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The Journal of Clinical Endocrinology & Metabolism Vol. 89, No. 1 384-391
Copyright © 2004 by The Endocrine Society

A Longitudinal Study of Intrauterine Growth and the Placental Growth Hormone (GH)-Insulin-Like Growth Factor I Axis in Maternal Circulation: Association between Placental GH and Fetal Growth

M. Chellakooty, K. Vangsgaard, T. Larsen, T. Scheike, J. Falck-Larsen, J. Legarth, A. M. Andersson, K. M. Main, N. E. Skakkebæk and A. Juul

University Department of Growth and Reproduction, Rigshospitalet (M.C., A.M.A., K.M.M., N.E.S., A.J.); University Department of Obstetrics and Gynecology, Herlev Hospital (K.V., T.L., J.F.-L., J.L.); and Department of Biostatistics, University of Copenhagen (T.S.), DK-2100 Copenhagen, Denmark

Address all correspondence and requests for reprints to: Marla Chellakooty, M.D., University Department of Growth and Reproduction, GR 5064, Rigshospitalet, Blegdamsvej 9, DK-2100 Copenhagen, Denmark. E-mail: rh04632{at}rh.dk.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
The aim of the study was 1) to evaluate the association of maternal serum levels of placental GH and IGF-I with fetal growth, and 2) to establish reference data for placental GH, IGF-I, and IGF-binding protein-3 (IGFBP-3) in normal pregnancies based on longitudinal measurements. A prospective longitudinal study of 89 normal pregnant women was conducted. The women had, on the average, seven blood samples taken and three ultrasound examinations performed. All had normal umbilical artery pulsatility indexes during pregnancy and gave birth to singletons between 37 and 42 wk gestation with birth weights above -2 SD. Placental GH levels were detectable in all samples from as early as 5 wk gestation and increased significantly throughout pregnancy to approximately 37 wk when peak levels of 22 ng/ml (range, 4.64–69.22 ng/ml) were reached. Subsequently, placental GH levels decreased until birth. The change in placental GH during 24.5–37.5 wk gestation was positively associated with fetal growth rate (P = 0.027) and birth weight (P = 0.027). Gestational age at peak placental GH values (P = 0.007) was associated with pregnancy length. A positive association between the change in placental GH and the change in IGF-I levels throughout gestation was found in a multivariate analysis (r2 = 0.42; P < 0.001). There was no association between placental GH and IGFBP-3 levels. The change in IGF-I throughout gestation (P = 0.039), but not placental GH, was significantly positively associated with placental weight at birth. We found a significant association between placental GH and fetal growth. In addition, we found a highly significant association between the increase in placental GH and the increase in IGF-I. The gestational age at peak placental GH levels was associated with pregnancy length.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
RECENTLY, CONSIDERABLE FOCUS has been directed toward the importance of fetal growth, as intrauterine growth restriction (IUGR) is associated with increased perinatal morbidity and mortality. Furthermore, low birth weight adjusted for gestational age may have negative long-term consequences particularly for cardiopulmonary and endocrinological disorders in adult life (1, 2, 3). However, the regulation of normal fetal growth still remains unclear.

Placental GH, a product of the GH-V gene, predominantly expressed in the syncytiotrophoblast cells (4) of the placenta, is thought to be involved in the regulation of fetal growth (5). Maternal serum levels of placental GH increase throughout pregnancy from 7 wk gestation (6) until term and gradually replace the pulsatile pituitary GH secretion (7, 8). With the onset of labor and the removal of the placenta after childbirth, there is a rapid fall in serum placental GH levels (placental GH half-life, 15 min) (6). In contrast to pituitary GH, placental GH is secreted continuously (8), which permits evaluation of placental GH levels from a single measurement. Several cross-sectional studies have shown that in both normal and pathological pregnancies the rise in placental GH is associated with a rise in maternal IGF-I levels (9, 10) and that reduced levels of both placental GH and maternal IGF-I are seen in women with IUGR pregnancies (5). Placental GH is not detectable in the fetal circulation, but it is believed to influence fetal growth indirectly by regulating the maternal substrate supply to the fetus. The physiological role, however, may also include a direct influence on placental development through an autocrine or paracrine mechanism, as suggested by the presence of GH receptors in the placenta (11).

To our knowledge no longitudinal data exist on the progressive rise in placental GH, IGF-I, and IGFBP-3 in relation to ultrasound assessment of intrauterine fetal growth in women with normal pregnancies. The aim of this study was 1) to evaluate the relationship of placental GH and maternal IGF-I with fetal growth, and b) to establish reference data for placental GH, IGF-I, and IGFBP-3 throughout normal pregnancies based on longitudinal measurements.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Study participants and design

During the period of May 1999 to October 2001, 103 pregnant women were recruited consecutively from the first routine contact (between gestational wk 6–12) at a University Hospital in Copenhagen. After informed consent, all mothers were scheduled to have blood samples obtained approximately every 4–6 wk throughout pregnancy. All pregnant women were scheduled to have 3 ultrasound examinations. Eighty-nine women had normal singleton pregnancies and gave birth between 37–42 wk gestation to newborns with birth weights above -2 SD (12). Thus, 14 women were excluded due to preterm birth or small for gestational age newborn (n = 4), postmaturity (n = 2), miscarriage (n = 1), or personal reasons (n = 7). A total of 650 blood samples were obtained (with an average of 7 samples/woman; range, 3–9). All women had normal placental function as assessed by umbilical artery pulsatility index. Information regarding mother’s diseases, smoking, parity, parturition, and childbirth history were obtained from medical records during the course of pregnancy and after birth.

Ultrasound scan

One examiner performed all ultrasound examinations using an ultrasound color Doppler equipment (2102 Scanner, B-K Medical, Copenhagen, Denmark) with a convex abdominal array 2.5–5 MHz MFI (multifrequency imaging) probe. The test-retest coefficient (same observer same fetus) was 4.6% (13). All women had a dating scan at approximately 17 wk gestation (range, 15–22). Fetal weight estimations were calculated at approximately 28 (range, 27–33) and 33 (range, 32–35) wk gestation from biparietal diameter and abdominal circumference using Warsof’s equation (14).

Ethical aspects

The study was performed according to the Helsinki II Declaration and was approved by the local ethics committee and the Danish Registry Agency.

Laboratory methods

Nonfasting peripheral venous blood samples were taken from an antecubital vein between midmorning and early afternoon. Samples were separated by centrifugation and stored at -20 C until analysis.

Assays

Placental GH was measured in a solid phase 125I-labeled immunoradiometric assay (Biocode, Liege, Belgium) using two specific monoclonal antibodies as previously described (4). In our laboratory the intraassay coefficients of variation were less than 8% (at 24.6 ng/ml; n = 20) and 6.3% (at 5.0 ng/ml; n = 20), and the interassay coefficients of variation were 6.1% (at 4.1 ng/ml; n = 20), 9.7% (at 22.2 ng/ml; n = 20), and 8.1% (at 35.6 ng/ml; n = 20). The limit of detection was less than 0.1 ng/ml, defined as zero standard +3 SD.

IGF-I was measured in all subjects with a RIA originally described by Bang et al. (15) with some modifications. Serum was extracted by acid/ethanol and cryoprecipitated before analysis to remove interfering binding proteins using monoiodinated Tyr31-[125I]des-(1–3) IGF-I as radioligand (16). Inter- and intraassay variations were both below 11% in the range measured. The limit of detection was 21 ng/ml. IGFBP-3 was determined by RIA, as described by Blum et al. (17). IGFBP-3 was measured on unprocessed serum using a polyclonal rabbit antiserum and a purified human IGFBP-3 fragment as standard and radioligand. Reagents for the analysis were obtained from Mediagnost GmbH (Tubingen, Germany). Inter- and intraassay variations were 7.3% and 3.5%, respectively. The limit of detection was 300 ng/ml.

Statistical analysis

The statistical analyses were carried out using the statistical package SPSS (version 11, SPSS, Inc., Chicago, IL) and SAS (version 6.12, SAS Institute, Cary, NC).

Descriptive statistics are given as median values and ranges, and the study population is grouped according to gender of the fetus. Square root and log transformation were applied to all hormones values to improve the approximation of normal distribution and linearize relationships.

The reference charts were constructed by use of random effects models to account for correlation within each subject. We assumed that the individual developments were approximately piecewise linear with individual variation of slopes and intercepts. The fitted random effects models were validated, and data were transformed to obtain residuals that were approximately normal. Based on the effects model with estimates of residual variation as well as variation within subjects, we constructed the model-based reference charts.

A linear regression model, fitted on every subject’s data over time was applied to yield a slope value representing the rate of change in hormone levels per unit of time (gestational age in days) with corresponding intercepts (baseline values). Slope values and intercepts were calculated on individual hormonal changes throughout gestation and on the change between 24.5–37.5 wk gestation, as this time window represents a period when fetal weight velocity is at its maximum (18). The maximal hormone levels as well as the difference between maximal hormone level and hormone concentration in the last blood sample for placental GH and IGF-I were calculated. To determine factors of influence on placental GH, IGF-I, and IGFBP-3, the slopes were used as dependent variables in linear regression analyses describing the increase in individual hormone levels throughout gestation. All models included smoking habits, maternal age, social-economic status, parity, prepregnancy body mass index (BMI; weight/height2), placental weight, and hormone levels (depending on model) as explanatory variables. Backward stepwise regression models were adopted to determine factors predicting changes in placental GH, IGF-I, and IGFBP-3. To describe the fetal growth rate, individual slopes were calculated from assessment of birth weight and two fetal weight estimations at approximately 28 and 33 wk of gestation. Fetal growth rate, birth weight, and placental weight were used as univariate dependent variables in linear regression models with the slope of placental GH, IGF-I, and IGFBP-3 together with prepregnancy BMI, maternal age, smoking, parity, and fetal sex as explanatory variables. The intercepts of the biochemical markers were excluded because they were nonsignificant in these models. To determine whether placental GH or IGF-I had an influence on the time of parturition, maximal hormone values, the difference between maximal values and the last taken blood sample ({Delta} value), and gestational age at maximal concentrations were used as explanatory variables in a regression model, with gestational age at birth as the dependent variable. Residual plots were used to validate all regression models.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
The basic clinical characteristics of the study population are shown in Tables 1Go and 2Go. We found no statistical significant differences between maternal and fetal characteristics of the study population with regard to the gender of the fetus.


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  		TABLE 1. Description of study population

 

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  		TABLE 2. Descriptive fetal ultrasound data

 
Fetal growth

Median fetal weights during gestation in the three birth weight tertiles are shown in Fig. 1AGo. Fetal growth was linear in the period studied (approximate gestational wk 28–40) and estimated to a mean of 174 g/wk (range, 150–227 g/wk; Fig. 2AGo).



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  		FIG. 1. A, Trend curves for estimated fetal weights and corresponding birth weights grouped by median birth weight tertiles in low (•), median ({blacksquare}), and high ({blacktriangleup}) birth weights. B, Median placental GH levels in normal pregnant women grouped corresponding to the above-mentioned birth weight tertiles.

 


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  		FIG. 2. Individual curves from a longitudinal study of 89 normal singleton pregnancies. All parameters are plotted against gestational age. A, Fetal weight estimates and birth weight; B, maternal plasma placental GH; C, maternal plasma IGFBP-3; D, maternal plasma IGF-I levels. The thick red lines represent the mean and 95% confidence interval.

 
Longitudinal levels of placental GH

Placental GH levels were detectable in all available samples from as early as 5 wk gestation and increased significantly throughout pregnancy to a peak of 22 ng/ml (range, 4.64–69.22 ng/ml) at approximately 37 wk gestation (Fig. 2BGo). Subsequently, placental GH levels decreased until the time of birth, with the lowest values seen in women giving birth to the lightest children (Fig. 1BGo). In late second trimester and third trimester, placental GH levels showed large interindividual variation (Fig. 2BGo). The total change in placental GH was significantly negatively associated with maternal BMI (P = 0.031) and positively with the change in maternal IGF-I (P = 0.037) when the model was adjusted for fetal sex (P = 0.128). The change in placental GH between wk 24.5 and 37.5 was significantly related to fetal sex (P = 0.048); women carrying female fetuses had a tendency toward steeper placental GH slopes (Table 3Go).


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  		TABLE 3. Univariate linear regression models with square root values of the change in placental GH, IGF-I, and IGFBP-3 used as dependent variables during total gestation or during 24.5–37.5 wk gestation

 
Longitudinal levels of IGF-I and IGFBP-3

Individual maternal IGF-I levels increased throughout pregnancy, reached a maximum of 436 ng/ml (range, 215–705) at approximately 37 wk gestation, and decreased before parturition (Fig. 2DGo). In late gestation IGF-I levels showed marked interindividual variation. The change in IGF-I was positively associated with the change in placental GH throughout gestation in a linear regression analysis (r2 = 0.1519; P < 0.001; Fig. 3Go). In a multivariate analysis, the change in IGF-I was even more strongly associated with the change in placental GH (P < 0.001), the change in IGFBP-3 (P < 0.001), and maternal prepregnancy BMI (P = 0.003; Table 3Go). IGFBP-3 levels increased significantly throughout gestation (P = 0.001; Fig. 2CGo), and the peak of 5116 ng/ml (range, 3074–9924) was reached at approximately 37 wk gestation. The change in IGFBP-3 throughout gestation was positively associated with the change in IGF-I (P < 0.001; Table 3Go).



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  		FIG. 3. Association between the change in maternal placental GH and the change in maternal IGF-I levels throughout gestation. Data shown here are square root transformed (sqrt).

 
Relationship of placental GH and maternal IGF-I to fetal growth rate, birth weight, and placental weight

Fetal growth rate was significantly positively associated with the change in placental GH (P = 0.027) between gestational wk 24.5–37.5 in a model adjusted for confounders (Table 4Go). Using birth weight as the dependent variable, both the change in placental GH during 24.5–37.5 wk gestation (P = 0.027) and gestational age at birth (P = 0.021) were significantly positively associated with birth weight (Table 4Go). Inclusion of placental weight in the model eliminated the significant associations of placental GH and gestational age with birth weight, as placental weight is strongly associated with birth weight. Placental weight was significantly positively associated with gestational age at birth (P = 0.049) and the change in IGF-I throughout gestation (P = 0.039), but not with the change in placental GH (Table 4Go).


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  		TABLE 4. Fetal growth rate, birth weight, and placental weight, as dependent variables in linear regression models where confounders known to have effect on the above mentioned variables are included together with the slope of the square root of placental GH or IGF-I

 
Relationship of maximal placental GH and IGF-I to age at time of birth

We found that the gestational age when maximum placental GH concentrations were reached was significantly positively associated with pregnancy length in days (P = 0.007). Neither the maximal concentration of placental GH, the difference between maximal levels and last taken blood sample, gestational age at maximal IGF-I levels, or maximum IGF-I level was significantly associated with pregnancy length.


   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
In a large cohort of normal pregnant women we found a significant positive association between maternal serum levels of placental GH and fetal growth. To our knowledge this association has not been demonstrated previously in a prospective longitudinal study. Placental GH levels increased during pregnancy, with large interindividual variation up to approximately 37 wk gestation and a decline thereafter. Interestingly, we found that the gestational age when peak concentrations of placental GH were reached was associated with the length of pregnancy, i.e. early maximal placental GH levels were associated with early onset of labor. In addition, we found a highly significant positive association between the increase in placental GH and the increase in IGF-I during pregnancy.

In the present study placental GH was positively associated with fetal growth during a period when fetal weight gain is large. The pregnancy-induced rise in placental GH explains less than 10% of the variation in fetal growth rate, which may reflect the limited number of subjects in our study. Nevertheless, our present findings, based on longitudinal assessments, are in accordance with data from a previous cross-sectional study of 455 pregnant women, in whom placental GH was positively associated with fetal weight at approximately 28 wk gestation (19). In addition, data from studies of pathological pregnancies suggested that placental GH levels were lower in women with IUGR compared with normal pregnancies (5, 9, 10). Placental GH mRNA expression per cell did not differ between normal and IUGR placentas (20), although controversy exists (21). Chowen et al. (20) found that the mean number of cells expressing placental GH mRNA per area was significantly greater in normal placentas. This suggests that decreased levels of placental GH in the maternal circulation in IUGR are not only due to a reduced placental size, but also to a reduced number of placental cells per area that are capable of producing this peptide.

Intriguingly, we found that the age at which placental GH peaks was positively associated with pregnancy length. Thus, the earlier the time of the placental GH peak during gestation, the earlier the child was born within 37–42 wk gestation. A preliminary study reported on significantly reduced placental GH levels at the onset of labor compared with levels obtained 2–4 d before birth (22). However, it remains to be seen whether placental GH may be implicated in the mechanisms of the onset of labor.

Placental GH, a product of the GH-V gene, is predominantly expressed in syncytiotrophoblast cells, and transcript levels increase with increasing formation of syncytiotrophoblasts (23, 24). Receptors for GH are present in the villous trophoblasts as well as the extravillous trophoblasts (25) and bind placental GH with similar affinity compared with pituitary GH. In addition, activation of the GH receptor by placental GH leads to same intracellular signaling compared with 22-kDa, pituitary-derived GH (26). Therefore, it has been speculated that placental GH acts as an auto- or paracrine trophic hormone on placental growth or, alternatively, affects placental function. We did not find any association between placental size at birth and the change in placental GH levels, which could suggest that placental GH may not be the primary trophic regulator of placental growth. However, this does not exclude placenta as the target organ for placental GH. Placental GH may still regulate the transport of nutrients across the placenta to the fetus. Glucose transporters are localized in the placenta. The GLUT1 glucose transporter, present on both the microvillous and basal membranes of the syncytium, is the primary isoform involved in the transplacental movement of glucose. The GLUT3 protein is localized to the arterial component of the fetal vascular endothelium, where it may play a role in enhancing transplacental glucose transport (27). Transgenic mice overexpressing placental GH were severely insulin resistant, as manifested by fasting and postprandial hyperinsulinemia (28). Placental GH is therefore a likely candidate to mediate the insulin resistance of pregnancy. Whether placental GH stimulates placental expression of glucose transporters, thereby regulating fetal glucose uptake, remains speculative.

The correlations between the rise in placental GH and IGF-I levels validates previous observations based on small cross-sectional studies (5, 9, 10, 29). In our study this association was seen after adjusting for other factors, such as BMI and fetal sex, which have previously been shown to influence maternal placental GH levels (19, 30, 31). It has been shown that placental GH and maternal IGF-I levels increase in pregnancies of GH-deficient women (6, 32), supporting the hypothesis of placental GH, and not pituitary GH, being the main regulator of maternal IGF-I during pregnancy. We found that maternal IGF-I levels increased throughout gestation until 37 wk gestation, with a subsequent decrease until birth. In line with this finding, previous cross-sectional studies of normal and pathological pregnancies (diabetes or IUGR) (33, 34, 35, 36) reported elevated IGF-I levels in late gestation compared with early gestation.

We found that the rate of increase in maternal IGF-I was not associated with fetal growth rate or birth weight. The possible mechanisms by which maternal IGF-I levels could influence fetal growth are uncertain. Decreased placental transport of certain amino acids has been described in IUGR pregnancies (37), and some animal studies suggest that maternal IGF-I may play a role in placental transfer of such nutrients. IGF-I treatment of pregnant sheep leads to an increase in glucose concentrations and amino acid uptake to the fetus (38). IGF-I infusions in pregnant mice and rats stimulate fetal weight with increasing litter size. thereby removing maternal constraint (39). Maternal IGF-I has been associated with intrauterine growth and birth weight in several species (40, 41). In humans, conflicting results exist on the relationship between maternal IGF-I levels in pregnancy and birth weight (36, 42, 43, 44). In our study of normal pregnant women without signs of placental dysfunction, there was no correlation of IGF-I to either fetal growth rate or birth weight. This is comparable to the finding of Holmes et al. (35), who reported an association between maternal IGF-I and birth weight in women with placental dysfunction, but not in healthy pregnant women. We found a positive association between the change in IGF-I throughout gestation and placental size, thereby suggesting a role for IGF-I in the regulation of placental growth. The increase in placental size may be associated with an increased transport of nutrients to the fetus due to an increase in the surface area for exchange.

Thus, we found that placental GH, but not IGF-I, was associated with fetal growth (but that they were interrelated). We believe that this could hypothetically suggest that placental GH influences fetal growth, whereas IGF-I may stimulate fetal growth indirectly by affecting placental size or function. Alternatively, maternal IGF-I may not be important for fetal growth at all. However, we cannot exclude that the differences may reflect the limited number of women in our study.

We found an increase in IGFBP-3 levels determined by RIA during pregnancy in accordance with the finding of Wang et al. (45). In our study the increase in IGFBP-3 was significantly positively associated with the changes in IGF-I levels, but was not associated with the changes in placental GH. To our knowledge, no previous data exist on the relationship between IGFBP-3 and placental GH. However, we have not investigated IGFBP-3 protease activity, which is known to occur in human third trimester pregnancies (46). Therefore, we cannot take into account relative changes in affinity or binding kinetics of IGFBP-3 that occur during pregnancy due to proteolytic modification.

In conclusion, placental GH was positively associated with fetal growth rate between 24.5–37.5 wk gestation as well as with birth weight, whereas this association was not found for IGF-I. We found that the gestational age at which peak values of placental GH were reached was associated with the length of pregnancy. In addition, this paper presents longitudinal reference ranges for maternal serum levels of placental GH, IGF-I, and IGFBP-3 throughout normal pregnancies.


   Acknowledgments
 
We are very grateful to all of the pregnant women who participated in the study. We thank midwife Elsebeth Bøgh, who helped recruit the pregnant women; Consultant Dr. Med. Sci. Niels Fogh Andersen, who provided all of the technicians who assisted in taking blood samples at the Department of Biochemistry, Herlev Hospital; and the technicians Ole Nielsen and Kirsten Jørgensen, who analyzed the blood samples. We thank Prof. Dr. Med. Sci. Gorm Greisen, who added valuable comments on the analysis of the longitudinal data.


   Footnotes
 
This work was supported by European Union Contract QLK4-CT1999-01422, Environmental Reproductive Health, and Novo Nordisk A/S (Bagsvaerd, Denmark).

Abbreviations: BMI, Body mass index; IGFBP, IGF-binding protein; IUGR, intrauterine growth restriction.

Received March 25, 2003.

Accepted September 29, 2003.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

  1. Barker DJ, Martyn CN 1992 The maternal and fetal origins of cardiovascular disease. J Epidemiol Community Health 46:8–11[Medline]
  2. Barker DJ, Gluckman PD, Godfrey KM, Harding JE, Owens JA, Robinson JS 1993 Fetal nutrition and cardiovascular disease in adult life. Lancet 341:938–941[CrossRef][Medline]
  3. Gluckman PD, Harding JE 1997 Fetal growth retardation: underlying endocrine mechanisms and postnatal consequences. Acta Paediatr 422(Suppl):69–72
  4. Igout A, Van Beeumen J, Frankenne F, Scippo ML, Devreese B, Hennen G 1993 Purification and biochemical characterization of recombinant human placental growth hormone produced in Escherichia coli. Biochem J 295(Pt 3):719–724
  5. Caufriez A, Frankenne F, Hennen G, Copinschi G 1993 Regulation of maternal IGF-I by placental GH in normal and abnormal human pregnancies. Am J Physiol 265:E572–E577
  6. Lonberg U, Damm P, Andersson AM, Main KM, Chellakooty M, Lauenborg J, Skakkebaek NE, Juul A 2003 Increase in maternal placental growth hormone during pregnancy and disappearance during parturition in normal and growth hormone-deficient pregnancies. Am J Obstet Gynecol 188:247–251[CrossRef][Medline]
  7. Frankenne F, Closset J, Gomez F, Scippo ML, Smal J, Hennen G 1988 The physiology of growth hormones (GHs) in pregnant women and partial characterization of the placental GH variant. J Clin Endocrinol Metab 66:1171–1180[Abstract]
  8. Eriksson L, Frankenne F, Eden S, Hennen G, Von Schoultz B 1989 Growth hormone 24-h serum profiles during pregnancy-lack of pulsatility for the secretion of the placental variant. Br J Obstet Gynaecol 96:949–953[Medline]
  9. Mirlesse V, Frankenne F, Alsat E, Poncelet M, Hennen G, Evain-Brion D 1993 Placental growth hormone levels in normal pregnancy and in pregnancies with intrauterine growth retardation. Pediatr Res 34:439–442[Medline]
  10. McIntyre HD, Serek R, Crane DI, Veveris-Lowe T, Parry A, Johnson S, Leung KC, Ho KK, Bougoussa M, Hennen G, Igout A, Chan FY, Cowley D, Cotterill A, Barnard R 2000 Placental growth hormone (GH), GH-binding protein, and insulin-like growth factor axis in normal, growth-retarded, and diabetic pregnancies: correlations with fetal growth. J Clin Endocrinol Metab 85:1143–1150[Abstract/Free Full Text]
  11. Hill DJ, Clemmons DR, Wilson S, Han VK, Strain AJ, Milner RD 1989 Immunological distribution of one form of insulin-like growth factor (IGF)-binding protein and IGF peptides in human fetal tissues. J Mol Endocrinol 2:31–38[Abstract]
  12. Marsal K, Persson PH, Larsen T, Lilja H, Selbing A, Sultan B 1996 Intrauterine growth curves based on ultrasonically estimated foetal weights. Acta Paediatr 85:843–848[Medline]
  13. Larsen T, Petersen S, Greisen G, Larsen JF 1990 Normal fetal growth evaluated by longitudinal ultrasound examinations. Early Hum Dev 24:37–45[CrossRef][Medline]
  14. Warsof SL, Gohari P, Berkowitz RL, Hobbins JC 1977 The estimation of fetal weight by computer-assisted analysis. Am J Obstet Gynecol 128:881–892[Medline]
  15. Bang P, Eriksson U, Sara V, Wivall IL, Hall K 1991 Comparison of acid ethanol extraction and acid gel filtration prior to IGF-I and IGF-II radioimmunoassays: improvement of determinations in acid ethanol extracts by the use of truncated IGF-I as radioligand. Acta Endocrinol (Copenh) 124:620–629[Medline]
  16. Juul A, Bang P, Hertel NT, Main K, Dalgaard P, Jorgensen K, Muller J, Hall K, Skakkebaek NE 1994 Serum insulin-like growth factor-I in 1030 healthy children, adolescents, and adults: relation to age, sex, stage of puberty, testicular size, and body mass index. J Clin Endocrinol Metab 78:744–752[Abstract]
  17. Blum WF, Ranke MB 1990 Use of insulin-like growth factor-binding protein 3 for the evaluation of growth disorders. Horm Res 33(Suppl 4):31–37
  18. Lockwood CJ, Weiner S 1986 Assessment of fetal growth. Clin Perinatol 13:3–35[Medline]
  19. Chellakooty M, Skibsted L, Skouby SO, Andersson AM, Petersen JH, Main KM, Skakkebaek NE, Juul A 2002 Longitudinal study of serum placental GH in 455 normal pregnancies: correlation to gestational age, fetal gender, and weight. J Clin Endocrinol Metab 87:2734–2749[Abstract/Free Full Text]
  20. Chowen JA, Evain-Brion D, Pozo J, Alsat E, Garcia-Segura LM, Argente J 1996 Decreased expression of placental growth hormone in intrauterine growth retardation. Pediatr Res 39:736–739[Medline]
  21. Sheikh S, Satoskar P, Bhartiya D 2001 Expression of insulin-like growth factor-I and placental growth hormone mRNA in placentae: a comparison between normal and intrauterine growth retardation pregnancies. Mol Hum Reprod 7:287–292[Abstract/Free Full Text]
  22. Evain-Brion D, Alsat E, Igout A, Frankenne F, Hennen G 1994 Placental growth hormone variant: assay and clinical aspects. Acta Paediatr 399(Suppl):49–51
  23. Frendo JL, Vidaud M, Guibourdenche J, Luton D, Muller F, Bellet D, Giovagrandi Y, Tarrade A, Porquet D, Blot P, Evain-Brion D 2000 Defect of villous cytotrophoblast differentiation into syncytiotrophoblast in Down’s syndrome. J Clin Endocrinol Metab 85:3700–3707[Abstract/Free Full Text]
  24. Tarrade A, Schoonjans K, Guibourdenche J, Bidart JM, Vidaud M, Auwerx J, Rochette-Egly C, Evain-Brion D 2001 PPAR gamma/RXR alpha heterodimers are involved in human CG beta synthesis and human trophoblast differentiation. Endocrinology 142:4504–4514[Abstract/Free Full Text]
  25. Frankenne F, Alsat E, Scippo ML, Igout A, Hennen G, Evain-Brion D 1992 Evidence for the expression of growth hormone receptors in human placenta. Biochem Biophys Res Commun 182:481–486[CrossRef][Medline]
  26. Silva CM, Kloth MT, Lyons CE, Dunn CR, Kirk SE 2002 Intracellular signaling by growth hormone variant (GH-V). Growth Horm IGF Res 12:374–380[CrossRef][Medline]
  27. Illsley NP 2000 Glucose transporters in the human placenta. Placenta 21:14–22[CrossRef][Medline]
  28. Barbour LA, Shao J, Qiao L, Pulawa LK, Jensen DR, Bartke A, Garrity M, Draznin B, Friedman JE 2002 Human placental growth hormone causes severe insulin resistance in transgenic mice. Am J Obstet Gynecol 186:512–517[CrossRef][Medline]
  29. Caufriez A, Frankenne F, Englert Y, Golstein J, Cantraine F, Hennen G, Copinschi G 1990 Placental growth hormone as a potential regulator of maternal IGF-I during human pregnancy. Am J Physiol 258:E1014–E1019
  30. Coutant R, Boux dC, Douay O, Mathieu E, Rouleau S, Beringue F, Gillard P, Limal JM, Descamps P 2001 Relationships between placental GH concentration and maternal smoking, newborn gender, and maternal leptin: possible implications for birth weight. J Clin Endocrinol Metab 86:4854–4859[Abstract/Free Full Text]
  31. Verhaeghe J, Pintiaux A, Van Herck E, Hennen G, Foidart JM, Igout A 2002 Placental GH, IGF-I, IGF-binding protein-1, and leptin during a glucose challenge test in pregnant women: relation with maternal body weight, glucose tolerance, and birth weight. J Clin Endocrinol Metab 87:2875–28782[Abstract/Free Full Text]
  32. Verhaeghe J, Bougoussa M, Van Herck E, de Zegher F, Hennen G, Igout A 2000 Placental growth hormone and IGF-I in a pregnant woman with Pit-1 deficiency. Clin Endocrinol (Oxf) 53:645–647[CrossRef][Medline]
  33. Langford KS, Nicolaides KH, Jones J, Abbas A, McGregor AM, Miell JP 1995 Serum insulin-like growth factor-binding protein-3 (IGFBP-3) levels and IGFBP-3 protease activity in normal, abnormal, and multiple human pregnancy. J Clin Endocrinol Metab 80:21–27[Abstract]
  34. Langford K, Nicolaides K, Miell JP 1998 Maternal and fetal insulin-like growth factors and their binding proteins in the second and third trimesters of human pregnancy. Hum Reprod 13:1389–1393[Abstract/Free Full Text]
  35. Holmes RP, Holly JM, Soothill PW 1998 A prospective study of maternal serum insulin-like growth factor-I in pregnancies with appropriately grown or growth restricted fetuses. Br J Obstet Gynaecol 105:1273–1278[Medline]
  36. Lauszus FF, Klebe JG, Flyvbjerg A 2001 Macrosomia associated with maternal serum insulin-like growth factor-I and -II in diabetic pregnancy. Obstet Gynecol 97:734–741[Abstract/Free Full Text]
  37. Paolini CL, Marconi AM, Ronzoni S, Di Noio M, Fennessey PV, Pardi G, Battaglia FC 2001 Placental transport of leucine, phenylalanine, glycine, and proline in intrauterine growth-restricted pregnancies. J Clin Endocrinol Metab 86:5427–5432[Abstract/Free Full Text]
  38. Liu L, Harding JE, Evans PC, Gluckman PD 1994 Maternal insulin-like growth factor-I infusion alters feto-placental carbohydrate and protein metabolism in pregnant sheep. Endocrinology 135:895–900[Abstract]
  39. Gluckman PD, Morel PC, Ambler GR, Breier BH, Blair HT, McCutcheon SN 1992 Elevating maternal insulin-like growth factor-I in mice and rats alters the pattern of fetal growth by removing maternal constraint. J Endocrinol 134:R1–R3
  40. Gluckman PD, Breier BH, Davis SR 1987 Physiology of the somatotropic axis with particular reference to the ruminant. J Dairy Sci 70:442–466
  41. Breier BH, Gluckman PD, Bass JJ 1988 Plasma concentrations of insulin-like growth factor-I and insulin in the infant calf: ontogeny and influence of altered nutrition. J Endocrinol 119:43–50[Abstract]
  42. Caufriez A, Frankenne F, Hennen G, Copinschi G 1994 Regulation of maternal insulin-like growth factor I by placental growth hormone in pregnancy. Possible action of maternal IGF-I on fetal growth. Horm Res 42:62–65[Medline]
  43. Wang HS, Lim J, English J, Irvine L, Chard T 1991 The concentration of insulin-like growth factor-I and insulin-like growth factor-binding protein-1 in human umbilical cord serum at delivery: relation to fetal weight. J Endocrinol 129:459–464[Abstract]
  44. Hills FA, English J, Chard T 1996 Circulating levels of IGF-I and IGF-binding protein-1 throughout pregnancy: relation to birthweight and maternal weight. J Endocrinol 148:303–309[Abstract]
  45. Wang HS, Cheng BJ, Soong YK 1995 Serum levels of insulin-like growth factor-binding protein-3 in normal pregnancy. Eur J Obstet Gynecol Reprod Biol 61:157–160[Medline]
  46. Giudice LC, Farrell EM, Pham H, Lamson G, Rosenfeld RG 1990 Insulin-like growth factor binding proteins in maternal serum throughout gestation and in the puerperium: effects of a pregnancy-associated serum protease activity. J Clin Endocrinol Metab 71:806–816[Abstract]



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