No influence of prednisolone on IGFBP-3 proteolysis in healthy young men.

AIMS: The impact of growth hormone (GH) and prednisolone on the GH/insulin-like growth factor (IGF) axis with special emphasis on IGF binding protein-3 (IGFBP-3) proteolysis was studied in 8 healthy adults in a double-blind cross-over study with four periods: (1) placebo; (2) s.c. GH 0.1 IU/kg/day; (3) oral prednisolone 50 mg/day, and (4) co-administration of GH and prednisolone. METHODS: Each treatment period lasted for 4 days followed by a washout period of 10 days. We measured IGF-I, IGF-II, IGFBP-1, IGFBP-2, IGFBP-3 by immunoassays, IGFBP-3 by Western ligand blotting (WLB) and finally in vitro IGFBP-3 proteolysis by a (125)I-IGFBP-3 degradation assay. RESULTS: IGF-I levels increased by 99% during GH administration and 67% during co-administration of GH and prednisolone (p < 0.0005), whereas no significant change was seen during prednisolone alone. IGFBP-1 levels decreased 55% during the prednisolone period (p < 0.002), but the between period changes were not significant (p < 0.1). IGFBP-2 decreased 33% during co-administration of GH and prednisolone (p < 0.002). IGFBP-3 increased 12% during GH and 7% during co-administration of GH and prednisolone (p < 0.003 and p < 0.03 compared to placebo, respectively), whereas prednisolone alone induced no significant changes. IGFBP-3 measured by WLB did not change significantly, neither did IGFBP-3 proteolysis. CONCLUSIONS: Prednisolone administration induces only minimal changes in circulating components of the IGF axis and is not accompanied by alterations in IGFBP-3 proteolysis. This indicates that the metabolic effects of glucocorticoids do not depend on serum IGF-I.

Lp(a) and lipids in adult Turner's syndrome: impact of treatment with 17beta-estradiol and norethisterone.

Turner's syndrome is associated with a high incidence of cardiovascular disease and hypothyreosis; conditions which are associated with abnormal lipid metabolism. To test whether alterations of lipid metabolism is present in healthy Turner's women, we compared lipids in a group of adult women with Turner's syndrome with an age matched group of healthy women. In addition the impact of sex steroid replacement therapy was studied in the women with Turner's syndrome. Patients were studied before and during treatment with hormonal replacement therapy, consisting of either oral 17beta-estradiol or transdermal 17beta-estradiol, and oral norethisterone. Control subjects were studied once in the early follicular stage of the menstrual cycle. The study group consisted of 26 (33.2+/-7.9 years) patients with Turner's syndrome and an age matched control group of 24 (32.7+/-7.6 years) normal women. Body composition measures, apolipoprotein (apo) B and apo A-I, Lp(a), cholesterol, HDL, LDL, triglycerides, thyroxine (TT4), free thyroxine (FT4), triiodothyronine (TT3), free triiodothyronine (FT3), TSH, and leptin were determined. Apo A-I levels were higher in Turner's patients (P45 g/l) Lp(a), more women with Turner's syndrome had high levels of Lp(a) than controls (P=0.024), while all other measures of lipid metabolism were comparable to controls. The level of TSH, FT3, and FT4 were significantly higher in Turner's patients, while TT4, TT3 and adjusted 24h energy expenditure were comparable to controls. Lp(a) (P=0.005), HDL (P=0.045) and apo A-I (P=0.039) decreased significantly, while there was a tendency towards a decrease in apo B (P=0.063) during treatment with sex hormones. In conclusion more women with Turner's syndrome than controls have high levels of apolipoprotein A-I and Lp(a), but only after dichomitization, while other markers of lipid metabolism are normal. Replacement therapy with female sex hormones lowered Lp(a), HDL cholesterol and apolipoprotein A-I.

Circadian variation in serum free and total insulin-like growth factor (IGF)-I and IGF-II in untreated and treated acromegaly and growth hormone deficiency.

OBJECTIVE: It is generally accepted that there is no clinically significant circadian variation in total insulin-like growth factor (IGF)-I or total IGF-II in healthy subjects. In contrast there is a significant nocturnal decrease in free IGF-I in healthy subjects, corresponding to the nocturnal increase in IGF binding protein-1. In this study we have investigated the circadian variation in circulating free IGF-I and IGF-II in patients with acromegaly and patients with adult onset growth hormone deficiency. PATIENTS: Seven acromegalic patients were studied with and without treatment with a slow-release formulation of octreotide. Seven GH-deficient patients were studied without GH replacement. In addition 5 of the GH-deficient patients were studied during GH replacement. DESIGN: Serum samples were obtained every hour for 24 h. Free IGF-I and IGF-II were measured every 2nd hour. Total IGF-I and IGF-II were measured every 2nd hour (acromegalic patients) or every 4th hour (GH deficient patients). IGF binding protein (IGFBP)-1 was measured every 2nd hour (acromegalic patients) or every hour (GH deficient patients). RESULTS: In the untreated acromegalic patients there was a significant nocturnal decrease in free IGF-I, but not free IGF-II, before treatment. During treatment there was a significant nocturnal decrease in both free IGF-I and free IGF-II. Peak values of free IGF-I were 112% and 75% above trough (treatment and withdrawal, respectively). In the GH-deficient patients there were no significant circadian variations in free IGF-I or free IGF-II in either of the two occasions. In contrast, there was a significant circadian variation of total IGF-I after adjustment for changes in plasma volume in both treated and untreated acromegaly and GH deficiency in all cases with a peak between 0300 h and 0400 h. The nocturnal increase in total IGF-I ranged from 20% to 35%. CONCLUSIONS: A significant circadian variation in free IGF-I and IGF-II was demonstrated in acromegalic patients. In contrast no significant circadian variation in free IGF-I and IGF-II was found in GH-deficient patients. Part of the variations may be due to poorly understood variations in IGF-I release. It is not clear whether and to what extent the observed circadian changes in free and total IGF-I are involved in circadian changes in IGF-I bioactivity.

Reduced androgen levels in adult turner syndrome: influence of female sex steroids and growth hormone status.

BACKGROUND AND OBJECTIVES: In girls with Turner syndrome androgen levels are reduced. In order to assess androgen status in women with Turner syndrome, we compared untreated adult women with Turner syndrome with a group of normal women. In addition, the effects of female sex hormone replacement therapy and GH status on the levels of circulating androgens in Turner syndrome was examined. DESIGN: All patients were receiving female hormone replacement therapy (HRT), which was discontinued four months prior to the initial examination. Patients were studied before and during HRT. Following the initial evaluation, patients were given cyclical HRT for six months consisting of either oral substitution (17beta-oestradiol with norethisterone from day 13-22), or transdermal oestrogen substitution (17beta-oestradiol) with 1 mg norethisterone administered orally from day 13-22. Control subjects were studied once in the early follicular stage of the menstrual cycle. SUBJECTS: The study group consisted of 27 (33.2 +/- 7.9 years) patients with Turner syndrome and an age matched control group of 24 (32.7 +/- 7.6 years) normal women. MEASUREMENTS: Body composition measures, SHBG, testosterone (T), free testosterone (FT), dihydrotestosterone (DHT), alpha-4-androstendione (A), dehydroepiandrosterone sulphate (DHEAS), 17beta-oestradiol (E2), oestrone (E1), oestrone sulphate (ES), 24 h integrated GH concentration (ICGH), insulin-like growth factor I (IGF-I), insulin-like growth factor binding protein (IGFBP-3) were determined at baseline and after six months in women with Turner syndrome, and at baseline in control women. RESULTS: Circulating levels of A, T, FT, DHT, and SHBG were reduced by 25-40% in comparison with age matched normal women. The level of DHEAS was normal. The level of E2 was undetectable and levels of E1 and ES were very low in untreated Turner women. Treatment with 17beta-oestradiol and norethisterone increased oestrogen to levels comparable to those of normal women, while further decreasing FT (P = 0.02), DHT (P = 0.04), and T (P = 0.1). In untreated women with Turner syndrome IGF-I correlated significantly with DHEAS (R = 0.503, P < 0.01), while in normal women IGF-I correlated with A (R = 0.637, P < 0.01), T (R = 0.536, P < 0.01), and FT (R = 0.700, P < 0.01). During hormonal replacement in women with Turner syndrome IGF-I correlated significantly with DHEAS (R = 0.547, P < 0.01). Employing multiple regression analysis IGFBP-3, ICGH, DHEAS and fat free mass explained 85% (adjusted R = 0.92, P < 0.0005) of the variation in the level of IGF-I in untreated Turner syndrome. In treated Turners IGFBP-3, ICGH, SHBG, T, and FT explained 78% (adjusted R = 0.88, P < 0.0005). In controls IGFBP-3, SHBG, BMI and age explained 74% (adjusted R = 0.86, P < 0.0005) of the variation in IGF-I, while GH status did not contribute at all. CONCLUSION: The present study shows that many adults with Turner syndrome have reduced levels of circulating androgens, compared with an age-matched group of normal women. Conditions associated with Turner syndrome such as increased prevalence of sexual problems, reduced bone mineral content, osteoporosis, and an increased incidence of fractures and alterations in body composition could perhaps be alleviated or abolished by substitution with a low dose of androgens. Treatment with female hormonal replacement therapy is associated with a decrease in testosterone, free testosterone and dihydrotestosterone, possibly mediated by the androgenic effect of norethisterone. Furthermore significant differences in sex steroid levels, GH status and indices of body composition can be compatible with comparable levels of IGF-I in two very different groups of individuals.

Correlation between blood glucose concentration in diabetics and noninvasively measured tissue optical scattering coefficient.

Diabetics would benefit greatly from a device capable of providing continuous noninvasive monitoring of their blood glucose levels. The optical scattering coefficient of tissue depends on the concentration of glucose in the extracellular fluid. A feasibility study was performed to evaluate the sensitivity of the tissue reduced scattering coefficient in response to step changes in the blood glucose levels of diabetic volunteers. Estimates of the scattering coefficient were based on measurements of the diffuse reflectance on the skin at distances of 1-10 mm from a point source. A correlation was observed between step changes in blood glucose concentration and tissue reduced scattering coefficient in 30 out of 41 subjects measured.

Enhancement of glomerular filtration rate and renal plasma flow by oral glucose load in well controlled insulin-dependent diabetics.

Glomerular filtration rate (GFR) and renal plasma flow (RPF) were measured in 27 patients with uncomplicated insulin-dependent diabetes (IDDM) before and after an oral glucose load of 1.1 g glucose/kg body wt. In the 18 patients showing near-normoglycaemia (blood glucose less than or equal to 8 mmol/l) before the glucose challenge the increase in blood glucose from 4.2 +/- 1.7 to 15.2 +/- 2.3 mmol/l was accompanied by an enhancement of GFR from 128 +/- 15 to 132 +/- 14 ml/min X 1.73 m2 (2p = 0.030) and of RPF from 534 +/- 116 to 562 +/- 105 ml/min X 1.73 m2 (2p = 0.023). By contrast oral glucose load to the nine patients with hyperglycaemia (greater than 8 mmol/l) during baseline conditions raising blood glucose from 11.9 +/- 2.0 to 19.6 +/- 1.5 mmol/l was accompanied by a reduction in GFR from 149 +/- 15 to 139 +/- 9 ml/min X 1.73 m2 (2p less than 0.001) while RPF was unchanged. No changes in blood pressure or urinary albumin excretion rates took place in either group. The reduction in plasma protein and in plasma growth hormone concentration were similar in the two groups. No change was seen in plasma arginine vasopressin concentration. There was no difference in the qualitative GFR response in patients with high initial GFR values (greater than or equal to 130 ml/min X 1.73 m2) as compared to patients with initial values below 130 ml/min X 1.73 m2. It is concluded that the induction of moderate hyperglycaemia in IDDM patients is followed by an enhancement of GFR and RPF-provided near-normoglycaemia before the glucose challenge.

Diurnal pattern of insulin requirements in insulin-dependent diabetics.

A total of 35 experiments in which insulin-dependent diabetics were connected to an artificial beta cell (Biostator) for feedback control of blood glucose during at least 24 h, were evaluated. Only 14 experiments, however, were available for analysis, since interruptions of more than 45 min/24 h in feedback control due to clots in analyser tubing occurred in those remaining. In these 14 experiments the 24-h insulin-infusion pattern was analysed. Basal insulin requirements (BIR), (between 01.00 and 04.00 hours) was found to be 0.178 +/- 0.044 (SD) mU/kg X min. Insulin requirements increased in the early morning (04.00-07.00 hours) to 0.231 +/- 0.084 mU/kg X min (P less than 0.01). A significant correlation between BIR and 24-h insulin requirement was found (r = 0.53, P less than 0.05). Insulin requirements per kJ following breakfast were higher than after lunch, 0.57 +/- 0.20 muU/kg X min X kJ versus 0.41 +/- 0.29 muU/kg X min X kJ (P less than 0.05).