hypothesized that exercise-induced utilization of ectopic lipids is significantly decreased in GHD patients and normalized by GHRT. GHD (4 females, 6 males) and age/gender/waist-matched control subjects (CS) were studied. VO2max was assessed on a treadmill and insulin sensitivity determined by a two-step hyperinsulinaemic-euglycaemic clamp. Visceral (VAT) and subcutaneous (SAT) fat were quantified by MR-imaging. IHCL and IMCL were measured before and after a 2 h exercise at 50-60% of VO2max using MR-spectroscopy (∆IMCL, ∆IHCL). Identical investigations were performed after 6 months of GHRT. VO2max was similar in GHD and CS and significantly increased after GHRT; GHRT significantly decreased SAT and VAT. 2 h-exercise resulted in a decrease in IMCL (significant in CS and GHRT) and a significant increase in IHCL in CS and GHD pre and post GHRT. GHRT didn't significantly impact on ∆IMCL and ∆IHCL. We conclude that aerobic exercise affects ectopic lipids in patients and controls. GHRT increases exercise capacity without influencing ectopic lipids.

Growth Hormone Deficiency in a Child with Neurofibromatosis-Noonan Syndrome.

Neurofibromatosis-Noonan syndrome (NFNS) is a distinct entity which shows the features of both NF1 (neurofibromatosis 1) and Noonan syndrome (NS). While growth hormone deficiency (GHD) has been relatively frequently identified in NF1 and NS patients, there is limited experience in NFNS cases. The literature includes only one case report of a NFNS patient having GHD and that report primarily focuses on the dermatological lesions that accompany the syndrome and not on growth hormone (GH) treatment. Here, we present a 13-year-old girl who had clinical features of NFNS with a mutation in the NF1 gene. The case is the first NFNS patient reported in the literature who was diagnosed to have GHD and who received GH treatment until reaching final height. The findings in this patient show that short stature is a feature of NFNS and can be caused by GHD. Patients with NFNS who show poor growth should be evaluated for GHD.

Pituitary dysfunction following cranial radiotherapy for adult-onset nonpituitary brain tumours.

OBJECTIVE: There are limited data concerning the evolution of radiation-induced hypopituitarism in adult-onset brain tumour (AO-BT) survivors, in part the consequence of the limited survival of many of these individuals. We aim to characterize the pituitary-related outcomes following cranial radiotherapy (cXRT) for adult-onset primary nonpituitary brain tumours. DESIGN: We retrospectively analysed longitudinal data of patients with AO-BT who received cXRT within a tertiary cancer referral centre. PATIENTS: A total of 107 adults (age 40·0 ± 13·1 years) followed for a median duration of 8 years following cXRT. MEASUREMENTS: Prevalence of radiotherapy-induced hypopituitarism. RESULTS: 94·4% received fractionated photon radiotherapy (median dose 54 Gy), while the remaining patients received proton beam or stereotactic radiotherapy. 88·8% of patients developed hypopituitarism during follow-up. The frequency of GH, gonadotrophin, ACTH and TSH deficiencies was 86·9% (severe GHD 64·5%, partial GHD 22·4%), 34·6%, 23·4% and 11·2%, respectively. ACTH deficiency was clinically significant, necessitating glucocorticoid replacement, in only 10·3% of cases. Hyperprolactinaemia developed in 15% of patients, which was persistent in only 50% of cases. Multiple pituitary hormone deficiencies were present in 47·7% of patients, encountered more frequently in patients with tumours in proximity to the sella. Longitudinal data analysis revealed accumulation of hormone deficits throughout the follow-up period, with incidence of all pituitary hormone deficiencies almost doubling between years 2 and 7 of follow-up. CONCLUSIONS: Pituitary dysfunction in AO-BT survivors following cXRT is a common, evolving, time-dependent phenomenon. It is important that deficits are identified early and replacement therapies introduced to optimize quality of life in these individuals, where prognosis is often guarded.

Growth hormone replacement therapy regulates microRNA-29a and targets involved in insulin resistance.

UNLABELLED: Replacement of growth hormone (GH) in patients suffering from GH deficiency (GHD) offers clinical benefits on body composition, exercise capacity, and skeletal integrity. However, GH replacement therapy (GHRT) is also associated with insulin resistance, but the mechanisms are incompletely understood. We demonstrate that in GH-deficient mice (growth hormone-releasing hormone receptor (Ghrhr)(lit/lit)), insulin resistance after GHRT involves the upregulation of the extracellular matrix (ECM) and the downregulation of microRNA miR-29a in skeletal muscle. Based on RNA deep sequencing of skeletal muscle from GH-treated Ghrhr(lit/lit) mice, we identified several upregulated genes as predicted miR-29a targets that are negative regulators of insulin signaling or profibrotic/proinflammatory components of the ECM. Using gain- and loss-of-function studies, five of these genes were confirmed as endogenous targets of miR-29a in human myotubes (PTEN, COL3A1, FSTL1, SERPINH1, SPARC). In addition, in human myotubes, IGF1, but not GH, downregulated miR-29a expression and upregulated COL3A1. These results were confirmed in a group of GH-deficient patients after 4 months of GHRT. Serum IGF1 increased, skeletal muscle miR-29a decreased, and miR-29a targets were upregulated in patients with a reduced insulin response (homeostatic model assessment of insulin resistance (HOMA-IR)) after GHRT. We conclude that miR-29a could contribute to the metabolic response of muscle tissue to GHRT by regulating ECM components and PTEN. miR-29a and its targets might be valuable biomarkers for muscle metabolism following GH replacement. KEY MESSAGES: GHRT most significantly affects the ECM cluster in skeletal muscle from mice. GHRT downregulates miR-29a and upregulates miR-29a targets in skeletal muscle from mice. PTEN, COL3A1, FSTL1, SERPINH1, and SPARC are endogenous miR-29a targets in human myotubes. IGF1 decreases miR-29a levels in human myotubes. miR-29a and its targets are regulated during GHRT in skeletal muscle from humans.

Growth hormone deficiency in monozygotic twins with autosomal dominant pseudohypoparathyroidism type Ib.

Pseudohypoparathyroidism (PHP) is associated with compromised signal transductions via PTH receptor (PTH-R) and other G-protein-coupled receptors including GHRH-R. To date, while GH deficiency (GHD) has been reported in multiple patients with PHP-Ia caused by mutations on the maternally expressed GNAS coding regions and in two patients with sporadic form of PHP-Ib accompanied by broad methylation defects of maternally derived GNAS differentially methylated regions (DMRs), it has not been identified in a patient with an autosomal dominant form of PHP-Ib (AD-PHP-Ib) accompanied by an STX16 microdeletion and an isolated loss of methylation (LOM) at exon A/B-DMR. We studied 5 4/12-year-old monozygotic twins with short stature (both -3.4 SD) and GHD (peak GH values, <6.0 µg/L after arginine and clonidine stimulations). Molecular studies revealed maternally derived STX16 microdeletions and isolated LOMs at exon A/B-DMR in the twins, confirming the diagnosis of AD-PHP-Ib. GNAS mutation was not identified, and neither mutation nor copy number variation was detected in GH1, POU1F1, PROP1, GHRHR, LHX3, LHX4, and HESX1 in the twins. The results, in conjunction with the previous finding that GNAS shows maternal expression in the pituitary, suggest that GHD of the twins is primarily ascribed to compromised GHRH-R signaling caused by AD-PTH-Ib. Thus, resistance to multiple hormones including GHRH should be considered in AD-PHP-Ib.

A rare case of type 1 diabetes mellitus with pituitary hypoplasia.

Growth failure and pubertal abnormalities are not uncommon in chronic uncontrolled metabolic diseases like diabetes mellitus. We present a young girl with uncontrolled type 1 diabetes mellitus, who presented with short stature and primary amenorrhea, and on evaluation was found to have anterior pituitary hypoplasia. In addition to uncontrolled diabetes mellitus, she presented with early onset growth failure and lack of spontaneous secondary sexual characteristics. She had central hypothyroidism and inappropriately normal gonadotropin levels. However her serum cortisol levels were normal. MRI of the sellar-suprasellar region revealed a small anterior pituitary gland with thinning of the pituitary stalk consistent with pituitary hypoplasia. While uncontrolled type 1 diabetes itself may cause growth retardation and pubertal abnormalities, this girl had coexisting pituitary maldevelopment - a rare co-existence of two major illnesses of unrelated etiologies. The partial pituitary hormonal deficiency, which spared the hypothalamo-pituitary-adrenal axis, may be due to a transcription factor defect.

Isolated growth hormone deficiency (GHD) in childhood and adolescence: recent advances.

The diagnosis of GH deficiency (GHD) in childhood is a multistep process involving clinical history, examination with detailed auxology, biochemical testing, and pituitary imaging, with an increasing contribution from genetics in patients with congenital GHD. Our increasing understanding of the factors involved in the development of somatotropes and the dynamic function of the somatotrope network may explain, at least in part, the development and progression of childhood GHD in different age groups. With respect to the genetic etiology of isolated GHD (IGHD), mutations in known genes such as those encoding GH (GH1), GHRH receptor (GHRHR), or transcription factors involved in pituitary development, are identified in a relatively small percentage of patients suggesting the involvement of other, yet unidentified, factors. Genome-wide association studies point toward an increasing number of genes involved in the control of growth, but their role in the etiology of IGHD remains unknown. Despite the many years of research in the area of GHD, there are still controversies on the etiology, diagnosis, and management of IGHD in children. Recent data suggest that childhood IGHD may have a wider impact on the health and neurodevelopment of children, but it is yet unknown to what extent treatment with recombinant human GH can reverse this effect. Finally, the safety of recombinant human GH is currently the subject of much debate and research, and it is clear that long-term controlled studies are needed to clarify the consequences of childhood IGHD and the long-term safety of its treatment.

Growth hormone deficiency: an unusual presentation of floating harbor syndrome.

Floating-Harbor Syndrome (FHS) is a very rare condition of unknown etiology characterized by short stature, delayed bone age, characteristic facial features, delayed language skills and usually normal motor development. This syndrome has only once been associated with growth hormone deficiency and precocious puberty in the same patient. We describe a 5 4/12 year-old girl with the typical features of FHS in whom growth hormone deficiency was diagnosed and two years later central precocious puberty was noted. The patient showed a good response to human recombinant growth hormone as well as gonadotropin releasing hormone analogue treatment.

Quality of life and exercise capacity in obesity and growth hormone deficiency.

OBJECTIVES: A great similarity exists between growth hormone (GH) deficiency and obesity in terms of disturbances of organ morphology and function. The aim of the study was to compare health-related quality of life (HR-QoL) as well as exercise capacity and its subjective assessment in adult patients with GH deficiency and in adult patients with obesity. METHODS: Ten (10) GH-deficient, thirty (30) obese, and thirty (30) healthy subjects participated in the study. HR-QoL comprised two parameters: QoL measured by using the Quality of Life Assessment of Growth Hormone Deficiency in Adults (QoL-AGHDA) questionnaire, and subjective evaluation of general health state by using the Visual Analogue Scale. The exercise capacity was determined in Six Minute Walking Test and it was subjectively assessed by Borg Scale for Rating Perceived Exertion and the modified Medical Research Council scale. RESULTS: Decreased HR-QoL (both parameters) was observed in both GH-deficient and obese patients, with that effect being much more pronounced in the former group. Both, GH-deficient and obese patients, revealed decreased exercise capacity, which was also subjectively assessed as decreased, especially by GH-deficient patients. Positive relationships between HR-QoL and exercise capacity or its subjective assessment, observed in healthy subjects, partially lost their significance in obese, whereas they completely disappeared in GH-deficient subjects. CONCLUSION: A decrease in HR-QoL is more pronounced in GH-deficient than in obese patients, whereas exercise capacity is unfavourably affected by both disorder to a similar extent, with the lack of clear relationship between these two parameters especially in GH-deficient patients.

Different degrees of somatotroph ablation compromise pituitary growth hormone cell network structure and other pituitary endocrine cell types.

We have generated transgenic mice with somatotroph-specific expression of a modified influenza virus ion channel, (H37A)M2, leading to ablation of GH cells with three levels of severity, dependent on transgene copy number. GH-M2(low) mice grow normally and have normal-size pituitaries but 40-50% reduction in pituitary GH content in adult animals. GH-M2(med) mice have male-specific transient growth retardation and a reduction in pituitary GH content by 75% at 42 d and 97% by 100 d. GH-M2(high) mice are severely dwarfed with undetectable pituitary GH. The GH secretory response of GH-M2(low) and GH-M2(med) mice to GH-releasing peptide-6 and GHRH was markedly attenuated. The content of other pituitary hormones was affected depending on transgene copy number: no effect in GH-M2(low) mice, prolactin and TSH reduced in GH-M2(med) mice, and all hormones reduced in GH-M2(high) mice. The effect on non-GH hormone content was associated with increased macrophage invasion of the pituitary. Somatotroph ablation affected GH cell network organization with limited disruption in GH-M2(low) mice but more severe disruption in GH-M2(med) mice. The remaining somatotrophs formed tight clusters after puberty, which contrasts with GHRH-M2 mice with a secondary reduction in somatotrophs that do not form clusters. A reduction in pituitary beta-catenin staining was correlated with GH-M2 transgene copy number, suggesting M2 expression has an effect on cell-cell communication in somatotrophs and other pituitary cell types. GH-M2 transgenic mice demonstrate that differing degrees of somatotroph ablation lead to correlated secondary effects on cell populations and cellular network organization.