Growth Hormone, Vasopressin, Cortisol, and Catecholamine Responses to Insulin Hypoglycemia in Alcoholics

The hormonal responses to insulin-induced hypoglycemia were studied in 15 abstinent alcoholics with varying degrees of central and peripheral nerve damage and in six normal controls. Blood samples were taken at intervals after the injection of soluble insulin (0.1 U/kg of body weight). Growth hormone responses were significantly depressed (p less than 0.05) in nine alcoholics with severe central nerve damage (Korsakoff's psychosis) as compared to other alcoholic subjects. The alcoholic subjects with Korsakoff's psychosis also showed significant depression (p less than 0.01) of glucose recovery from hypoglycemia as compared with controls. However, responses of vasopressin, cortisol, and catecholamines (epinephrine and norepinephrine) were generally normal in the Korsakoff patients. Our results do not support previous suggestions that impairment of memory in alcoholism may be related to altered vasopressin secretion, even though the reduced growth hormone secretion in brain-damaged alcoholics does indicate some hypothalamic-pituitary dysfunction.     

Abstinent Alcoholics Exhibit an Exaggerated Stress Response to 2-Deoxy-D-Glucose Challenge

Chronic excessive alcohol consumption can significantly disturb the hypothalamic control of glucose metabolism; however, the mechanism and clinical significance of this disturbance are poorly understood. We used 2-deoxy-o-glucose (2-DG), which produces intracellular glucoprivation, to compare neurochemical, physiological, and behavioral responses to glucoprivic stress between alcoholics abstinent for 3 weeks and healthy volunteers. Twenty-six male alcoholics and 15 male healthy volunteers received intravenous infusions of placebo, 12.5 mg/kg, and 25.0 mg/kg of body weight of 2-DG over 30 min on three separate days, following a random-ordered, double-blind procedure. Minimal effects were obsewed following administration of the 12.5 mg/kg of body weight dose of 2-DG. Following 25.0 mg/kg, alcoholics showed both exaggerated ACTH and cortisol responses and greater increases in caloric intake when compared with controls. Although anxiety, desire to consume alcohol, plasma progesterone, and sympathetic and adrenal medullary activity all increased following 2-DG, these responses did not differ between alcoholics and controls. The present findings suggest certain specificity for the exaggerated hypothalamic and adrenocortical responses to mild glucoprivic stress in 3-week-abstinent alcoholics.     

Motor functioning and alcohol dependence

BACKGROUND: Autopsy and neuroimaging research in stably abstinent alcoholics illuminated structural and functional abnormalities in brain areas that organize and coordinate motor functioning. Researchers that used behavioural tasks to measure motor functioning found that abstinent alcoholics perform worse than healthy controls. These researchers however did not analyze timed responses into their cognitive and motor components. They thus were unable to decide which aspects of information processing are impaired. We here used a Fitts' task to examine differences in cognitive and motor components between abstinent alcoholics and healthy controls. METHODS: Fifty-two abstinent alcoholics and 52 healthy controls participated in this research design. Fine motor functioning was assessed by means of the Fitts' task. RESULTS: Abstinent alcoholics needed more time to perform timed responses than healthy controls. As both reaction and movement times were higher in abstinent alcoholics, both cognitive and motor processes seem to be impaired. When the task became more difficult (small targets instead of large targets) abstinent alcoholics needed proportionally more time to give the correct response than healthy controls. This phenomenon solely applied to movement times. CONCLUSIONS: These research data indicate that abstinent alcoholics are somewhat impaired on a behavioral level. The execution of timed responses indeed was lengthier in abstinent alcoholics than in healthy controls. As both cognitive and motor processes were impaired, we here assume that both central and peripheral processes are affected by progressive alcohol intake. Abstinent alcoholics also have more difficulties to adapt their motor responses to changing task conditions.     

Cortisol dysregulation and cognitive impairment in abstinent male alcoholics

BACKGROUND: Alcoholics have impaired cortisol response to stress, indicating dysregulation in the extrahypothalamic systems responsible for activating cortisol secretion in response to stressor exposure. There is a growing literature indicating a relationship between hypothalamic-pituitary-adrenocortical axis activity and neurocognitive functioning. This study examined the hypothesis that dysregulation of the hypothalamic-pituitary-adrenocortical axis may be associated with some neuropsychological impairments in alcoholics. METHODS: Serum cortisol was obtained during cognitive testing and after exposure to cold pressor and mental arithmetic stress in 48 male alcoholics abstinent for 32 +/- 6.7 days and in 30 controls; cortisol was also obtained from 18 of the alcoholic patients during withdrawal. Neurocognitive tasks included the Wechsler Memory Scale and Wisconsin Card Sorting Test. Relationships among alcoholics' cognitive test scores, cortisol levels, and drinking practices were examined by correlation and regression analyses. RESULTS: Verbal memory deficits were more severe in alcoholics who had more withdrawals and ingested a higher typical quantity of alcohol during the prior year ( p< 0.05). Higher levels of cortisol during withdrawal, an index of withdrawal severity, were associated with more errors on the Wisconsin Card Sorting Test ( p< 0.005). As previously reported, the alcoholics had lower cortisol levels after stress compared with controls. Lower poststress cortisol levels were associated with poorer logical memory on the Wechsler Memory Scale and more errors on the Wisconsin Card Sorting Test ( p< 0.05). Among controls, memory deficits occurred only in relation to higher poststress cortisol levels. CONCLUSIONS: Poorer cognitive performance in alcoholics was related to more withdrawals, heavier alcohol consumption, and higher cortisol levels during a recent withdrawal. Alcoholics' cognitive impairment was also related to attenuated stress cortisol responses. Altered stress regulation of the hypothalamic-pituitary-adrenal axis should be studied further as a potential factor related to impaired cognitive function in recovering alcoholics.     

The effects of alcoholism on the hypothalamic-pituitary-adrenal axis: interaction with endogenous opioid peptides

BACKGROUND Abnormal baseline hypothalamic-pituitary-adrenal axis function and dexamethasone suppressibility seen in withdrawing alcoholics returns to normal on abstinence, but some studies report blunting of the ACTH response to CRH persisting during the early abstinence phase. Reduced central levels of endogenous oplold peptides have been postulated to have an aetiological role In alcohol addiction. AIMS To evaluate hypothalamic-pituitary-adrenal axis function in a group of recently abstinent alcoholics using basal hormone data, naloxone (an oplold receptor antagonist), and ovine CRH. SUBJECTS Nine alcoholics (age 41.4±3.1 years) studied more than one week after the acute withdrawal period but within 6 weeks of cessation of drinking, and nine age and sex matched non-alcoholic controls. PROTOCOL Cortisol, ACTH, CRH and AVP levels were measured every 20 minutes for 2 hours between 0900 and 1100h. Twenty mg naloxone I.v. was administered at 1100h (0 minutes) and further samples for the above hormones were taken at 15, 30, 45, 60, 90 and 120 minutes. On a separate occasion, again at 1100h, oCRH 1μg/kg (n= 7 alcoholics, n = 6 controls) was administered, with samples for cortisol, ACTH and AVP taken at the same times. STATISTICS Results were examined by analysis of variance for repeated measures (ANOVA), while Incremental hormone response and area under the secretory curve (AUC) in alcoholics versus controls were compared by the two-tailed Student's t-test. Linear regression analysis was carried out to examine the relation between basal cortisol and hormone responses to naloxone and oCRH. RESULTS Basal hormone levels did not differ between the groups. The alcoholics had a blunted ACTH incremental response to naloxone (11.4±3.0 vs 21.1±25 pmol/l, P< 0.05) but the cortisol response was not signiflcantly different (205±51 vs 305±42 nmol/l, P= 0.15). The alcoholics also had a blunted ACTH incremental response to oCRH (28.7 ± 4.2 vs 41.2 ± 3.7 pmol/l, P= 0.052) and by ANOVA a significant main effect of group (alcoholic vs control) was seen (P < 0.02) for the ACTH response to oCRH. There was no difference between the groups in the cortisol Incremental response to oCRH. In the control subjects, a negative correlation was found between basal cortisol and the cortisol Increment (r=-0.82, P< 0.05) and ACTH Increment (r=-0.81, P = 0.052) following oCRH, while In contrast, basal cortisol correlated positively with cortisol increment (r= 0.72, P < 0.05) following naloxone. There was also a trend for basal cortisol to correlate positively with ACTH increment following naloxone In the controls (r= 0.63, P < 007). In the alcoholics, the normal negative effect of basal cortisol on the cortisol Increment after oCRH was reversed, with a positive correlation between basal cortisol and cortisol increment (r= 0.75, P= 0.05). CONCLUSIONS Recently abstinent alcoholics with normal basal HPA axis hormone levels have a blunted ACTH response to naloxone and oCRH. While reduced levels of central endogenous oplold peptides may be a factor in the blunted ACTH response to naloxone In the alcoholics, it Is proposed that the alcoholics have reduced pituitary responsiveness to CRH. This may be via a direct pituitary effect of the chronic ethanol exposure or by a reduction in hypothalamic-hypophyseal vasopressin levels.     

Desmopressin and hexarelin tests in alcohol-induced pseudo-Cushing's syndrome

BACKGROUND: A challenge in clinical endocrinology is the distinction between Cushing's disease (Cushing's syndrome dependent by adrenocorticotrophic hormone (ACTH)-secreting tumours of pituitary origin) and alcohol-dependent pseudo-Cushing's syndrome. Patients with Cushing's disease are known to have high ACTH/cortisol responses to desmopressin (DDAVP, a vasopressin analogue) and to hexarelin (HEX, a synthetic GH-releasing peptide). OBJECTIVE: To compare the ACTH/cortisol responses to desmopressin and to hexarelin of subjects with alcohol pseudo-Cushing's syndrome with those obtained in patients with Cushing's disease and in normal controls. DESIGN: Randomized, single-blind study. SETTING: University medical centre. SUBJECTS: Eight alcoholics with pseudo-Cushing's syndrome, six patients with Cushing's disease and nine age-matched normal controls. INTERVENTION: Three tests at weekly intervals. The dexamethasone (1 mg) suppression test (DST) was carried out first. The desmopressin (10 microg intravenously at 09:00 h) test and hexarelin (2 microgram kg-1 intravenously at 09:00 h) test were carried out in random order. MEASUREMENTS: Plasma ACTH and cortisol levels. RESULTS: The basal plasma levels of ACTH and cortisol were significantly lower in normal subjects than in patients with Cushing's disease and in alcoholic subjects; these latter groups showed similar basal hormonal values. All normal controls, two patients with Cushing's disease and two alcoholics showed suppression of plasma cortisol levels (<5 microgram dL-1) after dexamethasone administration. Both desmopressin and hexarelin induced striking ACTH/cortisol responses in patients with Cushing's disease, whereas hexarelin, but not desmopressin, slightly increased ACTH/cortisol secretion in the normal controls. Neither desmopressin nor hexarelin administration induced any significant change in ACTH/cortisol secretion in alcoholics. CONCLUSIONS: These data suggest that either the hexarelin or desmopressin test can be used to differentiate patients with Cushing's disease from subjects with alcohol-dependent pseudo-Cushing's syndrome.     

Long-Term Abstinent Alcoholics Have Normal Memory

It is generally believed that many non-Korsakoff alcoholics have subtle defects in memory. To determine whether such defects vary as a function of length of abstinence (LOA), we performed extensive memory testing with: (1) recently detoxified (n = 31; LOA-29 days); (2) intermediate-term abstinent (n = 28; LOA = 1.9 years); (3) long-term abstinent (n = 32; LOA-7.0 years) alcoholics; and (4) nonalcoholic controls (n = 37). All subjects were matched on age and education. Alcoholics were matched on years of alcoholic drinking. Memory measures were divided into the following domains: verbal learning, verbal recall, visual learning, visual recall, and paired associate learning. A series of MANOVAs were conducted that revealed a significant relationship between visual learning and length of abstinence, and a significant interaction between age and length of abstinence on visual recall. Long-term abstinent subjects were not significantly different from controls on any test. We conclude that memory disturbance demonstrable among recently detoxified alcoholics in the early weeks of their abstinence is not evident in demographically matched long-term abstinent alcoholics with similar drinking histories.     

Hypothalamic function in response to 2-deoxy-D-glucose in long-term abstinent alcoholics

BACKGROUND: The body adapts to diverse stressful stimuli with a response characterized by activation of the hypothalamic-pituitary-adrenal (HPA) axis. Chronic alcohol consumption can cause changes in the function of this neuroendocrine system. Although many studies have examined this phenomenon in drinking and recently sober alcoholics, few studies have examined HPA axis function in long-term sober alcoholics. METHODS: To characterize HPA axis function in long-term sober alcoholics, we used a challenge paradigm with 2-deoxy-d-glucose (2-DG). An infusion of 2-DG (a nonmetabolizable glucose analog) induces a well-characterized stress response. In a previous study, our laboratory found an exaggerated corticotropin and cortisol response in alcoholics abstinent 3 weeks; in this investigation we compared the effects of an infusion of 2-DG on 19 healthy volunteers and 20 community-living alcoholics who had been abstinent more than 6 months. RESULTS: In contrast to the previous study, long-term sober alcoholics did not have an exaggerated corticotropin and cortisol response after 2-DG. CONCLUSIONS: Previously observed abnormalities in cortisol regulation in 3-week-sober alcoholics may be related to the acute effects of recent alcohol consumption and withdrawal. Future investigations into the metabolic function of alcoholics, particularly investigations involving the HPA system, should consider the possibility that normalization may not occur until long-term abstinence has been achieved.     

Elevated Plasma Homocysteine in Alcoholics

A significantly higher concentration of plasma homocysteine compared with controls was noted in a group of alcoholics ( n = 42) hospitalized for detoxication. Normal concentrations of plasma homocysteine were reached within 1 or 2 weeks after admission to the hospital. In another group of abstinent alcoholics ( n = 16) plasma homocysteine did not deviate from that of controls. Since hyperhomocysteinemia has been associated with premature vascular disease, we speculate that the increased plasma homocysteine in alcoholics might cause the increased incidence of stroke found in these patients.     

Hormone responses to social stress in abstinent alcohol-dependent subjects and social drinkers with no history of alcohol dependence

BACKGROUND: Previous studies have described blunted stress hormone responses after pharmacological activation of the hypothalamic-pituitary-adrenal (HPA) axis in sober alcoholics. The aim of the present study was to compare ACTH, cortisol, and prolactin responses to a psychological stressor in abstinent alcohol-dependent subjects matched to healthy control subjects. METHODS: Individuals who met DSM-IV diagnostic criteria for a history of alcohol dependence but not for other axis I disorders were included in the study (n = 18; mean duration of abstinence +/- SEM, 3.5 +/- 5.7 years). Social drinkers (n = 23) served as control subjects. The sober alcohol-dependent and control subjects were matched for demographic measures including levels of stress symptoms. All subjects underwent the Trier Social Stress Test (TSST), a laboratory-based psychological stressor. Prestress and poststress plasma ACTH, cortisol, and prolactin levels, as well as a self-report measure of anxiety (State-Trait Anxiety Inventory), were obtained. RESULTS: Nondepressed, abstinent alcoholics and control subjects did not differ with regard to age, racial composition, or baseline or poststress ratings of anxiety. Whereas ACTH and cortisol levels increased in response to the TSST, prolactin levels did not. Stress hormone response curves for the three hormones did not differ between the alcoholics and control subjects. CONCLUSIONS: When matched for levels of stress, a laboratory-based psychological stress test did not induce differential hormone response curves for abstinent alcoholics and control subjects.     

Endocrine and Hemodynamic Effects of Stress Versus Systemic CRF in Alcoholics during Early and Medium Term Abstinence

In alcoholics, disturbances of the autonomie nervous system as well as of the hypothalamic-pituitary-adrenal axis (HPA) are known. However, these two systems have never been analyzed, under stimulated conditions, in parallel in the same patients. Moreover, studies using intravenous (iv) corticotropin releasing factor (CRF) to assess neuroendocrine function bypass the hypothalamic component of the HPA axis. Therefore, iv human (h) CRF (pituitary stimulation/exogenous CRF) and a multifaceted stress test (hypothalamic activation/ endogenous CRF) were compared with respect to their effects on hemodynamics as well as plasma norepinephrine (NE), epinephrine (E), ACTH, and cortisol in abstinent alcoholics (n= 11) versus healthy men (n= 10). Each stimulus was tested twice, 12 weeks apart, in two separate experimental blocks (I and II). Alcoholics entered block 18 days after the last ethanol ingestion and were controlled for abstinence up to block II. hCRF caused a fall in mean arterial pressure (MAP), most pronounced in alcoholics, particularly in block II. In contrast, stress testing raised MAP in both groups and blocks. A sustained increase in ACTH, cortisol, and NE occurred after hCRF, although the ACTH response in alcoholics was blunted in both blocks. Stress testing elevated NE in both groups and blocks, while raising plasma ACTH and cortisol during block I only in controls. However, unlike the persistently blunted ACTH response to iv CRF, a normalization of the stress-induced ACTH output occurred in alcoholics after 12 weeks of abstinence. During block I, basal E levels were elevated in alcoholics whereas NE levels tended to be lower than in controls, resulting in a significantly decreased NE/E ratio that returned to near control values in block II. Neither CRF nor stress had any effect on circulating E in either group or block. To conclude: (1) Normalization of the ACTH response to stress, but not to iv CRF, after 12 weeks of abstinence, suggests that other ACTH secretagogues may be compensating for CRF dysfunction in alcoholics. (2) Despite the dramatically lowered plasma NE/E ratio in alcoholics, the NE response to stimuli was unaffected. (3) The exaggerated hypotensive reaction and blunted ACTH response to iv CRF may reveal a long-term dissociative dysregulation of CRF actions in alcoholics.     

Hormonal (ACTH, Cortisol, β-Endorphin, and Met-Enkephalin) and Cardiovascular Responses to Hyperthermic Stress in Chronic Alcoholics

Chronic alcohol drinking causes profound alterations in hypothalamic-pituitary function. In the present study, endocrine [corticotropin (ACTH), β-endorphin, cortisol, and met-enkephalin] and cardiovascular (blood pressure) changes in response to hyperthermic stress (sauna at 90°C for 30 min) were evaluated in 25 normal men (25 to 50 years old) and in 48 male alcoholic subjects (34 to 56 years old) after 5 weeks of abstinence. Significantly lower increments in systolic blood pressure were observed in alcoholics than in control subjects. Furthermore, alcoholics showed lower ACTH, β-endorphin, and cortisol increments in response to sauna than normal controls. In contrast, sauna-induced hyperthermia did not change significantly the circulating met-enkephalin levels in either normal controls or chronic alcoholics. These data suggest that an impairment in the adaptive response to stress affects alcoholic men even after a few weeks of abstinence from alcohol.     

Blunted stress cortisol response in abstinent alcoholic and polysubstance-abusing men

BACKGROUND: This study tested cortisol responses to a psychological stressor in controls (CT) versus patients who were diagnosed as alcohol dependent (AD) or alcohol and stimulant dependent (ADSD) by DSM-IV criteria and who were abstinent for 3 to 4 weeks from alcohol and illicit drugs. Alcohol increases cortisol secretion acutely and during withdrawal. However, there is little information about abnormalities of hypothalamic-pituitary-adrenocortical (HPA) reactivity in recovering alcoholics. METHODS: Accordingly, we tested HPA function in the laboratory between 7:00 and 9:30 AM on control versus stress days. Stress consisted of a 20-min public speaking challenge with preparation and delivery of two short speeches, ostensibly evaluated for quality of delivery, whereas control involved relaxing for the same period. Cortisol was measured in saliva collected at baseline, stress or control, and recovery period, and also at home at 9:00 PM on one of the two days. RESULTS: The three groups did not differ in diurnal patterns of cortisol secretion on the rest day and 9:00 PM sample, which indicated that AD and ADSD patients had intact diurnal HPA regulation at rest. During speech stress, the CT subjects showed the expected cortisol increase (p < 0.0001), whereas neither AD nor ADSD patients responded significantly. Cortisol values were not accounted for by covariates such as depression, posttraumatic stress disorder, glucose metabolism, or anthropometric or demographic characteristics. CONCLUSIONS: The apparent stress hyporesponsiveness of the AD and ADSD patients suggests a persistent disruption of HPA function, perhaps due to incomplete recovery from prior abuse, or to a preexisting alteration in neural systems that regulate HPA responses to stress.     

Auditory Brainstem Potentials in Sons of Alcoholic Fathers

With the use of event-related brain potentials we have observed sensory as well as cognitive deficits in abstinent alcoholics. By recording auditory brainstem potentials (BSP) from abstinent alcoholics we demonstrated significant delays in brainstem transmission time. We have also reported that P3 amplitudes are significantly reduced in abstinent alcoholics compared to control subjects. Although the neurophysiological deficits observed in abstinent alcoholics are presumed to be alcohol-related effects, it is possible that some of these deficits may exist prior to alcohol exposure, and may be present in subjects at high risk for alcoholism. We have recently observed significantly reduced P3 components in young sons of alcoholics similar to those observed in abstinent alcoholics. In the present study, we examined auditory BSPs in young boys at high risk for alcoholism and matched controls. We found no statistically significant difference in brainstem transmission time between high risk individuals and matched control subjects. These findings suggest that while some brain deficits observed in abstinent alcoholics may antecede the development of alcoholism (P3) and may represent a predisposing factor, other deficits (BSP) appear to be the consequence of alcohol and/or nutritional-related effects.     

Adrenocorticotropic hormone/cortisol response to physical exercise in abstinent alcoholic patients

BACKGROUND: Alterations in the hypothalamic-pituitary-adrenal (HPA) axis in alcoholic patients have been reported in various experimental conditions. METHODS: To establish whether alcoholism affects the HPA axis activation during physical exercise, 10 recent abstinent alcoholic patients (age range: 33-45 years; duration of alcohol dependence: range 4-6 years) were tested by exercising on a bicycle ergometer. Ten age-matched healthy nonalcoholic men participated as controls. The workload was gradually increased at 3-minute intervals until exhaustion and lasted about 15 minutes for all subjects. Alcoholic patients were tested at 3 time points, at 4, 6, and 8 weeks after alcohol withdrawal, whereas controls were tested only once. Main outcome measurements were circulating levels of adrenocorticotropic hormone (ACTH) and cortisol and physiological variables during physical exercise [heart rate, blood pressure, ventilation, frequency of breathing, tidal volume, oxygen consumption (VO2), carbon oxide production (VCO2), and respiratory exchange ratio (R)]. RESULTS: Similar basal and exercise-induced changes in physiological variables were observed in controls and alcoholic patients in all tests. Basal levels of ACTH and cortisol were similar in all tests performed on alcoholic patients and on normal controls. In normal subjects, exercise induced a significant increase in plasma ACTH and serum cortisol levels, with peak levels at 20 minutes for ACTH (84% higher than baseline) and at 30 minutes for cortisol (70% higher than baseline). After 4 weeks of abstinence, slight but not significant ACTH/cortisol responses to physical exercise were observed in alcoholic patients (mean peaks were 10 and 18% higher than baseline, respectively, for ACTH and cortisol). By contrast, when the exercise test was repeated after 6 weeks abstinence, ACTH/cortisol levels rose significantly versus baseline (mean peak levels of ACTH and cortisol were 48 and 38% higher than baseline, respectively, for ACTH and cortisol). However, the hormonal responses were significantly lower than in the normal controls. At 8 weeks of abstinence, ACTH/cortisol responses were significantly higher than 2 weeks previously, and were not distinguishable from the increments observed in the normal controls (76 and 68% higher than baseline, respectively, for ACTH and cortisol). CONCLUSIONS: In concurrence with previous reports showing alterations of the HPA axis in the central nervous system in alcohol-dependent subjects, these data show a defect of the neuroendocrine mechanism(s) underlying the ACTH/cortisol response to physical exercise for at least a month after alcohol withdrawal, with reconstitution of a normal hormonal response at 8 weeks.     

Medroxy-progesterone acetate administration to ovariohysterectomized, oestradiol-primed beagle bitches. Effect on secretion of growth hormone, prolactin and cortisol

Growth hormone (GH), prolactin (Prl) and cortisol secretion was studied in 5 ovariohysterectomized dogs before and after oestradiol implantation and medroxyprogesterone acetate (MPA) administration. MPA was given at regular intervals during a period of 10 months in a total of 12 injections. Short-term effects of oestradiol were restricted to significantly enhanced Prl responses to thyrotropin-releasing hormone (TRH). MPA treatment after oestradiol implantation resulted in significantly elevated basal GH levels in all dogs, with a continuing increase in one dog. Only in the latter dog was a significant decrease in basal Prl levels seen. MPA administration did not significantly change Prl responses to TRH. The GH responses to clonidine were significantly reduced at 9 and 16 weeks of oestradiol and MPA treatment. In the one dog which exhibited the greatest rise in basal GH levels, GH responses were completely abolished at 9, 16 and 43 weeks of oestradiol and MPA treatment. TRH never evoked significant GH responses. Both basal and lysine-vasopressin (LVP)-stimulated cortisol levels were significantly suppressed during combined oestradiol-MPA treatment. These findings denote that in the dog. Oestradiol rapidly induces an enhanced Prl response to TRH. The oestradiol-MPA induced GH overproduction is associated with a reduced responsiveness of GH to clonidine and is not accompanied by GH responsiveness to TRH. Oestradiol-MPA treatment suppresses both basal and LVP-stimulated cortisol secretion.     

Dissection of hypothalamic-pituitary-adrenal axis pathology in 1-month-abstinent alcohol-dependent men, part 2: response to ovine corticotropin-releasing factor and naloxone

BACKGROUND: Pituitary and adrenal responsiveness is suppressed in abstinent alcohol-dependent individuals. To clarify the specific organizational disruption in hypothalamic-pituitary-adrenal functioning during early abstinence, the authors separately assessed each level of the stress-response axis. In this second of a two-part study, ovine corticotropin-releasing factor (oCRH) was used to stimulate the pituitary corticotrophs, and naloxone was used to activate the axis at the hypothalamic level. In addition, pulsatile characteristics of corticotropin and cortisol were assessed over a 12-hr period (0800 to 2000 hr). METHODS: Eleven abstinent alcohol-dependent men and 10 healthy comparison participants were assessed. All participants were between the ages of 30 and 50 years, and alcohol-dependent patients were abstinent from 4 to 6 weeks. Basal concentrations of corticotropin and cortisol were obtained every 10 min from 0800 to 2000 hr and subjected to pulsatile analysis. Plasma corticotropin and cortisol concentrations were then obtained every 5 to 10 min after low-dose, intravenously administered doses of oCRH (0.4 microg/kg) or naloxone (0.125 mg/kg). Medications were administered at 2000 hr and the two challenge studies were separated by 48 hr. RESULTS: Pulsatile analysis revealed that the mean corticotropin amplitude was increased in alcohol-dependent patients relative to controls (p <0.05). Other pulsatile characteristics of corticotropin and all cortisol pulsatile measures were not significantly different between the two groups. The integrated cortisol response to oCRH was significantly lower in alcohol-dependent patients compared with controls (p <0.01), but the integrated corticotropin response was not significantly different. In contrast, neither the corticotropin nor the cortisol response to naloxone was significantly different between groups. CONCLUSIONS: Adrenocorticoid hyposensitivity persists after oCRH infusion for at least 1 month after cessation of drinking, whereas hyporesponsiveness of the pituitary corticotrophs to CRH seems to resolve with continued abstinence. The authors suggest that adrenocortical hyporesponsiveness during prolonged abstinence may impact relapse risk.     

Elevated myo-inositol in gray matter of recently detoxified but not long-term abstinent alcoholics: a preliminary MR spectroscopy study

BACKGROUND: Individuals in short-term abstinence from chronic alcohol consumption commonly have neuropsychological impairments with parallel abnormalities in brain structure. Stable, long-term sobriety often results in improvements in both brain structure and function, although the mechanisms underlying these changes are currently not well understood. METHODS: To investigate further the neurobiological underpinnings of alcohol-associated brain abnormalities in short-term and long-term abstinence from alcohol, proton magnetic resonance spectroscopy (echo time, 35 msec; repetition time, 1.5 sec) was used to assay metabolites in the anterior centrum semiovale, anterior cingulate gyrus, and right thalamus of two groups of non-Korsakoff alcoholic men, at different stages of abstinence, compared with a control group of alcohol-nonabusing men. Absolute concentrations of N-acetylaspartate, choline, myo-inositol, and creatine were measured in four recently detoxified alcoholics (mean age, 48.7 years; median abstinence, 41.5 days), five long-term abstinent alcoholics (mean age, 45.1 years; median abstinence, 1.7 years), and five nonalcoholic controls (mean age, 45.0 years). RESULTS: Although there were no between-group differences in concentrations of N-acetylaspartate, choline, or creatine, recently detoxified alcoholics had significantly higher myo-inositol in the thalamus, compared with controls and long-term abstinent alcoholics, and significantly higher myo-inositol in the anterior cingulate gyrus, compared with the controls. CONCLUSIONS: Elevations in myo-inositol in recently detoxified alcoholics are compatible with an acute alcohol cytotoxicity model. myo-Inositol is elevated in hyperosmolar states such as hypernatremia, renal failure, and diabetes; alcohol-induced hyperosmolarity may trigger accumulation of myo-inositol to stabilize the intracellular environment. Increases in myo-inositol may also reflect proliferation or activation of glia. The reduction of myo-inositol to control group levels in long-term abstinent alcoholics may reflect osmolar stability in abstinent alcoholics and/or a reduction in glial cell activation.     

Preserved vasopressin response to osmostimulation despite decreased basal vasopressin levels in long-term abstinent alcoholics

BACKGROUND: Basal arginine vasopressin (AVP) plasma levels in alcoholic patients are persistently decreased over months of controlled alcohol abstinence. As a potential explanation of this phenomenon, a reduction of AVP immunoreactive neurons was described in the hypothalamus of alcohol-dependent humans and rodents. This study was therefore designed to examine whether long-term abstinent alcoholics have a compromised response of AVP to osmostimulation. METHODS: Fifteen male alcoholics, aged 42 +/- 2 years, were examined (1) over 12 months of strictly controlled abstinence (longitudinal study) and (2) during an osmostimulation test (5% NaCl infusion at 0.06 ml/kg/min over 2 hr) and were compared with 15 healthy male subjects, aged 41 +/- 2 years. AVP and routine laboratory parameters, including electrolytes and osmolality, were measured. RESULTS: Starting from lower basal concentrations, alcoholics showed increases similar to those of controls in AVP and plasma osmolality after osmostimulation. The first sensation of thirst was announced significantly later by alcoholics than by controls. Twenty-hour-posttest urine volume and sodium excretion were reduced in alcoholics compared with controls. CONCLUSIONS: Despite their persistently decreased basal AVP plasma levels, long-term abstinent alcoholics have a well preserved AVP response to osmostimulation. This finding indicates a peripheral suppression of AVP levels that is most likely due to a regulatory set-point shift toward hypotonic hyperhydration, rather than to a reduced central capacity of AVP secretion.     

Chromosomal Aberrations in Peripheral Lymphocytes of Abstinent Alcoholics

The frequency of structural and/or numerical chromosomal aberrations in human metaphasic cells of lymphocyte cultures from abstinent alcoholics who were abstinent for 1 month up to 32 years was compared with those from controls not selected for alcohol consumption. Cytogenetic analyses revealed a significant increase of the frequencies of cells with structural aberrations in the abstinent alcoholics (7.1 %), compared with controls (2.4%). The frequency of numerical aberrations showed a significant regression on ages in abstinent alcoholics and controls. These results suggest specific action of chronic alcohol consumption impairing biological repair with aging. The increased frequency of chromosome-type aberrations associated with alcohol consumption, even after long withdrawal, could be due to an action of ethanol or its metabolites on primordial leukopoietic cells.