OBJECTIVES: Patients with prolactinomas and patients with acromegaly often have heterogenous adenomas. In this study we have focused on patients with prolactinomas who developed acromegaly and acromegalic patients with hyperprolactinaemia. Our hypothesis is that some patients with hyperprolactinaemia may develop clinical acromegaly. METHODS: We have included patients examined at department M, Odense University Hospital between 1996 and 2001. Seventy-eight patients with prolactinomas, 65 females and 13 males, with a median age (range) of 30 Years (14-74) and 47 Years (20-66), respectively, were included in the study. RESULTS: In females and males the median prolactin (PRL) levels were 90 microg/l (27-4700; normal values (NV) <or=23) and 1075 microg/l (24-6500; NV <or=14), respectively. The PRL levels were significantly higher in males compared with females (P<0.002). Fifty-nine patients with acromegaly, 24 females and 35 males, with a median age (range) of 45 Years (24-70) and 53 Years (19-70), respectively, were included. Seven of the 24 females had hyperprolactinaemia, with PRL levels of 90 microg/l (27-494). Thirteen of the 35 males had hyperprolactinaemia with PRL levels of 47 microg/l (17-251). Three females with prolactinomas developed acromegaly clinically and biochemically. These patients had a normal low GH level and/or a normal IGF-I level at first diagnosis. CONCLUSIONS: Our findings suggest that there is a common group of patients with a pituitary adenoma who secrete PRL and GH unsynchronously. Some of these patients have clinical acromegaly at diagnosis and some patients diagnosed as prolactinomas will develop acromegaly. We suggest an annual IGF-I measurement as a screening test.
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M Andersen, C Hagen, J Frystyk, and HD Schroeder
J-W Chen, J Frystyk, T Lauritzen, and J S Christiansen
Objective: This study aimed to evaluate the impact of insulin antibodies on insulin aspart pharmaco-kinetics and pharmacodynamics after 12-week multiple daily injections of biphasic insulin aspart 30 (30% fast-acting and 70% protamine-crystallised insulin aspart, BIAsp30) in patients with type 1 diabetes.
Methods: Twenty-three patients (8 women, 15 men) aged 44.8 (20.6–62.5) years (median and range) with diabetes duration of 19.5 (1.6–44.6) years and haemoglobin (Hb)A1C of 9.2% (8.1–12.3%) participated in the study, which consisted of 12-week treatment with multiple injections of BIAsp30. At the end of the treatment period, all patients attended two 24-h profile days 1 week apart for pharmacokinetic and pharmacodynamic assessments. HbA1C and insulin antibodies were also determined.
Results: Patients were stratified into two groups depending on whether the level of insulin binding to insulin antibodies was below or above 75% (moderate vs high (%, median and range): 62 (15–74) vs 80 (75–89)). High levels of insulin antibodies resulted in about threefold increase in AUC(0 – 24 h) (the area under the concentration-time curve during 24 h) for total insulin aspart (analysis of variance, P < 0.05). The differences in free insulin aspart pharmacokinetics, insulin pharmacodynamics and HbA1C were not statistically significant between patients with different levels of insulin antibodies. Total daily insulin dosage was significantly lower in patients with high than moderate levels of insulin antibodies.
Conclusions: In type 1 diabetic patients, high levels of circulating insulin antibodies result in elevated total, but not free, insulin aspart profiles. Consistent with the finding of similar insulin pharmacodynamics, the long-term glycaemic control is not significantly different between patients with different levels of insulin antibodies.
Ana Pokrajac, Jan Frystyk, Allan Flyvbjerg, and Peter J Trainer
Background
Somatostatin analogues are frequently used for medical treatment of acromegaly. The rationale for their use is based on the inhibition of pituitary GH secretion; however, there is in vitro evidence that octreotide also acts to inhibit hepatic IGF1 generation.
Aim & design
We studied the pituitary-independent effects of octreotide on IGF1 generation in 11 severely GH-deficient (GHD) humans (age 38, range 23–52; seven males; body mass index 24.7±3 kg/m2; peak-stimulated GH <3 μg/l; 3±1 pituitary hormone deficiencies) on a stable dose of GH replacement (0.4±0.1 mg) for at least 6 months. Patients were studied before and after 50 μg of s.c. octreotide three times a day for 7 days.
Results
At study entry, all patients had total IGF1 within age- and gender-related reference range (SDS 0.4±1.0). Octreotide treatment resulted in a significant decrease in total IGF1 (by 18%, 208±89 vs 173±62 μg/l, P=0.04), free IGF1 (by 13%, 0.83±0.36 vs 0.70±0.33 μg/l, P=0.01) and IGFBP3 (6%, 4475±745 vs 4209±912 μg/l, P=0.02). Octreotide suppressed fasting insulin from 8.1±3.4 to 6.3±4.1 mU/l (P=0.01) and was associated with an increase in fasting glucose from 5.2±0.9 to 5.8±0.9 mmol/l (P<0.01). IGFBP1 increased by 84% from 42±26 to 95±52 μg/l (P=0.04).
Conclusion
Our study demonstrates that octreotide induces a significant decrease in IGF1 in severely GHD adults on a fixed dose of GH replacement. This is the evidence for a non-pituitary action of octreotide on the GH/IGF1 axis, most likely by antagonising the action of GH on hepatic IGF1 generation and indirectly, by suppressing insulin secretion.
C Hoybye, JM Bruun, B Richelsen, A Flyvbjerg, and J Frystyk
OBJECTIVE: Obesity and growth hormone (GH) deficiency are common in Prader-Willi syndrome (PWS) and these patients are at risk of metabolic diseases in adult life and of reduced life span. Low adiponectin values are associated with obesity and the metabolic syndrome. We therefore found it of interest to measure adiponectin levels in PWS. PATIENTS AND METHODS: 17 adults, nine men and eight women, 17 to 32 years of age, with a mean body mass index (BMI) of 35+/-3.2 kg/m2 participated. All had clinical PWS. They were randomized to treatment with placebo or GH (Genotropin) for six months, and subsequently all received GH for 12 months. At baseline, serum total adiponectin levels in the PWS patients were compared with 25 lean and 34 obese controls. Body composition and various metabolic parameters, including adiponectin, were studied every six months in the PWS group. RESULTS: Serum adiponectin levels in PWS subjects were significantly lower (P<0.001) compared with lean and significantly higher (P<0.001) compared with obese controls. In PWS patients, no correlation was found between adiponectin and anthropometrical parameters or measures of insulin sensitivity (e.g. fasting insulin and insulin sensitivity as estimated by the homeostasis model assessment), or between adiponectin and IGF binding protein-1 or IGF-I. Adiponectin did not change during GH intervention. CONCLUSION: In this study of adults with PWS serum total adiponectin levels were higher than in controls with simple obesity and were independent of anthropometrical parameters. In accordance with this the metabolic syndrome is not necessarily present in all PWS patients. Correction of GH deficiency had no effect on serum adiponectin levels.
K Yuen, N Wareham, J Frystyk, S Hennings, J Mitchell, L Fryklund, and D Dunger
OBJECTIVE: Modest elevations in circulating IGF-I levels have been suggested to protect against the development of glucose intolerance in insulin-resistant subjects. To further understand the interactions of GH and IGF-I on beta-cell function and post-load glucose tolerance in glucose-intolerant subjects predisposed to diabetes, we performed a pilot study in 12 subjects with impaired glucose tolerance and the metabolic syndrome using a low GH dose (1.7 microg/kg per day) known to increase endogenous IGF-I production. DESIGN: Fourteen daily GH or placebo injections in a double-blind cross-over study. METHODS: Baseline and post-treatment oral glucose tolerance tests were performed. The homeostasis model assessment and the insulinogenic index was used to estimate fasting insulin sensitivity (S(I)) and beta-cell function respectively, whereas changes in the incremental area under the curve were used to estimate post-load glucose tolerance (DeltaAUC(glu)) and post-load insulin levels (DeltaAUC(ins)). RESULTS: GH increased total IGF-I (P<0.02), free IGF-I (P<0.04) and fasting insulin (P<0.04) levels, but did not modify plasma IGF-binding proteins (IGFBPs)-1 and -3, fasting glucose, non-esterified fatty acid and C-peptide levels, and fasting S(I). After oral glucose intake, glucose tolerance improved (P<0.03), but post-load insulin levels and beta-cell function remained unchanged. CONCLUSION: Short-term low-dose GH administration induced fasting hyperinsulinaemia possibly by reducing insulin clearance but improved post-load glucose tolerance, suggesting that increased bioavailable IGF-I enhanced post-load S(I) without altering beta-cell function. Longer-term studies are required to ascertain whether these positive effects on post-load glucose tolerance and the preservation of beta-cell function can be sustained by this GH dose in these high-risk subjects.
C Skjaerbaek, N Vahl, J Frystyk, TB Hansen, JO Jorgensen, C Hagen, JS Christiansen, and H Orskov
The objective of the present study was to compare fasting levels of free IGF-I in serum from patients with adult onset growth hormone deficiency (GHD) and from healthy volunteers, and to examine the effect of GH replacement therapy in GHD on serum free IGF-I. Free IGF-I was measured using separation of free IGF-I by ultrafiltration in serum samples from 42 healthy volunteers and 27 patients with GHD, in the latter before and after 1 year of treatment with GH (2 IU/m2) (n = 13) or placebo (n = 14). Free IGF-I was significantly decreased in patients with GHD (700 +/- 100 ng/l (mean +/- S.E.M.), range 55-2618 ng/l) compared with controls (1010 +/- 70 ng/l, range 231-2431 ng/l; P = 0.0016). Total IGF-I was 85 +/- 10 micrograms/l (GHD) and 160 +/- 10 micrograms/l (controls) (P < 0.0001). The ratio of free over total IGF-I was increased in GHD to 0.85 +/- 0.08% compared with 0.66 +/- 0.05% in controls (P = 0.04). In both GHD and controls, free IGF-I correlated significantly (P < 0.05) with total IGF-I (GHD r = 0.78; controls r = 0.42), IGFBP-1 (GHD r = -0.67; controls r = -0.46) and the molar ratio of total IGF-I over IGFBP-3 (GHD r = 0.58; controls r = 0.62). After 1 year of GH treatment, free IGF-I was increased to 2780 +/- 320 ng/l (P = 0.003) and total IGF-I was increased to 270 +/- 30 micrograms/l (P = 0.006) both of which values were greater than those in healthy volunteers. There were no changes in free or total IGF-I in the placebo-treated group. In conclusion, levels of free IGF-I are decreased in GHD, but measurements of free IGF-I in a single, fasting serum sample do not offer a better separation of patients with GHD from individuals with normal GH status than can be achieved by measurement of total IGF-I. One year of treatment with 2IU/m2 GH caused an increase of serum free IGF-I to supraphysiological levels.
M B Snijder, A Flyvbjerg, C D A Stehouwer, J Frystyk, R M A Henry, J C Seidell, R J Heine, and J M Dekker
Objective
To investigate whether adiponectin is associated with arterial stiffness, and whether adiponectin explains the association between body composition and arterial stiffness.
Design
Cross-sectional cohort study.
Methods
Subjects were participants (n=456, mean age 68.9±6.1 years; age range 60–86 years) of the third follow-up examination of the Hoorn Study. Trunk fat, leg fat, trunk lean, and leg lean mass were measured by dual-energy X-ray absorptiometry. Ultrasound was used to measure distensibility and compliance of the carotid, femoral, and brachial arteries, and carotid Young's elastic modulus (as estimates of peripheral arterial stiffness).
Results
Trunk fat mass was negatively associated with (ln-transformed) adiponectin (standardized β=−0.49, P<0.001), while leg fat mass was positively associated with adiponectin (β=0.44, P<0.001), after adjustment for each other, age, and lean mass. After adjustment for age, sex, mean arterial pressure, and estimated glomerular filtration rate, higher adiponectin was associated with decreased peripheral arterial stiffness (β of mean Z-scores of all three arteries=0.14, P=0.001). However, the associations of trunk fat (β=−0.26, P<0.001) and leg fat (β=0.16, P=0.006) with peripheral arterial stiffness were only minimally explained by adiponectin levels.
Conclusion
Trunk fat and leg fat are oppositely associated with adiponectin. Although low adiponectin was a determinant of increased peripheral arterial stiffness, it only explained a small part of the association between body fat and peripheral arterial stiffness. This indicated that factors other than adiponectin may be more important in the pathophysiological mechanisms by which abdominal obesity leads to arterial stiffness.
L Frederiksen, K Højlund, D M Hougaard, T H Mosbech, R Larsen, A Flyvbjerg, J Frystyk, K Brixen, and M Andersen
Objective
Testosterone therapy increases lean body mass and decreases total fat mass in aging men with low normal testosterone levels. The major challenge is, however, to determine whether the metabolic consequences of testosterone therapy are overall positive. We have previously reported that 6-month testosterone therapy did not improve insulin sensitivity. We investigated the effect of testosterone therapy on regional body fat distribution and on the levels of the insulin-sensitizing adipokine, adiponectin, in aging men with low normal bioavailable testosterone levels.
Design
A randomized, double-blinded, placebo-controlled study on 6-month testosterone treatment (gel) in 38 men, aged 60–78 years, with bioavailable testosterone <7.3 nmol/l, and a waist circumference >94 cm.
Methods
Central fat mass (CFM) and lower extremity fat mass (LEFM) were measured by dual X-ray absorptiometry. Subcutaneous abdominal adipose tissue (SAT), visceral adipose tissue (VAT), and thigh subcutaneous fat area (TFA) were measured by magnetic resonance imaging. Adiponectin levels were measured using an in-house immunofluorometric assay. Coefficients (b) represent the placebo-controlled mean effect of intervention.
Results
LEFM was decreased (b=−0.47 kg, P=0.07) while CFM did not change significantly (b=−0.66 kg, P=0.10) during testosterone therapy. SAT (b=−3.0%, P=0.018) and TFA (b=−3.0%, P<0.001) decreased, while VAT (b=1.0%, P=0.54) remained unchanged. Adiponectin levels decreased during testosterone therapy (b=−1.3 mg/l, P=0.001).
Conclusion
Testosterone therapy decreased subcutaneous fat on the abdomen and lower extremities, but visceral fat was unchanged. Moreover, adiponectin levels were significantly decreased during testosterone therapy.
Jan Frystyk, Anders J Schou, Carsten Heuck, Henrik Vorum, Mikkel Lyngholm, Allan Flyvbjerg, and Ole D Wolthers
Objective
End-point bioassays based on thymidine or sulfate incorporation have demonstrated that glucocorticoid (GC) treatment inhibits serum IGF1 action, but the mechanism is unknown as serum IGF1 concentrations have been reported to either increase or remain unchanged.
Aim
To investigate whether GC treatment affects the ability of serum to activate the IGF1 receptor (IGF1R) in vitro (i.e. bioactive IGF1), using a specific cell-based IGF1 kinase receptor activation assay.
Subjects and methods
Twenty children with stable asthma (age 7.7–13.8 years) treated for 1 week with 5 mg prednisolone in a randomized, double-blind, placebo-controlled crossover study. Non-fasting serum samples were collected in the afternoon after each 7-day period and assayed for bioactive IGF1, free IGF1, total IGFs, IGF-binding proteins (IGFBPs), and insulin.
Results
Prednisolone treatment reduced IGF1 bioactivity by 12.6% from 2.22±0.18 to 1.94±0.15 μg/l (P=0.01) compared with placebo. In contrast, no changes were observed for (μg/l; placebo vs prednisolone) total IGF1 (215±27 vs 212±24), free IGF1 (1.50±0.16 vs 1.43±0.17), total IGF2 (815±26 vs 800±31), IGFBP3 (3140±101 vs 3107±95), IGFBP2 (238±21 vs 220±19), IGFBP1 (32±6 vs 42±10), or IGFBP1-bound IGF1 (24±5 vs 26±7). Insulin remained unchanged as did IGFBP levels as estimated by western ligand blotting. Prednisolone had no direct effects on IGF1R phosphorylation.
Conclusions
Our study gives evidence that GC treatment induces a circulating substance that is able to inhibit IGF1R activation in vitro without affecting circulating free or total IGF1. This may be one of the mechanisms by which GC inhibits IGF1 action in vivo. However, the nature of this circulating substance remains to be identified.