help button home button Endocrine Society JCEM
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Submit a related Letter to the Editor
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow Request Copyright Permission
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Halhali, A.
Right arrow Articles by Larrea, F.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Halhali, A.
Right arrow Articles by Larrea, F.
The Journal of Clinical Endocrinology & Metabolism Vol. 85, No. 5 1828-1833
Copyright © 2000 by The Endocrine Society

Original Studies

Preeclampsia Is Associated with Low Circulating Levels of Insulin-Like Growth Factor I and 1,25-Dihydroxyvitamin D in Maternal and Umbilical Cord Compartments1

Ali Halhali, Armando R. Tovar, Nimbe Torres, Hector Bourges, Michele Garabedian and Fernando Larrea

Departments of Reproductive Biology (A.H., F.L.) and Physiology of Nutrition (A.R.T., N.T., H.B.), Instituto Nacional de la Nutrición Salvador Zubirán, Mexico D.F., Mexico; and Unité Centre National de la Recherche Scientifique, UPR 1524, Endocrinologie, Métabolisme, et Développement, Hôpital Saint Vincent de Paul (M.G.), Paris, France

Address all correspondence and requests for reprints to: Dr. Ali Halhali, Department of Reproductive Biology, Instituto Nacional de la Nutrición Salvador Zubirán, Vasco de Quiroga No. 15, Col. Tlalpan, C.P. 14000, Mexico D.F., Mexico.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Insulin-like growth factor I (IGF-I) stimulates renal and placental 1,25-dihydroxyvitamin D [1,25-(OH)2D] and is considered an important regulator of fetal growth. As 1,25-(OH)2D and birth weight are low in preeclampsia, this study was undertaken to determine whether circulating levels of IGF-I were associated with serum 1,25-(OH)2D concentrations in preeclamptic (PE group) and normotensive (NT group) pregnancies. Maternal and umbilical cord serum levels of IGF-I and 1,25-(OH)2D were significantly (P < 0.01) lower in the PE group than in the NT group. The concentrations of these two hormones correlated significantly in the umbilical cord (P < 0.05) and in the maternal (P < 0.001) compartments of the PE and NT groups, respectively. The amount of IGFBP-3 was 64% lower whereas that of IGFBP-1 was 2.9-fold higher in umbilical cord serum of the PE group compared with the NT group. In addition, maternal and umbilical cord serum IGF-I correlated significantly (P < 0.05) with weight and length at birth only in the PE group. In conclusion, the results of this study indicate that circulating IGF-I and 1,25-(OH)2D levels in both maternal and umbilical cord compartments are low in preeclampsia. Furthermore, this study suggests a differential regulatory effect of IGF-I on 1,25-(OH)2D synthesis and fetal growth depending on the presence or absence of preeclampsia.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
PREECLAMPSIA is a disorder of pregnancy characterized by hypertension and proteinuria (1). This condition is also associated with reduced uteroplacental blood flow and fetal intrauterine growth retardation (1, 2). Insulin-like growth factor I (IGF-I) may be involved in both normal and abnormal fetal growth (3). IGF-I circulates in blood bound to six binding proteins (IGFBPs) that modulate IGF-I action by inhibiting or enhancing its effects (4). Under physiological conditions, approximately 75% of IGF-I circulates as a high molecular mass (150-kDa) ternary complex formed by IGF-I, IGFBP-3, and an acid-labile subunit; 24% is bound to other IGFBPs, and the remaining 1% circulates as free IGF-I (5). Birth weight is positively associated with maternal and fetal serum IGF-I and IGFBP-3 concentrations and negatively correlated with maternal and fetal serum IGFBP-1 levels (6, 7, 8, 9, 10, 11, 12, 13, 14).

During preeclampsia, maternal serum IGF-I concentrations are lower compared with those in normal pregnant women (15, 16). In addition to its effects on fetal growth, it has been reported that IGF-I stimulates renal 1,25-dihydroxyvitamin D [1,25-(OH)2D] synthesis in nonpregnant humans and rodents (17, 18, 19, 20, 21, 22, 23, 24, 25, 26). Furthermore, previous results from this laboratory have showed that IGF-I stimulates human placental 1,25-(OH)2D production (27). Interestingly, maternal serum 1,25-(OH)2D concentrations are lower in preeclampsia than in normotensive pregnant women (15, 28, 29, 30).

During normal pregnancy, umbilical cord serum IGF-I and 1,25-(OH)2D levels are significantly lower than those in maternal serum, which are probably derived from placental and fetal tissues (31, 32, 33, 34, 35). As the umbilical cord serum concentrations of these two hormones have not been assessed during preeclampsia, the aim of the present work was to study maternal and umbilical cord serum concentrations of 1,25-(OH)2D and IGF-I, and other parameters involved in their regulation, as well as potential correlations between IGF-I and birth weight, and 1,25-(OH)2D levels in normal and preeclamptic pregnancies.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Subjects

Maternal and umbilical cord blood samples were obtained from patients in accordance with the guidelines of the Declaration of Helsinki, and the protocol of this study was approved by the human ethics committee of the Instituto Nacional de la Nutrición Salvador Zubirán. The study was performed cross-sectionally at delivery and included 24 preeclamptic (PE group) and 24 normotensive (NT group) pregnant women and their respective newborns. The mean gestational ages of the NT and PE groups were 40.3 ± 1.0 and 39.6 ± 1.2 weeks, respectively. All subjects signed a written informed consent. Diagnosis of preeclampsia was based on the simultaneous presence of hypertension (systolic blood pressure >=140 mm Hg and/or diastolic blood pressure >=90 mm Hg) and marked proteinuria (at least 2+ on dipstick; >100 mg/dL) (1). Exclusion criteria were known preexisting hypertension or previous preeclampsia; liver, renal, heart, or endocrine disorders; and use of nutritional supplements (calcium or vitamin D), diuretics, any kind of hormonal treatment, or magnesium sulfate therapy. Only women giving birth to a clinically healthy single infant were included in the study.

Newborns small for gestational age (below the 10th percentile) were classified according to the criteria of Lubchenco et al. (36). Maternal and umbilical cord blood samples were collected at delivery; after centrifugation, serum samples were aliquoted and frozen at -70 C until assayed.

Serum calcium, magnesium, and phosphorus determinations

Serum ionic calcium and magnesium were determined by ion-selective electrodes using a Nova 8 CRT electrolyte analyzer (Nova Biomedical, Waltham, MA). Serum total calcium and serum total magnesium were measured by atomic absorption spectrophometry (2380, Perkin-Elmer Corp., Norwalk, CT). Serum inorganic phosphorus concentrations were assessed by the Fiske and SubbaRow method (37).

Serum 1,25-(OH)2D, vitamin D-binding protein, IGFBP-3, PTH, and IGF-I quantification

Serum 1,25-(OH)2D concentrations were measured as previously described (38) using a commercial RRA kit (Nichols Institute Diagnostics, San Juan Capistrano, CA). The sensitivity was 2 pg/mL, and the intra- and interassay coefficients of variation were 5–11% and 9–15%, respectively. Serum vitamin D-binding protein (DBP) concentrations were assessed by the method of Bouillon et al. (39). Serum IGFBP-3 concentrations were measured using a commercial immunoradiometric assay kit (Diagnostics Systems Laboratories, Inc., Webster, TX). The sensitivity was 0.5 ng/mL, and the intra- and interassay coefficients of variation were less than 5%. Serum intact PTH concentrations were measured using a commercial immunoradiometric assay kit (Nichols Institute Diagnostics). The sensitivity was 1 pg/mL, and the intra- and interassay coefficients of variation were less than 5% and 10%, respectively. Serum IGF-I was quantified using a commercial RIA kit (Nichols Institute Diagnostics) after separation from its binding proteins, as previously described (40). The sensitivity was 60 pg/mL, and the intra- and interassay coefficients of variation were less than 5% and 10%, respectively.

SDS-PAGE, Western ligand blotting (WLB), and Western immunoblotting (WIB)

Analysis of serum IGFBPs by WLB and WIB was performed as previously described (41, 42, 43). A 20-µL aliquot of a serum pool from each group was diluted in 280 µL buffer (2.5% SDS, 10% glycerol, and 0.02% bromophenol in 0.06 mol/L Tris-HCl, pH 6.8). An aliquot of 50 µL of each sample was applied to 11% SDS-PAGE in the absence of a reducing agent and run overnight. Proteins were then electroblotted onto a nitrocellulose membrane (Bio-Rad Laboratories, Inc., Hercules, CA). The nitrocellulose membrane was blocked at 4 C with 1.5 mol/L NaCl in 100 mmol/L Tris base, pH 7.4 (TBS)/0.5% gelatin, washed with TBS/0.1% Tween-20, and incubated for 48 h with 600,000 cpm [125I]IGF-I (Amersham Pharmacia Biotech, Aylesbury, UK) at 4 C. Membranes were washed twice with TBS/0.1% Tween-20 and three times with TBS. The concentrations of IGFBPs in nitrocellulose membranes were determined using electronic autoradiography with an Instant Imager (Packard Instrument Co, Downers Grove, NJ). Membranes were also exposed to Extascan film (Eastman Kodak Co., Rochester, NY) at -80 C with an intensifying screen. For WIB analysis, nitrocellulose membranes were incubated overnight at 4 C with a polyclonal anti-IGFBP-3 (Upstate Biotechnology, Inc., Lake Placid, NY). After thorough washing, membranes were incubated for 1 h with horseradish peroxidase-conjugated antirabbit IgG (Bio-Rad Laboratories, Inc.). Peroxidase-conjugated antibody was detected with diaminobenzidine as substrate.

Statistical analysis

Results are presented as the mean ± SD. Analysis of statistical differences between the NT and PE groups was performed by the Mann-Whitney U test, and comparisons of frequencies of newborns small for gestational age were made using {chi}2 test. Associations between variables were tested using Spearman rank correlation test. Differences were considered statistically significant at P < 0.05.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
Clinical characteristics

Table 1Go summarizes the clinical characteristics of mothers and their newborns belonging to NT and PE groups. Maternal and gestational ages and newborn birth lengths were similar in both groups. Birth weights of newborns were significantly lower in the PE group (P < 0.05), and the frequency of newborns small for gestational age (SGA) newborns was higher in the PE group (P < 0.05).


View this table:
[in this window]
[in a new window]
  		Table 1. Clinical characteristics of the NT and PE groups

 
Mineral and hormonal serum concentrations

Maternal circulating levels of total calcium, 1,25-(OH)2D, and IGF-I levels were significantly lower (P < 0.001) in the PE group than in the NT group (Table 2Go). No differences were found in maternal circulating levels of ionic calcium, total and ionic magnesium, inorganic phosphorus, DBP, IGFBP-3, and intact PTH between the two groups studied. In umbilical cord blood (Table 3Go), significantly lower serum concentrations of total calcium (P < 0.001), IGF-I (P < 0.001), and 1,25-(OH)2D (P < 0.05) were observed in the PE group compared with the NT group.


View this table:
[in this window]
[in a new window]
  		Table 2. Maternal serum concentrations of calcium, 1,25-(OH)2D, DBP, IGF-I, IGFBP-3, and PTH in the NT and PE groups

 

View this table:
[in this window]
[in a new window]
  		Table 3. Umbilical cord serum concentrations of calcium, 1,25-(OH)2D, DBP, IGF-I, IGFBP-3, and PTH in the NT and PE groups

 
In umbilical cord serum, circulating levels of ionic calcium, total and ionic magnesium, inorganic phosphorus, DBP, IGFBP-3, and PTH were similar in both groups. Analysis of WLB and WIB of IGFBPs from pools of maternal and umbilical cord serum from each group is shown in Fig. 1Go. As depicted in Fig. 1AGo, WLB analysis of serum umbilical cord showed a group of different bands with molecular masses between 24–43 kDa. These bands corresponded to IGFBP-3 (38–43 kDa), IGFBP-2 (34 kDa), IGFBP-1 (30 kDa), and IGFBP-4 (24 kDa), respectively. In umbilical cord serum of the PE group, WLB analysis showed that the amount of IGFBP-3 was 64% lower than that in the NT group. In contrast, the amount of IGFBP-1 was 2.9-fold higher in umbilical cord blood of the PE group compared with the NT group. WIB analysis of umbilical cord serum using a specific anti-IGFBP-3 antiserum revealed two bands that corresponded to IGFBP-3 and to one of the proteolytic immunoreactive fragments of this protein (Fig. 1BGo). In maternal serum, WLB analysis showed the complete disappearance of IGFBP-3 in both groups. Also, this analysis revealed an increment of 7-fold in IGFBP-1 in the PE group (Fig. 1AGo). Furthermore, WIB showed three proteolytic immunoreactive fragments of IGFBP-3 with molecular masses of 29, 18, and 15 kDa (Fig. 1BGo).



View larger version (70K):
[in this window]
[in a new window]
  		Figure 1. Characterization of IGFBPs by WLB (A) and WIB (B) in maternal and umbilical cord serum pools from 24 NT and 24 PE pregnant women. Molecular weight (MW) markers are shown on the left.

 
To know whether low maternal and umbilical cord serum concentrations of 1,25-(OH)2D and IGF-I observed in the PE group were associated with low newborn birth weight, the concentrations of these two hormones were compared according with birth weights. As shown in Table 4Go, maternal and umbilical cord serum concentrations of IGF-I and maternal serum 1,25-(OH)2D were significantly (P < 0.01) lower in the PE group compared to the NT group despite an adequate newborn birth weight. In the PE group with newborns SGA, both IGF-I and 1,25-(OH)2D were significantly (P < 0.05) lower in maternal and umbilical cord compartments compared with those in the NT group.


View this table:
[in this window]
[in a new window]
  		Table 4. Newborn birth weights and maternal and umbilical cord serum concentrations of 1,25-(OH)2D and IGF-I in AGA of the NT group and in AGA and SGA of the PE group

 
Association studies

The association between 1,25-(OH)2D and IGF-I concentrations was analyzed (Fig. 2Go). Maternal serum 1,25-(OH)2D concentrations correlated significantly with IGF-I ({rho} = 0.69; P = 0.001) only in the NT group (Fig. 2AGo). A similar result was obtained when intact PTH concentrations were positively correlated with 1,25-(OH)2D serum levels in the maternal compartment of the NT group ({rho} = 0.74; P = 0.0005). In contrast, in the umbilical cord serum, a significant association between 1,25-(OH)2D and IGF-I was observed only in the PE group ({rho} = 0.41; P < 0.05; Fig. 2BGo). In this group, the association between umbilical 1,25-(OH)2D and IGF-I was seen in newborns AGA ({rho} = 0.65; P = 0.01), but not in newborns SGA.



View larger version (15K):
[in this window]
[in a new window]
  		Figure 2. Associations between IGF-I and 1,25-(OH)2D in maternal serum of NT pregnant women (A) and in umbilical cord serum of the PE group (B).

 
As shown in Table 5Go, maternal and umbilical cord serum IGF-I concentrations correlated significantly with newborn birth weight and length in the PE group ({rho} = 0.59; P = 0.005 and {rho} = 0.48; P = 0.02, respectively). These associations were maintained in both compartments of the SGA PE group, whereas in the AGA PE group these associations were of significance only in the umbilical cord compartment.


View this table:
[in this window]
[in a new window]
  		Table 5. Correlation between serum IGF-I concentrations and newborn birth weight and length in the indicated groups

 

   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
The results of the present study confirmed previous observations regarding the higher proportion of newborns SGA (44) and lower maternal serum concentrations of IGF-I (15, 16) and 1,25-(OH)2D (15, 16, 28, 29, 30) in PE women compared with those in NT pregnant controls. Furthermore, this study demonstrated that 1) umbilical cord serum concentrations of IGF-I and 1,25-(OH)2D were lower in the PE group than in NT group; 2) low umbilical cord serum IGF-I concentrations were observed even in the AGA PE group; 3) in the NT group, 1,25-(OH)2D correlated significantly with IGF-I in the maternal compartment, whereas in the PE group this correlation was only seen in the umbilical cord; and 4) maternal and umbilical cord serum IGF-I concentrations in the PE group correlated significantly with newborn birth weight and length.

As previously observed (15, 16), maternal serum IGF-I concentrations were significantly lower in the PE group than in the NT group. In postnatal life, IGF-I is synthesized mainly in the liver and is primarily regulated by GH (45), whereas during pregnancy the synthesis of this growth factor also occurs in placental and fetal tissues (31, 32, 33, 34). The increase in serum IGF-I levels during pregnancy (3, 46) may not be associated with an elevation in pituitary GH production, as circulating levels of this hormone do not increase during this physiological stage (47). Therefore, stimulation of IGF-I synthesis during normal pregnancy may be associated with an increase in GH production by the placenta (48), and the reduced circulating IGF-I levels in the PE group could probably be attributed to a decrease in placental GH synthesis (16). In addition, the finding in this study of similar concentrations of IGFBP-3 in both NT and PE groups may indicate the low bioavailability of IGF-I during preeclampsia. During pregnancy, serum IGFBP-3 concentrations decreased markedly, and this decrease has been attributed to an endogenous pregnancy-related serum IGFBP-3 proteolytic activity (33, 42, 46, 49). In this regard, IGFBP-3 is functionally different during pregnancy, and this protease-induced alteration of IGFBP-3 is considered to be a fundamental mechanism in regulating IGF-I bioavailability (50). In the present study, the data obtained by WLB analysis showed a complete disappearance of IGBP-3 in maternal serum of both groups. Also, this analysis revealed an increment in IGFBP-1 in the PE group, which was consistent with previous studies (16, 51, 52, 53). On the other hand, WIB analysis of IGFBP-3 in maternal serum showed the presence of three bands with molecular masses of 29, 18, and 15 kDa, which might correspond to the proteolytic immunoreactive fragments of IGFBP-3. These results may also indicate a low IGF-I bioavailability in preeclampsia.

We observed that maternal serum 1,25-(OH)2D concentrations were lower in PE than in NT pregnant women. This decrease was not associated with changes in serum calcium, phosphate, or PTH concentrations. Although IGF-I is considered a stimulatory factor of renal and placental 1,25-(OH)2D synthesis (17, 18, 19, 20, 21, 22, 23, 24, 25, 26), these two hormones were only significantly associated in NT group. The finding of a similar association of PTH and 1,25-(OH)2D in the maternal compartment of the NT group may indicate that IGF-I is also involved in 1,25-(OH)2D synthesis during normal pregnancy. In the PE group, the lack of association between these two hormones in the maternal compartment suggests an IGF-I resistance condition similar to that observed with insulin during preeclampsia (54). This condition could be independent of fetal growth, as no association was found between 1,25-(OH)2D and IGF-I even when newborns were AGA. Even though it has been speculated that low 1,25-(OH)2D levels impair intestinal calcium absorption leading to hypocalciuria during preeclampsia (28, 29), fractional intestinal absorption of calcium is not reduced in preeclamptic women despite low serum 1,25-(OH)2D levels and low urinary calcium excretion (30). Thus, the effects of low 1,25-(OH)2D levels on calcium metabolism during preeclampsia need to be further investigated.

In this and other studies (44), the body weights of newborns from PE women were lower than those of newborns from NT pregnant women. Low birth weight could be due to insufficient fetal nutrient supply as a consequence of reduced uteroplacental blood flow in preeclampsia (1, 2). The alteration in fetal nutrient supply could also explain the low umbilical cord serum IGF-I levels observed in the PE group. Indeed, low IGF-I levels have been observed in newborns SGA (6, 7, 8, 9, 10, 11, 12, 13, 14). In our study, the proportion of newborns SGA was higher in the PE than in the NT group, and serum IGF-I levels correlated positively with birth weight and birth length only in the PE group. The significant association between IGF-I and birth weight and length observed in the PE group suggests that IGF-I is an important regulatory factor of fetal growth, particularly in newborns SGA. It has been shown that IGF-I binding to erythrocytes increases in preeclamptic women compared with that in normotensive pregnant women (55), suggesting that the number of IGF-I erythrocyte receptors increases in preeclampsia. Whether this observation could take place in other IGF-I targets is unknown and deserves to be further investigated. However, in our study this mechanism could occur, because in the AGA PE group low maternal and umbilical cord IGF-I serum concentrations were observed despite adequate birth weight. Interestingly, this hypothetical compensatory effect of low IGF-I and high number of IGF-I receptors appeared to be insufficient to correct the low newborn birth weight in the SGA PE group. The umbilical cord serum IGFBP profile observed in the PE group revealed lower IGFBP-3 and higher IGFBP-1 amounts compared with those in the NT group. The finding that low umbilical cord serum IGFBP-3 levels did not correlate with a concomitant increase in immunoreactive fragments of IGFPB-3 in the PE group may indicate the absence of proteolysis of this protein in the umbilical cord, as previously demonstrated (8). This observation suggests a decrease in IGFBP-3 synthesis rather than proteolysis of this binding protein in preeclampsia.

High amounts of IGFBP-1 have been associated with intrauterine growth retardation (8, 11, 12). Furthermore, high IGFBP-1 is found during hypoxia (3, 56), and it has been suggested that hypoxia regulation of IGFBP-1 is a mechanism operating in the human fetus to restrict IGF-I-mediated growth in utero under conditions of chronic hypoxia and limited substrate availability (56). Hypoxia and a possible reduced fetal availability of substrate due to decreased uteroplacental blood flow are conditions often observed during preeclampsia (1, 2). In fact, it has been suggested that levels of IGFBP-1 could be a sensitive indicator of fetal nutrition and the short or long term response to reduced fetal nutrient supply (3). Studies in rodents show that nutritional status modulates the expression of IGF-I and IGFBPs (57, 58, 59), giving additional evidence that a high IGFBP-1/IGFBP-3 ratio and low IGF-I levels are involved in intrauterine growth retardation.

A low umbilical cord 1,25-(OH)2D serum concentration was observed in the PE group. Although synthesis of 1,25-(OH)2D occurs in placenta and fetal kidney, its role in fetal calcium metabolism has not yet been well defined (35). Although IGF-I stimulates renal and placental 1,25-(OH)2D synthesis (17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27), association between these two hormones was observed only in the maternal compartment and the umbilical cord serum of the NT and PE groups, respectively. These observations suggested a differential regulation of 1,25-(OH)2D synthesis by IGF-I in the maternal and fetal compartments depending on the presence or absence of preeclampsia. However, whether preeclampsia is a condition affecting IGF-I-mediated effects on 1,25-(OH)2D synthesis deserves to be further investigated.

In summary, maternal and umbilical cord serum IGF-I and 1,25-(OH)2D levels were low in preeclampsia, and umbilical cord serum IGF-I, IGFBP-1 and IGFBP-3 concentrations were associated with low newborn birth weights. Thus, low IGF-I and 1,25-(OH)2D in umbilical cord serum observed in preeclampsia may be implicated in fetal growth and skeletal mineralization, particularly in newborns SGA.


   Footnotes
 
1 This work was supported by grants from the National Council of Science and Technology (CONACYT, Mexico; 26238-M), the Nord/Sud INSERM (France; 493 NS4), and the Special Program of Research, Development, and Research Training in Human Reproduction of the WHO (Geneva, Switzerland). Back

Received September 8, 1999.

Revised December 15, 1999.

Accepted December 29, 1999.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

  1. National High Blood Pressure Education Program Working Group. 1990 National high blood pressure education program working group on high blood pressure in pregnancy. Am J Obstet Gynecol. 163:1689–1712.
  2. Redman CWG. 1991 Current topic: pre-eclampsia and the placenta. Placenta. 12:301–308.[Medline]
  3. Chard T. 1994 Insulin-like growth factors and their binding proteins in normal and abnormal human fetal growth. Growth Regul. 4:91–100.[Medline]
  4. Jones JI, Clemmons DR. 1995 Insulin-like growth factors and their binding proteins: biological actions. Endocr Rev. 16:3–34.[Abstract/Free Full Text]
  5. Rajaram S, Baylink DJ, Mohan S. 1997 Insulin-like growth factor-binding proteins in serum and other biological fluids: regulation and functions. Endocr Rev. 18:801–831.[Abstract/Free Full Text]
  6. Lassarre C, Hardouin S, Daffos F, Forestier F, Frankenne F, Binoux M. 1991 Serum insulin-like growth factors and insulin-like growth factor binding proteins in the human fetus. Relationships with growth in normal subjects and in subjects with intrauterine growth retardation. Pediatr Res. 29:219–225.
  7. Verhaeghe J, Van Bree R, Van Herck R, Laureys J, Bouillon R, Van Assche FA. 1993 C-Peptide, insulin-like growth factors-I and II, and IGF-binding protein 1 in umbilical cord serum: correlations with birthweight. Am J Obstet Gynecol. 169:89–97.[Medline]
  8. Giudice LC, de Zegher F, Gargosky SE, et al. 1995 Insulin-like growth factors and their binding proteins in the term and preterm human fetus and neonate with normal and extremes of intrauterine growth. J Clin Endocrinol Metab. 80:1548–1555.[Abstract/Free Full Text]
  9. Nieto-Diaz A, Villar J, Matorras-Weinig R, Valenzuela-Ruiz P. 1996 Intrauterine growth retardation at term: association between anthropometric and endocrine parameters. Acta Obstet Gynecol Scand. 75:127–131.[Medline]
  10. Ostlund E, Bang P, Hagenas L, Fried G. 1997 Insulin-like growth factor I in fetal serum obtained by cordocentesis is correlated with intrauterine growth retardation. Hum Reprod. 12:840–844.[Abstract/Free Full Text]
  11. Cianfarani S, Germani D, Rossi P, et al. 1998 Intrauterine growth retardation: evidence for the activation of the insulin-like growth factor (IGF)-related growth-promoting machinery and the presence of a cation-independent IGF binding protein-3 proteolitic activity by two months of life. Pediatr Res. 44:374–380.[Medline]
  12. Cianfarani S, Germani D, Rossi L, et al. 1998 IGF-I and IGF-binding protein-1 are related to cortisol in human cord serum. Eur J Endocrinol. 138:424–529.
  13. Cance-Rouzaud A, Laborie S, Bieth E, et al. 1998 Growth hormone, insulin-like growth factor-I and insulin-like growth factor binding protein-3 are regulated differentially in small-for-gestational-age and appropriate-for-gestational-age neonates. Biol Neonate. 73:347–355.[CrossRef][Medline]
  14. Stafanidis K, Solomou E, Mouzakioti E, Stefos T, Farmakides G. 1998 Comparison of somatomedin-C (SMC/IGF-I), human placental lactogen and Doppler velocimetry between appropriate and small-for-gestational-age pregnancies. Clin Exp Obstet Gynecol. 25:20–22.[Medline]
  15. Halhali A, Bourges H, Carrillo A, Garabedian M. 1995 Lower circulating insulin-like growth factor-I and 1,25-dihydroxyvitamin D levels in preeclampsia. Rev Invest Clin. 47:259–266.[Medline]
  16. Giudice LC, Martina NA, Crystal RA, Tazuke S, Druzin M. 1997 Insulin-like growth factor binding protein-1 at the maternal-fetal interface and insulin-like growth factor-I, insulin-like growth factor-II, and insulin-like growth factor binding protein-1 in the circulation of women with severe preeclampsia. Am J Obstet Gynecol. 176:751–758.[CrossRef][Medline]
  17. Nesbitt T, Drezner MK. 1993 Insulin-like growth factor-I regulation of renal 25-hydroxyvitamin D-1-hydroxylase activity. Endocrinology. 132:133–138.[Abstract/Free Full Text]
  18. Gray RW. 1987 Evidence that somatomedins mediate the effect of hypophosphatemia to increase serum 1,25-dihydroxyvitamin D3 levels in rats. Endocrinology. 121:504–512.[Abstract/Free Full Text]
  19. Halloran BP, Spencer EM. 1988 Dietary phosphorus and 1,25-dihydroxyvitamin D metabolism: influence of insulin-like growth factor I. Endocrinology. 123:1225–1229.[Abstract/Free Full Text]
  20. Caverzasio J, Montessuit C, Bonjour JP. 1990 Stimulatory effect of insulin-like growth factor-1 on renal Pi transport and plasma 1,25-dihydroxyvitamin D3. Endocrinology. 127:453–459.[Abstract/Free Full Text]
  21. Condamine L, Vztovsnik F, Friedlander G, Menaa C, Garabedian M. 1994 Local action of phosphate depletion and insulin-like growth factor 1 on in vitro production of 1,25-dihydroxyvitamin D by cultured mammalian kidney cells. J Clin Invest. 94:1673–1679.
  22. Menaa C, Vrtovsnik F, Friedlander G, Corvol M, Garabedian M. 1995 Insulin-like growth factor I, a unique calcium-dependent stimulator of 1,25-dihydroxyvitamin D3 production. J Biol Chem. 270:25461–25467.[Abstract/Free Full Text]
  23. Wong MS, Sriussadaporn S, Tembe VA, Favus MJ. 1997 Insulin-like growth factor I increases renal 1,25-(OH)2D3 biosynthesis during low-P diet in adult rats. Am J Physiol. 272:F698–F703.
  24. Bianda T, Hossain MA, Glatz Y, Bouillon R, Froesch ER, Schmid C. 1997 Effects of short-term insulin-like growth factor-I or growth hormone treatment on bone turnover, renal phosphate reabsorption and 1,25-dihydroxyvitamin D3 production in healthy man. J Intern Med. 241:143–150.[CrossRef][Medline]
  25. Bianda T, Glatz Y, Bouillon R, Froesch ER, Schmid C. 1998 Effects of short-term insulin-like growth factor-I (IGF-I) or growth hormone (GH) treatment on bone metabolism and on production of 1,25-dihydroxycholecalciferol in GH-deficient adults. J Clin Endocrinol Metab. 83:81–87.[Abstract/Free Full Text]
  26. Wei S, Tanaka H, Seino Y. 1998 Local action of exogenous growth hormone and insulin-like growth factor-I on the dihydroxyvitamin D production in LLC-PK1 cells. Eur J Endocrinol. 139:454–460.[Abstract]
  27. Halhali A, Díaz L, Sánchez I, Garabedian M, Bourges H, Larrea F. 1999 Effects of IGF-I on 1,25-dihydroxyvitamin D3 synthesis by human placenta in culture. Mol Hum Reprod. 5:771–776.[Abstract/Free Full Text]
  28. August P, Marcaccio BG, Gertner JM, Druzin ML, Resnick LM, Laragh JH. 1992 Abnormal 1,25-dihydroxyvitamin D metabolism in preeclampsia. Am J Obstet Gynecol. 166:1295–1299.[Medline]
  29. Seely EW, Wood RJ, Brown EM, Graves SW. 1992 Lower serum ionized calcium and abnormal calciotropic hormone levels in preeclampsia. J Clin Endocrinol Metab. 74:1436–1440.[Abstract]
  30. Tolaymat A, Sanchez-Ramos L, Yergey AL, Vieira NE, Abrams SA, Edelstein P. 1994 Pathophysiology of hypocalciuria in preeclampsia: measurement of intestinal calcium absorption. Obstet Gynecol. 83:239–243.[Medline]
  31. Han VKM, Lund PK, Lee DC, D’Ercole AJ. 1988 Expression of somatomedin/insulin-like growth factor messenger ribonucleic acids in the human fetus: identification, characterization, and tissue distribution. J Clin Endocrinol Metab. 66:422–429.[Abstract/Free Full Text]
  32. Hill DJ, Clemmons DR, Riley SC, Bassett N, Challis JRG. 1993 Immunohistochemical localization of insulin-like growth factors (IGFs) and IGF binding proteins-1, -2 and -3 in human placenta and fetal membranes. Placenta. 14:1–12.[Medline]
  33. Nonoshita LD, Wathen NC, Dsupin BA, Chard T, Giudice LC. 1994 Insulin-like growth factors (IGFs), IGF-binding proteins (IGFBPs), and proteolyzed IGFBP-3 in embrionic cavities in early human pregnancy: their potential relevance to maternal-embrionic and fetal interactions. J Clin Endocrinol Metab. 79:1249–1255.[Abstract]
  34. Han VKM, Bassett N, Walton J, Challis JRG. 1996 The expression of insulin-like growth factor (IGF) and IGF-binding protein (IGFBP) genes in the human placenta and membranes: evidence for IGF-IGFBP interactions at the feto-maternal interface. J Clin Endocrinol Metab. 81:2680–2693.[Abstract]
  35. Kovacs CS, Kronenberg HM. 1997 Maternal-fetal calcium and bone metabolism during pregnancy, puerperium, and lactation. Endocr Rev. 18:832–872.[Abstract/Free Full Text]
  36. Lubchenco LO, Hansman C, Dressler M, Boyde E. 1963 Intrauterine growth as estimated from liveborn birth weight data at 24 to 42 weeks of gestation. Pediatrics. 32:793–800.[Abstract/Free Full Text]
  37. Fiske CH, SubbaRow Y. 1925 The colorimetric determination of phosphorus. J Biol Chem. 66:375–400.[Free Full Text]
  38. Reinhardt TA, Horst RL, Orf JW, Hollis BW. 1984 A microassay for 1,25-dihydroxyvitamin D not requiriing high performance liquid chromatography: application to clinical studies. J Clin Endocrinol Metab. 58:91–98.[Abstract/Free Full Text]
  39. Bouillon R, Van Baelen H, De Moor P. 1977 The measurement of the vitamin D-binding protein in human serum. J Clin Endocrinol Metab. 45:225–231.[Abstract/Free Full Text]
  40. Daughaday WH, Mariz IK, Blethen SL. 1980 Inhibition of access of bound somatomedin to membrane receptor and immunobinding sites: a comparison of radioreceptor and radioimmunoassay of somatomedin in native and acid-ethanol-extracted serum. J Clin Endocrinol Metab. 51:781–788.[Abstract/Free Full Text]
  41. Laemmli UK. 1970 Cleavage of structural proteins during the assembly of the head of bacteriophage T4. Nature. 227:680–685.[CrossRef][Medline]
  42. Hossenlopp P, Seurin D, Segovia-Quinson B, Hardouin S, Binoux M. 1986 Analysis of serum insulin-like growth factor binding proteins using Western blotting: use of the method for titration of the binding proteins and competitive binding studies. Anal Biochem. 154:138–143.[CrossRef][Medline]
  43. Nivot S, Benelli C, Clot J-P, et al. 1994 Nonparallel changes of growth hormone (GH) and insulin-like growth factor-I, insulin-like growth factor binding protein-3, and GH-binding protein, after craniospinal irradiation and chemotherapy. J Clin Endocrinol Metab. 78:597–601.[Abstract]
  44. Long PA, Abell DA, Beischer NA. 1980 Fetal growth retardation and preeclampsia. Br J Obstet Gynaecol. 87:13–18.[Medline]
  45. Florini JR, Ewton DZ, Coolican SA. 1996 Growth hormone and the insulin-like growth factor system in myogenesis. Endocr Rev. 17:481–517.[Abstract/Free Full Text]
  46. Hasegawa T, Hasegawa Y, Takada M, Tsuchida Y. 1995 The free form of insulin-like growth factor I increases in crculation during normal human pregnancy. J Clin Endocrinol Metab. 80:3284–3286.[Abstract]
  47. Luthman M, Bremme K, Jónsdóttir I, Hall K, Roos P, Werner S. 1991 Serum levels and molecular sizes of growth hormone during pregnancy in relation to levels of lactogens, insulin-like growth factor I and insulin-like growth factor binding protein-1. Gynecol Obstet Invest. 31:67–73.[Medline]
  48. 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.
  49. Giudice LC, Dsupin BA, De las Fuentes L, et al. 1993 Insulin-like growth factor binding proteins in sera of pregnant nonhuman primates. Endocrinology. 132:1514–1526.[Abstract/Free Full Text]
  50. Lassarre C, Binoux M. 1994 Insulin-like growth factor binding protein-3 is functionally altered in pregnancy plasma. Endocrinology. 134:1254–1262.[Abstract/Free Full Text]
  51. Than GN, Csaba IF, Szabo DG, Arany AA, Bognar ZJ, Bohn H. 1984 Serum levels of placenta-specific tissue protein 12 (PP12) in pregnancies complicated by pre-eclampsia, diabetes or twins. Arch Gynecol. 236:41–45.[CrossRef][Medline]
  52. Iino K, Sjoberg J, Seppala M. 1986 Elevated circulating levels of a decidual protein, placental 12, in preeclampsia. Obstet Gynecol. 68:58–60.[Medline]
  53. Howell RJ, Economides D, Teisner B, Farkas AG, Chard T. 1989 Placental proteins 12 and 14 in pre-eclampsia. Acta Obstet Gynecol Scand. 68:237–240.[Medline]
  54. Berkowitz KM. 1998 Insulin resistance and preeclampsia. Clin Perinatol. 25:873–885.[Medline]
  55. Sowers JR, Jacobs DB, Simpson L, al-Homsi B, Grunberger G, Sokol R. 1995 Erythrocyte insulin and insulin-like growth factor-I receptor tyrosine kinase activity in hypertension in pregnancy. Metabolism. 44:1308–1313.[CrossRef][Medline]
  56. Tazuke SI, Mazure NM, Sugawara J, et al. 1998 Hypoxia stimulates insulin-like growth factor binding protein 1 (IGFBP-1) gene expression in HepG2 cells: a possible model for IGFBP-1 expression in fetal hypoxia. Proc Natl Acad Sci USA. 18:10188–10193.
  57. Ketelslegers J-M, Maiter D, Maes M, Underwood LE, Thissen J-P. 1995 Nutritional regulation of insulin-like growth factor-I. Metabolism. 44:50–57.[Medline]
  58. Tovar AR, Santos A, Halhali A, Bourges H, Torres N. 1998 Hepatic histidase gene expression responds to protein rehabilitation in undernourished growing rats. J Nutr. 128:1631–1635.[Abstract/Free Full Text]
  59. Tovar AR, Halhali A, Torres N. 1999 Effect of nutritional rehabilitation of undernourished rats on serum insulin-like growth factor(IGF)-I and IGF-binding proteins. Rev Invest Clin. 51:99–106.[Medline]



This article has been cited by other articles:


Home page
 Am J EpidemiolHome page
M. B. Terry, M. Perrin, C. M. Salafia, F. F. Zhang, A. I. Neugut, S. L. Teitelbaum, J. Britton, and M. D. Gammon
Preeclampsia, Pregnancy-related Hypertension, and Breast Cancer Risk
Am. J. Epidemiol., May 1, 2007; 165(9): 1007 - 1014.
[Abstract] [Full Text] [PDF]

Home page
 CMAJHome page
C. A. Mannion, K. Gray-Donald, and K. G. Koski
Association of low intake of milk and vitamin D during pregnancy with decreased birth weight.
Can. Med. Assoc. J., April 25, 2006; 174(9): 1273 - 1277.
[Abstract] [Full Text] [PDF]

Home page
 Endocr. Rev.Home page
V. E. Murphy, R. Smith, W. B. Giles, and V. L. Clifton
Endocrine Regulation of Human Fetal Growth: The Role of the Mother, Placenta, and Fetus
Endocr. Rev., April 1, 2006; 27(2): 141 - 169.
[Abstract] [Full Text] [PDF]

Home page
 Biol. Reprod.Home page
E. Maioli, V. Fortino, and A. Pacini
Parathyroid Hormone-Related Protein in Preeclampsia: A Linkage Between Maternal and Fetal Failures
Biol Reprod, December 1, 2004; 71(6): 1779 - 1784.
[Abstract] [Full Text] [PDF]

Home page
 J. Clin. Endocrinol. Metab.Home page
S. Ten and N. Maclaren
Insulin Resistance Syndrome in Children
J. Clin. Endocrinol. Metab., June 1, 2004; 89(6): 2526 - 2539.
[Abstract] [Full Text] [PDF]

Home page
 J. Clin. Endocrinol. Metab.Home page
L. Diaz, C. Arranz, E. Avila, A. Halhali, F. Vilchis, and F. Larrea
Expression and Activity of 25-Hydroxyvitamin D-1{alpha}-Hydroxylase Are Restricted in Cultures of Human Syncytiotrophoblast Cells from Preeclamptic Pregnancies
J. Clin. Endocrinol. Metab., August 1, 2002; 87(8): 3876 - 3882.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Pathol.Home page
D. Zehnder, K. N. Evans, M. D. Kilby, J. N. Bulmer, B. A. Innes, P. M. Stewart, and M. Hewison
The Ontogeny of 25-Hydroxyvitamin D3 1{alpha}-Hydroxylase Expression in Human Placenta and Decidua
Am. J. Pathol., July 1, 2002; 161(1): 105 - 114.
[Abstract] [Full Text] [PDF]

Home page
 J. Clin. Endocrinol. Metab.Home page
M. Sowers, T. Scholl, J. Grewal, X. Chen, and M. Jannausch
IGF-I, Osteocalcin, and Bone Change in Pregnant Normotensive and Pre-Eclamptic Women
J. Clin. Endocrinol. Metab., December 1, 2001; 86(12): 5898 - 5903.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Submit a related Letter to the Editor
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow Request Copyright Permission
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Halhali, A.
Right arrow Articles by Larrea, F.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Halhali, A.
Right arrow Articles by Larrea, F.

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Endocrinology Endocrine Reviews J. Clin. End. & Metab.
Molecular Endocrinology Recent Prog. Horm. Res. All Endocrine Journals