F. de Zegher

Premature pubarche, ovarian hyperandrogenism, hyperinsulinism and the polycystic ovary syndrome: From a complex constellation to a simple sequence of prenatal onset

Adolescent girls with a history of premature pubarche have an increased incidence of functional ovarian hyperandrogenism [a form of polycystic ovary syndrome (PCOS)] at adolescence, which is usually associated with hyperinsulinemia and dyslipemia. The hyperinsulinemia and lipid disturbances can often be detected in the prepubertal period and throughout puberty, and are associated with an exaggerated ovarian androgen synthesis. Birthweight SD scores are lower in premature pubarche girls than in control girls, and particularly so in those girls who show hyperinsulinemia and subsequently develop ovarian hyperandrogenism. Therefore, although the mechanisms interlinking the triad of premature pubarche, hyperinsulinism and ovarian hyperandrogenism remain enigmatic, these data indicate that the triad may result, at least in part, from a common early origin, rather than from a direct interrelationship later in life.

Androgens and fetal growth

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.

Growth hormone treatment of short children born small for gestational age: Metanalysis of four independent, randomized, controlled, multicentre studies

A minority of children born small for gestational age (SGA) fail to achieve sufficient catch‐up growth during infancy and remain short throughout childhood, apparently without being growth hormone (GH) deficient. The effect of GH administration was evaluated over 2 years in short prepubertal children born SGA. The children (n= 244), who were taking part in four independent multicentre studies, had been randomly allocated to groups receiving either no treatment or GH treatment at a daily dose of 0.1, 0.2 or 0.3 IU/kg (0.033, 0.067 or 0.1 mg/kg) s.c. At birth, their mean length SD score (SDS) was ‐3.6 and their mean weight SDS ‐2.6; at the start of the study, mean age was 5.2 years, bone age 3.8 years, height SDS ‐3.3, height SDS adjusted for parental height ‐2.4, weight SDS ‐4.7 and body mass index (BMI) SDS ‐1.4. The untreated children had a low‐normal growth velocity and poor weight gain. Although bone maturation progressed more slowly than chronological age, final height prognosis tended to decrease, according to height SDS for bone age. GH treatment induced a dose‐dependent effect on growth, up to a near doubling of height velocity and weight gain; BMI SDS was not altered. Bone maturation was also accelerated differentially; however, final height prognosis increased in all GH treatment groups. The more pronounced growth responses were observed in younger children with a lower height and weight SDS. In conclusion, GH administration is a promising therapy for normalizing short stature and low weight after insufficient catch‐up growth in children born SGA. Long‐term strategies incorporating GH therapy now remain to be established.

Male Pseudohermaphroditism Related to Complications at Conception, in Early Pregnancy or in Prenatal Growth

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.

Puberty after Prenatal Growth Restraint

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.

HYPERSOMATOTROPISM IN THE DYSMATURE INFANT AT TERM AND PRETERM BIRTH

Growth hormone (GH) concentrations were measured in cord serum of small (less than 2.4 kg), appropriate (3.4 +/- 0.1 kg) and large (greater than 4.4 kg) infants born at term (38-42 weeks), and in cord serum of prematurely born twins (28-36 weeks) which were either appropriate (greater than P10) or small (less than P10) for gestational age. Cord serum GH levels were found to be significantly elevated in small for gestational age infants, both at term and preterm birth. In view of the insulin-antagonizing action of fetal GH, these results further support a homeostatic function for GH in the late-gestational human fetus.

Craniofacial Growth in Short Children Born Small for Gestational Age: Effect of Growth Hormone Treatment

The effects of growth hormone (GH) therapy in children have yet to be completely catalogued. In the present study, the effect of high-dose GH treatment on craniofacial growth was evaluated once yearly in 21 pre-pubertal, non-GH-deficient children born small for gestational age. These children were randomly allocated to be either untreated or treated with GH at a daily subcutaneous dose of 0.2 or 0.3 IU/kg for 2 yrs. The group consisted of 12 girls and 9 boys with a mean age of 5.1 yr (range, 2 to 8 yr), bone age of 3.4 yr, and height SDS of -3.6. At the start of the study, all children showed an overall delay of craniofacial growth. This cohort of short children born small for gestational age showed a small SNB angle and a large ANB angle; all other angular measurements were within normal range. GH treatment accelerated growth in several craniofacial components, especially the posterior total facial height, the cranial base length, and the overall mandibular length. The increase of the mandibular length increased the SNB angle; no other angular measurements were affected. Age at start of treatment differently influenced the increase in posterior and total cranial base length, the increase in mandibular corpus length, and the position of the mandible in relation to the cranial base. Although GH treatment for 2 yrs led to a craniofacial growth acceleration, the position of the mandible in relation to the cranial base and the craniofacial size in lateral aspect were not normalized in the majority of the GH-treated children. No signs of disproportional growth were evidenced after 2 yrs of high-dose GH treatment. In conclusion, short pre-pubertal SGA children display an overall delay of linear craniofacial growth and a retrognathic mandible. High-dose GH treatment over 2 yrs leads to craniofacial catch-up growth, which is pronounced in regions where interstitial cartilage is involved and results in a less convex face in profile.

Placental growth hormone and IGF-I in a pregnant woman with Pit-1 deficiency

The respective contributions of pituitary and placental GH to circulating IGF‐I in pregnant women have not been well established. We measured the serum concentrations of placental growth hormone (PGH) and IGF‐I in a woman with pit‐1 deficiency before, during and after pregnancy, resulting in the birth of a healthy child (not pit‐1 deficient). Both PGH and IGF‐I concentrations were below the assay detection limit before and after pregnancy. During pregnancy, PGH and IGF‐I levels increased steadily; the concentrations of PGH and IGF‐I in late pregnancy were comparable with levels previously measured in normal pregnancies. PGH and IGF‐I concentrations were strongly correlated throughout pregnancy (r = 0.90; P = 0.002). PGH was undetectable in cord serum, whilst the IGF‐I concentration was within the normal range. The findings of this case study corroborate the notion that PGH is the prime regulator of maternal serum IGF‐I during pregnancy.

Serum Levels of Immunoreactive Inhibin, FSH, and LH in Human Infants at Preterm and Term Birth

Serum levels of immunoreactive inhibin, follicle-stimulating hormone (FSH), and luteinizing hormone (LH) were determined in 112 fetal cord blood samples obtained at birth between 26 and 40 weeks of gestation. High levels of inhibin immunoreactivity were detected in all samples. Between the gestational age of 26 and 28 weeks, the levels (mean +/- SE) were higher (p less than 0.05) in male (21.6 +/- 1.0 U/ml; n = 12) than in female (12.8 +/- 0.2 U/ml; n = 12) fetuses. With ongoing gestation, the serum inhibin immunoreactivity decreased and was found to be similar in male (12.1 +/- 0.3 U/ml; n = 13) and female (9.1 +/- 0.7 U/ml; n = 8) fetuses at term. Serum FSH and LH levels were elevated at the beginning of the 3rd trimester of pregnancy and decreased with ongoing gestation to undetectable values at term birth. Between 26 and 32 weeks of gestation, the FSH levels were higher in females (p less than 0.02), whereas the LH levels were higher in males (p less than 0.01). These observations suggest that in the human fetus the pituitary-gonadal axis is active and presents sexual dimorphism; both characteristics are pronounced early during the 3rd trimester of gestation and decrease towards term.

Final Height in Children with Idiopathic Growth Hormone Deficiency Treated with Recombinant Human Growth Hormone: The Belgian Experience

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.