Biomedical subjects
Publications and source records attributed to J Ellingboe.
Nine male heroin addicts maintained on L-alpha-acetylmethadol (LAAM) for about 5 mo had normal plasma levels of testosterone and luteinizing hormone 72 hr after a dose of LAAM and also during 2 wk after abrupt LAAM withdrawal.
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Female macaque monkeys self-administered high doses of alcohol (2.9 to 4.4 grams per kilogram per day) for 3 to 6 1/2 months. Amenorrhea, atrophy of the uterus, decreased ovarian mass, and significant depression of luteinizing hormone levels were associated with chronic alcohol intoxication. Reproductive system failure in female primates following self-induced dependence on alcohol parallels the results of clinical studies of alcoholic women.
A study was conducted to investigate the effects of acute alcohol administration on affective states and verbal behavior during the ascending and descending limbs of the blood alcohol curve. Sixteen male social drinkers were given alcohol (1.0 g/kg) or placebo in a double-blind crossover research design. Subjects tested while blood alcohol levels (BAL) were ascending close to peak concentration (0.11 g%) described themselves as more elated, friendly, and vigorous than when tested under placebo conditions. As BAL declined, subjects described themselves as more angry, depressed, and fatigued. Cognitive confusion, hostile verbal interaction, and aggressive thematic content were also greater during alcohol intoxication, but these measures were unrelated to direction of change in the BAL curve. It was concluded that (1) the effects of alcohol on affect are biphasic and are closely related to direction of change in the BAL curve, (2) the disinhibition of certain types of verbal behavior is related neither to affective state or to direction of the BAL curve, and (3) the perception of cognitive disorientation may mediate the effects of alcohol on those behaviors normally suppressed by various controlling influences.
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Luteinizing hormone (LH) levels were determined in postmortem blood samples obtained from twenty-eight men who sustained sudden traumatic deaths. Violent antemortem behavior (committing suicide by gunshot or hanging, or killed during a violent attack or physical struggle) was associated with significantly higher LH levels than nonviolent antemortem behavior (pedestrians struck by vehicles, crime victims, and those shot during verbal arguments). Within both the violent and nonviolent groups, LH levels were higher in men with detectable alcohol in blood than in men with no alcohol in blood but these differences were not statistically significant. In the nonviolent group, men without alcohol in blood had LH levels within the normal range for healthy adult males. The stability of LH was established in serial studies of normal human male blood specimens over a range of temperatures and time durations comparable to conditions in postmortem blood sampling procedures. These findings suggest that postmortem LH levels in males may be a biological indicator of violent behavior immediately preceding death.
The role of endogenous opiates in the neuroendocrine regulation of episodic LH secretion in normal men was examined in seven adult males before and after the administration of a potent and specific opiate receptor antagonist, naltrexone. The quantitative pattern of pulsatile LH secretion was analyzed in serum derived by continuous exfusion of blood in 20-min samples over 8-h period. The administration of naltrexone markedly increased the following: 1) total area under the continuous LH secretion curve [22,725 +/- 2,026 (control) vs. 33,442 +/- 2,226 ng/ml . min (after naltrexone); P less than 0.0006]; 2) mean serum concentration of LH, which increased from 47.3 +/- 4.2 to 69.7 +/- 5.0 ng/ml; 3) the absolute amplitude of Lh peaks, which rose from 62.7 +/- 6.2 tp 85.2 +/- 5.8 ng/ml; and 4) the number of LH secretory peaks observed over the 8-h interval (4.3 +/- 0.4 basally and 5.4 +/- 0.6 after the drug; P less than 0.0003). Naltrexone administration did not significantly alter the most rapid component of LH elimination calculated after each pulse or alter the fractional arise in LH above interpulse baseline. These data suggest that endogenous opioids tonically suppress frequency- and amplitude-dependent neuromodulation of LH production, probably through hypothalamic mechanisms that impinge upon gonadotropin-releasing hormone-secreting peptidergic neurons.
Buprenorphine, a mixed opiate agonist-antagonist, suppressed plasma luteinizing hormone (LH) and increased prolactin levels after 12 consecutive days of ascending dose administration (0.5-8 mg/day s.c.) in comparison to drug-free control conditions. During a subsequent 10-day period of buprenorphine maintenance at a dose of a 8 mg s.c., LH levels remained suppressed and prolactin levels continued to be elevated. Tolerance to buprenorphine effects on LH and prolactin levels did not occur during chronic drug administration. Buprenorphine-induced changes in plasma LH and prolactin after chronic administration to human males were smaller than those observed with less potent opiate agonist drugs. Effects of buprenorphine on LH and prolactin levels are more consistent with the actions of opiate agonists rather than opiate antagonists.
Plasma prolactin, luteinizing hormone and estradiol levels were determined in six normal adult females before and during a period of acute alcohol intoxication. Plasma hormone levels found in these studies were compared with values obtained after administration of an isocaloric beverage. Each woman served as her own control for both studies which were carried out on the same day of the menstrual cycle (day 8, 9 or 10) over two consecutive menstrual cycles. Integrated plasma samples were obtained every 20 min for 6 consecutive hr before acute alcohol administration and during the ascending, peak and descending portions of the blood alcohol curve. After acute alcohol administration, all women achieved a moderate degree of intoxication, with mean peak blood alcohol levels of 88 mg/100 ml. No significant differences in levels of luteinizing hormone and estradiol were detected during any phase of the blood alcohol curve when compared to prealcohol administration values. No significant differences were found between luteinizing hormone and estradiol after alcohol administration when compared with values obtained after isocaloric beverage. The only significant difference in hormone levels was a small elevation in prolactin during the descending phase of the blood alcohol curve when nausea and vomiting coincident with alcohol-induced intoxication occurred. These data contrast sharply with the significant effects of acute alcohol intake on pituitary gonadal hormones in normal human males.
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Healthy male subjects ingested 1.0 g ethanol/kg (Alcohol Day) and caloric equivalents of sucrose (Control Day). Plasma prolactin was determined on samples collected at 20-min intervals by serial constant blood exfusion, from 2 hr before to 4 hr after the drink. In 14 of the 15 men studied, plasma prolactin levels during the 2-hr period after alcohol administration were elevated an average of 31% above values for the preceding 2-hr period. Data pooled for all subjects revealed a small but statistically significant increase in prolactin coinciding with ascending and peak concentrations of blood alcohol. A significant increment in prolactin was associated with peak blood alcohol levels when values were compared between control and alcohol treatment days. Although of statistical significance, these transient and variable increases were within the normal range of basal prolactin levels for most subjects and are unlikely to be physiologically meaningful.
Plasma levels of prolactin were increased following intravenous self-administration of heroin by young men with a history of heroin addiction. Following 10 days of controlled heroin usage, tolerance could be demonstrated to the acute prolactin-releasing effect of heroin. There was no evidence that a single dose of naltrexone affected basal prolactin levels.
Although opiate addicts often equate the drug experience with sexual orgasm, diminished libido and impaired sexual performance are common sequelae of chronic use. Early clinical studies suggested that opiates may interfere with sex hormone secretion. The authors carried out three sequential studies which demonstrated that heroin use in man results in acute suppression of luteinizing hormone (LH) release from the pituitary followed by a secondary drop in plasma testosterone levels. The time course of these neuroendocrine events correlates well with the tension-reducing effects of heroin and suggests that drive reduction is an important component of opiate reinforcement.
The acute and chronic effects of heroin, and the opiate antagonist naltrexone, on integrated plasma samples analyzed for luteinizing hormone (LH) and testosterone (T) levels were studied in six adult males with a history of heroin addiction. Acute doses of heroin (10 mg i.v.) significantly suppressed LH levels. Chronic heroin use was also associated with a significant decrease in plasma T levels. LH levels after chronic heroin use were lower than control levels but the degree of LH suppression was approximately the same as after the acute doses of heroin. Acute naltrexone administration did not alter T levels appreciably but was associated with a significant elevation in LH levels. After 22 days of chronic naltrexone maintenance, T levels were in the high normal range and LH levels were in the low normal range. These data suggest the development of tolerance and supersensitivity to opiate agonist and antagonist effects on pituitary-gonadal hormones involves interaction between the direct effects of these drugs on LH followed by steroid feedback effects of T on gonadotrophin secretory activity.
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Ethanol was found to suppress gonadotropin-stimulated testosterone biosynthesis in sexually mature male rats in vivo and in intact Leydig cells in vitro. A similar ethanol dose-response inhibition curve was also observed when either whole or homogenized cells were stimulated by dibutyryl cyclic AMP. In the presence of pharmacologically relevant ethanol concentrations, added NAD+ restored testosterone production to stimulated control levels. These results demonstrate a direct inhibitory effect of ethanol on testicular testosterone synthesis. The site of inhibition is primarily intracellular and the mechanism is probably through a decrease in the NAD+/NADH ratio caused by ethanol oxidation.
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The findings obtained in this study indicate that the major effect of ethanol on plasma testosterone levels is occurring at a peripheral (testicular) rather than central (hypothalamic-pituitary) site.