Pubertal growth and growth hormone secretion

A dramatic increase in linear growth velocity, often referred to as the pubertal growth spurt, is a central feature of pubertal development. Despite the existence of numerous investigative attempts, a precise understanding of the hormonal events subserving this process has proved elusive. Nevertheless, evidence has gradually accumulated that indicates that sex steroid-induced modulation of growth hormone secretion is a central and critical feature of the pubertal growth spurt. As a result, disorders of either growth hormone or sex steroid hormone production may result in clinical growth disorders during puberty.     

The growth hormone receptor in growth.

The growth hormone receptor (GHR) is a major effector of Human growth. Functional variants of the GHR include very rare loss-of-function mutations (pathology) and very common polymorphisms (physiology). Recent experimental data have clarified the mechanisms through which mutations of the GHR or Stat5 lead to growth hormone insensitivity and major monogenic growth defects. Recent pharmacogenetic studies support that the response to growth-promoting administration of growth hormone is influenced by exon 3 polymorphism of the GHR.     

Normal growth and techniques of growth assessment

The shape of the human growth curve is described and illustrated. Growth studies may be longitudinal, cross-sectional, mixed longitudinal or linked-longitudinal; each has advantages and disadvantages, and each requires appropriate statistical methods for handling the data. Standards for height and height velocity for use in a clinical setting wherein follow-up over several years is presumed are described and illustrated. Such standards have to take into account tempo of growth at ages over nine years. Cross-sectionally derived standards do not do this and are not suitable for clinical use. The techniques of measurement of height, sitting height and skinfolds are described and illustrated. Growth and development during puberty is described; there are changes in body composition as well as in body size and shape. Standards for pubertal stages of breasts, pubic hair and genitalia are given and emphasis is laid on the great variation in both the timing and the duration of these pubertal changes. Measurement of developmental age is discussed. The Greulich-Pyle and Tanner-Whitehouse methods for skeletal age are described. These methods can be used for predicting adult height which is useful both in diagnosis and in following the effects of treatment. In diagnosis the predicted adult height is compared to the range of expected heights in the children of the particular pair of parents concerned (the so-called 'target' range of heights) to see if smallness is simply due to delay. Change in Tanner-Whitehouse predicted height occurs on successful treatment of, for example, growth hormone deficient short stature, and is thus a guide to the success of treatment. Standards are also given for height of children from age two to nine inclusive, with allowance for height of their parents.     

Mammalian epidermal growth factor promotes plant growth

Application of mouse submaxillary gland epidermal growth factor to young sorghum seedlings at low concentrations (≈0.4-4 μM) increased shoot growth significantly over 3- and 6-day periods. The effects were dose dependent.     

Predicting the growth response to growth hormone in patients with intrauterine growth retardation

OBJECTIVE Human GH treatment of short children who had intrauterine growth retardation (IUGR) results in a highly variable growth response. The object of this study was to test the hypothesis that differences in responsiveness to exogenously administered GH might reflect differences in endogenous GH secretion or sensitivity. DESIGN Prospective study evaluating the growth response to GH therapy in short individuals with prior IUGR. PATIENTS Ten short, prepubertal children with prior IUGR were studied. Mean age was 6 years (3.39–8.61). Mean bone age was 4.6 years (2.3–8.3). Mean body mass index was 13.2 kg/m² (9.9–14.0; normal 13.5–19.0). MEASUREMENTS Overnight spontaneous GH release was measured using a constant withdrawal pump and stimulated GH release was measured following clonidine (0.15 mg/m²) administration. IGF-I concentrations were measured at baseline and 12, 24, 36 and 48 hours after sequential doses of GH (0.05 and 0.2 mg/kg/dose) given 48 hour apart. Patients were treated with GH (0.125 mg/kg three times a week) and growth response was assessed. In the second and third year, attempts were made to improve the growth rate by nutritional supplementation and increasing the dose of GH to 0.25 mg/kg three times a week. RESULTS All patients had normal integrated nocturnal GH secretion (>3 μg/l, 6mU/l) and normal peak GH secretion in response to clonidine (>7 μg/l). In the first year of the trial, mean growth velocity (GV) increased from 5.39 cm/year ± 0.29 to 7.32 cm/year ± 0.39 (P = 0.004). Changes in GV correlated inversely with integrated GH (r = ? 0.69; P = 0038), baseline IGF-I concentration (r = ? 0.88; P = 0.002) and baseline GV-SDS (r = ? 0.68; P = 0.043). There was no correlation between change in GV and GH binding protein, baseline height SDS or age. The effect of GH waned in the second year, but tended to remain greater than the pretreatment growth rate (6.54 ± 0.49 vs 5.53 cm/year ± 0.29; P = 0.09). No significant advancement of bone age over chronological age was observed over the first 2 years. Increasing nutritional intake by 17% did not result in significant weight gain nor increase in height velocity. Doubling the dose of GH in the second or third year did not result in a significant increase in GV. CONCLUSION The variable response to GH therapy in short children with a history of intrauterine growth retardation may partly reflect relative sufficiency or insufficiency of GH. Baseline IGF-I levels and baseline growth velocity appear to be useful and practical predictors of response to GH.     

Interactions between growth hormone, insulin-like growth factor I, and basic fibroblast growth factor in melanocyte growth.

Melanocytes, highly differentiated neural crest-derived cells, are located in the basal layer of the epidermis, where they play a role in protecting against UV damage in the skin. Previous studies suggest that both growth hormone (GH) and the insulin-like growth factor I (GH/IGF-I) system may be important for melanocyte growth and function. We have therefore characterized the role of the GH/IGF system in melanocyte growth in vitro and its interaction with the local growth factor basic fibroblast growth factor (bFGF). Analysis of the effects of GH, IGF-I, and bFGF and combinations of these growth factors on melanocyte growth in vitro revealed that 1) GH stimulates the growth of melanocytes when combined with IGF-I, des(1-3)IGF-I [an analog of IGF-I that has a reduced binding affinity for IGF-binding proteins (IGFBPs)], or bFGF, either separately or in combination; 2) in contrast to the lack of effect of GH or bFGF alone, both IGF-I and des(1-3)IGF-I enhance melanocyte growth in a dose-dependent manner; and 3) IGF-I is more efficacious in eliciting a growth response at low concentrations compared to des(1-3)IGF-I. Using Western ligand blotting, affinity cross-linking, immunoprecipitation, RIA, and Northern analysis, we show that cultured human melanocytes synthesize and secrete minimal amounts of IGFBP. IGFBP-4 is the major IGFBP produced by these cells when cultured in complete growth medium or in the presence of either IGF-I or des(1-3)IGF-I alone. In conclusion, these studies provide support for a role for both GH and IGF-I in the growth of human melanocytes in vitro, involving synergy with bFGF. Low levels of melanocyte-derived IGFBP-4 may play a role in enhancing the modulation of IGF action.     

Growth cartilage expression of growth hormone/insulin-like growth factor I axis in spontaneous and growth hormone induced catch-up growth

IntroductionCatch-up growth following the cessation of a growth inhibiting cause occurs in humans and animals. Although its underlying regulatory mechanisms are not well understood, current hypothesis confer an increasing importance to local factors intrinsic to the long bones' growth plate (GP).AimThe present study was designed to analyze the growth-hormone (GH)-insulin-like growth factor I (IGF-I) axis in the epiphyseal cartilage of young rats exhibiting catch-up growth as well as to evaluate the effect of GH treatment on this process.Material and methodsFemale Sprague–Dawley rats were randomly grouped: controls (group C), 50% diet restriction for 3 days + refeeding (group CR); 50% diet restriction for 3 days + refeeding &; GH treatment (group CRGH). Analysis of GH receptor (GHR), IGF-I, IGF-I receptor (IGF-IR) and IGF binding protein 5 (IGFBP5) expressions by real-time PCR was performed in tibial growth plates extracted at the time of catch-up growth, identified by osseous front advance greater than that of C animals.ResultsIn the absence of GH treatment, catch-up growth was associated with increased IGF-I and IGFBP5 mRNA levels, without changes in GHR or IGF-IR. GH treatment maintained the overexpression of IGF-I mRNA and induced an important increase in IGF-IR expression.ConclusionsCatch-up growth that happens after diet restriction might be related with a dual stimulating local effect of IGF-I in growth plate resulting from overexpression and increased bioavailability of IGF-I. GH treatment further enhanced expression of IGF-IR which likely resulted in a potentiation of local IGF-I actions. These findings point out to an important role of growth cartilage GH/IGF-I axis regulation in a rat model of catch-up growth.     

Predicting growth in response to growth hormone treatment

The use of growth hormone (GH) to treat children who have disturbances of growth is complicated by variability both within and across diagnostic groups, and at the start of and throughout treatment. Growth prediction models are important tools in the effort to account for these sources of variability and tailor GH treatment to each patient’s needs. This review considers the methodological approach taken to the development of models from data in large databases such as the Pfizer International Growth Database (KIGS); it also assesses the limitations of these models and their data sources, and the potential for improvements. While all aspects of model development bear continued scrutiny and improvement, the incorporation of more predictors is key if treatment outcomes are to be optimized in terms of efficacy, safety and cost.     

Dose dependence of growth response to human growth hormone in growth hormone deficiency.

A trial of the relative effect on growth of 20 IU/week and 10 IU/week of human growth hormone has been made in 38 patients with "isolated" growth hormone deficiency over 1 year of treatment, 18 patients over 2 years and 10 over 3 years, and in 17 patients with surgically treated craniopharyngiomata over 1 year. The velocity of height growth in the first year of treatment, compared with a full year of pre-treatment control, was 1.3 times as great in both groups of patients on the larger dose as it was in those on the smaller one. Second-degree equations fitted to the treatment catch-up curve gave estimates of 1.7 cm more height gained on the larger dose by the end of the first year, 2.7 cm by the end of the second, and 3.4 cm by the end of the third. Adjusting treatment increment by covariance for bone age at the beginning of treatment, pre-treatment velocity, and body surface area did not alter these mean differences. Bone age velocity during treatment was the same in both treatment groups (mean 1.09 "years"/year in the first year); thus we anticipate a gain in final adult height of the order of 10 cm from employing the larger dose. The decrease in skin folds occurring on treatment, however, was no different with the larger than with the smaller dose. This reinforces previous observations that the short-term metabolic and longer-term auxologic effects of hGH are not necessarily related.     

肝硬化生长激素-胰岛素样生长因子轴的基础与临床研究

生长激素(GH)是由脑腺垂体前叶嗜酸性粒细胞分泌的一种含191个氨基酸的蛋白质多肽。肝脏是生长激素最主要的靶器官。生长激素可直接与靶组织特异性受体结合发挥其生物学作用；另一方面，生长激素又可通过生长激素-肝-胰岛素样生长因子轴(GH—IGF轴)，刺激肝、肾及其他部位产生胰岛素样生长因子(insulin—like growth factors，IGFs)而间接发挥其生物学效应。     

Normal growth hormone secretion in growth hormone insufficient children retested after completion of linear growth

OBJECTIVE The recognition of the syndrome of adult GH deficiency suggests that young GH deficient adults, deprived of GH replacement at completion of linear growth, may suffer effects of GH deficiency. We assessed GH reserve in young adults previously diagnosed as having idiopathic GH insufficiency, who were treated with hGH replacement (14 IU/m²/week) in childhood. DESIGN Eight patients (7 males, 1 female) diagnosed as having GH insufficiency by insulin tolerance test (ITT) in childhood (ages 8.5–15.6 years) were retested by ITT at completion of linear growth (ages 15.1–19.6 years), 3 months after discontinuation of hGH therapy. MEASUREMENTS GH reserve was measured during ITT at diagnosis and at retesting. Height velocity (HV) and HV SDS were calculated before and during GH therapy. RESULTS At diagnosis, the mean peak GH response to ITT was 10.5 ± 2.0 mU/l (range 7.7–13.6). At retesting, mean GH was 52.4 ± 33.2 mU/l (range 10.4–100), 7/8 subjects having peak GH levels greater than 15 mU/l. During hGH therapy mean HV increased from 4.0 ± 1.5 cm/year at diagnosis to 7.3 ± 1.9 cm/year during the 1st year (P = 0.004) and 6.9 ± 2.3 cm/year during the 2nd year (P = 0.02). Mean HVSDS increased from ?1.6 ± 2.1 at diagnosis to 3.1 ± 2.9 during the 1st year (P = 0.004) and 2.2 ± 4.2 during the 2nd year (P = 0.05, NS) of treatment. CONCLUSIONS Seven out of 8 children diagnosed as having idiopathic GH insufficiency had normal GH secretion at completion of linear growth. Children with GH insufficiency cannot be assumed to become GH deficient adults and should not continue on GH therapy into adult life without reinvestigation. All who were GH insufficient children should be retested at completion of linear growth to identify those who are truly GH insufficient adults and may benefit from replacement therapy.     

Insulin-like growth factor I is essential for postnatal growth in response to growth hormone.

Insulin-like growth factor I (IGF-I) is essential for cell growth and intrauterine development while both IGF-I and GH are required for postnatal growth. To explore the possibility of direct GH action on body growth, independent of IGF-I production, we have studied the effects of GH in an IGF-I-deficient mouse line created by the Cre/loxP system. The IGF-I null mice are born with 35% growth retardation and show delayed onset of peripubertal growth, grow significantly slower, and do not attain puberty. Their adult body weight was approximately one third and body length about two thirds that of their wild-type litter mates. Injection of recombinant human GH (rhGH, 3 mg/kg, twice daily, sc) between postnatal day 14 (P14) to P56 failed to stimulate their growth as measured as both body weight and length. In contrast, wild-type mice receiving the same doses of rhGH exhibited accelerated growth starting at P21 that continued until P56, when their body weight was increased by 30% and length by 12% compared with control mice treated with diluent. Despite the lack of response in growth, IGF-I null mice have normal levels of GH receptor expression in the liver and increased liver Jun B expression and liver size in response to rhGH treatment. Our results support an essential role for IGF-I in GH-induced postnatal body growth in mice.     

Longitudinal bone growth in vitro: effects of insulin-like growth factor I and growth hormone

Longitudinal growth was studied using an in vitro model system of intact rat long bones. Metatarsal bones from 18- and 19-day-old rat fetuses, entirely (18 days) or mainly (19 days) composed of chondrocytes, showed a steady rate of growth and radiolabelled thymidine incorporation for at least 7 days in serum-free media. Addition of recombinant human insulin-like growth factor-I to the culture media resulted in a direct stimulation of the longitudinal growth. Recombinant human growth hormone was also able to stimulate bone growth, although this was generally accomplished after a time lag of more than 2 days. A monoclonal antibody to IGF-I abolished both the IGF-I and GH-stimulated growth. However, the antibody had no effect on the growth of the bone explants in control, serum-free medium. Unlike the fetal long bones, bones from 2-day-old neonatal rats were arrested in their growth after 1-2 days in vitro. The neonatal bones responded to IGF-I and GH in a similar fashion as the fetal bones. Thus in this study in vitro evidence of a direct effect of GH on long bone growth via stimulating local production of IGF by the growth plate chondrocytes is presented. Furthermore, endogenous growth factors, others than IGFs, appear to play a crucial role in the regulation of fetal long bone growth.     

Expression of insulin-like growth factor I stimulates normal somatic growth in growth hormone-deficient transgenic mice

A line of transgenic mice expressing insulin-like growth factor-I (IGF-I) under the control of the mouse metallothionien-1 promoter was crossed to a line of dwarf transgenic mice lacking GH expressing cells that were genetically ablated by diphtheria toxin expression. Mice generated from this cross that carry both transgenes express IGF-I in the absence of GH. These mice grew larger than their GH-deficient transgenic littermates and exhibited weight and linear growth indistinguishable from that of their nontransgenic siblings. These results confirm the suspected role of IGF-I in mediating GH's stimulation of somatic growth, including that of long bones, and illustrates the essential role of GH and IGF-I in the modulation of postnatal growth. Analysis of differences in organ growth among these mice, however, suggests that GH and IGF-I also have growth promoting actions that are independent of one another; GH appears to be necessary for the attainment of normal liver size, while IGF-I can stimulate brain growth.     

Effects of growth hormone and insulinlike growth factor-I on body growth and adult bone metabolism

The anabolic action of growth hormone (GH) on bone is well demonstrated by the short stature and delayed bone maturation in children with GH deficiency and in acromegalic patients with increased cortical bone mass. The body growth is regulated by growth hormone and insulin-like growth factor-I (IGF-I). The classic somatomedin hypothesis of this regulation is that most IGF-I in the blood originates in the liver and that body growth is controlled by the concentration of IGF-I in the blood. We have recently abolished IGF-I production in the livers of mice by using the Cre/loxP recombination system. The mice, in which IGF-I production had been inactivated in the liver, displayed a more than 80% reduction in serum IGF-I. In contrast, they demonstrated a normal postnatal growth, indicating that extrahepatic, autocrine/paracrine-acting IGF-I is the main determinant of postnatal growth. GH is also important for normal adult bone remodeling. Adults with GH deficiency have reduced bone mass, and GH treatment increases bone mass in GH-deficient adults. Future clinical studies will determine whether some patients with decreased bone mass for other reasons will benefit from treatment with GH alone or in combination with other treatments.