Growth Hormone Research Society perspective on the development of long-acting growth hormone preparations

Objective The Growth Hormone (GH) Research Society (GRS) convened a workshop to address important issues regarding trial design, efficacy, and safety of long-acting growth hormone preparations (LAGH). Participants A closed meeting of 55 international scientists with expertise in GH, including pediatric and adult endocrinologists, basic scientists, regulatory scientists, and participants from the pharmaceutical industry. Evidence Current literature was reviewed for gaps in knowledge. Expert opinion was used to suggest studies required to address potential safety and efficacy issues. Consensus process Following plenary presentations summarizing the literature, breakout groups discussed questions framed by the planning committee. Attendees reconvened after each breakout session to share group reports. A writing team compiled the breakout session reports into a draft document that was discussed and revised in an open forum on the concluding day. This was edited further and then circulated to attendees from academic institutions for review after the meeting. Participants from pharmaceutical companies did not participate in the planning, writing, or in the discussions and text revision on the final day of the workshop. Scientists from industry and regulatory agencies reviewed the manuscript to identify any factual errors. Conclusions LAGH compounds may represent an advance over daily GH injections because of increased convenience and differing phamacodynamic properties, providing the potential for improved adherence and outcomes. Better methods to assess adherence must be developed and validated. Long-term surveillance registries that include assessment of efficacy, cost-benefit, disease burden, quality of life, and safety are essential for understanding the impact of sustained exposure to LAGH preparations

Growth Hormone Research Society perspective on the development of long-acting growth hormone preparations: Table 1

The Growth Hormone (GH) Research Society (GRS) convened a workshop to address important issues regarding trial design, efficacy, and safety of long-acting growth hormone preparations (LAGH)

Transcriptional Regulation of Insulin-Like Growth Factor : Binding Protein-4 by Protein Kinase A and Protein Kinase C Signal Transduction Pathways in Human Bone Cells

The Insulin-like Growth Factor (IGF) system is an important local regulator of osteoblast proliferation, the primary determinant of bone formation. Six IGF Binding Proteins (IGFBPs) either inhibit or enhance IGF actions. Previous studies have shown that IGFBP-4 is an important negative regulator of osteoblast cell proliferation and that agents such as PTH which increase intracellular cAMP significantly increase expression of IGFBP-4 at the protein and mRNA levels. The underlying molecular mechanism which accounted for IGFBP-4 expression had not been determined and was the focus of my dissertation. Agents which increase intracellular cAMP rapidly increased IGFBP-4 mRNA levels. Nuclear run-off experiments indicated that cAMP increased the IGFBP-4 gene transcription rate at 2 hours. Cloning and sequence analysis of the human IGFBP-4 gene promoter and first intron revealed the presence of putative cAMP responsive elements which might function to mediate the cAMP effect. To investigate mechanisms regulating osteoblast IGFBP-4 expression, I determined the role of two major post-receptor signal transduction pathways, the Protein Kinase A (PKA) and Protein Kinase C (PKC) pathways, on IGFBP-4 mRNA expression. PKA inhibitors and PKC stimulators reduced IGFBP-4 mRNA levels. PKC inhibitors increased IGFBP-4 expression and synergistically interacted with cAMP to increase IGFBP-4 mRNA levels. These studies indicated the PKA and PKC pathways had opposing effects on IGFBP-4 gene expression. These findings increase our understanding of parathyroid hormone (PTH) action on bone. PTH acts through the PKA and PKC pathways to affect bone cell proliferation. High doses of PTH (10-8 M) inhibit bone cell proliferation. We found that high concentrations of PTH increased IGFBP-4 expression while PKA inhibitors blocked this stimulation. These findings were used to propose a model for catabolic PTH actions. In this model, high doses of PTH activate PKA, stimulate IGFBP-4 expression and inhibit cell proliferation

A Significant Increase in the Incidence of Central Precocious Puberty among Korean Girls from 2004 to 2010.

BACKGROUND:Few studies have explored the trends in central precocious puberty (CPP) in Asian populations. This study assessed the prevalence and annual incidence of CPP among Korean children. METHODS:Using data from the Korean Health Insurance Review Agency from 2004 to 2010, we reviewed the records of 21,351 children, including those registered with a diagnosis of CPP for the first time and those diagnosed with CPP who were treated with gonadotropin-releasing hormone analogs. RESULTS:The prevalence of CPP was 55.9 per 100,000 girls and 1.7 per 100,000 boys, respectively. The overall incidence of CPP was 15.3 per 100,000 girls, and 0.6 per 100,000 boys. The annual incidence of CPP in girls significantly increased from 3.3 to 50.4 per 100,000 girls; whereas in boys, it gradually increased from 0.3 to 1.2 per 100,000 boys. The annual incidence of CPP in girls consistently increased at all ages year by year, with greater increases at older ages (≥6 years of age), and smaller increases in girls aged < 6 years. In contrast, the annual incidence remained relatively constant in boys aged < 8 years, while a small increase was observed only in boys aged 8 years. The increase of annual incidence showed significant differences depending on age and gender (P <0.0001). CONCLUSIONS:The annual incidence of CPP has substantially increased among Korean girls over the past 7 years. Continued monitoring of CPP trends among Korean children will be informative

Murine maternal dietary restriction affects neural Humanin expression and cellular profile

To understand the cellular basis for the neurodevelopmental effects of intrauterine growth restriction (IUGR), we examined the global and regional expression of various cell types within murine (Mus musculus) fetal brain. Our model employed maternal calorie restriction to 50% daily food intake from gestation day 10-19, producing IUGR offspring. Offspring had smaller head sizes with larger head:body ratios indicating a head sparing IUGR effect. IUGR fetuses at embryonic day 19 (E19) had reduced nestin (progenitors), β-III tubulin (immature neurons), Glial fibrillary acidic protein (astrocytes), and O4 (oligodendrocytes) cell lineages via immunofluorescence quantification and a 30% reduction in cortical thickness. No difference was found in Bcl-2 or Bax (apoptosis) between controls and IUGR, though qualitatively, immunoreactivity of doublecortin (migration) and Ki67 (proliferation) was decreased. In the interest of examining a potential therapeutic peptide, we next investigated a novel pro-survival peptide, mouse Humanin (mHN). Ontogeny examination revealed highest mHN expression at E19, diminishing by postnatal day 15 (P15), and nearly absent in adult (3&nbsp;months). Subanalysis by sex at E19&nbsp;yielded higher mHN expression among males during fetal life, without significant difference between sexes postnatally. Furthermore, female&nbsp;IUGR mice at E19&nbsp;had a greater increase in cortical mHN versus the male fetus over their respective controls. We conclude that maternal dietary restriction-associated IUGR interferes with neural progenitors differentiating into the various cellular components populating the cerebral cortex, and reduces cerebral cortical size. mHN expression is developmental stage and sex specific, with IUGR, particularly in the females, adaptively increasing its expression toward mediating a pro-survival approach against nutritional adversity

The annual and overall incidence of central precocious puberty.

<p>The annual and overall incidence of central precocious puberty.</p