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There is still a lack of data from randomized, controlled, long-term studies of growth hormone (GH) treatment in children born small for gestational age (SGA), but the available evidence indicates consistently that GH therapy is a valid growth-promoting treatment in these children, particularly if started early. Whilst side effects appear uncommon, ongoing surveillance is required and treated children should be monitored for changes in glucose homeostasis, lipid profiles and blood pressure, especially during puberty. We provide an update on the safety and efficacy of GH treatment in short children born SGA., (Copyright 2006 S. Karger AG, Basel.)

There is increasing evidence for a link between prenatal growth and pubertal development. Here we highlight a selection of pubertal characteristics in children who were born small for gestational age (SGA). Boys born SGA are at risk of high levels of follicle-stimulating hormone (FSH) and low levels of inhibin B and a small testicular volume during adolescence. In girls born SGA, the age at pubertal onset and the age at menarche are advanced by about 5-10 months; prenatal growth restraint may also be associated with higher FSH levels and smaller internal genitalia in adolescence. The ovulation rate was found to be reduced in adolescent girls born SGA, and an insulin-sensitizing therapy was capable of raising this low ovulation rate. Menarche is definitely advanced in girls born SGA with precocious pubarche and in those with an early-normal onset of puberty. Current evidence suggests that insulin resistance is a key mechanism linking a post-SGA state to early menarche; hence, insulin sensitization may become a valid approach to prevent early menarche and early growth arrest in girls born SGA., (Copyright 2006 S. Karger AG, Basel.)

Mutations of the PIT1/POU1F1 gene are responsible for a rare variant of anterior hypopituitarism, including deficiency of growth hormone, prolactin and thyrotropin. In 8 ethnically diverse POU1F1-deficient patients (4 different mutations) with normal circulating levels of cortisol and adrenocorticotropic hormone, and with spontaneous onset and progression of puberty, we observed an absence or delay of adrenarche (median circulating dehydroepiandrosterone-sulfate -6.2 SD); in each of the 4 postmenarcheal females, pubarche (i.e. appearance of pubic hair) was also absent or delayed. The absence/delay of adrenarche in POU1F1-deficient patients and the absence/delay of pubarche in POU1F1-deficient females suggest that a POU1F1-dependent factor contributes to the normal development of adrenarche and female pubarche., ((c) 2005 S. Karger AG, Basel.)

Background: The growth response to recombinant hGH (rhGH) treatment and final height of 61 Belgian children (32 boys) with idiopathic growth hormone deficiency (GHD) were studied., Patients/methods: Two patient groups were compared: Group 1 with spontaneous puberty (n = 49), Group 2 with induced puberty (n = 12). The patients were treated with daily subcutaneous injections of rhGH in a dose of 0.5-0.7 IU/kg/week (0.17-0.23 mg/kg/week) from the mean +/- SD age of 11.9 +/- 3.1 years during 5.1 +/- 2.1 years., Results: rhGH treatment induced a doubling of the height velocity during the first year and resulted in a normalisation of height in 53 (87%) patients. Final height was -0.7 +/- 1.1 SDS, being 170.4 +/- 7.2 cm in boys and 158.0 +/- 6.4 cm in girls. Corrected for mid-parental height, final height was 0.0 +/- 1.1 SDS. Ninety-two percent of the patients attained an adult height within the genetically determined target height range. Although height gain during puberty was smaller in the patients with induced puberty (boys: 17.1 +/- 7.0 cm vs. 27.5 +/- 6.6 cm (p < 0.005); girls: 9.6 +/- 7.4 cm vs. 22.2 +/- 6.1 cm (p < 0.005)), no differences in final height after adjustment for mid-parental height were found between patients with spontaneous or induced puberty., Conclusions: We conclude that patients with idiopathic GHD treated with rhGH administered as daily subcutaneous injections in a dose of 0.5-0.7 IU/kg/week reach their genetic growth potential, resulting in a normalisation of height in the majority of them, irrespective of spontaneous or induced puberty., (Copyright 2001 S. Karger AG, Basel)

Objective: To study the effects of different regimens of growth hormone (GH) treatment on serum leptin levels in 78 short prepubertal children born small for gestational age (SGA)., Methods: The children were originally included in two independent multicenter trials, one in Belgium and one in the Nordic countries. SGA children were randomized either to remain untreated or to be treated with GH at a daily dose of 0.1, 0.2 or 0.3 IU/kg for 2 years. Thereafter, treatment was continued for another 2 years in the Nordic children, whereas it was discontinued in the Belgian children., Results: In the GH treatment groups, a significant dose-dependent decrease in leptin levels was found during the first year of therapy, with a mean decrease of 13, 23 and 32% in the groups receiving GH at 0.1, 0.2 and 0.3 IU/kg, respectively. When high-dose treatment was interrupted, serum leptin increased within 1 year to pretreatment levels., Conclusion: Serum leptin levels in short children born SGA are transiently reduced by GH treatment in a dose-dependent fashion. The most pronounced changes in serum leptin were documented within the first year after initiation and withdrawal of high-dose GH treatment., (Copyright 2001 S. Karger AG, Basel)

Background: Hyperinsulinism and hyperandrogenism have the capacity to increase bone mineral density (BMD) and serum leptin, independently of body fat mass. We therefore assessed lumbar BMD and serum leptin in girls with the sequence of a low birthweight and precocious pubarche (PP) in childhood, in whom hyperinsulinism and hyperandrogenism have been described., Methods: Fifty-two non-obese PP girls were studied (age range 6.9-14.9 years). Serum leptin was also measured in 42 control girls, matched for age, body mass index and pubertal stage., Results: BMD SDS, measured by dual-energy X-ray absorptiometry, was elevated in PP girls compared to the population reference (0.39 +/- 0.18 SDS; p = 0.03) and bone age, assessed from hand radiographs, was significantly advanced compared to chronological age (1.2 +/- 0.1 years; p < 0.0005)., Conclusion: Compared to control girls, PP girls had higher leptin levels for degree of body mass index (PP girls: 9.4 +/- 0.6 ng/ml; controls: 7.8 +/- 0.6 ng/ml; p = 0.01). In PP girls, serum leptin was inversely related to birthweight (r = -0.32, p = 0.01) and positively related to free androgen index (FAI) (r = 0.71, p < 0.0005). BMD SDS was also inversely related to birthweight (r = -0.26, p < 0.05) and positively related to serum leptin (r = 0.42, p < 0.05), FAI (r = 0.45, p < 0.05) and mean serum insulin during oral glucose tolerance testing (MSI) (r = 0.59, p < 0.0005). In multiple regression, MSI was the strongest determinant of BMD SDS (beta = 0.50, p = 0.002). In conclusion, elevated BMD and serum leptin in non-obese PP girls were related to degrees of low birthweight, hyperinsulinism and hyperandrogenism. The characteristic hyperinsulinism of PP girls is proposed to be the key variable in this constellation., (Copyright 2001 S. Karger AG, Basel)

To assess whether fetal luteinizing hormone releasing hormone (LH-RH) neurosecretory neurons have the capacity to respond to an exogenous stimulus, a synthetic excitatory amino acid analogue, N-methyl-D-L-aspartate (NMDA; 15 mg/kg), was given rapidly intravenously to 8 chronically catheterized fetuses (130-142 days of gestation; term 147 +/- 3 days). All 8 fetuses exhibited a rise in plasma ovine luteinizing hormone (oLH) and ovine follicle-stimulating hormone (oFSH) within 5 min. The mean maximal increments of oLH (2.25 +/- 0.36 ng/ml) and oFSH (1.21 +/- 0.32 ng/ml) were significantly greater than in 6 normal saline-injected controls (oLH p < 0.0002; oFSH p < 0.03). The secretion of ovine prolactin (oPRL) and ovine growth hormone (oGH) was unaffected. LH-RH (5 microg) evoked a greater oLH response (p < 0.0009) and a greater oFSH response (p < 0.03) than NMDA (n = 6). Desensitization of the fetal gonadotrope by a potent LH-RH agonist, D-Trp6Pro9NEt-LH-RH (10 microg/day i.v. x 4 days), abolished the fetal oLH and the oFSH response to NMDA (n = 5). Moreover, D, L-2-amino-5-phosphonovalerate, a specific competitive antagonist for the NMDA receptor, completely inhibited the fetal oLH and oFSH response to NMDA, whereas D-L-2-amino-5-phosphonovalerate alone did not affect the plasma oLH or oFSH levels, the gonadotropin response to LH-RH, or the release of oGH or oPRL (n = 3). In primary ovine fetal pituitary cell cultures, NMDA (10(-10) to 10(-6) M) had no effect on oLH, oFSH, oGH, or oPRL secretion, whereas LH-RH stimulated oLH (10(-8) M; p < 0.0004) and oFSH (10(-8) M; p < 0. 0001) release, evidence that NMDA did not have a direct pituitary effect. The results suggest that NMDA induces oLH and oFSH secretion by stimulation of the fetal LH-RH pulse generator and is mediated by central NMDA receptors. Fetal LH and FSH secretion and the response to LH-RH decrease in late gestation in the ovine and human fetus. The relative importance of sex steroid dependent and sex steroid independent central nervous system inhibition in this developmental change is unclear. It appears that central neural inhibition in addition to sex steroid negative feedback contributes to the decrease in fetal gonadotropin concentrations in late gestation. NMDA did not affect fetal oGH or oPRL secretion.

We examined whether male pseudohermaphroditism, when unexplained, is associated with reduced prenatal growth. Birth weight SD scores of 29 children with male pseudohermaphroditism were compared. The scores of children with an unexplained condition (median -2.1 SD) were found to be lower (p = 0.0001) than those of children with an explained condition (median -0.4 SD). In the majority of cases of unexplained male pseudohermaphroditism, there was a complicated history before conception or in early pregnancy. In conclusion, hitherto unexplained male pseudohermaphroditism was found to be associated with reduced prenatal growth and complications at conception or in early pregnancy.

In girls, pronounced adrenarche with precocious pubarche (PP) has been related to reduced fetal growth and to a cluster of endocrine-metabolic abnormalities. We examined whether these associations are also evident in boys with PP. The study population consisted of matched groups of boys (n = 58; age range 5-15 years) without or with a history of PP. After stratification for pubertal development, non-PP and PP boys displayed comparable results for the studied variables, including serum insulin-like growth factor I, sex hormone binding globulin, insulin-like growth factor binding proteins 1 and 3, indices of circulating glucose and insulin responsiveness to an oral glucose load, and birth weight SD score. In conclusion, the present results indicate that adrenarche-driven PP in boys is, in contrast to PP in girls, not associated with a cluster of endocrine-metabolic abnormalities and is not related to reduced fetal growth. These observations support the view that adrenarche-driven PP in boys may be regarded as a variant of normal development. Copyrightz1999S.KargerAG,Basel

At term birth, boys are heavier than girls. This difference is thought to be generated in part by androgen action; its time course has not been deciphered. Androgen action may not only increase weight gain, but may also alter its time course. We have tested this hypothesis by examining the difference in gestational age of 281,894 boys and girls with weights between 500-4,749 g. The age at which children are born with a given weight was found to depend on gender: boys were consistently younger than girls (p < 0.001), the age difference being most pronounced in the lower birth weight classes. Thus, the gender difference in fetal growth appears to be rather pronounced before the third trimester and relatively less marked towards term. In conclusion, the male conceptus seems to grow not only more, but also earlier than the female. Hence, some critical time windows of development may be slightly different in boys and girls, and this phenomenon may be one of the bases for gender differences in the sensitivity to fetal programming. Copyrightz1999S. KargerAG,Basel

Short children born small for gestational age (SGA) may be candidates for treatment with growth hormone (GH). We examined craniofacial growth and dental maturation in a cohort of short SGA children. The general growth failure of these children is reflected to a differential extent within the craniofacial complex. As a group, these children have a small retrognathic face with a relatively increased lower anterior face height; in contrast to skeletal maturation, dental age is not delayed. GH treatment in short prepubertal SGA children leads to craniofacial catch-up growth, which is particularly pronounced in regions where interstitial cartilage is involved, the result being that the facial profile becomes less convex; dental maturation does not appear to be influenced by GH treatment. In conclusion, in short SGA children, GH treatment does not only result in an increase of body stature but also in a trend towards normalization of craniofacial growth and this without notable advancement of dental maturation.

Boys are heavier than girls at term birth. Children with a 46,XY karyotype and androgen insensitivity syndrome (clinically complete form and/or proven mutations in the androgen receptor gene) were found to have a birth weight comparable to that of girls. These findings support the hypothesis that the difference in birth weight between boys and girls is generated by androgen action.

In the present study, data from 230 short children born small for gestational age, who were participating in four clinical trials, were pooled and analysed. At the start of GH treatment, median age and height SDS were 5.3 years and -3.2 SDS, respectively. A dose-dependent increase in height SDS was observed following 2 years of GH treatment: 1.1, 1.7 and 2.5 SDS for the three GH treatment groups (0.1, 0.2 and 0.3 IU/kg/day, respectively), compared with an increase of 0.14 SDS in the control group. In a multiple regression analysis, four variables were found to correlate independently with the gain in height SDS following 2 years of GH treatment. These are given below in order of importance: gain in height SDS = 7.7 x dose of GH (IU/kg/day) -0.11 x age (years) -0.08 x parental-adjusted height SDS + 0.05 x birth length SDS (SD = 0.5; r2 = 0.64). At the end of the 2-year study period, a total of 48%, 66% and 90% of patients in the groups given GH at 0.1, 0.2 and 0.3 IU/kg/day, respectively, had a parental-adjusted height greater than -1.0 SDS.

We report on a girl with the kabuki makeup syndrome, including short stature, premature thelarche and partial growth hormone deficiency of hypothalamic origin, without stalk interruption. Treatment with recombinant human growth hormone resulted in an increase of annualized growth velocity from 3.6 to 11.2 cm. The kabuki makeup syndrome may be associated with hypothalamopituitary dysfunction.