Influence of subchronic intake of melatonin at various times of the day on fatigue and hormonal levels: a placebo-controlled, double-blind trial.

In a double-blind study, melatonin (50 mg) or placebo was administered daily to 25 subjects at 9 am or 7 pm for 1 week. Self-rated fatigue as evaluated by the Stanford Sleepiness Scale (SSS) was significantly increased during the 3 hours following melatonin intake in the morning, whereas, after administration in the evening, no difference between melatonin and placebo could be distinguished. Sleep onset latency slightly decreased in both melatonin groups without reaching statistical significance. No cumulative effects on sleep or behavior were observed. Twelve pituitary and peripheral hormones measured under baseline and partly (in the evening groups) under stimulated conditions before and after the trial did not change. The two most important conclusions are that: 1) the sedative potency of exogenous melatonin depends on the daily time of administration; and 2) the high pharmacological doses used for acute sedation do not seem to have cumulative effects after prolonged application.

Influence of dexamethasone on nocturnal melatonin production in healthy adult subjects.

There is no conclusive evidence supporting an interaction between the pineal gland and the hypothalamic-pituitary-adrenal axis. In this study, 11 healthy adults (six women, five men; aged 18-47 years) received a placebo the first night and 1 mg dexamethasone the next night at either 1800 or 2300 h. Administration of 1 mg of dexamethasone was followed by an attenuation of the nocturnal production of melatonin in 9 of 11 subjects. A significant reduction was found between melatonin plasma levels before and after dexamethasone at 0400 h (P less than 0.01, t test for dependent groups). It is suggested that dexamethasone affects nocturnal production of melatonin by means of mechanisms within the pineal gland.

Treatment of severe chronic insomnia with L-tryptophan: results of a double-blind cross-over study.

Thirty-nine subjects with chronic insomnia were treated with L-tryptophan (L-TRP) in a double-blind, cross-over study. Instead of a placebo, a very low dose of 0.04 g L-TRP was used. The subjects suffered from a sleeping disorder classified as "psychophysiological, persistent". In the subgroup taking the full L-TRP (2 g) dose first, there was a significant difference between the treatment period with the full L-TRP dose and the ineffective dose (placebo). If the placebo was given first, however, there was no significant difference between the two treatment periods. It is suggested that psychological factors are responsible for the diverging results in the two subgroups of patients. On the basis of subjective ratings, it appears that L-TRP is effective in promoting sleep in cases of chronic insomnia.

Treatment of severe chronic insomnia with L-tryptophan and varying sleeping times.

Twenty-five subjects suffering from severe chronic insomnia were treated for four weeks with 2 g of L-tryptophan in combination with a schedule of varying sleeping times which caused a sleep deficiency at the beginning of treatment. A second four-week period without L-tryptophan was used as a control. Nineteen subjects (76%) experienced a markedly improved sleeping pattern after four weeks; the sleeping behavior of ten of these subjects, however, deteriorated again after the control period. Daily self-rating protocols revealed that the subjects' sleep improved significantly between the 10th and 15th day after starting treatment. Further sleep-related items such as "activity", "mood", "nervous tension", "contentment", and "quality of the preceding day" were also evaluated. This treatment schedule can thus be recommended for the treatment of severe chronic insomnia.

The influence of acute and subchronic administration of various antidepressants on early morning melatonin plasma levels in healthy subjects: increases following fluvoxamine.

The influence of various antidepressants on the morning levels of plasma melatonin was studied in human volunteers after acute and subchronic administration in weekly increasing doses over a period of three weeks. Two monoamine oxidase (MAO) inhibitors (tranylcypromine: irreversible type A and B; pirlindole: reversible type A), two reuptake inhibitors (maprotiline: selective for noradrenaline; fluvoxamine: selective for serotonin) and an alpha 1/alpha 2-adrenergic and serotonin S2-receptor antagonist (mianserin) were administered to groups of 4 to 7 healthy volunteers each. Two hours after a single oral dose at 9 a.m., at the end of each week and one week after the last dose, morning levels of melatonin were measured using a radioimmunological method. In addition, platelet MAO activity and the uptake of 14C-5-HT into platelets were determined. Plasma melatonin concentrations at 9 a.m. were significantly increased after the intake of 150 mg fluvoxamine the night before; whereas, administration of the same dose in the morning did not lead to increases in melatonin during the day. Following subchronic administration, plasma melatonin levels were significantly increased after the 1st (50 mg/day), 2nd (100 mg/day) and 3rd (150 mg/day) week of fluvoxamine intake in comparison to pre-drug levels. No changes in early morning levels of plasma melatonin were measured in the subjects receiving the other antidepressants, after acute as well as after subchronic administration. The results seem to indicate that following fluvoxamine intake at night, the early morning decline of melatonin is delayed. It is suggested that the underlying mechanism leading to a rise in morning melatonin levels cannot be explained solely on the basis of an inhibition of 5-HT reuptake and that other pharmacological properties of fluvoxamine may be involved.

ERG and VECP in chronic progressive external ophthalmoplegia (CPEO).

Eleven patients suffering from chronic progressive external ophthalmoplegia (CPEO) were investigated by means of electroretinograms (ERG) and visually evoked cortical potentials (VECP) to flash and checkerboard-reversal stimuli. One patient exhibited a Kearns syndrome, in two patients fundoscopy revealed pigmentary retinopathy, and the other eight patients had normal fundi. In the three patients with pigmentary retinopathy the ERGs were slightly disturbed or normal, the P100-latencies in the VECPs being normal. Three out of eight patients without pigmentary changes had reduced ERGs indicating unsuspected retinopathy. This nonpigmentary retinopathy was only detected by means of ERG and may be the electrophysiological correlate of a reduced visual acuity. One patient had a considerably prolonged P100-latency in the pattern-reversal VECP of one eye, which may indicate lesions of the visual pathway along with CPEO.

[ERG and VECP in chronic progressive external ophthalmoplegia]. / ERG und VECP bei chronisch-progressiver externer Ophthalmoplegie.

Eleven patients suffering from chronic progressive external ophthalmoplegia (CPEO) were examined by means of electroretinography (ERG) and the visually evoked cortical potential (VECP) with flash and checkerboard-reversal stimuli. One patient exhibited a Kearns-Sayre syndrome, and in two patients fundoscopy revealed pigmentary retinopathy; the fundi of the other 8 patients were normal. In 3 of the patients with pigmentary retinopathy the ERG was slightly disturbed or normal, the P100 latency in the VECP being normal. In three out of 8 patients without retinal pigmentary changes the ERG indicated retinopathy. In 2 cases this was the only finding offering an explanation for the reduced visual acuity. One patient exhibited a considerably prolonged P100 latency in the pattern-reversal VECP of one eye, which might have been indicative of lesions of the visual pathway associated with CPEO.

Comparison of the ACTH suppression test and dexamethasone suppression test in depressed patients.

Fourteen depressed patients were given the dexamethasone and ACTH suppression tests. The results of 71% agreed, suggesting that in a subgroup of depressed patients dexamethasone resistance reflects a central rather than peripheral dysfunction of the hypothalamic-pituitary-adrenal axis.

Studies on cortisol substitution therapy in patients with adrenal insufficiency.

To eight patients with Addison's disease 25 mg of cortisone acetate or cortisol, respectively, was given orally. Thereafter blood samples were taken and analysed for total cortisol, "free" (not protein bound) cortisol and ACTH. Furthermore, urine cortisol excretion and the cortisol binding capacity of the plasma were determined. We found that after the substitution therapy the increase of the plasma cortisol was variable and reached its maximum after 45 to 240 minutes. However, if the resorption time was subtracted the individual differences were less pronounced and plasma cortisol levels above 8 micrograms/dl could be maintained for about six hours. When cortisol was taken instead of cortisone acetate the increase of the plasma cortisol was steeper, decreasing then more rapidly. Plasma "free" cortisol ranged from 2.75 to 6.19% in relation to total cortisol and closely paralleled the level of total cortisol in each patient during the course of the experiment. The excretion of unconjugated cortisol in urine amounted to 56.5 +/- 26 micrograms (SE) and was better correlated to the concentration of "free" cortisol than to total plasma cortisol. The behaviour of plasma ACTH levels was variable. Great fluctuations with high morning levels and good suppression was observed in patients having their substitution tablet only in one single morning dose. From these biochemical data recommendations for the substitution therapy in patients with adrenal insufficiency were given.

Distribution of testosterone in plasma proteins during replacement therapy with testosterone enanthate in patients suffering from hypogonadism.

In five hypogonadal men treated with 250 mg of testosterone enanthate once every three weeks, total testosterone, "free" testosterone and the percent of testosterone bound to the sex hormone-binding globulin (SHBG) and albumin were determined during three weeks. Immediately after the injection total plasma testosterone rapidly increased about four times the starting level closely paralleled by the concentration of "free" testosterone. We found that if the concentration of SHBG had been reached albumin took over the surplus of the testosterone. Whereas in the first and second week after the injection, high and sufficient levels of testosterone were determined, both total and "free" testosterone approached the lower limit of the normal male range in the third week, i.d. 300 ng/dl, or 5 ng/dl, respectively. In one patient with hypalbuminemia, "free" testosterone decreased during the third week below 3 ng/dl though his total testosterone remained sufficient high. This patient complained about symptoms of androgen deficiency. We explained this with his impaired capacity to bind the excess of testosterone by albumin. We concluded that though the concentration of total testosterone may be sufficient high, "free" testosterone can decrease to very low levels due to disturbance in the distribution of the androgen between the plasma proteins.

Correlation of platelet MAO activity with introversion: a study on a German rural population.

Platelet monoamine oxidase (MAO) activity and personality characteristics were correlated in a sample of 52 men (37 +/- SD 13 years) and 54 women (37 +/- SD 15 years) from a rural community. Personality characteristics were measured by using the Freiburger Persönlichkeitsinventar (FPI-A). In males, weak but significant linear correlations (Pearson product-moment and Spearman rank correlations) were found between platelet MAO activity (p-tyramine and benzylamine as substrates) and the extraversion/introversion dimension. In the females, however, there were no consistent significant correlations between MAO activity and FPI test scores. Comparing the top and bottom 25% of the platelet MAO distribution resulted in a significant difference for the second order factor extraversion in the group of men but not in the group of women. The significant correlation between MAO and introversion could not be attributed to cigarette smoking, food consumption, alcohol, or drugs. In accord with previous biochemical-behavior research, it is suggested that reduced platelet MAO activity may, to some extent, reflect an impulsive personality type.

Factors altering platelet monoamine oxidase. The influence of oral glucose intake.

The specific activity of human platelet monoamine oxidase from control subjects undergoing glucose tolerance tests is reduced drastically. Three hours after intake of 100 g of glucose only 25%-30% of the MAO-baseline activity was measured with tryptamine. beta-phenylethylamine and p-tyramine as substrates. At about 5 hr, platelet MAO activity has increased again. Inhibition was not due to small molecular weight inhibitors or other diffusible factors. Studies of other platelet enzymes, including succinate dehydrogenase and isocitrate dehydrogenase (NADP+ dependent) showed no parallel reductions; hGH, insulin, blood glucose and platelet glycogen concentrations did not correlate with platelet MAO activity. The changes of MAO activity in respect with p-tyramine and tryptamine as substrates 24 hr after glucose ingestion suggest changes of the lipid microenvironment of this enzyme of the outer mitochondrial membrane.

Treatment of cryptorchidism with pernasal gonadotropin-releasing hormone therapy.

Twenty-five boys between 1 and 10 years of age with unilateral or bilateral cryptorchidism were treated with 200 microgram of gonadotropin-releasing hormone (GnRH) pernasally six times daily until descensus was completed, or for 10 weeks at most. Complete descent of the tests occurred in 16 patients, usually after 2 to 5 weeks of treatment. No adverse side effects have been observed. Radioimmunologic measurements of serum luteinizing hormone (LH), follicle-stimulating hormone (FSH), testosterone, and prolactin, carried out before treatment, at the end of treatment, and 6 months after treatment, showed a transitory increase of the LH responsiveness to GnRH in only four of the patients and in the group as a whole a slight but significant decrease of FSH responsiveness. There were no signs of precocious puberty. GnRH antibodies were not found.