Ahmet Selcuklu

Antipituitary antibodies after traumatic brain injury: is head trauma-induced pituitary dysfunction associated with autoimmunity?

OBJECTIVEnTraumatic brain injury (TBI) is a devastating public health problem that may result in hypopituitarism. However, the mechanisms responsible for hypothalamic-pituitary dysfunction due to TBI are still unclear. Although the antibodies against neurons have been demonstrated in injured animal studies, investigations regarding the occurrence of antipituitary antibodies (APAs) in patients with TBI are lacking in the literature. In order to investigate whether autoimmune mechanisms could play a role in the pituitary dysfunction after TBI, we have planned this study aimed at investigating the presence of APA at the third year of TBI and association between the TBI-induced hypopituitarism and APA.nnnPATIENTS AND DESIGNnTwenty-nine (25 males and 4 females; age 36.5+/-2.3 years) patients who had completed a 3-year follow-up after TBI were included in the present study. APA and pituitary function were evaluated in all the patients 3 years after TBI; moreover, APAs were tested also in sera of 60 age-/sex-matched normal controls. The APAs were investigated by an indirect immunofluorescence method. Results APAs were detected in 13 out of the 29 TBI patients (44.8%), but in none of the normal controls. Pituitary dysfunction development ratio was significantly higher in APA-positive patients (46.2%) when compared with APA-negative ones (12.5%; P=0.04). There was a significant association between APA positivity and hypopituitarism due to TBI (odds ratio: 2.25, 95% confidence intervals 1.1-4.6). Moreover, there was a significant positive correlation (r=0.74, P=0.004) between APA titer ratio and peak GH response to GHRH+GH related peptide (GHRP)-6 test, suggesting that high APA titers were associated with low GH response to GHRH+GHRP-6 test.nnnCONCLUSIONSnThis study shows for the first time the presence of the APA in TBI patients 3 years after head trauma. Moreover, present investigation indicates preliminary evidence that APA may be associated with the development of TBI-induced pituitary dysfunction, thus suggesting that autoimmunity may contribute in the development of TBI-induced hypopituitarism. The presence of the association between APA and TBI-induced hypopituitarism may provide a new point of view in this field and promote further clinical and experimental studies.

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

Investigation of antihypothalamus and antipituitary antibodies in amateur boxers: is chronic repetitive head trauma-induced pituitary dysfunction associated with autoimmunity?

OBJECTIVEnCurrent data clearly demonstrate that sports-related chronic repetitive head trauma due to boxing might result in hypopituitarism. However, the mechanism of sports-related traumatic brain injury-induced pituitary dysfunction is still unclear. In order to understand whether autoimmune mechanisms could play a role in the pituitary dysfunction due to sports-related head trauma, we investigated the presence of antipituitary antibodies (APAs) and antihypothalamus antibodies (AHAs) in amateur boxers.nnnPATIENTS AND DESIGNnSixty-one actively competing (n=44) or retired (n=17) male boxers (mean age, 26 years; range, 17-53) who had been evaluated regarding pituitary functions previously were included in the study. In all boxers and in 60 age/sex-similar normal controls, AHAs and APAs were investigated by an indirect immunofluorescence method.nnnRESULTSnAHAs were detected in 13 of 61 boxers (21.3%), and APAs were detected in 14 of 61 boxers (22.9%), but in none of the normal controls. Pituitary dysfunction was significantly higher in AHA-positive boxers (46.2%) than in AHA-negative boxers (10.4%) (P=0.003). There was a significant association between AHA positivity and hypopituitarism due to boxing (odds ratio: 7.37, 95% confidence interval 1.8-30.8). There was no significant association between APA positivity and hypopituitarism.nnnCONCLUSIONSnThis study demonstrates for the first time the presence of AHAs and APAs in boxers who were exposed to sports-related head trauma. Moreover, the present investigation provides preliminary evidence that AHAs are associated with the development of pituitary dysfunction in boxers, thus suggesting that autoimmunity may have a role in the pathogenesis.

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.

The effects of octreotide in a patient with Nelson's syndrome

We have administered octreotide, 100 micrograms tid, to a 27-year-old man with Nelsons syndrome. After seven days of therapy, adrenocorticotropin levels fell to 54% of initial values, and some shrinkage of the tumour was observed. This study indicates that octreotide therapy may have a role in the treatment of Nelsons syndrome.

Empty sella developing during thyroxine therapy in a patient with primary hypothyroidism and hyperprolactinaemia.

A 35 year old woman presented with severe primary hypothyroidism and galactorrhea. A very high prolactin level was also detected and computerized tomography scan of the sellar region demonstrated an enlarged pituitary gland associated with contrast enhancement. Replacement therapy with thyroxine corrected both biochemical and clinical abnormalities but empty sella developed during this therapy. It is concluded that empty sella may be related to thyroxine-induced shrinkage of lactotroph and/or thyrotroph cell hyperplasia.