Glucose metabolism, insulin secretion and insulin sensitivity in juvenile hemochromatosis. A case report and review of the literature.

Among specific diabetes subtypes secondary to pancreatopathies, hereditary hemochromatosis is an inherited disorder of iron metabolism resulting in excessive iron overload and tissue damage in various organs. We here report the case of a man with the young-onset form of the disease and describe his glycaemic status before and during venesection therapy. A 25-year old man visited our clinic in Athens, Greece, with hypogonadotropic hypogonadism due to hereditary hemochromatosis. Genetic analysis revealed that he was suffering from the juvenile aggressive form and treatment was initiated with frequent phlebotomies in conjunction with androgen substitution. Within 18 months of therapy ferritin level was normalized and hypogonadism was fully restored. Despite severe iron overload, glucose tolerance remained normal during the various stages of the disease, although alterations in both insulin secretion and sensitivity were detected. Present data indicate that in juvenile hemochromatosis, the efficacy of the chelation therapy and probably the chronic interval required to restore normal iron concentration both play important roles in the formation of glucose metabolism characteristics.

Sporadic hypoparathyroidism treated with teriparatide: a case report and literature review.

Herein we describe the case of a 64-year-old woman with hypoparathyroidism diagnosed at the age of 40, after an acute episode of tetany and seizures due to severe hypocalcemia. She was treated for more than 20 years with calcitriol and calcium supplementation but she presented with marked hypercalciuria and recently nephrolithiasis, although serum calcium was maintained at levels below normal range. Provided that any attempt to increase the recommended dose of calcitriol was leading to an exacerbation of hypercalciuria, we decided to enroll an alternative tool in the treatment strategy. In order to avoid further deterioration of renal function she was administered once-daily a subcutaneous (sc) injection of synthetic human parathyroid hormone (PTH 1-34) while doses of calcium and calcitriol were gradually decreased depending on the response of calcium metabolism in serum and urine samples taken periodically. Within two months of administration, PTH (1-34) significantly reduced the level of urine calcium excretion compared with calcitriol therapy and maintained serum calcium in the normal range. The relevant literature is reviewed in light of this alternative therapeutic approach in long-standing hypoparathyroidism, illustrating the potential benefits and the unresolved issues in parathyroid hormone replacement.

Reduced insulin secretion in normoglycaemic patients with beta-thalassaemia major.

AIMS: To assess insulin sensitivity and secretion in the fasting state in regularly transfused patients with beta-thalassaemia major with normal glucose response during an oral glucose tolerance test and to estimate its possible relation to iron overload. METHODS: We measured fasting glucose, insulin and C-peptide levels in 24 patients with beta-thalassaemia major and 18 control subjects matched for age and body mass index. Insulin sensitivity and insulin release index were calculated according to the homeostasis model assessment (HOMA). Correlations with age, body mass index and serum ferritin were also calculated. RESULTS: Fasting glucose levels in patients were increased compared with control subjects (5.5 +/- 0.12 vs. 4.7 +/- 0.13 mmol/l, mean +/- SEM, P < 0.001). Pancreatic B-cell insulin secretion in the fasting state (estimated by SC(HOMA)) was lower in thalassaemic patients (SC(HOMA) 88.5 +/- 11.11 vs. 184.3 +/- 23.72 in control subjects, P < 0.001). Patients were then divided into those with impaired (IFG) and normal (NFG) fasting glucose. SC(HOMA) was higher in the patients with NFG compared with those with IFG patients (110.6 +/- 17.63 vs. 66.3 +/- 10.88, respectively, P < 0.05) but estimated insulin sensitivity (ISI(HOMA)) was similar. Plasma values of C-peptide correlated positively with ferritin (r = 0.42, P = 0.04) and SC(HOMA) (r = 0.45, P = 0.02) and negatively with ISI(HOMA) (r = -0.43, P = 0.03). CONCLUSIONS: These results support the concept that impaired B-cell function, as reflected by a reduction in the insulin secretion index, is present in beta-thalassaemic patients with normoglycaemia before changes in oral glucose tolerance tests are apparent.

The role of luteinizing hormone activity in controlled ovarian stimulation.

The role of LH in the natural menstrual cycle is undisputed. The active participation of LH in both steroidogenesis and ovulation is well established, but its potential effect on oocyte maturation in the issue of assisted reproduction protocols remains a topic of debate. Although several studies have added to our understanding of the specific actions of androgens in human follicular development, some discrepancies persist regarding their role in oocyte atresia. Clinical situations, where LH is either decreased or absent (e.g. in women with hypogonadotrophic hypogonadism or LH-receptor gene mutations), provide important data supporting the necessity for a minimal amount of LH to evoke ovulation. Recent use of GnRH antagonists, which results in profound suppression of LH concentration, in combination with the pharmacological production of recombinant gonadotrophins, has attracted the attention of investigators. Identification of sub-fertilized women, in whom LH administration could be beneficial and should be indicated, is arousing ever more interest. Based on the available data in the literature, the aims of this review are to assess the role of both endogenous and exogenous LH activity in stimulated cycles, and to evaluate the effects of recombinant human LH supplementation on the ovarian hormonal milieu and on the main outcomes of controlled stimulated cycles.

Effects of estrogen deprivation due to breast cancer treatment.

Breast cancer is one of the main life-threatening diseases that a woman may have to face during her lifetime. The increasing incidence of breast neoplasia reported over the last few decades has led to widespread screening of women resulting in early diagnosis. One common but challenging question for most doctors, after the surgical excision of the lesion, is determination of the ideal adjuvant therapy for their patients for the achievement of maximum life expectancy with the best quality of life. Since the beginning of the last century, the knowledge that breast cancer arises from hormone-responsive tissues has long made use of hormone-blocking agents in the beneficial treatment of breast neoplasia. The discovery of new molecules with endocrine actions has rendered the use of adjuvant therapy in a tailor-made pattern too complicated, as these agents have a different mode of action, different adverse effects and probably different indications. The aim of the present review is to clarify these issues, analyzing the mechanism of action of available drugs and their actions on specific areas of uncertainty: cognitive function, cardiovascular system, urogenital tract, bone metabolism, weight gain, hot flushes and premature menopause. Regarding the efficacy of adjuvant therapy, there has been particular focus on the multiple hormonal-induced consequences of each regimen in order to provide the clinician with the available data for choosing the ideal therapy for the patient.

European Union diabetes indicators: fact or fiction?

Diabetes mellitus is one of the major causes of morbidity and mortality in EU/EFTA countries. Monitoring risk factors for diabetes and its complications will offer the possibility to evaluate the development in time as well as the influence of possible interventions. In this investigation a list with core and secondary indicators is proposed. Availability of these indicators and their data sources is discussed. An important variability of data sources is used in EU/EFTA countries, interfering with the comparability of the outcome. Further harmonisation as well as continuous evaluation of data sources will be necessary to provide reliable tools to monitor diabetes mellitus and its outcome on a routine basis.

Psychophysiological correlates in male to female transsexuals studied with a P300 investigation.

BACKGROUND: Transsexualism is thought to be related to cortical processes reflecting a complex mosaic of biological, psychological and social/cultural information. Since the P300 component of event-related potentials is considered as an index of attentional processes, the present study focuses on auditory P300 elicited during a short memory test in male to female (MF) transsexuals, compared with that in healthy controls. METHOD: The P300 component was evaluated during the anticipatory period of a short memory test in 13 MF transsexuals who had a gender reassignment operation, at least 3 years previously (mean time 17-6 years, range 3-31 years) and 26 healthy subjects (11 males and 15 females) matched for age and educational level. RESULTS: MF transsexuals exhibited significant reduction of P300 amplitude in the left frontal and temporoparietal areas in comparison to the control group. Furthermore, the group of transsexuals showed a significant delay of P300 latency in comparison to the controls, at the central frontal region. CONCLUSIONS: These findings point to significant psychophysiological alterations of distributed cortical circuits in MF transsexuals. These alterations may be critically related to the biological substrate of MF transsexualism.

Human growth hormone and gonadotropin releasing hormone analog combination therapy increases predicted height in short normal girls.

The "short normal" child constitutes a real challenge for the pediatric endocrinologist. In a subgroup of short normal children, puberty starts at a normal age but with low height, and hence, the final height is expected to be quite compromised. Efforts to improve the outcome in this group have been made in the past with equivocal results. We present the growth data of 8 short girls with normal growth hormone values on provocative testing and low height at puberty initiation. At intervention the height and the stage of puberty were 129.3 +/- 5 cm and II to III, respectively, and the predicted height was 148.8 +/- 2.6 cm. Gonadotropin releasing hormone analog, triptorelin (3.6 +/- 0.5 microg/kg/day) and growth hormone (0.5 IU/kg/week) were used in different sequential order and simultaneously in each child. The mean total treatment period was 47.6 +/- 11.2 months. The mean predicted and the mean final height in the total group were 148.8 +/- 2.6 and 154.5 +/- 3.6 cm, respectively (p:0.028). The final height did not differ from the target height (154.8 +/- 8 cm versus 154.5 +/- 3.6 cm), while in 4 children, the final height was greater than the target height. The height gain (delta Final height - Predicted height) was 5.7 +/- 1.3 cm. If we analyze separately the girls in whom growth hormone was started first and gonadotropin releasing hormone analog followed versus those who started the analog first, the delta Final height - Predicted height was 8 +/- 3 cm in the former and 4.8 +/- 3.1 cm in the latter (p:0.03). It seemed that the difference was accounted for by duration of growth hormone therapy (51.3 +/- 10.6 months versus 28.6 +/- 10.6 months) (p:0.026), rather than by other factors. In conclusion, under the conditions of the present study, the combination of puberty arrest and growth hormone therapy significantly improved predicted height. The most significant determinant of the height gain was the duration of growth hormone therapy.

Pituitary non-secreting macroadenoma apoplexy in an adolescent. patient report and review of the literature.

Pituitary macroadenomas are rare in children and adolescents, and when encountered are usually hormone secreting. Symptomatic pituitary non-secreting macroadenoma apoplexy in an adolescent is rare and potentially life-threatening. A 15 year-old patient is described, hospitalized due to headache, fever and photophobia 4 days prior to admission. A meningeal syndrome was postulated, based on clinical examination and cerebrospinal fluid testing. However, clinical examination and hormone testing revealed partial failure of the anterior pituitary. Computed tomography of the brain demonstrated a space-occupying lesion of the pituitary. Magnetic nuclear resonance imaging suggested the presence of a pituitary macroadenoma. Hypophysectomy was performed. Histological examination revealed an extensive infarction of a pituitary adenoma. Hormonal substitution with thyroxine and corticosteroids was administered. This report emphasizes that pituitary non-secreting macroadenoma apoplexy may rarely be the cause of headache and fever in an adolescent, thus causing difficulties in differential diagnosis from acute meningitis.

Elevated prolactin to cortisol ratio and polyclonal autoimmune activation in Hashimoto's thyroiditis.

Cortisol and prolactin, which are considered to have an immunomodulatory effect, and selected autoantibodies were determined in Hashimoto's thyroiditis. 37 patients (8 males and 29 females) (54 +/- 13.8 years) and an equal number of sex- and age-matched normal subjects (52.6 +/- 14.2 years) were studied. None of the 74 subjects suffered from any other immunological, infectious, hepatic, renal or malignant diseases. Patients with Hashimoto's thyroiditis exhibited significantly higher (p < 0.016) prolactin values (14.0 +/- 3.8 ng/ml) than did control subjects (6.5 +/- 1.3 ng/ml). In contrast, cortisol levels were lower in Hashimoto's thyroiditis (13.5 +/- 3.2 microg/dl) vs. normal state (16.0 +/- 1.13 microg/dl), (p < 0.05). The prevalence of anti-TPO and anti-Tg antibodies was 100 % and 43 % in the patients with Hashimoto's disease. In contrast, no subject of the control group was positive for anti-TPO, although 9 subjects (24 %) were positive for anti-Tg autoantibodies. The percentage of positive autoantibodies to nucleus, smooth-muscle, and parietal cells in the patients (36.0, 10.9 and 18.5 %, respectively) was higher than that in healthy group (11.0 and 0 % respectively). Notably, neither group was positive for antibodies against double-stranded DNA or mitochondria. In conclusion, our results provide evidence for a polyclonal activity in Hashimoto's thyroiditis, an organ-specific autoimmune disease, associated with an altered prolactin-adrenocortical status. Such information should initiate longitudinal studies to clarify the exact time sequence of these events related to the disease's activity.

Inferior vena cava and right atrial thrombosis in children with nephroblastoma: diagnostic and therapeutic problems.

BACKGROUND: The neoplastic thrombus in Wilms' tumor rarely can extend in to the inferior vena cava or to the right atrium. The neoplastic thrombus usually is diagnosed concurrently with the tumor, although in some cases the diagnosis of the thrombus may precede the diagnosis of nephroblastoma. METHODS: Among 90 children with Wilms' tumor who were treated in the authors' unit, 4 had extensive tumor thrombosis of the inferior vena cava or the right atrium. One of these patients was found with a life-threatening thrombosis of the inferior vena cava and the right atrium, which was treated surgically; in this case, the diagnosis of nephroblastoma was made postoperatively. As for the 3 remaining patients the diagnosis of neoplastic thrombosis and Wilms' tumor was made simultaneously. RESULTS: In the first case, the patient underwent surgical excision of the thrombus with cardiopulmonary bypass and a short period of hypothermic cardiopulmonary arrest. In the other 3 cases the thrombus resolved with chemotherapy only. CONCLUSIONS: Surgical excision of extensive neoplastic thrombosis is suggested in the case of life-threatening thrombosis even with cardiopulmonary bypass. Chemotherapy is suggested in cases lacking clinical symptoms of thrombosis.

Cardiomyopathy due to a pheochromocytoma. A reversible entity.

A 45-year-old male presented with acute pulmonary oedema, chest pain and electrocardiographic manifestations of acute myocardial ischaemia in the setting of hypertension crisis from a hyperfunctioning large left-sided pheochromocytoma. Coronary artery disease was excluded on the basis of thallium stress testing and coronary angiography. The latter revealed a picture consistent with dilated cardiomyopathy. After surgical resection of the tumour, both the hypercatecholaminaemia and the arterial hypertension subsided promptly with gradual improvement of the cardiomyopathy and complete resolution of the congestive heart failure symptoms.

Orexis, anorexia, and thyrotropin-releasing hormone.

The hypothalamus, long known to play a determinant role in food intake and satiety, has recently been shown to exert this homeostatic function via peptidergic neuronal circuits. The major peptide that has been identified as orexigenic, namely neuropeptide Y (NPY), is suppressed by leptin, an adipocyte-derived hormone, in a potential circuit that seems to function as an adipostat. Information regarding energy balance is fed back to the paraventricular nucleus of the hypothalamus where a complex interplay between thyrotropin-releasing hormone (TRH) and corticotrophin-releasing hormone (CRH) determines consequent effects in thermogenesis and stress reactions. Inflammatory mediators that have been implicated in anorexia simultaneously suppress TRH in a dominant way that overcomes the feedback effects of the thyroid hormones. Moreover, endogenous opioids and melanotropic peptides modulate orexigenic and thermogenic effects in a complex, yet poorly understood, way. However, TRH metabolism, which is affected by dietary modifications, seems to be involved in the orexigenic events that take place in the hypothalamus. It is, therefore, evident that TRH is directly involved in the complex hypothalamic networks that establish energy balance by modulation of food intake, satiety, thermogenesis, and other autonomic responses.

Dissociation of ACTH, beta-endorphin and cortisol in graded sepsis.

The function of the hypothalamic-pituitary-adrenal axis as related to the degree of severity of a septic process was assessed by measuring plasma levels of beta-endorphin, ACTH and cortisol. Sixty-one cases of postoperative patients treated at the intensive care unit were classified into four groups according to the severity of infection: Group 1 (control) included patients who did not show any sign of infection, group 2 patients with sepsis, group 3 patients with septic syndrome and group 4 patients with septic shock. Compared to G1 patients' ACTH values (4.16+/-2.6pg/ml), a statistically significant increase in ACTH values in various stages of septicemia (p < 0.005) with a noticeable difference also between G3 (7.11 +/-3.7pg/ml) and G4 (11.5+/-6.6pg/ml) (p<0.05) was found. Differences were also observed in beta-endorphin (with a level of significance between the several groups of p = 0.0001). Also, beta-endorphin values in G4 (40.6+/-30.3 pg/ml) differed significantly from each of G1 (17.5 +/-6.6 pg/ml), G2 (21.1+/-11.3 pg/ml) and G3 (23.5+/-12 pg/ ml) (p<0.05). A progressive hypercortisolemia was obvious, with values of G4 (37.2+/-15.6 microg/dl) differing significantly from those of G1 (18+/-4.6microg/dl) and G2 (24-/+8.4microg/dl) (p<0.05) and of G3 (28.5+/-12.3 microg/dl) from that of G1 (p < 0.05). Interestingly, a dissociation of ACTH, beta-endorphin and cortisol was observed, in that the increased values of beta-endorphin and cortisol, detected in the G3 were not associated with a parallel increase in ACTH. These findings might be interpreted in the sense of an impairment of the stress stimulation of the hypothalamic pituitary adrenal axis. Provided that such a situation can be lethal, our results further confirm the idea that a low-dose, steroid replacement might be beneficial to critical illness.

Valve replacement under retrograde warm-blood cardioplegia. Results in 287 patients.

We studied 287 consecutive patients who underwent valve replacement procedures under retrograde warm-blood cardioplegia between 1 March 1992 and 30 June 1997 (64 months). Some of the procedures were performed in combination with other operations (70), but most (217) were isolated. Thirty patients had undergone previous "open" procedures and another 25 patients had undergone prior "closed" procedures. The 30-day postoperative mortality rate was 3.8% (11 deaths). In 7 patients, the cause of death was not cardiogenic. We did not observe any instance of right ventricular failure, perforation of the coronary sinus, phrenic nerve palsy, or wound infection. These results indicate that retrograde warm-blood cardioplegia provides excellent myocardial protection of both ventricles during valve replacement.

The effect of a pure antiandrogen receptor blocker, flutamide, on the lipid profile in the polycystic ovary syndrome.

Polycystic ovary syndrome (PCOS) is one of the most common endocrinopathies affecting women of reproductive age; it is associated with hyperandrogenism, hyperinsulinemia, and dyslipidemia. This study was designed to assess the long term effects of a pure androgen receptor blocker, flutamide, on the lipid profile in women with PCOS and to examine the possible mechanisms by which androgens may exert their influence. Seventeen women with PCOS (10 obese and 7 lean) were studied. All subjects received a 12-week course of oral flutamide (500 mg/day). The baseline and posttreatment evaluations included lipid profile, androgen levels, insulin sensitivity, and serum catecholamine determinations. The primary outcome was the change in the ratio of low density lipoproteins (LDL) to high density lipoproteins (HDL). Treatment with flutamide was associated with a significant decrease in the LDL/HDL ratio by 23% (P = 0.005), in total cholesterol by 18% (P < 0.0001), in LDL by 13% (P = 0.002), and in triglycerides by 23% (P = 0.002). Flutamide treatment was also associated with a trend toward an increase in HDL (by 14%; P = 0.14). The effects on lipid profile were found regardless of obesity and were not associated with a change in weight. Furthermore, actions of flutamide on lipid metabolism were not associated with significant changes in circulating adrenaline or noradrenaline, glucose metabolism, or insulin sensitivity. This report has demonstrated for the first time that treatment with the pure antiandrogen, flutamide, may improve the lipid profile and that this effect may be due to direct inhibition of androgenic actions.

Sex hormonal preparations and the liver.

The long-term use of oral contraceptives (OCs) may be associated with an increased, though quite small, risk of certain types of liver disease: acute intrahepatic canalicular idiosyncratic cholestasis, benign hepatic tumors (hepatic adenoma, focal nodular hyperplasia, hemangiomas), hepatocellular carcinoma, peliosis hepatis, hepatic vein thrombosis, and portal vein thrombosis. Estrogens have lithogenic properties, as shown by a rise in biliary cholesterol secretion and cholesterol saturation index, yet no substantial increase in the risk of gallstones among estrogen users has been found. Hormone replacement therapy (HRT), given after oophorectomy or menopause, is not associated with clinically significant liver injury. Generally speaking, synthetic sex hormones should not be used in patients with acute and chronic liver disease. A trial of a low-dose estrogen can be instituted under close monitoring for adverse reactions and HRT preparations are not contraindicated in patients with chronic liver disease. Moreover, OCs and HRT can be prescribed quite safely following successful liver transplantation. The incidence of hepatic abnormalities in patients taking androgen hormones is very high. Liver adenomas, cholestasis, peliosis, nodular regenerative hyperplasia and, particularly, hepatocellular carcinoma may complicate long-term use of C17-substituted testosterone and anabolic steroids.