Rafael Luboshitzky

Risk Factors for Cardiovascular Disease in Women with Subclinical Hypothyroidism

Overt hypothyroidism may result in accelerated atherosclerosis and coronary heart disease (CHD) presumably because of the associated hypertension, hypercholesterolemia, and hyperhomocysteinemia. As many as 10%-15% of older women have subclinical hypothyroidism (SH) and thyroid autoimmunity. Whether SH is associated with risk for CHD is controversial. We examined 57 women with SH and 34 healthy controls. SH was defined as an elevated thyrotropin (TSH) (>4.5 mU/L) and normal free thyroxine (FT(4)) level (8.7-22.6 nmol/L). None of the patients had been previously treated with thyroxine. In all participants we determined blood pressure, body mass index (BMI), and fasting TSH, FT(4), antibodies to thyroid peroxidase and thyroglobulin, total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), triglycerides, folic acid, vitamin B(12), creatinine, and total plasma homocysteine levels. The SH and control groups did not differ in their total homocysteine values. Mean diastolic blood pressure was increased in SH patients versus controls (82 vs. 75 mm Hg; p < 0.01). Mean values of TC, HDL-C, LDL-C, triglycerides, TC/HDL-C, and LDL-C/HDL-C were not different in patients with SH compared with controls. Individual analysis revealed that the percentage of patients with SH having hypertension (20%), hypertriglyceridemia (26.9%), elevated TC/HDL-C (11.5%), and LDL-C/HDL-C (4%) ratios were higher than the percentages in controls. Hyperhomocysteinemia (> or = 10.98 micromol/L) was observed in 29.4% of SH and was not significantly different from the percentage in controls (21.4%). No significant correlation between TSH and biochemical parameters was detected. We conclude that subclinical hypothyroidism in middle-aged women is associated with hypertension, hypertriglyceridemia, and elevated TC/HDL-C ratio. This may increase the risk of accelerated atherosclerosis and premature coronary artery disease in some patients.

Plasma Levels of Nitric Oxide and L-Arginine in Sleep Apnea Patients

Sleep apnea syndrome has been shown to be associated with decreased levels of circulating nitric oxide (NO) after waking up from sleep. In this study we investigated overnight plasma concentrations of NO in sleep apnea patients before and after nasal continuous positive airway pressure (nCPAP) treatment and the effects of nCPAP on morning levels of L-arginine. In experiment 1, NO concentrations measured hourly during sleep were found to be significantly lower in a group of eight sleep apnea patients in comparison with six age-similar snorers and six normal young adults. In experiment 2, overnight NO concentrations were compared in 5 sleep apnea patients before and 9.3±3.9 mo after treatment with nCPAP. A significant increase in NO concentrations was found in four out of five patients, and a significant increase in L-arginine was found in all five patients after treatment. In experiment 3, removal of nCPAP for a single night in seven sleep apnea patients caused a significant decrease in morning levels of NO and L-arginine. These results demonstrate that sleep apnea is associated with a chronic state of diminished circulating NO concentrations that can be ameliorated by nCPAP treatment.

Melatonin replacement corrects sleep disturbances in a child with pineal tumor

Article abstract-A child with a germ cell tumor involving the pineal region had marked suppressed melatonin secretion associated with severe insomnia. Exogenous melatonin (3 mg in the evening) for 2 weeks restored sleep continuity, as demonstrated by objective monitoring of rest-activity cycles. This case report provides direct evidence of the essential role of melatonin in normal sleep. NEUROLOGY 1996;46: 261-263

Melatonin dysregulation, sleep disturbances and fatigue in multiple sclerosis

BACKGROUND Sleep disruption and fatigue are common in Multiple Sclerosis (MS). Melatonin is one of the major regulators of sleep-wake cycle. The role of melatonin in MS-related sleep disturbances and fatigue as well as the interaction between melatonin and Interferon beta (IFN-β) treatment were the subject of this study. OBJECTIVE To assess the influence of IFN-β treatment on melatonin secretion, fatigue and sleep characteristics in patients with MS. METHODS 13 MS patients and 12 healthy controls participated. Fatigue was evaluated using the Fatigue Impact Scale (FIS), sleep was assessed by actigraphy and day/night levels of 6-sulphatoxy-melatonin (6-SMT) in urine were determined using a highly specific ELISA assay. RESULTS Naïve MS patients demonstrated significantly decreased levels of 6-SMT and disrupted circadian regulation of its secretion, which were increased with IFN-β treatment, in association with improved fatigue. Sleep Efficiency was significantly lower in the MS group compared to controls. CONCLUSION Our findings suggest dysregulation of Melatonin secretion in MS, which may be influenced by IFN-β treatment. The results call for further characterization of the role of neuro-hormones such as melatonin in MS, and their cross-regulation with immune-mediators.

Thyroid dysfunction in patients with systemic lupus erythematosus (SLE): relation to disease activity

We examined the prevalence of thyroid dysfunction and the production of anti-thyroid antibodies (ATA) in patients with systemic lupus erythematosus (SLE) and assessed the association between ATA production and SLE disease activity status. Seventy-seven patients who met the American College of Rheumatology classification criteria for SLE participated in the study. Fifty-two individuals served as a control group. Demographic, clinical information and SLE disease activity (SLEDAI) status were collected from all patients. The sera of all participants were tested for free thyroxine (FT4), thyroid-stimulating hormone (TSH), anti-thyroglobulin (ATg) and anti-thyroid peroxidase (TPO). A SLEDAI score of ≥6 was considered clinically significant. The results of the thyroid function tests and ATA were compared between the study group and the control group. ATA levels were compared between the patients with a SLEDAI score of ≥6 to those with a SLEDAI score of <6. Hypothyroidism was detected in 11.6% of SLE patients compared to 1.9% in the control group. None of the patients or controls had evidence of hyperthyroidism. No statistically significant difference was observed in the levels of ATg or TPO between the study group and the control group. No correlation was found between ATA levels and the degree of the disease activity. Among the different variables tested in this study, hypothyroidism was the only significant abnormal finding in SLE patients. No association was found between the SLEDAI score and the prevalence of ATA production. Larger controlled, longitudinal studies are necessary to confirm these findings and elucidate the role played by ATA in the pathogenesis of thyroid dysfunction in SLE patients.

Daily and seasonal variations in the concentration of melatonin in the human pineal gland

To elucidate whether pineal melatonin secretion is affected by changes in day length, we determined the concentration of melatonin in human pineal glands obtained at autopsy from 66 male subjects, aged 16-84 years over a period of 12 consecutive months. Based on the time of death, a day-night difference in pineal melatonin levels was evident only in the long photoperiod (April-September) with significantly higher melatonin concentrations occurring at night (2200-1000 h). Nighttime values in the long photoperiod were significantly higher than the nighttime values during the short photoperiod (October-March). During the short photoperiod, the data suggested a possible phase-delay in melatonin secretion. Day-night difference was evident in young subjects (30-60 years), but not in elderly subjects (61-84 years). Elderly subjects had lower total melatonin levels (day and night values) although statistically not significant. Therefore, melatonin levels did not decline with age and when the data were analyzed by age there was no significant day-night difference in melatonin levels. These data indicate that the concentration of melatonin in the human pineal is augmented only during the long photoperiod. The results suggest a partial effect of photoperiod on melatonin secretion in humans. This may result from living in an artificial light environment or due to other nonphotic signals involved in generating melatonin rhythm.

SEMINAL PLASMA MELATONIN AND GONADAL STEROIDS CONCENTRATIONS IN NORMAL MEN

The authors determined semen quality and the concentrations of estradiol, testosterone, and melatonin in blood and seminal plasma of 8 normal men. To investigate the reproducibility of these parameters, semen analysis and hormone concentrations were determined on 3 occasions, 6 weeks apart. All 8 men had normal semen analysis. Blood melatonin (9.7-45.4 pg/mL) and testosterone (3.5-12.3 ng/mL) levels were significantly higher than the comparable seminal plasma levels (0.6-5.0 pg/mL, p <. 02; 0.1-0.9 ng/mL, p <. 0001, respectively). Seminal plasma estradiol levels (46.9-91.3 pg/mL) were significantly higher than the blood levels (13.3-44.7 pg/mL) ( p <. 0001). The intraindividual variations in seminal plasma estradiol levels ranged between 8.7 and 13.8%. There was no correlation between sperm concentration, motility or morphology and blood or seminal plasma hormone levels. Also, blood and seminal plasma hormone levels were not correlated. These results indicate that in normospermic men seminal plasma estradiol levels are higher than blood hormone levels, suggesting local production of estradiol. This may imply that estrogen and/or the balance andorgen/estrogen is important in normal human spermatogenesis.

ACTIGRAPHIC SLEEP-WAKE PATTERNS AND URINARY 6-SULFATOXYMELATONIN EXCRETION IN PATIENTS WITH ALZHEIMER'S DISEASE

Recent studies suggest melatonin, due to its antioxidant and free-radical- scavenging actions, may play a role in the neuroprotection against amyloid, which is implicated in the pathogenesis of Alzheimers disease (AD). In this study, we determined urinary 6-sulfatoxymelatonin (aMT6s) excretion together with actigraphic sleep-wake patterns of untreated male patients with AD who lived at home. Results were compared with those obtained from normal age-matched elderly and normal young male subjects. Similar measurements were also performed in another group of patients with AD who were treated with a cholinesterase inhibitor (Donepezil, Aricept). Total 24h aMT6s values were significantly reduced in elderly controls (19.9h ± 5.2 μg/24h), in those with untreated AD (12.7 ± 4.4 μg/24h), and in patients treated for AD (12.4 ± 4.4 μ g/24h) compared with normal young men (32.8 ± 3.1 μ g/24h). A day-night difference in aMT6s was evident in all young controls, in 50% of elderly controls, in only 20% of patients with untreated AD, and in 67% of those with AD receiving Aricept. Sleep quality (expressed as sleep efficiency, wake time, and long undisturbed sleep duration) was better in young and elderly controls compared with the two groups of patients with AD. There was no significant correlation between aMT6s values or sleep patterns and the severity of cognitive impairment in patients with AD. Taken together, these data suggest that disrupted sleep, decreased melatonin production, and partial lack of day-night difference in melatonin secretion were observed equally in normal elderly and in patients with AD. Our results do not permit drawing any conclusion as to whether changes in urinary aMT6s excretion is correlated with disturbed sleep in patients with AD. (Chronobiology International, 18(3), 513–524, 2001)

Abnormal melatonin secretion in hypogonadal men: the effect of testosterone treatment

We have recently demonstrated that GnRH deficient male patients have increased nocturnal melatonin secretion, whereas hypergonadotrophic hypogonadal males have decreased melatonin levels. We were interested in determining whether testosterone (T) treatment (when T levels were well matched with pubertal control values) has an effect on melatonin secretory profiles in these patients.

Effects of successful parathyroidectomy on metabolic cardiovascular risk factors in patients with severe primary hyperparathyroidism.

OBJECTIVE To evaluate the effect of parathyroidectomy on metabolic abnormalities associated with cardiovascular disease in patients with primary hyperparathyroidism (PHPT). METHODS Thirty-four patients with PHPT (aged 51.0 ± 11.8 years, mean ± standard deviation) underwent assessment before and 1 year after successful parathyroidectomy. A control group of 42 normocalcemic healthy subjects, matched for age and body mass index, was also examined at baseline. We measured serum lipids, glucose, insulin, uric acid, calcium, parathyroid hormone, C-reactive protein, and bone density. Insulin resistance index was evaluated by homeostasis model assessment, and the presence of metabolic syndrome was determined. Because of multiple tests, the level of statistical significance was set at .01. RESULTS After parathyroidectomy, there was a decrease in diastolic blood pressure (P<.02) and in serum concentrations of uric acid (P<.04) and insulin (P<.009). No difference was observed in rates of metabolic syndrome in patients before and 1 year after parathyroidectomy (23.5% versus 17.6%; P>.46). Insulin resistance index values were also unchanged from before to after parathyroidectomy (1.3 ± 0.9 and 1.1 ± 0.9, respectively; P>.68). A substantial increase in spine bone density (5%; P<.05) was noted postoperatively. Multivariate logistic regression analysis, after adjustment for age and body mass index, revealed that parathyroidectomy did not lead to a significant decrease in likelihood of cardiovascular risk-odds ratio (OR), 1.82; 95% confidence interval (CI), 0.53 to 6.21 (P>.34) for the metabolic syndrome and OR, 0.82; 95% CI, 0.17 to 3.88 (P>.8) for the insulin resistance index. CONCLUSION In this study, surgical treatment had no beneficial effect on cardiovascular risk, as assessed by the metabolic syndrome and insulin resistance markers in patients with PHPT 1 year after parathyroidectomy.