Marina Djurovic

Hypopituitarism as a consequence of traumatic brain injury (TBI) and its possible relation with cognitive disabilities and mental distress

Recent studies have demonstrated that hypopituitarism, in particular GH deficiency, is common among survivors of traumatic brain injury (TBI) tested several months or yr following head trauma. We present the results of endocrine, neurological, neuropsychological and psychiatric evaluation in a group of 67 patients who suffered TBI at least one yr ago. Our study shows that decreased endocrine function is either restricted to one or more anterior pituitary hormones and is present in 34% of patients with any pituitary hormone deficit, while multiple pituitary hormone deficiencies are found in 10% of patients. GH/ IGF-I axis was evaluated by GHRH+GHRP-6 test and IGF-I measurement. Severe GHD is the most frequent deficiency present in 15% of TBI patients. Gonadotrophin deficiency was present in 9% of patients with TBI, while thyrotroph and corticotroph function seemed more refractory to impairment. Patients with moderate-to-severe trauma are not necessarily more likely to have hypopituitarism than those with mild injury. Neuropsychological testing revealed a significant positive correlation of peak GH levels after GHRH+GHJRP-6 test with verbal learning and verbal short term memory (RAVLT total score p=0.06, immediate free recall p=0.02 and delayed free recall p=0.04). Verbal and visual memory was significantly lower in elderly patients and in males. Visoconstructional abilities (RCF copy) were significantly lower in the elderly (p<0.01) and undereducated (p=0.02). Visual memory (free recall of complex figure after 30 min) significantly correlated with lower IGF-I levels (p=0.01). Gonadotrophins and testosterone correlated significantly with visoconstructional abilities. Simple and complex conceptual tracking (TMT A and B) was significantly more impaired in older TBI patients (p<0.01) and with longer time from trauma (TMT B only, p=0.03). The psychiatric evaluation by using two different scales showed depression, phobic anxiety and psychoticism to be more prominent in the TBI group. Paranoid ideation and somatization negatively correlated with the peak GH responses to GHRH+GHRP-6 test (p=0.04 and p=0.03, respectively). Depression scale showed that nearly half of patients suffered from mild to moderate depression. The benefits of hormone replacement therapy on cognitive functioning and mental distress in TBI patients are eagerly awaited.

Changes in Neuroendocrine and Metabolic Hormones Induced by Atypical Antipsychotics in Normal-Weight Patients with Schizophrenia

Context: Atypical antipsychotics (SGA) have the propensity to induce weight gain. Objective: The aim was to evaluateearly changes in hormones involved in neuroendocrine regulations (serum cortisol, growth hormone and prolactin) and positive energy balance (serum insulin, leptin and ghrelin) during SGA treatment in normal-weight patients with schizophrenia with the purpose of exploring the possibility to combat weight gain early through manipulation of circulating hormone levels. Design: We conducted a randomized, partly cross-sectional and partly longitudinal, prospective study. Setting and Patients: Eighteen normal-weight in-patients with schizophrenia treated with FGA (first-generation antipsychotics) were referred to the Institute of Psychiatry. Twenty age-, gender- and BMI-matched healthy subjects were investigated at the Neuroendocrine Unit, Belgrade University. Intervention: Oral glucose tolerance test (OGTT) was performed at baseline in all and then 13 patients were assigned to receive SGA (risperidone or clozapine) and OGTT was repeated after 1 and 3 months. Results: At baseline, patients with schizophrenia had higher peak glucose levels (p < 0.05), glucose area under the curve (AUC; p < 0.05), peak insulin levels (p < 0.05), insulin AUC values during OGTT (p < 0.01) and the calculated homeostasis model assessment (HOMA-IR) value than control subjects (p < 0.05). Patients with schizophrenia showed higher morning cortisol (p < 0.05) levels than control subjects. After 1 and 3 months of SGA therapy patients with schizophrenia gained bodyweight by 3.5 and 8.6%, respectively. Leptin levels steadily increased while cortisol levels decreased in the first month and remained so. Serum glucose, insulin and ghrelin levels on SGA were similar as at baseline. Circulating ghrelin levels decreased after OGTT during SGA which is consistent with a role for ghrelin in the initiation of meals. Conclusions: Treatment with SGA was associated with continuous weight gain, with an early increase in serum leptin levels and decrease in cortisol levels. Elevated circulating leptin was ineffective in the control of fat deposition. Similar plasma ghrelin levels and similar decrease pattern of ghrelin after OGTT compared to healthy subjects signify intact meal-promoting effects of ghrelin during SGA therapy, which at the same time renders anorexigenic pathways ineffective. This may lead to weight gain and further studies with a ghrelin antagonist may provide support for this hypothesis.

Neuroendocrine dysfunction in patients recovering from subarachnoid hemorrhage.

OBJECTIVE: Subarachnoid hemorrhage (SAH) is a recently identified risk factor for hypopituitarism, particularly growth hormone (GH) and corticotrophins deficiencies. The aim of our study was to identify possible predictor(s) for neuroendocrine dysfunction in SAH survivors. DESIGN: Pituitary function was evaluated in 93 patients (30 males, 63 females), aged 48.0±1.1 years (mean±SE), and with a Glasgow Outcome Scale score of 4.6±0.6 (mean±SE) more than one year following SAH. In the acute phase, SAH was complicated by vasospasm (VS) in 18 and by hydrocephalus (HDC) in 9 patients. Baseline serum values of Insulin Growth Factor 1 (IGF-I), cortisol, Thyroxine (T4), Thyroid Stimulating Hormone (TSH), Follicle Stimulating Hormone (FSH), Luteinizing Hormone (LH), testosterone (in males), estradiol (in females) and prolactin were determined. RESULTS: According to the results of baseline hormonal evaluation, 47 patients (50.5%) had no hormonal abnormalities. Seven patients (7.5%) had multiple pituitary hormone deficiencies: Four patients (4.3%) had two (GH and cortisol), one patient had three (gonadal, adrenal and GH) and two patients had deficiency of all pituitary axes. Thirty-nine patients (42%) had one abnormal axis (13 adrenal, 2 thyroid, 4 gonadal and 20 GH). None of the subjects was treated with desmopressin or exhibited symptomatic polyuria. The VS and HDC during the acute phase of SAH were related to abnormal pituitary status (VS with low IGF-I levels and HDC with low cortisol levels). CONCLUSION: Through a screening procedure, neuroendocrine dysfunction was identified in a substantial number of asymptomatic patients with previous SAH. Cerebral VS and HDC at the time of SAH emerged as risk factors possibly predicting development of pituitary dysfunction. Low basal levels of IGF 1 and cortisol may help in selecting patients requiring further evaluation of pituitary function.

Gonadotropin response to clomiphene and plasma leptin levels in weight recovered but amenorrhoeic patients with anorexia nervosa

Anorexia nervosa (AN) is a state of leptin and gonadotropin deficiency. Leptin levels are decreased in normal weight women with hypothalamic amenorrhea and leptin may be a sensitive marker of overall nutritional status. The aim of the study is to provide additional information on plasma leptin levels and on gonadotropin responses after clomiphene testing in patients with AN who recovered weight but were still amenorrheic. We evaluated 17 patients with AN, female age 20±1.2 yr who reached goal weight [body mass index (BMI) 14.9±0.5 to 19.3±0.4 kg/m2]. At diagnosis serum leptin levels were 2.2±0.1 μg/l while after behavioural therapy and hypercaloric diet for 6–12 months serum leptin levels rose to 6.4±1.4 μg/l significantly lower compared with those in the control (no.=10, age 28±6.2 yr, BMI 21.1±0.3 kg/m2, leptin 9.3±0.7 μg/l; p<0.05). None of the patients resumed spontaneous menstrual cycles after weight gain. They were tested with a 10-day administration of clomiphene citrate. All had a significant rise in LH secretion (from 1.7±0.3 IU/l to 8.3±0.9 IU/l, p<0.01) and serum estradiol levels (from 19.0±5.4 to 937.7±241.2 pg/ml, p<0.03). Nine out of 17 patients menstruated after clomiphene. Serum leptin levels were not different in those who menstruated from those who did not (6.4±1.4 to 6.8±1.4 μg/l, p>s0.05). Body compositon was studied in 12 additional carefully matched patients with AN who recovered weight. Six of them resumed spontaneous menstrual cycles. Neither BMI, body fat, nor leptin appeared as significant determinants of menstrual status. In conclusion, relative hypoleptinemia persists, independent of fat mass, in weight recovered patients with AN. A normal response to clomiphene in weight-recovered yet still amenorrhoeic patients with AN, offers reassurance that the axis is intact and that the problem lies in the hypothalamus. It is reasonable to believe that nutritional disturbances, fat intake and persisting psychological factors still affect plasma leptin levels and reproductive functions in weightrecovered patients with amenorrhea.

ACTH and Cortisol responses to ghrelin and desmopressin in patients with Cushing’s disease and adrenal enlargement

Background: Overexpression of ghrelin and vasopressin (V3) receptors demonstrated on corticotrophe adenomas accounts for exaggerated ACTH and cortisol responses to ghrelin and desmopressin (DDAVP) in patients with Cushing’s disease (CD). Aim: In this study we have compared ACTH and cortisol responsiveness to DDAVP and ghrelin in CD patients with and without adrenal enlargemenent. Subjects and methods: Ghrelin and DDAVP tests were performed in 15 patients with CD (7 with and 8 without signs of adrenal enlargement) with CRH test in 8 patients. In 7 ageand sex-matched healthy subjects, ghrelin test was performed. Plasma ACTH and serum cortisol concentrations were measured after ghrelin, DDAVP and CRH. Growth hormone was measured after stimulation with ghrelin. Results: Significantly higher baseline and peak ACTH and cortisol concentrations after ghrelin were observed in all patients with CD compared to healthy control subjects. Patients with CD and adrenal enlargement had significantly lower baseline and peak ACTH concentrations after stimulation with ghrelin compared to CD patients without adrenal enlargement, while cortisol levels at baseline and after ghrelin administration were similar. Three out of seven patients with CD and adrenal enlargement did not respond to DDAVP while they responded well to CRH and ghrelin. Conclusion: Patients with CD and adrenal enlargement pose special diagnostic problems. They may have lower baseline ACTH levels and may not respond to DDAVP while they respond to ghrelin and CRH. Despite increased endogenous cortisol levels in CD, cortisol responses to ghrelin and CRH are preserved in patients with CD and adrenal enlargement.

Retroperitoneal malignant fibrous histiocytoma mimicking pheochromocytoma

We report the case of a 52-yr-old man with a mass in the area of the left adrenal. The clinical features, MIBG uptake, and elevated urinary dopamine levels suggested the diagnosis of pheochromocytoma. He presented with unstable hypertension, tachycardia, weight loss, and the “inflammatory syndrome” (fever, leukocytosis, and high sedimentation rate). Clinical findings, preoperative radiographic (sonography, CT scan, [131I]MIBG scintigraphy), and endocrine evaluations (elevated 24-h urinary dopamine) were suggestive of a dopamine-secreting adrenal tumor. The mass was resected and on histologic examination showed the characteristic features of a malignant fibrous histiocytoma (MFH). The tumor cells were immunopositive for neuron-specific enolase (NSE), vimentin, CD-68, S-100, desmin, and immunonegative for chromogranin A, synaptophysin, neurofilament protein, and lowmolecular-weight keratin, indicating that this tumor was not able to synthesize catecholamines. The prolonged retention of the tracer (MIBG) was interpreted as a consequence of obstructive hydronephrosis, while elevated urinary dopamine levels were assumed to be due to compression of the renal vessels by the large retroperitoneal mass.

PITUITARY ENLARGEMENT DUE TO PRIMARY HYPOTHYROIDISM : GROWTH HORMONE RESPONSE TO GHRH, GHRP-6 AND GHRH PLUS GHRP-6

GH secretion after growth hormone-releasing hormone (GHRH), growth hormone releasing peptide-6 (GHRP-6) and after combined administration of both peptides was studied in a patient with lactotrope and thyrotrope hyperplasia due to primary hypothyroidism. Pituitary pseudotumor disappeared after thyroid hormone replacement; this was evidenced by magnetic resonance imaging (NMR). There was no difference between areas under the curve (AUCzero-120 min) during GHRH test before and after thyroid hormone replacement (136.5 vs 129.0 micrograms/l min). Maximal GH increases over basal values (delta GH) did not change (1.5 and 1.9 micrograms/l). GH secretion induced by GHRP-6 increased after treatment (AUCzero-120 min 197.2 vs 650.4 micrograms/l min). delta GH increments were 4.0 and 18.3 micrograms/l before and after therapy respectively. When the peptides were administered together a synergistic effect on GH secretion was observed but GH release was much more powerful after pituitary pseudotumor disappearance (AUCzero-120 min 1043.2 vs 2046.7 micrograms/l min). This was accompanied by increased delta GH (22.7 vs 35.5 micrograms/l). The synergic action of peptides normalized in euthyroid condition and after the resolution of pituitary pseudotumor mainly due to improved GH response to GHRP-6. Blunted response of GH to GHRP-6 and GHRP-6 plus GHRH were in part due to known effects of hypothyroidism on GH secretion. Hypothalamopituitary disconnection and/or decrease in the synthesis of an unknown factor in the hypothalamus which mediates the effects of GHRP-6 may have participated in the GH responsiveness of this patient. This case adds to in vivo evidence that GHRP-6 operates through a non-GHRH dependent mechanism.

Case report of hypopituitarism with suspected syndrome of inappropriate VP secretion (SIADH) due to a large aneurysm of the internal carotid in the sellar region

Hypopituitarism and hyponatremia, especially when severe, are infrequent findings particularly when the cause of hypopituitarism at presentation is unknown and untreated. Interestingly, hyponatremia is usually seen in elderly patients with hypopituitarism due to various causes. We present a case with unrecognized and untreated hypopituitarism due to a large aneurysm of the internal carotid artery in the sellar region causing the syndrome of inappropriate secretion of antidiuretic hormone (SIADH).

Intracerebral hemorrhage as a first sign of pheochromocytoma: case report and review of the literature

Pheochromocytomas and sympathetic paragangliomas are rare catecholamine-secreting tumors and represent very rare causes of intracerebral hemorrhage in young, with only few cases reported. A 32-year-old man presented to our emergency department because of sudden onset of severe headache. He had a six months history of paroxysmal headache, palpitations and sweating. During examination he became somnolent and developed left-sided hemiplegia. A computed tomographic (CT) scan of the brain showed a right temporoparietal hematoma. He was admitted to the Clinic for Neurosurgery and hematoma was evacuated. The patient was comatous, on assisted respiration, with frequent hypertensive crises. An examination for possible secondary causes of hypertension was undertaken. Plasma metanephrine value was elevated (414 pg/ml, reference values < 90pg/ml). Abdominal CT scans revealed a large mass (6cm) in the right adrenal gland. After adequate control of the hypertension was achieved with an nonselective α and β adrenergic blockers, the tumor was excised. The histopathologic findings confirmed the diagnosis of pheochromocytoma. The genetic analysis demonstrated a duplication in exon 1 of VHL gene. We reported a rare, potentially fatal complication of pheochromocytoma, an intracerebral hemorrhage. This case and review of the similar rare cases in the literature illustrate the importance of early recognition of the characteristic symptoms of catecholamine excess in young patients with hypertension.

Cognitive functioning and quality of life in patients with Hashimoto thyroiditis on long-term levothyroxine replacement

ObjectiveIntrinsic imperfections of thyroid hormone replacement therapy may affect long-term general well-being. In patients with Hashimoto thyroiditis (HT), cognitive functioning may be affected via altered thyroid hormones action as well as by the autoimmune process. The aim of this study was to evaluate cognitive function and quality of life (QoL) in patients on long-term levothyroxine replacement for HT in relation to thyroid function tests and TPO (thyroid-peroxidase) antibody (TPOAb) status.DesignRetrospective cross-sectional study.Patients and measurementsOne-hundred-and thirty patients with HT on long-term levothyroxine replacement and 111 euthyroid control subjects. Both groups were divided into two age subgroups, 20–49 years (N = 59 vs N = 79) and > 50 years (N = 71 vs N = 32). Evaluation included biochemical and neuropsychological tests, evaluating attention, global cognitive status, verbal and working memory, executive function, depression and anxiety, and quality of life. We used ANOVA and partial correlations to test for significant associations.ResultsFT4 (free-thyroxine), FT3 (free-triiodothyronine) levels and FT3/FT4 ratio were not different between patients and controls. Mean TSH (thyroid-stimulating hormone) was normal in all subjects but significantly higher in the patients (20–49 yrs:3.64 ± 2.74 vs 1.93 ± 1.10, >50 yrs:3.93 ± 2.84 vs 1.91 ± 0.90). Antibodies (TgAb,TPOAb) were higher in patients. Global cognitive function (MMSE-Mini mental state examination), conceptual tracking (TMT-Trail Making Test:A/B), verbal divergent thinking (like Phonemic fluency test), and anxiety and depression scores were significantly worse in patients vs controls. QoL was impaired in patients. there was a significant negative correlation between antibodies (TPOAb, TgAb) and quality in life (total SF36 score).ConclusionPatients on long-term levothyroxine replacement show persistent impairments in both cognitive functioning and general well-being.