Longitudinal bone growth occurs at the growth plate by endochondral ossification. Within the growth plate, chondrocyte proliferation, hypertrophy, and cartilage matrix secretion result in chondrogenesis. The newly formed cartilage is invaded by blood vessels and bone cells that remodel the newly formed cartilage into bone tissue. This process of longitudinal bone growth is governed by a complex network of endocrine signals, including growth hormone, insulin-like growth factor I, glucocorticoid, thyroid hormone, estrogen, androgen, vitamin D, and leptin. Many of these signals regulate growth plate function, both by acting locally on growth plate chondrocytes and also indirectly by modulating other endocrine signals in the network. Some of the local effects of hormones are mediated by changes in paracrine factors that control chondrocyte proliferation and differentiation. Many human skeletal growth disorders are caused by abnormalities in the endocrine regulation of the growth plate. This review provides an overview of the endocrine signals that regulate longitudinal bone growth, their interactions, and the mechanisms by which they affect growth plate chondrogenesis.

In the past, the growth hormone (GH) – insulin-like growth factor-I (IGF-I) axis was thought to be the central system regulating childhood growth and therefore responsible for short stature and tall stature. However, recent findings have revealed that the GH-IGF-I axis is just one of many regulatory systems that control chondrogenesis in the growth plate, the biological process that drives height gain. Consequently, normal growth in children depends not only on GH and IGF-I but on multiple hormones, paracrine factors, extracellular matrix molecules, and intracellular proteins that regulate growth plate chondrocytes. Mutations in genes encoding many of these local proteins cause short stature or tall stature. Similarly genome-wide association studies have revealed that the normal variation in height appears to be due largely to genes outside the GH-IGF-I axis that affect growth at the growth plate through a wide variety of mechanisms. These findings point to a new conceptual framework for understanding short and tall stature, which is centered not on two particular hormones but rather on the growth plate, the structure responsible for height gain.

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OBJECTIVE -To characterize the insulin sensitivity of overweight and obese 5-to 10-yearold (Tanner stage 1-3) African-American children screened for participation in a diabetes prevention study and to identify the association of insulin sensitivity with obesity, hyperlipidemia, and hypertension.RESEARCH DESIGN AND METHODS -Measures of insulin resistance (homeostasis model assessment) and insulin sensitivity (Matsuda and DeFronzo's whole-body insulin sensitivity) were calculated from a 2-h oral glucose tolerance test in 137 African-American children recruited into a diabetes prevention study. Measures of lipids (LDL, HDL, total cholesterol, and triglycerides), blood pressure, and body composition were obtained for a subset of the children.RESULTS -In response to a glucose challenge, girls and older and heavier children produced significantly more insulin. As BMI increased, there was a statistically significant decrease in insulin sensitivity, particularly in girls. Insulin sensitivity was inversely correlated with increases in blood pressure, triglycerides, subcutaneous fat, the percentage of total body fat, and Tanner stage, but it was not correlated with LDL and HDL.CONCLUSIONS -Reduced insulin sensitivity and the cluster of risk factors known as the insulin resistance syndrome (IRS) are already apparent in these overweight African-American children. Young African-American girls, in particular, already show evidence of hyperinsulinemia in response to a glucose load, suggesting that the early stages of metabolic decompensation that lead to type 2 diabetes are already occurring. Monitoring of those risk factors known to be part of IRS should become part of routine medical care for overweight or obese African-American children. Diabetes Care 24:1359 -1364, 2001T he prevalence of overweight/obesity is increasing in children, as is the diagnosis of type 2 diabetes (1-3). Obesity and insulin resistance are known risk factors for the development of type 2 diabetes in adults (4). For adults, type 2 diabetes and obesity are more prevalent in the African-American population than in European-Americans, especially among African-American women (5). Minority populations have also seen the greatest increase in childhood and adolescent diagnoses of type 2 diabetes (6).Studies in adults have consistently shown insulin resistance and hyperinsulinemia to be strong predictors of the development of type 2 diabetes (7). In addition to insulin resistance and ␤-cell dysfunction, obesity (specifically central adiposity [8]), dyslipidemia (9 -10), and genetic predisposition (11) are risk factors for the development of impaired glucose tolerance and type 2 diabetes in adults.The clustering of insulin resistance, obesity, hypertension, dyslipidemia, and atherosclerosis has been referred to as the insulin resistance syndrome (IRS), the metabolic syndrome, or syndrome X (12). Increasing rates of type 2 diabetes in the pediatric population suggest the need to explore the development of insulin resistance and other risk factors (13) for type ...

To evaluate the features and the course of cardiomyopathy in Becker muscular dystrophy, 68 patients--identified by clinical assessment and by reduced dystrophin labeling and/or DNA analysis--were followed in the years 1976-1993, for periods ranging from 3 to 18 years (mean 8). Patients periodically underwent clinical, electrocardiographic, echocardiographic, nuclear, and radiological assessments. Preclinical cardiac involvement was found in 67.4% of patients under 16 years of age, decreasing to 30% in patients older than 40. Clinically evident cardiomyopathy was found in 15% of patients under 16 years of age, increasing to 73% in patients older than 40. A real, dilated cardiomyopathy is the most frequent type of myocardial involvement after the age of 20. Results show that the severity of cardiac involvement can be unrelated to the severity of skeletal muscle damage and confirm that cardiac dysfunction is a primary feature of Becker muscular dystrophy.

What's known on the subject? and What does the study add?• The management of patients with non-obstructive azoospermia (NOA) involves testicular sperm extraction (TESE or microdissection TESE) combined with intracytoplasmic sperm injection (ICSI). Sperm retrieval is successful in up to 50% of men with NOA; however, there is no single clinical finding or investigation that can accurately predict a positive outcome. Several studies have concluded that testicular biopsy is the best predictor of a successful TESE.• The present study shows that the strongest predictor of the success of TESE is when tubules with mature spermatozoa (Johnsen score Ն8) are found in the histopathology specimen, irrespective of the overall state of spermatogenesis. The findings suggest that a lower limit threshold value of 2% of tubules with spermatogenesis in the histopathology specimen will result in a positive sperm retrieval.• However, it is not practical to perform a diagnostic biopsy before TESE because this would mean that patients undergo two surgeries, which adds to the cost and increases the complications.• The diagnostic biopsy is best coupled with an initial TESE before starting the ICSI cycle. Based on the findings of the histopathology specimen, patients may be then offered a repeat TESE if more sperm is needed on the day of ovum pick-up and ICSI. Also, if the initial TESE was negative, the biopsy result will help in the decision to offer a repeat TESE. This regimen is more cost-effective because the ICSI cycle will be started only if adequate sperm is retrieved. Objective• To assess whether testicular histopathology can predict the outcome of testicular sperm extraction (TESE) in men with non-obstructive azoospermia (NOA) and therefore the role of preoperative diagnostic testis biopsy. Patients and Methods• The study comprised a retrospective analysis of 388 patients with azoospermia who were referred from 2005 to 2010.• Information collected included a clinical history and an examination including age and testicular size, serum follicle-stimulating hormone, two semen analyses and testicular histology collected at the time of surgical sperm retrieval (TESE or microdissection TESE). Results• In total, 388 patients with a mean (range) age of 37 (18-66) years were included in the present study.• Based on the history, clinical and laboratory findings, 112 patients had obstructive azoospermia and 276 patients had NOA. • All patients in the obstructed group had a positive sperm retrieval. The sperm retrieval rate for the NOA group was 50%. • An analysis of the results showed that the best predictor of a positive sperm retrieval was when tubules with mature spermatozoa were seen at biopsy, irrespective of the overall state of spermatogenesis (P < 0.001). Conclusions• The presence of tubules with spermatazoa on biospy is the best predictor of a positive surgical sperm retrieval in patients with NOA.• The diagnostic biopsy is best coupled with an initial TESE before starting the intracytoplasmic sperm injection (ICSI) cycle. Sexual ...

Reduced caloric intake in mammals causes reduced skeletal growth and GH insensitivity. However, the underlying molecular mechanisms are not fully elucidated. The aim of this study was to determine whether the increased activity of fibroblast growth factor 21 (FGF21) during chronic undernutrition in mice causes GH insensitivity and growth failure. After 4 wk of food restriction, fgf21 knockout (KO) mice exhibited greater body and tibial growth than their wild-type (WT) littermates. Daily injections of recombinant human FGF21 in a subgroup of food-restricted fgf21 KO mice prevented these differences in body and tibial growth. At the end of the 4-wk food restriction, GH binding and GH receptor expression were reduced in the liver and in the growth plate of food-restricted WT mice (compared to WT mice fed ad libitum), whereas they were similar between food-restricted and ad libitum KO mice. In addition, a single injection of GH induced greater liver signal transducer and activator of transcription 5 phosphorylation and IGF-I mRNA in food-restricted KO mice than in WT mice. Lastly, in the tibial growth plate of food-restricted WT mice, FGF21 mRNA and protein expression was greater than that of WT mice fed ad libitum. In contrast, the IGF-I mRNA and protein expression was smaller. Our findings support a causative role for FGF21 in the inhibition of skeletal growth during prolonged undernutrition. Such role may be mediated by the antagonistic effect of FGF21 on GH action in the liver and, possibly, in the growth plate.

Background: Evidence suggests that fibroblast growth factor 21 (FGF21) inhibits longitudinal bone growth. Results: FGF21 antagonizes the growth hormone (GH) stimulatory effects on thymidine incorporation and collagen X expression in chondrocytes. Conclusion: FGF21 inhibits bone growth by antagonizing GH effects on chondrocyte proliferation and differentiation. Significance: Increased FGF21 during food restriction may contribute to growth failure by directly inhibiting chondrogenesis.