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.

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.

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.

Peripheral hyperinsulinemia of simple obesity: pancreatic hypersecretion or impaired insulin metabolism?

Insulin and C-peptide levels in peripheral blood in the fasting state and after an oral glucose load were measured in 65 nondiabetic, obese subjects and 65 age- and sex-matched nondiabetic normal weight subjects. Fasting insulin and C-peptide levels were significantly higher in obese than in nonobese subjects, whereas 1 and 2 h after the oral glucose load only insulin concentrations were significantly higher in the obese subjects. C-peptide to insulin molar ratios, as well as the relation between the incremental areas of the two peptides, were used as relative measures of hepatic insulin extraction. In the fasting state the ratios between C-peptide and insulin were similar in obese and nonobese subjects, whereas after glucose they were significantly lower in the obese individuals. Similarly, the relations between C-peptide and insulin incremental areas were significantly lower in obese than in nonobese subjects. The comparison of the corresponding plasma levels and areas of C-peptide and insulin after glucose showed that for the same C-peptide value, the insulin value was higher in the obese group. Last, in obese subjects the parameter used as an estimate of hepatic removal of insulin after oral glucose inversely correlated with the fasting insulin concentration and the insulin incremental area after glucose. These results suggest that in obesity peripheral hyperinsulinemia depends on pancreatic hypersecretion of insulin in the fasting state and impaired hepatic insulin metabolism after oral glucose loading.

Evidence for an independent relationship between plasma insulin and concentration of high density lipoprotein cholesterol and triglyceride.

Increased plasma insulin and triglycerides and decreased high density lipoprotein concentrations are primary risk factors in the development of coronary artery disease. The aim of the present study was to verify whether there was an independent relationship between plasma insulin levels and both HDL cholesterol and triglyceride in a worker population of 607 subjects, 389 men and 218 women, aged 23-73 years. An oral glucose tolerance test (75 g) was performed. Plasma glucose, insulin, triglyceride and HDL cholesterol were measured at fasting, plasma glucose and insulin were determined also 1 h and 2 h after glucose load. The results, examined separately in men and women documented a significant negative relationship between plasma insulin and HDL cholesterol level, as well as pointing out that both HDL cholesterol and insulin are significantly correlated to degree of hypertriglyceridemia, degree of obesity and level of glucose tolerance. The partial correlation coefficients between HDL cholesterol and plasma insulin levels at fasting in men and post-glucose load in women, demonstrated an independent relationship between increased plasma insulin and decreased plasma HDL concentration. However, the strongest relationship, revealed by partial correlation coefficient analysis, was between the degree of hyperinsulinemia and hypertriglyceridemia.

Effect of age and environmental factors on glucose tolerance and insulin secretion in a worker population.

The effect of age on glucose tolerance, as differentiated from the effects of obesity, work and leisure physical activity, family history of diabetes, and the use of drugs known to adversely affect glucose tolerance and/or insulin secretion, has been analyzed in 732 factory workers aged 22 to 73 years. Glucose tolerance, as evaluated by the plasma glucose response to 75 g of oral glucose deteriorated with age, associated with an increase in plasma insulin levels. However, the age-related decrease in glucose tolerance also correlated significantly with degree of obesity, leisure-time physical activity, and the use of potential diabetogenic drugs. Partial correlation coefficients were calculated to define the effect of age per se on glucose tolerance, controlling for the presence of these other age-related variables. When this was done, the degree of correlation between age and glucose tolerance was reduced, particularly in women, to where it became of marginal statistical significance. The effect of age on insulin response was affected to a greater degree by age-related variables, and was no longer statistically significant when these other factors were taken into consideration. These data suggest that the elevation in plasma glucose and insulin levels associated with age are to a certain extent due to age-related environmental factors, and the deterioration in glucose tolerance with age is relatively modest in magnitude in a generally healthy population.

Glucose tolerance in chronic alcoholics after alcohol withdrawal: effect of accompanying diet.

The effect of alcoholism or acute alcohol ingestion on carbohydrate metabolism is not clear. The metabolic features of alcoholics cannot be easily achieved in normal men submitted to investigations concerning the effects of alcohol on glucose tolerance. Undernutrition and/or malnutrition characterize the eating behavior of alcoholics. It is also well-known that diet is an important determinant of carbohydrate tolerance. Thus, we studied the effects of a controlled diet on glucose tolerance and insulin release in a group of chronic alcoholics, with or without withdrawal from alcohol. Twenty-two subjects took part in the study; their mean caloric intake was 2,805 +/- 91 kcal/d, 58% of which was due to alcohol. In all subjects five days after an isocaloric diet and no alcohol, we performed an oral glucose tolerance test (OGTT). After that, the subjects were divided into three subgroups: group A, eight subjects with alcohol withdrawal and an 17.5 kcal/kg/d diet; group B, eight subjects with alcohol withdrawal and a 35 kcal/kg/d diet, and group C, six subjects with a 35 kcal/kg/d diet plus ethanol 200 g/d. After 3 weeks a second OGTT was performed. We found a significant improvement of the glucose tolerance and of the release of insulin in group B as well as group C; the alcohol withdrawal per se was irrelevant to the observed modifications of the glucose tolerance. Our data suggest that a poor diet would be a major cause of carbohydrate intolerance in alcoholics.

Basal and glucose- and arginine-stimulated serum concentrations of insulin, C-peptide, and glucagon in hyperthyroid patients.

The effect of oral glucose and arginine infusion on plasma glucose, glucagon, serum insulin, and C-peptide concentrations was evaluated in 16 patients with hyperthyroid Graves' disease and in ten euthyroid age- and sex-matched normal subjects. Basal plasma glucose concentrations were significantly higher in the hyperthyroid patients, but the plasma glucose response following glucose and arginine administration was similar in the two groups. The insulin response was similar in the hyperthyroid and normal subjects after glucose administration and significantly lower during arginine infusion in the hyperthyroid patients. The serum C-peptide response to both glucose and arginine administration was markedly blunted in the hyperthyroid patients, and the plasma glucagon response to arginine infusion was decreased. These results suggest that pancreatic beta and alpha cell secretory function is impaired in hyperthyroidism as assessed by C-peptide and glucagon secretion following oral glucose administration and arginine infusion. The apparent discrepancy between C-peptide and insulin secretion in the hyperthyroid patients following glucose administration might be due to diminished hepatic extraction of insulin or enhanced metabolism of C-peptide.

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.

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.

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.

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.

[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.

[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.

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.

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.

Possible role of glucagon in cyproheptadine-induced increase of insulin secretion.

In order to test the hypothesis that insulin secretion may be affected by increased glucagon levels during cyproheptadine (CPH) administration, an arginine-glucose test was performed in 8 normal women and repeated after three days of CPH administration at a dose of 16 mg/day. Both the glucagon and the insulin response were increased by CPH treatment and so were their incremental areas. For glucagon, the increase was present at all times tested, for insulin this rise was significant only during the first 60 min of the arginine test and during the rapid secretory phase following glucose injection. The difference between the incremental areas of glucagon before and after CPH treatment was significantly correlated to the above mentioned insulin areas and to insulin peak values. These data are in agreement with the hypothesis that in vivo CPH action on insulin secretion may be partly mediated by its effects on circulating glucagon levels.

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.