Ferdinand Roelfsema

High prevalence of long‐term cardiovascular, neurological and psychosocial morbidity after treatment for craniopharyngioma

Introduction  The treatment of craniopharyngiomas is associated with long‐term morbidity.

Disease-specific impairments in quality of life during long-term follow-up of patients with different pituitary adenomas

Objective  Quality of life (QoL) is impaired in patients treated for pituitary adenomas. However, differences in age and gender distributions hamper a proper comparison of QoL. Therefore, we compared age‐ and gender‐specific standard deviations (SD) scores (Z‐scores) of QoL parameters in patients treated for pituitary adenomas.

Coexpression of Dopamine and Somatostatin Receptor Subtypes in Corticotroph Adenomas

CONTEXT Previous studies have demonstrated the expression of somatostatin receptor subtypes (mainly sst(5)) and dopamine (DA) receptor subtypes (mainly D(2)) in smaller series of human corticotroph adenomas. In line with these findings, sst(5) and D(2)-targeting agents have already been used clinically in patients with Cushings disease (CD) and have shown promising results in subsets of patients. To what extent these receptor subtypes are coexpressed within individual adenomas, is not known however. OBJECTIVE The aim of the study was to investigate the (co-)expression of both sst and DA receptors in a large series of human corticotroph adenomas. DESIGN We performed in vitro analysis of corticotroph adenoma tissue obtained via transsphenoidal adenomectomy. SETTING The study was conducted at two university medical centers. PATIENTS Adenoma tissue from 30 patients with CD was analyzed in this study. RESULTS Analyzed by quantitative RT-PCR, D(2) and sst(5) were significantly (co-) expressed in the majority (60%) of adenomas, whereas 23% of adenomas only expressed D(2), but not sst(5). The remaining 17% of adenomas did not significantly express either sst(5) or D(2). Overall, expression of sst(1-4) and D(4) was low to nondetectable. Corticotroph adenomas with invasive growth invariably showed loss of sst(5) and D(2) expression. Autoradiography revealed clear D(2) and/or SS-14 binding in a subset of cases, which correlated well with their respective mRNA data. CONCLUSIONS Sst(5) and especially D(2) are highly expressed in the majority of human corticotroph adenomas, with coexpression of sst(5) and D(2) being a common phenomenon. These findings support the current studies with sst(5) and D(2)-targeting agents in patients with CD and highlight the rationale behind sst(5)-D(2) combination therapy.

Hypopituitarism following traumatic brain injury: prevalence is affected by the use of different dynamic tests and different normal values

OBJECTIVE Traumatic brain injury (TBI) has emerged as an important cause of hypopituitarism. However, considerable variations in the prevalence of hypopituitarism are reported. These can partly be explained by severity of trauma and timing of hormonal evaluation, but may also be dependent on endocrine tests and criteria used for diagnosis of hypopituitarism. METHODS Systematic review of studies reporting prevalence of hypopituitarism in adults >or=1 year after TBI focusing on used (dynamic) tests and biochemical criteria. RESULTS We included data from 14 studies with a total of 931 patients. There was considerable variation in definition of hypopituitarism. Overall, reported prevalences of severe GH deficiency varied between 2 and 39%. Prevalences were 8-20% using the GHRH-arginine test (cutoff <9 microg/l), 11-39% using the glucagon test (cutoff 1-5 microg/l), 2% using the GHRH test (no cutoff), and 15-18% using the insulin tolerance test (ITT; cutoff <3 microg/l). Overall, the reported prevalence of secondary adrenal insufficiency had a broad range from 0 to 60%. This prevalence was 0-60% with basal cortisol (cutoff <220 or <440 nmol/l), 7-19% using the ACTH test, and 5% with the ITT as first test (cutoff <500 or <550 nmol/l). Secondary hypothyroidism was present in 0-19% (free thyroxine) or 5-15% (thyroid-releasing hormone stimulation). Secondary hypogonadism was present in 0-29%. CONCLUSION The reported variations in the prevalence rates of hypopituitarism after TBI are in part caused by differences in definitions, endocrine assessments of hypopituitarism, and confounding factors. These methodological issues prohibit simple generalizations of results of original studies on TBI-associated hypopituitarism in the perspective of meta-analyses or reviews.

LONG‐TERM RESULTS OF TRANSSPHENOIDAL PITUITARY MICROSURGERY IN 60 ACROMEGALIC PATIENTS

Sixty patients with clinically and biochemically active acromegaly were treated by transsphenoidal surgery. All patients underwent a full assessment of pituitary function both preoperatively and postoperatively; these studies were repeated 6 months after surgery and every year, when possible. The mean follow‐up period was 3.3 years (range 0.5‐7 years). The GH level normalized in 62% of patients after surgery. A paradoxical reaction of GH to TRH was present in 35 patients before surgery and had normalized in 17 after surgery. Large tumours were associated with higher GH levels than smaller tumours. A prognostic factor in terms of normalization of both the GH level and an eventual paradoxical reaction to TRH or a glucose challenge was a low preoperative GH level. Three out of seven patients with either a positive postoperative TRH test but a normal GH level, or a slightly elevated GH level suffered a biochemical and clinical recurrence and two of them underwent reoperation. In contrast, when the TRH test had normalized (always in association with normal GH levels) no recurrence was found. The impact of surgery on the other pituitary functions was generally slight and the numbers of patients with preoperative and postoperative impairment were about equal. Postsurgical radiation therapy was administered to patients with an elevated GH level, a non‐normalized TRH test irrespective of whether the GH level had normalized, or local invasion of the tumour. In 11 out of 17 patients with elevated GH levels after surgery, normalization was achieved by radiation therapy after a mean period of 2.7 years. The incidence of pituitary failure after irradiation appeared to be high; gonadal function in men and the GH reserve function were especially vulnerable. From this study we conclude that in many cases the adenoma can be removed effectively, without compromising the other pituitary functions. However, a substantial number of the patients require additional radiation therapy, leading to an inevitable loss of other pituitary functions.

Increased Hypothalamic-Pituitary-Adrenal Axis Activity in Huntington’s Disease

CONTEXT Huntingtons disease (HD) is a fatal hereditary neurodegenerative disorder characterized by motor, cognitive, and behavioral disturbances. Hypothalamic-pituitary-adrenal (HPA) axis dysfunction could contribute to a number of HD signs and symptoms; however, no data are available on cortisol diurnal variations and secretory dynamics in HD patients. OBJECTIVE The aim of the study was to perform a detailed analysis of HPA axis function in HD patients in relation to clinical signs and symptoms. DESIGN, SETTING, AND PARTICIPANTS Twenty-four-hour cortisol secretion was studied in eight early-stage, medication-free HD patients and eight age-, sex-, and body mass index-matched controls in a clinical research laboratory. Cortisol levels were measured every 10 min. MAIN OUTCOME MEASURES Multiparameter autodeconvolution and cosinor regression were applied to quantify basal, pulsatile, and total cortisol secretion rates as well as diurnal variations in cortisol levels. RESULTS Total cortisol secretion rate and the amplitude of the diurnal cortisol profile were both significantly higher in HD patients compared with controls (3490 +/- 320 vs. 2500 +/- 220 nmol/liter/24 h, P = 0.023; and 111 +/- 14 vs. 64 +/- 8 nmol/liter, P = 0.012, respectively). Cortisol concentrations in patients were particularly increased in the morning and early afternoon period. In HD patients, mean 24-h cortisol levels significantly correlated with total motor score, total functional capacity, as well as body mass index. CONCLUSIONS HPA axis hyperactivity is an early feature of HD and is likely to result from a disturbed central glucocorticoid feedback due to hypothalamic pathology. HPA axis dysfunction may contribute to some signs and symptoms in HD patients.

Obesity due to Melanocortin 4 Receptor (MC4R) Deficiency Is Associated with Increased Linear Growth and Final Height, Fasting Hyperinsulinemia, and Incompletely Suppressed Growth Hormone Secretion

CONTEXT Melanocortin receptor 4 (MC4R) deficiency is characterized by increased linear growth greater than expected for the degree of obesity. OBJECTIVE The objective of the investigation was to study the somatotroph axis in obese MC4R-deficient patients and equally obese controls. PATIENTS AND METHODS We obtained anthropometric measurements and insulin concentrations in 153 MC4R-deficient subjects and 1392 controls matched for age and severity of obesity. We measured fasting IGF-I, IGF-II, IGF binding protein (IGFBP)-1, IGFBP-3, and acid-labile subunit levels in a subset of 33 MC4R-deficient patients and 36 control subjects. We examined pulsatile GH secretion in six adult MC4R-deficient subjects and six obese controls. RESULTS Height sd score was significantly greater in MC4R-deficient children under 5 yr of age compared with controls (mean ± SEM: 2.3 ± 0.06 vs. 1.8 ± 0.04, P < 0.001), an effect that persisted throughout childhood. Final height (cm) was greater in MC4R-deficient men (mean ± SEM 173 ± 2.5 vs. 168 ± 2.1, P < 0.001) and women (mean 165 ± 2.1 vs. 158 ± 1.9, P < 0.001). Fasting IGF-I, IGF-II, acid-labile subunit, and IGFBP-3 concentrations were similar in the two groups. GH levels were markedly suppressed in obese controls, but pulsatile GH secretion was retained in MC4R deficiency. The mean maximal GH secretion rate per burst (P < 0.05) and mass per burst (P < 0.05) were increased in MC4R deficiency, consistent with increased pulsatile and total GH secretion. Fasting insulin levels were markedly elevated in MC4R-deficient children. CONCLUSIONS In MC4R deficiency, increased linear growth in childhood leads to increased adult final height, greater than predicted by obesity alone. GH pulsatility is maintained in MC4R deficiency, a finding consistent with animal studies, suggesting a role for MC4R in controlling hypothalamic somatostatinergic tone. Fasting insulin levels are significantly higher in children carrying MC4R mutations. Both of these factors may contribute to the accelerated growth phenotype characteristic of MC4R deficiency.

Postoperative radiotherapy in acromegaly is effective in reducing GH concentration to safe levels

Several studies have established that in treated acromegaly mortality is only normalized in patients achieving a serum GH concentration below 5 mU/l. Few studies however, have addressed results of radiotherapy using this strict criterion. The aim of our study was to assess the efficacy of postoperative radiotherapy in reducing serum GH concentration below 5 mU/l.

Effects of Olanzapine and Haloperidol on the Metabolic Status of Healthy Men

BACKGROUND A large body of evidence suggests that antipsychotic drugs cause body weight gain and type 2 diabetes mellitus, and atypical (new generation) drugs appear to be most harmful. The aim of this study was to determine the effect of short-term olanzapine (atypical antipsychotic drug) and haloperidol (conventional antipsychotic drug) treatment on glucose and lipid metabolism. RESEARCH DESIGN AND METHODS Healthy normal-weight men were treated with olanzapine (10 mg/d; n = 7) or haloperidol (3 mg/d, n = 7) for 8 d. Endogenous glucose production, whole body glucose disposal (by [6,6-(2)H(2)]glucose dilution), lipolysis (by [(2)H(5)]glycerol dilution), and substrate oxidation rates (by indirect calorimetry) were measured before and after intervention in basal and hyperinsulinemic condition. RESULTS Olanzapine hampered insulin-mediated glucose disposal (by 1.3 mg x kg(-1) x min(-1)), whereas haloperidol did not have a significant effect. Endogenous glucose production was not affected by either drug. Also, the glycerol rate of appearance (a measure of lipolysis rate) was not affected by either drug. Olanzapine, but not haloperidol, blunted the insulin-induced decline of plasma free fatty acid and triglyceride concentrations. Fasting free fatty acid concentrations declined during olanzapine treatment, whereas they did not during treatment with haloperidol. CONCLUSIONS Short-term treatment with olanzapine reduces fasting plasma free fatty acid concentrations and hampers insulin action on glucose disposal in healthy men, whereas haloperidol has less clear effects. Moreover, olanzapine, but not haloperidol, blunts the insulin-induced decline of plasma free fatty acids and triglyceride concentrations. Notably, these effects come about without a measurable change of body fat mass.

Dynamic metabolomic data analysis : A tutorial review

In metabolomics, time-resolved, dynamic or temporal data is more and more collected. The number of methods to analyze such data, however, is very limited and in most cases the dynamic nature of the data is not even taken into account. This paper reviews current methods in use for analyzing dynamic metabolomic data. Moreover, some methods from other fields of science that may be of use to analyze such dynamic metabolomics data are described in some detail. The methods are put in a general framework after providing a formal definition on what constitutes a ‘dynamic’ method. Some of the methods are illustrated with real-life metabolomics examples.