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Jens Bollerslev, Thor Ueland, Anders P Jørgensen, Kristian J Fougner, Ragnhild Wergeland, Thomas Schreiner and Pia Burman

Objective: GH deficiency is associated with an increased cardiovascular mortality. Fifty-five patients with adult-onset GH deficiency (AO-GHD) (24 female, 31 male, mean age 49 years) were enrolled in a placebo-controlled double-blind crossover study to investigate the effects of GH therapy on a variety of cardiovascular risk factors representing different aspects of atherogenesis, including apolipo-proteins (Apo A-1, Apo B), markers of subclinical inflammation (high-sensitivity C-reactive protein (CRP) and interleukin-6) and markers of endothelial function (intercellular adhesion molecule-1, von Willebrand factor and sCD40L (a pro-atherogenic factor and marker for plaque destabilization)).

Methods: GH therapy was individually dosed to obtain an IGF-I concentration within the normal range for age and sex. GH and placebo were administered for 9 months each, separated by a 4 month washout period.

Results: The final mean dose of GH was 50% higher for women and IGF-I increased to the same level in both sexes. Compared with placebo, substitution with GH showed a significant effect on Apo B (mean change −0.15 (−0.22 to −0.08) mg/l) and CRP (−1.8 (−3.3 to −0.3) mg/l). The baseline level of and change in IGF-I during treatment with GH contributed significantly to the improvement in both markers. No effects were found on interleukin-6 or Apo A-1, or on markers of endothelial function. No gender differences were observed for any of the markers at baseline or following intervention.

Conclusions: GH substitution to naïve patients with AO-GHD at a low, individually titrated dose aiming at normalizing IGF-I was followed by significant reductions in Apo B and CRP, indicating a positive effect of GH on cardiovascular risk.

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Jens Bollerslev, Jostein Hallén, Kristian J Fougner, Anders Palmstrøm Jørgensen, Cybele Kristo, Hans Fagertun, Ola Gudmundsen, Pia Burman and Thomas Schreiner

Fifty-five patients with adult-onset GH deficiency (mean age, 49 years) were enrolled in a placebo-controlled, crossover study to investigate the effects of GH therapy on exercise capacity, body composition, and quality of life (QOL). GH and placebo were administered for 9 months each, separated by a 4-month washout period. GH therapy was individually dosed to obtain an IGF-I concentration within the normal range for age and sex. The final mean daily dose of GH was 1.2 IU/day for men and 1.8 IU/day for women. Mean IGF-I concentration at baseline was higher in men than in women (95±33 vs 68±41 μg/l respectively; P < 0.04) and increased to a similar level on GH therapy. Body fat mass was reduced by 1.9±2.9 kg and lean body mass was increased by 1.8±2.8 kg (P = 0.0001 for each) with GH treatment. Total and low-density cholesterol levels decreased. Absolute maximal oxygen uptake increased by 6% (P = 0.01), relative to body weight by 9% (P = 0.004), and there was a trend toward increased endurance performance by 7% (P = 0.07). There were no significant effects on QOL. In conclusion, treatment with a low, physiologic dose of GH produced positive effects on body composition and lipids and improved exercise capacity, likely to be of clinical relevance. No changes in QOL were seen, possibly because of a good QOL at baseline.

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Einar Osland Vik-Mo, Marianne Øksnes, Paal-Henning Pedersen, Tore Wentzel-Larsen, Eyvind Rødahl, Frits Thorsen, Thomas Schreiner, Sylvi Aanderud and Morten Lund-Johansen

Objective

Gamma knife radiosurgery (GKR) can be used as primary or adjuvant therapy for the treatment of an ACTH-producing pituitary tumor after bilateral adrenalectomy, called Nelson syndrome (NS). We have examined the effect of GKR on tumor growth and ACTH-hypersecretion, and characterized the adverse events of this treatment in patients with NS.

Design

Cross-sectional follow-up study. First, retrospective data pre- and post-GKR were collected. Patients then underwent a predefined survey including radiological, endocrinological, ophthalmological, and neurosurgical evaluation.

Subjects

Ten patients treated with GKR for NS after previous bilateral adrenalectomy. The mean follow-up was 7 years. No patient was lost to follow-up.

Results

Tumor growth was stopped in all patients. The ACTH levels declined in eight patients, and normalized in one patient. There was a significant drop in ACTH levels, with a half-time of 2.8 years. No patient developed visual field defects or any other cranial nerve dysfunction as a result of treatment. Four patients started hormone substitution therapy during the follow-up period. The substitution therapy of three pituitary axes present at GKR treatment could be stopped during the same period. One patient developed a glioblastoma in the left parieto-occipital region 14 years after GKR, far from the field of treatment. As the radiation level was below 1Gy to this area, it is unlikely that the GKR treatment itself induced the malignant tumor.

Conclusion

In patients with NS, GKR is an effective adjuvant treatment, carrying relatively few adverse effects. Although the risk of developing a secondary neoplasia after GKR is present, it is probably extremely low.

Free access

Einar Osland Vik-Mo, Marianne Øksnes, Paal-Henning Pedersen, Tore Wentzel-Larsen, Eyvind Rødahl, Frits Thorsen, Thomas Schreiner, Sylvi Aanderud and Morten Lund-Johansen

Background: Gamma knife radiosurgery (GKR) is an adjuvant treatment for acromegaly if surgery fails to normalize GH hypersecretion.

Objective: To examine the effect of GKR on tumor growth and hypersecretion, and to characterize the adverse effect of this treatment.

Design: Cross-sectional follow-up study. First, retrospective data pre- and post-GKR were collected. Patients then underwent a predefined survey including radiological, endocrinological, ophthalmological, and neurosurgical evaluation.

Setting: Norwegian National Center for gamma knife treatment.

Patients: Sixty-one patients treated with GKR for acromegaly. Out of 55, 53 living patients underwent a detailed survey. The mean follow-up was 5.5 years. No patient was lost to follow-up.

Results: Tumor growth was stopped in all patients. At 3, 5, and 10 years after GKR, 45, 58, and 86% of patients had normal IGF-I levels. Consecutive hormone value analysis showed that patients receiving GH-suppressive medication had a more rapid decline in hypersecretion than those who did not receive such medication. Evaluated by survey baseline values alone, non-elevated IGF-I and GH levels below 5 mIU/l were found in 38%. GH-suppressive medication was terminated in 16 out of 40 patients following GKR. Nine out of 53 surveyed patients (17%) had normal IGF-I and GH nadir below 2.6 mIU/l at glucose tolerance tests, while not on hormone-suppressive medication. Two patients developed minor visual field defects. Eight patients started hormone substitution therapy during the follow-up period.

Conclusion: GKR is an effective adjuvant treatment for residual acromegaly, carrying few side effects.

Free access

Thomas G Papathomas, Jose Gaal, Eleonora P M Corssmit, Lindsey Oudijk, Esther Korpershoek, Ketil Heimdal, Jean-Pierre Bayley, Hans Morreau, Marieke van Dooren, Konstantinos Papaspyrou, Thomas Schreiner, Torsten Hansen, Per Arne Andresen, David F Restuccia, Ingrid van Kessel, Geert J L H van Leenders, Johan M Kros, Leendert H J Looijenga, Leo J Hofland, Wolf Mann, Francien H van Nederveen, Ozgur Mete, Sylvia L Asa, Ronald R de Krijger and Winand N M Dinjens

Objective

Although the succinate dehydrogenase (SDH)-related tumor spectrum has been recently expanded, there are only rare reports of non-pheochromocytoma/paraganglioma tumors in SDHx-mutated patients. Therefore, questions still remain unresolved concerning the aforementioned tumors with regard to their pathogenesis, clinicopathological phenotype, and even causal relatedness to SDHx mutations. Absence of SDHB expression in tumors derived from tissues susceptible to SDH deficiency is not fully elucidated.

Design and methods

Three unrelated SDHD patients, two with pituitary adenoma (PA) and one with papillary thyroid carcinoma (PTC), and three SDHB patients affected by renal cell carcinomas (RCCs) were identified from four European centers. SDHA/SDHB immunohistochemistry (IHC), SDHx mutation analysis, and loss of heterozygosity analysis of the involved SDHx gene were performed on all tumors. A cohort of 348 tumors of unknown SDHx mutational status, including renal tumors, PTCs, PAs, neuroblastic tumors, seminomas, and adenomatoid tumors, was investigated by SDHB IHC.

Results

Of the six index patients, all RCCs and one PA displayed SDHB immunonegativity in contrast to the other PA and PTC. All immunonegative tumors demonstrated loss of the WT allele, indicating bi-allelic inactivation of the germline mutated gene. Of 348 tumors, one clear cell RCC exhibited partial loss of SDHB expression.

Conclusions

These findings strengthen the etiological association of SDHx genes with pituitary neoplasia and provide evidence against a link between PTC and SDHx mutations. Somatic deletions seem to constitute the second hit in SDHB-related renal neoplasia, while SDH x alterations do not appear to be primary drivers in sporadic tumorigenesis from tissues affected by SDH deficiency.