Marie Degerblad

Adrenocorticotropic hormone-producing pituitary tumors: 12- to 22-year follow-up after treatment with stereotactic radiosurgery.

OBJECTIVETo study retrospectively long-term outcomes of patients with adrenocorticotropic hormone-producing pituitary tumors that were treated with stereotactic Leksell gamma knife unit radiosurgery. METHODSEighty-nine patients aged 5 to 67 years were treated between 1976 and 1985. Eighteen patients aged 18 to 68 years (mean age, 41 yr) were followed in detail. Fifteen patients were women. None had previously received conventional radiotherapy, but pituitary microsurgery had been performed in two patients, and one patient had had an adrenalectomy. In the remaining 15 patients, radiosurgery was the primary therapy. RESULTSSixty-four patients had one stereotactic treatment, and 25 patients had two or more treatments. No complications were observed during treatment and the immediate follow-up period. At follow-up, 17 patients had died 1 to 20 years after the first treatment. No deaths were related to the treatment. In our 18 patients, the follow-up time after the first radiosurgical treatment was 12 to 22 years (mean follow-up period, 17 yr). Urinary cortisol levels gradually normalized in 83% of the patients. No recurrences were observed. Pituitary hormone insufficiencies developed in about two of every three patients and occurred even more than 10 years after treatment. Eight patients had transient hyperprolactinemia. The patients’ vision and visual fields were unaffected, and none of them had signs of radiation-induced side effects such as brain tumors or brain necrosis. CONCLUSIONStereotactic radiosurgery is a safe and effective method in the treatment of patients with adrenocorticotropic hormone-producing pituitary tumors, and the effect of treatment is long-lasting. Stereotactic radiosurgery is mainly a complement to microsurgery because of its gradually appearing effect and the occurrence of pituitary insufficiency. New pituitary deficiencies may be found more than 10 years after treatment.

Serum Levels of Insulin-like Growth Factor Binding Proteins (IGFBP)–4 and –5 Correlate with Bone Mineral Density in Growth Hormone (GH)–Deficient Adults and Increase with GH Replacement Therapy†

Adults with growth hormone deficiency (GHD) exhibit low bone mineral density (BMD) which improves by growth hormone (GH) replacement therapy. The insulin‐like growth factor (IGF) system has an established role in mediating the effects of GH on bone and IGF binding proteins (IGFBP)‐4 and IGFBP‐5 have been shown to modulate the effects of IGFs in bone. Therefore, we studied serum levels of IGFBP‐4 and IGFBP‐5 and their relationship to serum levels of bone biochemical markers and BMD in adults with GH deficiency (GHD) before and during GH therapy. Serum levels of IGFBP‐5 and IGFBP‐4 were measured on samples from 20 patients (11 males) 22–57 years of age. All had IGF‐I serum values below –2 standard deviation score. The first 6 months were placebo controlled and all recieved 3 years of active treatment with the mean dose 0.23 ± 0.01 IU/kg/week divided into daily subcutaneous injections. Serum IGFBP‐5 levels in GHD adults were low at baseline and positively related to total body, femoral neck, trochanter, and Wards triangle BMD (r = 0.471, 0.549, 0.462, and 0.470, respectively, p < 0.05). The mean serum IGFBP‐5 level increased by about 2‐fold within 3 months after the initiation of GH therapy and was correlated with serum IGF‐I (r = 0.719, 0.801, and 0.722 before and after 18 and 36 months, respectively, p < 0.001). A positive correlation between serum IGFBP‐5 levels and lumbar spine BMD was found during GH treatment but not before. The percentage increase of serum IGFBP‐5 after GH therapy showed a positive correlation with the percentage increase of total alkaline phosphate activity (r = 0.347 p < 0.05). In contrast to IGFBP‐5, serum IGFBP‐4 levels were positively related to body mass index (r = 0.607, p < 0.01). Baseline serum IGFBP‐4 levels also correlated with total body, femoral neck, trochanter, and Wards triangle BMD (r = 0.502, 0.590, 0.612, and 0.471, respectively, p < 0.05). The mean serum IGFBP‐4 level was increased by 25% within 3 months after initiation of GH therapy and did not correlate with serum IGF‐I levels. Although the above findings are consistent with the idea that GH‐induced changes in serum IGFBP‐5 and IGFBP‐4 levels may in part mediate the anabolic effects of GH on bone tissue in adults with GHD, further studies are needed to establish the cause and effect relationship.

Different Responses of Bone Alkaline Phosphatase Isoforms During Recombinant Insulin‐like Growth Factor‐I (IGF‐I) and During Growth Hormone Therapy in Adults with Growth Hormone Deficiency

We studied serum bone alkaline phosphatase (ALP) isoforms and other markers of bone turnover in growth hormone–deficient (GHD) adults (n = 22). The patients were followed during 1 week of insulin‐like growth factor‐I (IGF‐I) administration, 40 μg/kg of body weight/day (n = 6), and during 24 months of growth hormone (GH) therapy, 0.125 IU/kg of body weight/week for the first month, and then 0.250 IU/kg of body weight/week (n = 20). Six ALP isoforms were separated and quantified by high‐performance liquid chromatography: one bone/intestinal, two bone (B1, B2), and three liver ALP isoforms. At baseline, the mean levels of B1, B2, and osteocalcin were higher in GHD adults than in healthy adults. After 1 week of IGF‐I administration and 1 month of GH therapy, only B1 was decreased. We suggest that the initial decrease of B1 during GH therapy could be an effect of endocrine IGF‐I action mediated by GH. After 3 months of GH therapy, both B1 and B2 increased as compared with placebo. Osteocalcin, carboxy‐terminal propeptide of type I procollagen (PICP), cross‐linked carboxy‐terminal telopeptide of type I collagen (ICTP), and urinary pyridinoline cross‐links/creatinine ratio increased during GH therapy. PICP increased significantly before bone ALP and osteocalcin, indicating an early stimulation of type I collagen synthesis as previously demonstrated by in vitro models. Different responses of the bone ALP isoforms during IGF‐I and during GH therapy suggest different regulations in vivo.

The role of gamma knife radiosurgery in the management of pituitary adenomas

No treatment modality has been entirely successful in the management of pituitary adenomas. Although most patients with pituitary microadenomas can be cured by transsphenoidal surgery, the results are less satisfactory in macroadenomas in particular with suprasellar and/or parasellar extension. Additional treatment is then called for. Conventional fractional radiotherapy can often control tumour growth but is limited to 45–50 Gy with a very slow reduction in elevated pituitary hormones and a high incidence of pituitary insufficiency. Stereotactic radiosurgery allows the delivery of radiation with high precision to the target with low doses to the surrounding tissues permitting higher radiation doses. Gamma knife radiosurgery using photon energy with gamma beams from multiple cobalt 60 radiation sources is now used in many centers. It can be carried out in an outpatient setting with one single treatment. A more rapid normalization of pituitary hormone hypersecretion than with conventional radiation can be achieved as well as arrest of tumour growth and reduction of tumour mass. We therefore consider gamma knife radiosurgery as a valuable compliment to pituitary surgery. Long-term prospective studies are needed to evaluate the frequency of pituitary insufficiency in patients where the target area is determined with stereotactic magnetic resonance imaging (MRI).

No Effect of High-Dose Vitamin D Treatment on β-Cell Function, Insulin Sensitivity, or Glucose Homeostasis in Subjects With Abnormal Glucose Tolerance: A Randomized Clinical Trial

OBJECTIVE There has been conflicting evidence regarding the potential role of vitamin D in glucose homeostasis. This study was designed to investigate the effect of high-dose vitamin D3 treatment on β-cell function, insulin sensitivity, and glucose tolerance in subjects with prediabetes or diet-treated type 2 diabetes. RESEARCH DESIGN AND METHODS Subjects (n = 44) were randomized to 30,000 IU vitamin D3 once weekly or placebo for 8 weeks. Hyperglycemic clamp assessed first-phase (0–12 min) and second-phase (12–120 min) insulin response, insulin sensitivity, and disposition index (DI). An oral glucose tolerance test assessed glucose tolerance and glycosylated hemoglobin assessed glycemic control. RESULTS A total of 21 (vitamin D) and 22 (placebo) subjects completed the study, respectively. Season-adjusted 25-OH-vitamin D [25(OH)D] levels were doubled in the active treated group (43–82 nmol/L). No effect of vitamin D treatment, compared with placebo, was seen on first-phase or second-phase insulin secretion. There were no group differences in insulin sensitivity, DI, or any measures of glycemic control. No hypercalcemia or other adverse effects of vitamin D treatment were seen compared with placebo. Subgroup analyses of those with the lowest basal and greatest increase in 25(OH)D levels did not change these results. CONCLUSIONS This study gives no support for any substantial effect of high-dose vitamin D treatment for 8 weeks in prediabetes or diet-treated type 2 diabetes on β-cell function, insulin sensitivity, or glycemic control.

The hypothalamus–pituitary function after pituitary stereotactic radiosurgery: evaluation of growth hormone deficiency

Abstract.  Degerblad M, Brismar K, Rähn T, Thorén M (Karolinska Hospital, Stockholm, Sweden). The hypothalamus–pituitary function after pituitary stereotactic radiosurgery: evaluation of growth hormone deficiency. J Intern Med 2003; 253: 454–462.

Different Isoforms of Bone Alkaline Phosphatase Exist

We welcome the letter written by Drs. Bianda and Schmid, which offers us an opportunity to emphasize the awareness of the two main bone alkaline phosphatase (ALP) isoforms (B1 and B2) and our findings of isoform changes during short-term (1 week) insulin-like growth factor I (IGF-I) and long-term (24 months) growth hormone (GH) therapy in GH-deficient (GHD) adults. We agree that bone ALP isoforms probably do not increase after short-term IGF-I or GH administration in GHD adults. We did not measure any markers of bone turnover until after 1 month of GH therapy. We did, however, find a decrease of the bone ALP isoform B1 after the short-term IGF-I administration. A decrease was also found of B1 after 1 month of GH therapy, followed by an increase after 3 months. The other bone ALP isoform, B2, was not influenced by the IGF-I administration but was increased after 3 months of GH therapy. Several commercially available ALP assays show good correlations with each other in serum samples from healthy adults. However, differences between assays have previously been reported in samples from patients with Paget’s disease and in children during the pubertal growth spurt, probably due to the different bone ALP isoforms. Selective differences between the bone ALP isoforms have previously been described during the pubertal growth spurt and in disease states such as hypophosphatasia, hypophosphatemic vitamin D–resistant rickets, Paget’s disease, stress fractures, and in metastatic bone disease. We do not agree with Bianda and Schmid on the statement that “the conflicting data concerning ALP are not due to different technologies for determination of serum ALP.” In our opinion, it is necessary to compare different bone ALP assays by analyzing serum from well-defined patient groups, e.g., GHD. We reported a mean activity of B1 in the GHD group, 0.62 mkat/l, which was higher than the upper reference interval level, 0.60 mkat/l. This observation and our findings of decreased bone ALP isoform B1 activities during short-term IGF-I administration cannot be detected by the commonly used bone ALP assays but requires a sensitive high-performance liquid chromatography assay specific for the isoforms of bone ALP. The antibodies used by Bianda and Schmid in the immunoradiometric assay were raised against bone ALP from SAOS-2 cells. These cells express more of the bone ALP isoform B2 in relation to the B1 isoform (unpublished observations). These antibodies

Improvement of insulin sensitivity in response to exercise training in type 2 diabetes mellitus is associated with vascular endothelial growth factor A expression

Purpose: Insulin sensitivity changes in response to exercise training demonstrate a large variation. Vascular endothelial growth factor A could promote increased insulin sensitivity through angiogenesis. We investigated associations between changes in expression of key genes and insulin sensitivity, aerobic capacity and glycaemic control following exercise training in diabetes mellitus type 2. Methods: Subjects with diabetes mellitus type 2 underwent 12 weeks of structured exercise. Euglycaemic clamp, exercise test and HbA1c were performed. Muscle biopsies were obtained for mRNA expression. Results: A total of 16 subjects completed the study. Change in vascular endothelial growth factor A expression was positively associated with an increase in insulin sensitivity (p = 0.004) and with a decrease in HbA1c (p = 0.034). Vascular endothelial growth factor A receptor-1 expression showed similar associations. Conclusion: The variation in physical adaptation to exercise training in diabetes mellitus type 2 was associated with changes in expression of vascular endothelial growth factor A in muscle. This difference in induced gene expression could contribute to the variation in exercise training effects on insulin sensitivity. Measures of capillary blood flow need to be assessed in future studies.