Serum levels of insulin-like growth factor I and its binding proteins in health and disease.
Explore the source record for details and available documents.
Animals↗
Biomedical subjects
Anders Juul
Publications and source records attributed to Anders Juul.
Increase in maternal placental growth hormone during pregnancy and disappearance during parturition in normal and growth hormone-deficient pregnancies.
OBJECTIVE: The purpose of this study was to evaluate placental growth hormone levels in maternal circulation throughout pregnancy in normal and growth hormone-deficient women with the use of a specific assay and to determine the clearance of placental growth hormone from maternal circulation after birth. STUDY DESIGN: Seventeen healthy pregnant women and 1 patient with growth hormone deficiency substituted with recombinant growth hormone during pregnancy participated in a longitudinal study from early pregnancy until birth with repetitive blood sampling and measurement of placental growth hormone levels throughout pregnancy. Furthermore, serial blood samples were drawn before, during, and after elective caesarean deliveries in 5 healthy women to calculate the half-life of placental growth hormone. Placental growth hormone was measured with the use of two monoclonal antibodies in a commercially available solid-phase iodine 125-labeled immunoradiometric assay (Biocode, Liège, Belgium). RESULTS: Placental growth hormone levels were detectable from as early as 8 weeks of gestation in some of the women and increased throughout gestation, with a maximum at approximately 35 to 36 weeks of gestation (13.7 ng/mL; range, 5.9-24.4 ng/mL) and large interindividual variations. Placental growth hormone levels did not correlate with birth weight or placental weight. In the patient with isolated growth hormone deficiency, placental growth hormone levels were detectable from 11 weeks of gestation (3.4 ng/mL) and increased throughout pregnancy to 13.9 ng/mL, which is similar to values that are obtained in the healthy pregnant women. Substitution therapy with recombinant human growth hormone did not suppress the increase in placental growth hormone. We found a mean half-life of placental growth hormone of 13.8 minutes (range, 11.5-15.2 minutes) in healthy pregnant women and an apparently similar half-life of placental growth hormone (15.8 minutes) in the growth hormone-deficient patient, assuming a monoexponential disappearance of placental growth hormone during the first 30 minutes after the delivery. After the initial 30 minutes, approximately 75% (range, 65%-89%) of the placental growth hormone had been cleared from the maternal circulation. CONCLUSION: Levels of placental growth hormone in maternal circulation increase throughout pregnancy from as early as 8 weeks of pregnancy, with maximum levels around the week 35 of gestation. The pregnancy-induced rise in placental growth hormone levels in the growth hormone-deficient patient was comparable to the rise seen during normal pregnancies and was not suppressed by the concurrent human growth hormone treatment. We speculate that maternal serum levels of placental growth hormone reflect placental function and fetal growth. However, further studies are needed to evaluate the potential clinical use of placental growth hormone determinations.
Adult↗
Does breast feeding influence liver biochemistry?
OBJECTIVE: It is assumed that early feeding can affect liver biochemistry because breast-fed infants have a higher risk of hyperbilirubinemia than formula-fed infants. The authors sought to determine how feeding mode affected liver biochemistry in healthy term infants. METHODS: Healthy term infants were followed up during infancy with a monthly questionnaire about feeding mode. Blood samples were obtained at 2, 6, and 9 months. Liver biochemistry (serum albumin, alkaline phosphatase, lactic dehydrogenase, aspartate aminotransferase [AST], and bilirubin), total insulin-like growth factor 1 (IGF-I), and insulin growth factor binding protein 3 (IGFBP-3) were determined at all ages. RESULTS: Mean AST and bilirubin were significantly higher in breast-fed infants at 2 and 6 months. In addition, mean albumin levels were higher in breast-fed infants at 2 months. Alkaline phosphatase, IGF-I, IGFBP-3, and lactic dehydrogenase levels did not differ between the feeding groups. AST levels did not correlate significantly with bilirubin, albumin, alkaline phosphatase, or lactic dehydrogenase values. There was a strong positive association between AST and IGF-I at 2 months (r = 0.47, P = 0.004). CONCLUSION: Cytomegalovirus infection, vitamin K deficiency, and macromolecular forms of AST could be an explanation for a higher AST level among breast-fed infants. However, no other clinical or paraclinical sign of liver disease was seen, all infants were given oral vitamin K, and the AST did not rise to levels comparable to those seen in individuals with macromolecular AST. The authors speculate the most likely explanation of the elevated AST is induction of hepatocytes by factors in human milk. This is supported by the higher albumin levels in breast-fed infants and the positive association between AST and IGF-I.
Alkaline Phosphatase↗
Growth hormone treatment and risk of solid tumours. A statement from the Drugs and Therapeutics Committee of the European Society for Paediatric Endocrinology (ESPE).
Explore the source record for details and available documents.
Human Growth Hormone↗
Intrauterine growth retardation and consequences for endocrine and cardiovascular diseases in adult life: does insulin-like growth factor-I play a role?
Low birth weight has been associated with an increased incidence of ischaemic heart disease (IHD) and type 2 diabetes. Endocrine regulation of fetal growth by growth hormone (GH) and insulin-like growth factor (IGF)-I is complex. Placental GH is detectable in maternal serum from the 8th to the 12th gestational week, and rises gradually during pregnancy where it replaces pituitary GH in the maternal circulation. The rise in placental GH may explain the pregnancy-induced rise in maternal serum IGF-I levels. In the fetal compartment, IGF-I levels increase significantly in normally growing fetuses from 18 to 40 weeks of gestation, but IGF-I levels are four to five times lower than those in the maternal circulation. Thus IGF-I levels in fetal as well as in maternal circulation are thought to regulate fetal growth. Circulating levels of IGF-I are thought to be genetically controlled and several IGF-I gene polymorphisms have been described. IGF-I gene polymorphisms are associated with birth weight in some studies but not in all. Likewise, IGF-I gene polymorphisms are associated with serum IGF-I in healthy adults in some studies, although some controversy exists. Serum IGF-I decreases with increasing age in healthy adults, and this decline could hypothetically be responsible for the increased risk of IHD with ageing. A recent nested case-control study found that adults without IHD, but with low circulating IGF-I levels and high IGF binding protein-3 levels, had a significantly increased risk of developing IHD during a 15-year follow-up period. In summary, the GH/IGF-I axis is involved in the regulation of fetal growth. Furthermore, it has been suggested that low IGF-I may increase the risk of IHD in otherwise healthy subjects. Hypothetically, intrauterine programming of the GH/IGF axis may influence postnatal growth, insulin resistance and consequently the risk of cardiovascular disease. Thus IGF-I may serve as a link between fetal growth and adult-onset disease.
Adult↗
The timing of normal puberty and the age limits of sexual precocity: variations around the world, secular trends, and changes after migration.
During the past decade, possible advancement in timing of puberty has been reported in the United States. In addition, early pubertal development and an increased incidence of sexual precocity have been noticed in children, primarily girls, migrating for foreign adoption in several Western European countries. These observations are raising the issues of current differences and secular trends in timing of puberty in relation to ethnic, geographical, and socioeconomic background. None of these factors provide an unequivocal explanation for the earlier onset of puberty seen in the United States. In the formerly deprived migrating children, refeeding and catch-up growth may prime maturation. However, precocious puberty is seen also in some nondeprived migrating children. Attention has been paid to the changing milieu after migration, and recently, the possible role of endocrine- disrupting chemicals from the environment has been considered. These observations urge further study of the onset of puberty as a possible sensitive and early marker of the interactions between environmental conditions and genetic susceptibility that can influence physiological and pathological processes.
Age Factors↗
High risk of adrenal insufficiency in adults previously treated for idiopathic childhood onset growth hormone deficiency.
The aim was to reevaluate a group of adults treated for idiopathic childhood onset GH deficiency (GHD) after 18 yr without GH treatment. Twenty-six (11 females) patients participated. All but two had isolated GHD. Childhood diagnosis was established by insulin tolerance test (ITT). The patients were retested with an ITT to evaluate adult GH status. In five patients, an arginine and a synacthen test were performed instead of an ITT. Eleven of 25 patients had a subnormal cortisol response to ITT or synacthen. Ten patients had a GH peak less than 3.0 microg/liter (0.5. +/- 0.5 microg/liter), whereas 16 patients displayed a normal GH response (12.3 +/- 10.6 microg/liter) after ITT. IGF-I values were decreased in the patients with a pathological retest as well as in patients with a normal GH response compared with controls (P < 0.005). In 26 idiopathic childhood onset GHD patients, 44% of the patients had developed adrenal insufficiency; 38.5% had persistent GHD in adulthood, using the same test in both childhood and adulthood. Patients having a normal GH test had decreased IGF-I levels, compared with controls, indicating impaired function of a seemingly normal GH axis. It is imperative that pituitary axes other than the GH axis are tested at regular intervals, even in the absence of GHD in adulthood.
Adrenal Insufficiency↗
[Testosterone treatment of elderly men. The so called andropause doesn't exist].
Explore the source record for details and available documents.
Aged↗
Low serum insulin-like growth factor I is associated with increased risk of ischemic heart disease: a population-based case-control study.
BACKGROUND: Insulin-like growth factor I (IGF-I) has been suggested to be involved in the pathogenesis of atherosclerosis. We hypothesize that low IGF-I and high IGFBP-3 levels might be associated with increased risk of ischemic heart disease (IHD). METHODS AND RESULTS: We conducted a nested case-control study within a large prospective study on cardiovascular epidemiology (DAN-MONICA). We measured IGF-I and IGFBP-3 in serum from 231 individuals who had a diagnosis of IHD 7.63 years after blood sampling and among 374 control subjects matched for age, sex, and calendar time. At baseline when all individuals were free of disease, subjects in the low IGF-I quartile had significantly higher risk of IHD during the 15-year follow-up period, with a relative risk (RR) of 1.94 (95% CI, 1.03 to 3.66) of IHD compared with the high IGF-I quartile group, when IGFBP-3, body mass index, smoking, menopause, diabetes, and use of antihypertensives were controlled for. Conversely, individuals in the high IGFBP-3 quartile group had an adjusted RR of 2.16 (95% CI, 1.18 to 3.95) of having IHD. Identification of a high-risk population with low IGF-I and high IGFBP-3 levels resulted in markedly higher risk of IHD (RR 4.07; 95% CI, 1.48 to 11.22) compared with the index group. CONCLUSIONS: Individuals without IHD but with low circulating IGF-I levels and high IGFBP-3 levels have significantly increased risk of developing IHD during a 15-year follow-up period. Our findings suggest that IGF-I may be involved in the pathogenesis of IHD.
Adult↗
Subcutaneous abdominal adipose tissue lipolysis during exercise determined by arteriovenous measurements in older women.
OBJECTIVES: To characterize the lipolytic response in the subcutaneous abdominal adipose tissue in older women to endurance exercise. DESIGN: Cross-sectional exercise study. SETTING: Exercise laboratory, Copenhagen, Denmark. PARTICIPANTS: Seven healthy, older women (mean age +/- standard error = 75 +/- 2 years); weight: 67.8 +/- 4.9 kg; body fat: 40 +/- 3; maximal oxygen uptake (VO2max): 1.43 +/- 0.07 L.min 1). MEASUREMENTS: Body composition (dual energy x-ray absorptiometry (DEXA)), maximal oxygen uptake (VO2max, maximal cycling test), lipolytic response to exercise (arterial and adipose tissue venous catheterization at rest and during 60 minutes of continuous cycling at a load corresponding to 60 of VO2max), adipose tissue blood flow (ATBF) (133Xenon (133Xe) washout), oxygen consumption and respiratory exchange ratio during exercise (indirect calorimetry), whole blood glycerol, plasma nonesterified fatty acids (NEFA), lactate, glucose, epinephrine, norepinephrine, insulin, serum growth hormone, and hematocrit. RESULTS: Glycerol and NEFA mobilization rates increased by 250 and 180, respectively, from rest to exercise. This was achieved primarily by an increase in veno-arterial differences, because ATBF did not increase significantly. NEFA:glycerol mobilization ratio was about two at rest and remained at that level during exercise, indicating significant local reesterification in both conditions. After an initial decrease, arterial plasma NEFA concentration increased significantly, by 26, indicating that NEFA delivery exceeded muscle uptake. CONCLUSIONS: Older women are capable of prompt and substantial increase in subcutaneous abdominal adipose tissue glycerol and NEFA mobilization rates in response to moderate acute endurance exercise. The lipolytic response matches skeletal muscle NEFA uptake, and decreased ability to mobilize fat during exercise is therefore not likely to cause increased fat mass with advancing age.
Abdomen↗
Putative effects of endocrine disrupters on pubertal development in the human.
Pubertal development is regulated by gonadotrophins and sex hormones. There has been a clear secular trend in the timing of puberty during the last century, puberty becoming earlier. Although improved nutrition is assumed to be the cause, this could partly be associated with exposure to so-called endocrine disrupters. Precocious puberty has been described in several case reports of accidental exposure to oestrogenic compounds in cosmetic products, food and pharmaceuticals. Local epidemics of premature thelarche have also been suggested to be linked to endocrine disrupters. Children adopted from developing countries to industrialized countries often develop precocious puberty. Not only precocious puberty, but also delayed puberty can, theoretically, be associated with exposure to endocrine disrupters. While it is very plausible that endocrine disrupters may disturb pubertal development, there is very little research on this and, therefore, we do not yet have any clear cause-effect relationships in humans.
Adolescent↗
European audit of current practice in diagnosis and treatment of childhood growth hormone deficiency.
BACKGROUND: The present survey among members of the ESPE on current practice in diagnosis and treatment of growth hormone (GH) deficiency (GHD) is of great clinical relevance and importance in the light of the recently published guidelines for diagnosis and treatment of GHD by the Growth Hormone Research Society. We have found much conformity but also numerous discrepancies between the recommendations of the Growth Hormone Research Society and the current practice in Europe. RESULTS: We found that 80% of the pediatric endocrinologists included insulin-like growth factor I (IGF-I) in their initial evaluation of a short child suspected of having GHD, whereas only 22% used GH provocative testing alone in the initial evaluation of a short child. Sixty-eight percent confirmed the diagnosis of GHD using two separate provocative tests. In the present survey cutoff values for GH provocative testing clustered around two values; 10 ng/ml and 20 mU/l. Interestingly, these two values, differing by a factor of 2, were also the most prevalent cutoff values among those who reported their assay to be calibrated against the WHO International Reference Preparation 80/505 where the conversion factor between milligrams and milliunits is 2.6. This suggests that the selection of cutoff values is based on tradition rather than on specific GH assay characteristics. In addition, only 63% of the respondents actually knew what GH assay they were using, and only 57% knew how their GH assay was calibrated. Dosing of GH at the start of treatment was reported according to body surface by 39%, whereas 59% were dosing according to body weight. GH dose adjustment was primarily based on growth response and height during auxological assessment every 3-4 months (height velocity, change in height velocity or change in height standard deviation scores) as indicated by almost 70% of the respondents. However, dose adjustment according to body surface (38%) and body weight (44%) was also quite common. Sixty-five percent measures IGF-I regularly (at least once a year) during GH therapy in children, and to our surprise 17% reported that they adjust the GH dose according to the IGF-I levels. SUMMARY: In summary, we have found large heterogeneity in the current practice of diagnosis and treatment of childhood GHD among European pediatric endocrinologists. Especially standardizations of GH assays and cutoff values are urgently required to ensure a uniform and correct diagnosis and therapy of GHD in the future.
Adolescent↗
GH administration changes myosin heavy chain isoforms in skeletal muscle but does not augment muscle strength or hypertrophy, either alone or combined with resistance exercise training in healthy elderly men.
GH administration, either alone or combined with resistance exercise training (RT), has attracted interest as a means of increasing muscle mass and strength in the elderly. In the present study, 31 healthy, elderly men [age, 74 +/- 1 yr (mean +/- SEM)] were assigned to either RT [3 sessions/wk, 3-5 sets of 8-12 repetition maximum (RM)/session] + placebo (n = 8), RT + GH (n = 8), GH (n = 8), or placebo (n = 7) in a randomized, placebo-controlled, double-blinded (RT + placebo and RT + GH) or single-blinded (GH or placebo) design. Measurements of: 1) isokinetic quadriceps muscle strength; 2) quadriceps muscle power; 3) quadriceps muscle fiber type, size, and myosin heavy chain (MHC) composition; 4) quadriceps cross-sectional area (CSA) [nuclear magnetic resonance imaging (NMRI)]; 5) body composition (dual-energy x-ray absorptiometry scanning); and 6) GH-related serum markers were performed at baseline and after 12 wk. The final GH dose was 1.77 +/- 0.18 IU x d(-1) (approximately 7.2 +/- 0.8 microg x kg(-1) x d(-1)). GH alone had no effect on isokinetic quadriceps muscle strength, power, CSA, or fiber size. However, a substantial increase in MHC 2X isoform was observed with GH administration alone, and this may be regarded as a change into a more youthful MHC composition, possibly induced by the rejuvenating of systemic IGF-I levels. RT + placebo caused substantial increases in quadriceps isokinetic strength, power, and CSA; but these RT induced improvements were not further augmented by additional GH administration. In the RT + GH group, there was a significant decrease in MHC 1 and 2X isoforms, whereas MHC 2A increased. RT, therefore, seems to overrule the changes in MHC composition induced by GH administration alone. Changes in body composition confirmed previous reports of decreased fat mass, increased fat-free mass, and unchanged bone mineral content with GH administration. A high incidence of side effects was reported. Our results do not support a role for GH as a means of increasing muscle strength or mass, either alone or combined with RT, in healthy elderly men; although GH administration alone may induce changes in MHC composition.
Absorptiometry, Photon↗
Longitudinal study of serum placental GH in 455 normal pregnancies: correlation to gestational age, fetal gender, and weight.
Placental GH is thought to be responsible for the rise in maternal IGF-I during pregnancy and is considered to be important for fetal growth. In this prospective longitudinal study of healthy pregnant women, we investigated determinants of placental GH in maternal serum. Serum was obtained from 455 women with normal singleton pregnancies at approximately 19 and 28 wk gestation. Serum placental GH concentrations were measured by a highly specific immunoradiometric assay, and fetal size was measured by ultrasound. Data on birth weight, gender, prepregnancy body mass index (BMI), parity, and smoking habits were obtained from medical records. Serum placental GH concentrations were detectable in serum from all women as early as 14 wk gestation and increased during pregnancy in all individuals (P < 0.001). Placental GH levels at second examination were found to be higher in women carrying female fetuses [median, 9.0 ng/ml; 95% confidence interval (CI), 4.7-23.0] compared with women carrying male fetuses (median, 8.2 ng/ml; 95% CI, 3.96-19.4; P = 0.004). Similarly, the increase in placental GH between 19 and 28 wk gestation was significantly larger in female fetus bearers than in male fetus bearers (P = 0.002). Placental GH at second examination was positively correlated with gestational age (P = 0.002) and negatively correlated with prepregnancy BMI (P = 0.039). Placental GH correlated with fetal weight at approximately 28 wk gestation (P = 0.002) but did not predict birth weight at term. Our study supports the role of maternal placental GH in the regulation of fetal growth. In conclusion, we found that 1) placental GH levels correlated significantly with fetal size at 28 wk gestation; 2) GH levels were measurable in serum from all women as early as 14 wk gestation; 3) maternal prepregnancy BMI and smoking were determinants of placental GH levels, although their specific effects on the serum maternal levels of placental GH remain to be seen; and 4) women carrying female fetuses have significantly higher placental GH levels compared with women carrying male fetuses at 28 wk gestation.
Female↗
An audit of the insulin-tolerance test in 255 patients with pituitary disease.
OBJECTIVE: The insulin-tolerance test (ITT) is currently considered to be the gold standard for evaluating adults suspected of GH deficiency (GHD). The aim of this study was to determine factors that may influence nadir blood glucose (BG) when using a mean insulin dose of 0.1 IU/kg body weight. Furthermore, we wanted to evaluate the safety and GH-related aspects of the ITT. DESIGN: ITT was performed in 277 patients, of whom 255 (129 females) were eligible for evaluation. RESULTS: Multiple regression analysis, including the whole population, showed that the major determining factors for nadir BG were basal BG and body mass index (BMI) (P<0.02). No serious adverse event was recorded. Sixty-three percent of all patients tested had severe GHD with peak GH response to hypoglycaemia below 7.8 mIU/l. The positive predictive value for IGF-I was 0.82 and the negative predictive value was 0.47, using a cut-off value corresponding to -2 s.d. GH peak response to hypoglycaemia decreased with increasing numbers of other pituitary hormone deficiencies. CONCLUSIONS: When determining the dose of insulin based on weight, factors like pre-test BG and BMI should also be considered. We propose an algorithm stating that the dose of insulin should be 0.1 IU insulin/kg body weight minus 2 IU if pre-test BG is <4.0 mmol/l and minus 2 IU if BMI is <20 kg/m(2) in order to take these factors into account. Our findings furthermore support the concept that the low-dose ITT is a safe test in adults, when performed in experienced hands. It was confirmed that IGF-I is not sufficient when diagnosing GHD in adults, and reliable stimulation tests like ITT are required in the diagnosis.
Adolescent↗
Continuation of growth hormone therapy versus placebo in transition-phase patients with growth hormone deficiency: impact on body composition, insulin sensitivity, and thyroid function.
In a placebo-controlled, parallel study of 18 patients with a mean age of 20 years who had confirmed growth hormone (GH) deficiency, we evaluated body composition, insulin sensitivity, and glucose turnover at baseline (when all were receiving GH replacement); after 12 months of continued GH therapy or placebo; and after a 12-month open phase of GH therapy. In the placebo group, insulin sensitivity and fat mass increased and lipid oxidation decreased, whereas glucose oxidation increased (p <0.05). During the open phase, insulin sensitivity decreased in the former placebo group although body fat decreased and fat-free mass increased. Throughout the study, most hormonal and metabolic parameters remained unchanged in those receiving continued GH therapy. These results indicate that: 1-year discontinuation of GH therapy induces fat accumulation in GH-deficient adolescents without compromising insulin sensitivity; the beneficial effects of continued GH treatment on body composition do not fully counterbalance its direct insulin antagonistic effects; and GH replacement has favorable effects on iodothyronine metabolism and quality of life.
Adult↗
Androgens and the ageing male.
Hypogonadal men share a variety of signs and symptoms such as decreased muscle mass, osteopoenia, increased fat mass, fatigue, decreased libido and cognitive dysfunctions. Controlled trials have demonstrated favourable effects of androgen substitution therapy on these signs and symptoms in men with severe primary or secondary hypogonadism. Thus, androgen substitution therapy is warranted in men with true hypogonadism at all ages. Symptoms experienced by otherwise healthy ageing males are non-specific and vague, although some may be similar to symptoms of hypogonadism. Therefore, the term 'andropause' has been suggested. However, testosterone levels show no or only modest variation with age in men; with large prospective studies suggesting a maximal decline of total testosterone of 1.6% per year. Thus, in contrast to the sudden arrest of gonadal activity in females around menopause, men do not have an andropause. As large placebo-controlled studies of androgen treatment in elderly males are lacking, proper risk assessment of adverse effects such as prostate cancer following testosterone treatment in elderly males is completely lacking. In the future, testosterone therapy may prove beneficial in some elderly males with low-normal testosterone levels. However, at this point in time, widespread use of testosterone in an elderly male population outside controlled clinical trials seems inappropriate.
Aging↗