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R Koistinen

Publications and source records attributed to R Koistinen.

At least 19 recordsLinked to original sources
PubMed2002

High serum insulin-like growth factor binding protein-1 is associated with increased cardiovascular mortality in elderly men.

Insulin-like growth factor binding protein-1 (IGFBP-1) has been implicated in the development of cardiovascular disease, but it is not known whether IGFBP-1 is related to cardiovascular mortality. We examined the relation of circulating IGFBP-1 to death from coronary heart disease, cardiovascular disease, and all causes in a cohort study consisting of 622 men aged 65 - 84 years, at baseline in 1984. Fasting serum IGFBP-1 and other risk factors were measured in 1984 and 1989. Cardiovascular events for those who died between 1984 and 1995 were analyzed, and cardiovascular diagnoses were coded centrally according to standardized procedures. Of the 622 men, 358 died between 1984 and 1995; 160 deaths were due to cardiovascular causes, 113 of which were coronary deaths. High fasting serum IGFBP-1 concentration (> 75 percentile) in 1984 was associated with increased five-year total mortality (OR 2.05, 95 % CI 1.41 - 2.99; p < 0.0002), cardiovascular mortality (OR 2.20, 95 % CI 1.37 - 3.50; p < 0.0009) and coronary heart disease mortality (OR 2.29, 95 % CI 1.35 - 3.88; p < 0.002). After adjustment for age, high serum IGFBP-1 concentrations still carried an increased risk of total mortality due to (OR 1.73, 95 % CI 1.16 - 2.59; p < 0.007), cardiovascular (OR 1.91 95 % CI 1.18 - 3.09; p < 0.008) and coronary heart disease (OR 2.02. 95 % CI 1.18 - 3.47; p < 0.01). In conclusion, high fasting serum IGFBP-1 is related to increased five-year total and cardiovascular mortality in elderly men.

Age Factors↗
PubMed2002

The synthesis and fate of glycodelin in human ovary during folliculogenesis.

The ontogeny of glycodelin in human ovarian follicles during folliculogenesis was studied. Glycodelin immunoreactivity began to be detected in the granulosa cells and thecal cells of late secondary follicles. Immunoreactivity was also found in both the luteinized granulosa cells and cumulus cells obtained from women undergoing the assisted reproduction treatment. However, only the luteinized granulosa cells, and not the cumulus cells, expressed glycodelin mRNA. Results also showed that the cumulus cells took up radiolabelled glycodelin and partially deglycosylated some of it. Glycodelin (and a partially deglycolsylated form of glycoldelin) appeared to complex with two cytoplasmic or membrane components of the cumulus cells. The data also demonstrated that ZIF-1, a glycoprotein isolated from human follicular fluid, was immunologically similar to glycodelin. In conclusion, we suggest that glycodelin is synthesized in the granulosa cells of ovarian follicles at late secondary follicle stage. It then may be released into the follicular fluid from where it is taken up and partially modified by the cumulus cells.

Binding, Competitive↗
PubMed2001

Endometrial expression of glycodelin in women with levonorgestrel-releasing subdermal implants.

OBJECTIVE: To determine whether subdermal levonorgestrel implants induce endometrial expression of glycodelin. DESIGN: Cross-sectional, blinded study. SETTING: University clinic. PATIENT(S): One hundred and eight women with subdermal implants and 19 postmenopausal women. INTERVENTION(S): Endometrial biopsies, curettages, and hysterectomies. MAIN OUTCOME MEASURE(S): Endometrial glycodelin expression was examined through immunohistochemistry, in situ hybridization, and morphologic endometrial dating. RESULT(S): Overall, 80% of the endometrial specimens obtained from women with subdermal levonorgestrel implants stained positive for glycodelin. Endometrial morphology of these women showed proliferative (71%), inactive/weakly proliferative (19%), menstrual or regenerating (6.5%), and other patterns (2.8%). Of these, 79%, 71%, 100%, and 100% were glycodelin positive, respectively. Nineteen specimens were obtained during the midcycle when glycodelin is not normally expressed: of these, 89% stained positive for glycodelin. Implant-related amenorrhea was associated with endometrial glycodelin expression in 58% of the women, whereas the endometrium specimens obtained from women with postmenopausal hypoestrogenic amenorrhea contained no detectable glycodelin. CONCLUSION(S): Subdermal levonorgestrel implant use is often associated with endometrial expression of glycodelin. Because glycodelin has been shown to inhibit sperm-egg binding, the induction of glycodelin may contribute to the contraceptive activity of the implant.

Adult↗
PubMed2001

Factors regulating insulin-like growth factor binding protein-3 secretion from human hepatoma (HepG2) cells.

Insulin-like growth factor (IGF) binding protein-3 (IGFBP-3) is a growth hormone (GH) dependent carrier of the IGFs in human serum. Apart from GH regulation the hormonal control of IGFBP-3 production is not well established and although the liver is considered to be the main source of circulating IGFBP-3, there are no in vitro studies of the effect of both insulin and IGFs on the IGFBP-3 produced in human hepatoma cells. The effect of sex hormones as well as cortisol has not been studied. To elucidate this we performed cell culture studies on HepG2 cells in the presence of various effectors. Insulin, IGF-I and IGF-II brought about a 1.5-2-fold enhancement of IGFBP-3 release at 7.5-30 nM concentrations. In contrast, cortisol decreased IGFBP-3 secretion by 30-40% whereas estradiol, tamoxifen and testosterone had no effect at physiological concentrations. We conclude that, in addition to GH, also insulin, IGF-I and IGF-II and glucocorticoids can modulate IGFBP-3 secretion by human hepatoma cells.

Adrenal Cortex Hormones↗
PubMed2001

Glycodelins.

Glycodelin is a major glycoprotein that is synthesized in the endometrium in response to progesterone and relaxin exposure. Endometrium-derived glycodelin-A has contraceptive and immunosuppressive properties. Glycodelin is absent from the endometrium during the fertile periovulatory phase, but is synthesized in this tissue during the peri-implantation phase and is abundant during the last week of the luteal phase. Changes in local and/or circulating glycodelin concentrations have been observed in women with reproductive disorders. The chemical modification of glycodelins has resulted in compounds with antiviral activity.

Amino Acid Sequence↗
PubMed2001

Markers of type I and type III collagen turnover, insulin-like growth factors, and their binding proteins in cord plasma of small premature infants: relationships with fetal growth, gestational age, preeclampsia, and antenatal glucocorticoid treatment.

Disorders affecting fetal growth are commonly associated with premature birth. IGFs and their binding proteins (IGFBPs) are potent regulators of fetal growth. In vitro evidence suggests that they regulate collagen turnover. Collagen turnover can be monitored by serum markers of type I collagen synthesis (PINP) and degradation (ICTP) and a marker of type III collagen synthesis (PIIINP). We examined whether these markers in fetal circulation reflect intrauterine growth and maturity, and whether any interrelationship exists between them and fetal IGFs and IGFBPs in preterm infants before 32 wk of gestation. Cord plasma PINP, ICTP, PIIINP, IGF-I, IGF-II, IGFBP-1, and IGFBP-3 were determined for 98 preterm infants. To express birth weight in units adjusted for gestational age, a birth weight SD score (SDS) was calculated. Negative correlations existed between gestational age and PINP (r = -0.43; p < 0.0001), ICTP (r = -0.34; p = 0.002), and PIIINP (r = -0.34; p = 0.0001). Positive correlations existed between birth weight SDS and PINP (r = 0.40; p = 0.0002) and ICTP (r = 0.48; p < 0.0001) but not PIIINP. Moreover, birth weight SDS was positively correlated with IGF-I (r = 0.58; p < 0.0001) and IGFBP-3 (r = 0.44; p < 0.0001) and negatively correlated with IGF-II (r = -0.36; p = 0.003) and IGFBP-1 (r = -0.50; p < 0.0001). Gestational age correlated with IGFBP-3 (r = 0.25; p = 0.03). In preeclampsia, IGF-I was lower (p = 0.002) and IGFBP-1 higher (p < 0.0001), also after adjustment for fetal size. The number of antenatal glucocorticoid treatments was associated with lower ICTP (p = 0.04), higher IGF-I (p = 0.002), lower IGF-II (p = 0.02), lower IGFBP-1 (p = 0.05), and higher IGFBP-3 (p = 0.004), also after adjustment for potential confounders. In multiple regression analysis, the factors significantly associated with PINP (R:(2) = 0.47) were gestational age and IGF-I, and those associated with ICTP (R:(2) = 0.54) were IGF-I, gestational age, and antenatal glucocorticoid treatment. We conclude that IGF-I may be involved in regulation of type I collagen turnover in the growing fetus. Cord blood PINP and ICTP reflect both fetal growth and maturity and deserve evaluation as potential indicators of postnatal growth velocity in preterm infants, whereas PIIINP reflects fetal maturity.

Biomarkers↗
PubMed2001

Insulin reduction with metformin increases luteal phase serum glycodelin and insulin-like growth factor-binding protein 1 concentrations and enhances uterine vascularity and blood flow in the polycystic ovary syndrome.

We hypothesized that hyperinsulinemia contributes to early pregnancy loss in the polycystic ovary syndrome by adversely affecting endometrial function and environment. Serum glycodelin, a putative biomarker of endometrial function, is decreased in women with early pregnancy loss. Insulin-like growth factor-binding protein-1 may also play an important role in pregnancy by facilitating adhesion processes at the feto-maternal interface. We studied 48 women with polycystic ovary syndrome before and after 4 weeks of administration of 500 mg metformin (n = 26) or placebo (n = 22) 3 times daily. Oral glucose tolerance tests were performed, and serum glycodelin and insulin-like growth factor-binding protein-1 were measured during the follicular and clomiphene-induced luteal phases of menses. In the metformin group, the mean (+/-SE) area under the serum insulin curve after glucose administration decreased from 62 +/- 6 to 19 +/- 2 nmol/L.min (P < 0.001). Follicular phase serum glycodelin concentrations increased 20-fold from 150 +/- 46 to 2813 +/- 1192 pmol/L (P < 0.001), and serum insulin-like-growth factor-binding protein-1 concentrations increased from 936 +/- 152 to 2396 +/- 300 pmol/L (P < 0.001). Similarly, luteal phase serum glycodelin concentrations increased 3-fold from 3434 +/- 1299 to 10624 +/- 1803 pmol/L (P < 0.001), and serum insulin-like growth factor-binding protein-1 concentrations increased from 1220 +/- 136 to 4916 +/- 596 pmol/L (P < 0.001). Uterine vascular penetration also increased in the metformin group, as did blood flow of spiral arteries, as demonstrated by a 20% decrease in the resistance index from 0.71 +/- 0.02 to 0.57 +/- 0.03 (P < 0.001). These variables did not change in the placebo group. We conclude that insulin reduction with metformin increases follicular and luteal phase serum glycodelin and insulin-like growth factor-binding protein-1 concentrations and enhances luteal phase uterine vascularity and blood flow in the polycystic ovary syndrome. These changes may reflect an improved endometrial milieu for the establishment and maintenance of pregnancy.

Adult↗
PubMed2000

Recombinant glycodelin carrying the same type of glycan structures as contraceptive glycodelin-A can be produced in human kidney 293 cells but not in chinese hamster ovary cells.

We have produced human recombinant glycodelin in human kidney 293 cells and in Chinese hamster ovary (CHO) cells. Structural analyses by lectin immunoassays and fast atom bombardment mass spectrometry showed that recombinant human glycodelin produced in CHO cells contains only typical CHO-type glycans and is devoid of any of the N, N'-diacetyllactosediamine (lacdiNAc)-based chains previously identified in glycodelin-A (GdA). By contrast, human kidney 293 cells produced recombinant glycodelin with the same type of carbohydrate structures as GdA. The presence of a beta1-->4-N-acetylgalactosaminyltransferase functioning in the synthesis of lacdiNAc-based glycans in human kidney 293 cells is concluded to be the cause of the occurrence of lacdiNAc-based glycans on glycodelin produced in these cells. Furthermore, human kidney 293 cells were found to be particularly suited for the production of recombinant glycodelin when they were cultured in high glucose media. Lowering the glucose concentration and the addition of glucosamine resulted in higher relative amounts of oligomannosidic-type glycans and complex glycans with truncated antennae. Human glycodelin is an attractive candidate for the development of a contraceptive agent, and this study gives valuable information for selecting the proper expression system and cell culture conditions for the production of a correctly glycosylated recombinant form.

Animals↗
PubMed2000

The decrease in luteinizing hormone secretion in response to weight reduction is inversely related to the severity of insulin resistance in overweight women.

Controversial effects of weight reduction on gonadotropin secretion in obesity have been reported. As a result of pulsatility, single serum samples or frequent sampling studies are somewhat limited with regard to monitoring LH and FSH concentrations. We studied follicular phase nocturnal urinary (nu) LH and FSH secretion and glucose metabolism (150-min euglycemic hyperinsulinemic clamp) during 1 menstrual cycle/30-day period before and after weight reduction in 10 severely overweight infertility patients (age, 29 +/- 3.1 yr; body mass index, 37.1 +/- 3.3 kg/m2; +/-SEM). A 6-week very low calorie diet was followed by a 4-week normocaloric period. The urinary LH and FSH results reported represent samples taken 12 to 2 days before the LH surge, or 10 consecutive samples in the case of amenorrhea. We observed a decrease of 8% (P < 0.001) in percent body fat mass and a 5% (P < 0.005) reduction in waist to hip ratio. Mean nu-LH decreased by 45% [6.06 +/- 1.05 (+/-SEM) to 3.22 +/- 0.71 IU/L], whereas mean nu-FSH remained unchanged. Insulin-stimulated glucose uptake increased by 41% (P < 0.01), which was accounted for by a significant increase in nonoxidative glucose disposal (P = 0.003). Serum sex hormone-binding globulin concentrations increased by 39% (P < 0.01), and insulin-like growth factor (IGF)-binding protein-1 (IGFBP-1) levels increased by 46% (P < 0.05). Fasting serum insulin concentrations decreased by 38%, those of leptin by 37%, those of androstenedione by 32%, those of testosterone by 20% (all P < 0.01), and those of dehydroepiandrosterone sulfate by 13% (P < 0.05). The percent change in nu-LH correlated negatively with glucose uptake (r = -0.76; P < 0.01) and the increase in serum sex hormone-binding globulin (r = -0.85; P < 0.005) and positively with the percent change in waist to hip ratio (r = 0.79; P < 0.01). The absolute nu-LH levels after weight reduction correlated significantly with fasting insulin concentrations (r = 0.88; P < 0.001) and negatively with glucose uptake (r = -0.67; P < 0.05). No significant relationships were found between absolute levels or changes in nu-LH concentrations and leptin, IGF-I, IGFBP-3, or IGFBP-1 concentrations. Our findings suggest that weight reduction with a very low calorie diet results in a decrease in nu-LH concentrations, a reduction in the LH/FSH ratio, and FSH predominance favoring folliculogenesis. The decrease in LH concentrations is inversely related to the severity of insulin resistance. It is possible that the decrease in LH secretion with weight reduction is more dependent on the absolute levels of insulin sensitivity than on the degree of general adiposity.

Adult↗
PubMed2000

Low serum insulin-like growth factor-binding protein-1 is associated with an unfavourable cardiovascular risk profile in elderly men.

Serum insulin-like growth factor-binding protein-1 (IGFBP-1) is regulated by insulin and has been suggested to be a marker of the insulin resistance syndrome. The aim of this study was to investigate whether serum IGFBP-1 is associated with cardiovascular risk factors. Serum insulin-like growth factor-I and IGFBP-3 were also determined. 331 men aged 70-89 years were examined from the Finnish cohort of the Seven Countries Study. Serum IGFBP-1 concentrations were measured by immunofluorometric assay, and the results were analysed with respect to markers of cardiovascular risk, insulin resistance, and insulin secretion that were determined by using the homeostasis model assessment. Fasting serum IGFBP-1 correlated inversely with fasting serum insulin, serum insulin 2 h after oral glucose challenge test, body mass index, and serum triglycerides, and it correlated positively with age and serum high-density lipoprotein (HDL) cholesterol. After adjustment for age, fasting serum IGFBP-1 correlated positively with HDL cholesterol and inversely with fasting serum insulin and triglycerides. Serum IGFBP-1 correlated positively with insulin sensitivity and negatively with beta-cell function. In conclusion, low serum IGFBP-1 levels in elderly men are associated with a number of cardiovascular risk factors.

Aged↗
PubMed1999

Expression of glycodelin in human breast and breast cancer.

Glycodelin is a 28 kDa glycoprotein with structural homology to beta-lactoglobulins, particularly expressed in steroid-responsive tissues of the female reproductive tract. We previously found that transfection of glycodelin cDNA into MCF-7 breast cancer cells induces differentiation into organized acinar epithelium and up-regulation of epithelial markers. In this study, we used immunohistochemistry, Northern blotting and reverse transcription-polymerase chain reaction (RT-PCR) analyses to study glycodelin expression in normal and in malignant breast tissues. The results were compared with the expression of estrogen (ER) and progesterone receptors (PR) and p53 tumor suppressor protein. Glycodelin was found in ductal and lobular epithelium of 6/6 normal breast tissues, 27/29 morphologically normal breast tissues from breast cancer patients, 6/6 benign lactating adenomas, 21/35 ductal carcinomas, 9/9 tubular carcinomas, 9/9 mucinous carcinomas, 3/3 mixed ductal/tubular carcinomas and 7/11 lobular carcinomas. In the latter, of particular interest was the presence of glycodelin in paranucleolar vacuoles of carcinoma cells. Northern blot analysis of fresh frozen tissues revealed the normal full length 0.9 kb mRNA of glycodelin in ductal breast carcinoma. Using RT-PCR analysis, glycodelin messenger ribonucleic acid was found in 13/13 ductal and in 3/3 tubular tumor tissues. We also detected a splicing variant lacking exon 4, which includes the nucleotide sequence encoding the potential N-glycosylation site at Asn-85. Our results demonstrate the synthesis of glycodelin in normal breast and breast cancer. In addition, we show that the paranuclear vacuole, characteristically present in lobular breast cancer cells, contains abundant amounts of glycodelin.

Adenoma↗
PubMed1999

Glycodelin and beta-lactoglobulin, lipocalins with a high structural similarity, differ in ligand binding properties.

Human glycodelin, a lipocalin with a high amino acid similarity to beta-lactoglobulins, appears as various glycoforms with different biological activities in endometrium (glycodelin-A) and seminal plasma (glycodelin-S). We found that the structures of these glycodelins and beta-lactoglobulin are similar. Despite this structural similarity, unlike beta-lactoglobulin, glycodelin-A binds neither retinoic acid nor retinol. It was impossible to detect any endogenous retinoids or steroids in any of the two purified glycodelins. Both their glycoforms share similar thermodynamic parameters of reversible denaturation suggesting that native folding of glycodelin-A and glycodelin-S is not influenced by the differences in glycosylation or by ligand binding.

Base Sequence↗
PubMed1999

Estradiol increases the production of sex hormone-binding globulin but not insulin-like growth factor binding protein-1 in cultured human hepatoma cells.

OBJECTIVE: To study the effects of E2 on insulin-like growth factor binding protein-1 (IGFBP-1) and sex hormone-binding globulin (SHBG) production with cultured human HepG2 hepatoma cells. DESIGN: Experimental cell culture. SETTING: Academic medical center. PATIENT(S): None. INTERVENTION(S): Addition of E2 to cell culture medium. MAIN OUTCOME MEASURE(S): Intracellular and released concentrations of IGFBP-1 and SHBG. RESULT(S): Estradiol did not affect the intracellular or extracellular IGFBP-1 concentration, whereas the intracellular SHBG concentration increased significantly in response to 0.5-2.5 microM of E2. CONCLUSION(S): Whereas the two binding proteins share a number of regulatory factors, their regulation by E2 is dissimilar in human hepatoma cells. Estradiol does not affect the intracellular or secreted IGFBP-1 concentration, but it does increase the production of SHBG.

Carcinoma, Hepatocellular↗
PubMed1998

Growth hormone induced increase in serum IGFBP-3 level is reversed by anabolic steroids in substance abusing power athletes.

OBJECTIVE: Body builders may use growth hormone (GH) and anabolic steroids to increase fitness and muscle mass. GH increases serum concentrations of IGF-I and IGFBP-3. The combined effects of GH and anabolic androgenic steroids on IGFBP-3 and IGF-I levels are not known under authentic substance-abusing conditions. The aim of this study was to investigate this in substance-abusing power athletes. DESIGN AND PATIENTS: Nine healthy, non-obese and non-competing male power athletes, all aggressive substance abusers, used GH and/or anabolic steroids independently of this study. Blood samples were taken both during and between the drug intake. Sixteen substance non-abusing wrestlers served as controls. MEASUREMENTS: Serum IGF-I concentration was measured by radioimmunoassay and the IGFBP-3 concentration was measured by two immunofluorometric assays, one detecting proteolytic fragments of IGFBP-3. The capacity of serum to proteolytically cleave IGFBP-3 was studied by the proteolysis assay. RESULTS: While growth hormone increased the IGFBP-3 and IGF-I concentrations, anabolic steroids decreased the same. Concomitant use of growth hormone and anabolic steroids decreased the IGFBP-3 concentration in five out of six abuse periods in spite of the fact that the IGF-I concentration remained elevated in four of them. However, in two men who were on low calorie diet both the IGF-I and IGFBP-3 concentrations decreased during combined GH/anabolic steroid abuse. No proteolytic fragmentation of IGFBP-3 was observed. CONCLUSION: Massive abuse of anabolic steroids decreases both the basal and GH-stimulated IGFBP-3 concentrations, whereas its effects on serum IGF-I concentration are variable and affected by low calorie diet. This study demonstrates that detection of GH doping by measuring the IGF-I and/or IGFBP-3 levels has notable confounding factors.

Adult↗
PubMed1998

Glycodelins: role in regulation of reproduction, potential for contraceptive development and diagnosis of male infertility.

Glycodelins are glycoproteins synthesized in various glands, with sequence homology to beta-lactoglobulins, and named according to their unique oligosaccharide structures. We purified, cloned and sequenced endometrium- and seminal plasma-derived glycodelins (GdA and GdS respectively) and found that they are involved in various types of cell-cell communications. These include interactions between the spermatozoon and the egg, and between immune cells and their targets. Endometrial GdA inhibits sperm-egg binding, whereas the differently glycosylated GdS in seminal plasma does not. These observation are of interest for reproductive physiology, detection of causes of infertility, and they also may have potential for contraceptive development.

Biomarkers↗
PubMed1997

Regulation of insulin-like growth factor-binding protein-1 and progesterone secretion from human granulosa-luteal cells: effects of octreotide and insulin.

OBJECTIVE: To examine the effects of the synthetic somatostatin-analogue octreotide and human recombinant insulin on the release of insulin-like growth factor binding protein-1 (IGFBP-1) and P from human granulosa-luteal cells. DESIGN: Primary culture of human granulosa-luteal cells. SETTING: Academic research laboratory. PATIENT(S): Women undergoing oocyte retrieval for IVF-ET because of tubal infertility. INTERVENTION(S): Octreotide or insulin were added to the cultures; sampling of culture medium was performed after 48 hours. MAIN OUTCOME MEASURE(S): Insulin-like growth factor binding protein-1 and P. RESULT(S): Octreotide significantly inhibited IGFBP-1 (58.8% compared with controls) and P release (66.1% compared with controls). Insulin abolished IGFBP-1 release while stimulating P release (200.7% compared with controls). There was a significant and positive correlation between IGFBP-1 and P levels. CONCLUSION(S): Octreotide and insulin have a significant effect on human granulosa-luteal cell function in terms of IGFBP-1 and P release. Our results suggest a local ovarian mechanism for the recently observed effects of octreotide in the treatment of women with polycystic ovary syndrome.

Cells, Cultured↗