Assessment of wear and periacetabular osteolysis using dual energy computed tomography on a pig cadaver to identify the lowest acceptable radiation dose.

OBJECTIVES: Computed tomography (CT) plays an important role in evaluating wear and periacetabular osteolysis (PAO) in total hip replacements. One concern with CT is the high radiation exposure since standard pelvic CT provides approximately 3.5 millisieverts (mSv) of radiation exposure, whereas a planar radiographic examination with three projections totals approximately 0.5 mSv. The objective of this study was to evaluate the lowest acceptable radiation dose for dual-energy CT (DECT) images when measuring wear and periacetabular osteolysis in uncemented metal components. MATERIALS AND METHODS: A porcine pelvis with bilateral uncemented hip prostheses and with known linear wear and acetabular bone defects was examined in a third-generation multidetector DECT scanner. The examinations were performed with four different radiation levels both with and without iterative reconstruction techniques. From the high and low peak kilo voltage acquisitions, polychrmoatic images were created together with virtual monochromatic images of energies 100 kiloelectron volts (keV) and 150 keV. RESULTS: We could assess wear and PAO while substantially lowering the effective radiation dose to 0.7 mSv for a total pelvic view with an accuracy of around 0.5 mm for linear wear and 2 mm to 3 mm for PAO. CONCLUSION: CT for detection of prosthetic wear and PAO could be used with clinically acceptable accuracy at a radiation exposure level equal to plain radiographic exposures.Cite this article: B. Sandgren, M. Skorpil, P. Nowik, H. Olivecrona, J. Crafoord, L. Weidenhielm, A. Persson. Assessment of wear and periacetabular osteolysis using dual energy computed tomography on a pig cadaver to identify the lowest acceptable radiation dose. Bone Joint Res 2016;5:307-313. DOI: 10.1302/2046-3758.57.2000566.

Three-dimensional movements of the lumbar spine facet joints and segmental movements: in vivo examinations of normal subjects with a new non-invasive method.

INTRODUCTION: Examination with CT and image registration is a new technique that we have previously used to assess 3D segmental motions in the lumbar spine in a phantom. Current multi-slice computed tomography (CT) offers highly accurate spatial volume resolution without significant distortion and modern CT scanners makes it possible to reduce the radiation dose to the patients. Our aim was to assess segmental movement in the lumbar spine with the aforementioned method in healthy subjects and also to determine rotation accuracy on phantom vertebrae. MATERIAL AND METHOD: The subjects were examined in flexion-extension using low dose CT. Eleven healthy, asymptomatic subjects participated in the current study. The subjects were placed on a custom made jig which could provoke the lumbar spine into flexion or extension. CT examination in flexion and extension was performed. The image analysis was performed using a 3D volume fusion tool, registering one of the vertebrae, and then measuring Euler angles and distances in the registered volumes. RESULTS: The mean 3D facet joint translation at L4-L5 was in the right facet joint 6.1 mm (3.1-8.3), left facet joint 6.9 mm (4.9-9.9), at L5-S1: right facet joint 4.5 mm (1.4-6.9), and for the left facet joint 4.8 mm (2.0-7.7). In subjects the mean angles at the L4-L5 level were: in the sagittal plane 14.3°, coronal plane 0.9° (-0.6 to 2.8), and in the transverse plane 0.6° (-0.4 to 1.5), in the L5-S1 level the rotation was in sagittal plane 10.2° (2.4-16.1), coronal plane 0° (-1.2 to 1.2), and in the transverse plane 0.2° (-0.7 to 0.3). Repeated analysis for 3D facet joint movement was on average 5 mm with a standard error of mean of 0.6 mm and repeatability of 1.8 mm (CI 95%). For segmental rotation in the sagittal plane the mean rotation was 11.5° and standard error of mean 1°. The repeatability for rotation was 2.8° (CI 95%). The accuracy for rotation in the phantom was in the sagittal plane 0.7°, coronal plane 1°, and 0.7 in the transverse plane. CONCLUSION: This method to assess movement in the lumbar spine is a truly 3D method with a high precision giving both visual and numerical output. We believe that this method for measuring spine movement is useful both in research and in clinical settings.

Computed tomography analysis of radiostereometric data to determine flexion axes after total joint replacement: application to the elbow joint.

Kinematic analysis for in vivo assessment of elbow endoprostheses requires knowledge of the exact positions of motion axes relative to bony landmarks or the prosthesis. A prosthesis-based reference system is required for comparison between individuals and studies. The primary aim of this study was to further develop an earlier described algorithm for fusion of radiostereometric analysis (RSA) data and data obtained in 3D computed tomography (CT) for application to the elbow after total joint replacement. The secondary aim was to propose a method for marking of prostheses in 3D CT, enabling definition of a prosthesis-based reference system. Six patients with elbow endoprostheses were investigated. The fusion of data made it possible to visualize the motion axes in relation to the prostheses in the 3D CT volume. The differences between two repeated positioning repetitions of the longitudinal prosthesis axis were less than 0.6 degrees in the frontal and sagittal planes. Corresponding values for the transverse axis were less than 0.6 degrees in the frontal and less than 1.4 degrees (in four out of six less than 0.6 degrees ) in the horizontal plane. This study shows that by fusion of CT and RSA data it is possible to determine the accurate position of the flexion axes of the elbow joint after total joint replacement in vivo. The proposed method for implant marking and registration of reference axes enables comparison of prosthesis function between patients and studies.

A potential means of improving the evaluation of deformity corrections with Taylor spatial frames over time by using volumetric imaging: preliminary results.

OBJECTIVE: In this study we explore the possibility of accurately and cost-effectively monitoring tibial deformation induced by Taylor Spatial Frames (TSFs), using time-separated computed tomography (CT) scans and a volume fusion technique to determine tibial rotation and translation. MATERIALS AND METHODS: Serial CT examinations (designated CT-A and CT-B, separated by a time interval of several months) of two patients were investigated using a previously described and validated volume fusion technique, in which user-defined landmarks drive the 3D registration of the two CT volumes. Both patients had undergone dual osteotomies to correct for tibial length and rotational deformity. For each registration, 10 or more landmarks were selected, and the quality of the fused volume was assessed both quantitatively and via 2D and 3D visualization tools. First, the proximal frame segment and tibia in CT-A and CT-B were brought into alignment (registered) by selecting landmarks on the frame and/or tibia. In the resulting "fused" volume, the proximal frame segment and tibia from CT-A and CT-B were aligned, while the distal frame segment and tibia from CT-A and CT-B were likely not aligned as a result of tibial deformation or frame adjustment having occurred between the CT scans. Using the proximal fused volume, the distal frame segment and tibia were then registered by selecting landmarks on the frame and/or tibia. The difference between the centroids of the final distal landmarks was used to evaluate the lengthening of the tibia, and the Euler angles from the registration were used to evaluate the rotation. RESULTS: Both the frame and bone could be effectively registered (based on visual interpretation). Movement between the proximal frame and proximal bone could be visualized in both cases. The spatial effect on the tibia could be both visually assessed and measured: 34 mm, 10 degrees in one case; 5 mm, 1 degrees in the other. CONCLUSION: This retrospective analysis of spatial correction of the tibia using Taylor Spatial Frames shows that CT offers an interesting potential means of quantitatively monitoring the patient's treatment. Compared with traditional techniques, modern CT scans in conjunction with image processing provide a high-resolution, spatially correct, and three-dimensional measurement system which can be used to quickly and easily assess the patient's treatment at low cost to the patient and hospital.

Model studies on segmental movement in lumbar spine using a semi-automated program for volume fusion.

OBJECTIVE: To validate a new non-invasive CT method for measuring segmental translations in lumbar spine in a phantom using plastic vertebrae with tantalum markers and human vertebrae. MATERIAL AND METHODS: One hundred and four CT volumes were acquired of a phantom incorporating three lumbar vertebrae. Lumbar segmental translation was simulated by altering the position of one vertebra in all three cardinal axes between acquisitions. The CT volumes were combined into 64 case pairs, simulating lumbar segmental movement of up to 3 mm between acquisitions. The relative movement between the vertebrae was evaluated visually and numerically using a volume fusion image post-processing tool. Results were correlated to direct measurements of the phantom. RESULTS: On visual inspection, translation of at least 1 mm or more could be safely detected and correlated with separation between the vertebrae in three dimensions. There were no significant differences between plastic and human vertebrae. Numerically, the accuracy limit for all the CT measurements of the 3D segmental translations was 0.56 mm (median: 0.12; range: -0.76 to +0.49 mm). The accuracy for the sagittal axis was 0.45 mm (median: 0.10; range: -0.46 to +0.62 mm); the accuracy for the coronal axis was 0.46 mm (median: 0.09; range: -0.66 to +0.69 mm); and the accuracy for the axial axis was 0.45 mm (median: 0.05; range: -0.72 to + 0.62 mm). The repeatability, calculated over 10 cases, was 0.35 mm (median: 0.16; range: -0.26 to +0.30 mm). CONCLUSION: The accuracy of this non-invasive method is better than that of current routine methods for detecting segmental movements. The method allows both visual and numerical evaluation of such movements. Further studies are needed to validate this method in patients.

A new computed tomography-based radiographic method to detect early loosening of total wrist implants.

BACKGROUND: Diagnosis of loosening of total wrist implants is usually late using routine radiographs. Switching modality to computed tomography (CT) should aid in early diagnosis. PURPOSE: To propose and evaluate the accuracy of a new CT method for assessing loosening of the carpal component in total wrist arthroplasty. MATERIAL AND METHODS: A protocol encompassing volume registration of paired CT scans of patients with unexplained pain in a prosthetically replaced wrist (used in clinical routine) is presented. Scans are acquired as a dynamic examination under torsional load. Using volume registration, the carpal component of the prosthesis is brought into spatial alignment. After registration, prosthetic loosening is diagnosed by a shift in position of the bones relative to the prosthesis. This study is a preclinical validation of this method using a human cadaverous arm with a cemented total wrist implant and tantalum markers. Seven CT scans of the arm were acquired. The scans were combined into 21 pairs of CT volumes. The carpal component was registered in each scan pair, and the residual mismatch of the surrounding tantalum markers and bone was analyzed both visually and numerically. RESULTS: The detection limit for prosthetic movement was less than 1 mm. CONCLUSION: The results of this study demonstrate that CT volume registration holds promise to improve detection of movement of the carpal component at an earlier stage than is obtainable with plain radiography.

Fusion of radiostereometric analysis data into computed tomography space: application to the elbow joint.

Improvement of joint prostheses is dependent upon information concerning the biomechanical properties of the joint. Radiostereometric analysis (RSA) and electromagnetic techniques have been applied in previous cadaver and in vivo studies on the elbow joint to provide valuable information concerning joint motion axes. However, such information is limited to mathematically calculated positions of the axes according to an orthogonal coordinate system and is difficult to relate to individual skeletal anatomy. The aim of this study was to evaluate the in vivo application of a new fusion method to provide three-dimensional (3D) visualization of flexion axes according to bony landmarks. In vivo RSA data of the elbow joint's flexion axes was combined with data obtained by 3D computed tomography (CT). Results were obtained from five healthy subjects after one was excluded due to an instable RSA marker. The median error between imported and transformed RSA marker coordinates and those obtained in the CT volume was 0.22 mm. Median maximal rotation error after transformation of the rigid RSA body to the CT volume was 0.003 degrees . Points of interception with a plane calculated in the RSA orthogonal coordinate system were imported into the CT volume, facilitating the 3D visualization of the flexion axes. This study demonstrates a successful fusion of RSA and CT data, without significant loss of RSA accuracy. The method could be used for relating individual motion axes to a 3D representation of relevant joint anatomy, thus providing important information for clinical applications such as the development of joint prostheses.

Standard orientation of the pelvis: validation on a model and ten patients.

PURPOSE: To validate an image post-processing method for re-orienting the pelvis in CT volumes to a standardized orientation in a model and in 10 patients. MATERIAL AND METHODS: Twenty-four CT volumes of a pelvic model and 10 pairs of postoperative total hip arthroplasty (THA) patient CT scans were rotated to a defined pelvic standard orientation and the rotation was recorded. For precision, a test-retest procedure was used. For accuracy, three exactly represented coordinate points were used. For clinical application, the standard orientation was used for calculating the direction of acetabular cup migration from a previous model study. RESULTS: Precision of pelvic standard orientation, calculated as maximal directional error, was better than 1 degrees in the model study and better than 1.5 degrees in the patient study. Accuracy, expressed as angle between ideal and measured coordinate axes, was 0.1 degrees for x, y, z axes. No measurable systematic errors were found. When applied to acetabular cup migration in the model, standardization of pelvic orientation had no significant effect on the measurements. CONCLUSION: Reorienting the pelvis during image post-processing was shown to be accurate. It enables measurements relative to the pelvis and minimizes the dependency of patient positioning.

Assessing wear of the acetabular cup using computed tomography: an ex vivo study.

PURPOSE: To validate a clinically useful method for measuring acetabular cup wear using computed tomography (CT). MATERIAL AND METHODS: Eight uncemented acetabular cups were scanned twice ex vivo using CT. The linear penetration depth of the femoral component head into the cup and the thickness of the remaining polyethylene liner were measured in the CT volumes using dedicated software. Two independent examiners twice assessed each volume. The CT measurements were compared to direct measurements using a coordinate measuring device and micrometer measurements. RESULTS: Accuracy of wear measurements expressed as penetration depth was +/-0.6 and +/- 1.0 mm for the two examiners, respectively, with no significant differences between examiners, trials, and CT scans. Accuracy of measurements of remaining polyethylene was +/- 1.3 and +/- 1.0 mm, respectively, for the two examiners. Systematic differences between examiners were found, but no significant differences between trials and CT scans. These differences were due to different interpretations of metal artifacts in the volumes. CONCLUSION: The proposed CT method for evaluating wear as head penetration depth allows for reliable wear detection at a clinically relevant level. Measurements of remaining polyethylene on CT volumes are not as reliable as wear measurements owing to metal artifacts.

Stability of acetabular axis after total hip arthroplasty, repeatability using CT and a semiautomated program for volume fusion.

PURPOSE: To validate a CT method for detecting changes in acetabular cup orientation after THA. MATERIAL AND METHODS: 26 CT examinations were obtained from a pelvic model with an uncemented acetabular cup. The model position was altered between acquisitions, but the cup axis angle vis-à-vis the pelvis was maintained. Data sets were combined into 37 pairs, each containing a unique positioning error. The pelvi in different examinations were fused, creating transformed volumes. Landmarks corresponding to the cup before and after fusion were placed interactively by two independent examiners. The orientation of the acetabular axis was calculated for each volume and compared across volumes. RESULTS: Before fusion the mean angle error between the acetabular axes was 4.17 degrees (SD +/- 1.95 degrees ). After fusion the mean angle error was 0.36 degrees (SD +/- 0.17). The 95% repeatability limits were below 0.7 degrees. There was no significant interobserver difference. Analysis of the cup landmarking pattern by condition numbers and individual landmark errors showed stability. CONCLUSION: Non-invasive fusion of CT volumes and a stable landmarking pattern for the acetabular cup outperforms routine plain radiography in detecting changes in the orientation of the acetabular axis over time. The method delivers both visual and numerical output and could be used in clinical practice.

Model studies on acetabular component migration in total hip arthroplasty using CT and a semiautomated program for volume merging.

PURPOSE: Validation of a non-invasive CT method for detection of acetabular cup migration after total hip arthroplasty in a phantom study. MATERIAL AND METHODS: 26 CT examinations were obtained of a pelvic model while altering the position of the acetabular cup. Using a previously described program for volume merging, the pelvi in different examinations were fused and the 3D alterations of the position of the acetabular cup were evaluated visually and numerically and correlated to direct measurements on the model. RESULTS: Visually, two independent examiners differentiated between 0, 1 and 2 to 3 mm migration with 100% specificity and sensitivity. Numerically, the mean error over all cases between model and CT measurements was 0.04 mm (SD +/- 0.33). The mean absolute error between model and CT data was 0.26 mm (SD +/- 0.19). Intra- and interobserver 95% accuracy and repeatability limits were below 0.5/0.7 mm, respectively. No significant interobserver difference occurred. The data were normally distributed and not dependent on observer. CONCLUSION: The accuracy of this non-invasive method out-performs routine plain radiography. The method gives both visual and numerical correlates to migration and can be used in clinical practice.

Distribution of genetic variants in preneoplastic areas of colorectal tumours.

AIMS: Loss of heterozygosity (LOH) may vary almost randomly within a colorectal tumour due to the heterogeneous morphologic character of these tumours. Despite this, as a rule, single biopsies are the source of genetic material used in studies of markers important for prognosis, clinical behaviour of the disease, or susceptibility of specific tumours to different treatment modalities. METHODS: To evaluate the importance of intratumoural variation for the results of analysis of LOH and point mutations in colorectal cancer and to determine the frequency of genetic alterations in different types of pre-neoplastic areas of the tumours, 36 consecutively operated patients with colorectal cancer were studied. After fixation, specimens were mounted on large slides containing the whole tumour. The specimens were sub classified into different areas defined as normal tissue, normal tissue closely adjacent the tumour mass, adenoma, dysplasia and invasive cancer cells. These areas were dissected and subjected to DNA extraction. RESULTS: The extracted genomic DNA was studied for LOH at chromosome 5q, 17p, and 18q and for k-ras mutations. Overall, a correlation between the intratumoural degree of neoplastic progression and the frequency of LOH and k-ras mutations was seen. These correlations were significant (p<0.008) except for dysplasia/adenomatous tissue versus invasive cancer. Microsatellite instability was found in 9% of the tumours, all except one in invasive parts of the tumours. CONCLUSIONS: This study demonstrates a statistical correlation between intratumoural differences in neoplastic degree of dedifferentiation and genetic instability in terms of LOH and point mutations of the k-ras gene in colorectal carcinoma. The importance of a careful dissection in order to localise the region with the highest probability of genetic aberrations and multiple biopsing must not be neglected. The observation that the prevalence of k-ras mutations and LOH are correlated to the degree of dedifferentiation within a colorectal tumour is in line with the concept that selected cell clones are responsible for the neoplastic progression of the tumour.

Spatial component position in total hip arthroplasty. Accuracy and repeatability with a new CT method.

PURPOSE: 3D detection of centerpoints of prosthetic cup and head after total hip arthroplasty (THA) using CT. MATERIAL AND METHODS: Two CT examinations, 10 min apart, were obtained from each of 10 patients after THA. Two independent examiners placed landmarks in images of the prosthetic cup and head. All landmarking was repeated after 1 week. Centerpoints were calculated and compared. RESULTS: Within volumes, all measurements of centerpoints of cup and head fell, with a 95% confidence, within one CT-voxel of any other measurement of the same object. Across two volumes, the mean error of distance between center of cup and prosthetic head was 1.4 mm (SD 0.73). Intra- and interobserver 95% accuracy limit was below 2 mm within and below 3 mm across volumes. No difference between intra- and interobserver measurements occurred. A formula for converting finite sets of point landmarks in the radiolucent tread of the cup to a centerpoint was stable. The percent difference of the landmark distances from a calculated spherical surface was within one CT-voxel. This data was normally distributed and not dependent on observer or trial. CONCLUSION: The true 3D position of the centers of cup and prosthetic head can be detected using CT. Spatial relationship between the components can be analyzed visually and numerically.

Acetabular component migration in total hip arthroplasty using CT and a semiautomated program for volume merging.

PURPOSE: To develop a non-invasive method for detection of acetabular cup migration after total hip arthroplasty (THA) with a higher degree of accuracy than routine plain radiography. MATERIAL AND METHODS: Two CT examinations, 10 min apart, were obtained from each of 10 patients that had undergone THA. Using an in-house developed semiautomated program for volume merging, the pelves in the two examinations were fused and the acetabular cup was visually and numerically evaluated to test the method's accuracy in detecting migration. RESULTS: In the visual evaluation of the best match a 1-mm translation of the cup was detectable. The numerical evaluation, comparing landmarks placed in the images of the acetabular cup and the head of the femur component in the two examinations, showed the mean difference in orientation of acetabular axes to be 2.5 degrees, the mean distance between centre of cup face to be 2.5 mm and the mean distance between centre of the head of the prosthetic femoral component to be 1 mm. CONCLUSION: This method has a significantly higher accuracy than routine plain radiography in detecting acetabular cup migration and could be used in clinical practice. It gives both a visual and a numerical correlate to migration.

GH is a regulator of IGF2 promoter-specific transcription in human liver.

The regulation of the insulin-like growth factor-II gene (IGF2) is complex and involves the usage of four promoters resulting in different 5' untranslated regions, but with a common translated product. The IGF2 gene product is a mitogenic and survival factor that has been suggested to be important for a normal fetal development and cancer. In this paper we present evidence suggesting that the human IGF2 gene is regulated by GH, and that this regulation occurs in a promoter-specific way. Three lines of evidence support this finding. First, in vivo data from patients treated with GH (one injection or daily injections for 5 consecutive days) showed an increase in the IGF2 P2 promoter derived transcript after acute treatment, and of the P4 promoter transcript after short-term treatment while the P1 promoter derived transcript did not show any significant change. Secondly, isolated human liver cells treated with GH for 2 h displayed an upregulation of the P2 promoter derived transcript. Thirdly, employing transfection experiments in GH-receptor positive CHO cells with P2 and P4 promoter-luciferase constructs, an upregulation by GH was evident, while a P1 promoter construct was unresponsive. We suggest that GH may be a physiological regulator of IGF2 in humans.

Allelic loss is heterogeneous throughout the tumor in colorectal carcinoma.

BACKGROUND: Loss of heterozygosity (LOH) at 17p and 18q in colorectal carcinoma has been depicted as a potential prognostic marker for the disease. However, conclusions vary among reports, and evidence of clinically useful genetic prognostic markers is still lacking. As a rule, single biopsies are used. In this study, the authors hypothesized that an important cause of earlier contradictory results was the heterogeneity of colorectal neoplasms. METHODS: In this study, DNA originating in each quadrant of tumors from 64 patients with colorectal carcinoma was analyzed. Microsatellite markers for chromosome 18q and 17p were amplified by polymerase chain reaction and automatically analyzed. RESULTS: The authors found that, regardless of stage, LOH and non-LOH in both 17p and 18q varied among biopsies within the tumors in a random fashion. LOH in 18q was detected in all 4 quadrants in 22% and in 1 of 4, 2 of 4, or 3 of 4 quadrants in 56% of the tumors, whereas 22% of the tumors were homogeneously without LOH in 18q. LOH 17p was distributed similarly throughout the tumors and was present in 1 of 4, 2 of 4, or 3 of 4 of the quadrants in 44%. The authors also reexamined a subset of tumors by subdividing one biopsy from each into four. Analysis of the microsatellite markers then yielded identical results. No correlation between the degree of LOH status and patient survival was observed. CONCLUSIONS: LOH status within a colorectal tumor is extensively heterogeneous. However, it is more homologous on a lower macroscopic level. For relevant genetic analysis, multiple biopsies and DNA sampling preceded by careful morphologic examination must be standard in the preparation of DNA.

Depression of liver protein synthesis during surgery is prevented by growth hormone.

This study was undertaken to elucidate the specific effects of growth hormone (GH) on liver protein metabolism in humans during surgery. Otherwise healthy patients scheduled for elective laparoscopic cholecystectomy were randomized into controls (n = 9) or pretreatment with 12 units of GH for 1 day (GH 1, n = 9) or daily for 5 days (GH 5, n = 10). The fractional synthesis rate of liver proteins, as assessed by flooding with [2H5]phenylalanine, was higher in the GH 5 group (22.0 +/- 6.9%/day, mean +/- SD, P < 0.05) than in the control (16.1 +/- 3.1%/day) and GH 1 (16.5 +/- 5.5%/day) groups. During surgery, the fraction of polyribosomes in the liver, as assessed by ribosome analysis, decreased in the control group by approximately 12% (P < 0.01) but did not decrease in the GH-treated groups. In addition, the concentrations of the essential amino acids and aspartate in the liver decreased in response to GH treatment. In conclusion, GH pretreatment decreases hepatic free amino acid concentrations and preserves liver protein synthesis during surgery.

Acute and short-term effects of growth hormone on insulin-like growth factors and their binding proteins: serum levels and hepatic messenger ribonucleic acid responses in humans.

We investigated the acute (4-5 h) and short-term (5 days) effects of GH treatment on hepatic messenger RNA (mRNA) levels of the genes for the insulin-like growth factors (IGFs), insulin-like growth factor binding protein-1, -2, and -3 (IGFBPs), and the acid labile subunit (ALS), as well as serum levels of these proteins in humans. At the mRNA level, we observed an increase in IGF-1 transcription (+173%) following GH treatment in the acute group, which remained elevated in the short-term treatment group. IGFBP-2 mRNA decreased after short-term GH treatment, without changes in IGFBP-1 or -3 expression. The ALS transcript level increased after 5 days. In serum, we found increased levels of IGF-I and insulin, and decreased levels of IGF-II, in the short-term treatment group. IGFBP-1 decreased in both treatment groups, whereas IGFBP-2 was reduced after 5 days treatment. ALS increased in the short-term group. We observed increased IGFBP-3 serum levels after 5 days of GH treatment, likely due to increased formation of the ternary complex. Our results show that the metabolic effects by GH on the IGF axis are complex. In addition to a direct stimulation of IGF-I and ALS expression, GH inhibits IGFBP-1 serum levels and IGFBP-2 expression in an indirect manner, possibly facilitating enhanced IGF bioavailability to target tissues.

Regulation of rat hepatic low density lipoprotein receptors. In vivo stimulation by growth hormone is not mediated by insulin-like growth factor I.

Growth hormone (GH) has an important role in the regulation of hepatic LDL receptor expression and plasma lipoprotein levels. This investigation was undertaken to evaluate if these effects of GH on hepatic LDL receptors are direct or mediated by insulin-like growth factor I (IGF-I). Two models were studied in which substitution with GH is important for the regulation of hepatic LDL receptors: hypophysectomized rats receiving high-dose ethynylestradiol or challenge with dietary cholesterol. The hypophysectomized rats were hormonally substituted by infusion with dexamethasone and L-thyroxine, and either GH or IGF-I. In both models, GH was essential for maintaining normal expression of LDL receptors. In contrast, despite fully normalized plasma levels, IGF-I did not support the expression of hepatic LDL receptors. Analysis of plasma lipoproteins revealed that substitution with GH, but not with IGF-I, reduced LDL and intermediate density lipoproteins. In addition, determination of hepatic mRNA levels for apo B-100 and apo B-48 indicated that GH may be more effective than IGF-I in the promotion of apo B mRNA editing. In conclusion, GH has specific effects on hepatic LDL receptor expression and plasma lipoprotein levels that are not mediated by IGF-I.

Hormonal regulation of serum lipoprotein(a) levels. Contrasting effects of growth hormone and insulin-like growth factor-I.

In response to treatment with growth hormone, serum levels of lipoprotein(a) increase, while those of LDL cholesterol decrease. To establish if increased levels of insulin-like growth factor-I may be of importance for these changes, we analyzed serum lipoprotein concentrations in 11 male patients with idiopathic osteoporosis who were treated with growth hormone (2 IU.m-2.d-1) or insulin-like growth factor-I (80 micrograms.kg-1.d-1) in a randomized, double-blind, cross-over study. LDL cholesterol was reduced by 0.7 mmol/L (P < .01) during growth hormone treatment but was not affected when the same patients received insulin-like growth factor-I. In contrast, mean lipoprotein(a) levels increased from 519 to 571 mg/L (P < .03) in response to growth hormone but were reduced from 538 to 478 mg/L (P < .04) during treatment with insulin-like growth factor-I. These results indicate that growth hormone exerts its effects on lipoprotein metabolism independent of insulin-like growth factor-I. Furthermore, the results suggest that treatment with insulin-like growth factor-I may reduce lipoprotein(a) levels.