U. VON BARDELEBEN, O.A. MÜLLER, G.K. STALLA and F. HOLSBOER
A Kopczak, F von Rosen, C Krewer, H J Schneider, G K Stalla and M Schneider
The insulin tolerance test (ITT) is the gold standard for the diagnosis of GH deficiency (GHD) and hypocortisolism. As hypopituitarism is a common disorder after traumatic brain injury (TBI) and subarachnoid hemorrhage (SAH), the test is increasingly used in patients with pre-existing brain damage.
A cross-sectional, observational study.
Fifty-six patients (41 TBI and 15 SAH) were tested with the ITT (0.15 IE/kg body weight, mean glucose 33 mg/dl). In 38 patients, the test was performed in a supine position; the other 18 patients were in a sitting position during the ITT.
Hypocortisolism and GHD were more often diagnosed in a supine than in a sitting position (hypocortisolism: 55.3% supine versus 0% sitting, P<0.0001; GHD: 42.1% supine versus 11.1% sitting, P=0.03). Patients in a sitting position suffered more often from symptoms such as tachycardia (61.1% sitting versus 15.8% supine, P=0.001), trembling (22.2 vs 7.9%, NS), and sweating (66.7 vs 28.9%, P=0.007). There were no significant differences between the groups in drowsiness (72.2% sitting versus 65.8% supine, NS), dizziness (44.4 vs 44.7%, NS), and fatigue (33.3 vs 15.8%, NS). Because of somnolence, the hypoglycemic state could only be stopped with i.v. administration of glucose in 25 supine patients (66%). In contrast, none of the 18 patients (0%) tested in a sitting position got somnolent or was in need of i.v. application of glucose (P<0.001).
In patients with brain injury, posture might affect rates of diagnosing GHD and hypocortisolism and sympathetic symptoms in the ITT. These findings are exploratory and need replication in a standardized setting.
C Dimopoulou, J Schopohl, W Rachinger, M Buchfelder, J Honegger, M Reincke and G K Stalla
Transsphenoidal surgery (TSS) presents the treatment of choice for Cushing's disease (CD). Remission and recurrence rates vary dependent on tumor size, extension, adenoma visibility on magnetic resonance imaging, and neurosurgical expertise. Other than published from single-surgeon neurosurgical series so far, we have aimed to describe long-term remission and recurrence rates of CD in a series incorporating different neurosurgeons, trying to reflect care reality in the Munich Metropolitan Region, which is accommodated by three tertiary university and multiple, smaller neurosurgical centers.
We conducted a retrospective analysis of 120 patients who underwent first and 36 patients who underwent second TSS as treatment for CD between 1990 and 2012.
Patients were divided into three groups according to remission status. Potential risk factors for recurrence, pituitary function, and strategy in persistent disease were assessed.
Three outcome groups were identified according to remission status after first TSS (mean follow-up 79 months): remission, 71% (85/120), disease persistence, 29% (35/120), and disease recurrence, 34% (29/85) (mean time to recurrence 54 months). After second TSS (n=36, mean follow-up 62 months), we documented remission in 42% (15/36), disease persistence in 58% (21/36), and disease recurrence in 40% (6/15) (mean time to recurrence 42 months). Postoperative hypocortisolism after first, though not after second, TSS was associated with a lower risk of suffering disease recurrence (risk=0.72; 95% CI 0.60–0.88; exact significance (two-sided) P=0.035).
Our study shows higher recurrence rates of CD after first TSS than previously reported. Second TSS leads an additional 8% of the patients to long-term CD remission.
H J Schneider, B L Herrmann, M Schneider, C Sievers, L Schaaf and G K Stalla
Objective: Patients with traumatic brain injury (TBI) are at moderate risk of GH deficiency (GHD), requiring a diagnostic test with high specificity. The GHRH + arginine (GHRH + ARG) test has been recommended as a reliable alternative to the insulin-tolerance test (ITT) as a standard test with a cutoff level of 9 ng/ml. However, it has recently been questioned for its low specificity in obese subjects, and now BMI-dependent cut-off levels are available. In this study, we compared the ITT and GHRH + ARG test in patients with TBI.
Design: A cross-sectional study
Methods: We performed an ITT and a GHRH + ARG test in 21 patients with TBI (6 women, 15 men; mean age 40.2 ± 12.1 years; BMI 30.7 ± 6.2). The number of patients classified discordantly as GH deficient by the ITT and the GHRH + ARG test with both classical and BMI-dependent cut-off levels was assessed.
Results: Using the GHRH + ARG test with the classical cut-off (≤ 9 ng/ml), we identified 12 patients as GH deficient who had a normal GH response to ITT (> 3 ng/ml), and one patient as GH sufficient who had a blunted GH response to ITT (discordance rate 61.9%). All patients discordantly classified as GH deficient by the GHRH + ARG test had a BMI of ≥ 28. With the BMI-dependent cut-offs (4.2, 8.0, and 11.5 ng/ml in obese, overweight, and lean subjects respectively), only 3 of the 21 patients were discordantly classified (discordance rate 14.3%).
Conclusions: Our results discourage the use of a cut-off level of 9 ng/ml for the GHRH + ARG test in obese subjects. The diagnostic reliability of this test is improved with the BMI-dependent cut-offs.
H J Schneider, S Rovere, G Corneli, C G Croce, V Gasco, R Rudà, S Grottoli, G K Stalla, R Soffietti, E Ghigo and G Aimaretti
Objective: Hypopituitarism frequently follows pituitary neurosurgery (NS) and/or irradiation. However, the frequency of hypothalamic–pituitary dysfunction after NS of non-pituitary intracranial tumors is unclear. The aim of this study was to assess the presence of endocrine alterations in patients operated on for intracranial tumors.
Design: This is a retrospective study.
Methods: We studied 68 consecutive adult patients (28 female, 40 male, age 45.0 ± 1.8 years; body mass index (BMI): 26.5 ± 0.6) with intracranial tumors who underwent NS only (n = 17) or in combination with radiotherapy (RT) and/or chemotherapy (CT) (n = 51). In all subjects, basal endocrine parameters and the GH response to GHRH + arginine test (using BMI-dependent cut offs) were evaluated.
Results: In 20.6% of the patients, peripheral endocrinopathy related to CT and/or RT was present. Hypopituitarism was found in 38.2% of the patients. Total pituitary hormone, multiple pituitary hormone, and isolated pituitary hormone deficits were present in 16.2, 5.8, and 16.2% respectively. The most common pituitary deficits were, in decreasing order: LH/FSH 29.4%, GH 27.9%, ACTH 19.1%, TSH 17.7%, and diabetes insipidus 4.4%. Hyperprolactinemia was present in 13.2%. The prevalence of hypopituitarism was higher in patients who underwent NS only and with tumors located closely to the sella turcica, but a substantial proportion of patients with tumors not directly neighboring the sella also showed hypopituitarism.
Conclusions: Hypopituitarism frequently occurs after NS for intracranial tumors. Also, exposure of these patients to CT and/or RT is frequently associated with peripheral endocrinopathies. Thus, endocrine evaluation and follow-up of patients treated for intracranial tumors should be performed on a regular basis.
H J Schneider, M Schneider, B Saller, S Petersenn, M Uhr, B Husemann, F von Rosen and G K Stalla
Objective: Cross-sectional studies report a high prevalence of hypopituitarism after traumatic brain injury (TBI); however, no longitudinal studies on time of manifestation and reversibility exist. This study was conducted to assess hypopituitarism 3 and 12 months after TBI.
Design: This was a prospective, longitudinal, diagnostic study.
Methods: Seventy-eight patients (52 men, 26 women, mean age 36.0 years) with TBI grades I–III and 38 healthy subjects (25 men, 13 women, mean age 36.4 years) as a control group for the GHRH + arginine test were studied. The prevalence ofhypopituitarism was assessed 3 and 12 months after TBI by GHRH + arginine test, short adrenocorticotropic hormone (ACTH) test, and basal hormone measurements in patients.
Results: After 3 months, 56% of all patients had impairments of at least one pituitary axis with axes being affected as follows: gonadotropic 32%, corticotropic 19%, somatotropic 9% and thyrotropic 8%. After 12 months, fewer patients were affected, but in some cases new impairments occurred; 36% still had impairments. The axes were affected as follows after 12 months: gonadotropic 21%, somatotropic 10%, corticotropic 9% and thyrotropic 3%.
Conclusions: Hypopituitarism occurs often in the post-acute phase after TBI and may normalize later, but may also develop after the post-acute phase of TBI.
C Sievers, M Ising, H Pfister, C Dimopoulou, H J Schneider, J Roemmler, J Schopohl and G K Stalla
Although neuropsychiatric and morphological brain alterations in acromegalic patients have been described and a distinct disease personality is clinically suspected, this has never been systematically investigated. We examined whether patients with acromegaly showed an altered personality profile compared with patients with non-functioning pituitary adenomas and healthy controls.
Design and methods
In this cross-sectional study, 70 acromegalic patients and 58 patients with non-functioning pituitary adenomas were compared with 140 mentally healthy population controls, matched for age and gender. Personality traits were measured by standardized personality questionnaires (Eysenck personality questionnaire-RK and tridimensional personality questionnaire).
Compared with healthy controls, acromegalic patients described themselves as distinctly more harm avoidant and neurotic and presented themselves with high social conformity. On harm avoidant subscales, they reported more anticipatory worries and pessimism, higher fear of uncertainty, higher fatigability and asthenia. This personality pattern was not specific for acromegaly, but could similarly be observed in patients with non-functioning pituitary adenomas. However, specific for patients with GH-producing adenomas was an even more reduced novelty-seeking behaviour, especially in terms of lower impulsiveness, compared with patients with non-functioning pituitary adenomas.
Patients with pituitary adenomas show a distinct pattern of increased anxiety-related personality traits compared with the general population, potentially as a result of the pituitary lesion and/or associated hormonal dysregulations and comorbidities. Acromegaly is additionally associated with reduced impulsivity and novelty-seeking behaviour, which might affect patients' management and their quality of life.
A P Athanasoulia, C Sievers, M Ising, A C Brockhaus, A Yassouridis, G K Stalla and M Uhr
Treatment with dopamine agonists in patients with prolactin (PRL) adenomas and Parkinson's disease is associated with central side effects. Central side effects may depend on a substance's ability to pass the blood–brain barrier, which can be actively controlled by transporter molecules such as the P-glycoprotein (P-gp) encoded by the ABCB1 gene.
Materials and methods
We aimed to determine whether cabergoline is transported by the P-gp and whether polymorphisms of its encoding ABCB1 gene predict central side effects of cabergoline therapy in patients with PRL adenomas. i) In an experimental mouse model lacking the homologues of the human ABCB1 gene (Abcb1ab double knockout mouse model), we examined whether cabergoline is a substrate of the P-gp using eight mutant and eight wild-type mice. ii) In a human case–control study including 79 patients with PRL adenomas treated with cabergoline at the Max Planck Institute of Psychiatry in Munich, we investigated the association of four selected ABCB1 gene single nucleotide polymorphisms (SNPs) (rs1045642, rs2032582, rs2032583 and rs2235015), with the occurrence of central side effects under cabergoline therapy.
i) In the experimental mouse model, we observed that brain concentrations of cabergoline were tenfold higher in the mutant mice compared with their wild-type littermates, implying that cabergoline is indeed a substrate of the transporter P-gp at the blood–brain barrier level. ii) In the human study, we observed significant negative associations under cabergoline for the C-carriers and heterozygous CT individuals of SNP rs1045642 with two central side effects (frequency of fatigue and sleep disorders) and for the G-carriers of SNP rs2032582 with the enhancement of dizziness. For the SNPs rs2235015 and rs2032583, no associations with central side effects under cabergoline were found.
This is the first study demonstrating that individual ABCB1 gene polymorphisms, reflecting a different expression and function of the P-gp, could predict the occurrence of central side effects under cabergoline. Our findings can be viewed as a step into personalised therapy in PRL adenoma patients.
J Roemmler-Zehrer, V Geigenberger, S Störmann, M Losa, V Crippa, B Otto, M Bidlingmaier, C Dimopoulou, G K Stalla and J Schopohl
Patients with craniopharyngioma (CP) have disturbances of the hypothalamic–pituitary axis and serious comorbidities such as obesity. We hypothesized that the secretion of hormones regulating the nutritional status is altered in adult patients with CP compared with patients with non-functioning pituitary adenoma (NFPA).
We included 40 CP (50% males, mean age: 49.6±14.3 years) and 40 NFPA (72.5% males, mean age: 63.4±9.8 years) patients. We measured glucose, insulin, leptin, total ghrelin, peptide-YY (PYY) and cholecystokinin (CCK) during oral glucose tolerance test (OGTT). Fat mass (FM) was determined by dual X-ray absorptiometry.
Gender distribution was not significantly different, but CP patients were significantly younger (P<0.001). CP patients had significantly higher BMI and FM than NFPA patients (BMI 32±8 vs 28±4 kg/m2, P=0.009 and FM 37±9 vs 33±9%, P=0.02). Fasting glucose level (84±12 vs 78±11 mg/dl, P=0.03), leptin (27.9±34.2 vs 11.9±11.6 μg/l, P=0.008) and leptin levels corrected for percentage FM (0.66±0.67 vs 0.32±0.25 μg/l%, P=0.005) were significantly higher in CP than in NFPA patients, whereas ghrelin was significantly lower (131±129 vs 191±119 ng/l, P=0.035). Insulin, PYY and CCK did not differ significantly between groups. After glucose load, leptin decreased significantly in CP patients (P=0.019). In both groups, ghrelin decreased significantly during OGTT (both P<0.001). The percentage decline was significantly smaller for CP. PYY and CCK increased equally after glucose in both groups.
Our patients with CP have more metabolic complications than our patients with NFPA. The levels of leptin and ghrelin at fasting status and after glucose seem to be altered in CP, whereas changes in insulin, PYY and CCK do not seem to be responsible for the metabolic changes in these patients.
C Dimopoulou, A P Athanasoulia, E Hanisch, S Held, T Sprenger, T R Toelle, J Roemmler-Zehrer, J Schopohl, G K Stalla and C Sievers
Clinical presentation of pituitary adenomas frequently involves pain, particularly headache, due to structural and functional properties of the tumour. Our aim was to investigate the clinical characteristics of pain in a large cohort of patients with pituitary disease.
In a cross-sectional study, we assessed 278 patients with pituitary disease (n=81 acromegaly; n=45 Cushing's disease; n=92 prolactinoma; n=60 non-functioning pituitary adenoma).
Pain was studied using validated questionnaires to screen for nociceptive vs neuropathic pain components (painDETECT), determine pain severity, quality, duration and location (German pain questionnaire) and to assess the impact of pain on disability (migraine disability assessment, MIDAS) and quality of life (QoL).
We recorded a high prevalence of bodily pain (n=180, 65%) and headache (n=178, 64%); adrenocorticotropic adenomas were most frequently associated with pain (n=34, 76%). Headache was equally frequent in patients with macro- and microadenomas (68 vs 60%; P=0.266). According to painDETECT, the majority of the patients had a nociceptive pain component (n=193, 80%). Despite high prevalence of headache, 72% reported little or no headache-related disability (MIDAS). Modifiable factors including tumour size, genetic predisposition, previous surgery, irradiation or medical therapy did not have significant impact neither on neuropathic pain components (painDETECT) nor on headache-related disability (MIDAS). Neuropathic pain and pain-related disability correlated significantly with depression and impaired QoL.
Pain appears to be a frequent problem in pituitary disease. The data suggest that pain should be integrated in the diagnostic and therapeutic work-up of patients with pituitary disease in order to treat them appropriately and improve their QoL.