Twenty-four-hour serum growth hormone, insulin, C-peptide and blood glucose profiles and serum insulin-like growth factor-I concentrations in women with polycystic ovaries.

Raised insulin levels are now recognized as a characteristic feature of women with polycystic ovaries (PCO), and hyperinsulinism has been shown to stimulate androgen production in such women. We have, however, recently shown that hyperinsulinaemia is present only in the obese subjects with PCO in whom insulin concentrations correlate with those of luteinizing hormone. We therefore studied 24-hour blood profiles of growth hormone (GH) and insulin-like growth factor-I (IGF-I) in obese and non-obese women with PCO, for comparison with their levels of insulin, C-peptide and other hormones, such as androgens which are known to be disturbed in PCO. Mean 24-hour GH levels were higher overall in PCO than in control subjects, although the difference was not significant. When, however, a separate analysis was made in obese as compared with non-obese PCO patients, GH concentrations were significantly higher in the non-obese group than in the obese (p = 0.0005). There was a significant negative correlation between body mass index and mean 24-hour GH concentrations (r = -0.641; p = 0.0006). IGF-I concentrations were however similar in the PCO group overall and in controls, as well as in the obese and non-obese PCO patients. The 24-hour blood glucose profile pattern was significantly different in PCO women from controls (p = 0.009), with absence of post-prandial peaks in blood glucose concentrations. These changes were most marked in the non-obese PCO group, who also had significantly lower blood glucose levels than either controls or obese PCO subjects.(ABSTRACT TRUNCATED AT 250 WORDS)     

Altered placental insulin and insulin-like growth factor-I receptors in diabetes

We have compared the characteristics of IGF-I and insulin receptors in placentas of normals and insulin dependent diabetic patients. Specific binding of both IGF-I and insulin in placental membranes from patients with good glycemic control (as reflected by blood hemoglobin content) was unaltered while that in the placental membranes from the patients with poor glycemic control was increased to approximately 20% of the normals. This observed small but significant (p less than 0.05) increase in binding of IGF-I and insulin to placental membranes from diabetic patients with poor glycemic control was further magnified, approximately twice (p less than 0.001) the normal, when the membrane receptors were purified by lectin chromatography. The kinetic analysis of IGF-I and insulin binding in both membranes and lectin purified receptors revealed that the increased binding of insulin and IGF-I to the placentas from diabetic patients with poor glycemic control was due to an approximately 2 fold increase (p less than 0.001-0.05) in the receptor numbers without any significant changes of the affinities. The molecular characteristics of the receptors in these diabetic patients, as revealed by the cross-linking studies, did not reveal any changes when compared to the normals. The parallel changes of IGF-I and insulin receptors, shown here, are in accordance with the homologous nature of these two receptors. The increased receptor numbers of these two interrelated hormones in placentas of diabetics with poor glycemic control may be relevant to the altered placental functions in diabetic pregnancy.     

Growth hormone secretion during pregnancy: altered effects of growth hormone releasing factor and insulin-like growth factor-I in vitro

Growth hormone (GH) secretion is controlled by growth hormone releasing factor (GRF) but changes in the circulating level of this hormone are difficult to measure. Insulin-like growth factor (IGF-I) is a GH-dependent growth factor which significantly but slightly inhibits stimulated GH release in vitro. We have tested the effects of GRF and IGF-I on GH release in pregnancy, a state in which serum concentrations of GH are elevated and levels of IGF-I are lowered. We have found, in a system of acutely dispersed adenohypophysial cells prepared from pregnant (day 21-23) or control cycling female rats, that adenohypophysial cells from pregnant rats have an increased GH release with GRF. In contrast, IGF-I inhibition is similar but slightly smaller. These altered responses may result in elevated serum GH levels during pregnancy.     

The effect of cyclosporine administration on growth hormone release and serum concentrations of insulin-like growth factor-I in male rats.

The aim of this work was to study the effect of cyclosporine on the somatotropic axis. Accordingly, growth hormone (GH) secretion, circulating insulin-like growth factor I (IGF-I) and IGF binding proteins (IGFBPs) in response to cyclosporin A (CsA) treatment were examined in adult male Wistar rats. Cyclosporine administration (5, 10 or 20 mg/Kg daily) over 8 days did not modify the body weight, but it did decrease serum concentration of corticosterone and increased serum IGF-I and GH levels. Rats treated with 5 and 10 mg/Kg of cyclosporine had similar levels of serum IGFBPs to control rats, but there was an increase in circulating IGFBP-3 and IGFPB-1,2 in the group treated with 20 mg/Kg of CsA. The increase in circulating GH correlates with a decrease in pituitary GH content in CsA treated rats, with no modification in hypothalamic somatostatin content, suggesting an increase in pituitary GH release. In order to test this hypothesis, anterior pituitary cell cultures were exposed to different CsA concentrations during a 4 h incubation period. Cyclosporine increased GH secretion in cultured pituitary cells (p<0.05). These data suggest that cyclosporine increases circulating IGF-I and GH by stimulating pituitary GH release.     

Growth hormone secretion during sleep. II. Interrelationships between growth hormone secretion, insulin-like growth factor I and sex steroids

The serum levels of insulin-like growth factor I (IGF I), dehydroepiandrosterone sulfate (DHAS), testosterone (T) and estradiol (E2) have been measured in 78 prepubertal and 57 early pubertal patients referred for short stature, at the same time when their secretion of GH was evaluated both during nocturnal sleep and by two conventional stimulation tests. According to the results of GH measurements they were considered as having a normal secretion of GH (group I), a complete GH deficiency (group II), a partial GH deficiency (group III), low responses to stimuli with normal secretion during sleep (group IV) or a nocturnal neurosecretory dysfunction (group V). Though widely scattered, the IGF I levels showed the following characteristics: a significant increase at puberty from 0.77 to 1.29 U/ml (p less than 0.001) in the so-called endocrinologically normal patients of group I, not in the other groups; in the prepubertal patients of group I, a correlation of IGF I with chronological age (r = 0.47, p less than 0.005) and bone age (r = 0.52, p less than 0.002); significantly reduced IGF I levels in patients of group II having complete GH deficiency (p less than 0.001); no significant differences between prepubertal patients with partial or atypical GH deficiency from groups III, IV, V and prepubertal patients from group I; lower pubertal levels in groups III, IV, V than in pubertal patients from group I (p less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)     

Growth hormone dependence of somatomedin-C/insulin-like growth factor-I and insulin-like growth factor-II messenger ribonucleic acids

The GH dependence of somatomedin-C/insulin-like growth factor I (Sm-C/IGF-I) and insulin like growth factor II (IGF-II) mRNAs was investigated by Northern blot hybridizations of polyadenylated RNAs from liver, pancreas, and brain of normal rats, untreated hypophysectomized rats, and hypophysectomized rats 4 h or 8 h after an ip injection of human GH (hGH). Using a 32P-labeled human Sm-C/IGF-I cDNA as probe, four Sm-C/IGF-I mRNAs of 7.5, 4.7, 1.7, and 1.2 kilobases (kb) were detected in rat liver and pancreas but were not detectable in brain. In both liver and pancreas, the abundance of these Sm-C/IGF-I mRNAs was 8- to 10-fold lower in hypophysectomized rats than in normal rats. Within 4 h after injection of hGH into hypophysectomized animals, the abundance of liver and pancreatic Sm-C/IGF-I mRNAs was restored to normal. A human IGF-II cDNA was used as a probe for rat IGF-II mRNAs which were found to be very low in abundance in rat liver and showed no evidence of regulation by GH status. In pancreas, IGF-II mRNA abundance was below the detection limit of the hybridization procedures. The brain contained two IGF-II mRNAs of 4.7 and 3.9 kb that were 5-fold lower in abundance in hypophysectomized rats than in normal rats. These brain IGF-II mRNAs were not, however, restored to normal abundance at 4 or 8 h after ip hGH injection into hypophysectomized animals. To investigate further, the effect of GH status on abundance of Sm-C/IGF-I and IGF-II mRNAs in rat brain, a second experiment was performed that differed from the first in that hypophysectomized rats were given an injection of hGH into the lateral ventricle (intracerebroventricular injection) and a rat Sm-C/IGF-I genomic probe was used to analyze Sm-C/IGF-I mRNAs. In this experiment, a 7.5 kb Sm-C/IGF-I mRNA was detected in brain polyadenylated RNAs. The abundance of the 7.5 kb mRNA was 4-fold lower in hypophysectomized rats than in normal rats and was increased to 80% of normal within 4 h after icv administration of hGH to hypophysectomized animals. As in the first experiment, the abundance of the 4.7 and 3.9 kb brain IGF-II mRNAs was lower than normal in hypophysectomized rats. Brain IGF-II mRNAs were increased to 50% of normal in hypophysectomized rats given an icv injection of hGH but within 8 h after the injection rather than at 4 h as with Sm-C/IGF-I mRNAs.     

Growth hormone and insulin-like growth factor-I measurements in high growth (hg) mice

Effects of a recessive gene causing high growth (hg) were studied on two major components of the growth axis in mice. Plasma and pituitary levels of growth hormone and plasma levels of insulin-like growth factor I (IGF-I) were measured in three lines homozygous for hg, each compared with a control line of alike genetic background but wild type for the hg locus (Hg). Line Gh (hghg) and line GH (HgHg) are from a line which had undergone long-term selection for high postweaning weight gain; line Ch (hghg) and line CH (HgHg) were extracted from the second backcross of Gh to C57BL/6J; line L54 (hghg) was from the sixth backcross to C57BL/6J (B6) (HgHg). Pituitary GH levels and plasma IGF-I levels were measured in both sexes at 3, 4.5, 6 and 9 wk of age. Plasma growth hormone was measured in 8- to 12-wk-old males at hourly intervals from 08.00 to 17.00. Body weight in lines homozygous for hg at 6 and 9 wk of age was 10-30% greater than in control lines. The ontogeny of this increased growth depended on genetic background. Pituitary growth hormone content was 52% lower in the two hghg lines measured (lines Ch and Gh) than in control lines at 4.5, 6 and 9 wk. Plasma growth hormone levels were also much lower in hg mice, with values only 20-30% of those in their respective controls. hg lines showed consistently low plasma growth hormone levels throughout the 9 hr sampling period, while control lines expressed the characteristic pulsatile hormone secretion.(ABSTRACT TRUNCATED AT 250 WORDS)     

A novel role of growth hormone and insulin-like growth factor-I. Priming neutrophils for superoxide anion secretion.

Growth hormone (GH) and the GH-dependent growth promoting peptide, insulin-like growth factor-I (IGF-I), are both potent signals for priming human and porcine polymorphonuclear neutrophils (PMN) to secrete superoxide anion (O2-). PMA, opsonized-zymosan, or FMLP could all be used as triggering stimuli to demonstrate priming by GH or IGF-I. As positive controls, IFN-gamma and LPS also primed both human and porcine PMN for enhanced O2- release. However, only the LPS-mediated enhancement was inhibited by polymyxin B, which demonstrates that the priming induced by GH, IGF-I, or IFN-gamma was not caused by LPS contamination. Furthermore, a specific antibody to GH abrogated priming induced by this molecule. In contrast to IGF-I, the closely related molecule insulin was unable to prime PMN even at pharmacologic levels. Insulin, at pharmacologic levels, antagonized the priming mediated by IGF-I but had no effect on GH priming. A mAb directed against the human IGF-I receptor blocked the enhanced secretion of O2- by human PMN that was caused by IGF-I, but not GH, indicating that neutrophil priming induced by GH was not mediated by inducing extracellular release of IGF-I. However, priming PMN by both GH and IGF-I required de novo protein synthesis, because cycloheximide completely abrogated enhanced O2- secretion that was caused by these growth factors. These data show that a classic pituitary hormone (GH), as well as its widely recognized growth promoting peptide (IGF-I), are involved in regulating an important functional activity of both porcine and human PMN. Inasmuch as GH and IGF-I have recently been demonstrated to be synthesized by leukocytes, these data support the possibility that both of these proteins could act in a paracrine fashion as cytokines to prime PMN for an enhanced respiratory burst.     

Chronic alcohol consumption,type 2 diabetes mellitus,insulin-like growth factor-I (IGF-I), and growth hormone (GH) in ethanol-treated diabetic rats

Aims

Alcohol has deleterious influences on glucose metabolism which may contribute to the development of type 2 diabetes mellitus (T2DM). Insulin-like growth factor I (IGF-I) and growth hormone (GH), which interact with insulin to modulate metabolic control, have been shown to be related to impaired glucose tolerance. This study was conducted to assess the possibility that altered circulating IGF-I and GH levels contribute to the exacerbation of T2DM by alcohol use in type 2 diabetic Otsuka Long-Evans Tokushima Fatty (OLETF) rats and non-diabetic Long-Evans Tokushima Otsuka (LETO) rats.

Main method

OLETF rats were pair-fed a Lieber-DeCarli Regular Ethanol diet and LETO rats were pair-fed a control diet for 6 weeks. At 6 weeks, an Intraperitoneal Glucose Tolerance Test (IP-GTT) was performed and IGF-I and GH levels were evaluated.

Key findings

Prior to an IP-GTT, OLETF-Ethanol (O-E) group had significantly a decrease in the mean glucose levels compared to OLETF-Control (O-C) group. At 120 min post IP-GTT, the O-E group had significantly an increase in the mean glucose levels compared to O-C group. The serum IGF-I levels were significantly lower and the serum GH levels were significantly higher in the O-E group than in L-C group.

Significance

These results suggest that IGF-I and GH are prominent in defining the risk and development of T2DM, and may be adversely affected by heavy alcohol use, possibly mediating its diabetogenic effects. Thus, the overall glucose intolerance in the setting of alcoholism may be attributable to inappropriate alteration of IGF-I and GH levels.     

Growth hormone and insulin-like growth factor I concentrations in bulls of various growth hormone genotypes

A leucine/valine substitution at amino acid position 127 was identified by the polymerase chain reaction and restriction fragment length polymorphism in the bovine growth hormone gene. Genotyping was performed in 84 AI bulls of three different breeds, in which plasma concentrations of growth hormone (GH) and insulin-like growth factor I (IGF-1) were also measured. Gene frequencies of variants L (leucine) und V (valine) were 0.80/0.20 (Black and White), 0.90/0.10 (Brown), 0.71/0.29 (Simmental). Hormone concentrations were measured during different physiological conditions (normal feeding, fasting, realimentation) in the majority of animals. Generally, genotype LL was associated with higher concentrations of GH than LV. This difference was significant in Black and White bulls (P < 0.05). In contrast, IGF-1 concentrations were higher in LV than in LL animals. This was most pronounced in mature, realimented Simmental bulls. We conclude that the various GH alleles influence the circulating concentrations of GH and IGF-1.     

Ovariectomy during the luteal phase influences secretion of prolactin, growth hormone, and insulin-like growth factor-I in the bitch

A decline in circulating progesterone concentration plays an important role in the ethiopathogenesis of pseudopregnancy in the bitch. Because growth hormone (GH) and prolactin (PRL) are essential for normal mammogenesis and the secretion of these hormones is influenced by changes in the circulating progesterone concentration, the purpose of this study was to investigate the effects of mid-luteal phase ovariectomy on the 6-h pulsatile plasma profiles of GH and PRL and the basal plasma concentrations of GH, PRL, and insulin-like growth factor-I (IGF-I) in six beagle bitches. Ovariectomy was followed by only mild or covert signs of pseudopregnancy. The sharp decrease of the plasma progesterone concentration was accompanied by decreased basal plasma concentrations of GH and IGF-I and a rise in basal plasma PRL concentration. GH and PRL were secreted in a pulsatile fashion both prior to and after ovariectomy. The mean basal plasma GH concentration was significantly higher before ovariectomy than on days 1 and 7 after ovariectomy. The mean area under the curve above the zero level (AUC(0)) for GH was significantly higher before than at 7 days after ovariectomy. The mean area under the curve above basal level (AUC(b)) and the frequency of GH pulses at 7 days after ovariectomy were significantly higher than before and 1 day after ovariectomy. Both the mean basal plasma PRL concentration and the mean AUC(0) for PRL increased after ovariectomy. In conclusion, ovariectomy of bitches in the mid-luteal phase stops progesterone-induced GH release from the mammary gland, as evidenced by the lowering of basal plasma GH levels, the recurrence of GH pulsatility, and the lowering of circulating IGF-I levels. The sudden lowering of plasma progesterone concentration is probably a primary cause of a prolonged increase in PRL secretion. These observations underscore the importance of similar, albeit less abrupt, hormonal changes in the cyclical physiological alterations in the mammary gland and in the development of pseudopregnancy.     

Gonadotropins increase concentrations of immunoreactive insulin-like growth factor-I in porcine follicular fluid in vivo

To evaluate the regulation of ovarian insulin-like growth factor-I (IGF-I) during follicular growth in vivo, we measured the concentration of this peptide in follicular fluid (FFL) of immature gilts during the induction of follicular development by pregnant mare's serum gonadotropin (PMSG) and human chorionic gonadotropin (hCG). FFL concentrations of immunoreactive (i) IGF-I were compared with those of intrafollicular steroids and with concentrations of iIGF-I, estradiol (E2), and porcine growth hormone (GH) in serum. PMSG, administered at Time 0, induced a significant (p less than 0.01), time-dependent increase in intrafollicular iIGF-I that peaked 72 h after administration of the hormone, before the administration of hCG. During the first 72 h, the changes in ovarian iIGF-I paralleled those for progesterone and E2. After the administration of hCG at 72 h, FFL levels of E2 fell, those of iIGF-I remained constant, and progesterone rose. Serum E2 concentrations paralleled those in FFL. Since serum GH and IGF-I levels rise during spontaneous puberty in some species, these levels were also monitored. However, a significant treatment effect on serum GH and iIGF-I was not demonstrated. In summary, ovarian concentrations of iIGF-I are increased by gonadotropic hormones in vivo. The absence of concomitant changes in circulating levels of iIGF-I and GH suggests that the gonadotropin effects are exerted directly on the ovary. These results, together with more abundant data regarding secretion and action of IGF-I in cultured granulosa cells, suggest that IGF-I may function in an autocrine or paracrine fashion to amplify the actions of gonadotropins at an ovarian level.     

Growth hormone or insulin-like growth factor-I extends longevity of equine spermatozoa in vitro

Growth hormone (GH) and insulin-like growth factor-I (IGF-I) are both present in blood plasma and IGF-I has been measured in epididymal fluid and seminal plasma. This study was designed to investigate the direct effects of GH or IGF-I on the motility of mature equine spermatozoa in vitro. We compared the effects of one concentration (100 ng/ml) of recombinant bovine GH (rbGH) and recombinant human IGF-I (rhIGF-I) on motility and motion characteristics of equine spermatozoa over a 24 h period. Motility was maintained longer in spermatozoa treated with either rbGH or rhIGF-I during a 24 h period at room temperature (P < 0.05). Spermatozoa motion characteristics at time 0, 1, 2, 4, 6, 12 and 24 h for both rbGH and rhlGF-I were not significantly different from the respective controls. This study has shown that GH and IGF-I are effective in promoting the in vitro longevity of spermatozoa.     

Age-related changes in plasma porcine growth hormone (GH) profiles and insulin-like growth factor-I (IGF-I) concentrations in Large White and Meishan pigs

Plasma GH profiles and IGF-I concentrations were determined in Large White intact male (LW-M), female (LW-F) and castrated male (LW-C) and in Meishan intact male (MS-M) pigs between 10 and 140 d of age. Mean GH levels slightly increased between 10 and 45 d of age in LW pigs, in connection with an alteration in the temporal distribution of GH peaks, whereas neither interpulse GH level nor maximum GH level were affected. Mean GH levels decreased after 45 d of age, in connection with a decline in maximum and interpulse GH levels. IGF-I concentrations were low between 10 and 45 d of age and increased thereafter. GH secretory profiles did not differ significantly between LW-M and LW-F at either age. Castration had no effect at 45 d of age whereas LW-C exhibited lower mean, maximum and interpulse GH levels and smaller sum of GH pulse areas and widths than LW-M or LW-F at 140 d of age. IGF-I was lower in LW-C or LW-F than in LW-M at 140 d of age. The pattern of age-related changes in GH and IGF-I was similar in MS and LW pigs. However, interpulse GH level was higher and sum of GH pulse widths was smaller in MS-M than in LW-M, whatever the age. The results indicate that: i), GH and IGF-I secretions were similar in Meishan, and Large White pigs; ii), in both breeds, GH secretion declined after 45 d of age, due to decreased maximum and interpulse GH levels; iii), sex and/or castration effects on GH and IGF-I secretion were observed after 45 d of age only.     

Polysomnographic sleep, growth hormone insulin-like growth factor-I axis, leptin, and weight loss

Short sleep appears to be strongly associated with obesity and altered metabolic function, and sleep and growth hormone (GH) secretion seems interlinked. In obesity, both the GH-insulin-like-growth-factor-I (GH-IGF-I) axis and sleep have been reported to be abnormal, however, no studies have investigated sleep in relation to the GH-IGF-I axis and weight loss in obese subjects. In this study polygraphic sleep recordings, 24-h GH release, 24-h leptin levels, free-IGF-I, total-IGF-I, IGF-binding protein-3 (IGFBP-3), acid-labile subunit (ALS), cortisol and insulin sensitivity were determined in six severely obese subjects (BMI: 41+/-1 kg/m(2), 32+/-2 years of age), cross-sectional at baseline, and longitudinal after a dramatically diet-induced weight loss (36+/-7 kg). Ten age- and gender-matched nonobese subjects served as controls. Sleep duration (360+/-17 vs. 448+/-15 min/night; P<0.01), 24-h GH (55+/-9 vs. 344+/-55 mU/l.24 h; P<0.01), free-IGF-I (2.3+/-0.42 vs. 5.7+/-1.2 microg/l; P<0.01), and total-IGF-I (186+/-21 vs. 301+/-18 microg/l; P<0.01) were significantly decreased and 24-h leptin levels were increased (35+/-5 vs. 12+/-3 microg/l; P<0.01) in obese subjects at pre-weight loss compared with nonobese subjects After diet-induced weight loss the differences in GH, free IGF-I, and leptin were no longer present between previously obese and nonobese subjects, whereas a significant difference in sleep duration and total IGF-I levels persisted. Rapid eye movement (REM) sleep, non-REM sleep, IGFBP-3, ALS, and cortisol levels were similar in obese and nonobese subjects. Sleep duration, 24-h GH, and IGF-I levels were decreased and 24-h leptin levels were increased in obese subjects. We conclude that hyposomatotropism and hyperleptinemia in obesity are transient phenomena reversible with weight loss, whereas short sleep seems to persist after weight has been reduced dramatically.     

Regulation of prostaglandin synthesis by thyrotropin, insulin or insulin-like growth factor-I, and serum in FRTL-5 rat thyroid cells.

The present report shows that thyrotropin (TSH) regulates all three steps involved in prostaglandin synthesis in FRTL-5 rat thyroid cells, i.e. arachidonic acid release from membrane phospholipids, cyclooxygenase (prostaglandin H synthase) action, and individual prostaglandin formation; however, its action at specific steps may require the presence of, or can be duplicated by, insulin, insulin-like growth factor-I (IGF-I), and/or a serum factor. Thus, TSH releases free arachidonic acid from rat FRTL-5 thyroid cells whose phospholipid fraction is radiolabeled with [3H]arachidonic acid; this action involves a pertussis toxin-sensitive G protein, is not cAMP mediated, and does not require insulin or 5% serum. To quantitate TSH effects on cyclooxygenase activity and on individual prostaglandin formation, a homogenate system and a rapid reversed-phase high pressure liquid chromatography procedure have been developed to measure cyclooxygenase metabolites. TSH increased cyclooxygenase activity in homogenates only if the cells were also exposed to insulin, IGF-I, and/or 5% calf serum; TSH alone had no apparent effect on the activity. Maximal activation, 4-fold over basal/micrograms of DNA, took 36 h to achieve and reflected, at least in part, an increase in cyclooxygenase gene expression. Like cyclooxygenase activity, induction of prostaglandin E2 production required 2 or more factors, i.e. TSH plus insulin/IGF-I or TSH plus insulin/IGF-I plus serum. Increased production of prostaglandin D2, could, however, be detected if cells were treated with TSH alone and the TSH activity could be duplicated by insulin, IGF-I, or calf serum alone.