Fatih Tanriverdi

Three years prospective investigation of anterior pituitary function after traumatic brain injury: a pilot study

Objectiveu2002u2003 It has been recently demonstrated that traumatic brain injury (TBI)‐mediated hypopituitarism could be more frequent than previously known. However, most of the previous data were obtained from retrospective studies, and the natural history of the hypopituitarism due to TBI is still unclear. So far no study has been reported in which the pituitary function of the same patients has been investigated more than 1 year after TBI. Therefore, we report the results of 3 years prospective follow‐up of anterior pituitary function in patients with mild, moderate and severe TBI.

Kickboxing sport as a new cause of traumatic brain injury‐mediated hypopituitarism

Objectiveu2002 Traumatic brain injury, which is a frequent and a worldwide important public health problem, may result in pituitary dysfunction. Concussion, a common type of lesion after traumatic brain injury, is an injury associated with sports including boxing and kickboxing. Kickboxing is one of the most popular martial arts and approximately 1‐million people around the world participate in kickboxing sport. Head is the most common site of injury in amateur and professional kickboxers. Pituitary consequences of chronic repetitive head trauma in kickboxing have not been investigated until now. Therefore, the present study was designed to investigate the pituitary function in both retired and active amateur kickboxers.

Brief communication: pituitary volume and function in competing and retired male boxers.

Context Reports suggest that 25% to 50% of patients with traumatic brain injury have pituitary dysfunction. Boxing carries a high risk for traumatic brain injury, yet there has been little systematic study of pituitary function in boxers. Contribution In this cross-sectional study of 61 active and retired boxers from the Turkish National Boxing Team, growth hormone and adrenocorticotropic hormone deficiencies were more frequent than would be expected in a general population. Nearly one half of retired boxers, the study participants with the longest boxing histories, had growth hormone deficiency. Implication Physicians should be alert for pituitary dysfunction in patients who have participated in boxing. The Editors Recent data clearly demonstrated that traumatic brain injury (TBI) is an important public health problem and may result in hypopituitarism (1, 2). After TBI, 25% to 50% of patients have some degree of pituitary dysfunctiongrowth hormone (GH) deficiency in particular (13). Concussion is reported to be the main diagnosis after TBI. This injury is associated with such sports as boxing, kickboxing, and football (4). Recent data suggest that sports injury may cause TBI and pituitary dysfunction (57). Boxing, which is among the most common combative sports, is associated with chronic head trauma that may cause unconsciousness, brain injury, and neurologic abnormalities (8). Although the relationship between boxing and TBI is well documented, pituitary consequences of chronic head trauma in boxing have not been investigated in detail. We investigated pituitary function in 61 retired or active amateur boxers. Methods After obtaining permission from the Turkish Boxing Federation, we approached all amateur, elite boxers on the Turkish National Boxing Team. We included all 61 actively competing (n= 44) or retired (n= 17) male boxers (mean age, 26 years [range, 17 to 53 years]) (Table 1). The ethics committee of Erciyes University Medical School, Kayseri, Turkey, approved this study, and we obtained informed consent from each participant. None of the boxers reported any comorbid conditions or previous pituitary disorders, and none was currently taking any medications. Table 1. Age Categories and Measured Variables Variables Assessed in the Participants Age categories and measured variables of the boxers are shown in Table 1. Assessment of Lipid Profile and Body Composition We measured total serum cholesterol (reference range, 1.8 to 5.7 mmol/L [70 to 220 mg/dL]), high-density lipoprotein cholesterol (0.8 to 1.8 mmol/L [30 to 70 mg/dL]), and triglyceride (0.4 to 2.3 mmol/L [40 to 200 mg/dL]) by using an autoanalyzer (Konelab, Espoo, Finland). We estimated low-density lipoprotein cholesterol (1.5 to 4.4 mmol/L [60 to 170 mg/dL]) levels according to the formula suggested by Friedewald and colleagues (9). We also measured body mass index (BMI) and waist circumference. We assessed body composition variables, including fat ratio, fat mass, abdominal fat ratio, and abdominal fat mass, by using a bioelectrical impedance analyzer (Tanita Body Composition Analyser BC-418, Tokyo, Japan). Assessment of Pituitary Volume We performed pituitary volume measurement with magnetic resonance imaging in 38 of 61 boxers who were randomly selected by a computerized random-number generator. We used coronal- and sagittal-weighted 3-dimensional magnetic resonance imaging volumetry to obtain the pituitary volume as described elsewhere (Philips Gyroscan Intera 1.5 Tesla, Best, the Netherlands) (10). Two radiologists, who were blinded to demographic data of the groups and hormone status of the boxers, measured the volume. Assessment of Pituitary Function Basal Hormone Levels We measured serum-free triiodothyronine (normal range, 1.8 to 5.7 pmol/L), free thyroxine (9.9 to 21.8 pmol/L [7.7 to 17.1 ng/dL), thyroid-stimulating hormone (TSH) (0.2 to 3.7 mU/mL), adrenocorticotropic hormone (ACTH) (3.9 to 23.3 pmol/L), prolactin (0.09 to 0.81 nmol/L), follicle-stimulating hormone (1.4 to 18 U/L), luteinizing hormone (1.5 to 9.3 U/L), total testosterone (4.6 to 21.7 nmol/L [134 to 625 ng/dL]), free testosterone (39.9 to 85.0 pmol/L [11.5 to 24.5 pg/mL]), and insulin-like growth factor I (IGF-I). The IGF-I reference ranges were 25 to 62 nmol/L for 18- to 30-year-olds, 13 to 64 nmol/L for 31- to 40-year-olds, and 13 to 39 nmol/L for 41- to 50-year-olds. We defined gonadotropin deficiency (follicle-stimulating hormone and luteinizing hormone) as both basal total and free testosterone levels below the normal range in the presence of normal or low gonadotropin values. We defined TSH deficiency as a free thyroxine level below the normal range in the presence of normal or low TSH values (11, 12). Assessment of Somatotropic and Corticotropic Function We used GH-releasing hormone (GHRH) plus GH-releasing peptide-6 (GHRP-6) test and glucagon-stimulation test (GST) to assess the GHIGF-I axis in boxers. We used the GHRH plus GHRP-6 test as described elsewhere (13). We performed the GST to assess ACTH deficiency (14). The details of the tests and the cutoff values for the diagnosis of GH and ACTH deficiencies were recently published (7). Analytic Hormone Measurement We measured all other serum hormones by using radioimmunoassay, immunoradiometric assay, or chemiluminescent methods with commercial kits. Statistical Analysis We performed statistical analysis by using SPSS software, version 10.0 (SPSS, Chicago, Illinois). All data are presented as means (SDs); P< 0.050 was considered statistically significant. We compared the differences between 2 groups by using unpaired t tests and among more than 2 groups by using 1-way analysis of variance (post hoc Scheffe analysis). We used Pearson correlation analysis to determine whether statistically significant correlations existed between chosen variables. Role of the Funding Source This study was funded by the Scientific and Technical Research Council of Turkey. The funding source had no role in the study design, data collection, data analysis, or data interpretation or in the decision to submit the manuscript for publication. Results Sixty-one actively competing (21 young boxers [age range, 17 to 19 years] and 23 adult boxers [age range, 19 to 28 years]) and retired boxers (age range, 32 to 53 years) were included. Evaluation of Pituitary Hormone Deficiencies The boxers had no TSH or follicle-stimulating hormone and luteinizing hormone deficiencies. Nine of 61 boxers (15%) had GH deficiency on the GH-stimulation test. All boxers with GH deficiency except 1 were retired. Therefore, 8 of the 17 retired boxers (47%) had GH deficiency. On the basis of GST results, 5 of 61 boxers (3 on the active team and 2 retired) (8%) had peak cortisol levels lower than the cutoff value; we classified them as ACTH-deficient. Of the 61 boxers, 8 (13%) had isolated hormone deficiencies (6 had isolated GH deficiency and 2 had isolated ACTH deficiency) and 3 (5%) had combined GH and ACTH deficiencies. Overall, 11 of 61 boxers (18%) had pituitary dysfunction. Comparison of Boxers with Normal versus Abnormal Pituitary Function Table 2 compares boxers who had normal (n= 50) versus abnormal (n= 11) pituitary function. Age, age at retirement, total number of bouts, body composition variables, and triglyceride levels were statistically significantly higher in boxers with abnormal pituitary function (P< 0.050). Levels of high-density lipoprotein cholesterol, IGF-I, peak cortisol after GST, peak GH after GST, and peak GH after the GHRH plus GHRP-6 test were statistically significantly (P< 0.050) lower in boxers with pituitary dysfunction than in those with normal pituitary function. Table 2. Body Composition, Hormone Variables, and Lipid Profiles in Boxers with Normal and Abnormal Pituitary Function Results of Volumetric Pituitary MRI We measured pituitary volume in 11 young boxers (mean age, 17 years [SD, 0.3]), 17 adult boxers (mean age, 22 years [SD, 2.8]), and 10 retired boxers (mean age, 44 years [SD, 4.7]). Mean pituitary volume was statistically significantly lower in adult (446 mm3 [SD, 140]) and retired (423 mm3 [SD, 120]) boxers than in young boxers (681 mm3 [SD, 141]) (P= 0.001). When we compared the pituitary volumes of 7 GH-deficient boxers (6 retired and 1 active) and 31 GH-normal boxers (4 retired and 27 active), mean pituitary volume was statistically significantly lower in GH-deficient boxers (373 mm3 [SD, 93]) than GH-normal boxers (538 mm3 [SD, 173]) (P= 0.019). In addition, GH-deficient retired boxers had statistically significantly lower pituitary volume (364 mm3 [SD, 99]) than GH-normal retired boxers (510 mm3 [SD, 101]) (P= 0.040), and mean ages were similar in both groups (45 years [SD, 3.9] and 43 years [SD, 6.2], respectively). Correlation Analysis in Boxers There were statistically significant (P< 0.050) negative correlations between GH peak values after GHRH plus GHRP-6 testing versus all body composition variables (data not shown). We also demonstrated statistically significant negative correlations between length of boxing career and IGF-I level (Pearson r= 0.46; P 0.001), GH peak value after GHRH plus GHRP-6 testing (r= 0.28; P= 0.026), and GH peak value after GST (r= 0.36; P= 0.005). Discussion This systematic study of pituitary function and volume in amateur competing and retired male boxers suggests that chronic head trauma due to sports injury in boxers may be associated with pituitary dysfunction and decreased pituitary volume. Growth hormone deficiency was the most frequent hormone deficiency, particularly in retired boxers. A literature search (English-language studies in MEDLINE to December 2007) identified only 2 studies evaluating the pituitary function in combative sports (5, 7); both were done in Turkey. The first study included 11 amateur boxers, 5 (45%) of whom had isolated GH deficiency (5). The second study included 22 male and female kickboxers, of whom 5 (23%) had GH deficiency and 2 (9%) had ACTH

Anti-hypothalamus and anti-pituitary antibodies may contribute to perpetuate the hypopituitarism in patients with Sheehan's syndrome.

OBJECTIVEnWhile anti-pituitary antibodies (APAs) were detected in some patients with Sheehans syndrome (SS) suggesting an autoimmune pituitary involvement in the development of their hypopituitarism, hypothalamic cell anti-hypothalamus antibodies (AHAs) have not been investigated so far.nnnDESIGNnThe aim of this study was to evaluate the presence of AHA and APA in SS patients to verify whether an autoimmune hypothalamic-pituitary process can contribute to their late hypopituitarism.nnnMETHODSnTwenty women with SS with a duration of disease ranging from 3 to 40 years (median 25.5 years) were enrolled into the study. Out of 20 patients, 12 (60%) had panhypopituitarism and the others had partial hypopituitarism well corrected with appropriate replacement therapy. None of them had clinical central diabetes insipidus. AHA and APA were investigated by immunofluorescence method in all patients. In addition, a four-layer immunofluorescence method was used to verify whether AHA immunostained vasopressin-secreting cells (AVP-c) or not.nnnRESULTSnAHAs were found in 8 out of 20 (40%) and APAs in 7 out of 20 (35%) patients with titers ranging from 1:32 to 1:128 and 1:16 to 1:32 respectively; however, in none of these positive patients AHA immunostained vasopressin cells. None of controls resulted positive for both antibodies.nnnCONCLUSIONSnPatients with SS, even many years after the onset of SS, can show antibodies to pituitary and/or hypothalamic but not AVP-secreting cells. Antibodies to unknown hypothalamic cells (releasing factor-secreting cells) other than APAs suggest that an autoimmune process involving both the hypothalamus and pituitary gland may contribute to late pituitary dysfunction in SS patients.

High risk of pituitary dysfunction due to aneurysmal subarachnoid haemorrhage: a prospective investigation of anterior pituitary function in the acute phase and 12 months after the event

Objectiveu2002 Recent investigations have provided evidence for a high prevalence of pituitary dysfunction in patients with subarachnoid haemorrhage (SAH). However, apart from one study, all of the previous data were obtained from retrospective studies. To our knowledge there is no previously reported study in which pituitary function was investigated in the same patients immediately after SAH and 12 months later. The aim of this study was to understand the prevalence and progression of anterior pituitary hormone deficiencies both in the acute phase of SAH and 12 months after the event.

A Five Year Prospective Investigation of Anterior Pituitary Function after Traumatic Brain Injury: Is Hypopituitarism Long-Term after Head Trauma Associated with Autoimmunity?

Traumatic brain injury (TBI) has been recently recognized as a common cause of pituitary dysfunction. However, there are not sufficient numbers of prospective studies to understand the natural history of TBI induced hypopituitarism. The aim was to report the results of five years prospective follow-up of anterior pituitary function in patients with mild, moderate and severe TBI. Moreover, we have prospectively investigated the associations between TBI induced hypopituitarism and presence of anti-hypothalamus antibodies (AHA) and anti-pituitary antibodies (APA). Twenty five patients (20 men, five women) were included who were prospectively evaluated 12 months and five years after TBI, and 17 of them also had a third-year evaluation. Growth hormone (GH) deficiency is the most common pituitary hormone deficit at one, three, and five years after TBI. Although most of the pituitary hormone deficiencies improve over time, there were substantial percentages of pituitary hormone deficiencies at the fifth year (28% GH, 4% adrenocorticotropic hormone [ACTH], and 4% gonadotropin deficiencies). Pituitary dysfunction was significantly higher in strongly AHA- and APA-positive (titers ≥1/16) patients at the fifth year. In patients with mild and moderate TBI, ACTH and GH deficiencies may improve over time in a considerable number of patients but, although rarely, may also worsen over the five-year period. However in severe TBI, ACTH and GH status of the patients at the first year evaluation persisted at the fifth year. Therefore, screening pituitary function after TBI for five years is important, especially in patients with mild TBI. Moreover, close strong associations between the presence of high titers of APA and/or AHA and hypopituitarism at the fifth year were shown for the first time.

Posterior pituitary function in Sheehan's syndrome.

OBJECTIVEnWe studied posterior pituitary function in 27 patients with Sheehans syndrome and 14 controls.nnnDESIGNnAll patients were investigated by water deprivation test and 26 of them by 5% hypertonic saline infusion test. None of the patients had symptoms of diabetes insipidus and all patients were on adequate glucocorticoid and thyroid hormone replacement therapy before testing.nnnRESULTSnAccording to dehydration test, 8 (29.6%) patients had partial diabetes insipidus (PDI group) and 19 (70.3%) had normal response (non-DI group). During the 5% hypertonic saline infusion test, the maximal plasma osmolality was higher in PDI (305 +/- 4.3) and non-DI (308 +/- 1.7) groups when compared with controls (298 +/- 1.7 mOsm/kg; P < 0.005), but the maximal urine osmolality was lower in PDI group (565 +/- 37) than in non-DI (708 +/- 45) and control (683 +/- 17 mOsm/kg) groups (P < 0.05). The osmotic threshold for thirst perception was higher in PDI (296 +/- 4.3) and non-DI (298 +/- 1.4) groups when compared with control group (287 +/- 1.5 mOsm/kg) (P < 0.005). Basal plasma osmolalities were also higher in PDI (294 +/- 1.0) and non-DI (297 +/- 1.1) groups than in controls (288 +/- 1.2 mOsm/kg; P < 0.001).nnnCONCLUSIONSnOur findings demonstrated that patients with Sheehans syndrome have an impairment of neurohypophyseal function. The thirst center may be affected by ischemic damage and the osmotic threshold for the onset of thirst in patients with Sheehans syndrome is increased.

Apolipoprotein E3/E3 genotype decreases the risk of pituitary dysfunction after traumatic brain injury due to various causes: preliminary data.

Traumatic brain injury (TBI) is a devastating public health problem which may result in hypopituitarism. However, the mechanisms and the risk factors responsible for hypothalamo-pituitary dysfunction due to TBI are still unclear. Although APO E is one of the most abundant protein in hypothalamo-pituitary region, there is no study investigating the relation between APO E polymorphism and TBI-induced hypopituitarism. This study was undertaken to determine whether APO E genotypes modulate the pituitary dysfunction risk after TBI due to various causes, including traffic accident, boxing, and kickboxing. Ninety-three patients with TBI (mean age, 30.61 +/- 1.25 years) and 27 healthy controls (mean age, 29.03 +/- 1.70 years) were included in the study. Pituitary functions were evaluated, and APO E genotypes (E2/E2; E3/E3; E4/E4; E2/E3; E2/E4; E3/E4) were screened. Twenty-four of 93 subjects (25.8%) had pituitary dysfunction after TBI. The ratio of pituitary dysfunction was significantly lower in subjects with APO E3/E3 (17.7%) than the subjects without APO E3/E3 genotype (41.9%; p = 0.01), and the corresponding odds ratio was 0.29 (95% confidence interval [CI], 0.11-0.78). In conclusion, this study provides strong evidence for the first time that APO E polymorphism is associated with the development of TBI-induced pituitary dysfunction. Present data demonstrated that APO E3/E3 genotype decreases the risk of hypopituitarism after TBI. The demonstration of the association between the APO E polymorphism and TBI may provide a new point of view in this field and promote further studies.

Can basal cortisol measurement be an alternative to the insulin tolerance test in the assessment of the hypothalamic–pituitary–adrenal axis before and after pituitary surgery?

BACKGROUNDnThe aims of this study were to evaluate the validity of preoperative basal serum cortisol levels measured in predicting preoperative adrenal insufficiency and also the validity of basal serum cortisol levels and early postoperative insulin tolerance test (ITT) in predicting postoperative adrenal insufficiency.nnnMETHODSnThe study was prospectively designed and included 64 patients who underwent pituitary surgery for conditions other than Cushings disease. An ITT was performed preoperatively, on the 6th postoperative day and at the 1st postoperative month. Basal serum cortisol levels were measured on the 2nd, 3rd, 4th, 5th, and 6th postoperative days.nnnRESULTSnPatients with a preoperative basal cortisol level of <165 nmol/l (6 microg/dl) showed insufficient cortisol response and those with levels higher than 500 nmol/l (18 microg/dl) had sufficient cortisol response to the preoperative ITT. The positive predictive value of the ITT performed on the 6th postoperative day was 69.7%, and the negative predictive value in predicting adrenal insufficiency at the 1st postoperative month was 58%. Patients were considered to have an insufficient cortisol response to ITT at the 1st postoperative month if their basal cortisol levels were <193 nmol/l (7 microg/dl) or 220 nmol/l (8 microg/dl) or 193 nmol/l (7 microg/dl) or 165 nmol/l (6 microg/dl) or 83 nmol/l (3 microg/dl) on the 2nd-6th postoperative days respectively.nnnCONCLUSIONnSerum basal cortisol levels may be used as the first-line test in the assessment of the hypothalamic-pituitary-adrenal axis both preoperatively and postoperatively. Dynamic testing should be limited to the patients with indeterminate basal cortisol levels.

VEGFR1 expression is related to lymph node metastasis and serum VEGF may be a marker of progression in the follow-up of patients with differentiated thyroid carcinoma

OBJECTIVEnVascular endothelial growth factor (VEGF) and VEGF receptor 1 (VEGFR1) are known to be related to thyroid tumorigenesis. The aim of the study was to examine the expressions and serum levels of VEGF, VEGFR1, IGF1, and IGF1 receptor (IGF1R) in patients with differentiated thyroid carcinoma (DTC) compared with patients with nodular goiter (NG).nnnMETHODSnWe examined 39 patients with DTC who had a clinical history of at least 2 years and compared them with 25 patients who had a pathological diagnosis of NG after thyroidectomy. Serum VEGF, VEGFR1, and IGF1 levels were measured in both patient groups. The expressions of VEGF, VEGFR1, IGF1, and IGF1R were analyzed by the immunohistochemical method in the paraffin blocks of patients thyroidectomy samples of the patients.nnnRESULTSnThe immunostainings scores for VEGF, VEGFR1, IGF1, and IGF1R were found to be higher in patients with DTC than in those with NG. Only VEGFR1 expression was related to lymph node metastasis at the time of surgery. None of the expressions were related to the long-term prognosis of the patients. Serum VEGF was found to be higher in patients with progressive DTC than in patients in clinical remission.nnnCONCLUSIONnThe expressions of VEGF and VEGFR1 were shown to be correlated with the expression of IGF1 and IGF1R. VEGFR1 expression may be an important index for the presence of lymph node metastasis at the time of thyroidectomy. Increased serum levels of VEGF may reflect disease recurrence in DTC.