Susan R. Rose

A review of guidelines for use of growth hormone in pediatric and transition patients.

Growth hormone (GH) is approved by the US Food and Drug Administration (FDA) for use in pediatric patients with disorders of growth failure or short stature and in adults with growth hormone deficiency (GHD) and HIV/AIDS wasting and cachexia. For pediatric patients, guidelines for the use of GH have been developed by several organizations that have identified specific criteria for initiating GH therapy for each FDA-approved indication. Guidelines for adults have also been developed and include recommendations for transition (adolescent) patients with GHD. These patients are often treated with GH as children but may require continued treatment as young adults to attain full skeletal mineralization and improve cardiovascular risk factors. Adult and pediatric guidelines are supported by efficacy and safety studies, which show that, when started at an early age, GH treatment can increase growth velocity and that GH is safe and well-tolerated. We summarize the guidelines that are available for all FDA-approved indications among pediatric and transition patients. Adherence to these guidelines will help to ensure that patients with disorders of growth failure or short stature receive the necessary therapy to increase linear growth and transition smoothly to healthy adulthood.

Inhaled Growth Hormone (GH) Compared with Subcutaneous GH in Children with GH Deficiency: Pharmacokinetics, Pharmacodynamics, and Safety

BACKGROUND Delivery of GH via inhalation is a potential alternative to injection. Previous studies of inhaled GH in adults have demonstrated safety and tolerability. OBJECTIVE We sought to assess safety and tolerability of inhaled GH in children and to estimate relative bioavailability and biopotency between inhaled GH and sc GH. DESIGN/METHODS This pediatric multicenter, randomized, double-blind, placebo-controlled, crossover trial had two 7-d treatment phases. Patients received inhaled GH and sc GH in the alternate phase. Placebo was administered by the route opposite from active drug. GH and IGF-I levels were measured at multiple time points. Pharmacokinetics were assessed using noncompartmental methods. RESULTS Twenty-two GH-deficient children aged 6-16 yr were treated. Absorption of GH appeared to be faster after inhalation with maximum serum concentrations measured at 1-4 h compared with 2-8 h for sc GH. Mean relative bioavailability for inhaled GH was 3.5% (90% confidence interval 2.7-4.4%). Mean relative biopotency, based on IGF-I response, was 5.5% (confidence interval 5.2-5.8%). Similar dose-dependent increases in mean serum GH area under the curve and IGF-I changes from baseline were seen after inhaled and sc GH doses. Inhaled GH was well tolerated and preferred to injection. No significant changes in pulmonary function tests were seen. CONCLUSIONS In this first pediatric trial of GH delivered by inhalation, it was well tolerated and resulted in dose-dependent increases in serum GH and IGF-I levels. This study establishes that delivery of GH via the deep lung is feasible in children.

Fanconi Anemia Links Reactive Oxygen Species to Insulin Resistance and Obesity

AIMS Insulin resistance is a hallmark of obesity and type 2 diabetes. Reactive oxygen species (ROS) have been proposed to play a causal role in insulin resistance. However, evidence linking ROS to insulin resistance in disease settings has been scant. Since both oxidative stress and diabetes have been observed in patients with the Fanconi anemia (FA), we sought to investigate the link between ROS and insulin resistance in this unique disease model. RESULTS Mice deficient for the Fanconi anemia complementation group A (Fanca) or Fanconi anemia complementation group C (Fancc) gene seem to be diabetes-prone, as manifested by significant hyperglycemia and hyperinsulinemia, and rapid weight gain when fed with a high-fat diet. These phenotypic features of insulin resistance are characterized by two critical events in insulin signaling: a reduction in tyrosine phosphorylation of the insulin receptor (IR) and an increase in inhibitory serine phosphorylation of the IR substrate-1 in the liver, muscle, and fat tissues from the insulin-challenged FA mice. High levels of ROS, spontaneously accumulated or generated by tumor necrosis factor alpha in these insulin-sensitive tissues of FA mice, were shown to underlie the FA insulin resistance. Treatment of FA mice with the natural anti-oxidant Quercetin restores IR signaling and ameliorates the diabetes- and obesity-prone phenotypes. Finally, pairwise screen identifies protein-tyrosine phosphatase (PTP)-α and stress kinase double-stranded RNA-dependent protein kinase (PKR) that mediate the ROS effect on FA insulin resistance. INNOVATION These findings establish a pathogenic and mechanistic link between ROS and insulin resistance in a unique human disease setting. CONCLUSION ROS accumulation contributes to the insulin resistance in FA deficiency by targeting both PTP-α and PKR.

Late endocrine effects of childhood cancer

The cure rate for paediatric malignancies is increasing, and most patients who have cancer during childhood survive and enter adulthood. Surveillance for late endocrine effects after childhood cancer is required to ensure early diagnosis and treatment and to optimize physical, cognitive and psychosocial health. The degree of risk of endocrine deficiency is related to the childs sex and their age at the time the tumour is diagnosed, as well as to tumour location and characteristics and the therapies used (surgery, chemotherapy or radiation therapy). Potential endocrine problems can include growth hormone deficiency, hypothyroidism (primary or central), adrenocorticotropin deficiency, hyperprolactinaemia, precocious puberty, hypogonadism (primary or central), altered fertility and/or sexual function, low BMD, the metabolic syndrome and hypothalamic obesity. Optimal endocrine care for survivors of childhood cancer should be delivered in a multidisciplinary setting, providing continuity from acute cancer treatment to long-term follow-up of late endocrine effects throughout the lifespan. Endocrine therapies are important to improve long-term quality of life for survivors of childhood cancer.

Overnight Levels of Luteinizing Hormone, Follicle-Stimulating Hormone and Growth Hormone before and during Gonadotropin-Releasing Hormone Analogue Treatment in Short Boys Born Small for Gestational Age

Aims: To evaluate if 3 months of gonadotropin-releasing hormone analogue (GnRHa) treatment results in sufficient suppression of pubertal luteinizing hormone (LH) and follicle-stimulating hormone (FSH) profile patterns in short pubertal small for gestational age (SGA) boys. To compare growth hormone (GH) profiles and fasting insulin-like growth factor (IGF)-I and IGF-binding protein-3 (IGFBP-3) levels after 3 months of GnRHa treatment with those at baseline. Methods: After measurement of baseline overnight profiles and IGF-I and IGFBP-3 levels, 14 short pubertal SGA boys received leuprorelide acetate depots of 3.75 mg subcutaneously, every 4 weeks. Results: At baseline, mean GH levels were comparable with those of controls, whereas IGF-I and IGFBP-3 standard deviation scores (SDS) were significantly lower than zero SDS. After 3 months of GnRHa treatment, all boys showed clinical arrest of puberty. The area under the curve above zero, mean and maximum LH and FSH had significantly decreased to prepubertal levels. Peak LH during the GnRH agonist test, however, indicated insufficient pubertal suppression in 43% of boys. Overnight GH profile characteristics and IGF-I and IGFBP-3 levels did not significantly change. Conclusions: Puberty was sufficiently suppressed by GnRHa treatment, as shown by the prepubertal LH and FSH profiles. After 3 months of GnRHa treatment, overnight GH profile characteristics had not significantly changed, reflecting that GH levels are comparable for prepubertal and early pubertal boys.

Poor growth, thyroid dysfunction and vitamin D deficiency remain prevalent despite reduced intensity chemotherapy for hematopoietic stem cell transplantation in children and young adults

Myeloablative conditioning regimens for hematopoietic stem cell transplant (HSCT) are known to affect endocrine function, but little is known regarding reduced intensity conditioning (RIC) regimens. We retrospectively reviewed 114 children and young adults after single RIC HSCT. The analysis was grouped by age (<2 and ⩾2 years) and diagnosis (hemophagocytic lymphohistiocystosis/X-linked lymphoproliferative syndrome (HLH/XLP), other immune disorders, metabolic/genetic disorders). All groups displayed short stature by mean height-adjusted Z-score (HAZ) before (−1.29) and after HSCT (HAZ −1.38, P=0.47). After HSCT, younger children with HLH/XLP grew better (HAZ −3.41 vs −1.65, P=0.006), whereas older subjects had decline in growth (HAZ −0.8 vs −1.01, P=0.06). Those with steroid therapy beyond standard GVHD prophylaxis were shorter than those without (P 0.04). After HSCT, older subjects with HLH/XLP became thinner with a mean body mass index (BMI) Z-score of 1.20 vs 0.64, P=0.02, and similar to metabolic/genetic disorders (BMI-Z= 0.59 vs −0.99, P<0.001). BMI increased among younger children in these same groups. Thyroid function was abnormal in 24% (18/76). 25-OH vitamin D levels were insufficient in 73% (49/65), with low bone mineral density in 8 of 19 evaluable subjects. Despite RIC, children and young adults still have significant late endocrine effects. Further research is required to compare post-transplant endocrine effects after RIC to those after standard chemotherapy protocols.

Optimal Therapy of Growth Hormone Deficiency in the Child and Adolescent

Optimal therapy of growth disorders depends on accurate diagnosis and clear goals for therapy. Understanding normal patterns of growth hormone (GH) and insulin-like growth factor secretion are necessary to appreciate the different hormone pattern induced by therapy. Finally, monitoring efficacy and safety, identifying interfering factors, and adjusting doses, are all part of optimizing GH therapy in childhood GH deficiency (GHD). Prevention of development of GHD would avoid the need for therapy. Options for optimizing GH therapy in childhood GHD include initiating treatment as young as possible, facilitating adherence to therapy plan, and adjusting GH dose on an individual basis to achieve ‘target’ results. In addition, there can be consideration of regulating timing of puberty, use of higher GH doses, and improving the process of transition from pediatric to adult care. Future prospects include improved depot GH preparations or alternative delivery systems. Development of depot GH-releasing hormone/peptide therapy could allow a more physiologic pattern of GH secretion. GH therapy should be targeted to yield the best growth response, best safety profile, and the best psychosocial adjustment.

How can we apply the new american thyroid association treatment guidelines for children and adolescents with thyroid cancer to improve patient management? Novel insights into clinical experience

Background: Ultrasound reveals thyroid abnormalities in 18% of children and adolescents, of which, 22% are malignant. This creates a dilemma for practitioners who must distinguish lesions that require removal (high risk for malignancy) from lesions that can be observed (low risk for malignancy). Furthermore, treatment of children with differentiated thyroid cancer (DTC) is evolving. Previous treatments were based on adult protocols prescribing total thyroidectomy, lymph node dissection, and radioactive iodine (RAI) ablation for children with DTC, regardless of disease extent. This achieved excellent disease-free survival but high, and potentially avoidable, surgical and medical complications including an increase in secondary non-thyroid malignancies. Methods: This manuscript is a synopsis of cases presented during a symposium at the 2015 Pediatric Endocrine Society meeting (San Diego, CA) with recommendations based on the American Thyroid Association (ATA) management guidelines for children and adolescents with thyroid nodules and DTC. Results: The cases were selected to demonstrate application of the guidelines across a variety of pediatric patients with DTC highlighting key points of the ATA guidelines. The cases will assist practitioners in learning how to apply these guidelines to patient management. Conclusion: Treatment of children with thyroid nodules and DTC is evolving. Current guidelines emphasize the importance of surgery by experienced teams and deferral of RAI ablation for low-risk patients.