Somatomedin activity in human cord plasma and relationship to birth size, insulin, growth hormone, and prolactin

Early Human Development, 1978, 2/2,115-122 0 Elsevier/North-Holland Biomedical Press

Somatomedin activity in human cord plasma and relationship insulin, growth hormone, and prolactin

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to birth size,

I.K. ASHTON’ and J. VESEY2 ’Nuffield Department of Orthopaedic Surgery, Nuffield Orthopaedic Centre, and 2 Department of Paediatrics, John Radcliffe Hospital, Oxford, United Kingdom

Accepted for publication 5 January 1978

SUMMARY

Somatomedin activity was determined by a rabbit chondrocyte bioassay in cord plasma from babies of between 37 and 41 wk gestation. A positive correlation (P< 0.001) was found between plasma somatomedin activity and birthweight. The mean somatomedin activity in infants whose birthweights were within 1 SD of the mean (3293 g) was 0.76 f 0.27 U/ml. Mean somatomedin activity in infants whose weight was (a) greater than the mean weight +l SD was 1.3 f. 0.17 U/ml, and (b) less than the mean weight - 1 SD was 0.48 f 0.15 U/ml. Plasma somatomedin activity was also correlated with placental weight, P
INTRODUCTION

Although considerable evidence suggests that the growth-promoting peptides, collectively known as the somatomedins may be important for skeletal growth and development in normal children [12,19,21], the role of somatomedin in the fetus is unknown. Reduced birth length has been reported in children with Laron dwarfism, which is characterized by the absence of plasma somatomedin activity [5,22] and low levels of somatomedin activity in amniotic fluid have been associated with brain damage and growth retardation in utero [ 171 . *The work was supported by the Medical Research Council and The Smith and Nephew Foundation.

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Somatomedin activity is lower in cord plasma than in normal adult plasma [10,14,15,20], and a positive correlation of cord somatomedin activity with birth size and with gestational age has been reported [ 111. We have determined somatomedin activity in the cord plasma of normal neonates in relation to several parameters of birth size and to growth hormone, and also to insulin and prolactin, hormones which are thought to influence somatomedin production [6,9] .

METHODS

Umbilical venous blood was obtained from normal neonates at delivery. In all cases plasma was separated aseptically within 4 h and stored in several aliquots at - 20°C until assay. In a preliminary study (group 1) plasma was collected from 9 randomly selected infants (5 female, 4 male) and birthweights were recorded. The newborns selected for the second study were delivered after spontaneous labour at 37-41 wk gestational age (LMP or Dubowitz) to primigravidae without history of endocrine disturbance, diabetes or hypertension. Plasma from 4 infants was later rejected because of invalid bioassay results (see below); therefore group 2 comprised 14 babies (8 female, 6 male). In addition plasma was obtained from 1 male newborn of 43 wk gestational age. Maternal age, blood group and height were obtained from records and maternal non-pregnant weight and paternal height and weight by report from the mother. Skinfold thickness of the maternal triceps was determined with Harpenden calipers read at 60 set after application. Coefficient of variation was 3.7%. Birthweight of the babies and placental weight were measured by nursing staff. Birth length (crown-heel) was determined by the paediatrician using a Cardiff neonatometer [7], two readings being obtained from each leg and the mean calculated. Coefficient of variation was 0.8%. OFC was measured with a paper tape, coefficient of variation was 0.3%. Skinfold thickness in the infant was measured at 4 sites, i.e. triceps, biceps, subscapular and suprailiac [ 41. Plasma somatomedin activity was determined with an isolated rabbit chondrocyte assay [ 11. The internal standard was pooled human adult plasma, activity by definition 1 U/ml. Analysis of variance was performed on all assay results and assays were rejected if variance ratios did not meet satisfactory criteria of linearity, regression and parallelism. Sufficient plasma was available from 3 infants of group 2 for repeat somatomedin determinations. Mean interassay difference (n=3) was 0.09 U/ml. Mean precision (h) of all valid assays was 0.3 (n=26). In addition to somatomedin activity, immuno-reactive growth hormone was determined in plasma from 12, and insulin and prolactin from 13 infants of group 2. Standards for radioimmunoassay were as follows; human growth hormone (MRC 66/217), human insulin (Wellcome Reagents), and prolactin (NIH VLS/3).

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RESULTS

Mean somatomedin activity in group 1 (n=9) was 0.84 f 0.39 U/ml (range 1.4-0.4 U/ml). The mean birthweight was 3437 * 517 g (range 4480-2750 g). Correlation coefficient, r, between somatomedin activity and birthweight was 0.69, Pmean weight +l SD, was 1.3 f 0.17 U/ml (n=3) and (b)
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thickness at other sites, i.e. biceps, subscapular and suprailiac, or the sum of skinfold thickness at all sites was not related to somatomedin activity. No measurements of skinfold thickness were correlated with cord plasma insulin levels. Somatomedin activity and gestational age showed a significant positive correlation (r = 0.59, P
DISCUSSION

The range of somatomedin activity which we have determined in cord plasma is compatible with previously reported values of other authors using a variety of bioassays [ 10,11,14,15,20] . The mean value is slightly higher than that previously reported; however, no indication of birthweight has been given in the other reports. Our observations that an increase in somatomedin activity is associated with greater birthweight and gestational age is in agreement with the findings of Gluckman and Brinsmead [ll] . D’Ercole et al. [8] have used a radioreceptor assay specific for somatomedin C and have found levels of 0.3 U/ml in cord serum with only small differences between groups of normal weight, or small-for-dates infants. The chemical identity of the somatomedin activity which we have determined in cord plasma has not been established and may be a combination of several growth hormone-dependent growth peptides which are at present collectively termed ‘somatomedins’. If somatomedin activity in cord plasma reflects the somatomedin activity in late intrauterine life, the fact that the activity is lower than in the human adult is interesting in view of the relatively rapid rate of growth taking place in the fetus. It has been proposed that cartilage sensitivity decreases with age [24] , and a decreasing sensitivity of cartilage to somatomedin during postnatal life has been shown in rat, pig and rabbit [3,13,18]. We have found

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human fetal cartilage to be very sensitive to plasma somatomedin activity as early as 14 wk gestation [2], although this has not been compared with neonatal cartilage. Cord plasma somatomedin activity may also reflect the changes in levels of other hormones, notably growth hormone, oestrogens and corticosteroids at the time of birth. Both oestrogen and corticosteroids may inhibit somatomedin production [23,26], although Tato et al. [20] have shown that high levels of oestradiol in cord plasma are not solely responsible for lower levels of somatomedin activity observed. Van den Brande [23] found that differences in plasma somatomedin activity in children at different times of the day disappeared when correction was made for the diurnal variation in plasma cortisol. Our measurements on a small number of cord plasma (data not given) suggest that differences in plasma cortisol were not responsible for the differences in plasma somatomedin activity which we observed. During postnatal life a major site of somatomedin synthesis is the liver. Recent evidence suggests that synthesis is not solely growth hormone dependent but that both prolactin and insulin may also be effective in promoting somatomedin generation [6,9]. It is well established that hyperinsulinism has a marked effect on fetal growth and this could be mediated partly through an increase in somatomedin production. We did not find, however, any correlation between plasma somatomedin activity and either growth hormone, prolactin or insulin in these normal infants. Lack of a direct relationship may be because circulating somatomedin levels in the fetus are probably controlled not only by liver production, but by supply across the placenta, or by the placenta itself which has specific binding sites for somatomedin distinct from its insulin sites [ 161, and may thus remove somatomedin activity from the circulation. Somatomedin has insulin-like activity in adipose tissue and it has been suggested that hyperinsulinism stimulates increased triglyceride synthesis and thus leads to an increase in subcutaneous fat [25]. We did not find any relationship between somatomedin activity and most measurements of skinfold thickness, nor between skinfold thickness and insulin in this group of normal babies in which insulin levels were within the normal range. Although somatomedin has specific effects on cartilage growth and metabolism in vitro and has been related to skeletal growth in children, no correlation was found between somatomedin activity in cord plasma and birth length. This may be the result of the small range of birth lengths of these babies relative to the error in measurement. No data are available on fetal plasma somatomedin activity during the period of most rapid skeletal growth earlier in gestation. In the weeks immediately before birth the human fetus increases rapidly in weight and it may be that the cord somatomedin activity reflects this more recent change in growth rate. Our findings of a correlation between somatomedin activity and birthweight and gestational age suggest that the somatomedins may be additional contributory factors in the growth and development of the human fetus.

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ACKNOWLEDGEMENTS

We thank Professor A.C. Turnbull for his advice in the initiation of this work, Dr. A. Aynsley-Green for help and suggestions, Dr. G. Jenkins for prolactin determinations, Mrs. I. Nairn for growth hormone and insulin measurement, and nursing staff at the John Radcliffe Hospital.

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Reprint requests to Dr. I.K. Ashton.