**2.4 IGFBPs**

152 From Preconception to Postpartum

in m RNA and protein expression in preeclamptic placentas, by different research groups [Giudice et al., 1999; Shin et al., 2003]. Published data indicate that IGF-II stimulates proliferation and migration of cytotrophoblasts, regulates nutrient exchange but is not implicated in placental cell differentiation so the decreased levels of this factor may alter the invasive nature of cytotrophoblasts resulting in placental dysfunction [Shin et al., 2003]. On the contrary, Gratton et al. observed increased IGF-II m RNA abundance in the intermediate trophoblast surrounding placental infracts suggesting a role in placental repair or remodeling and decreased IGFBP-1 m RNA levels [Gratton et al., 2002]. Besides, in an invivo analysis of term placentas of gestations complicated by acute or chronic hypoxic ischemia, IGF-2 m RNA levels were elevated only in chronic hypoxia in contrast to IGF-I and PGH m RNA levels which did not significantly change, maybe as a part of a local

IGF-II level in maternal serum is less investigated and up to now it seems not to significantly vary between preeclamptic and normotensive women [Giudice et al., 1997; Lewitt et al., 1998]. A possible explanation is that it does not share exactly the same regulation pattern with IGF-I as it is not primarily GH-dependent [Giudice et al., 1997]. On the contrary, there is a remarkable inconsistency among published results about the concentration of IGF-I in pregnancies destined to be preeclamptic. The only prospective cohort study that measured free rather than total IGF-I and IGFBP-1 levels and made adjustment for several confounding factors such as gestational age at blood collection, maternal age, parity, and prepregnacy adiposity, reported lower concentrations of these factors apparent in first trimester [Ning et al., 2004]. The attenuation of IGF-1 synthesis may result from impaired PGH synthesis as a consequence of the compromised placentation observed in preeclampsia [Ning et al., 2004]. Although several cross-sectional and longitudinal studies have found a positive correlation between serum PGH and IGF-1 values in pregnancies with fetoplacental unit disorders, our recent results do not provide support to the upper speculation as lower IGF-I levels but no alteration in PGH levels were observed in 11-13 weeks of gestation in pregnancies subsequently complicated by preeclampsia of either early or late onset [Sifakis et al., 2010; Sifakis et al. 2011a]. To elucidate this matter, it would be of special interest to investigate the range of the IGF-I levels in parallel with the change of PGH production throughout the disease transition from

does speculation

Given that IGF-I acts positively on insulin sensitivity and the tissue availability of IGF-I is a significant determinant of insulin sensitivity in patients with essential hypertension, it could be presumed that decreased circulating levels of this factor would be responsible, at least in part, for insulin resistance in preeclampsia [Kocyigit et al., 2004]. However, Bartha et al. supported that increased insulin resistance is associated with gestational hypertension rather than preeclampsia and that there is no significant correlation between insulin sensitivity index and serum IGF-I levels [Bartha et al., 2002]. Also, there is no obvious explanation for the findings of other studies which recruited women before the clinical manifestation of the disease and reported that the maternal serum levels of IGF-I were either increased or not significantly altered [Hubinette et al., 2003; Vatten et al., 2008]. Based on a similar prospective approach, an increase in IGF-I from the first to second trimester and not within each trimester was associated with higher risk of preterm preeclampsia possibly interpreted as a compensatory mechanism to preserve fetal growth or/and a possible

metabolic adjustment [Trollmann et al., 2007].

a latent preclinical stage to the clinically manifested preeclampsia.
