Abstract
Objectives. Placental growth hormone (PGH) is a pregnancy-specific protein produced by syncytiotrophoblast and extravillous cytotrophoblast. No other cells have been reported to synthesize PGH Maternal. PGH Serum concentration increases with advancing gestational age, while quickly decreasing after delivery of the placenta. The biological properties of PGH include somatogenic, lactogenic, and lipolytic functions. The purpose of this study was to determine whether the maternal serum concentrations of PGH change in women with preeclampsia (PE), women with PE who deliver a small for gestational age neonate (PE + SGA), and those with SGA alone.
Study design. This cross-sectional study included maternal serum from normal pregnant women (n = 61), patients with severe PE (n = 48), PE + SGA (n = 30), and SGA alone (n = 41). Fetal cord blood from uncomplicated pregnancies (n = 16) and PE (n = 16) was also analyzed. PGH concentrations were measured by ELISA. Non-parametric statistics were used for analysis.
Results. (1) Women with severe PE had a median serum concentration of PGH higher than normal pregnant women (PE: median 23,076 pg/mL (3473–94 256) vs. normal pregnancy: median 12 157 pg/mL (2617–34 016); p < 0.05), pregnant women who delivered an SGA neonate (SGA: median 10 206 pg/mL (1816–34 705); p < 0.05), as well as pregnant patients with PE and SGA (PE + SGA: median 11 027 pg/mL (1232–61 702); p < 0.05). (2) No significant differences were observed in the median maternal serum concentration of PGH among pregnant women with PE and SGA, SGA alone, and normal pregnancy (p > 0.05). (3) Compared to those of the control group, the median umbilical serum concentration of PGH was significantly higher in newborns of preeclamptic women (PE: median 356.1 pg/mL (72.6–20 946), normal pregnancy: median 128.5 pg/mL (21.6–255.9); p < 0.01). (4) PGH was detected in all samples of cord blood.
Conclusions. (1) PE is associated with higher median concentrations of PGH in both the maternal and fetal circulation compared to normal pregnancy. (2) Patients with PE + SGA had lower maternal serum concentrations of PGH than preeclamptic patients without SGA. (3) Contrary to previous findings, PGH was detectable in the fetal circulation. The observations reported herein are novel and suggest that PGH may play a role in the mechanisms of disease in preeclampsia and fetal growth restriction.
Introduction
Placental growth hormone (PGH) is a pregnancy-specific hormone that has been proposed to play a role in trophoblast invasion Citation[1] and fetal growth Citation[2-6], as well as maternal adaptation to pregnancy Citation[7-9]. PGH demonstrates somatotrophic, lactogenic, and lipolytic properties similar to pituitary growth hormone (GH), although its growth-promoting activity surpasses its other functions Citation[10-13]. Syncytiotrophoblast and extravillous cytotrophoblast (EVCT) express PGH mRNA and protein Citation[14-16]. This hormone is secreted in a non-pulsatile fashion Citation[17], in contrast to the pulsatile secretion of GH. PGH can be detected in maternal blood at as early as 5 weeks of gestation Citation[4], and increases throughout pregnancy until term Citation[3], at which time PGH concentration has been observed to either plateau Citation[2],Citation[18],Citation[20-22] or slightly decrease Citation[4].
Given the effect of PGH upon fetal growth and trophoblast invasion, several studies have investigated the relationship between the maternal serum concentration of PGH and fetal growth restriction Citation[2],Citation[6],Citation[21],Citation[24]. Consistently lower concentrations of PGH were detected in small for gestational age neonates (SGA). There is, however, only minimal information about PGH in preeclampsia.
The aims of this study were to: (1) determine the maternal serum concentrations of PGH in the following groups: patients with severe preeclampsia, women with preeclampsia who delivered SGA neonates, patients with SGA alone, and normal pregnancies; and (2) evaluate the serum concentrations of PGH in umbilical cord blood in both normal pregnancies and those complicated by preeclampsia.
Materials and methods
Study population
A cross-sectional study was conducted through a search of our clinical database and biological sample bank. This study included normal pregnant women (n = 61), patients with severe preeclampsia (n = 48), those with preeclampsia who delivered an SGA neonate (n = 30), and patients who delivered SGA neonates without preeclampsia (n = 41). Blood samples were drawn between 20 and 42 weeks of gestation. Patients with multiple gestations, fetal anomalies or fetal demise, chronic hypertension, diabetes mellitus, systemic lupus erythematosus, or chronic renal diseases were excluded. In addition, cord blood was collected from patients with preeclampsia (n = 16) and uncomplicated pregnancies (n = 16). Eligible patients were enrolled at the Detroit Medical Center/Hutzel Women's Hospital in Detroit, Michigan. Preeclampsia was defined as hypertension (systolic blood pressure ≥140 mmHg or diastolic blood pressure ≥90 mmHg on at least two occasions, 4 hours to 1 week apart) and proteinuria (≥300 mg in a 24 hour urine collection or one dipstick measurement ≥2+). Severe preeclampsia was defined as either severe hypertension (diastolic blood pressure ≥110 mmHg) plus mild proteinuria or mild hypertension plus severe proteinuria (a 24 hour urine sample containing 3.5 grams of protein or a urine specimen with ≥3+ protein by dipstick measurement). Patients with abnormal liver function tests (aspartate aminotransferase >70 IU/L) plus thrombocytopenia (platelet count <100 000/cm3), as well as those with eclampsia, were also classified in the severe preeclampsia category Citation[25]. SGA was diagnosed if the neonatal birth weight was below the 10th percentile for gestational age Citation[26]. The control group consisted of pregnant women with no medical or obstetrical complications, who delivered at term.
Sample collection and placental growth hormone assay
Samples of maternal peripheral blood were obtained by venipuncture and collected directly into tubes containing EDTA. The samples were centrifuged for 10 minutes at 4°C and stored at −70°C until assayed. Umbilical cord blood was collected at the time of delivery by umbilical vein venipuncture. Samples were collected directly into tubes containing EDTA, processed, and stored as described above.
Maternal and fetal serum PGH concentrations were determined using specific and sensitive immunoassays obtained from Diagnostics Systems Laboratories, Inc. (Webster, TX, USA). Briefly, standards and unknown maternal serum samples were incubated in duplicate wells of the microtiter plates, which had been pre-coated with PGH antibodies. During this incubation, PGH present in the standards or maternal and fetal serum samples was immobilized by the pre-coated antibodies (forming antigen–antibody complexes). Repeated washing and aspiration removed all other unbound materials from the assay plate. This step was followed by incubation with another anti-PGH antibody labeled with biotin. Following incubation, the wells were washed and incubated with a streptavidin–horseradish peroxidase (HRP) conjugate solution. After incubation and washing to remove excess and unbound materials, a substrate solution (containing TMB, tetramethylbenzidine) was added to the wells of the microtiter plate and color developed in proportion to the amount of antigen bound in the initial step of the assay. The color development was stopped with the addition of an acid solution, and the intensity of color was read using a programmable microtiter plate spectrophotometer (SpectraMax M2 micro plate workstation, Molecular Devices, Sunnyvale, CA, USA). The concentrations of PGH in maternal and fetal serum samples were determined by interpolation from individual standard curves composed of purified human PGH. The calculated inter- and intra-assay coefficients of variation (CV) for PGH immunoassays in our laboratory were 9.3% and 9.3%, respectively. The sensitivity of the PGH immunoassay was calculated to be 16.1 pg/mL.
All patients provided written informed consent prior to the collection of maternal and umbilical cord blood samples. The collection and utilization of the samples for research purposes was approved by the Institutional Review Board of the National Institute of Child Health and Human Development (NICHD/NIH/DHHS, Bethesda, Maryland), as well as the Human Investigation Committee of Wayne State University (Detroit, Michigan). Many of these samples have been previously used to evaluate the biology of inflammation, angiogenesis regulation, hemostasis, and growth factor concentrations in normal and complicated pregnancies.
Statistical analysis
Kolmogorov–Smirnov tests were used to determine if the data were normally distributed. Comparisons among the groups were performed with Kruskal–Wallis test, followed by post-hoc analysis for continuous variables. The statistical package employed was SPSS v.12 (SPSS Inc., Chicago, IL, USA). A p value of less than 0.05 was considered significant.
Results
displays the demographic and clinical characteristics of the study groups. There were no significant differences among the groups in gestational age at delivery. The patients with normal pregnancies delivered larger neonates at a later gestational age than the preeclampsia group. All patients with preeclampsia were diagnosed with severe preeclampsia according to the diagnostic criteria previously noted.
Table I. Demographic and clinical characteristics of the study groups.
Maternal serum PGH results
Patients with preeclampsia had a significantly higher maternal serum concentration of PGH than women with normal pregnancies (preeclampsia: median 23 076 pg/mL, range 3473–94 256 vs. normal pregnancy: median 12 157 pg/mL, range 2617–34 016; p < 0.05). The median PGH concentration in the maternal serum of patients with preeclampsia and SGA was significantly lower than in those with preeclampsia group (preeclampsia + SGA: median 11 027 pg/mL, range 1232–61 702; p < 0.05), but comparable to the median PGH concentration of the normal pregnancy group (p > 0.05). Patients with SGA alone had a significantly lower concentration of PGH in maternal serum (SGA alone: median 10 206 pg/mL, range 1816–34 705; p < 0.05) than those with preeclampsia. While a trend was observed for the median serum concentration of PGH in the SGA alone group to be lower than the median serum concentration in both the normal pregnancy and preeclampsia + SGA groups, the difference was not significant (p > 0.05) ().
Figure 1. Maternal serum placental growth hormone (PGH) concentrations among the study groups. Patients with severe preeclampsia had a significantly higher median maternal serum PGH concentration than women with normal pregnancies (severe preeclampsia: median 23 076 pg/mL, range 3473–94 256 vs. normal pregnancy: median 12 157 pg/mL, range 2617–34 016; p < 0.05), women with preeclampsia + small for gestational age (SGA) (median 11 027 pg/mL, range 1232–61 702; p < 0.05), as well as women with pregnancies complicated by SGA alone (median 10 206 pg/mL, range 1816–34 705; p < 0.05). Multiple comparisons among normal pregnancy, preeclampsia + SGA, and SGA showed no significant differences in median maternal serum PGH concentration among these groups.
Umbilical cord serum PGH results
PGH was measurable in all samples of umbilical cord blood. The median concentration of PGH in umbilical cord serum from neonates of women with preeclampsia was higher than the concentration detected in the case of normal pregnancies (preeclampsia: median 356.1 pg/mL, range 72.6–20 946 vs. normal pregnancy: median 128.5 pg/mL, range 21.6–255.9; p < 0.01) ().
Figure 2. Umbilical cord blood median placental growth hormone (PGH) concentrations from normal pregnant women and women with severe preeclampsia. The median umbilical cord serum concentration of PGH was significantly higher in pregnancies complicated by severe preeclampsia when compared to normal pregnancies (preeclampsia: median 356.1 pg/mL, range 72.6–20 946 vs. normal pregnancy: median 128.5 pg/mL, range 21.6–255.9; p < 0.01).
The median birth weight of those of normal pregnancies was greater than neonates of women with preeclampsia (normal pregnancy: median 3425 g, range 2850–3910 vs. preeclampsia: median 3105 g, range 1960–3780; p = 0.2). Of the 16 neonates from women with preeclampsia, four were SGA (median 2170 g, range 1960–2400).
Discussion
Principal findings of this study
(1) Patients with preeclampsia had a significantly higher concentration of PGH in both the maternal and fetal serum. (2) The maternal serum concentration of PGH in pregnancies complicated by both preeclampsia and SGA, as well as SGA alone, was significantly lower than in the case of pregnancies with preeclampsia alone. However, there were no significant differences in serum PGH concentration between normal pregnancies and those with preeclampsia and SGA, or SGA alone. (3) Contrary to previous reports, PGH is detectable in cord blood. Furthermore, the concentration of PGH in cord blood is also significantly higher in patients with severe preeclampsia.
What is PGH?
PGH was first described in 1985 as a product of the growth hormone variant (GH-V) gene Citation[27]. GH-V belongs to a family of five highly related genes located on chromosome 17, q22–24, which demonstrate 91–99% structural homology Citation[28]. This family includes GH, GH-V, and three placental lactogens, or chorionic somatomammotropins (hCS-A, hCS-B, and hCS-L) Citation[29]. PGH is a 22-kD polypeptide structural variant of pituitary growth hormone and differs from GH by 13 amino acids. In 1989, Liebhaber et al. demonstrated that unlike GH, GH-V mRNA is expressed in the placenta, but not in the pituitary Citation[14]. Except for GH, all genes in this family are expressed by the placenta.
In situ hybridization studies originally localized the GH-V transcript to the syncytiotrophoblast Citation[14], Citation[15],Citation[30]. Unlike the homogenous expression of placental lactogen, GH-V yielded “dense but highly dispersed spots”Citation[14]. GH-V mRNA has been detected in the placenta at as early as 9 weeks of gestation Citation[14]. Recently, LaCroix et al. demonstrated the effect of PGH on EVCT invasiveness using an in vitro model, as well as its expression by EVCT. While both GH and PGH stimulated EVCT to invade in a dose-dependent manner, PGH did so more effectively and to a greater extent. Furthermore, EVCT expressed PGH as they acquired a more invasive phenotype Citation[1]. This suggests a direct role of PGH in trophoblast invasion.
PGH in angiogenesis
PGH has also been implicated in angiogenesis. In in vitro and as in vivo models, Struman et al. described both the pro-angiogenic and anti-angiogenic functions of the growth hormone family Citation[31]. Specifically, intact PGH increased blood vessel formation while its 16-kDa fragment prevented angiogenesis. The exact function of PGH in angiogenesis has yet to be described, but this data supports a role for PGH in the development of pathologic pregnancies, as both preeclampsia and SGA have been associated with an imbalance between pro- and anti-angiogenic factors Citation[32-63].
Metabolic effects of PGH
PGH demonstrates somatotrophic effects, as is observed with GH. Transgenic mice expressing GH-V showed a 40–90% increase in growth over controls Citation[13], similar to the effect of mice compared to expressing GH. PGH, however, has a lower lactogenic effect than GH, and preferentially binds to the somatogen receptor Citation[11], Citation[12]. Overall, PGH affects all target cells that express the GH receptor Citation[67]. In in vitro studies utilizing the adipose tissue of rats, Goodman et al. demonstrated that PGH binds to adipocytes and engenders a lipolytic response Citation[10]. In addition, transgenic mice models and in vitro studies have suggested that PGH is likely to play a major role in the insulin resistance normally seen in pregnancy, thus increasing the amount of substrate available to the fetus Citation[8],Citation[69]. However, these effects have not yet been confirmed in human in vivo studies.
PGH and fetal growth
Based on the observations that maternal serum concentrations of PGH and insulin-like growth factor-1 (IGF-1) are strongly correlated throughout gestation, it has been proposed that PGH influences fetal growth through IGF-1 Citation[2],Citation[4],Citation[6],Citation[18]. Moreover, the role of PGH and IGF-1 in fetal growth is supported by investigations of patients with GH deficiency. These pregnancies generally proceed normally Citation[71], with increasing concentrations of both PGH and IGF-1 akin to controls, and result in average weight neonates Citation[72], Citation[73]. But while the expression and basic physiology of PGH has been described, its regulation is not currently understood.
PGH in normal pregnancies
In a longitudinal studies, Chellakooty et al. demonstrated that PGH is detectable in maternal serum as early as the fifth week of gestation, and increases to peak at 34–37 weeks Citation[3], Citation[4]. As PGH production increases, it gradually replaces GH as the main form of growth hormone, to the point where GH becomes undetectable in maternal serum by the third trimester Citation[20],Citation[21], Citation[27]. Of interest, an association between the time at which PGH maternal serum concentration peaks and the interval to delivery has been reported. Specifically, the earlier the peak PGH concentration was reached, the earlier labor began Citation[3]. However, among the cohort of patients observed, all delivered at greater than 37 weeks of gestation. At this time, no studies have been performed to specifically investigate any relationship between PGH peak concentrations and delivery at less than 37 weeks of gestation.
Though there is a wide inter-individual variation of maternal serum PGH concentrations among patients at any given gestational age, the individual's increase in PGH is positively associated with fetal growth Citation[4]. Furthermore, patients who experienced a greater fall in maternal serum PGH concentration after the peak level delivered smaller neonates Citation[4]. Following delivery, maternal serum PGH values rapidly decline. With a half-life of approximately 15 minutes Citation[20], 75% of PGH is cleared from maternal serum within 30 minutes after delivery.
PGH in fetal growth restriction and preeclampsia
Given the observations asserting the association between PGH and fetal growth, the majority of studies concerning PGH in pathologic pregnancies have focused on fetal growth restriction (FGR). Mirlesse et al. first investigated this association measuring PGH in maternal serum from 22 cases of FGR after 31 weeks of gestation Citation[21]. The cases were characterized as idiopathic (n = 14), in conjunction with preeclampsia (n = 6), chromosomal (n = 1), and materno-fetal infection (n = 1). When compared with 31 normal pregnancies, the PGH concentration in maternal serum at term was significantly lower in patients with FGR. These results were supported by those of Caufriez et al. in a cross-sectional study including 80 patients with disorders of the ‘fetoplacental unit’. Within this group were 32 pregnant women with FGR and 42 patients who experienced preterm contractions. The concentration of PGH in patients with disorders of the ‘fetoplacental unit’ was significantly lower (p = 0.003) than in the case of the control group (n = 93) Citation[2]. More recently, McIntyre et al. reported a significant reduction of maternal serum PGH in 16 cases of FGR, when compared with 23 controls Citation[6].
The observation that severe preeclampsia is associated with a significantly higher maternal serum plasma concentration of PGH than normal pregnancies is novel and suggests that PGH may participate in the mechanism of disease of preeclampsia. These results are consistent with two previous reports indicating that patients destined to develop preeclampsia have significantly higher maternal serum concentrations of PGH in the mid-trimester than those with normal pregnancies. It is possible that the high maternal serum plasma concentration of PGH observed in women with preeclampsia may be a compensatory mechanism to preserve fetal growth. Failure of this mechanism may result in the delivery of an SGA neonate, as indicated by the observation that patients with preeclampsia and SGA had a lower maternal serum concentration of PGH than patients with preeclampsia alone. Alternatively, the lower maternal serum concentration of PGH may be a reflection of a lower placental mass, which is frequently associated with FGR.
PGH in the fetal circulation
The observation that PGH was detected in all cord blood samples is novel. Prior investigations have suggested that PGH is secreted by the placenta only into the maternal circulation and, therefore, acts indirectly to affect fetal growth Citation[20]. In this study, not only have we shown that PGH is measurable in cord blood, but also that the concentration is increased in pregnancies affected by preeclampsia, which is in concordance with the results in maternal serum in preeclampsia. Original studies assessing the presence of PGH in the fetal circulation utilized a sensitive solid-phase immunoradiometric assay (Biocode, Liege, Belgium), whose lowest limit of detection was 0.4 ng/mL. In contrast, the highly sensitive enzyme-linked immunosorbent chemiluminiscent assay used in this investigation has a lowest limit of detection of 0.01 ng/mL, and is not affected by the presence of growth hormone binding protein Citation[22], a potential confounder in earlier assays. Given this original finding, the current understanding of PGH physiology and function in the fetus needs to be re-evaluated.
Conclusions
The concentration of PGH in maternal serum is significantly increased in patients with preeclampsia who delivered infants with appropriate growth for gestational age, compared to normal pregnancies. In contrast, patients with preeclampsia delivering SGA infants have a decreased concentration of PGH compared with preeclampsia alone. This finding supports the relationship between PGH and fetal growth, while suggesting an increase of PGH production in preeclampsia in order to enable continued fetal growth. In light of the finding that PGH does enter the fetal circulation and is not limited to the maternal circulation, the physiological role and effect of PGH on fetal growth needs to be re-examined. Further prospective clinical and histological studies will clarify the role of PGH in preeclampsia and fetal development.
Acknowledgements
This research was supported by the Intramural Research Program of the National Institute of Child Health and Human Development, NIH, DHHS.
References
- Lacroix M C, Guibourdenche J, Fournier T, Laurendeau I, Igout A, Goffin V, Pantel J, Tsatsaris V, Evain-Brion D. Stimulation of human trophoblast invasion by placental growth hormone. Endocrinology 2005; 146: 2434–2444
- Caufriez A, Frankenne F, Hennen G, Copinschi G. Regulation of maternal IGF-I by placental GH in normal and abnormal human pregnancies. Am J Physiol 1993; 265: E572–577
- Chellakooty M, Skibsted L, Skouby S O, Andersson A M, Petersen J H, Main K M, Skakkebaek N E, Juul A. Longitudinal study of serum placental GH in 455 normal pregnancies: Correlation to gestational age, fetal gender, and weight. J Clin Endocrinol Metab 2002; 87: 2734–2739
- Chellakooty M, Vangsgaard K, Larsen T, Scheike T, Falck-Larsen J, Legarth J, Andersson A M, Main K M, Skakkebaek N E, Juul A. 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. J Clin Endocrinol Metab 2004; 89: 384–391
- Coutant R, de Boux C F, Douay O, Mathieu E, Rouleau S, Beringue F, Gillard P, Limal J M, Descamps P. Relationships between placental GH concentration and maternal smoking, newborn gender, and maternal leptin: Possible implications for birth weight. J Clin Endocrinol Metab 2001; 86: 4854–4859
- McIntyre H D, Serek R, Crane D I, Veveris-Lowe T, Parry A, Johnson S, Leung K C, Ho K K, Bougoussa M, Hennen G, et al. 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 2000; 85: 1143–1150
- Takata K, Kasahara T, Kasahara M, Ezaki O, Hirano H. Localization of erythrocyte/HepG2-type glucose transporter (GLUT1) in human placental villi. Cell Tissue Res 1992; 267: 407–412
- Barbour L A, Shao J, Qiao L, Pulawa L K, Jensen D R, Bartke A, Garrity M, Draznin B, Friedman J E. Human placental growth hormone causes severe insulin resistance in transgenic mice. Am J Obstet Gynecol 2002; 186: 512–517
- Lacroix M C, Bolifraud P, Durieux D, Pauloin A, Vidaud M, Kann G. Placental growth hormone and lactogen production by perfused ovine placental explants: Regulation by growth hormone-releasing hormone and glucose. Biol Reprod 2002; 66: 555–561
- Goodman H M, Tai L R, Ray J, Cooke N E, Liebhaber S A. Human growth hormone variant produces insulin-like and lipolytic responses in rat adipose tissue. Endocrinology 1991; 129: 1779–1783
- MacLeod J N, Worsley I, Ray J, Friesen H G, Liebhaber S A, Cooke N E. Human growth hormone-variant is a biologically active somatogen and lactogen. Endocrinology 1991; 128: 1298–1302
- Ray J, Okamura H, Kelly P A, Cooke N E, Liebhaber S A. Human growth hormone-variant demonstrates a receptor binding profile distinct from that of normal pituitary growth hormone. J Biol Chem 1990; 265: 7939–7944
- Selden R F, Wagner T E, Blethen S, Yun J S, Rowe M E, Goodman H M. Expression of the human growth hormone variant gene in cultured fibroblasts and transgenic mice. Proc Natl Acad Sci U S A 1988; 85: 8241–8245
- Liebhaber S A, Urbanek M, Ray J, Tuan R S, Cooke N E. Characterization and histologic localization of human growth hormone-variant gene expression in the placenta. J Clin Invest 1989; 83: 1985–1991
- Scippo M L, Frankenne F, Hooghe-Peters E L, Igout A, Velkeniers B, Hennen G. Syncytiotrophoblastic localization of the human growth hormone variant mRNA in the placenta. Mol Cell Endocrinol 1993; 92: R7–13
- Lacroix M C, Guibourdenche J, Frendo J L, Muller F, Evain-Brion D. Human placental growth hormone—a review. Placenta 2002; 23(Suppl A)S87–94
- Eriksson L, Frankenne F, Eden S, Hennen G, Von Schoultz B. Growth hormone 24-h serum profiles during pregnancy—lack of pulsatility for the secretion of the placental variant. Br J Obstet Gynaecol 1989; 96: 949–953
- Caufriez A, Frankenne F, Englert Y, Golstein J, Cantraine F, Hennen G, Copinschi G. Placental growth hormone as a potential regulator of maternal IGF-I during human pregnancy. Am J Physiol 1990; 258: E1014–1019
- Frankenne F, Closset J, Gomez F, Scippo M L, Smal J, Hennen G. The physiology of growth hormones (GHs) in pregnant women and partial characterization of the placental GH variant. J Clin Endocrinol Metab 1988; 66: 1171–1180
- Mirlesse V, Frankenne F, Alsat E, Poncelet M, Hennen G, Evain-Brion D. Placental growth hormone levels in normal pregnancy and in pregnancies with intrauterine growth retardation. Pediatr Res 1993; 34: 439–442
- Wu Z, Bidlingmaier M, Friess S C, Kirk S E, Buchinger P, Schiessl B, Strasburger C J. A new nonisotopic, highly sensitive assay for the measurement of human placental growth hormone: Development and clinical implications. J Clin Endocrinol Metab 2003; 88: 804–811
- Evain-Brion D. Hormonal regulation of fetal growth. Horm Res 1994; 42: 207–214
- Sibai B M, Ewell M, Levine R J, Klebanoff M A, Esterlitz J, Catalano P M, Goldenberg R L, Joffe G. Risk factors associated with preeclampsia in healthy nulliparous women. The Calcium for Preeclampsia Prevention (CPEP) Study Group. Am J Obstet Gynecol 1997; 177: 1003–1010
- Alexander G R, Himes J H, Kaufman R B, Mor J, Kogan M. A United States national reference for fetal growth. Obstet Gynecol 1996; 87: 163–168
- Hennen G, Frankenne F, Pirens G, Gomez F, Closset J, Schaus C, el Khayat N. New chorionic GH-like antigen revealed by monoclonal antibody radioimmunoassays. Lancet 1985; 1: 399
- George D L, Phillips J A, III, Francke U, Seeburg P H. The genes for growth hormone and chorionic somatomammotropin are on the long arm of human chromosome 17 in region q21 to qter. Hum Genet 1981; 57: 138–141
- Fuglsang J, Ovesen P. Aspects of placental growth hormone physiology. Growth Horm IGF Res 2006; 16: 67–85
- Cooke N E, Ray J, Emery J G, Liebhaber S A. Two distinct species of human growth hormone-variant mRNA in the human placenta predict the expression of novel growth hormone proteins. J Biol Chem 1988; 263: 9001–9006
- Struman I, Bentzien F, Lee H, Mainfroid V, D'Angelo G, Goffin V, Weiner R I, Martial J A. Opposing actions of intact and N-terminal fragments of the human prolactin/growth hormone family members on angiogenesis: An efficient mechanism for the regulation of angiogenesis. Proc Natl Acad Sci U S A 1999; 96: 1246–1251
- Aggarwal P K, Jain V, Sakhuja V, Karumanchi S A, Jha V. Low urinary placental growth factor is a marker of pre-eclampsia. Kidney Int 2006; 69: 621–624
- Boutsikou T, Malamitsi-Puchner A, Economou E, Boutsikou M, Puchner K P, Hassiakos D. Soluble vascular endothelial growth factor receptor-1 in intrauterine growth restricted fetuses and neonates. Early Hum Dev 2006; 82: 235–239
- Chaiworapongsa T, Romero R, Espinoza J, Bujold E, Mee K Y, Goncalves L F, Gomez R, Edwin S. Evidence supporting a role for blockade of the vascular endothelial growth factor system in the pathophysiology of preeclampsia. Young Investigator Award. Am J Obstet Gynecol 2004; 190: 1541–1547
- Chaiworapongsa T, Romero R, Kim Y M, Kim G J, Kim M R, Espinoza J, Bujold E, Goncalves L, Gomez R, Edwin S, et al. Plasma soluble vascular endothelial growth factor receptor-1 concentration is elevated prior to the clinical diagnosis of pre-eclampsia. J Matern Fetal Neonatal Med 2005; 17: 3–18
- Crispi F, Dominguez C, Llurba E, Martin-Gallan P, Cabero L, Gratacos E. Placental angiogenic growth factors and uterine artery Doppler findings for characterization of different subsets in preeclampsia and in isolated intrauterine growth restriction. Am J Obstet Gynecol 2006; 195: 201–207
- Espinoza J, Romero R, Nien J K, Kusanovic J P, Richani K, Gomez R, Kim C J, Mittal P, Gotsh F, Erez O, et al. A role of the anti-angiogenic factor sVEGFR-1 in the ‘mirror syndrome’ (Ballantyne's syndrome). J Matern Fetal Neonatal Med 2006; 19: 607–613
- Espinoza J, Romero R, Nien J K, Gomez R, Kusanovic J P, Goncalves L F, Medina L, Edwin S, Hassan S, Carstens M, et al. Identification of patients at risk for early onset and/or severe preeclampsia with the use of uterine artery Doppler velocimetry and placental growth factor. AM J Obstet Gynecol 2007; 196: 326, E1–13
- Girardi G, Yarilin D, Thurman J M, Holers V M, Salmon J E. Complement activation induces dysregulation of angiogenic factors and causes fetal rejection and growth restriction. J Exp Med 2006; 203: 2165–2175
- Koga K, Osuga Y, Yoshino O, Hirota Y, Ruimeng X, Hirata T, Takeda S, Yano T, Tsutsumi O, Taketani Y. Elevated serum soluble vascular endothelial growth factor receptor 1 (sVEGFR-1) levels in women with preeclampsia. J Clin Endocrinol Metab 2003; 88: 2348–2351
- Krauss T, Pauer H U, Augustin H G. Prospective analysis of placenta growth factor (PlGF) concentrations in the plasma of women with normal pregnancy and pregnancies complicated by preeclampsia. Hypertens Pregnancy 2004; 23: 101–111
- Kupferminc M J, Daniel Y, Englender T, Baram A, Many A, Jaffa A J, Gull I, Lessing J B. Vascular endothelial growth factor is increased in patients with preeclampsia. Am J Reprod Immunol 1997; 38: 302–306
- Levine R J, Maynard S E, Qian C, Lim K H, England L J, Yu K F, Schisterman E F, Thadhani R, Sachs B P, Epstein F H, et al. Circulating angiogenic factors and the risk of preeclampsia. N Engl J Med 2004; 350: 672–683
- Levine R J, Thadhani R, Qian C, Lam C, Lim K H, Yu K F, Blink A L, Sachs B P, Epstein F H, Sibai B M, et al. Urinary placental growth factor and risk of preeclampsia. JAMA 2005; 293: 77–85
- Levine R J, Karumanchi S A. Circulating angiogenic factors in preeclampsia. Clin Obstet Gynecol 2005; 48: 372–386
- Levine R J, Lam C, Qian C, Yu K F, Maynard S E, Sachs B P, Sibai B M, Epstein F H, Romero R, Thadhani R, et al. Soluble endoglin and other circulating antiangiogenic factors in preeclampsia. N Engl J Med 2006; 355: 992–1005
- Lyall F, Greer I A, Boswell F, Fleming R. Suppression of serum vascular endothelial growth factor immunoreactivity in normal pregnancy and in pre-eclampsia. Br J Obstet Gynaecol 1997; 104: 223–228
- Malamitsi-Puchner A, Boutsikou T, Economou E, Sarandakou A, Makrakis E, Hassiakos D, Creatsas G. Vascular endothelial growth factor and placenta growth factor in intrauterine growth-restricted fetuses and neonates. Mediators Inflamm 2005; 2005: 293–297
- Maynard S E, Min J Y, Merchan J, Lim K H, Li J, Mondal S, Libermann T A, Morgan J P, Sellke F W, Stillman I E, et al. Excess placental soluble fms-like tyrosine kinase 1 (sFlt1) may contribute to endothelial dysfunction, hypertension, and proteinuria in preeclampsia. J Clin Invest 2003; 111: 649–658
- Maynard S E, Venkatesha S, Thadhani R, Karumanchi S A. Soluble Fms-like tyrosine kinase 1 and endothelial dysfunction in the pathogenesis of preeclampsia. Pediatr Res 2005; 57: 1R–7R
- McKeeman G C, Ardill J E, Caldwell C M, Hunter A J, McClure N. Soluble vascular endothelial growth factor receptor-1 (sFlt-1) is increased throughout gestation in patients who have preeclampsia develop. Am J Obstet Gynecol 2004; 191: 1240–1246
- Padavala S, Pope N, Baker P, Crocker I. An imbalance between vascular endothelial growth factor and its soluble receptor in placental villous explants of intrauterine growth-restricted pregnancies. J Soc Gynecol Investig 2006; 13: 40–47
- Rajakumar A, Michael H M, Rajakumar P A, Shibata E, Hubel C A, Karumanchi S A, Thadhani R, Wolf M, Harger G, Markovic N. Extra-placental expression of vascular endothelial growth factor receptor-1 (Flt-1) and soluble Flt-1 (sFlt-1), by peripheral blood mononuclear cells (PBMCs) in normotensive and preeclamptic pregnant women. Placenta 2005; 26: 563–573
- Robinson C J, Johnson D D, Chang E Y, Armstrong D M, Wang W. Evaluation of placenta growth factor and soluble Fms-like tyrosine kinase 1 receptor levels in mild and severe preeclampsia. Am J Obstet Gynecol 2006; 195: 255–259
- Sibai B M. The HELLP syndrome (hemolysis, elevated liver enzymes, and low platelets): Much ado about nothing?. Am J Obstet Gynecol 1990; 162: 311–316
- Staff A C, Braekke K, Harsem N K, Lyberg T, Holthe M R. Circulating concentrations of sFlt1 (soluble fms-like tyrosine kinase 1) in fetal and maternal serum during pre-eclampsia. Eur J Obstet Gynecol Reprod Biol 2005; 122: 33–39
- Stepan H, Faber R. Elevated sFlt1 level and preeclampsia with parvovirus-induced hydrops. N Engl J Med 2006; 354: 1857–1858
- Thadhani R, Mutter W P, Wolf M, Levine R J, Taylor R N, Sukhatme V P, Ecker J, Karumanchi S A. First trimester placental growth factor and soluble fms-like tyrosine kinase 1 and risk for preeclampsia. J Clin Endocrinol Metab 2004; 89: 770–775
- Tidwell S C, Ho H N, Chiu W H, Torry R J, Torry D S. Low maternal serum levels of placenta growth factor as an antecedent of clinical preeclampsia. Am J Obstet Gynecol 2001; 184: 1267–1272
- Torry D S, Wang H S, Wang T H, Caudle M R, Torry R J. Preeclampsia is associated with reduced serum levels of placenta growth factor. Am J Obstet Gynecol 1998; 179: 1539–1544
- Venkatesha S, Toporsian M, Lam C, Hanai J, Mammoto T, Kim Y M, Bdolah Y, Lim K H, Yuan H T, Libermann T A, et al. Soluble endoglin contributes to the pathogenesis of preeclampsia. Nat Med 2006; 12: 642–649
- Wallner W, Sengenberger R, Strick R, Strissel P L, Meurer B, Beckmann M W, Schlembach D. Angiogenic growth factors in maternal and fetal serum in pregnancies complicated by intrauterine growth restriction. Clin Sci (Lond) 2007; 112: 51–57
- Zhou Y, McMaster M, Woo K, Janatpour M, Perry J, Karpanen T, Alitalo K, Damsky C, Fisher S J. Vascular endothelial growth factor ligands and receptors that regulate human cytotrophoblast survival are dysregulated in severe preeclampsia and hemolysis, elevated liver enzymes, and low platelets syndrome. Am J Pathol 2002; 160: 1405–1423
- Barbour L A, Shao J, Qiao L, Leitner W, Anderson M, Friedman J E, Draznin B. Human placental growth hormone increases expression of the p85 regulatory unit of phosphatidylinositol 3-kinase and triggers severe insulin resistance in skeletal muscle. Endocrinology 2004; 145: 1144–1150
- Curran A J, Peacey S R, Shalet S M. Is maternal growth hormone essential for a normal pregnancy?. Eur J Endocrinol 1998; 139: 54–58
- Fuglsang J, Lauszus F, Orskov H, Ovesen P. Placental growth hormone during pregnancy in a growth hormone deficient woman with type 1 diabetes compared to a matching diabetic control group. Growth Horm IGF Res 2004; 14: 66–70
- Verhaeghe J, Bougoussa M, Van Herck E, de Zegher F, Hennen G, Igout A. Placental growth hormone and IGF-I in a pregnant woman with Pit-1 deficiency. Clin Endocrinol (Oxf) 2000; 53: 645–647
- Eriksson L. Growth hormone in human pregnancy. Maternal 24-hour serum profiles and experimental effects of continuous GH secretion. Acta Obstet Gynecol Scand Suppl 1989; 147: 1–38
- Alsat E, Guibourdenche J, Luton D, Frankenne F, Evain-Brion D. Human placental growth hormone. Am J Obstet Gynecol 1997; 177: 1526–1534
- Eriksson L, Frankenne F, Eden S, Hennen G, Von Schoultz B. Growth hormone secretion during termination of pregnancy. Further evidence of a placental variant. Acta Obstet Gynecol Scand 1988; 67: 549–552
- Lonberg U, Damm P, Andersson A M, Main K M, Chellakooty M, Lauenborg J, Skakkebaek N E, Juul A. Increase in maternal placental growth hormone during pregnancy and disappearance during parturition in normal and growth hormone-deficient pregnancies. Am J Obstet Gynecol 2003; 188: 247–251
- Moghadam S, Engel W, Bougoussa M, Hennen G, Igout A, Sancken U. Maternal serum placental growth hormone and insulin-like growth factor binding proteins 1 and 3 in pregnancies affected by fetal aneuploidy and other abnormalities: Implications for prenatal diagnosis of trisomy 21. Fetal Diagn Ther 1998; 13: 291–297
- Papadopoulou E, Sifakis S, Giahnakis E, Fragouli Y, Karkavitsas N, Koumantakis E, Kalmanti M. Increased human placental growth hormone at midtrimester pregnancies may be an index of intrauterine growth retardation related to preeclampsia. Growth Horm IGF Res 2006; 16: 290–296
- Evain-Brion D, Alsat E, Igout A, Frankenne F, Hennen G. Placental growth hormone variant: Assay and clinical aspects. Acta Paediatr Suppl 1994; 399: 49–51
- Fisker S, Ebdrup L, Orskov H. Influence of growth hormone binding protein on growth hormone estimation in different immunoassays. Scand J Clin Lab Invest 1998; 58: 373–381