Independent association between insulin-like growth factor-I and dehydroepiandrosterone sulphate in women in middle adulthood

OBJECTIVE: The age-related decrease in circulating dehydroepiandrosterone sulphate (DHEAS) and insulin-like growth factor (IGF)-I levels is suggested to be involved in various age-related changes. As both hormones are regulated differently, by ACTH and GH, respectively, reasons for the almost parallel changes of their circulating levels during ageing remain unknown. The objectives of this study were to verify variables that influence serum IGF-I as well as DHEAS levels in subjects in middle adulthood. SUBJECTS AND METHODS: We determined serum DHEAS and IGF-I levels in 362 Japanese subjects aged 30-65 years (225 men and 137 women) undergoing health examinations, who had no hepatic disease, renal disease, malignant disease, diabetes mellitus, or asthma. Variables influencing DHEAS and IGF-I were analysed. RESULTS: DHEAS as well as IGF-I levels were higher in men than in women. DHEAS was positively associated with IGF-I and negatively with age, in both men and women. By multivariate regression analysis, age was negatively associated with DHEAS in both men and women. IGF-I was found to be independently associated with DHEAS in women. Age was the only negative independent factor for IGF-I in both men and women, while DHEAS was the only positive independent factor in women. CONCLUSIONS: The present study demonstrates that DHEAS and IGF-I levels are associated with each other, independent of age, in women in middle adulthood.     

Relationships between environmental changes, maturity, growth rate and plasma insulin-like growth factor-I (IGF-I) in female rainbow trout

Size reflecting growth rate, energy balance or nutritional status is regarded as an important determinant of the ability of trout to undergo puberty. The relationship of a change in photoperiod, either natural (SNP) or advancing (ADV), with growth, IGF-I and reproduction was investigated in virgin female rainbow trout. Under SNP 63% of the population attained maturity while only 29% spawned 6 months in advance in the ADV regime. Under SNP both size and growth rate in late spring-early summer appeared to determine whether an individual may initiate reproduction while condition factor appeared to be a better predictor in the ADV regime. A complete seasonal relationship between plasma IGF-I, daylength and temperature was demonstrated under natural conditions, and provides direct evidence for the relationship between reproduction and IGF-I. Conversely, trout maintained under ADV exhibited a significantly different plasma IGF-I profile relative to those under a natural photoperiod. Furthermore, IGF-I levels accurately reflected growth rate prior to elevations in sex steroids, suggesting that IGF-I may provide an endocrine signal between the somatotropic and reproductive axes that growth rate and/or size is sufficient to initiate gonad development. In addition, maturing individuals under SNP typically expressed higher circulating IGF-I levels than those that remained immature and may reflect a greater opportunity for IGF-I to act on the pituitary to stimulate gonadotropin production. We observed elevated levels in maturing fish for 3 months under SNP compared to only 1 month under ADV were observed. This may reflect a reduction in the window of opportunity to initiate reproduction under advancing photoperiods and hence explain the reduction in fish successfully recruited.     

The relationship between insulin-like growth factor-I, adiposity, and aging

Aging is associated with both a relative accumulation of body fat and a reduction in growth hormone (GH) secretion. This study was devised to investigate the relationship between plasma insulin-like growth factor-I (IGF-I), an index of GH secretion, and anthropometric indices of body fat in normal subjects of various ages. Somatic and biochemical indices of nutrition were assessed in 107 subjects between the ages of 17 and 83 years who attended an outpatient clinic for general health supervision. Plasma IGF-I correlated negatively with age in both males (r = -.44, P = .001) and females (r = -.40, P = .005). In addition, plasma IGF-I correlated negatively with body mass index (BMI) (r = .35, P = .006), percentage of standard triceps skinfold (TSF) (r = -.26, P = .05), and percentage of standard weight (r = -.35, P = .006) in males, but not in females. Multiple regression analysis indicated that in males, BMI and percentage of standard weight correlated with plasma IGF-I independent of the effect of age. We conclude that adiposity and aging are independently associated with decreased plasma IGF-I concentrations. The negative correlations between indices of adiposity and IGF-I were observed only in males, whereas the age-associated decline in IGF-I was present in both males and females. We speculate that sex differences in the gonadal steroid milieu, combined with declining GH secretion in both sexes, may contribute to the age-associated development of obesity in males.     

Relationship between serum leptin and the insulin-like growth factor-I system in humans.

The growth hormone (GH)/insulin-like growth factor-I (IGF-I) system and leptin both play an important role in the regulation of body composition. Although the regulation of these two hormonal systems by insulin has been under intense investigation, the physiologic interactions between leptin and the GH/IGF-I system remain unknown. In this study, we examined the relationships among circulating leptin and key elements of the IGF-I system in 60 subjects (27 nondiabetic lean, 21 nondiabetic obese, and 12 type 1 diabetic subjects) with a wide range of insulin secretory capacity. Leptin, glucose, insulin, free IGF-I, total IGF-I, IGF-binding protein-1 (IGFBP-1), and IGFBP-3 levels were measured in the basal state after an overnight fast, and the acute insulin response to glucose (AIRG) was determined after intravenous glucose injection. AIRG was significantly higher (P < .01) in the obese (3,365+/-562 pmol/L x min) versus lean subjects (1,624+/-155 pmol/L x min). In simple regression analysis, the serum leptin concentration was positively correlated with the body mass index ([BMI] men, r = .51, P = .005; women, r = .71, P < .001), IGFBP-3 (men, r = .20, P = nonsignificant; women, r = .41, P < .025), and AIRG (men, r = .73, P < .001; women, r = .62, P < .01). There was a nonlinear correlation between leptin and IGFBP-1, but there was no correlation between leptin and free or total IGF-I. In multiple regression analysis with leptin as the dependent variable, gender, BMI, and IGFBP-3 entered the equations at a statistically significant level. The correlation of leptin with IGFBP-3 was independent of obesity and persisted after correction for AIRG, suggesting a link between leptin and GH action.     

Plasma dehydroepiandrosterone sulphate and insulin-like growth factor I levels in obstructive sleep apnoea syndrome

Context We aimed to assess whether obstructive sleep apnoea syndrome (OSAS) affects plasma IGF‐1 and dehydroepiandrosterone sulphate (DHEA‐S) levels in men, factors implicated in the development of age‐related metabolic disorders. Design We conducted a cross‐sectional and longitudinal clinical study. Patients and setting We measured plasma IGF‐1 and DHEA‐S levels in 191 non–drug‐treated Japanese men (34 primary snorers (PS), 88 patients with mild‐to‐moderate OSAS and 69 patients severe OSAS ). Results Plasma IGF‐1 and DHEA‐S were negatively correlated with age. Plasma IGF‐1 was also negatively correlated with plasma glucose, HOMA‐IR and systolic blood pressure and apnoea parameters such as the apnoea–hypopnea index, minimum oxygen saturation and slow‐wave sleep (SWS) time. Plasma DHEA‐S was associated with plasma glucose, HbA1c and free fatty acid and was negatively correlated with SWS time. To eliminate the influence of age, PS, patients with mild‐to‐moderate OSAS and severe OSAS were divided into three groups by age: young (<40 years), middle‐aged (40–59 years) and elderly (≥60 years). Patients with severe OSAS aged <40 or <60 years had lower plasma IGF‐1 or DHEA‐S levels, respectively, than did the corresponding snorers and mild‐to‐moderate OSAS groups. Continuous positive airway pressure therapy for generally 16–18 months increased plasma IGF‐1 levels in patients with severe OSAS aged <40 years (n = 18). Plasma DHEA‐S levels were increased in patients with severe OSAS aged <60 years, whose DHEA‐S level was below the mean value for that age (n = 23/41). Conclusion Severe OSAS could reduce plasma IGF‐1 and DHEA‐S levels in younger, but not elderly Japanese men, which is potentially associated with the development of metabolic abnormalities.     

Cortisol, dehydroepiandrosterone sulphate and dehydroepiandrosterone sulphate/cortisol ratio responses to physical stress in males are influenced by pubertal development

To evaluate the influence of chronological age and pubertal development on the hypothalamus-pituitary-adrenal (HPA) axis response to stress, we studied the possible correlations between male pubertal characteristics and salivary cortisol (C), DHEAS and the DHEAS/C ratio before (pre-stress) and after acute exercise-stress in young male volunteers (no. 87; 13.3+/-2.1 yr). In our overall study population, the mean pre-stress salivary C and DHEAS concentrations, significantly increased after exercise-related stress, whereas the DHEAS/C ratio significantly decreased. Pre-stress salivary C was positively correlated with chronological age, and after-stress salivary C concentration variations were negatively correlated with pubertal stage, mean testis volume and pre-stress salivary DHEAS. Furthermore, salivary DHEAS concentrations and the DHEAS/C ratio, before and after exercise stress, were positively correlated with chronological age, pubertal stage, pre-stress salivary testosterone (T), testis volume and body mass index (BMI). In contrast with late pubertal stages (P4, P5), young individuals at early stages of puberty (P1 to P3) showed higher C increase and lower DHEAS/C ratio after exercise-related stress. In conclusion, since C is also a mediator of stress-related negative effects on health and the DHEAS/C ratio has been hypothesized as an index for the degree to which an individual is buffered against the negative effects of stress, these data might suggest potentially increased stress-related risks at early stages of male puberty.     

The association between insulin-like growth factor-I and cardiac repolarization

ObjectivePrevious studies reported associations between insulin-like growth factor I (IGF-I) serum concentration and cardiac morbidity and mortality, but the association between IGF-I serum concentration and cardiac repolarization has not been investigated in a population-based study so far. Therefore, we analyzed the impact of IGF-I concentrations on QTc, QT and RR intervals in two population based studies, The Study of Health in Pomerania (SHIP) and the Rotterdam Study.Design457 individuals from SHIP and 155 individuals from the Rotterdam Study older than 55 years and without cardiovascular diseases and a left ventricular hypertrophy were investigated. IGF-I was determined by automated two-site chemiluminescence immunoassays and electrocardiograms were recorded by an ACTA electrocardiograph at a sampling frequency of 500 Hz. The association of IGF-I with QTc, QT and RR intervals was investigated by multivariable linear regression analyses adjusted for age, gender, diabetes mellitus, myocardial infarction, hypertension, body mass index, serum potassium and calcium in both studies separately and in pooled analysis.ResultsThere were no significant associations between log-transformed IGF-I and QTc interval in the single populations, whereas a significant inverse association was detectable in the pooled population (β, ? 15.6; 95%-confidence interval, ? 25.7, ? 5.5). The QTc interval was significantly higher in the first tertile of IGF-I compared to the third tertile (β, 5.4; 95%-confidence interval, 9.5–1.3) in the pooled analysis.ConclusionThe inverse association between IGF-I serum concentrations and QTc interval in our study is suggestive of a higher risk for cardiac arrhythmias and thus might provide additional evidence for increased cardiovascular mortality in subjects with low IGF-I secretion.     

Physical activity and dehydroepiandrosterone sulphate, insulin-like growth factor I and testosterone in healthy active elderly people.

OBJECTIVE: to examine the association of physical activity and cardio-respiratory fitness with dehydroepiandrosterone sulphate (DHEAS), insulin-like growth factor I (IGF-I) and testosterone in healthy elderly people. DESIGN: cross-sectional study. SETTING: university research department and department of geriatric medicine. PARTICIPANTS: 60 independent, community-dwelling elderly subjects (26 men and 34 women) aged 66-84 who volunteered to participate. MEASUREMENTS: physical activity was evaluated by the Questionnaire d'Activité Physique Saint-Etienne and expressed by three indices: mean habitual daily energy expenditure (MHDEE), daily energy expenditure (DEE) [comprising activities with intensities corresponding to at least three metabolic equivalents (MET; 3.5 ml.kg1 x min1 of oxygen consumption)] and sport activity. Cardio-respiratory fitness was expressed by maximal oxygen consumption (VO2max). RESULTS: In women, DHEAS correlated with VO2max (partial correlation: r=0.33; P=0.05), MHDEE (r=0.50; P=0.002), DEE > 3 METs (r=0.49; P=0.003) and sport activity (r=0.35; P=0.04) whereas IGF-I correlated with MHDEE (r=0.48; P=0.004). DHEAS was correlated with IGF-I (r=0.43; P < 0.02) and with testosterone (r=0.41; P < 0.02). No such correlation was found in men. CONCLUSION: lower habitual physical activity is related to lower levels of circulating DHEAS and IGF-I independently of age and anthropometric measures. Lower maximal aerobic capacity is associated with lower DHEAS concentrations, in healthy elderly women.     

Glucose metabolism, insulin-like growth factor-I, and insulin-like growth factor-binding protein-1 after alcohol withdrawal

Alcohol abusers often present with deteriorated glucose metabolism and insulin resistance. Changes in other glucoregulators, such as insulin-like growth factor-I (IGF-I) and IGF-binding protein-1 (IGFBP-1) may also be related to alcohol abuse. We studied the effects of alcohol withdrawal on blood glucose, serum insulin and C-peptide, and plasma IGF-I and IGFBP-1 levels in 27 noncirrhotic male alcoholics aged 43 +/- 9.0 (mean +/- SD) years on four consecutive days immediately after withdrawal. A 4-day monitoring period was conducted in four healthy nonalcoholic control men. The groups were similar in age and body mass index. Glucose, insulin, IGF-I, and IGFBP-1 did not differ significantly between the groups at the baseline, but C-peptide was higher in alcoholics (p < 0.01). After alcohol withdrawal, serum insulin and C-peptide levels increased in close correlation with each other (r = 0.82, p < 0.001). During the 4-day observation period in alcoholics, IGFBP-1 levels declined by 59%, whereas IGF-I increased by 41% (p < 0.001 for both comparisons). The change in insulin correlated inversely with the change in IGFBP-1 levels (r = -0.39, p < 0.05). In the control group, glucose, insulin, IGF-I, and IGFBP-1 remained unchanged during the 4-day monitoring period, whereas some reduction was observed in C-peptide. In conclusion, alcohol withdrawal enhances insulin production, as seen in increased C-peptide levels. An inverse correlation between the changes in insulin and that in IGFBP-1 might suggest that inhibition of IGFBP-1 by insulin remains largely unchanged during the acute phase of alcohol withdrawal.     

Serum insulin-like growth factor-I, insulin-like growth factor binding proteins, and bone mineral content in hyperthyroidism.

The mechanism by which thyroid hormones promote bone growth has not yet been elucidated. In vitro, thyroid hormones stimulate insulin-like growth factor-I (IGF-I) production by osteoblasts, which is important for the anabolic effects of the hormone on bone. To determine whether the IGF-I/IGF binding protein (IGFBP) profile is affected when thyroid hormone production is altered in vivo, we studied 36 women who had recently been diagnosed with hyperthyroidism (age: 29-67 years; 19 with Graves' disease, 17 with toxic nodular goiter) and 36 age-matched healthy women as controls. Serum IGF-I, and its binding proteins (IGFBP-3, IGFBP-4, and IGFBP-5), as well as bone mineral density (BMD) at the lumbar spine, femoral neck, and radius midshaft were measured before and 1 year after antithyroid (methimazole) treatment. Serum IGF-I levels were significantly increased in the hyperthyroid patients before treatment (214 +/- 18.2 ng/mL vs. 145 +/- 21.3 ng/mL; p < 0.05). There was no difference in IGF-I levels of patients with Graves' disease and toxic nodular goiter. Serum IGF-I concentrations returned to normal after treatment with methimazole. Serum IGFBP-3 and IGFBP-4 values were significantly elevated in the hyperthyroid group before treatment (3960 +/- 220 ng/mL and 749.7 +/- 53.1 ng/mL vs. 2701 +/- 180 ng/mL and 489.9 +/- 32.4 ng/mL; p < 0.05 and p < 0.01, respectively) and were reduced to those of controls after treatment. Serum IGFBP-5 of hyperthyroid subjects was not different from that of controls either before or after therapy. Serum free thyroxine showed a positive correlation with serum levels of IGF-I (r = 0.73, p < 0.05), IGFBP-3 (r = 0.59, p < 0.05), and IGFBP-4 (r = 0.67, p < 0.05) but not IGFBP-5. BMD at the radius midshaft was significantly lower in hyperthyroid patients at the start of the study and showed a positive correlation with serum IGF-I (r = 0.58; p < 0.001) and a negative correlation with IGFBP-4 (r = -0.61; p < 0.05). Radius BMD showed a 7.2% increase in the hyperthyroid group after 1 year of methimazole treatment, and the correlation between BMD and serum IGF-I disappeared. Our data indicate that thyroid hormones may influence the IGF-I/IGFBP system in vivo in hyperthyroidism. The anabolic effects of increased levels of IGF-I may be limited in hyperthyroidism due to the increases of inhibitory IGFBPs that can counteract the anabolic effects and contribute to the observed net bone loss.     

Involvement of insulin-like growth factor-I and insulin-like growth factor binding proteins in pro-B-cell development

OBJECTIVE: Insulin-like growth factor (IGF)-binding proteins (IGFBPs) are a family of proteins thought to modulate IGF function. By employing an in vitro culture system of human hematopoietic stem cells cocultured with murine bone marrow stromal cells, we examined the effects of IGF-I and IGFBPs on early B-cell development. MATERIALS AND METHODS: Human CD34(+) bone marrow cells were cocultured with murine stromal MS-5 cells for 4 weeks, and pro-B-cell number was analyzed by flow cytometry. After administration of reagents that are supposed to modulate IGF-I or IGFBP function to the culture, the effect on pro-B-cell development was examined. RESULTS: After cultivation for 4 weeks, effective induction of pro-B-cell proliferation was observed. Experiments using several distinct factors, all of which neutralize IGF-I function, revealed that impairment of IGF-I function results in a significant reduction in pro-B-cell development from CD34(+) cells. In addition, when the effect of recombinant proteins of IGFBPs and antibodies against IGFBPs were tested, IGFBP-3 was found to inhibit pro-B-cell development, while IGFBP-6 was required for pro-B-cell development. CONCLUSIONS: IGF-I is essential for development of bone marrow CD34(+) cells into pro-B cells. Moreover, IGFBPs are likely involved in regulation of pro-B-cell development.     

Relations between sex hormones, sex hormone binding globulin, insulin-like growth factor-I and insulin-like growth factor binding protein-I in post-menopausal breast cancer patients

OBJECTIVE Oestrogens, androgens and anti-endocrine drugs such as tamoxifen and aminoglutethimide influence plasma Insulin-like growth factor-I (IGF-I). IGF-I, in turn, has been found to stimulate the peripheral aromatase in vitro. The aim of this study was to examine relations between sex hormones, IGF-I and insulin-like growth factor binding protein-1 (IGFBP-1) In post-menopausal women with breast cancer. DESIGN To measure plasma sex steroids, sex hormone binding globulin (SHBG), IGF-I, IGFBP-1, Insulin and urinary oestrogen metabolites In post-menopausal women with breast cancer not receiving any endocrine therapy. PATIENTS Thirty-two patients had fasting blood samples obtained between 0800 and 1000h. A sub-group of 10 patients had 24-hour urine oestrogen metabolites determined. MEASUREMENTS Plasma steroids and proteins were measured by radioImmunoassays. Urinary oestrogens were measured by GC-MS. RESULTS SHBG correlated negatively with plasma androstenedione (P < 0·001), insulin (P < 0·001), IGF-I, height and plasma oestrone sulphate (P < 0·025 for all), but positively with plasma IGFBP-1 (P < 0·025). IGFBP-1 correlated negatively with IGF-I (P < 0·001) and the testosterone/SHBG ratio (P < 0·05). Neither IGF-I nor IGFBP-1 correlated with any of the plasma or urinary sex hormones or with the oestrone/androstenedione and oestradiol/testosterone ratios. Multivariate analysis revealed plasma SHBG to correlate positively with IGFBP-1 (P= 0·029) and negatively with Insulin (P= 0·031). Plasma IGFBP-1 correlated negatively with IGF-I (P < 0·0001) but not with insulin. CONCLUSION Our results do not suggest any influence of plasma sex steroids in physiological concentrations on IGF-I or IGFBP-1 in post-menopausal breast cancer patients, nor do they indicate IGF-I at physiological concentrations Influences the ratios between plasma oestrogens and their androgen precursors.     

Changes in concentrations of cortisol, dehydroepiandrosterone sulphate and progesterone in fetal and maternal serum during pregnancy

OBJECTIVE: In fetuses, adrenal steroids have been implicated in organ maturation and in some species in initiation of labour. The fetal adrenal gland differs from the adult in its complement of steroid metabolizing enzymes. This study sought to examine the changes in peripheral cortisol, progesterone and dehydroepiandrosterone sulphate (DHEAS) in unstressed fetuses during pregnancy. DESIGN: Paired maternal and fetal samples were collected from 47 patients. Fetal blood samples were collected by transabdominal needling. All fetuses were appropriately grown for age which ranged from 18 to 41 weeks. MEASUREMENTS: Hormones were measured using specific, validated immunoassays. RESULTS: Fetal progesterone (mean, 822 nmol/l; 95% data intervals 196-1449 nmol/l) varied considerably between individuals but there was no significant change in serum concentration with gestational age, nor was there any difference between male and female fetuses. There was a small, but significant (y = 0.339x2 - 13.5x + 231; r = 0.72, P = 0.0001) rise in cortisol in the fetal circulation from 32 to 41 weeks gestational age, whereas the mean fetal DHEAS concentration decreased linearly with gestational age from 4.1 mumol/l at 18 weeks to 2.6 mumol/l at 41 weeks (r = -0.41; P = 0.007). Mean progesterone concentration in the maternal serum increased linearly from 98 nmol/l at 18 weeks to 783 nmol/l at 41 weeks. In the fetus there was a significant correlation between progesterone and cortisol concentrations. CONCLUSIONS: These results are compatible with the proposed role of cortisol in fetal lung maturation, confirm high levels of progesterone in the fetus from an early stage of gestation, and provide further evidence for placental progesterone being the precursor of fetal cortisol.     

Treatment with growth hormone and insulin-like growth factor-I in critical illness

The wider availability of recombinant human growth hormone and insulin-like growth factor-I has resulted in an investigation into the potential benefits of the pharmacological administration of these anabolic peptides in a variety of clinical conditions, characterized by an increase in catabolic rate. The initial studies were small, often uncontrolled open investigations, but investigators have more recently concentrated on larger, controlled multi-centre trials. Studies to date have included patients with cardiac failure, sepsis, burns, cancer cachexia, end-stage renal failure, trauma and AIDS, and those prior to or following major surgery. The authors have in general cautiously interpreted positive effects of treatment with growth hormone and insulin-like growth factor-I, either alone or in combination, on net protein balance, body composition, well-being and performance. Two large, randomized, placebo-controlled European multi-centre studies have recently detailed the effects of growth hormone treatment in critically ill intensive care patients. Major increases in mortality and morbidity were associated with growth hormone treatment. The mechanism(s) accounting for the increased mortality remain poorly understood. These negative findings have led to a decrease in the clinical use of growth hormone and in research activity in the area of anabolic treatment in human illness.     

New concepts: growth hormone, insulin-like growth factor-I and the kidney.

Both growth hormone (GH) and IGF-1 have major effects on normal kidney growth, structure and function and participate in the pathogenesis of certain kidney diseases. Furthermore when the kidneys fail there are profound changes in the circulating GH-IGF-1 system and the renal and systemic responses to these hormones. In this brief review we address the advances that have been made in our understanding of the relationship between growth hormone GH and IGF-1 and the kidney in health and the systemic and local perturbations that occur in kidney disease and identify key unanswered questions.     

Dissociated recovery of cortisol and dehydroepiandrosterone sulphate after treatment for Cushing's syndrome.

We have studied the variation of ACTH, cortisol and DHEA-S plasma levels in 6 patients before and up to 15 months after surgical remission of Cushing's syndrome in order to compare the relative dependency of cortisol and adrenal androgens towards ACTH. Three patients with adrenal adenoma were treated by unilateral adrenalectomy. Three other patients with Cushing's disease underwent transsphenoidal pituitary tumorectomy. Preoperative ACTH was undetectable in patients with adrenal adenoma and high-normal or elevated in patients with Cushing's disease. All patients became rapidly hypocortisolemic after surgery and ACTH and cortisol levels eventually recovered at different intervals. Patients with adrenal adenoma had an initially low DHEA-S which failed to normalize for the entire follow-up period. Patients with Cushing's disease had normal or high-normal DHEA-S which became low immediately after surgery, following ACTH decrease, and it remained low during the entire follow-up period. In conclusion, after removal of corticotropic inhibition secondary to excess cortisol, DHEA-S remains suppressed for a longer period of time than cortisol. Moreover it only takes a short period of relatively low ACTH (after pituitary tumor excision) to induce a long lasting DHEA-S inhibition. Therefore the DHEA-S secreting adrenal cells seem to be more sensitive to the lack of corticotropic stimulation than cortisol secreting cells.