Phosphorylated isoforms of insulin-like growth factor binding protein-1 in the cervix as a predictor of cervical ripeness
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Objective: To study the isoforms of insulin-like growth factor binding protein-1 (IGFBP-1) in cervical secretion and to evaluate whether their assessment could serve in prediction of cervical ripeness at term. Methods: We measured the concentrations of IGFBP-1 in cervical swab samples of 64 women scheduled for labor induction by amniotomy or cervical ripening with prostaglandin E2 gel. Two immunoenzymometric assays were used: a previously described assay 1, which detects the nonphosphorylated and lesser phosphorylated isoforms, and a novel assay 2, which detects the lesser and highly phosphorylated isoforms of IGFBP-1. A set of 39 amniotic fluid (AF) samples also was analyzed to compare the phosphorylation status of IGFBP-1 in cervical secretion with that in AF. Results: In all cervical samples, IGFBP-1 concentration was higher by assay 2 than by assay 1, whereas in all AF samples, the results were the opposite. Initially, the median IGFBP-1 concentration in the ripe cervices (Bishop scores 6 or greater; n = 29) was approximately four times as high as that in the unripe cervices (Bishop scores 5 or less; n = 35). The cervical IGFBP-1 concentrations increased eight-fold in 6 hours after the first application of PGE2. Conclusion: Phosphorylated isoforms of IGFBP-1, different from those in AF, are present in the cervical secretion of women with intact fetal membranes and reflect cervical ripeness. A bedside test for those IGFBP-1 isoforms might help in predicting amenability for labor induction.Keywords:
Ripeness
The genetically obese Zucker rat is a widely used model of early-onset obesity. Like obese children, these obese rats are hyperinsulinemic and have low GH secretion. However, data on linear growth and insulin-like growth factor-I (IGF-I) levels in this model are scanty and contradictory. In the present study, we investigated linear growth and its hormonal control in Zucker rats (male and female) from 4-20 weeks of age. In the obese animals, compared to their lean littermates, the naso-anal length was normal or slightly greater, whereas the tails and femurs were shorter. The plasma concentration of IGF-I increased between 4-20 weeks of age, and IGF-I levels were normal or slightly higher in the obese animals. The serum level of IGF-binding protein-3 (IGFBP-3) measured by Western ligand blotting was not significantly different in lean vs. obese rats. To assess the IGF-I response to GH, bovine GH was administered (250 micrograms/100 g BW, ip, daily for 3 days) to 16- to 20-week-old female Zucker rats; plasma IGF-I concentrations increased more in the obese (percent increase over baseline, 347 +/- 44% vs. 194 +/- 31%; P < 0.01). These results show that despite low GH secretion, genetically obese Zucker rats have 1) normal linear (nasoanal) growth, 2) normal or increased circulating levels of IGF-I and IGFBP-3, and 3) increased plasma IGF-I responses to exogenous GH. These results suggest that the GH-independent growth in this model could result from direct effects of hyperinsulinism on circulating IGF-I and IGFBP-3 levels and/or indirect effects through increased GH receptor function.
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Growth hormone-binding protein
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Insulin-like growth factor binding protein-3 (IGFBP-3) is the major carrier of insulin-like growth factor I (IGF-1) in serum, and its production is growth hormone (GH) dependent. It is unclear whether in humans IGFBP-3 production is directly regulated by GH or mediated via IGF-I. We addressed this question in six patients with Laron-type dwarfism, a syndrome characterized by the absence of GH receptor activity (LTD), who were chronically treated with recombinant IGF-I. Analysis of the electrophoretic profiles of serum IGFBPs in these patients by Western ligand blotting revealed an extremely low IGFBP-3 level. A striking progressive increase in serum IGFBP-3 was observed with continuous treatment, despite the absence of GH action. In LTD children, serum IGFBP-3 increased up to 19-fold after six months of therapy and equalled levels observed in controls, whereas in adult LTD patients the increase was smaller. A rise in serum levels of 34, 30 and 24 kDa BPs (presumably IGFBP-2, -1 and -4, respectively was also noted with chronic IGF-I therapy. This proof of GH-independent induction of IGFBP-3 by IGF-1 may be a major advantage in the therapeutic use of biosynthetic IGF-I in several types of short stature children.
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Knip M, Tapanainen P, Pekonen F, Blum WF. Insulin-like growth factor binding proteins in prepubertal children with insulin-dependent diabetes mellitus. Eur J Endocrinol 1995:133:440–4. ISSN 0804–4643 To study the possible role of insulin-like growth factor binding proteins (IGFBPs) in the discrepancy between normal or only slightly retarded growth and substantially reduced concentrations of insulin-like growth factor I (IGF-I) in prepubertal children with insulin-dependent diabetes mellitus (IDDM), we measured the plasma concentrations of IGF-I, IGFBP-1, IGFBP-2 and IGFBP-3 and free insulin in 24 prepubertal diabetic subjects and 12 control children. In addition, the growth hormone response to exercise was evaluated. The diabetic children had significantly decreased peripheral IGF-I levels (8.2 + 1.1 ( sem ) vs 16.7 + 2.5 nmol/l; p < 0.001), whereas the concentrations of free insulin were increased (217 + 14 vs 103 + 21 pmol/l; p < 0.001). The concentrations of IGFBP-1 and IGFBP-3 were of the same magnitude in both groups. The diabetic children had significantly increased levels of IGFBP-2 (465 + 13 vs 416 + 14 μg/l; p = 0.029), which were inversely related to the circulating IGF-I levels (r = −0.35; p = 0.034). The diabetic and control children had comparable growth hormone responses to exercise. Diabetic children with poor glucose control had even lower IGF-I levels than those with moderate metabolic control (6.0 + 0.8 vs 10.3 + 1.7 nmol/l; p = 0.037). No differences could be observed in the plasma concentrations of various IGFBPs between these two groups of diabetic subjects. The absence in prepubertal diabetic children of increased IGFBP-1 levels observed in adolescent and adult patients with IDDM may contribute to their maintained linear growth, despite definitely decreased IGF-I concentrations. The role of increased IGFBP-2 levels in prepubertal children with IDDM remains open, but the inverse relationship between IGF-I levels and IGFBP-2 concentrations suggests that IGF-I may be involved in the regulation of IGFBP-2. Mikael Knip, Department of Pediatrics, University of Oulu, FIN-90220 Oulu, Finland
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The actions of insulin-like growth factor-I (IGF-I) are modulated by IGF binding proteins (IGFBPs). The effects of IGFBP-1 in vivo are insufficiently known, with respect to inhibitory or stimulatory actions on IGF-induced growth of specific organs. Therefore, we studied the effects of IGFBP-1 on IGF-I-induced somatic and organ growth in pituitary-deficient Snell dwarf mice. Human GH, IGF-I, IGFBP-1, and a preequilibrated combination of equimolar amounts of IGF-I and IGFBP-1 were administered sc during 4 weeks. Treatment with IGF-I alone induced a significant increase in body length (108% of control) and weight (112%) as well as an increase in weight of the submandibular salivary glands (135%), kidneys (124%), femoral muscles (111%), testes (129%), and spleen (126%) compared with saline-treated controls. IGFBP-1 alone induced a significant increase in weight of the kidneys (152% of control). Coadministration of IGF-I with IGFBP-1 neutralized the stimulating effects of IGF-I on body length and weight as well as on the femoral muscles and testes. In contrast, the weights of the submandibular salivary glands (143%) were not significantly different from those of IGF-I-treated animals, whereas the weights of the kidneys (171%) and spleen (156%) were significantly increased compared with IGF-I-treated mice. The effect of IGFBP-1 plus IGF-I on kidney weight was not significantly greater than the effect of IGFBP-1 alone. Western ligand blotting showed induction of the IGFBP-3 doublet as well as IGFBPs with molecular masses of 24 kDa, most probably IGFBP-4, by human GH, IGF-I alone, and IGF-I in combination with IGFBP-1. Our data show that coadministration of IGFBP-1 inhibits IGF-I-induced body growth of GH-deficient mice but significantly stimulates the growth promoting effects of IGF-I on the kidneys and the spleen. These data warrant further investigation because differences in concentrations of IGFBP-1 occurring in vivo may influence IGF-I-induced anabolic processes.
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The long-term effects of recombinant human insulin-like growth factor-I (rhIGF-I) and GH (rhGH) on body growth and the IGF-I/IGF binding protein (IGFBP)/acid-labile subunit (ALS) axis were investigated in hypophysectomized (hypox) rats given excipient, rhIGF-I (2 mg/kg.day s.c., minipumps), rhGH (2 mg/kg.day, s.c., daily injections), or rhIGF-I plus rhGH for 28 days. The relative growth-promoting activity of the treatments was rhGH plus rhIGF-I more than rhGH more than rhIGF-I. Weight gain induced by rhIGF-I progressively declined after 4 days, compared with a more maintained effect of rhGH. At day 28, growth responses did not correlate with serum IGF-I levels [rhGH plus rhIGF-I (492 +/- 140) > rhIGF-I (322 +/- 75) > rhGH (85 +/- 26) > control (39 +/- 7 ng/ml)]. Serum ALS concentrations in hypox rats were remarkably low (0.42 +/- 0.04 micrograms/ml) but were restored toward normal by rhGH (12.55 +/- 4.78) or rhGH plus rhIGF-I (12.85 +/- 6.64) but not by rhIGF-I alone (0.85 +/- 0.25). Antibodies against rhGH were present at day 28, with titer being negatively related to weight gain, IGF-I, and ALS levels. All treatments increased serum IGFBP-3. The molecular size distribution of IGFBP-3 in rhGH-treated rats was similar to that of normal rats (IGFBP-3 in the 150K mol wt range), due to rhGH increasing serum ALS, but was altered by rhIGF-I (IGFBP-3 in the 200-300K and 44K mol wt range). In a GH-deficient animal, restoring the IGF/IGFBP-3/ALS axis towards normal is associated with greater growth promotion.
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Insulin-like growth factor I (IGF-I) is essential for normal intrauterine and postnatal growth and development. Using the Cre/loxP-induced conditional knockout system, we have established a liver-specific IGF-I-deficient (LID) mouse model. Circulating IGF-I levels were decreased by approximately 75% without any apparent effect on their growth and development. To determine the role of extra-hepatic IGF-I in GH-induced postnatal growth, we tested the effects of GH on growth rates in these mice. Female, but not male, LID mice displayed significantly accelerated growth rates in response to daily injections of GH for 5 weeks. The GH-induced peripubertal growth in female LID mice was not affected by ovariectomy, nor did castration change the growth pattern in male LID mice. Thus, factors other than gonadal steroids mediate this sexual dimorphism. We postulate that the sexual dimorphic response to GH observed in LID mice may be related to genetically programmed differences in GH secretion patterns.
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We investigated pituitary regulation of growth during two critical stages of development in the rat, using hypophysectomy (Hx) with replacement of GH and/or T4. In the neonatal period (Hx on day 6), body weight and tail length were inhibited by 60% and 50%, respectively, while these parameters were inhibited by 80% and 85% by Hx in the juvenile period (Hx on day 45). Administration of T4 alone significantly increased skeletal growth (tail length) in neonatal Hx rats, while T4 alone proved ineffective in promoting somatic growth in juvenile Hx rats. GH effects were greater on body weight than on tail length at both stages of development. Replacement of both GH and T4 restored somatic growth to normal values during both time periods. The brain was the sole organ whose growth appeared to be independent of the pituitary. Hx reduced serum insulin-like growth factor-I (IGF-I) and -II in both age groups, and GH alone restored IGF-I and -II levels to the control range. The major IGF-binding proteins (IGFBPs) were analyzed by Western ligand blots. The effect of Hx on the predominant IGFBP was greater in the juvenile rat. T4 replacement in the neonate and GH replacement in the juvenile rat restored IGFBPs to control levels. We conclude that somatic growth in the rat is less pituitary dependent in the neonatal, period. There are also important agespecific differences in organ response to GH and T4. Serum IGFs and their binding proteins are pituitary dependent even in infancy, and GH is their primary regulator. The neonatal Hx rat is an important model for the study of the dynamic development of the pituitary-dopendent growth. (Endocrinology128: 1036–1047, 1991)
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The actions of insulin-like growth factor-I (IGF-I) are modulated by IGF binding proteins (IGFBPs). The effects of IGFBP-1 in vivo are insufficiently known, with respect to inhibitory or stimulatory actions on IGF-induced growth of specific organs. Therefore, we studied the effects of IGFBP-1 on IGF-I-induced somatic and organ growth in pituitary-deficient Snell dwarf mice. Human GH, IGF-I, IGFBP-1, and a preequilibrated combination of equimolar amounts of IGF-I and IGFBP-1 were administered sc during 4 weeks. Treatment with IGF-I alone induced a significant increase in body length (108% of control) and weight (112%) as well as an increase in weight of the submandibular salivary glands (135%), kidneys (124%), femoral muscles (111%), testes (129%), and spleen (126%) compared with saline-treated controls. IGFBP-1 alone induced a significant increase in weight of the kidneys (152% of control). Coadministration of IGF-I with IGFBP-1 neutralized the stimulating effects of IGF-I on body length and weight as well as on the femoral muscles and testes. In contrast, the weights of the submandibular salivary glands (143%) were not significantly different from those of IGF-I-treated animals, whereas the weights of the kidneys (171%) and spleen (156%) were significantly increased compared with IGF-I-treated mice. The effect of IGFBP-1 plus IGF-I on kidney weight was not significantly greater than the effect of IGFBP-1 alone. Western ligand blotting showed induction of the IGFBP-3 doublet as well as IGFBPs with molecular masses of 24 kDa, most probably IGFBP-4, by human GH, IGF-I alone, and IGF-I in combination with IGFBP-1. Our data show that coadministration of IGFBP-1 inhibits IGF-I-induced body growth of GH-deficient mice but significantly stimulates the growth promoting effects of IGF-I on the kidneys and the spleen. These data warrant further investigation because differences in concentrations of IGFBP-1 occurring in vivo may influence IGF-I-induced anabolic processes.
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