Pediatric endocrinology reviews : PER最新文献

Achondroplasia (ACH) is the most common form of skeletal dysplasia causing rhizomelic, short-limb short stature. Short- and long-term clinical trials have been conducted with rhGH, with similar results across these studies. At supraphysiological dose of GH, height gain of 1-1.5 SDS on the population curve was observed during the first 1-3 years, which was then followed by a smaller increase in growth rate persisting for 5-6 years. These studies led to the approval of rhGH for ACH in Japan where rhGH has been used for 20 years at 0.05 mg/kg/day. Although the available data are still limited, compared to untreated controls, total gain in adult height has been greater in males than in females, reported at 3.5-8.0 cm and 2.8-4.2 cm, respectively. Serious adverse events have been rare although some were potentially life-threatening and need careful monitoring. These results should serve as a comparator for novel emerging treatments for ACH.

Management of hypoparathyroidism (hypoPT), depends on the etiology and the severity of hypocalcemia. Treatment goals include control of hypocalcemic symptoms preserving serum calcium in the low-normal range and phosphate in the high normal range. While correction of serum calcium to low-normal range does not fully correct mineral and bone metabolism it may be associated with increased risk of complications such as nephrolithiasis, nephrocalcinosis and soft tissue calcifications. Therefore, it is imperative to find out ways to individualize treatment of patients with hypoPT to achieve the best prognosis while minimizing complications. Replacement therapy with recombinant human PTH (rhPTH) was recently tested for optimizing treatment of hypoPT in a small number of patients. For children and adolescents, further studies are needed to evaluate the long-term effects and safety of rhPTH. In this short review we summarize current knowledge on the management of hypoPT and debate our gaps on the long-term management of children and adolescents with hypoPT.

Despite the difficulty to define born small for gestational age (SGA), being SGA has been associated with a higher risk of short stature, early-onset and rapid progression of puberty, neurocognitive dysfunctions, alterations in body composition, bone density, glucose and lipid metabolism and increased risk for cardiovascular diseases later in life. The majority of children born SGA experience spontaneous catch-up growth during the first years of life. For those who remain with short stature, treatment with recombinant human growth hormone (rhGH) may be initiated, preferably after 2-4 years of age. Response to treatment is variable. However, the benefits of rhGH go beyond increase in stature as the therapy may also improve body composition. In this review we will cover the indication and effects of GH therapy in short children born SGA.

The safety of growth hormone (GH) therapy in children has been studied extensively. The identification of Creutzfeldt-Jacob disease in individuals who received pituitary-derived GH led to heightened surveillance for safety issues related to recombinant human GH (rhGH). An excellent safety profile of rhGH has been demonstrated in large Phase IV registries comprising > 600,000 patient-years of rhGH exposure and long-term safety cohorts of adults treated with GH as children. Increased mortality risk has been reported but eliminated when corrected for small size at birth. Increased risk of mortality from cerebrovascular disease has been reported but interpretation of these events remains difficult due to the lack of appropriate control groups and a lack of replication of these findings in other studies. The advent of new long-acting growth hormone (LAGH) products provides an opportunity for the development of cohorts of individuals receiving LAGH replacement therapy for continued long-term safety studies.

Recombinant human growth hormones were the products of a revolution in biotechnology that took place in the San Francisco Bay area of California in the 1970's. A combination of Herb Boyer's restriction enzymes with Stanley Cohen's bacterial plasmids provided the power to select and amplify virtually any gene. The complementary personalities and talents of Herb Boyer and Robert Swanson led to formation of Genentech and with it the development of a product that overcame the limitations of scarcity and the risks of slow virus contamination inherent in extracted pituitary growth hormone. The extra amino acid in metGH was dropped and other manufacturers joined in the effort to explore indications for rhGH beyond the replacement of a missing hormone. After more than thirty years of availability and careful study, we still have much to learn about the safe and effective use of rhGH.

It was initially thought that the growth-promoting effects of GH were exclusively mediated by liver-derived Insulin-like Growth Factor-I (IGF-I). Subsequent studies demonstrated that GH promotes IGF-I synthesis and activity in other organs and in the growth plate. GH has also IGF-I-independent growth-promoting effects. In Igf1 null mice, high circulating GH levels may be responsible for normal chondrocyte proliferation. Furthermore, tibial growth is reduced more in Ghr null mice than in Igf1 null mice, while the body of mice lacking both Ghr and Igf1 is smaller than that of mice lacking Igf1 or Ghr. The increased IGF-II expression in the growth plate in Igf1 null mice suggests that the IGF-I-independent effects of GH may be mediated by IGF-II. The effects of Igf1 receptor (Igf1r) gene deletion in chondrocytes indicate that GH may promote growth directly at the growth plate even when the local effects of IGF-I and IGF-II are abrogated.

The acute metabolic actions of hGH were discovered in GH-deficient adults (GHDA) 60 years ago and placebo controlled trials of prolonged rhGH replacement therapy appeared 30 years after. Untreated GHDA causes excess morbidity and mortality from cardiovascular disease and the clinical features include fatigue, reduced aerobic exercise capacity, abdominal obesity, reduced lean body mass, osteopenia, and elevated levels of circulating cardiovascular risk biomarkers. Several of these abnormalities normalize with GH replacement. Frequent side effects are fluid retention and insulin resistance, which are reversible and dose-dependent. The dose requirement declines with age and is higher in women. Continuation of GH replacement into adulthood is indicated in some patients with childhood-onset disease so the diagnosis must be reassessed. Observational data show that mortality in GH replaced patients is reduced compared to untreated patients. Thus, GH replacement in GHDA has proven beneficial and safe.

The purpose of this review is to describe and document the discovery of growth hormone (GH) and various activities associated with it. Crucial to this discourse will be a chronicle of results related to the structure of GH. Many individuals were instrumental in the early and current work. Throughout the review we present glimpses into their scientific lives as it affects the evolution of GH's story. We realize that we have not presented a comprehensive review of GH's history and its current and future status, and apologize for the omission of many individuals who contributed to this story.

Growth failure is nearly universal in individuals with Turner syndrome (TS). It is a consequence of haploinsufficiency of the short stature homeobox gene located on the short arm of the X chromosome (SHOX). Without treatment, individuals with TS are expected to be on average 20 cm shorter than unaffected adult females. Short stature is cited by patients as one of their biggest burdens and may have an adverse impact on psychosocial well-being, pubertal timing, and ability to complete a variety of daily living activities. The routine use of recombinant human growth hormone (rhGH) treatment has increased height outcomes. Clinical evidence has strongly supported the efficacy and safety of this treatment. In this article we review the rationale for rhGH treatment in TS, the factors that affect treatment response, safety and monitoring considerations, and potential changes in the way rhGH may be utilized in TS care in the future.