Insulin-like growth factor binding protein-1 (IGFBP-1): a multifunctional role in the human female reproductive tract

Insulin-like growth factor-1 (IGFBP-1) is particularly important in human female reproductive physiology, where it is involved with other factors in a complex system which regulates menstrual cycles, puberty, ovulation, decidualization, implantation and fetal growth. This has implications for clinical obstetrics and gynaecology, where there is evidence for a pathophysiological role for IGFBP-1 in pre-eclampsia, intrauterine growth restriction, polycystic ovarian syndrome and trophoblast and endometrial neoplasms.     

Gene expression and serum levels of insulin-like growth factors (IGFs) and IGF-binding proteins in a case of non-islet cell tumour hypoglycaemia

We describe a case of non-islet cell tumour hypoglycaemia (NICTH) associated with a renal cell carcinoma. Serum insulin-like growth factors (IGFs) (including IGF-II E peptide), IGF-binding proteins (IGFBPs), insulin and C-peptide were measured before and after surgical removal of the tumour. IGFBPs were visualized by Western ligand blotting. Preoperatively 'big' IGF-II and IGFBP-2 levels were raised. IGF-I, IGFBP-1 and IGFBP-3 were low, while insulin, C-peptide and GH were undetectable. These changes were reversed by 2 days postoperatively. Protease assays showed little IGFBP-3 protease activity preoperatively. Preoperatively, neutral chromatography demonstrated most of the immunoassayable IGFBP-3 in a high molecular weight form with a small amount of IGF-II. Most of the IGF-II and big IGF-II eluted in lower molecular weight forms. Postoperative samples showed a shift in IGF-II which became increasingly associated with IGFBP-3 in both low and high molecular weight complexes. By Northern blotting, expression of all species of IGF-II mRNA in the tumour was 10-fold greater than in normal human liver. The tumour did not express IGFBP-1 or IGFBP-2. IGFBP-3 was expressed in small amounts, while the expression of IGFBP-4 was two-fold higher than in liver. In conclusion, we have confirmed high levels of big IGF-II and IGFBP-2 in NICTH, changes which are reversed postoperatively. The IGF-II is derived from the tumour which overexpresses these genes but IGFBP-2 probably arises from extratumour upregulation.     

Levels of DHEA and DHEAS and responses to CRH stimulation and hydrocortisone treatment in chronic fatigue syndrome

Background: An association between chronic fatigue syndrome (CFS) and abnormalities of the hypothalamo-pituitary-adrenal axis has been described, and other adrenal steroid abnormalities have been suggested. Dehydroepiandrostenedione (DHEA) and its sulphate (DHEA-S), apart from being a precursor of sex steroids, have other functions associated with memory, depression and sleep. It has been suggested that CFS may be associated with a state of relative DHEA(-S) deficiency. Therefore we investigated basal levels of DHEA(-S), the cortisol/DHEA molar ratio and the responsiveness of DHEA to stimulation by corticotrophin-releasing hormone (CRH). Recent studies have also suggested that low dose hydrocortisone may be effective at reducing fatigue in CFS. We therefore also assessed these parameters prior to and following treatment with low dose oral hydrocortisone. Methods: Basal levels of serum DHEA, DHEAS and cortisol were measured in 16 patients with CFS without depression and in 16 controls matched for age, gender, weight, body mass index and menstrual history. CRH tests (1 g/kg i.v.) were carried out on all subjects and DHEA measured at 0, +30 and +90 min. In the patient group, CRH tests were repeated on two further occasions following treatment with hydrocortisone (5 or 10 mg, p.o.) or placebo for 1 month each in a double-blind cross over study protocol. Results: Basal levels of DHEA were higher in the patient, compared to the control, group (14.1+/-2.2 vs. 9.0+/-0.90 ng/ml, P=0.04), while levels of DHEAS in patients (288.7+/-35.4 microg/dl) were not different from controls (293.7+/-53.8, P=NS). Higher DHEA levels were correlated with higher disability scores. Basal cortisol levels were higher in patients, and consequently the cortisol/DHEA molar ratio did not differ between patients and controls. Levels of DHEA (8.9+/-0.97 ng/ml, P=0.015) and DHEAS (233.4+/-41.6 microg/dl, P=0.03) were lower in patients following treatment with hydrocortisone. There was a rise in DHEA responsiveness to CRH in the patients after treatment but this did not attain significance (AUCc: 2.5+/-1.7 ng/ml h pre-treatment vs. 6.4+/-1.2 ng/ml h post-hydrocortisone, P=0.053). However, those patients who responded fully to hydrocortisone in terms of reduced fatigue scores did show a significantly increased DHEA responsiveness to CRH (AUCc: -1.4+/-2.5 ng/ml h at baseline, 5.0+/-1.2 ng/ml h after active treatment, P=0.029). Conclusions: DHEA levels are raised in CFS and correlate with the degree of self-reported disability. Hydrocortisone therapy leads to a reduction in these levels towards normal, and an increased DHEA response to CRH, most marked in those who show a clinical response to this therapy.     

Diarrhea reduces the rates of cardiac protein synthesis in myofibrillar protein fractions in rats in vivo

Although chronic diarrhea affects heart function and morphology, the pathogenic mechanisms are unknown. It was our hypothesis that diarrhea imposes metabolic stress to inhibit the synthesis of new contractile proteins. To test this hypothesis, we investigated the effects of lactose-induced diarrhea in rats. The groups were: 1) freely fed controls, 2) rats with lactose-induced diarrhea or 3) pair-fed rats. After 1 wk, hearts from the rats were subjected to subcellular fractionation techniques to isolate the major protein fractions, including myofibrillar proteins. The rates of protein synthesis were measured with concomitant assay of cardiac composition and plasma analytes. In comparison with the control group, diarrhea induced the following changes (P < 0.05): a decrease in heart weight, reduced RNA and mixed protein contents and a reduction in the fractional rate of mixed protein synthesis. There was a reduction in the content of all protein fractions. The fractional synthesis rate was reduced only for the myofibrillar fraction. Plasma insulin-like growth factor-I, but not corticosterone, was reduced. Plasma cholesterol and triglyceride concentrations were also reduced. In comparison with the pair-fed group, diarrhea induced the following changes (P < 0.05): a reduction in heart weight and fractional rate of mixed protein synthesis, reduced myofibrillar absolute synthesis rate and increased sarcoplasmic/myofibrillar fractional synthesis rate ratio. Plasma bicarbonate, triglyceride and urea concentrations were reduced, with an increase in albumin. Diarrhea impaired cardiac biochemistry, including a reduction in protein content and synthesis. A substantial proportion of these changes is due to anorexia, but the selective reduction in the synthesis of contractile proteins is a feature exclusive to the diarrhea group and may be due to reductions in plasma insulin-like growth factor-I.     

Antenatal dexamethasone and the growth hormone-insulin-like growth factor axis

Dexamethasone administration has marked effects on the growth hormone-insulin-like growth factor axis (GH-IGF) in animal and human studies. During pregnancy in the rat, it is associated with fetal growth restriction due to inhibition of IGF bioactivity. In the human only repeated dosages have been associated with fetal growth restriction. The aim of this study is to test the hypothesis that antenatal dexamethasone administration to pregnant women is associated with reduced activity of the GH-IGF axis. To achieve this blood samples were taken from 12 pregnant women pre- and at 24 h and 48 h after dexamethasone administration. In these samples GH, IGF-I, IGF bioactivity and IGF binding protein (IGFBP)-3 protease activity were measured. In view of the interaction between insulin and the GH-IGF axis, glucose and insulin concentrations were also measured. There were no significant differences between the concentrations of GH, IGF-I, IGF bioactivity and IGFBP-3 protease activity before and after dexamethasone. The concentrations of glucose and insulin were significantly higher at 24 h, but not 48 h post-dexamethasone. It is concluded that a single antenatal course of dexamethasone does not alter the GH-IGF-I axis in pregnant women at the time points studied.     

Altered placental development and intrauterine growth restriction in IGF binding protein-1 transgenic mice

IGF binding protein-1 (IGFBP-1) is a secretory product of decidualized endometrium and a major constituent of amniotic fluid. It is thought to modulate the actions of the IGFs on trophoblast cells and is therefore potentially important in regulating placental development and fetal growth. To investigate this hypothesis, we have studied the effects of decidual IGFBP-1 excess on fetoplacental growth in transgenic mice overexpressing human IGFBP-1. Endogenous fetal IGFBP-1 overexpression is associated with a transient impairment of fetal growth in midgestation. Maternal decidual IGFBP-1 excess is also associated with impaired fetal growth in midgestation independent of fetal genotype, indicating placental insufficiency. Our data also demonstrate that amniotic fluid IGFBP-1 is derived almost exclusively from maternal sources. Decidual IGFBP-1 overexpression has a marked effect on placental development. Placental morphology is abnormal in transgenic females due to altered trophoblast invasion and differentiation. These changes result in an increase in placental mass throughout pregnancy. This study provides the first compelling in vivo evidence that IGFBP-1 plays a role in placentation and suggests that IGFBP-1 has a pathological role in preeclampsia, a disorder characterized by shallow uterine invasion and altered placental development.     

Dexamethasone treatment in man induces changes in 24-hour growth hormone (GH) secretion profile without altering total GH released

Glucocorticoids inhibit growth in man and laboratory animals and reduce the GH response to the majority of exogenously administered stimuli. Recently, however, glucocorticoids have been shown to have varying effects on GH secretion depending on the time of administration and, furthermore, to be potent secretagogues in their own right. To investigate this further, we have carried out sampling over two 24-h periods in six normal male volunteers both before and directly after treatment with dexamethasone (DEX; 2 mg twice daily) for 96 h. After DEX administration, all volunteers showed an increase in mean GH secretion during the first 9 h of sampling (0900-1800 h) compared with pre-DEX control profiles (5.1 +/- 1.2 vs. 1.7 +/- 0.5 micrograms/L; P less than 0.001). DEX treatment also had the effect of delaying and attenuating the nocturnal peak; mean GH secretion between 0000-0200 h was significantly greater before DEX (13.6 +/- 2.7 micrograms/L) than after DEX (3.6 +/- 0.7 micrograms/L; P less than 0.001), whereas that between 0300-0800 h was greater after DEX (5.5 +/- 0.8 vs. 0.7 +/- 0.2 micrograms/L; P less than 0.001). Individual nocturnal peaks ranged from 7.0-56.8 micrograms/L, occurring between 0030-0200 h before DEX, and 2.6-21.2 micrograms/L, occurring between 0300-0400 h after DEX. Overall mean GH secretion was not significantly altered by DEX treatment (3.8 +/- 0.6 vs. 4.2 +/- 0.5 micrograms/L; P = NS). Total insulin-like growth factor-I (IGF-I) levels, measured after acid-ethanol extraction, were significantly increased by DEX treatment, with mean IGF-I over the 24-h sampling period rising from 292.2 +/- 31.8 to 425.9 +/- 37 micrograms/L (P less than 0.005). All individuals showed an increase in mean 24-h IGF-I of between 10-75%. In a second study, 12 male volunteers were treated with DEX in an identical manner, and blood was taken at 0800 h daily. Total IGF-I levels rose steadily from 307.9 +/- 13.3 micrograms/L, reached a plateau at 72 h and remained elevated at 96 h (424.9 +/- 16.5 micrograms/L; P less than 0.001). These results suggest that glucocorticoids alter the normal pattern of GH secretion with an increase in daytime levels, but a delaying and attenuating effect on the nocturnal pulse. Previous studies have suggested that IGF-I concentrations are decreased by steroid treatment, but these have been based on bioassay systems. Total IGF-I, measured by RIA, would appear to be consistently elevated; the apparent decrease seen in bioassay systems may be due to glucocorticoid-induced changes in binding protein concentrations.