"Functional food" for acceleration of growth in short children born small for gestational age.

OBJECTIVE: To assess the effect of nutritional supplementation on growth in short children born small for gestational age (SGA). PATIENTS: Fifty four short but otherwise healthy children (26 boys), 6.4 +/- 1.8 years of age, were referred for growth retardation. METHODS: Following a 6 month observation period the participants were randomly allocated to receive growth hormone therapy (GH) 1.26 IU/kg/day (0.042 mg/kg/day) or nutritional program (NUT) or passive observation (OBS). Patients in the nutritional program received 10 mg/day iron, 11 mg zinc-three times a week and 10000 IU/week of vitamin A. The following parameters were obtained 3 monthly: height, weight, dietary intake and serum IGF-1. RESULTS: Six months of nutritional supplement induced growth acceleration somewhat lower than that seen in the growth hormone treated children, but significantly greater than noted in the observation group (OBS 4.6 +/- 1.3, NUT 7.9 +/- 1.7, GH 9.1 +/- 1.8 cm/yr, P<0.001). CONCLUSIONS: Six months of vitamin A, iron and zinc supplementation induces growth acceleration in short children born SGA with subnormal nutrients intake similar to growth hormone therapy.

Effect of polymorphism in insulin locus and HLA on type 1 diabetes in four ethnic groups in Israel.

This study examined a possible association of the insulin (INS) gene with type 1 diabetes (T1D) in patients and controls from four ethnic groups in Israel. We analyzed the distribution of -23HphI single nucleotide polymorphism (SNP) T/A alleles that correspond to INS variable number of tandem repeat short class I alleles (26-63 repeats) and class III alleles (141-209 repeats), respectively. The -23HphI T/T genotype was found to be positively associated with T1D in three Jewish groups (Yemenites: 93.9% patients vs 68.8% controls, P = 0.0002; Ashkenazi: 80.6% vs 50.8%, P < 10(-4); Ethiopians: 75% vs 40.5%, P = 0.002). The Yemenite healthy controls have the highest frequency of T allele from all Jewish groups studied (83.5% vs 68.8% in Ashkenazi and 64.3% in Ethiopians). The high frequency of a susceptibility allele in the Yemenites is in line with the high incidence of T1D in this population. No association was observed between T1D and the INS gene in Israeli Arabs studied (70.6% vs 66.7%). Variable incidence of T1D among different ethnicities in Israel is largely attributed to heterogeneous genetics. Human leukocyte antigen (HLA) results of our previous studies describing the susceptibility and protective haplotypes were used for combined analysis to determine possible interaction between the HLA and INS loci. Only in the Ashkenazi group such interaction was presented with statistical significance.

Type 1 diabetes in Jewish Ethiopian immigrants in Israel: HLA class II immunogenetics and contribution of new environment.

The interrelationship between human leukocyte antigen immunogenetics and environmental factors and their contribution to the emergence of type 1 diabetes (T1D) were studied in Jewish immigrants from Ethiopia in Israel. This community displays high incidence of T1D, and is unique both by its ethnic segregation and its rapid exposure to a new environment after the immigration. The study population consisted of 152 Ethiopian Jews living in Israel, 33 with T1D and 119 unrelated controls. Human leukocyte antigen class II susceptible and protective alleles in the Jewish Ethiopian patients were similar to those in patients of other ethnic groups in Israel and in non-Jewish Ethiopian patients, with a few exceptions. Three haplotypes were markedly associated with diabetes in Jewish Ethiopian patients: DRB1*0301 DQA1*05 DQB1*02 (OR 4.4, p < 0.001); DRB1*0404 DQA1 03 DQB1*0302 (OR 19.2, p = 0.006), and DRB1*0405 DQA1*03 DQB1*0302 (OR 87.8, p < 0.001). The highly susceptible allele DRB1*0301 was more common in the general Ethiopian population (25.2%) than in all other ethnic groups in Israel, which may render this community prone to the disease. The age at onset of disease in patients with two susceptible haplotypes was negatively correlated with the duration of living in Israel (r = -0.621, p = 0.04). We concluded that ongoing exposure of genetically predisposed immigrants from Ethiopia to diabetogenic environmental factors eventually leads to a high incidence of overt diabetes in this ethnic group.

Vitamin A and iron supplementation is as efficient as hormonal therapy in constitutionally delayed children.

OBJECTIVE: To assess the effect of nutritional supplementation on growth and puberty in constitutionally delayed children. PATIENTS: One hundred and two boys, 13.6-15.5 years of age, who were referred because of short stature and delayed puberty. METHODS: The boys were randomly allocated to one of the following treatment groups: oxandrolone therapy, 5 mg/day for 6 months (n = 15), testosterone depot, 100 mg monthly for 3 months (n = 15) or for 6 months (n = 20), nutritional programme (n = 17), oxandrolone and nutritional programme (n = 15) or passive observation (n = 20). Boys in the nutritional programmes received 12 mg/day iron and 6000 IU/week of vitamin A. Outcome measurements were of height, weight, pubertal signs, dietary intake, serum vitamin A, iron, GH and IGF-1. RESULTS: Six months of vitamin A supplementation induced growth acceleration similar to that seen in the oxandrolone- and testosterone-treated children, and significantly greater than in the observation group (9.3 +/- 2.9 vs. 4.0 +/- 0.9 crn/yr, P < 0.001). Whereas in the vitamin A-supplemented group, puberty (increase in testicular volume >/= 12 ml) was induced within 12 months. In all testosterone-treated patients, pubic hair was noted within 3 months and a testicular volume of >/= 12 ml was observed 9-12 months after the initiation of therapy. No pubertal signs were noted in the observation group during this time. CONCLUSIONS: Subnormal vitamin A intake is one of the aetiological factors in delayed pubertal maturation. Supplementation of both vitamin A and iron to normal constitutionally delayed children with subnormal vitamin A intake is as efficacious as hormonal therapy in the induction of growth and puberty.

Small for gestational age: towards 2004.

Children born small for gestational age are a non-homogeneous group and etiology and diagnostic needs vary among subgroups. In view of the knowledge accumulated about immediate and future risk factors for these children it is important to study the etiology and to invest in long-term prevention programs. The aim of this report is to summarize the current knowledge on mechanisms leading to intrauterine growth retardation and to review the intervention procedures.

Interrelationship between insulin, leptin and growth hormone in growth hormone-treated children.

OBJECTIVES: The aim of the study was to examine insulin homeostasis during growth hormone (GH) therapy, and to investigate the effect of GH treatment on insulin and leptin concentration in obese children. SUBJECTS: Nineteen obese children (8 with Prader-Willi Syndrome (PWS)) were treated with GH 0.1 IU/kg/day dose for 3 months and were compared with 29 non-treated age and sex matched obese children (9 PWS) and 49 GH treated non-obese short children. Mean age of the children was 10.3+/-1.8 (6.7-13.8) y, with body mass index of 23.6+/-10.4 (11.5-47) kg/m2. RESULTS: Leptin concentration decreased and was correlated inversely with initial leptin value (r2=-0.374, P<0.001) and decreased body mass (r2=0.338, P=0.001). Insulin sensitivity index was not significantly changed during therapy. Leptin decrease after 3 months of GH administration was correlated inversely with the increase in first phase insulin response to intravenous glucose tolerance test (IVGTT) (r2=-0.595, P<0.001). Results of long-term follow-up of treated patients demonstrated a decrease in insulin concentration after cessation of therapy. In GH-treated subjects, the glucose increase in response to glucose load appeared to be higher than in untreated subjects. CONCLUSION: The high insulin response to glucose load seen in GH-treated subjects was appropriate to their glucose concentration and the insulin sensitivity index was unchanged relative to the pretreatment period. Increased insulin dosage in our patients did not induce an increase in leptin concentrations as had been hypothesised.

Nocturnal integrated gonadotropin concentrations in evaluating pubertal transition in girls.

We assessed the utility of measuring the physiological levels of gonadotropins as a diagnostic tool for pubertal onset in girls. Two methods of gonadotropin measurements were compared: the standard frequent sampling method, in which blood samples were drawn every 20 min, and the multiple integrated sampling method, in which samples were obtained continuously at 30 min intervals by a withdrawal pump. The two methods were examined simultaneously overnight in a group of eight girls at different stages of puberty. The following parameters of both LH and FSH secretion, calculated by PULSAR program, were highly correlated between these methods: area under the curve (AUC), mean levels, mean from smoothed baseline and mean peak height. The diagnostic value of multiple integrated sampling of gonadotropins (performed over 6 h) was then assessed in five prepubertal girls and six girls at early puberty (Tanner stages 2 and 3), in whom peak gonadotropins levels in response to GnRH stimulation test were in the prepubertal range. Several parameters of LH (but none of FSH) were significantly higher (p<0.05) in early pubertal compared to prepubertal girls: AUC (5.61 +/- 2.40 vs 2.39 +/- 1.41), mean levels (0.52 +/- 0.21 vs 0.23 +/- 0.14), smoothed mean level (0.43 +/- 0.18 vs 0.18 +/- 0.11) and peak area (0.27 +/- 0.08 vs 0.11 +/- 0.06). We conclude that the technically simple method of multiple integrated sampling is useful in detecting pubertal transition and is superior to the GnRH-stimulation test. This method can be used in selective cases when the stimulation test yields equivocal results.

Testosterone effect on growth and growth mediators of the GH-IGF-I axis in the liver and epiphyseal growth plate of juvenile rats.

Several studies have suggested that testosterone may have a direct, GH-independent effect on growth. In order to assess possible mechanism(s) whereby testosterone exerts its growth-promoting effect, we evaluated its effect on growth mediators of the GH-IGF-I axis, in both the liver and the epiphyseal growth plate (EGP). Testosterone was administered to peripubertal rats and the responses of mRNA of GH receptor, IGF-I, IGF-I receptor and IGF-binding proteins-1 and -3 (IGFBP-1 and IGFBP-3) as well as circulating IGF-I were evaluated in two time-related models: over 12 h after a single injection (short-term study) and 10 days after continuous administration (long-term study). Rats in the short-term study were castrated and were killed 1, 4, 6 and 12 h post injection. Rats in the long-term study were divided into two groups: castrated vs castrated and hypophysectomized, in order to assess the effect of testosterone in the presence and absence of GH. mRNA levels were determined by RNase protection assay, and serum IGF-I by RIA. Testosterone enhanced weight gain in the rats treated for 10 days, a change that was similar in the presence or absence of GH. This effect was relatively small, however, by comparison with the total weight gained without testosterone. Testosterone had no effect on hepatic IGF-I mRNA abundance but induced a reduction in circulating IGF-I levels, in both the short- and long-term study. Testosterone had no effect on hepatic GH receptor and IGFBP-3 mRNA levels but resulted in a transient, short-term elevation in IGFBP-1 mRNA levels that was maximal 4 h post injection. In the EGP, neither testosterone administration nor hypophysectomy had any effect on IGF-I and IGF-I receptor mRNA levels. However, testosterone increased GH receptor mRNA abundance after 10 days of continuous administration in hypophysectomized rats only. These data suggest that the effect of testosterone on growth (as assessed by weight gain) is small and is not mediated by changes in hepatic gene expression of IGF-I, IGF-I receptor, IGFBP-1, IGFBP-3 or circulating IGF-I. At the EGP, the testosterone effect on linear growth is not mediated through changes in mRNA abundance of IGF-I and IGF-I receptor. The small but significant elevation of GH receptor mRNA levels in hypophysectomized rats may suggest a testosterone-mediated augmentation of a GH effect at the target organ.

Sertoli cell tumor causing precocious puberty in a girl with Peutz-Jeghers syndrome.

Distinctive ovarian and cervical tumors are associated with Peutz-Jeghers syndrome (PJS). The most common gynecological tumors in this syndrome are adenoma malignum of the uterine cervix and ovarian sex cord tumor, particularly sex cord tumor with annular tubules (SCTAT). Other kinds of ovarian tumors have been rarely reported in association of PJS, including Sertoli cell tumors. We report a case of a 4.5-year-old girl with PJS who presented with isosexual precocious puberty (IPP) due to ovarian lipid-rich Sertoli cell tumor. In addition to estrinizing effect of the tumor, the patient had decidual reaction secondary to tumor-derived progesterone secretion. The literature on gonadal tumors in PJS is reviewed, including one previous report of ovarian lipid-rich Sertoli cell tumor associated with this syndrome.

Effect of age on the response to parathyroid hormone.

Serum phosphate (PO4) levels and the tubular threshold for PO4 corrected for glomerular filtration (TP/GF) are age-dependent, being higher in children than in adults. We evaluated the effect of age on the response to infusion of parathyroid hormone(1-34) (PTH) in healthy children (n = 8) and adults (n = 12). In addition, six patients with pseudohypoparathyroidism (PHP) and two with PTH deficiency (hypoparathyroidism [HP]) were also studied. At baseline, TP/GF in normal subjects was inversely correlated with urinary cyclic adenosine monophosphate corrected for glomerular filtration (UcAMP/GF) (P < .0359). After PTH administration in the controls, UcAMP/GF was inversely correlated with TP/GF (P < .0007) and directly correlated with maximal fractional extraction of PO4 (FEP) (P < .0002). The slope of the regression of TP/GF (P < .0076) and FEP (P < .0034) with UcAMP/GF was steeper in children than in adults. Two HP patients had high PTH-stimulated UcAMP/GF levels, but stimulated TP/GF and FEP were not changed commensurate with levels that would expected from the normative data. In six patients with PHP, PTH-stimulated TP/GF was also correlated with peak UcAMP/GF (r = .96, P < .002). PHP patients could be distinguished from normal controls based on the combination of low peak FEP or high TP/GF together with low peak UcAMP/GF. Thus, in normal subjects, the phosphaturic response to PTH is correlated with the increase in urinary cAMP and is age-dependent, with a greater decrease of TP/GF in children than in adults.

Evolving growth hormone deficiency in children with a subnormal secretion of growth hormone.

Three growth-retarded children with a normal growth hormone (GH) response to provocative tests, but subnormal 24-hour integrated concentrations of GH and insulin-like growth factor-binding protein 3 (IGF-BP3) are presented. Retesting 3 to 4 years later demonstrated a subnormal GH response to stimulation. The initial subnormal growth rate and IGF-BP3, despite a normal GH response to stimulation, may be secondary to a subnormal integrated concentration of GH.

Growth hormone deficiency in autoimmune polyglandular syndrome.

We describe a boy with autoimmune adrenal failure and compensated hypothyroidism, associated with isolated growth hormone deficiency (GHD). We suggest an autoimmune mechanism as the underlying etiology for the GHD in this case.

Final height after growth hormone therapy in short children: correlation with siblings' height.

Sixteen prepubertal children (10 males, 6 females) were treated with growth hormone (GH) 0.75 U/kg/week for 4-5 years until final height was attained. Before initiation of GH therapy height was below 2 SDS for age and gender, growth velocity was <4.5 cm/year, bone age was more than 2 SD below the mean for age, and the GH response to provocative tests was more than 10 microg/l. The final height of 9 patients exceeded their predicted and target heights. The final height of the treated patients was highly correlated with their siblings' heights (r = 0.806, p < 0.001) and to a lesser degree with the target or the predicted height (r = 0.401, p = 0.124 and r = 0.465, p = 0.06, respectively). It is concluded that the secular trend should be taken into consideration when evaluating the success of GH therapy.

Growth of short children during and after discontinuation of growth hormone therapy.

We have attempted to evaluate the relationship between spontaneous growth hormone (GH) secretion and the response to GH therapy as well as the effect of discontinuation of GH therapy on further growth. The 24-h integrated concentration of GH (ICGH) was determined in 150 short children (< 2 SD for age) with a GH response to clonidine stimulation of more than 10 mcg/L. The patients were treated with GH for 4 yr and were observed for 1 yr following cessation of GH treatment. Twenty-two out of 52 patients who had an ICGH of less than 3.2 mcg/L (group LICGH) and 28 out of 60 patients who had an ICGH of more than 3.2 mcg/L (group NICGH) were followed without GH therapy. Only patients who remained prepubertal throughout the study were included in the analysis. The growth response of the LICGH to GH was better than that of the NICGH children. Patients regained normal growth velocity 6-12 months after discontinuation of GH therapy. Three children of the LICGH subsequently developed classic GH deficiency. These studies demonstrate that short-term GH therapy can improve the growth channel. Children with a low ICGH grow better on GH than children with a normal ICGH. Children with a low ICGH need continued observation and retesting when growth velocity is low.

Urinary cyclic adenosine 3',5'-monophosphate response in McCune-Albright syndrome: clinical evidence for altered renal adenylate cyclase activity.

The recent finding of an activating mutation in the Gs alpha protein, the protein that couples receptors to stimulation of adenylate cyclase, from endocrine and nonendocrine tissues of patients with McCune-Albright syndrome (MAS) suggests that alterations in adenylate cyclase activity may account for the clinical abnormalities in these patients. Many patients with MAS have hypophosphatemia. This may result from the presence of the activating Gs alpha mutation in proximal renal tubules or the elaboration of a phosphaturic factor from fibrous dysplasia. We, therefore, sought to characterize renal cAMP generation and phosphate handling in MAS patients. Intravenous infusion of PTH is a classic clinical test used to evaluate hormonal responsiveness of renal proximal tubule adenylate cyclase and examine PTH-dependent phosphate clearance. We performed PTH infusion in 6 MAS patients, 10 normal subjects, and 6 patients with pseudohypoparathyroidism (PHP). The basal urinary cAMP (UcAMP) level in the MAS group [5.5 +/- 2.6 nmol/dL glomerular filtration (GF)] was elevated (P < 0.05) compared to those in both normal subjects (3.2 +/- 1.2 nmol/dL GF) and patients with PHP (1.9 +/- 0.6 nmol/dL GF). However, PTH-stimulated peak UcAMP (15.0 +/- 7.0 nmol/dL GF) and the peak/basal UcAMP ratio (3.1 +/- 1.7) in MAS were significantly lower than the respective values in normal subjects (30.8 +/- 16.9 nmol/dL GF and 9.3 +/- 2.9; P < 0.05 for both) and were statistically similar to the blunted levels in PHP (respectively, 3.1 +/- 1.5 nmol/dL GF and 2.0 +/- 1.7). By contrast, the PTH-induced phosphaturic response in MAS patients was similar to that in the normal subjects. Our study provides clinical evidence that MAS patients have altered renal adenylate cyclase activity, manifested by an elevated basal UcAMP, but a blunted UcAMP response to PTH stimulation. These observations are presumably due to a mutation in the Gs alpha protein in the renal tubules. Despite the blunted UcAMP excretion, the phosphaturic response to PTH in MAS patients is intact.

The accumulation of IGF-I in kidneys of streptozotocin-diabetic adult rats is not associated with elevated plasma GH or IGF-I levels.

Nephropathy is a major complication of diabetes mellitus and is associated with expansion of the mesangium and an increase in kidney size in both humans and rats. Interestingly, early kidney enlargement occurs only in postpubertal animals, and is preceded by a significant increase in the levels of extractable renal IGF-I. This study examined the possibility that this difference is GH dependent, and that very early changes in plasma GH and/or IGF-I in the adult animal are associated with an early accumulation of renal IGF-I. Silastic jugular catheters were placed in adult (13-14 week) male Sprague-Dawley (S-D) rats for blood collection and drug injection. Serial blood samples were taken every 30 min in groups of saline control and streptozotocin (STZ) (50 µg/kg, IV) rats from 1-6 h, 9-15 h, and 24-30 h post-injection, and plasma GH profiles were determined by RIA. Renal IGF-I content was assessed following acid extraction. Following STZ, there was an immediate, step-wise reduction in peak GH levels (saline controls, 54±7 ng/mlvs 30±5 (1-6 h); 23±10 (9-15 h); and 13±3 ng/ml (24-30 h post-STZ);P<0.05 for all STZ groupsvs control). The same significant step-wise reduction was observed in the integrated area under the curve for GH. A separate group of rats were treated with a GH-releasing factor antagonist (GRF-AN) for 5 days prior to STZ, to suppress pulsatile GH release, and reduce plasma IGF-I. Chronic GRF-AN administration reduced plasma IGF-I levels significantly to 63% of control values (P<0.01). However, despite the reduction in plasma IGF-I, renal IGF-I remained significantly elevated 24 h post-STZ compared with controls and not significantly different from animals treated with STZ alone (467±49 ng IGF-I/g KW in control salinevs 778±100 in saline/STZ and 705±87 ng IGF-I/g KW in chronic GRF-AN/STZ rats (P<0.05)). In conclusion, following STZ administration in the adult rat, there is an immediate reduction in GH levels, indicating the renal IGF-I accumulation occurs without initial increases in plasma GH levels. Furthermore, when plasma IGF-I levels in the adult are significantly reduced renal IGF-I content remains elevated. These data suggest that early diabetic renal growth is not associated with elevated circulating GH levels, and that high basal plasma IGF-I levels are not necessary for IGF-I accumulation.

Effect of long-term growth hormone therapy on bone age and pubertal maturation in boys with and without classic growth hormone deficiency.

We evaluated the effect of growth hormone (GH) therapy on bone age, pubertal maturation and predicted adult height in two groups of boys treated for 4 years: 40 growth hormone-deficient boys who had growth hormone response to provocative stimulation < 10 micrograms/L (GHD group) and 43 boys whose stimulated growth hormone > or = 10 micrograms/L (group with neurosecretory dysfunction (NSD)). All patients had a subnormal integrated concentration of growth hormone < or = 3.2 micrograms/L, height < -2 SD, growth velocity < 4.5 cm/yr, and bone age < or = -2 SD for chronologic age. Patients were treated with recombinant growth hormone, 0.1 mg/kg per dose given three times a week. The pretreatment height SD of the GHD group (-3.6 +/- 1.0) was less than that of the NSD group (-2.7 +/- 0.7; p < 0.001). After 4 years of therapy, both groups had catch-up growth (GHD group to -2.0 +/- 1.3 height SD (n = 35), and NSD group to -1.4 +/- 0.7 height SD (n = 32)); the rate of height SD gain was better in patients with GHD (p < 0.01). The response to growth hormone was inversely related to pretreatment chronologic age (p < 0.001). The Tanner-Whitehouse II predicted adult height improved for both groups: +9.3 +/- 7.7 cm in the GHD group, giving an adult height SD of -0.9 +/- 1.0, and +5.4 +/- 5.5 cm in patients with NSD, for an adult height SD if -0.8 +/- 0.7. Testosterone levels became higher in the NSD group after 2 years and remained higher at year 4. We conclude that patients respond favorably to growth hormone therapy and in a manner similar to patients with GHD. Initiation of therapy at a younger age gives a greater improvement in gained height and predicted adult height.