Harald Meinhold

Neuroendocrinological investigations during sleep deprivation in depression I. Early morning levels of thyrotropin, TH, cortisol, prolactin, LH, FSH, estradiol, and testosterone ☆

Measurements of 12 hormones were conducted in patients with major depressive disorder at 8 AM on the morning before and at 8 AM on the morning after total sleep deprivation (SD). Thyrotropin (TSH), thyroxine (T4), triiodothyronine (T3), and free T3 (fT3) were measured in 50 patients, free T4 in 39 patients, reverse T3, cortisol, prolactin, luteinizing hormone, and follicle-stimulating hormone in 21, estradiol in 20 (women), and testosterone in 14 (men). After SD, there was a significant rise in TSH, T4, T3, and fT3 concentrations and a significant fall in testosterone levels. The increases in TSH levels were significantly correlated to clinical response. Responders to SD had higher T4, fT4, rT3, and testosterone concentrations before SD. Neither age, gender, polarity, nor antidepressant medication had a clearly significant effect on the response to SD.

Evidence for circadian variations of thyroid hormone concentrations and type II 5'-iodothyronine deiodinase activity in the rat central nervous system

Abstract: The 24‐h patterns of tissue thyroid hormone concentrations and type II 5′‐ and type III 5‐iodothyronine deiodinase (5′D‐II and 5D‐III, respectively) activities were determined at 4‐h intervals in different brain regions of male euthyroid rats entrained to a regular 12‐h light/12‐h dark cycle (lights on at 6:00 a.m.). Activity of 5′D‐II, which catalyzes the intracellular conversion of thyroxine (T4) to 3,3′,5‐triiodo‐l‐thyronine (T3) in the CNS, and the tissue concentrations of both T4 and T3 exhibited significant daily variations in all brain regions examined. Periodic regression analysis revealed significant circadian rhythms with amplitudes ranging from 9 to 23% (for T3) and from 15 to 40% (for T4 and 5′D‐II) of the daily mean value. 5′D‐II activity showed a marked nocturnal increase (1.3–2.1‐fold vs. daytime basal value), with a maximum at the end of the dark period and a minimum between noon and 4:00 p.m. 5D‐III did not exhibit circadian patterns of variation in any of the brain tissues investigated. Our results disclose circadian rhythms of 5′D‐II activity and thyroid hormone concentrations in discrete brain regions of rats entrained to a regular 12:12‐h light‐dark cycle and reveal that, in the rat CNS, T3 biosynthesis is activated during the dark phase of the photoperiod. For all parameters under investigation, the patterns of variation observed were in part regionally specific, indicating that different regulatory mechanisms may be involved in generating the observed rhythms.

Rat Brain Type II 5′-Iodothyronine Deiodinase Activity Is Extremely Sensitive to Stress

Abstract: The effects of different kinds of acute stressor on thyroid hormone concentrations and deiodinase activities were investigated in four brain regions (frontal cortex, amygdala, hypothalamus, and cerebellum) and in the pituitaries and livers of adult male rats. Five groups of rats were killed after each of the following stressors: (a) an intraperitoneal injection of saline, (b) intragastric intubation, (c) and (d) two different forms of handling, being grasped as for intraperitoneal injection and being moved from one cage to another, and (e) a 2‐h period spent in a slowly rotating drum. Two other groups were placed in the rotating drums for 10 and 19 h (sleep deprivation experiment), respectively. All stressors induced significant (in some cases up to 200%) increases in the activity of type II 5′‐iodothyronine deiodinase, which catalyzes the deiodination of the prohormone l‐thyroxine (T4) to the active metabolite 3,3′,5‐triiodo‐l‐thyronine (T3). As a consequence, the tissue concentrations of T4 fell, and those of T3 rose (sometimes by up to 300%). However, these changes were limited to selected areas of the brain that were specific for each stressor and were not seen in all brain regions investigated in any group. No clear‐cut effects of stress were seen on the activities of the type III 5‐iodothyronine deiodinase isoenzyme, which catalyzes the inactivation of T3, on liver or serum thyroid hormone concentrations or on liver of brain type I 5′‐iodothyronine deiodinase activities. In summary, our results show that even mild and very brief stress can induce marked increases in T3 concentrations specifically in brain but not in liver or blood. Thus, contrary to common opinion, thyroid hormones may play an important physiological role in stress reactions, at least in tissues that contain type II 5′‐iodothyronine deiodinase, such as brain and pituitary.

TRH-Stimulationstest mit alters- und geschlechtsabhängigem TSH-Anstieg bei Normalpersonen

Summary500 µg TRH (Thyrotropin-Releasing Hormone) were injected intravenously in 78 normal subjects aged between 20–85 years, TSH being estimated by radioimmunoassay from 0–120 min. The maximum increase of TSH (ΔTSHmax) was compared in age- and sex-specific groups.Results: 1) The rise of TSH is significantly lower in men than in women of 20–59 years. 2) In men, the TRH response is diminishing clearly but not significantly with increasing age, i.e. 9.73 µU/ml ± 4.49 SD for 20–39 years, 7.93 µU/ml ±4.94 SD for 40–59 years, 7.37 µU/ml ± 3.37 SD for 60–81 years (not significant). 3) In women, the two groups aged 20–39 and 40–59 years show both a high increase of TSH, ΔTSHmax 15.6 µU/ml±7.6 SD and 15.6 µU/ml±8.8 SD, whereas 60–85 year-old women have a significantly lower TSH elevation of 7.7 µU/ml±3.7 SD. 4) The TRH responses of women taking oral contraceptives and those of untreated women of the same age are similar. 5) In the women decreasing TSH responsiveness was observed after the onset of the menopause. 6) Basal TSH of 20–59 year-old women shows higher values than in males and older subjects. 7) There exists no correlation between serum thyroxine or triiodothyronine and the TRH response. 8) The increase of serum triiodothyronine 120 min after TRH injection is considerably inconstant and not significantly lower in subjects over 60 years.Conclusions: The different age- and sex-specific ranges for the normal values of the TRH test have to be taken into account in clinical use. It is proposed that the ranges of the normal values should be fixed rather by the double standard deviation than by the 3-fold standard error (SEM). For quantitative evaluation of the maximum TSH release, values at 20, 30 and 40 min after injection are necessary in order to find the TSH peak.ZusammenfassungNach intravenöser Gabe von TRH (Thyrotropin-Releasing Hormone) wurde bei 78 Normalpersonen zwischen 20 und 85 Jahren die radioimmunologisch meßbare TSH-Ausschüttung von 0–120 min bestimmt. Der maximale TSH-Anstieg (ΔTSHmax) wurde in geschlechtsspezifischen Altersgruppen verglichen. Ergebnisse: 1. Der TSH-Anstieg ist bei Männern zwischen 20 und 59 Jahren signifikant niedriger als bei Frauen gleichen Alters. 2. Die TRH -Antwort vermindert sich bei Männern mit steigendem Lebensalter von 9,73 µU/ml±4,49 SD bei 20–39jährigen über 7,93 µU/ml±4,94 SD bei 40–59jährigen auf 7,37 µU/ml ±3,37 SD bei 60–81jährigen (nicht signifikant). 3. Bei Frauen zeigen die 2 Gruppen der 20–39jährigen und der 40–59jährigen einen gleich hohen TSH-Anstieg, ΔTSHmax 15,6µU/ml±7,6 SD und 15,6µU/ml±8,8 SD, während die Werte der 60–85jährigen Frauen mit 7,7 µU/ml±3,7 SD signifikant tiefer liegen. 4. Frauen unter Einnahme von oralen Kontrazeptiva unterscheiden sich in ihrer TRH-Antwort nicht signifikant von gleichaltrigen Frauen. 5. In dem hier untersuchten weiblichen Kollektiv setzte die Abnahme der TRH-Antwort bei Eintritt der Menopause ein. 6. Die basalen TSH-Werte liegen bei 20–59jährigen Frauen höher als bei Männern und bei älteren Personen. 7. Es findet sich kein Zusammenhang zwischen Thyroxin- oder Trijodthyroninkonzentration im Serum und der TRH-Antwort. 8. Der Anstieg des Serum-Trijodthyronins 120 min nach TRH-Injektion schwankt erheblich und ist bei Personen über 60 Jahren nicht signifikant niedriger.Schlußfolgerungen: Bei klinischer Verwendung des TRH-Testes sind die unterschiedlichen alters- und geschlechts-spezifischen Normalgrenzen unbedingt zu beachten. Es wird vorgeschlagen zur Eingrenzung der Normalbereiche den 2fachen Wert der Standardabweichung (SD) und nicht den 3fachen Wert der mittleren Streuung des Mittelwertes (s...) zu verwenden Bei quantitativer Beurteilung der maximalen TSH-Ausschüttung muß die TSH-Spitze durch Mehrfachbestimmung 20, 30 und 40 min nach TRH-Injektion gesucht werden

Effects of age and diagnosis on thyrotropin response to thyrotropin-releasing hormone in psychiatric patients

The thyrotropin (thyroid-stimulating hormone; TSH) response to thyrotropin-releasing hormone (TRH) was studied in 64 age-matched healthy volunteers, 44 patients with endogenous depression, and 21 patients with schizophrenia. A significant negative correlation between delta TSH and age was found both in healthy subjects and in depressed patients. We based our comparison on normal ranges for delta TSH calculated from the delta TSH values in the healthy subjects related to age. It was then seen that blunted TSH response to TRH does not occur significantly more often in depression (13.6%) than in healthy controls (4.7%). Blunted TRH test results were also found in a considerable number of severely ill schizophrenic patients (19%). Application of an improved radioimmunoassay revealed a highly significant correlation between TSH values at baseline and after stimulation, and showed decreased baseline TSH levels in subjects with blunted TRH test results.

Effects of lithium and carbamazepine on thyroid hormone metabolism in rat brain

The effects of lithium (LI) and carbamazepine (CBM) on thyroid hormone metabolism were investigated in 11 regions of the brain and three peripheral tissues in rats decapitated at three different times of day (4:00 a.m., 1:00 p.m., and 8:00 p.m.). Interest was focused on the changes in the two enzymes that catalyze: (1) the 5′deiodination of T4 to the biologically active T3, i.e., type II 5′deiodinase (5′D-II) and (2) the 5 (or inner-ring) deiodination of T3 to the biologically inactive 3′3-T2, i.e., type III 5 deiodinase (5D-III). A 14-day treatment with both LI and CBM induced significant reductions in 5D-III activity. However, 5′D-II activity was elevated by CBM and reduced by LI, both administered in concentrations leading to serum levels comparable with those seen in the prophylactic treatment of affective disorders. The effects were dose dependent, varied according to the region of the brain under investigation, and strongly depended on the time of death within the 24-hour rhythm. The consequences of these complex effects of LI and CBM on deiodinase activities for thyroid hormone function in the CNS and also their possible involvement in the mechanisms underlying the mood-stabilizing effects of both LI and CBM remain to be investigated.

Relations between serum levels of TSH, TBG, T4, T3, rT3 and various histologically classified chronic liver diseases

Serum levels of TSH, thyroxine-binding globulin (TBG), T4, T3 and reverse T3 (rT3) were measured in 36 patients with fatty liver disease, 11 patients with chronic persistent hepatitis, 17 patients with chronic active hepatitis, and 29 patients with liver cirrhosis. TBG was significantly above normal levels in both groups of chronic hepatitis, the slight concomitant T4 and T3 increase was significant only for Tt in chronic persistent hepatitis. A significant decrease in T4 and T3 concentration was found in fatty liver disease and in hepatic cirrhosis. A shift in T4 conversion to rT3 could exclusively be demonstrated for the group of hepatic cirrhosis, reflected by a significant increase in rT3. As our findings indicate normal TSH levels and a lack of clinical signs of hypothyroidism in chronic liver disease, the possibility of diverse regulating changes must be considered.

Effects of a low selenium state in patients with phenylketonuria

Abstract Eighty‐seven participants of the German Collaboratory Study for Children with Phenylketonuria (PKU) presented low plasma, whole blood and hair selenium (Se) values, reduced urinary selenium excretion, and decreased plasma and erythrocyte glutathione peroxidase activity in comparison with a healthy reference group (all figures p < 0.001). Aspartate amino transferase and thyroxine (T4) concentrations in plasma were inversely correlated with the selenium blood values of the PKU children. Somatic measurements showed a negative standard deviation score of body height in the PKU children compared with reference values. Despite the different Se supply, the infants did not present any specific Se deficiency symptoms.

Thyrotropin (TSH) and thyroid hormone concentrations during partial sleep deprivation in patients with major depressive disorder

Thyrotropin (TSH), thyroxine (T4), free T4, triiodothyronine (T3), and free T3 (fT3) concentrations were measured in 25 patients with major depressive disorder at 8 a.m. both before and after partial sleep deprivation (PSD) during the second half of the night. Significant increases in TSH and T3 levels and a corresponding trend in fT3 levels were seen. No convincing correlations occurred between changes in the secretion of any of the hormones and the antidepressant effect of PSD. However, this does not rule out the possibility that the two phenomena, which occur in depression at different anatomical levels with presumably different degrees of disturbance in the respective receptor systems, have common underlying neurochemical mechanisms. Comparison of the effect of the PSD on changes in hormone secretion and mood with the corresponding effects in a sample of depressed patients who underwent total sleep deprivation showed no significant differences between the effects of these two forms of sleep deprivation on either variable.

Extraction and quantification of thyroid hormones in selected regions and subcellular fractions of the rat brain.

There is increasing evidence of an involvement of thyroid hormones in numerous physiological processes of the adult vertebrate brain. However, the only valid method available for measuring triiodothyronine (T3) in brain tissue is time-consuming and not sufficiently sensitive to determine hormone concentrations in small, but physiologically important areas such as the amygdala and septum. We therefore developed a protocol for reliable measurement of the concentrations of thyroxine (T4) and T3 in brain tissue. This was achieved by combining a new method of extracting iodothyronines with highly sensitive, accurate and reproducible radioimmunoassays (RIAs) in order to be able to detect T4 and T3 in homogenates and even subcellular fractions (nuclear, synaptosomal and mitochondrial) in up to 11 regions of the rat brain. The iodothyronines were extracted from tissue samples by adding 100% methanol containing 1 mM PTU. Recoveries of 72.8 +/- 5.5% and 83.2 +/- 3.3% for T4 and T3, respectively, were obtained. The RIA detection thresholds were 10 fmol/g for T4 and 18 fmol/g for T3. Only 0.2% of the antibody for T4 cross-reacted with T3 and 0.95% reverse T3. T3 antibody (0.05%) reacted with T4 and 0.01% with 3,5-T2. The T4 concentrations in the homogenates of selected areas of the brain ranged between 1 and 4 pmol/g, whereas those of T3 ranged between 0.5 and 4 pmol/g. The T3 levels ranged between 190 and 470 fmol/mg protein, 38 and 110 fmol/g protein and 25 and 180 fmol/mg protein in the nuclei, synaptosomes and mitochondriae, respectively. In conclusion, the newly developed method enabled us to determine both T4 and T3 concentrations in homogenates and T3 in subcellular fractions of regions of the brain as small as the septum and amygdala.