Zuleyha Karaca

The hypothalamo–pituitary–adrenal axis in chronic fatigue syndrome and fibromyalgia syndrome

The hypothalamo–pituitary–adrenal (HPA) axis plays a major role in the regulation of responses to stress. Human stress-related disorders such as chronic fatigue syndrome (CFS), fibromyalgia syndrome (FMS), chronic pelvic pain and post-traumatic stress disorder are characterized by alterations in HPA axis activity. However, the role of the HPA axis alterations in these stress-related disorders is not clear. Most studies have shown that the HPA axis is underactive in the stress-related disorders, but contradictory results have also been reported, which may be due to the patients selected for the study, the methods used for the investigation of the HPA axis, the stage of the syndrome when the tests have been done and the interpretation of the results. There is no structural abnormality in the endocrine organs which comprise the HPA axis, thus it seems that hypocortisolemia found in the patients with stress-related disorder is functional. It may be also an adaptive response of the body to chronic stress. In this review, tests used in the assessment of HPA axis function and the HPA axis alterations found in CFS and FMS are discussed in detail.

Pregnancy and pituitary disorders

Major hormonal changes emerge during pregnancy. The pituitary gland is one of the most affected organs with altered anatomy and physiology. The pituitary gland is enlarged as a result of lactotroph hyperplasia. Due to physiological changes in the pituitary and target hormone levels, binding globulins, and placental hormones, hormonal evaluation becomes more complex in pregnant women. As a consequence of physiological hormonal changes, the evaluation of pituitary functions in pregnant women is quite different from that done in the prepregnant state. Pituitary adenomas may cause problems by their hormone secretion that affects the mother and the fetus besides causing an increased risk of tumor growth. Furthermore, diagnosis, course, and treatment of pituitary diseases point out differences. The changes in anatomy and physiology of the pituitary gland during pregnancy are reviewed. Pituitary disorders namely Cushings disease; acromegaly; prolactinoma; TSH-secreting, gonadotropin-producing, and clinically nonfunctioning adenomas; craniopharyngioma; and Sheehans syndrome, which is one of the most common causes of hypopituitarism, lymphocytic hypophysitis, and hypopituitarism, in relation to pregnancy are discussed. Being aware of all this information will prevent any serious problems which mother and child will be exposed to.

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

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

Objective  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.

Investigation of insulin resistance in patients with normocalcemic primary hyperparathyroidism.

While derangements in glucose metabolism in patients with primary hyperparathyroidism are well-defined, this issue is not investigated in patients with normocalcemic primary hyperparathyroidism (NPHPT). The aim of this study was to investigate the presence of insulin resistance in patients with NPHPT. Eighteen patients with NPHPT (two males and 16 females) and 18 healthy volunteers were enrolled into the study. Secondary causes of parathyroid hormone elevations were excluded in all patients. Blood samples were obtained for the measurement of serum calcium, phosphate, alkaline phosphatase (ALP), albumin, creatinine, glucose, and serum lipid levels. Glucose and insulin responses to oral glucose tolerance test (OGTT) were obtained. Homeostasis model assessment (HOMA-IR) was also used as an indice of insulin resistance. Patients and control subjects had similar age, body mass index, and sex distribution. Although within normal limits, serum calcium and ALP levels were higher in patients than in the control subjects. None of the patients and the control subjects had diabetes mellitus, while eight patients and six control subjects had impaired glucose tolerance. Insulin responses to OGTT and HOMA-IR were not significantly different among the patient and control subjects. In addition, both groups have similar serum lipid levels. Patients with NPHPT do not exhibit insulin resistance and glucose intolerance. Since so little is known about this form of disease, subjects should be monitored regularly for the metabolic aspects of the disease as well as the progression of their disease.

Empty Sella may be the Final Outcome in Lymphocytic Hypophysitis

Introduction. Lymphocytic hypophysitis (LH) is an autoimmune disorder associated with the infiltration of the pituitary gland by lymphocytes leading to different degrees of hypopituitarism. Females are affected more frequently than males and the disease is usually associated with pregnancy or postpartum period. Case. We present a case of LH who was first diagnosed with diabetes insipidus and hyperprolactinemia. In the follow-up, the patient developed growth hormone, gonadotropin, and thyroid stimulating hormone deficiency. The typical appearance of increased stalk thickness and diffuse homogenous contrast enhancement of pituitary on magnetic resonance imaging resulted in empty sella by time. Conclusion. The present case demonstrates the natural course of LH over a 13-year period in which the empty sella was the final outcome.

A comparison of low‐dose ACTH, glucagon stimulation and insulin tolerance test in patients with pituitary disorders

Diagnosis of secondary adrenal insufficiency and GH deficiency requires evaluation by dynamic stimulation tests in most cases. Although insulin tolerance test (ITT) is accepted as the gold‐standard test for the evaluation of both hypothalamo‐pituitary‐adrenal (HPA) and (GH)‐IGF‐1 axes, the test is cumbersome. In clinical practice, low‐dose adrenocorticotrophic hormone (ACTH) stimulation test is a sensitive, safe and easily applicable alternative to ITT. Although it takes more time, glucagon stimulation test (GST) is also a good alternative to ITT and can evaluate both axes.

Pregnancy and other pituitary disorders (including GH deficiency)

The pituitary gland is one of the most affected organs with altered anatomy and physiology during pregnancy. Acromegaly is the second most common pituitary adenoma seen in relation to gestation after prolactinomas. Acromegaly should be treated before conception to prevent potential tumor growth in patients who desire fertility. Medical therapy can be ceased safely after confirmation of pregnancy in acromegalic patients, but octreotide may be used in selected cases with compressive signs. Other hormonal and non-functional tumors are rarer and have been presented as case reports. Sheehans syndrome, which is one of the most common causes of hypopituitarism in developing countries, and lymphocytic hypophysitis are known to be associated with pregnancy. They usually result in hypopituitarism, sometimes with delays in diagnosis and difficulties in differential diagnosis. Pregnancy is not common among patients with hypopituitarism or pituitary adenomas due to altered gonadotroph functions. Ovulation induction is essential for fertility achievement, but the replacement of other deficient pituitary hormones, including GH, seems to play an important role in the preparation of the uterus for implantation of the embryo.

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?

BACKGROUND The 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. METHODS The 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. RESULTS Patients 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. CONCLUSION Serum 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.

Evaluation of cognitive performance by using P300 auditory event related potentials (ERPs) in patients with growth hormone (GH) deficiency and acromegaly

CONTEXT Impaired cognitive performance has been demonstrated in adults with GH deficiency and acromegaly by using different neuropsychological tests. P300 event related potential (ERP) application is a well established neurophysiological approach in the assessment of cognitive performance. OBJECTIVES Evaluation of cognitive performance by using P300 ERPs has not been reported in acromegaly, and the comparisons of the P300 ERPs between the patients with GH deficiency and GH excess have not been done yet. Therefore present study was designed to investigate the effects of GH deficiency and GH excess on cognitive performance by using P300 ERPs. DESIGN AND METHODS The study comprised 19 patients with severe GH deficiency, 18 acromegalic patients and 16 age, education and sex matched healthy controls. Baseline auditory ERPs were obtained at Fz (frontal), Cz (central), Pz (parietal) and Oz (occipital) electrode sites in GH deficient group, GH excess group and control group. RESULTS There was a significant difference between mean serum IGF-I levels in the GH deficient and acromegalic patients (48+/-38 ng/ml and 742+/-272 ng/ml, respectively) (P=0.01). The mean P300 latency of the patients with GH deficiency was significantly (P=0.0001) prolonged when compared with that of normal controls and acromegalic patients at all electrode sites. The mean P300 amplitude of the patients with acromegaly was significantly (P=0.005) lower when compared with that of normal controls and GH deficient patients at all electrode sites. CONCLUSIONS Using ERPs recordings, the present study indicates the prolongation of P300 latencies in patients with severe GH deficiency and reduction of P300 amplitudes in patients with acromegaly. This study provides the electrophysiological evidence for the presence of cognitive dysfunction in both GH deficiency and GH excess, and different components of the cognitive performance are impaired in these conditions.