Nighttime Hypoxemia Is Increased in Abstaining Chronic Alcoholic Men

Previously we reported that abstaining chronic alcoholic men demonstrated significantly more nighttime hypoxemia than a control group. Here, we report a replication employing a larger sample of abstaining chronic alcoholics and a more appropriate control group than that used in the previous study. Forty-seven males, 48.4 +/- 1.7 years of age (mean +/- SEM), reporting 24.8 +/- 1.5 years of heavy alcohol use, comprised the abstaining alcohol group. Thirty-five age- and weight-matched males, 50.3 +/- 1.7 years were the control group. The alcohol group had significantly more nighttime oxygen desaturations below 90% than did the control group (16.9 +/- 3.3 vs. 6.2 +/- 1.4, F = 7.8, p less than 0.01), with significantly higher percentages of individuals in the alcohol group manifesting more than 10 or 20 oxygen desaturations below 90%. Regression analyses within the alcohol group revealed that severity of alcohol abuse, but not age, body mass index, days abstinent, or smoking significantly predicted levels of nighttime hypoxemia. These results confirm our original observation of increased nighttime hypoxemia in abstaining chronic alcoholic men and suggest that long-term alcohol abuse may be a risk factor for development of sleep apnea.     

Further Evidence for a Continuum-of-Impairment Encompassing Male Alcoholic Korsakoff Patients and Chronic Alcoholic Men

A battery of challenging tests was used to assess learning ability and short-term memory in groups of detoxified chronic alcoholics with and without complaints of memory impairment, alcoholic Korsakoff patients, and nonalcoholic controls. While alcoholics without memory complaints did not differ from controls on standardized clinical memory tests, their performance was significantly impaired on our more demanding experimental tests. In contrast, the performance of alcoholics reporting memory complaints was impaired, relative to the other alcoholics, on both clinical and experimental memory tests, overlapping that of the alcoholic Korsakoff patients. These results are consonant with Ryback's continuum-of-impairment hvnothesis.     

No Effect of Long-Term Oral Testosterone Treatment on Liver Morphology in Men with Alcoholic Cirrhosis

The effect of oral testosterone treatment (200 mg tid) on liver morphology was examined in a double-blind, placebo controlled study including men with alcoholic cirrhosis (n = 126). Liver biopsies obtained before randomization showed micronodular cirrhosis in 119 patients (94%), alcoholic hepatitis in 64 (51%), and fatty liver in 104 (83%). These and other morphological findings did not differ significantly in the patients randomized to testosterone (n = 76) and to placebo (n = 50) (skewed randomization 3:2). Follow-up liver specimens (biopsies or autopsies) obtained after a median treatment duration of 30 months demonstrated a significant (p less than 0.01) increase in the prevalence of macronodular cirrhosis (from 6 to 51%) and a significant (p less than 0.01) decrease in the prevalence of alcoholic hepatitis (to 21%) and of fatty liver (to 52%). Testosterone treatment did not significantly influence the prevalence of these changes. Further, testosterone treatment had no significant effect on the prevalence of other morphological changes, including vascular and malignant changes. However, in the testosterone-treated group one patient developed diffuse sinusoidal dilation and one patient showed Budd-Chiari's syndrome. The degree of fatty liver and of alcoholic hepatitis in follow-up liver specimens were significantly (p less than 0.002) higher among patients who consumed ethanol during follow-up than in patients who abstained (76 versus 22% and 30 versus 6%). In conclusion, this study does not establish any indication or any contraindication in terms of hepatic histopathology with the possible exception of hepatic venous thrombosis for the use of oral testosterone treatment in men with alcoholic cirrhosis.     

Thyroid Hormones and Thyroxine-binding Globulin in Relation to Liver Function and Serum Testosterone in Men with Alcoholic Cirrhosis

Abstract. In 73 euthyroid male patients with histologically verified alcoholic cirrhosis, thyroid hormones, thyroxine-binding globulin (TBG) and testosterone concentrations (total, non-protein- and non-SHBG-bound) were studied in relation to each other and to the degree of liver dysfunction. Serum concentrations of triiodothyronine (T₃) decreased significantly (p<0.05) and thyroid-stimulating hormone (TSH) increased with progressing liver dysfunction. Serum concentrations of tetraiodothyronine (T₄), TBG and T₄/TBG ratio did not correlate significantly with liver function. Serum T₃ concentrations correlated significantly (Kendall Tau-β=–0.33, p=0.001) with total serum testosterone concentrations, while there was a negative correlation (Kendall Tau-β=–0.20, p=0.025) between testosterone and TSH values. No correlation was found between testosterone concentrations and serum levels of TBG. It is proposed that the association between T₃ and TSH on one hand and testosterone concentrations on the other reflects a covariation of these variables with liver function. The TBG level was normal in most patients and was not correlated to testosterone concentrations.     

Reduction in Circulating Testosterone Relates to Exercise Capacity in Men With Chronic Heart Failure

BackgroundWe investigated whether anabolic deficiency was linked to exercise intolerance in men with chronic heart failure (CHF). Anabolic hormones (testosterone, dehydroepiandrosterone sulfate, insulin-like growth factor 1 [IGF1]) contribute to exercise capacity in healthy men. This issue remains unclear in CHF.Methods and ResultsWe studied 205 men with CHF (age 60 ± 11 years, New York Heart Association [NYHA] Class I/II/III/IV: 37/95/65/8; LVEF [left ventricular ejection fraction]: 31 ± 8%). Exercise capacity was expressed as peak oxygen consumption (peak VO₂), peak O₂ pulse, and ventilatory response to exercise (VE-VCO₂ slope). In multivariable models, reduced peak VO₂ (and reduced peak O₂ pulse) was associated with diminished serum total testosterone (TT) (P < .01) and free testosterone (eFT; estimated from TT and sex hormone globulin levels) (P < .01), which was independent of NYHA Class, plasma N-terminal pro-brain natriuretic peptide, and age. These associations remained significant even after adjustment for an amount of leg lean tissue. In multivariable models, high VE-VCO₂ slope was related to reduced serum IGF1 (P < .05), advanced NYHA Class (P < .05), increased plasma NT-proBNP (P < .0001), and borderline low LVEF (P = .07). In 44 men, reassessed after 2.3 ± 0.4 years, a reduction in peak VO₂ (and peak O₂ pulse) was accompanied by a decrease in TT (P < .01) and eFT (P ≤ .01). Increase in VE-VCO₂ slope was related only to an increase in plasma NT-proBNP (P < .05).ConclusionsIn men with CHF, low circulating testosterone independently relates to exercise intolerance. The greater the reduction of serum TT in the course of disease, the more severe the progression of exercise intolerance. Whether testosterone supplementation would improve exercise capacity in hypogonadal men with CHF requires further studies.     

Graded Neuropsychological Impairment and Elevated γ-Glutamyl Transferase in Chronic Alcoholic Men

This study hypothesizes that distinct biochemical and metabolic disturbances associated with liver injury may be related to specific cognitive changes in alcoholics. In 132 alcoholic men admitted to an alcohol treatment program, increases in gamma-glutamyl transferase (GGT) values were correlated with impairment in several measures of visuoperceptual and visuoconceptual functioning. The association between plasma levels of GGT and neuropsychological performance was independent of the relative contribution of other laboratory measures of liver injury and of alcohol consumption histories. These observations support the hypothesis that elevated levels of GGT are distinctly associated with neuropsychological deficits and suggest that possible mechanisms beyond severe hepatic dysfunction and alcohol consumption underlie cognitive deficits in alcoholics.     

Variables Associated with Alcoholic Blackouts in Men

Alcoholic blackouts are among the most frequently reported symptoms in the progression of alcoholism. The exact etiology of blackouts remains unknown, but relationships to memory disturbance, seizure disorders, underlying psychiatric conditions, head trauma, and drug use have all been suggested. We studied 72 alcoholics admitted to an alcohol inpatient treatment program. Seventy-five percent of the patients had experienced blackouts. Patients who had had blackouts experienced other alcohol-related symptoms such as a need to drink upon awakening, alcohol cravings, tremors, and hallucinations more frequently and they were more likely to have had a past history of depression and to have been arrested for driving while intoxicated than alcoholics who had never experienced blackouts. No significant differences were observed between patients who had experienced blackouts and those who did not in mild to moderate memory disturbance, seizure disorder, a variety of psychiatric conditions, head trauma, or drug use. No significant differences were found between the two groups in most drinking history variables. The present study does not lend support to most hypotheses made about the etiology of alcoholic blackouts. Blackouts in alcoholics were significantly associated with other symptoms resulting from excessive alcohol use.     

Elevated Basal and Abnormal Thyrotropin-Releasing Hormone-Induced Thyroid-Stimulating Hormone Secretion in Chronic Alcoholic Men with Liver Disease

Basal levels of serum thyroid-stimulating hormone (TSH). T₃, T₄, free T₃ and free T₄ were measured in 40 chronic alcoholic men and in 31 normal volunteers. Their serum TSH responses to provocative thyrotropin-releasing hormone (TRH) stimulation were then examined serially: in chronic alcoholics, every 5 days for a total of 3 studies; in 25 of the normal volunteers, before and 72 hr after daily ingestion of ethanol (2 cc/kg/day). Basal serum TSH levels were increased in the alcoholic men (3.5 ± 0.2 μU/ml) (mean ± SEM) compared to those of the normal controls (1.7 ± 0.1) (p < 0.01). Both basal serum T₃ and T₄ levels (T₃, 0.89 ± 0.10 ng/ml; T₄, 7.0 ± 0.4 μg/dl) were reduced in the alcoholic men when compared to those of the normal controls (T₃,1.20 ± 0.03 ng/ml; T₄, 8.6 ± 0.3 μg/dl) (p < 0.01 and p < 0.05, respectively). Basal serum free T₃ levels were reduced in the alcoholic men (169 ± 22 pg/dl) compared to the normal controls (380 ± 18) (p < 0.01). In contrast, basal serum free T₄ levels were increased in the alcoholics (4.0 ± 0.2 ng/dl) compared to those of the normal controls (2.9 ± 0.1) (p < 0.01). In response to TRH, the serum TSH levels of the alcoholic men achieved a peak of 13.5 ± 0.9 μU/ml compared to 14.9 ± 0.9 for the normal controls (no significant difference). Despite better nutrition and alcohol abstinence associated with hospitalization for 10 days, no improvement in either the basal levels of TSH, T₃, and T₄ or the TSH responses to provocative TRH was observed in the alcoholic men studied. In normal volunteers, ethanol had no effect on the basal or TRH-stimulated levels of serum TSH and thyroid hormones.     

Chronic Atrophic Gastritis and Metachronous Gastric Cancer in Japanese Alcoholic Men With Esophageal Squamous Cell Carcinoma

Background: The risk of metachronous gastric cancer is high in Japanese with esophageal squamous cell carcinoma (SCC), especially in alcoholic men, suggesting a common background underlying the gastric and esophageal cancers. Methods: Endoscopic follow‐up ranging from 7 to 160 months (median, 47 months) after the initial diagnosis was performed in 99 Japanese gastric‐cancer‐free alcoholic men (56.8 ± 6.4 years) with esophageal SCC detected by an endoscopic screening examination. Chronic atrophic gastritis (CAG) assessed by the serum pepsinogen test and Helicobacter pylori status was compared between 90 of the 99 esophageal SCC cases and 180 age‐matched Japanese gastric‐ and esophageal‐cancer‐free alcoholic men. Results: The serum pepsinogen test showed a higher seroprevalence of severe CAG among the cases than among the age‐matched controls (35.4% vs. 14.2% for H. pylori‐seropositive, 71.4% vs. 7.7% for H. pylori‐indeterminate, and 17.1% vs. 9.8% for H. pylori‐negative, respectively; H. pylori status‐adjusted p = 0.0008), whereas their H. pylori status was similar. The accelerated progression of severe CAG observed in the Japanese alcoholic men with esophageal SCC suggests the existence of common mechanisms by which both esophageal SCC and H. pylori‐related severe CAG develop in this population. Metachronous gastric adenocarcinoma was diagnosed in 11 of the 99 gastric‐cancer‐free patients, and the cumulative rate of metachronous gastric cancer within 5 years was estimated to be 15% according to the Kaplan–Meier method. The age‐adjusted hazard ratios were 7.87 (95% confidence interval: 1.43 to 43.46) and 4.84 (1.16 to 20.21), respectively, in the patients with severe CAG in comparison with those without CAG and those without severe CAG. Inactive heterozygous aldehyde dehydrogenase‐2, a very strong risk factor for esophageal SCC in the alcoholics, was not associated with an increased risk of metachronous gastric cancer. Conclusions: Accelerated development of severe CAG at least partially explained the very high frequency of development of metachronous gastric cancer in this population.     

Further Evidence for Hypothalamic-Pituitary Dysfunction in Alcoholic Men

Reduced plasma levels of testosterone and a high frequency of azoospermia have frequently been reported in alcoholic men. Despite the high grade of gonadal failure present, plasma gonadotropins have ranged from normal to only moderately increased. This has been interpreted as suggesting that a central hypothalamic-pituitary defect also might exist in these men. Clomiphene stimulation studies have been consistent with the hypothesis of a central defect. The present work consists of studies utilizing luteinizing hormone-releasing factor and thyrotropin-releasing factor in an effort to examine the hypothesis of whether this central defect exists and, if so, whether at an anatomic, hypothalamic, or pituitary level.     

Discordance between the Cortisol Response to Insulin-Hypoglycemia and 30-Minute ACTH Stimulation Test in Chronic Alcoholic Men

An insulin hypoglycemia test and a 30-min ACTH stimulation test was performed in 10 chronic alcoholic men, who had been abstinent from alcohol for at least one month. Attenuated serum cortisol responses were found in six of the patients despite a normal ACTH test. Four patients showed normal responses to both the insulin hypoglycemia test and the short ACTH test. No correlation was demonstrated between the cortisol response and the severity of alcoholism, cerebral atrophy, and peripheral neuropathy. It is concluded that in chronic alcoholism the short ACTH test may fail in disclosing hypofunction of the integrated hypothalamic-pituitary-adrenocortical (HPA) axis as assessed with the insulin hypoglycemia test.     

Cognitive Status of Sons of Alcoholic Men

Sons of community dwelling alcoholic, depressed, and normal men were administered a comprehensive battery of neuropsychological tests. A generalized cognitive deficit was not found in the sons of alcoholics. The sons of alcoholics demonstrated greater ataxia than offspring in the two control groups and also performed more poorly on tests measuring visual scanning and attention, planning ability, and impulse control. These findings raise the possibility that an anterior cerebral dysfunction underlies the cognitive deficit observed in children of alcoholics.     

Effect of Liver Transplantation on the Hypothalamic-Pituitary-Gonadal Axis of Chronic Alcoholic Men with Advanced Liver Disease

The hormones testosterone, follicle stimulating hormone (FSH), and luteinizing hormone (LH) were assayed in blood obtained from men with alcoholic liver disease before and after successful liver transplantation. The frequency and severity of self reported impotence, intercourse, and paternity were assessed before and 18 +/- 3 months post-transplantation. The results obtained were compared with those of age-matched males transplanted within the same month by the same surgical teams for advanced hepatocellular disease other than alcoholism. Little change for any parameter assessed pre- and post-transplantation was noted for the nonalcoholics. In contrast, the FSH, LH, and testosterone levels of the alcoholic men all increased significantly following successful transplantation. These data suggest that the liver disease associated with alcoholism contributes to some of the endocrine effects of alcohol-associated cirrhosis but not all. Because the transplanted alcoholics remain less adequate than controls, it is further suggested that some residual alcohol-induced injury to the hypothalamic-pituitary-gonadal axis persists despite successful liver transplantation.     

Learning and Memory Capacity in Sons of Alcoholic Men

Male offspring, ages 12–17, of alcoholic and normal social-drinking men were compared on a battery of tests measuring intellectual ability, academic achievement, and learning and memory. The sons of alcoholic men were found to have significantly lower verbal IQ and achievement scores but did not perform more poorly on tests of learning and memory.     

Role of Testosterone in the Pathogenesis,Progression, Prognosis and Comorbidity of Men With Chronic Kidney Disease

Testosterone deficiency and hypogonadism are common conditions in men with chronic kidney disease (CKD). A disturbed hypothalamic‐pituitary‐gonadal axis due to CKD is thought to contribute to androgen deficiency. Data from experimental studies support the hypothesis that exogenous administration of testosterone may induce the activation of the renin–angiotensin system (RAS), the production of endothelin and the regulation of anti‐ or/and proinflammatory cytokines involved in the pathogenesis of hypertension and kidney damage. On the other hand, low testosterone levels in male patients with CKD are paradoxically associated with a higher risk of morbidity and mortality, possibly explained by anemia, osteoporosis and cardiovascular disease. In this article, we present an overview of clinical and experimental studies of the impact of testosterone on the progression and prognosis of male patients with CKD; even today, this remains a controversial issue.