Goran Cvijovic

High Risk of Hypopituitarism in Patients Who Recovered from Hemorrhagic Fever with Renal Syndrome

CONTEXT Hemorrhagic fever with renal syndrome (HFRS) caused by hantaviruses, is a severe systemic infection, with acute shock, vascular leakage, hypotension, and acute renal failure. Pituitary ischemia/infarction and necrosis are known causes of hypopituitarism, often remaining unrecognized due to subtle clinical manifestations. Cases of hypopituitarism after HFRS were previously only sporadically reported. OBJECTIVE The aim of this study was to determine, for the first time, the prevalence of hypopituitarism among HFRS survivors. SUBJECTS AND METHODS In 60 adults (aged 35.8+/-1.3 yr) who recovered from HFRS 3.7 +/- 0.5 yr ago (median 2 yr), assessment of serum T(4), free T(4), TSH, IGF-I, prolactin, cortisol, and testosterone (in males) was followed by insulin tolerance test and/or GHRH+GH-releasing peptide-6 stimulation tests. RESULTS Severe GH deficiency was confirmed in eight of 60 patients (13.3%): in five with multiple pituitary hormone deficiencies (MPHDs) and isolated in three. Thyroid axis deficiency was confirmed in five of 60 patients (8.3%), all with MPHD. Hypothalamus-pituitary-adrenal axis deficiency was observed in six of 60 (10.0%); in five with MPHD and isolated in one. Gonadal axis deficiency was confirmed in seven of 56 male subjects (12.5%): five with MPHD and isolated in two. Overall six patients (10.0%) had a single pituitary deficit (three GH, two gonadal, and one adrenal), and five (8.3%) had MPHD. The prevalence of patients having any endocrine deficiency was 18% (11 of 60). CONCLUSION A high prevalence of hypopituitarism after recovery from HFRS is identified, with magnetic resonance imaging revealing atrophic pituitary and empty sella. Awareness is raised to neuroendocrine consequences of HFRS because unrecognized hypopituitarism significantly affects the physical and psychological well-being.

Therapeutic improvement of glucoregulation in newly diagnosed type 2 diabetes patients is associated with a reduction of IL-17 levels.

We explored the effect of therapeutic glucoregulation on the blood levels of proinflammatory T helper (Th)17 cytokines interleukin (IL)-17 and IL-23, and Th1 cytokines interferon (IFN)-γ and IL-12 in newly diagnosed type 2 diabetes patients. The investigated group consisted of 23 subjects (17 men and 6 women, age 26-64). The cytokine serum levels, glycated hemoglobin (HbA1c) as a marker of glucoregulation, homeostasis model assessment index as a measure of insulin resistance (HOMA-IR), and body mass index (BMI) were determined before and after 12 weeks of therapy consisting of standard lifestyle modification and metformin (1000 mg b.i.d.). The levels of Th17 and Th1 cytokines before treatment did not correlate with age, BMI or HOMA-IR. The patients with poor glucoregulation (HbA1c>7%, n=12), compared to those with good glucoregulation (HbA1c≤7%, n=11), had higher serum levels of Th17 and Th1 cytokines, but only the differences in IL-17 (median 21.2 pg/ml vs. 4.8 pg/ml) and IFN-γ 5 (0.6 pg/ml vs. 27.7 pg/ml) reached statistical significance (p=0.003 and p=0.012, respectively). The reduction of HbA1c values (from 8.6 to 5.9%, p=0.000) observed upon treatment in patients with poor glucoregulation was associated with a significant decrease in the concentration of IL-17 (from 21.2 to 12.9 pg/ml, p=0.020), but not IFN-γ (50.6 vs. 52.3, p=0.349). These data indicate that therapeutic improvement of glucoregulation might contribute to a reduction of IL-17 levels in newly diagnosed type 2 diabetes patients.

Hypopituitarism as a late complication of hemorrhagic fever.

We report three patients who developed hypopituitarism as a late complication of hemorrhagic fever with renal syndrome (HFRS). Their past history, physical examination, and endocrine investigation confirmed hypopituitarism. Magnetic resonance imaging of the pituitary revealed atrophic pituitary gland with an empty sella. Hemorrhagic fever is endemic in certain regions of the Balkans, and this preliminary report suggests the importance of investigating the endocrine status in every patient who survived HFRS.

Total ghrelin levels during acute insulin infusion in patients with polycystic ovary syndrome

Controversial data were reported concerning fasting ghrelin (decreased, normal or elevated) in polycystic ovary syndrome (PCOS). The aim of our study was to clarify ghrelin levels in non-obese, overweight, and obese PCOS patients; to investigate the effect of acute insulin infusion on ghrelin in PCOS as a chronic insulin-resistant state, with and without the impact of obesity, and to examine ghrelin-androgen interaction. In that order, we evaluated 1) ghrelin levels among 8 non-obese patients with PCOS [body mass index (BMI): 20.52±1.31 kg/m2], 8 overweight and obese patients with PCOS (BMI: 34.36±6.53 kg/m2) and their respective controls, 2) ghrelin suppression during euglycemic hyperinsulinemic clamp, and 3) ghrelin-androgen interrelationship. After overnight fast, 2-h euglycemic hyperinsulinemic clamp, was performed in all investigated women. Fasting ghrelin was significantly lower in non-obese PCOS than in controls (64.74±25.69 vs 108.36±52.60; p<0.05) as well as in overweight and obese PCOS in comparison with controls (38.71 ± 14.18 vs 98.77± 40.49; p<0.05). Insulin infusion significantly suppressed ghrelin in all subgroups of investigated women. Analysis of variance for repeatable measures confirmed that there was no significant difference in pattern of response between PCOS and controls. In conclusion, women with PCOS had lower fasting ghrelin and decreased insulin sensitivity independently of their BMI, compared to the controls. In addition, there were no differences between fasting ghrelin levels among non-obese, overweight, and obese women with PCOS. During euglycemic hyperinsulinemic clamp, ghrelin decreased in all studied groups to a similar extent, implying that, compared to chronic hyperinsulinemia, acute hyperinsulinemia reduces ghrelin levels independently of the degree of insulin resistance.

Growth hormone replacement normalizes impaired fibrinolysis: New insights into endothelial dysfunction in patients with hypopituitarism and growth hormone deficiency

BACKGROUND Cardiovascular morbidity in adult patients with growth hormone deficiency (GHD) and hypopituitarism is increased. Clustering of cardiovascular risk factors leading to endothelial dysfunction and impaired fibrinolysis has also been reported and may account for progression to overt vascular changes in these patients. However, effect of long lasting GH replacement therapy on fibrinolytic capacity in GH deficient patients has not been investigated so far. OBJECTIVE To investigate fibrinolysis before and after challenge with venous occlusion in GHD patients with hypopituitarism before and during one year of growth hormone replacement. DESIGN Hospital based, interventional, prospective study. INVESTIGATED SUBJECTS Twenty one patient with GHD and fourteen healthy control subjects matched for age, sex and body mass index (BMI). METHODS Anthropometric, metabolic and fibrinolytic parameters were measured at the start and after three, six and twelve months of treatment with human recombinant GH. RESULTS At baseline GHD patients had significantly impaired fibrinolysis compared to healthy persons. During treatment with GH, significant changes were observed in insulin like growth factor 1(IGF-1) [from baseline 6.9(2.4-13.5) to 22.0(9.0-33.0) nmol/l after one month of treatment; p<0.01] and fibrinolysis. Improvement in fibrinolysis was mostly attributed to improvement of stimulated endothelial tissue plasminogen activator (t-PA) release in response to venous occlusion [from baseline 1.1(0.4-2.6) to 1.9(0.5-8.8) after one year of treatment; p<0.01]. CONCLUSION Growth hormone replacement therapy has favorable effects on t-PA release from endothelium and net fibrinolytic capacity in GHD adults, which may contribute to decrease their risk of vascular complications.

Ectopic calcitonin secretion in a woman with large cell neuroendocrine lung carcinoma

OBJECTIVE: Serum calcitonin (CT) is a sensitive but not specific marker for medullary thyroid carcinoma (MTC). There are a large number of conditions that may elevate CT levels. CASE REPORT: Herein we present the case of a 47-year old woman with Hashimoto thyroiditis, goiter, cervical lymphadenopathy and high CT and CEA levels. After surgical extirpation of the lymph node neuroendocrine cancer metastasis was suspected. Computed tomography of the chest showed a tumor mass on the right lung. Bronchoscopy was performed and pathological and immunohistochemical analysis revealed large cell neuroendocrine lung cancer (LCNEC). After chemotherapy, significant reduction of tumor mass was achieved with a moderate decrease in CT levels in parallel. CONCLUSIONS: We present a female with LCNEC, a condition which is usually observed in older men (7th decade) and is not associated with CT secretion. Hashimoto thyroiditis is associated with increased incidence of different types of cancers (e.g. thyroid, colon). No reports at present exist on the incidence of lung cancers in patients with thyroid disease.

Pitfalls in diagnosing a small cystic insulinoma: a case report

Insulinoma is a rare pancreatic endocrine tumour and is typically sporadic and solitary. Over 90% of all insulinomas are benign. Cystic insulinomas are also rare. It is not difficult to determine the site of such neoplasm, as cystic insulinomas are usually 4–10 cm in diameter. We present the case of a patient with a histologically confirmed cystic insulinoma diagnosed after approximately 10 years of hypoglycaemia symptoms. This case is unique because of the small size (2.2 cm) of the tumour. Endoscopic ultrasound (EUS) was useful for localizing this tumour.

Low leptin level in an obese hyperandrogenic woman – potential marker for androgen-secreting tumor

Hyperandrogenism in postmenopausal women is due to ovarian hyperthecosis or an androgen-secreting ovarian/adrenal tumor. Making the correct diagnosis might be complicated due to the possible existence of an adrenal neoplasm secreting testosterone only, ectopic ovarian tissue or ectopic luteinizing hormone/human chorionic gonadotropin receptors in the adrenals, as well as the relatively low sensitivity of imaging techniques (computed tomography, magnetic resonance imaging) and vein catheterization for this type of pathology. We present the case of an obese postmenopausal woman with metabolic syndrome, hyperandrogenism (high testosterone levels, suppressed gonadotropins), adrenal macronodular hyperplasia and Leydig-cell ovarian tumor. At presentation she had low leptin levels despite high body fat content. After a catheter study left adrenalectomy was carried out but hyperandrogenism persisted. Then, bilateral oophorectomy with hysterectomy was performed and a small Leydig-cell tumor was found in the left ovary. Postoperatively, testosterone and gonadotropin levels were normal (postmenopausal) and leptin level became elevated without change in body mass index or body fat content. In conclusion, we speculate that low leptin levels in obese hyperandrogenic women might be a marker for androgen-secreting tumors.

Use of continuous subcutaneous insulin infusion by a portable insulin pump during pregnancy in women with type 1 diabetes mellitus

BACKGROUND/AIM Diabetes mellitus is associated with an increased risk for neonatal morbidity and mortality. One of the most important goals in treating pregnancies complicated with diabetes is keeping glucose level within the normal range, especially in the first trimester. A portable insulin pump for continuous subcutaneous insulin infusion (CSII) represents the best form of therapy for patients with type 1 diabetes mellitus during pregnancy. The aim of our study was to evaluate the effects of therapy with a portable insulin pump for continuous subcutaneous insulin infusion during the first trimester of pregnancy on the quality of glycoregulation and pregnancy outcome in women with type 1 diabetes mellitus. METHODS A total of 17 newly diagnosed pregnant women with type 1 diabetes mellitus were treated with CSII therapy for three months. The parameters of glycoregulation (hemoglobin A, glycosylated--HbAlc, mean blood glucose value in daily profiles--MBG, daily requirement for insulin--IJ/kg BM), lipid levels, blood preassure and renal function were estimated before and after the therapy. These parameters were correlated with parameters of pregnancy outcome: fetal weight, APGAR score, duration of pregnancy. RESULTS There was a significant improvement in HbA1c (8.94 +/- 1.62 vs. 6.90 +/- 1.22 %,p < 0.05), MBG (9.23 +/- 2.22 vs. 6.41 +/- 1.72 mmol/l, p < 0.01), and daily requirement for insulin (0.66 +/- 0.22 vs. 0.55 +/- 0.13 IJ/kg BM, p < 0.05) during the CSII therapy. There were significant correlations between fetal weight and HbAlc (r = -0.60, p < 0.05), triglyceride levels (r = -0.63, p < 0.01), and the number of pregnancies (r = -0.62, p < 0.01), as well as between APGAR score and MBG (r = -0.52, p < 0.05) and cholesterol levels (r = -0.65, p < 0,01) before a portable insulin pump was applicated. CONCLUSIONS There was a significant improvement in the quality of glycoregulation during CSII therapy in the pregnant women with type 1 diabetes mellitus. The quality of glycoregulation in the moment of conception was the important factor for pregnancy outcome.

Growth-hormone response to combined stimulation with GHRH plus GH-releasing peptide-6 in obese patients with polycystic ovary syndrome before and after short-term fasting.

Controversial data were reported on GH response to different provocative stimuli in obese patients with polycystic ovary syndrome (PCOS). The objective of our study was to assess the effect of short-term fasting on GH response to combined stimulus with GHRH+GH-releasing peptide-6 (GHRP-6) in obese patients with PCOS and possible relation with leptin and insulin changes during fasting. Twelve obese PCOS women and nine obese control women participated in 3-day fasting. GH response, IGF-I, insulin and leptin were measured after GHRH+ GHRP-6, before and after short-term fasting. Obese PCOS patients had significantly greater GH peak after GHRH+GHRP-6 before fasting. Enhanced response to GH stimulation was found after fasting without substantial differences between obese PCOS and obese controls. Insulin and leptin significantly decreased, while insulin sensitivity significantly improved in both groups during fasting. In conclusion, obese PCOS patients have peculiar type of GH response to GHRH+GHRP-6 before fasting, possibly due to enhanced sensitivity of somatotrophs. Observed changes in insulin and leptin may participate in modulation of enhanced GH response after short-term fasting to GHRH+GHRP-6 in PCOS and obese controls.