Effects of Oral Contraceptive Therapy on the Orcadian Patterns of Cortisol and Thyrotropin (TSH)

Abstract. The daily variation of serum Cortisol and thyrotropin (TSH) has been simultaneously recorded every 30-min. in 4 women taking the same oral contraceptive containing oestrogens and progestogens and in 4 control women. The circadian rhythm of Cortisol persisted under contraceptive therapy with about a 2. 5 fold elevat ion of the mean level and amplitude of the basal rhythm. Theoretical equilibrium calculations of the circadian variations of the free, transcortin-bound and albumin-bound Cortisol fractions showed that these elevations are explained qualitatively and quantitatively by an oestrogen-induced increase of the same order of the transcortin cortisol-binding sites. As a consequence of the already high saturation of transcortin in normal conditions, the magnitude of the variation of free Cortisol level resulting from a burst in Cortisol secretion varies with the time of day. The role of albumin as a buffer is thereby emphasized. The early morning maximum, characterizing the normal TSH daily pattern, appeared to be considerably enhanced in women under contraceptive therapy. If the circadian variations of TSH are driven by thyrotropin releasing hormone (TRH), these higher morning peaks probably reflect a higher burst of TRH secretion rather than an increased responsiveness of the pituitary to TRH secretion induced by contraceptive therapy. Finally these results do not support the hypothesis of a regulation of TSH circadian variations by an inhibiotry action of Cortisol. Contraceptive therapy does not appear to play a role at the level of the central clock or on the resetting mechanism.     

Reduced testosterone levels in cluster headache: a stress-related phenomenon?

The circadian changes in testosterone (T) and cortisol secretion and morning luteinizing hormone (LH) levels were evaluated in nine episodic cluster headache (CH) patients in active phase and in seven healthy volunteers, with collection of blood samples every 2 h for 24 h. CH showed a significant reduction of the 24-h integrated mean T value (mesor) (4.4 + 1.1 ng/ml; chi +/- SD) in comparison with controls (6.6 +/- 0.8 ng/ml) (P less than 0.01). Both groups had plasma T circadian rhythm with peak values in early morning, but in CH single cosinor analysis showed its absence in three out of nine CH patients. The rhythm showed an acrophase delay of 101 min in CH. Both patients and controls had a significant circadian rhythm of plasma cortisol concentration. CH patients, however, showed an acrophase delay of 106 min and significantly increased concentrations from 1200 h to 2000 h. Morning LH values were similar in the two groups. The reduced secretion of plasma T in CH patients in the active phase coexisted with an acrophase delay of its circadian rhythm. A similar delay was found in 24-h plasma cortisol levels. We suggest that stress accompanying attack expectancy in the active phase is the mechanism behind the elevated plasma cortisol levels. This in turn could reduce T concentrations, acting at the testicular level. These disturbances in internal chronoorganization support the hypothesis that cluster headache is basically a dyschronic disorder.     

A Diathermy Unit for Microsurgical Preparations

The urinary excretion of unconjugated cortisol and plasma levels of cortisol and non-protein-bound cortisol as well as the circadian rhythm of cortisol in blood were investigated in normal and pregnant women and in females on oral contraceptives. A definite increase in both urinary excretion of cortisol and in plasma levels of non-protein-bound hormone was found in pregnant and in estrogen-gestagen treated women. Furthermore, the normal day-night variation of plasma cortisol was lower in pregnant women, but not in women treated with estrogen-gestagen.     

Thyrotropin Response to Thyrotropin Releasing Hormone in Normal Subjects

Abstract. 200 (ig of synthetic thyrotropin releasing hormone (TRH) was administered intravenously to six normal men and six normal women on two occasions. A positive correlation between the basal TSH level and maximal serum TSH after TRH was found. The TSH responses in the mid-follicular and mid-luteal phase were similar. There was no difference in the response between the men and the women investigated. The variability was considerable, the intra-individual coefficient of variation of the TSH response being 30 per cent when expressed as per cent increase above the basal level.     

The effect of oral contraceptive use and pregnancy on the daily rhythm of cortisol and cortisone

The effect of oral contraceptives and of pregnancy on the daily rhythm of cortisol, and its metabolite cortisone in plasma and saliva has been investigated. In both conditions the total plasma cortisol levels were raised to the same extent, the mean values in saliva in the oral contraceptive users being intermediate between those in pregnancy and in the controls, particularly in the morning. Salivary cortisone levels were more related to salivary cortisol than to total plasma cortisone which exhibited a rather flat daily rhythm. There was a shift in peak values for salivary cortisol and cortisone towards late morning: this may be due to a delay in the daily activation of the hypothalamic-pituitary-adrenal axis in these patients.     

Value of free thyroxine (FT4), free triiodothyronine (FT3), and sensitive thyrotropin (TSH) assay in the assessment of optimal thyroxine therapy

We describe a sensitive thyrotropin (TSH) assay in the evaluation of thyroxine replacement therapy. Patients taking varying amounts of L-thyroxine replacement doses were studied using a thyrotropin-releasing hormone (TRH) test and a sensitive TSH assay as the indices of optimal replacement therapy. There were no differences in the mean thyroxine doses of those patients who had a normal TRH response and those who had a flat response. Similarly there were no significant differences in the serum free thyroxine (FT4), free triiodothyronine (FT3), or total triiodothyronine (TT3) levels between these two groups. The patients in both groups had normal basal serum TSH values as measured by a standard, HTSH RIABEAD (Abbott) method. However, serum TSH values, as measured by a sensitive TSH3 MAIACLONE (Serono) immunoradiometric method, were subnormal in all patients with flat TRH responses. The TSH (Serono) assay provided the best single blood test of optimal thyroxine replacement.     

Age- and sex-related differences in urinary excretion of 6 beta-hydroxycortisol in humans

A study of normal subjects showed that the 24-h urinary 6 beta-hydroxycortisol level is age-dependent, with a maximum at 14-20 yr in both men and women. The ratio of 6 beta-hydroxycortisol/cortisol also showed an age-dependent variation, being higher in children than adults. There was a significant difference between boys and girls aged 5-10 yr, but no difference in other subjects. No sex difference was demonstrable in the ratio of 6 beta-hydroxycortisol/cortisol. Examination of circadian rhythm revealed that 6 beta-hydroxycortisol and cortisol correlated well in children, but showed poor correlation in adults, with a lowered morning peak of 6 beta-hydroxycortisol.     

The Response of Thyrotropin and Triiodothyronine to Various Doses of Thyrotropin Releasing Hormone in Normal Man

Abstract. The relationship between serum thyrotropin (TSH) and serum triiodothyronine (T3) before and after injection of different doses of thyrotropin releasing hormone (TRH), given as single injections or as multiple injections with short intervals, was investigated in normal men. A positive correlation between prestimulated serum TSH and serum T₃ levels and between the increase in the serum TSH and the serum T3 levels after TRH was found when repeated tests were performed in the same individual. There was a dose dependent TSH and T3 response to TRH. The smallest dose that produced a maximal response of both TSH and T3 was only 30 ug TRH. After six injections of 30 ug TRH with an interval of 30 minutes the increase in TSH was two times and the increase in T3 was three times as high as the maximal increase after single injections of TRH. This test with multiple injections of TRH may prove to be of clinical value in the measurement of both pituitary and thyroid function in selected patients. The close positive correlation between the serum TSH and serum T3 levels in basal conditions, demonstrated in four normal subjects in this study, probably reflects the steady state level determined by the hypothalamus from which the feedback control of TSH secretion operates.     

Chronodisruption in lung cancer and possible therapeutic approaches

A customary temporal organization of physiological functions and biological processes is necessary to maintain body homeostasis and an altered body time structure may favour carcinogenesis. There is growing evidence that GH stimulates cancer growth, IGF1 may have a role in carcinogenesis and cancer promotion, GH-IGF1 axis, TRH, TSH, thyroxine, melatonin and cortisol modulate immune cell function and the immune system is often dysfunctional in patients with malignancies. The aim of our study was to evaluate GH-IGF1 axis, hypothalamus-pituitary-thyroid axis, melatonin, cortisol, lymphocyte subsets and IL2 in lung cancer patients. Peripheral blood samples were collected at 4-hour intervals in a 24-hour period from eleven healthy male subjects (age range 35-53 years) and nine male patients suffering from non-small cell lung cancer (age range 43-63 years). In each blood sample, lymphocyte subpopulations (CD3+, CD4+, CD8+, CD16+, CD20+, CD25+, HLA-DR+, γδTcR bearing cells) were analyzed and GH, IGF1, TRH, TSH, FT4, melatonin, cortisol and IL2 were measured. Circadian rhythmicity was evaluated and MESOR, amplitude and acrophase values were compared. In healthy subjects a significant circadian rhythm could be demonstrated with midday peaks for CD8+, CD16+, γδTCR expressing cells and cortisol, and peaks during the night for CD3+, CD4+, GH, TSH and melatonin. A borderline significant rhythm was also observed for CD20+, with a peak late in the evening. IGF1, TRH, FT4 and IL2 values did not show rhythmic variation. In cancer patients a significant circadian rhythm could be demonstrated with diurnal peak for CD16+ and peaks during the night for CD4+ and melatonin. GH, IGF1, TRH, TSH, FT4, cortisol and IL2 values did not show rhythmic variation. MESOR of CD8+ (P < 0.0001), CD20+ (P = 0.05), γδTCR expressing cells (P = 0.01), IGF1 (P < 0.001) and TSH (P = 0.032) was higher in healthy subjects, whereas MESOR of CD16+ (P < 0.0001), CD25+ (P = 0.001), GH (P < 0.001), TRH (P = 0.002), FT4 (P = 0.030), cortisol (P = 0.01) and IL2 (P = 0.02) was higher in cancer patients. Amplitude of circadian variation of γδTCR expressing cells (P = 0.01), TSH (P < 0.001) and cortisol (P = 0.01) was higher in healthy subjects, whereas amplitude of circadian variation of CD4+ was higher in cancer patients (P = 0.02). In conclusion, non-small cell lung cancer patients show severe alterations of periodic and quantitative characteristics of neuroendocrine and immune parameters with loss of circadian rhythmicity and internal desynchronization, leading to chronodisruption.     

Modulation of glucose regulation and insulin secretion by circadian rhythmicity and sleep.

To define the roles of circadian rhythmicity (intrinsic effects of time of day independent of the sleep or wake condition) and sleep (intrinsic effects of the sleep condition, irrespective of the time of day) on the 24-h variation in glucose tolerance, eight normal men were studied during constant glucose infusion for a total of 53 h. The period of study included 8 h of nocturnal sleep, 28 h of continuous wakefulness, and 8 h of daytime sleep. Blood samples for the measurement of glucose, insulin, C-peptide, cortisol, and growth hormone were collected at 20-min intervals throughout the entire study. Insulin secretion rates were derived from C-peptide levels by deconvolution. Sleep was polygraphically monitored. During nocturnal sleep, levels of glucose and insulin secretion increased by 31 +/- 5% and 60 +/- 11%, respectively, and returned to baseline in the morning. During sleep deprivation, glucose levels and insulin secretion rose again to reach a maximum at a time corresponding to the beginning of the habitual sleep period. The magnitude of the rise above morning levels averaged 17 +/- 5% for glucose and 49 +/- 8% for calculated insulin secretion. Serum insulin levels did not parallel the circadian variation in insulin secretion, indicating the existence of an approximate 40% increase in insulin clearance during the night. Daytime sleep was associated with a 16 +/- 3% rise in glucose levels, a 55 +/- 7% rise in insulin secretion, and a 39 +/- 5% rise in serum insulin. The diurnal variation in insulin secretion was inversely related to the cortisol rhythm, with a significant correlation of the magnitudes of their morning to evening excursions. Sleep-associated rises in glucose correlated with the amount of concomitant growth hormone secreted. These studies demonstrate previously underappreciated effects of circadian rhythmicity and sleep on glucose levels, insulin secretion, and insulin clearance, and suggest that these effects could be partially mediated by cortisol and growth hormone.     

Clinical utility and cost-effectiveness of sensitive thyrotropin assays in ambulatory and hospitalized patients

In either an ambulatory or a hospitalized patient setting, a normal serum sensitive thyrotropin (TSH) value is strongly suggestive of euthyroidism if the patient has intact hypothalamic-pituitary function and is not receiving drugs known to suppress pituitary TSH secretion. In stable ambulatory patients, an abnormal sensitive TSH value is strongly suggestive of clinical or subclinical thyroid hormone excess or deficiency, which can be confirmed by a free thyroxine (T4) index (FT4I) and evaluation for antimicrosomal antibody (AMA) as a marker of autoimmune thyroid disease. In a hospitalized patient, an abnormality in sensitive TSH or FT4I does not necessarily indicate a thyroid problem but may merely reflect a nonthyroidal illness or glucocorticoid or dopamine treatment. A thyrotropin releasing hormone (TRH) test may be needed to diagnose hyperthyroidism in a hospitalized patient with a basal sensitive TSH level of less than 0.1 microU/ml because a detectable TRH response contraindicates hyperthyroidism whereas hyperthyroid patients with nonthyroidal illness have the expected absent response. In a hospitalized patient, hypothyroidism must be diagnosed on the basis of both a high TSH level and a low FT4I because an isolated high TSH value may merely reflect the recovery phase of a nonthyroidal illness. No clinical urgency exists for establishing a diagnosis of subclinical hypothyroidism in a hospitalized patient; definitive determination of thyroid status can be deferred until recovery and discharge.     

Use of sensitive immunoradiometric assay for thyrotropin in clinical practice

Although measurement of thyrotropin (thyroid-stimulating hormone; TSH) by radioimmunoassay was a major advance in the laboratory diagnosis of thyroid failure--replacing the time-consuming TSH stimulation test--it was not sufficiently sensitive to discriminate reliably between euthyroid and hyperthyroid patients. Measurement of the TSH response to thyrotropin releasing hormone (TRH) served this purpose, however. The recent development of TSH assays that are severalfold more sensitive and more specific than conventional radioimmunoassays has allowed distinction of euthyroid from hyperthyroid patients and eliminated the need for the TRH test. Although undetectable levels of TSH, compatible with hyperthyroidism, are occasionally noted in euthyroid patients with severe nonthyroidal illness and during the first trimester of pregnancy, false-positive results are less often recorded for TSH than for free or total thyroid hormone measurements. Measurement of TSH by sensitive immunoradiometric assay is currently the most useful first-line test of thyroid function in patients with suspected thyroid disease and, in addition, has a valuable role in monitoring the dose of thyroxine replacement therapy.     

Cortisol dynamics following acute severe brain injury

Objective To study the diurnal rhythm of plasma cortisol and corticosteroid binding-globulin (CBG) in brain-injured patients managed in an intensive care unit (ICU).Design Observational clinical study.Setting Twelve-bed medical/surgical critical care facility.Patients and participants Fifteen acute brain-injured (coma-inducing) patients: nine following trauma and six with subarachnoid haemorrhage (SAH).Interventions One morning and one evening blood sample were obtained from each patient via an existing arterial line at times which coincided with clinically indicated blood tests.Measurements and results The total cortisol measurements in this sample of brain-injured patients is similar to the normal reference range. Only two patients had morning total cortisol measurements greater than the reference range, 140–690 nmol/l, and five patients had evening measurements greater than the 80–330 nmol/l reference range. Eight patients demonstrated diurnal variation of plasma cortisol. Plasma CBG was significantly decreased in all 15 brain-injured patients. All patients had a free cortisol percentage greater than the quoted reference of 5% and five patients had measurements between 12–23%. No diurnal variation in CBG was detected. There was no association between age or mode of injury and cortisol secretion.Conclusion Following acute severe brain injury, total serum cortisol is not elevated. This may indicate relative hypocortisolaemia in relation to the clinically assessed stress. However, because of the decline in plasma CBG, plasma free cortisol is increased after acute severe brain injury.     

A case of refetoff syndrome: selective venous sampling for TSH is useful in differentiating thyroid hormone resistance from TSH secreting tumor

A 22-year old man with a goiter and clinical manifestations of mild thyrotoxicosis (finger tremor, palpitation, tachycardia) was diagnosed as a syndrome of inappropriate secretion of TSH. Serum concentrations of T4, free T4, T3 and TSH were 24.1 micrograms/100 ml, 4.07 ng/100 ml, 261 ng/100 ml and 1.72 microU/ml, respectively. Thyroidal 131I uptake at 24 hr was 80%. The BMR was within the normal range. He had a normal TSH response to TRH (500 micrograms) with a peak level of 23.8 microU/ml. The basal level of alpha-subunit of TSH was not elevated (0.35 ng/ml). Oral 1-T3 administration (75 and 150 micrograms daily) raised serum T3 concentration, reduced basal TSH and blunted TSH response to TRH. The diurnal variation of TSH was maintained. There was no evidence of abnormalities in the secretion of other pituitary hormones. These findings were compatible with thyroid hormone resistance. However, the presence of a microadenoma in the pituitary gland was suspected with CT scan. Bilateral and simultaneous venous sampling for TSH from inferior petrosal sinus showed no gradient in TSH concentration indicating that a TSH secreting pituitary tumor was unlikely. These data suggest that inappropriate TSH secretion in the present patient is resulted from resistance to thyroid hormone. In the present study selective venous sampling is useful to differentiate the thyroid hormone resistance from a TSH secreting tumor.     

The Response of Thyrotropin and Triiodothyronine to Various Doses of Thyrotropin Releasing Hormone in Normal Man

Abstract. The relationship between serum thyrotropin (TSH) and serum triiodothyronine (T₃) before and after injection of different doses of thyrotropin releasing hormone (TRH), given as single injections or as multiple injections with short intervals, was investigated in normal men. A positive correlation between prestimulated serum TSH and serum T₃ levels and between the increase in the serum TSH and the serum T₃ levels after TRH was found when repeated tests were performed in the same individual. There was a dose dependent TSH and T₃ response to TRH. The smallest dose that produced a maximal response of both TSH and T₃ was only 30 μg TRH. After six injections of 30 μg TRH with an interval of 30 minutes the increase in TSH was two times and the increase in T₃ was three times as high as the maximal increase after single injections of TRH. This test with multiple injections of TRH may prove to be of clinical value in the measurement of both pituitary and thyroid function in selected patients. The close positive correlation between the serum TSH and serum T₃ levels in basal conditions, demonstrated in four normal subjects in this study, probably reflects the steady state level determined by the hypothalamus from which the feedback control of TSH secretion operates.     

Twenty-four-hour melatonin and cortisol plasma levels in relation to timing of cluster headache

The cyclic recurrence of cluster periods and the regular timing of headache occurrence in cluster headache (CH) induced us to study the circadian secretion of melatonin and cortisol in 12 patients with episodic CH, during a cluster period, and compare them with 7 age- and sex-matched healthy controls. Blood was sampled every 2, h for 24 h. All subjects were confined to a dark room from 22.00 to 08.00. Plasma melatonin levels were significantly reduced in CH patients (repeated measures ANOVA p < 0.03; mesor p < 0.02), and the cortisol mesor was significantly increased ( p < 0.03). Amplitudes and acrophases did not differ between the groups. Individual cosinor analysis showed that 412 (33.3%) CH patients had no significant melatonin rhythm, and that 5/11 (45.5%) had no cortisol rhythm. Group analysis of cosinor revealed significant rhythmicity of melatonin and cortisol secretion in both groups. In controls, the timing of melatonin and cortisol acrophase significantly correlated with each other, indicating that the biorhythm controllers for the secretion of these hormones were synchronized. Such correlation was not found in the CH patients; mesor, amplitude and acrophase of melatonin and cortisol did not correlate with duration of illness, duration of headache in course, or time since last headache attack.     

Inappropriate TSH secretion with abnormal thyrotroph sensitivity to dopamine

A 47-year-old male schizophrenic with hyperthyroidism was found to have non-neoplastic inappropriate thyrotropin (TSH) secretion. Anterior pituitary function, CT scan and alpha subunit determinations were normal. TSH rose after TRH (7.8 to 22.5 microU/ml) and propylthiouracil (26.1 microU/ml after 3 months) and decreased with oral T3 (Cytomel 25 micrograms po q.i.d.). Cytomel and glucocorticoid infusion blunted but did not completely suppress the TSH response to TRH. Intravenous dopamine infusion (4 micrograms/kg/min) completely suppressed the prolactin but not the TSH response to TRH. The association of schizophrenia and differential thyrotroph sensitivity to dopamine suggests a possible role for dopamine in the pathogenesis of selected cases of non-neoplastic inappropriate TSH secretion.     

Circadian rhythm of cytokine secretion following thermal injury in mice: implications for burn and trauma research

Although there are many reports of circadian variation in hormone secretion, there are only a few reports on the relationship between circadian rhythm and cytokine production. The aim of the present studies was to investigate whether there is a circadian effect on cytokine production of splenic lymphocytes and adherent splenocytes in mice after burn or sham injury. We selected day 7 after injury for our determinations because we have previously shown day 7 is the time of maximal suppression of T cell IL-2 and IFNgamma production and maximal increase in adherent cell proinflammatory cytokine secretion in this model. IL-2 and TNFalpha were chosen as reference cytokines since the former is known to be produced by T cells and the latter by adherent cells of the innate immune system. The results showed that seven days after sham or thermal injury both T cell IL-2 and adherent cell TNFalpha production were altered by time of injury or time of cell harvest. IL-2 secretion was significantly decreased in burn compared to sham animals when splenocytes were harvested in the morning; the decrease was non-significant when splenocytes were harvested in the afternoon. TNFalpha secretion was significantly increased in burn vs. sham adherent cells only when injury took place in the morning. The observed circadian variations in cytokine production could have a significant effect on cytokine levels measured in clinical and animal studies of injury and may explain some of the reported discrepancies among these studies.     

Cardiac systolic time intervals and thyroid hormone levels during treatment of hypothyroidism.

This study was undertaken to compare results of modern serum thyroid hormone assays with cardiac systolic time intervals (STI) during thyroxine treatment in hypothyroid patients. The patients were assessed clinically (Billewicz index) and the STI and serum thyrotropin (TSH), total and free thyroxine (T4) and total and free triiodothyronine (T3) were determined in 16 hypothyroid women (Group I) treated with 50 micrograms increments of thyroxine, and in 13 women who had a history of thyroid carcinoma and high-dose thyroxine replacement therapy and had elevated thyroid hormone concentrations (Group II). The STI of 24 matched healthy female controls were used for reference of STI. The pre-ejection period (PEP) index and the PEP/LVET ratio (left ventricular ejection period) were greater in untreated overtly and mildly hypothyroid patients (p less than 0.05) than in the controls. During stable thyroxine therapy [mean daily dosage for Group I 137.5 (7.3) micrograms and for Group II 220 (61) micrograms] the PEP correlated with serum free T4 (FT4), as measured by a two-step method (SpectriaR) (r = -0.55, p less than 0.01, n = 29) and total T4 (r = -0.51, p less than 0.05, n = 29), but not with TSH, T3, FT3 or FT4 measured by an analogue method Amerlex-M(R). The TRH test was not valuable in follow-up because of the strong correlation between basal TSH and stimulated TSH values (r = 0.95). In conclusion, STI are useful for assessment of the thyroid state in untreated hypothyroid patients. Serum TSH becomes normal in the same time as STI and is the best for follow-up. If serum TSH is low and the patient is on stable thyroxine therapy, we recommend serum FT4 for monitoring thyroxine replacement. Two-step FT4 assays had the best correlation with STI, which has significance in patients with non-thyroidal illness.     

The nocturnal serum thyrotropin surge is inhibited in patients with adrenal incidentaloma.

BACKGROUND: Alterations in hypothalamic-pituitary function have been described in patients with incidentally discovered adrenal adenomas and have been attributed to their subtle hypercortisolemic status. METHODS: To establish whether the central control of the hypothalamic-pituitary-thyroid axis is altered in these endocrine conditions, the nocturnal (10:30 PM-2:00 AM) serum thyroid-stimulating hormone (TSH) surge (measured by dividing the difference between nighttime and morning TSH values by the morning TSH value and then multiplying by 100), the TSH response to thyrotropin-releasing hormone (200 microg as an intravenous bolus) and serum free thyroid hormone levels were evaluated in patients with adrenal incidentaloma (experimental group) and in normal controls (control group). Urinary free cortisol concentrations were also measured. RESULTS: The nocturnal TSH surge was observed in the normal controls, whereas it was inhibited in the patients of the experimental group. Serum free triiodothyronine levels were similar in the two groups, whereas the TSH response to thyrotropin-releasing hormone was significantly lower in the experimental than in the control group. Urinary free cortisol levels were significantly higher in the experimental group. CONCLUSION: These data indicate that even conditions of slight glucocorticoid excess may exert inhibitory effects on TSH secretion, which suggests the presence of a slight central hypothyroidism in patients with adrenal incidentaloma.