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.

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.

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.

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.

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.

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.

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.

Survey of long-term follow-up programs in the United States for survivors of childhood brain tumors.

INTRODUCTION: Despite recognition that childhood brain tumor survivors often suffer multiple late effects following therapy, little is known regarding the long-term follow-up (LTFU) programs for these patients. METHODS: A 16-question survey was mailed to member institutions of the Children's Oncology Group in the United States. Institutions were asked about the size of their brain tumor program, activities of the LTFU programs and perceived barriers to follow-up. RESULTS: One hundred forty-five (74%) of 197 institutions returned surveys. Care for patients <21 years old at diagnosis who are >2 years following completion of therapy was provided at a designated neuro-oncology LTFU clinic (31.2%), a general LTFU program for childhood cancer survivors (30.4%), or a general pediatric oncology program (29.7%). Institutions with a neuro-oncology LTFU clinic were more likely to use neuro-psychological testing following radiation therapy (P = 0.001), have longer duration of continued surveillance imaging (P = 0.02), use growth hormone replacement for medulloblastoma survivors (P < 0.001) and continue the use of growth hormone into adulthood (P = 0.05) than those with a general pediatric oncology program. Perceived barriers to care of brain tumor survivors included limited access and lack of insurance (32.1%), lack of funding or dedicated time for providers (22.9%), patients' uncertainty about need to follow-up (20.6%), and patients' desire to not be followed in a pediatric cancer program (12.2%). CONCLUSIONS: Considerable variation exists across institutions in the United States in the delivery of follow-up care for survivors of childhood brain tumors. We encourage additional investigation to better define and implement optimal follow-up care for childhood brain tumor survivors.

[Late onset hypopituitarism due to hypoplasia of the adenohypophysis with invisible stalk and ectopic neurohypophysis in a 67-year-old patient]. / Inicio tardío de hipopituitarismo debido a hipoplasia adenohipofisaria y ausencia de tallo con neurohipófisis ectópica en un paciente de 67 años de edad.

Congenital hypopituitarism due to pituitary stalk and anterior pituitary hypoplasia accompanied by an ectopic posterior pituitary lobe is a rare disorder causing multiple hormone deficiencies. Clinical signs can be present at birth (hypoglycemia, prolonged jaundice and micropenis) and there can be severe growth restriction. Therefore, diagnosis is usually performed in childhood. We present the uncommon case of a 67-year-old man with hypopituitarism due to hypoplasia of the anterior pituitary and pituitary stalk together with an ectopic posterior pituitary who presented symptoms of hyponatremia due to adrenocorticotropic hormone deficiency.

Diagnosis of growth hormone (GH) deficiency: comparison of pituitary stalk interruption syndrome and transient GH deficiency.

BACKGROUND: Most patients with childhood non-organic growth hormone (GH) deficiency (GHD) produce a normal GH peak as young adults. Our objectives were to better define this transient GHD and evaluate the factors influencing the growth response of patients with pituitary stalk interruption syndrome (PSIS). METHODS: We studied 72 prepubertal patients with a GH peak < 6.7 ng/ml after 2 stimulation tests, treated with 0.2 mg GH/kg/w for at least 3 years. Group 1 (n = 53, 4.7 +/- 4.0 years) had PSIS and Group 2 (n = 19, 9.2 +/- 3.0 years) had transient GHD and normal pituitary. RESULTS: At diagnosis, 64% of Group 1 and one Group 2 were < 5 years old. The growth rate of 59% Group 1 and two Group 2 patients was < or = -2 SDS. The GH peak of 64% Group 1 patients and no Group 2 patients was < 3 ng/ml. The plasma insulin-like growth factor-1 of all Group 1 and all but one Group 2 patients was < or = -2 z scores.During the first year of GH treatment, the growth rate was > or = 2 SDS in 81% Group 1 and 37% Group 2 patients. In Group 1, it was negatively correlated with the GH peak before treatment (P < 0.03), and with the difference between the target and adult heights (P < 0.01).The height gain SDSs between diagnosis and adult height were 1.7 +/- 1.2 in Group 1 (n = 30) and 1.08 +/- 0.8 in Group 2 (n = 12, P = 0.05). CONCLUSION: The factors of the growth response to GH treatment should be analysed separately for each population: with and without PSIS or other markers.

[Growth hormone deficiency and pituitary stalk interruption in Fanconi anemia]. / Déficit en GH par interruption de la tige pituitaire dans l'anémie de Fanconi.

Fanconi anemia is a rare disorder inherited by recessive autosomic transmission belonging to the group of chromosomal instability syndromes. It is characterized by progressively developing medullary aplasia, various congenital malformations and especially a high risk of cancer, particularly acute myeloblastic leukemia and certain solid tumors. The association is quite common in patients with endocrine disease which constitutes an additional factor of morbidity and must be diagnosed and treated. We report a case of Fanconi anemia revealed by severe delay in statural growth and primary amenorrhea with a 21-year-old girl. The diagnosis was suggested by asymptomatic pancytopenia caused by a medullary hypoplasia and confirmed by a cytogenetic investigation using cross-linking agents that showed a large number of chromosomal breaks. Hormonal exploration revealed hypopituitarism with complete growth hormone (GH) deficiency and hypogonadotrophic hypogonadism caused by interruption of the pituitary stalk. The aim of this case report is to illustrate the importance of early exploration of retarded growth which, in some patients, can reveal potentially serious, and treatable, disease.

Impact of the primary aetiology upon the clinical outcome of adults with childhood-onset GH deficiency.

OBJECTIVE: The impact of the aetiology of childhood-onset GH deficiency (CO-GHD) on the clinical presentation during adulthood and the response to GH replacement has been poorly defined. Our study aims to characterize CO-GHD in adults due to different aetiologies and evaluate the effect of 2 years of GH replacement therapy. DESIGN AND METHODS: Data from 353 adults with CO-GHD from Pfizer International Metabolic Database KIMS were retrospectively grouped according to GHD aetiology: non-organic disorder (n=147), organic pituitary disease (n=159), and brain tumour (n=47). Extent of pituitary dysfunction, IGF-I concentration, lipid concentrations and quality-of-life (QoL) were assessed at baseline and after 2 years of GH replacement. RESULTS: GHD was diagnosed at a later age in the organic pituitary group than in the other groups, resulting in a shorter duration of GH treatment during childhood. However, the final height was greater in the organic pituitary group. Panhypopituitarism was most common in the non-organic disorder and in the organic pituitary groups, while isolated GHD was more prominent in the brain tumour group. Serum IGF-I levels were the lowest in the non-organic group. QoL was the poorest in the brain tumour group. Lipid profile and QoL improved significantly during GH replacement. CONCLUSION: The adverse consequences of CO-GHD in adulthood vary between aetiologies, but improve similarly with GH treatment. It is, therefore, important to consider retesting all patients with CO-GHD in early adulthood and, if persistent severe GHD is confirmed, recommence GH replacement.

Acquired prolactin deficiency in patients with disorders of the hypothalamic-pituitary axis.

UNLABELLED: Acquired PRL deficiency occurs when the anterior pituitary is functionally destroyed, and it usually accompanies other pituitary hormone deficiencies. We retrospectively investigated in an outpatient endocrine clinic of a major tertiary medical center the prevalence and clinical characteristics of acquired PRL deficiency in patients with diseases of the hypothalamic-pituitary axis. The study included 100 consecutive patients, 61 men and 39 women, aged 4-79 yr at diagnosis. Patients were divided by PRL level to normal (>5 ng/ml), mild (3-5 ng/ml), and severe deficiency (<3 ng/ml). Twenty-seven patients (27%) had PRL deficiency, 13 mild deficiency and 14 severe deficiency. Patients with severe PRL deficiency tend to be younger at diagnosis (mean age, 37.5+/-21.8 yr) than patients with normal PRL (46+/-18.5 yr; ns). Underlying diseases including pituitary apoplexy, non-functioning pituitary adenoma, craniopharyngioma, and idiopathic hypogonadotropic hypogonadism were associated with PRL deficiency. The incidence of severe PRL deficiency rose with an increase in the number of other pituitary hormone deficits (ACTH, TSH, gonadotropin, vasopressin), from 0 in patients with no other deficits to 38% in patients with 4 deficits (p=0.006). Patients with severe deficiency had a mean of 3 hormone deficits compared to 1.8 in the other groups (p=0.006). PRL deficiency was significantly associated with TSH, ACTH and GH deficiency. CONCLUSIONS: PRL deficiency is common in patients with hypothalamic-pituitary disorders, especially pituitary apoplexy and craniopharyngioma. Acquired severe PRL deficiency can be considered a marker for extensive pituitary damage and a more severe degree of hypopituitarism.

Small pituitary size in children with Fanconi anemia.

BACKGROUND: Fanconi anemia (FA) is a genetic disorder associated with multiple congenital anomalies, bone marrow failure, and pituitary hypofunction including hypogonadism, thyroid dysfunction, and growth hormone (GH) deficiency. PROCEDURE: Among 44 patients with FA referred to Cincinnati Children's Hospital Medical Center (CCHMC) between 1975 and 2005, 33 had neuroimaging studies, including 11 cranial magnetic resonance imaging (MRIs). Two separate measurements per patient from these MRIs were used to evaluate pituitary height compared to on-site control data of similar measurements of cranial MRIs on 22 age and gender-matched children without any pathology involving the hypothalamic-pituitary system. Growth pattern and endocrine studies were reviewed to assess potential correlation with pituitary size. RESULTS: When compared to the age-gender matched on-site control sample, the mean pituitary height of FA patients was significantly smaller (P < 0.0001; mean +/- SE from mixed effects model with age and gender as covariates: 3.96 +/- 0.32 vs. 5.76 +/- 0.24). Upon further adjusting for the effect of the small head size by including bi-parietal diameter (BPD) as a covariate, the difference remained statistically significant (P = 0.0013). Findings on the growth pattern and endocrinological measurements are as follows: 50% of patients with small pituitary gland were short. GH and adrenal function tests were normal in all tested patients. Thyroid, pubertal status, and glucose regulation were abnormal in 30, 50, and 75% of patients tested. CONCLUSIONS: Children with FA tend to have unsuspected small pituitary glands beyond what is expected from the effects of their stunted growth. Further studies are required to reveal the clinical implications of this finding.

Comparison of oral and subcutaneous iron chelation therapies in the prevention of major endocrinopathies in beta-thalassemia major patients.

While hypertransfusion and subcutaneous iron chelation therapy have increased longevity of patients with beta-thalassemia (thal) major, endocrinopathies have become more common and impair the quality of their lives. Additionally, subcutaneous iron chelation therapy is an uncomfortable experience and can prevent patients from regular compliance with iron chelation therapy. We compared the efficacy of oral deferiprone (L1) to subcutaneous desferrioxamine (DFO) chelation therapy for the prevention of major endocrinopathies (growth hormone insufficiency, diabetes mellitus and gonadal dysfunction) among patients with beta-thal major to see if we could offer these patients an easier and more painless way to reduce their body iron load and related endocrine complications.

Clinical characteristics, etiologies and pathophysiology of patients with severe short stature with severe GH deficiency: questionnaire study on the data registered with the foundation for growth science, Japan.

In this study, we sent questionnaires to doctors treating severe short stature with severe GH deficiency (GHD) (height SDS (HtSDS) below -4 and all peak GH to provocative stimuli below 2 micro/L) (abbreviated as Severe Case), and obtained effective replies of 51 cases. The clinical characteristics, etiologies, and pathophysiology of these patients were examined. Among the 51 Severe Cases no consanguinity was observed, 44 were IGHD (24 males and 20 females), 3 were GH-1 gene deletion, 2 were Pit-1 gene mutation, and 2 were achondroplasia. HtSDS in these Severe Cases was already remarkably low at 12 (-3.0) and 24 months old (-3.9), while their birth weight and birth length were within normal ranges. Among 44 patients with IGHD, 12 were isolated GHD, and the remaining 32 were combined pituitary hormone deficiency (CPHD). Pituitary MRI was undergone in 25 idiopathic GHD, and abnormal findings (pituitary atrophy, interruption of stalk, and ectopic posterior lobe) were observed in 21 patients with CPHD. More than half of these patients had the history of breech delivery. Three patients with GH-1 gene mutation showed normal pituitary MRI, whereas one of two patients with Pit-1 mutation showed pituitary atrophy and narrowing of pituitary stalk. In conclusion, Severe Cases tended to have CPHD, and the incidence of Severe Case was only 0.6% of total IGHD. Although GHD due to genetic disorders is considered to be extremely rare (0.06% of total IGHD), the incidence reaches high levels (9.8%) among Severe Cases. Growth disorders in these Severe Cases seem to occur soon after delivery. Much earlier diagnosis and hGH treatment are desirable to attain better final height in the Severe Cases. GH-1 and Pit-1 gene analyses are crucial, when genetic abnormalities other than achondroplasia are suspected.