Height Gain in Ullrich-Turner Syndrome after Early and Late Growth Hormone Treatment Start: Results from a Large Retrospective German Study and Potential Basis for an Individualized Treatment Approach

Background: Ullrich-Turner syndrome (UTS) girls often present with short stature in adolescence to the endocrinologist when the efficacy of growth hormone (GH) to improve growth remains unknown and parameters to estimate individual GH responsiveness have yet to be determined. Objective: Retrospective evaluation of adult height (AH) and predicted adult height at GH start (descriptive model of Ranke, Model PredAH) in early and late GH-treated German UTS patients. Subjects/Methods: 313 patients treated with GH, early [chronological age (CA) at GH start <12 years, n = 259] or late (CA at GH start ≥12 years, n = 54) who reached AH were selected from KIGS (Pfizer International Growth Database). Results: AH (152.5 ± 5.9 vs. 151.1 ± 5.4 cm, p = n.s.) after GH treatment for 7.5 ± 2.12 years (GH start early) and for 5.2 ± 1.2 years (GH start late) were similar (p = n.s.) as Model PredAH (155.7 ± 4.8 vs. 154.7 ± 4.8 cm; p = n.s.) but higher (p < 0.001) than projected adult height (Ranke, ProjAH; 148.2 ± 5.5 vs. 145.2 ± 6.7 cm; p = 0.001). Total height gain over ProjAH was 4.3 ± 4.6 cm (GH start early) and 5.8 ± 4.7 cm (GH start late, p = 0.021), respectively. Conclusions: GH may improve AH in UTS patients even when started late. The individual growth response could be estimated by the descriptive Model PredAH independent of age at treatment start

Results from an international multicenter trial evaluating the ease-of-use of and preference for a newly developed disposable injection pen for the treatment of growth hormone deficiency in treatment-naive children and adults

Previous research has reported that ease of use of and preference for a delivery device are associated with greater patient compliance - an important factor in achieving optimal therapeutic results. The objective of this study was to assess the ease-of-use of a new disposable pen (GoQuick((R)), Pfizer, Inc.) versus the current reusable pen (GENOTROPIN Pen((R)), Pfizer, Inc.) to inject a daily dose of recombinant DNA origin human growth hormone, Genotropin((R)) (somatropin) in standard practice. In this randomized, crossover, multicenter, multinational, openlabel study, ease-of-use of and preference for the two pens were assessed in three treatment-naive populations: 1) parents of very young children; 2) parent-child dyads; and 3) adults via use of a validated self-report Injection Pen Assessment Questionnaire (IPAQ) after 2 months of at-homeuse experience. The primary endpoint was the proportion of participants who reported the new disposable pen to be no different from or easier to use than the current reusable pen. Safety was also assessed and reported according to local legal requirements. Of the 120 screened patients, 119 were included in the ease-of-use analysis and all were included in the safety analyses. In all, 67.2% found the new somatropin disposable pen to be no different from or easier to use than the reusable pen (95% confidence interval: 58.8-75.7). Most adverse events were mild or moderate. No deaths or device-or treatment-related serious adverse events were reported. These results suggest that improvements made to the reusable somatropin pen are tangible and recognizable to treatment-naive patients and their caregivers, child-caregiver dyads, and adults, and may positively impact continued compliance with therapy

Cullin 7 and Fbxw 8 expression in trophoblastic cells is regulated via oxygen tension: implications for intrauterine growth restriction?

Objective:The F-box protein Fbxw8 is a cofactor of Cullin 7 (Cul7), which regulates protein transfer to the proteasome and cell growth. Cul7 or Fbxw8 deficiency is associated with intrauterine growth restriction (IUGR) due to abnormal placental development leading to poor oxygen supply to the fetus. We studied the role of hypoxia for Fbxw8 and Cul7 expression in trophoblastic cells. Methods: Immunomagnetic bead-separated extravillous trophoblast (EVT) and villous trophoblast (VT) and trophoblast cell lines were incubated with 1 or 8% O-2. Fbxw8 and Cul7 expression was determined in IUGR versus matched control placentas. Results: Fbxw8 was expressed uniformly in trophoblasts, whereas Cul7 expression was most prominent in trophoblast cell lines. Hypoxia reduced expression of Cul7 and Fbxw8 in all trophoblastic cells, except for villous trophoblasts. In vivo, Cul7 and Fbxw8 were detected in syncytiotrophoblast cells, VT, and EVT cells. Although no significant changes in expression levels of Fbxw8 or Cul7 were noted in IUGR compared with control placentas, Fbxw8 expression correlated negatively with gestational age in the control, but not in the IUGR group. Conclusion: Fbxw8 and Cul7 expression reveals a complex regulation in trophoblastic cells. Our findings suggest that dysregulation of Cul7 and Fbxw8 expression might affect trophoblast turnover in IUGR

Analysis of extracellular signal-regulated kinase (ERK) -1 and -2 activities via Western blot.

<p>(A) Tissue lysates from lumbar mammary glands at day 21 and day 28 were probed with an antibody recognizing phosphorylated (activated) and total (phosphorylated and non-phosphorylated) ERK1 (also known as p44, upper band 44kDa) and ERK2 (also known as p42, lower band 42kDa). Amidoblack (Ambl) served as control. (B+C) Densitometric analysis presented as the ratio of activated ERK-1/-2 to total ERK at day 21 (B) and day 28 (C). LP =  low protein (white bars); NP =  normal protein (black bars); d =  day; * =  p<0.05, ** =  p<0.01.</p

Auxologic data.

<p>Body weight (A), body length (B) and tail length (C) of the LP (white bars/squares) and NP (black bars/triangles) group during postnatal development (left), at day 1 (middle) and day 21 vs. day 28 (right). At d1 - d21 weight data was recorded from n = 40 LP and n = 47 NP animals, at d21-d28 from n = 20 LP and n = 24 NP rats. Length and tail length measurements came from n = 20 LP and n = 26 NP pups at d1 – d21, and from n = 20 LP and n = 24 NP rats at d21 – d28. LP =  low protein (white bars); NP =  normal protein (black bars); d =  day; * =  p<0.05, ** =  p<0.01; *** =  p<0.001; ns =  not significant.</p

Detection of Expressional Changes Induced by Intrauterine Growth Restriction in the Developing Rat Mammary Gland via Exploratory Pathways Analysis

<div><p>Background</p><p>Intrauterine growth restriction (IUGR) is thought to lead to fetal programming that in turn contributes to developmental changes of many organs postnatally. There is evidence that IUGR is a risk factor for the development of metabolic and cardiovascular disease later in life. A higher incidence of breast cancer was also observed after IUGR. This could be due to changes in mammary gland developmental pathways. We sought to characterise IUGR-induced alterations of the complex pathways of mammary development at the level of the transcriptome in a rat model of IUGR, using pathways analysis bioinformatics.</p><p>Methodology/Principal Findings</p><p>We analysed the mammary glands of Wistar rats with IUGR induced by maternal low protein (LP) diet at the beginning (d21) and the end (d28) of pubertal ductal morphogenesis. Mammary glands of the LP group were smaller in size at d28, however did not show morphologic changes. We identified multiple differentially expressed genes in the mammary gland using Agilent SurePrint arrays at d21 and d28. In silico analysis was carried out using Ingenuity Pathways Analysis. In mammary gland tissue of LP rats at d21 of life a prominent upregulation of WT1 and CDKN1A (p21) expression was observed. Differentially regulated genes were associated with the extracellular regulated kinase (ERK)-1/-2 pathway. Western Blot analysis showed reduced levels of phosphorylated ERK-1/-2 in the mammary glands of the LP group at d21. To identify possible changes in circulating steroid levels, serum LC-Tandem mass-spectrometry was performed. LP rats showed higher serum progesterone levels and an increased corticosterone/dehydrocorticosterone-ratio at d28.</p><p>Conclusions/Significance</p><p>Our data obtained from gene array analysis support the hypothesis that IUGR influences pubertal development of the rat mammary gland. We identified prominent differential regulation of genes and pathways for factors regulating cell cycle and growth. Moreover, we detected new pathways which appear to be programmed by IUGR.</p></div

Analysis of Wilms tumor suppressor gene 1 (WT1) expression in lumbar mammary glands at day 21 and day 28.

<p>WT1 stained positive (black arrow head) in epithelial cells (A, WT1-negative cells are indicated by arrows), with a significant increase of WT1 positive cells per area at day 28 in the LP group. RT-PCR indicates a significant induction of WT1 and CDKN1a (p21) expression at day 21 (B). LP =  low protein (white bars); NP =  normal protein (black bars); d =  day; * =  p<0.05 versus NP of the same time point.</p

Primers and probes.

<p>Primers and probes.</p