Euthyroid women with autoimmune disease undergoing assisted reproduction technologies: the role of autoimmunity and thyroid function.

UNLABELLED: Thyroid dysfunction and the presence of thyroid antibodies increase the risk of infertility and miscarriage. The aim of the present study was to assess if patients with autoimmune thyroid disease undergoing assisted reproduction technologies (ART) are afflicted by poor pregnancy and/or delivery rate and if the outcome is conditioned by pre-ART thyroid status. The study was retrospective (from January 2000 to January 2005) and was carried out at the Division of Physiopathology of Human Reproduction. Women who underwent ART were tested for TSH, free T4 (FT4), thyroid peroxidase antibodies (TPOAb) before and during pregnancy. A total of 416 euthyroid women were selected; 42 (10.1%) were TPOAb (+). Women >35 yr were excluded. The endpoints were pregnancy and delivery rates. RESULTS: no differences in pregnancy and delivery rates were observed between women with and without antibodies. In TPOAb (+), women who failed to become pregnant or miscarried displayed higher TSH values before ART (2.8 mIU/l) compared to the ones who delivered (1.6 mIU/l; p=0.032) and compared to TPOAb (-) (1.1 mIU/l; p=0.018). CONCLUSIONS: in euthyroid women undergoing ART the pregnancy and delivery rates are not affected by the presence of TPOAb. In TPOAb (+) high-normal TSH values are associated with increased risk of unsuccessful pregnancy or subsequent miscarriage. Further studies are required to ascertain possible benefits of levo-T4 (L-T4) in such patients.

Can gangrenous cholecystitis be prevented?: a plea against a "wait and see" attitude.

BACKGROUND/AIMS: A delay in recognizing and treating an inflamed gallbladder may increase the risk of a necrotic evolution and represent a critical factor affecting the progression of the inflammatory process. Aim of the study is to assess the therapeutic attitude in patients with histologically proved gangrenous cholecystitis, to find out whether it could play a role in the progression of the inflammatory condition. METHODOLOGY: Twenty-seven patients with gangrenous cholecystitis at histology were compared with a matched-control group with phlegmonous cholecystitis. RESULTS: Age, gender, ASA score, and concomitant diseases did not differ significantly in both groups. WBC was significantly higher (P = 0.026) in patients with gangrene. Ultrasounds were unhelpful in identifying the severity of the disease. Patients with gangrenous gallbladder showed a significantly increased (P = 0.0006) admission delay compared with controls (104.3+/-15.3 hours vs. 59.7+/-7.7 hours). Surgeon's delay, morbidity and mortality were not different in both groups. CONCLUSION: Patient's delay before hospitalization may represent a crucial factor in the progression toward a more severe disease in acute cholecystitis. The time between symptoms onset and hospital admission (and consequently surgery) was significantly longer in patients with gangrenous cholecystitis, further emphasizing the need for an early (if not urgent) surgical treatment in acute cholecystitis, even with mild symptoms.

Pioglitazone reduces blood pressure in non-dipping diabetic patients.

AIM: The association between insulin resistance and hypertension is firmly established and has been extensively investigated. Thiazolidinediones (TZD), a class of oral hypoglycemic agents that act as insulin sensitizers have been demonstrated, in many in vivo and in vitro studies, to possess antihypertensive properties. Whether the ability of TZD to lower blood pressure (BP) should be ascribed to a reduction of insulin resistance, or to a direct vasodilating effect, is matter of debate. Since blunted BP nocturnal dipping precedes overt hypertension and is associated with an increased risk of adverse cardiovascular events, we evaluated the pioglitazone effects on BP in non-dipper type 2 diabetic patients. METHODS: Forty non-dipper diabetic patients were randomly assigned to metformin + placebo (M) or metformin + pioglitazone 30 mg (MP) and submitted to 24 hours blood pressure monitoring at the beginning and after 8 weeks. RESULTS: After 8 weeks of treatment in subjects on metformin + pioglitazone 30 mg (group MP1), we found a reduction of nocturnal blood pressure values (mean nocturnal systolic BP 128.05+/- 1.23 vs 122.8+/-2.3 mmHg; p<0.02; mean nocturnal diastolic BP 81.2+/-0.99 vs 75.65+/-0.93 mmHg; p<0.005). The observed improvements in BP were independent from changes in metabolic parameters. CONCLUSION: The obtained data show that pioglitazone was effective in reducing BP values in non-dipping diabetic patients. The reduction of BP values was independent from amelioration of the metabolic picture: that suggest the hypothesis that these ameliorations may be also due to a direct antihypertensive action exerted by pioglitazone.

The management of thyroid disease by GPs.

BACKGROUND: Good medical practice depends on a collaborative relationship between a GP and a targeted specialist. OBJECTIVE: The aim of the present study was to assess knowledge and management by GPs of common endocrine disorders such as thyroid diseases. METHODS: We submitted to all the GPs (622) of the Province of Lecce an anonymous questionnaire with 11 questions which aimed to evaluate methods of approach to (questions 1 and 2) and knowledge about (questions 3-11) thyroid diseases. RESULTS: (i) Most GPs (72.1%) evaluate thyroid function on the basis of a clinical suspicion and perform preliminary investigations before referring the patient to a specialist. (ii) The ratio between right and wrong answers was significantly higher for four questions, significantly lower for one question and distributed by chance for four questions. (iii) The degree of knowledge strictly corresponds to the GP's attitude to patient's management. CONCLUSIONS: For a thyropathic patient to be diagnosed rapidly and treated efficiently, it is necessary to disseminate knowledge of standardized protocols to ensure a better utilization by both the GP and the endocrinologist of their respective competences.

The control of blood glucose in the critical diabetic patient: a neuro-fuzzy method.

Conventional algorithms for regulating insulin infusion rates in those critical diabetic patients submitted to parenteral glucose and insulin infusions do not allow to approach near normal blood glucose (BG) levels since traditional control systems are not fully effective in complex nonlinear systems as BG control is. Thus, we applied fuzzy logic principles and neural network techniques to modify intravenous insulin administration rates during glucose infusion. Forty critically ill, fasted diabetic subjects submitted to glucose and potassium infusion entered the study. They were randomly assigned to two treatment regimes: in group A, insulin infusion rates were adjusted, every 4 h at any step between -1.5 and +1.5 U/h, according to a neuro-fuzzy nomogram; in control group B, insulin infusion rates were modified according to a conventional algorithm. In group A, BG was lowered below 10 mmol/l faster than in group B (8.2+/-0.7 vs. 13+/-1.8 h, P<.02). Mean BG was 7.8+/-0.2 in group A and 10.6+/-0.3 mmol/l in group B (P<.00001). BG values below 4.4 mmol/l were: A=5.8% and B=10.2%. BG values lower than 2.5 mmol/l had never been observed. In conclusion, the neuro-fuzzy control system is effective in improving the BG control in critical diabetic patients without increasing either the number of BG determinations or the risk of hypoglycemia.

[Evaluation of the treatment with L-thyroxine: lack of correspondence between objectives and results]. / Valutazione del trattamento con L-Tiroxina: mancata corrispondenza fra obiettivi e risultati.

BACKGROUND: Hypothyroidism and nodular goiter are two frequent endocrine diseases which respectively require substitutive and suppressive treatment with L-Thyroxine. Objective of this work was to evaluate the correspondence between expected and obtained TSH values in patients affected with hypothyroidism and nodular goiter submitted to L-Thyroxine treatment. SETTING AND SUBJECTS: a questionnaire addressed to patients on L-Thyroxine has been available in consulting rooms of 12 family doctors of Lecce County (Italy) for a 6 month period. A hundred-twelve patients answered the questionnaire: 44 were on suppressive treatment for uni/multinodular goiter (group 1) and 68 were on substitutive treatment for hypothyroidism (group 2). RESULTS: TSH dosage had been performed since less than 1 year in 91% of group 1 patients and in 87% of group 2 patients (p = ns), in group 1, 25% of TSH values were < 0.3 microU/ml, 68.2% between 0.3 and 4.5 microU/ml, 6.8% > 4.5 microU/ml (p < 0.001); in group 2, 25% of TSH values was < 0.3 microU/ml, 63.3% between 0.3 and 4.5 microU/ml, 11.8% > 4.5 microU/ml: (p < 0.001). The distribution of TSH values between the two groups was not significantly different. In patients on suppressive treatment TSH was suppressed in a number of patients significantly less in respect to the ones with not suppressed TSH value: 11 vs 33; p < 0.01; in patients on substitutive treatment the number of those ones with TSH values in between the normal range was not different from patients with TSH values above or below the normal range: 43 vs 25; p = ns. Considering the two groups together, in 52% of patients TSH was not correspondent to therapeutical objectives. CONCLUSIONS: Inspite of regular checks of thyroid function, proper TSH values were achieved only in half of patients.

Effects of alcohol consumption and accompanying diet on metabolic response to arginine in chronic alcoholics.

OBJECTIVE: To evaluate, in chronic alcoholics, the effects of accompanying diet on the release of insulin (IRI) and glucagon (IRG) and on the hepatic glucose production. METHOD: We evaluated variations of the response to the infusion of arginine into 16 male and 8 female chronic alcoholics divided into three groups of eight subjects each before and after three weeks of treatment with: (1) an isocaloric diet plus 200 g/day of ethanol; (2) an hypocaloric diet without alcohol (17.5 kcal/kg/day); and (3) an isocaloric diet (35 kcal/kg/day). Statistical evaluation was done by Kruskall-Wallis ANOVA and by Wilcoxon matched-pairs signed rank test. RESULTS: After isocaloric diet plus ethanol both IRI/IRG ratios and plasma glucose during arginine testing remained unmodified; after the hypocaloric diet IRI/IRG remained unmodified and the arginine-induced plasma glucose rise was slightly but significantly reduced; after the isocaloric diet there was a strong decrease of the arginine-induced plasma glucose rise because of a significant increase in the insulin/glucagon ratio. CONCLUSIONS: In chronic alcoholics the replacement of the usual hypocaloric diet with an isocaloric one while maintaining alcohol consumption does not modify the metabolic response to arginine administration; the hypocaloric diet without alcohol increases insulin and glucagon release and slightly decreases liver glycogenolysis; the replacement of the usual hypocaloric diet with an isocaloric one together with alcohol withdrawal stimulates insulin, inhibits glucagon release and lowers glycogenolysis much more than observed with hypocaloric diet alone.

Thyrotropin-releasing hormone-induced GH release after cocaine withdrawal in cocaine addicts.

During cocaine addiction the hypothalamus-pituitary axis is widely affected and a blunted response of thyroid stimulating hormone (TSH) to thyroid releasing hormone (TRH) consistent with a hyperthyroid state has been observed. Since the thyroid status can affect the release of growth hormone (GH) the authors evaluated TSH and GH responses to TRH in cocaine addicts at the time of drug withdrawal and 30 days after. Twenty-six male cocaine addicts and 11 healthy male control subjects agreed to participate in the study. TRH and placebo tests were performed at random at 5 day intervals at the time of drug withdrawal and after 30 days. In drug addicts, at the time of the first test basal plasma levels of freeT3, freeT4 and TSH were normal, but the TSH response to TRH was impaired. After 30 days of cocaine abstinence basal freeT4 plasma levels were significantly lower, and TSH levels and the TSH response to TRH were higher than in the first test. At the first examination, basal GH concentrations were similar in cocaine addicts and in control subjects and GH did not respond to TRH. After 30 days of abstinence, basal GH plasma levels were unmodified, but the TRH became stimulatory of GH release in cocaine-deprived, but not in control subjects. In conclusion, in cocaine addicts, drug withdrawal is associated with a condition of subclinical hypothyroidism that makes the GH-releasing machinery sensitive to TRH.

Power spectral analysis of heart rate in hyperthyroidism.

The aim of the present study was to evaluate the impact of hyperthyroidism on the cardiovascular system by separately analyzing the sympathetic and parasympathetic influences on heart rate. Heart rate variability was evaluated by autoregressive power spectral analysis. This method allows a reliable quantification of the low frequency (LF) and high frequency (HF) components of the heart rate power spectral density; these are considered to be under mainly sympathetic and pure parasympathetic control, respectively. In 10 newly diagnosed untreated hyperthyroid patients with Graves' disease, we analyzed power spectral density of heart rate cyclic variations at rest, while lying, and while standing. In addition, heart rate variations during deep breathing, lying and standing, and Valsalva's maneuver were analyzed. The results were compared to those obtained from 10 age-, sex-, and body mass index-matched control subjects. In 8 hyperthyroid patients, the same evaluation was repeated after the induction of stable euthyroidism by methimazole. Heart rate power spectral analysis showed a sharp reduction of HF components in hyperthyroid subjects compared to controls [lying, 13.3 +/- 4.1 vs. 32.0 +/- 5.6 normalized units (NU; P < 0.01); standing, 6.0 +/- 2.7 vs. 15.0 +/- 4.0 NU (P < 0.01); mean +/- SEM]. On the other hand components were comparable in the 2 groups (lying, 64.0 +/- 6.9 vs. 62.0 +/- 6.5 NU; standing, 77.0 +/- 6.5 vs. 78.0 +/- 5.4 NU). Hence, the LF/HF ratio, which is considered an index of sympathovagal balance, was increased in hyperthyroid subjects while both lying (11.3 +/- 4.5 vs. 3.5 +/- 1.1; P < 0.05) and standing (54.0 +/- 12.6 vs. 9.8 +/- 2.6; P < 0.02). This parameter was positively correlated with both T3 (r = 0.61; P < 0.05) and free T4 (r = 0.63; P < 0.05) serum levels. Among traditional cardiovascular autonomic tests, the reflex response of heart rate during lying to standing was significantly lower in hyperthyroid patients than in controls (1.12 +/- 0.03 vs. 1.31 +/- 0.04; P < 0.002). No statistically significant difference in reflex responses between the two groups was found in deep breathing or Valsalva's maneuver. In the 8 patients reexamined after methimazole treatment, we observed complete normalization of altered cardiovascular parameters, with slight predominance of the vagal component compared with controls. These results suggest that thyroid hormone excess may determine reduced parasympathetic activity and, thus, a relative hypersympathetic tone.

Effects of maternal weight variations and gestational diabetes mellitus on neonatal birth weight.

We evaluated the effects of gestational weight gain on neonatal birthweight women in whom gestational diabetes mellitus (GDM) was diagnosed after the 32nd week of gestation. The prevalence of macrosomia, the birthweight differences from 50th percentile value of a reference population, and the relationships among plasma glucose values during oral glucose tolerance test and neonatal birthweight were evaluated in 60 newborns from mothers with gestational diabetes mellitus divided according to pregravid body-mass index. Serving as controls were 132 newborns of mothers with normal glucose tolerance. The prevalence of macrosomia was higher in the GDM group; the neonatal birthweight difference above 50th percentile value was higher in newborns of mothers with GDM; and a strong relationship between maternal gestational weight gain and neonatal birth weight was present in all pregnant women. In conclusion, (1) the gestational weight gain is a good predictor of neonatal birth weight in all pregnant women; (2) GDM enhances the increase in neonatal size induced by excessive gestational weight gain alone, and (3) a weight gain of more than 9 kg makes the relative risk of macrosomia twofold higher in GDM than in control mothers.

[Pre-pregnancy evaluation of the diabetic woman]. / Valutazione pre-gravidica della donna diabetica.

In this paper we examine the work that a diabetologist should do in a diabetic women before she starts a pregnancy. To program a pregnancy in diabetic women is an important medical problem that faces the need to avoid some maternal and fetal complications that can sometimes be life-threatening. We separately consider the problem in diabetic women and in women at risk for gestational diabetes. As main items to be previously considered to minimize the risk of fetal and/or maternal complications in the pregnant diabetic women we consider the compliance to treatment the evaluation of diabetic complications, the optimization of treatment, and mainly the availability of an enough time to start the pregnancy in a stable and good metabolic condition.

Blood pressure tracking in adolescents with insulin-dependent diabetes mellitus.

Hypertension, one of the most frequent and important complications of insulin-dependent diabetes mellitus (IDDM), usually begins in the second decade of the disease and is rare in childhood. We analysed the blood pressure (BP) levels of 106 patients (48 males, 58 females, aged 2-16 years) in relation to sex and age and we studied the modification of BP with years (tracking). BP levels, registered every three to six months, were compared with the local standard levels for age and expressed as standard deviation scores (SDS) of the means. For each subject a regression line describing the change of the SDS over time was calculated by the method of least squares. The slope of this line is called trend and represents the tendency of BP to increase or decrease with time, i.e. to develop (or not) hypertension. All patients, except one 16 year old girl, had normal BP and no microalbuminuria but ten of them presented with mean levels in the upper quartile and/or a constantly upward BP trend and were considered at risk. After a three year follow-up four of these ten patients became frankly hypertensive with increased microalbuminuria. These results agree with previous findings and with the hypothesis that an increase of intraglomerular and/or systemic BP may precede the appearance of (and even could be responsible for) microalbuminuria. The BP tracking study in IDDM children and adolescents could be useful for an early recognition of patients at risk of developing hypertension and diabetic nephropathy.

Non-paroxysmal arterioventricular junctional tachycardia during postprandial hypoglycaemia in an obese non-diabetic patient.

We have observed the simultaneous occurrence of postprandial hypoglycaemia and a rare cardiac arrhythmia: non-paroxysmal arteriovenous junctional tachycardia (NPJT) in a patient with suspected coronary heart disease (CHD) submitted to oral glucose tolerance testing (OGTT). To our knowledge the association between hypoglycaemia and NPJT has not been previously described. The pathogenesis of NPJT might involve a myocellular Ca2+ overloading determined by a hypoglycaemia-induced catecholamine discharge in a transiently ischaemic myocardium.

Glucose tolerance and insulin release in adolescent female.

The increase in insulin requirement at the onset of adolescence is compensated by an increase of insulin secretion. This metabolic pattern persists during adolescence but is no longer present in adults. It is supposed to depend on a decrease of insulin sensitivity of uncertain origin. We compared the metabolic pattern of late adolescent girls (13-16 year old) with young women (21-30 year old) with similar body mass indexes, testing subjects with iv glucose tolerance test (IVGTT) (glucose 0.33 g/kg) and arginine test (ATT) (arginine 30 g in 30 min). In late adolescent vs adult women we observed: i) IVTT: similar k of glucose tolerance and higher insulin and C-peptide responses; ii) ATT: unmodified plasma glucose, insulin and glucagon values, higher GH plasma levels; iii) in adolescent girls GH and CPR incremental areas significantly correlated (r = 0.755, p less than 0.05). These data show that: i) the adolescent pattern of glucose metabolism persists after completion of sexual development and, ii) there is a positive correlation between GH response to arginine and beta-cell response to glucose. So GH should play a role in the impairment of glucose metabolism during adolescence.

Insulin and glucagon levels in fulminant hepatic failure in man.

The behavior of insulin and glucagon and related metabolic substrates was assayed in plasma of patients with fulminant hepatic failure. All 12 subjects were provided the same nutritional support. High levels of insulin and glucagon were present at all times and no difference was observed between surviving patients (four) and those who died (8). Elevated values for branched-chain and aromatic amino acids as well as alanine were present. Statistically significant lower levels of aromatic amino acids and consequently a greater branched chain-aromatic amino acid ratio was found in surviving vs nonsurviving patients. A significantly greater level of alpha-fetoprotein was found in patients who survived as compared to those who died.

Lack of effect of nicardipine and diltiazem on glucose- and arginine-induced insulin release in obese subjects.

The metabolic effects of calcium channels blockers have already been studied both in normal and diabetic humans and results were quite controversial, depending on the drug used, the dose administered, and the type of patient. Little information exists on the use of Ca2+ antagonists in obese people, even if these persons are a population risk group for developing diseases in which these drugs may be requested for treatment. Thus, we evaluated, in obese humans, the metabolic effects of two Ca2+ antagonist drugs recently made commercially available to treat diseases such as hypertension and ischemic heart disease: nicardipine and diltiazem. Sixteen obese subjects were submitted to an intravenous glucose tolerance test (0.33 g/kg) (IVGTT) and an arginine test tolerance (30 g in 30 minutes) (ATT) before and after a week of oral treatment with nicardipine (60 mg/day) or diltiazem (360 mg/day). Plasma values of glucose, insulin, and C-peptide during IVGTT, and of glucose, insulin and glucagon during ATT did not show any modification during treatment with either drug. Thus the Ca2+ antagonists, nicardipine and diltiazem, at therapeutic doses in obese subjects do not significantly affect glucose tolerance or insulin and glucagon release.

Perioperative management of diabetic subjects. Subcutaneous versus intravenous insulin administration during glucose-potassium infusion.

The purpose of this study was to validate methods for the perioperative management of diabetic patients that meet the prerequisites of simplicity, applicability in the absence of a diabetologist, and flexibility, to rapidly meet changing metabolic requirements. The patients were divided into two groups that were comparable for age, sex distribution, type of diabetes, and type of surgical procedures. The results show that intravenous insulin administration achieved better glycemic control during the intraoperative period, whereas it did not offer advantages over the subcutaneous route during the pre- and postoperative periods. The satisfactory degree of steady glycemic control achieved and the absence of hypoglycemic episodes indicate that the separate administration of insulin and glucose plus electrolytes is an effective and safe management modality for diabetic patients undergoing major surgery.

Relationship between blood pressure and plasma insulin in non-obese and obese non-diabetic subjects.

In this study, we have measured plasma insulin at fasting and following an oral glucose load and blood pressure after glucose load in 367 (247 non-obese, 120 obese) normotensive and untreated mildly hypertensive subjects. Overall, there was no independent association between fasting plasma insulin levels and blood pressure values. After controlling for age and body weight, a significant relationship between postglucose plasma insulin levels and diastolic blood pressure was found. When non-obese and obese subjects were examined separately, significant relationships were identified between postglucose plasma insulin levels and both systolic and diastolic blood pressure values in the former but not in the latter. A comparison of sex-, age-, and weight-matched hyperinsulinaemic vs normoinsulinaemic subjects showed that the former had significantly higher values of blood pressure only if not obese. These results demonstrate that the plasma insulin response to glucose is independently correlated with blood pressure.

Influence of the menstrual cycle on glucose tolerance and insulin secretion.

To evaluate the impact of the menstrual cycle on glucose tolerance and insulin secretion, in the present study we have measured the plasma concentrations of glucose, insulin, and C-peptide during a 2-hour oral glucose tolerance test in 110 healthy, nonobese, regularly menstruating women. Fifty-five women were in the follicular phase, and 55 were in the luteal phase of the cycle. The two groups were well matched for age and body weight. Plasma concentrations of glucose, insulin, and C-peptide either in the fasting state or after the oral glucose load did not differ in the two groups. These results suggest that in nondiabetic women the menstrual cycle has no major effect on glucose tolerance and insulin secretion and that the phase of the menstrual cycle should not be considered in programming and interpreting an oral glucose tolerance test.