Secular Trends on Birth Parameters, Growth, and Pubertal Timing in Girls with Turner Syndrome.

BACKGROUND: Whether children with chromosomal disorders of growth and puberty are affected by secular trends (STs) as observed in the general population remains unanswered, but this question has relevance for expectations of spontaneous development and treatment responses. OBJECTIVES: The aim of the study was to evaluate STs in birth parameters, growth, and pubertal development in girls with Turner syndrome (TS). STUDY DESIGN: Retrospective analysis of KIGS data (Pfizer International Growth Database). We included all TS patients who entered KIGS between 1987 and 2012 and were born from 1975 to 2004, who were prepubertal and growth treatment naïve at first entry (total number: 7,219). Pretreatment height and ages at the start of treatment were compared across 5-year birth year groups, with subgroup analyses stratified by induced or spontaneous puberty start. RESULTS: We observed significant STs across the birth year groups for birth weight [+0.18 SD score (SDS), p < 0.001], pretreatment height at mean age 8 years (+0.73 SDS, p < 0.001), height at the start of growth hormone (GH) therapy (+0.38 SDS, p < 0.001) and start of puberty (+0.42 SDS, p < 0.001). Spontaneous puberty onset increased from 15 to 30% (p < 0.001). Mean age at the start of GH treatment decreased from 10.8 to 7.4 years (-3.4 years; p < 0.001), and substantial declines were seen in ages at onset of spontaneous and induced puberty (-2.0 years; p < 0.001) and menarche (-2.1 years; p < 0.001). CONCLUSION: Environmental changes leading to increased height and earlier and also more common, spontaneous puberty are applicable in TS as in normal girls. In addition, greater awareness for TS may underlie trends to earlier start of GH therapy and induction of puberty at a more physiological age

Identification of the forms of insulin-like growth factor-binding proteins produced by human fibroblasts and the mechanisms that regulate their secretion

Human fibroblasts secrete insulin-like growth factor-binding proteins (IGFBPs) that can modify insulin-like growth factor (IGF) I action. We have determined the molecular identities of three forms of IGFBPs that are secreted by human fibroblasts in vitro. Ligand blot analysis of fibroblast conditioned media revealed that the M(r) 43,000 and 39,000 forms were the most abundant, but that M(r) 31,000 and 24,000 forms were also present. An antiserum that was specific for IGFBP-5 reacted with the M(r) 31,000 form, and an IGFBP-4-specific antiserum recognized only the M(r) 24,000 form. The M(r) 39,000 and 43,000 forms were detected by IGFBP-3 antiserum. Further proof that fibroblasts synthesized these forms of IGFBPs was obtained by Northern blotting. A cDNA probe for IGFBP-3 hybridized with a 2.4-kilobase (kb) transcript, whereas a cDNA probe for IGFBP-5 recognized a single 6.0-kb transcript, and an IGFBP-4 cDNA probe recognized 2.2- and 2.0-kb transcripts. IGF-I and -II caused a minimal (less than 43%) increase in IGFBP-5 mRNA abundance and had no effect on IGFBP-4 mRNA abundance. IGF-I and -II (100 ng/ml) stimulated 6-8-fold increases in IGFBP-5 levels, whereas IGFBP-4 was inhibited. Insulin failed to elicit any change in IGFBP-5, suggesting that binding of the IGFs to IGFBPs was required to detect the increase. Immunoblotting for IGFBP-5 revealed an M(r) 23,000 (non-IGF-I-binding) fragment. To determine if the IGFs were influencing proteolytic degradation of IGFBP-5, pure IGFBP-5 was added to fibroblast cultures and incubated for 4 h at 37 degrees C. The amount of fragment formation was attenuated by the presence of IGF-I and -II, but not insulin, suggesting that this is a mechanism by which the IGFs act to modulate IGFBP-5 concentration. In contrast to the IGFs, forskolin, which increased IGFBP-4 and -5 mRNA abundance and secretion, had no effect on fragment formation. The results show that human fibroblasts synthesize and secrete IGFBP-3, -4, and -5 and that changes in intracellular cAMP regulate synthesis, whereas the IGFs regulate IGFBP-4 and -5 levels by post-transcriptional mechanisms

Extracellular matrix contains insulin-like growth factor binding protein-5: potentiation of the effects of IGF-I

Insulin-like growth factor binding proteins (IGFBPs) have been shown to serve as carrier proteins for the insulin-like growth factors (IGFs) and to modulate their biologic effects. Since extracellular matrix (ECM) has been shown to be a reservoir for IGF-I and IGF-II, we examined the ECM of cultured human fetal fibroblasts and found that IGFBP-5 was incorporated intact into ECM, while mostly inert proteolytic fragments were found in the medium. In contrast, two other forms of IGFBP that are secreted by these cells were either present in ECM in minimal amounts (IGFBP-3) or not detected (IGFBP-4). Likewise, when purified IGFBPs were incubated with ECM, IGFBP-5 bound preferentially. IGFBP-5 was found to bind to types III and IV collagen, laminin, and fibronectin. Increasing salt concentrations inhibited the binding of IGFBP-5 to ECM and accelerated the release of IGFBP-5 from ECM, suggesting an ionic basis for this interaction. ECM-associated IGFBP-5 had a sevenfold decrease in affinity for IGF-I compared to IGFBP-5 in solution. Furthermore, when IGFBP-5 was present in cell culture substrata, it potentiated the growth stimulatory effects of IGF- I on fibroblasts. When IGFBP-5 was present only in the medium, it was degraded to a 22-kD fragment and had no effect on IGF-I-stimulated growth. We conclude that IGFBP-5 is present in fibroblast ECM, where it is protected from degradation and can potentiate the biologic actions of IGF-I. These findings provide a molecular explanation for the association of the IGF's with the extracellular matrix, and suggest that the binding of the IGF's to matrix, via IGFBP-5, may be important in mediating the cellular growth response to these growth factors

Childhood Obesity

In March 2004 a group of 65 physicians and other health professionals representing nine countries on four continents convened in Israel to discuss the widespread public health crisis in childhood obesity. Their aim was to explore the available evidence and develop a consensus on the way forward. The process was rigorous, although time and resources did not permit the development of formal evidence-based guidelines. In the months before meeting, participants were allocated to seven groups covering prevalence, causes, risks, prevention, diagnosis, treatment, and psychology. Through electronic communication each group selected the key issues for their area, searched the literature, and developed a draft document. Over the 3-d meeting, these papers were debated and finalized by each group before presenting to the full group for further discussion and agreement. In developing a consensus statement, this international group has presented the evidence, developed recommendations, and provided a platform aimed toward future corrective action and ongoing debate in the international community

Secular Trends on Birth Parameters, Growth, and Pubertal Timing in Girls with Turner Syndrome

BackgroundWhether children with chromosomal disorders of growth and puberty are affected by secular trends (STs) as observed in the general population remains unanswered, but this question has relevance for expectations of spontaneous development and treatment responses.ObjectivesThe aim of the study was to evaluate STs in birth parameters, growth, and pubertal development in girls with Turner syndrome (TS).Study designRetrospective analysis of KIGS data (Pfizer International Growth Database). We included all TS patients who entered KIGS between 1987 and 2012 and were born from 1975 to 2004, who were prepubertal and growth treatment naïve at first entry (total number: 7,219). Pretreatment height and ages at the start of treatment were compared across 5-year birth year groups, with subgroup analyses stratified by induced or spontaneous puberty start.ResultsWe observed significant STs across the birth year groups for birth weight [+0.18 SD score (SDS), p &lt; 0.001], pretreatment height at mean age 8 years (+0.73 SDS, p &lt; 0.001), height at the start of growth hormone (GH) therapy (+0.38 SDS, p &lt; 0.001) and start of puberty (+0.42 SDS, p &lt; 0.001). Spontaneous puberty onset increased from 15 to 30% (p &lt; 0.001). Mean age at the start of GH treatment decreased from 10.8 to 7.4 years (−3.4 years; p &lt; 0.001), and substantial declines were seen in ages at onset of spontaneous and induced puberty (−2.0 years; p &lt; 0.001) and menarche (−2.1 years; p &lt; 0.001).ConclusionEnvironmental changes leading to increased height and earlier and also more common, spontaneous puberty are applicable in TS as in normal girls. In addition, greater awareness for TS may underlie trends to earlier start of GH therapy and induction of puberty at a more physiological age

Radiotherapy, especially at young age, increases the risk for de novo brain tumors in patients treated for pituitary tumors

Background: Excess mortality due to de novo malignant brain tumors was recently found in a national study of patients with hypopituitarism following treatment of pituitary tumors. Here, we examined a larger multi-national cohort to corroborate and extend this observation. Objective: To investigate the incidence of malignant brain tumors and benign meningiomas in a large cohort of patients treated for pituitary tumors. Patients and Methods: Between 1994-2012, 8917 hypopituitary patients with a pituitary tumor treated with growth hormone (GH) replacement were followed in KIMS (non-interventional Pfizer International Metabolic Database). For 4936 patients, pituitary tumor treatment was surgery/medical therapy, and in 3227 radiotherapy (RT) was used alone or with surgery. For 754 patients, tumor treatment data were missing. Reference incidence rates of malignant brain tumors (ICD10: C70-C72) stratified for age, gender and country (Cancer Incidence in 5 regions, Vol IX, IARC 2007) were used to calculate standardized incidence ratios (SIR). Risk indicators for 2nd central nervous system neoplasia (new malignant brain tumors and benign meningiomas) were analyzed by multiple Poisson regression.Relative risks (RRs) were based on internal comparisons. Results: During 53,881 patient-years at risk, 21 malignant brain tumors (SIR 3.92 95% CI: 2.43-6.00), and 27 benign meningiomas were reported. Fourteen malignant tumors occurred in patients treated with RT, SIR 6.50 (95% CI 3.55-10.91) vs 7 in those without RT. The RR of RT vs no RT for malignant brain tumors was 2.43 (95% CI 1.02-6.29), and for meningiomas was 5.43 (95% CI 2.06 -14.35).On average, the risk for malignant brain tumors increased by 5.9% per year of decreasing age at first radiotherapy (95% CI: 1.2% - 10.3%; p=0.01) and for meningiomas by 5.7% (95% CI: 1.6% - 9.6%; p=0.003). Median times from RT exposure to 2nd tumor diagnosis were 20.3, range 3.1-46.1 yrs, and 22.2, range 8.1-39.3 yrs, for malignant tumors and meningiomas, respectively. Meningiomas were more common in females (18 vs 9, RR=2.26, 95% CI: 1.01-5.05), but there was no difference between genders for malignant brain tumors. The underlying pituitary tumor etiology, number of surgeries, and IGF-I SDS on GH treatment did not influence the risk of 2nd tumors. Conclusion: Radiotherapy is associated with increased risk of developing malignant brain tumors and meningiomas, in particular when given at younger ages. In balancing risks and benefits of RT in the treatment of pituitary tumors, our findings emphasize that special consideration should be given to the age of the patient

Treatment of short stature in children with severe primary IGF-I deficiency with once daily rhIGF-1/rhIGFBP-3 administration

WOS: 000239630600099

Change in baseline characteristics over 20 years of adults with growth hormone (GH) deficiency on GH replacement therapy

Objective: Clinical observations over time of adults with growth hormone (GH) deficiency (GHD) have indicated a shift in patient characteristics at diagnosis. The objective of this study was to compare baseline characteristics of patients diagnosed with adult-onset GHD naive to GH replacement during t hree study periods (1994-1999 (P1), 2000-2004 (P2), and 2005-2012 (P3)) using the KIMS (Pfizer's International Metab olic) database. Methods: Data were retrieved for a total of 6069 patients with adult-on set GHD from six countries (Belgium, Germany, Netherlands, Spain, Sweden, and UK): P1 (n = 1705), P2 (n = 2397), and P3 (n = 1967). Results: The proportions of patients with pituitary/hypothalamic tumors and patients with multiple pituitary hormone deficiencies decreased per entry year period, while the proporti ons with hypertension and diabetes increased. The lag time from diagnosis of pituitary disease to start of GH treatme nt decreased by 2.9 years over the entry year periods. IGF-1 increased by 0.1 standard deviation score per entry year period. Maximum GH following various stimulation tests, BMI, and waist circumference increased. The use of radio therapy, glucocorticoid replacement doses, and the proportion of women >50 years on estrogen replacement therapy decreased. The effects of 1 year of GH replacement were similar over the entry year periods despite changes in the patients' baseline characteristics. An expected increase in fasting blood glucose was seen after 1 year of GH treatment. Conclusions: The degree of confirmed GHD became less pronounced and more pat ients with co-morbidities and diabetes were considered for GH replacement therapy, possibly r eflecting increased knowledge and confidence in GH therapy gained with time