Nocturnal TSH Research Articles

Increased thyrotrophin levels and loss of the nocturnal thyrotrophin surge in Sheehan's syndrome.

Since panhypopituitarism in patients with Sheehan's syndrome is due to massive pituitary necrosis with only minor hypothalamic involvement, we hypothesized that serum TSH levels would be low but its circadian rhythm preserved in these patients. Basal and TRH-stimulated mean afternoon (1500-1700 h) and nocturnal (0100-0300 h) TSH levels were determined in 10 patients with Sheehan's syndrome before and during T4/glucocorticoid replacement and in seven controls. Serum concentrations of T3, T4, free T4 (fT4) and cortisol were measured by radio-immunoassay; TSH, GH, PRL and LH were determined by immunofluorimetric assay. Afternoon TSH levels were markedly increased in Sheehan's syndrome patients compared with controls (3.3 +/- 1.0 vs 0.5 +/- 0.15 mU/l, respectively, P = 0.002). At night, TSH levels remained unchanged in Sheehan's syndrome patients (3.3 +/- 1.1 mU/l) but rose significantly in controls (1.1 +/- 0.34 mU/l, P = 0.016). The nocturnal TSH increment was significantly higher in controls than in patients (143 vs approximately 4.9%, respectively, P = 0.0001). In eight patients with normal serum fT4 levels during treatment, basal TSH levels decreased to 0.16 +/- 0.05 mU/l (P < or = 0.008), being barely detectable or undetectable in four patients. In the six patients with detectable TSH during treatment, nocturnal TSH increments were normal in four and blunted in two. There was a strong correlation between pre- and post-treatment basal TSH (r = 0.82, P = 0.012) and between pre- and post-treatment peak TSH after TRH (r = 0.91, P = 0.0017), but no significant correlation between TSH and thyroid hormone levels. The per cent ratio of peak TSH after TRH between treated patients and controls, an estimate of the relative size of the functional thyrotroph pool in Sheehan's syndrome patients, was 7%. Loss of TSH rhythm in Sheehan's syndrome is usually secondary to hormonal deficiency and results from maximally increased secretory activity of a decreased pool of thyrotrophs. The paradox of increased TSH levels and decreased thyroid function in Sheehan's syndrome could result from decreased TSH bioactivity and/or from a critically reduced thyrotroph population that fails to sustain sufficient TSH secretion in the face of rising serum thyroid hormone levels.

Influence of residual C-peptide secretion on nocturnal serum TSH peak in well-controlled diabetic patients.

Several alterations in hypothalamo-pituitary-thyroid (HPT) function have been described in diabetes mellitus and have been attributed to metabolic decompensation. The present study was performed in order to establish whether residual endogenous insulin secretion in patients with insulin-dependent diabetes mellitus (IDDM) may play a role in the control of HPT function. The nocturnal (2230 h-0200 h) serum TSH surge, the TSH response to TRH (200 microgram as an i.v. bolus) and serum free thyroid hormone levels were evaluated in C-peptide positive (CpP) (subjects with residual detectable endogenous pancreatic beta-cell activity) and C-peptide negative (CpN) patients both before and after optimization of metabolic status by 3 days of treatment with continuous subcutaneous insulin infusion, and in normal controls. TSH response to TRH and serum free thyroid hormone levels were assessed in the morning. Twenty male diabetic patients hospitalized to achieve a better control of hyperglycaemia were subdivided into 10 CpP (age: 33 +/- 1.5 years (mean +/- SE); body mass index (BMI): 22.6 +/- 0.3) and 10 CpN (age: 32 +/- 1.7 years; BMI: 22.5 +/- 0.4) patients. Nine normal men (age: 34.0 +/- 1.2 years; BMI: 23.1 +/- 0.4) served as controls. The nocturnal serum TSH peak was measured by dividing the highest night-time TSH value by the next morning TSH value and then multiplying by 100. Serum TSH levels were measured in samples taken just before (time 0) and 30 minutes, after TRH administration. Serum free thyroid hormone levels were measured in samples taken at time 0 of the TRH test. Before improvement of hyperglycaemia, CpP and CPN patients showed similar alterations in HPT function; i.e. serum free T3 levels and TSH responses to TRH were lower than normal; the nocturnal TSH surge was absent. Correction of hyperglycaemia normalized all examined HPT parameters in CpP diabetics, whereas normalization in serum free T3 levels and pituitary TSH responsiveness to TRH in CpN patients was not accompanied by restoration of the nocturnal TSH peak. These data indicate that the absence of residual pancreatic beta-cell function in patients with insulin-dependent diabetes mellitus is associated with neuroendocrine dysfunction in the regulation of circadian TSH secretion, which is not reversible after restoration of good glycaemic control.

Thyroid function tests and their interpretation.

For general screening of children who are in fairly good health and in whom CNS or pituitary disease is not strongly suspected, the newer THS assays are very useful in assessing the action of both endogenous and exogenous thyroid hormone. Those children in whom primary hypothyroidism is strongly suspected or who are already on thyroid hormone supplementation, the free T4 assay provides a useful adjunct to the TSH. If Grave's disease or factious hyperthyroidism is suspected, the total T3 assay is a useful adjunct to the TSH and the free T4. The screening of possible hypothyroidism as a result of hypothalamic or pituitary disease, the free T4 is relied on heavily, along with the response of TSH to TRH stimulation. Measurement of the nocturnal TSH surge may also be useful in this situation.

Nocturnal TSH Surge: A Sensitive Diagnostic Test for Central Hypothyroidism in Children

Nocturnal TSH Surge: A Sensitive Diagnostic Test for Central Hypothyroidism in Children

Hypothalamic-pituitary thyroid abnormalities in children after renal transplantation.

Patients with a successful renal transplant may have abnormalities in thyroid function. We evaluated serum thyroid hormone levels, serum thyrotropin (TSH) response to thyrotropin-releasing hormone (TRH), and the circadian pattern of serum TSH in 18 children aged 6.6-19.4 years (median 12.6 years), 4.0 +/- 2.9 years after renal transplantation. In 14 children, immunosuppressive therapy included methylprednisone [mean (+/-SD) 0.17 +/- 0.05 mg/ kg per day], while in 11 it included deflazacort (0.32 +/- 0.1 mg/kg per day). Seven children were studied twice, under methylprednisone and again while on deflazacort therapy. Mean total and free thyroxine (T4) values were significantly below the mean control levels (total T4 108.5 +/- 21.5 vs. 118.7 +/- 22.1 nmol/l, P < 0.05 and free T4 14.4 +/- 4.0 vs. 18 +/- 4.9 pmol/l, P < 0.001). Morning basal TSH levels were within the normal range. The mean TSH increment after TRH was 4.4 +/- 3.5 mU/l, significantly lower than that of controls (10.8 +/- 4.26, P < 0.001). Of 7 patients on methylprednisone, 4 had nocturnal TSH surges below the normal range (95% confidence limits 47%-300%); this occurred in 3 of 8 patients on deflazacort therapy. The TSH response to TRH was correlated with deflazacort dose. Patients on methylprednisone and deflazacort therapy had similar thyroid alterations. Our findings support the hypothesis that after renal transplantation some children have hypothalamic-pituitary thyroid abnormalities in which glucocorticoids may play a significant role.

Ethanol decreases nocturnal plasma levels of thyrotropin and growth hormone but not those of thyroid hormones or prolactin in man.

Previous studies on the effects of ethanol on circulating pituitary hormones have been carried out mostly during daytime when the secretion of these hormones is generally at a nadir. Therefore, we studied the effects of ethanol on the nocturnal secretion of GH, PRL, TSH, and thyroid hormones (protocol I, nine healthy subjects, five women) and on the TSH and PRL responses to synthetic TRH (protocol II, healthy subjects, four women). Ethanol was given in doses of 0, 0.5 or 1.0 g/kg of BW(protocol I) and 0 or 1.0 g/kg (protocol II) and ingested po at 1900-1945 h. In protocol I, plasma GH rose from 0.6 +/- 0.2 microgram/L (mean +/- SE) at 2200 h to 25.0 +/- 4.3 micrograms/L at 0100 h in control subjects and was almost completely inhibited at 4.5 +/- 1.7 micrograms/L at 0100 h in subjects receiving 1.0 g/kg ethanol (P < 0.01). In subjects receiving 0.5 g/kg ethanol, the inhibition was also significant (P < 0.01), plasma GH being 8.2 +/- 2.5 micrograms/L at 0100 h. Plasma GHRH was measured after solid phase separation in RIA, but it did not show any ethanol-related changes. Plasma PRL exhibited a clear diurnal rhythm in control subjects and rose from 77 +/- 16 at 1800 h to 248 +/- 62 micrograms/L at 0700 h (P < 0.01). The plasma PRL profile was not affected by ethanol. Plasma TSH was 1.4 +/- 0.2 mU/L at 1800-2200 h and rose to 2.3-2.4 mU/L for 0100-0700 h (P < 0.001) in the control subjects. Ethanol 1.0 g/kg suppressed plasma TSH to 1.4 +/- 0.2 mU/L (P < 0.05 at 0100 h and P < 0.01 at 0200 h). According to the area under the curve analyses, the suppression in the nocturnal TSH was 32% in the 0.5 g/kg group and 45% in the 1.0 g/kg group (P < 0.05 for both cases). Circulating free or total T3 and T4 did not show any statistically significant changes that could explain the ethanol-induced inhibition in the nocturnal TSH peak. In protocol II, synthetic TRH (1 microgram/kg BW) was given intravenously, and blood samples were collected before, at 20 and 60 min. TRH significantly stimulated plasma TSH and PRL, but ethanol (1.0 g/kg BW) had no effect on these responses. In conclusion, small amounts of ethanol have unexpectedly great effects on nocturnal surges of TSH, and especially on those of GH, that are apparently mediated by suprapituitary mechanisms. On the other hand, ethanol did not affect the nocturnal PRL surge. These inhibitory effects of ethanol may have unfavorable effects on growth and metabolism in adolescent drinkers.

Differential effects of short-term fasting on pulsatile thyrotropin, gonadotropin, and alpha-subunit secretion in healthy men--a clinical research center study.

In healthy subjects, short term fasting suppresses the hypothalamic-pituitary-thyroid and hypothalamic-pituitary-gonadal (HPG) axes, with decreased serum levels of TSH and LH. However, effects of fasting on pulsatile release of TSH, LH, FSH, and alpha-subunit are less clear. Eleven healthy young men each underwent two 2-day studies: a baseline study during normal caloric intake and a fasting study during 56 h of caloric deprivation. During the final 24 h of each study, blood samples were drawn every 15 min for measurement of serum TSH, LH, FSH, and alpha-subunit pulses. Fifty-six hours of fasting caused a 50% suppression of mean TSH levels and TSH pulse amplitude, without altering TSH pulse frequency. Nocturnal TSH pulse amplitude decreased by 60%, with abolition of the usual nocturnal TSH surge. Fasting suppressed mean LH levels and LH pulse amplitude by 30%, without affecting LH pulse frequency. In contrast, mean FSH levels only decreased by 13%, without changes in FSH pulse parameters, whereas mean alpha-subunit levels and pulse amplitude decreased by 20%. These data show that short term fasting has a greater suppressive effect on the hypothalamic-pituitary-thyroid axis than on the HPG axis. Within the HPG axis, FSH is more resistant to fasting-induced suppression than LH, implying discordant regulation of the two gonadotropins during nutritional deprivation. alpha-Subunit suppression during fasting appears to parallel that seen for LH.

Circadian variations of thyrotropin bioactivity in normal subjects and patients with primary hypothyroidism.

Circadian rhythm of TSH secretion is characterized by a pronounced nocturnal increment that is not followed by the expected rise of circulating thyroid hormone levels. These findings suggest that the nocturnal TSH surge may be constituted by molecules with reduced bioactivity. We, therefore, investigated TSH bioactivity (measured as cAMP accumulation in FRTL-5 cells) and its carbohydrate structure (by Concanavalin A affinity chromatography) in different blood pools taken during the day and night from seven normal subjects and from one patient with mild (mPH) and five with severe primary hypothyroidism (sPH). Patients with sPH were also studied during low dose L-T4 treatment. Cosinor analysis showed a significant TSH circadian rhythm in the control group and in L-T4-treated sPH patients. The nocturnal TSH surge was not followed by any increase in free thyroid hormone levels. In normal subjects, the daytime ratio of TSH bioactivity to immunoreactivity (TSH B/I) was higher than the nocturnal one [1.4 +/- 0.6 (+/- SD) vs. 1.1 +/- 0.6; P < 0.02]. The same pattern was observed in the only mPH patient (1.0 +/- 0.2 vs. 0.7 +/- 0.1; P < 0.01), but not in the sPH patients (0.8 +/- 0.3 vs. 0.7 +/- 0.1; P = 0.3). L-T4 administration to sPH patients caused the daytime TSH B/I to increase and restored the day/night difference in the TSH B/I (1.0 +/- 0.3 vs. 0.8 +/- 0.3; P < 0.02). Concanavalin A chromatography showed that a higher percentage of less mature forms of TSH are secreted during the night. These data indicate that TSH molecules secreted during the night are less bioactive and differently glycosylated than those circulating in the same individual during the day, thus explaining why thyroid hormone levels do not rise after the nocturnal TSH surge. In sPH patients, the TSH circadian rhythm is restored during L-T4 administration, and day/night differences in TSH B/I similar to those recorded in normal subjects are observed.

The seasonal variation in breast cancer detection: Its significance and possible mechanisms

We have demonstrated a number of temporal patterns in subjects with breast cancer including (a) an annual rhythm in the month of first sign or symptom of breast cancer (b) an increased frequency of tumour recurrence one year from diagnosis, and (c) abnormal annual and daily hormonal rhythms in breast cancer patients. Increased detection of breast cancer in spring‐summer appears to be influenced by hormonal parameters, as it was more pronounced in premenopausal women with progesterone receptor (PR) positive tumours. Also, oestrogen receptor (ER) positive and PR negative primary tumours recurred significantly more frequently in the same season that their primary cancer was initially detected. Women who initially detected their breast cancer in spring/summer had a significantly longer survival than those detecting their tumour at other times of the year, especially postmenopausal women with ER+ve and PR+ve tumours. Season of tumour detection also appeared to influence the predictive value of a number of prognostic factors for breast cancer, including ER and PR status, parity, lactational history and body mass index. Several possible mechanisms for seasonal effects in breast cancer were investigated. There was a significant circannual variation in the mean monthly PR concentration in parallel with changes in detection, with peak PR levels in April and nadir values in August/September. Women with previous breast cancer also showed an abnormal melatonin rhythm, with a paradoxical reduction of serum melatonin in wintertime in those who were winter detectors of breast cancer. Serum oestradiol levels measured in summertime were significantly higher in summer detectors than winter detectors of breast cancer. Serum insulin‐like growth factor‐I (IGF‐I) did not increase in summer in breast cancer cases as it did in controls. There was no increase in cortisol production in winter in breast cancer cases, but there was in control women; the normal nocturnal TSH peak was reduced in breast cancer cases compared with controls. Women with breast cancer thus have blunted seasonal hormone changes which may contribute to their tumour growth patterns. Unravelling the hormonal interactions between tumour and host in breast cancer patients will have to take into account daily, annual, and monthly rhythms in hormonal parameters.

18 NOCTURNAL TSH SURGE IN CHILDREN WITH HYPOTHALAMIC PITUITARY DISORDERS AND PRIMARY HYPOTHYROIDISM

The nocturnal TSH surge (ΔTSHn) was studied in 23 control children (group I), 33 with hypothalamic pituitary disease (group II) and 12 patients with primary hypothyroidism, 10 with mild (group III) and 2 with overt hypothyroidism. TSH was measured by IRMA; TSH was calculated as the % increase in the night TSH over day TSH. The results were (X±SE). *p > 0.01 vs group I.A ΔTSHn was found in 16/33 patients of group II (48.5%), in 10 of them the TRH test was normal; in the remaining 17 with ΔTSHn present the TRH test was normal in 9. Group II was divided into patients who were hypothyroid FT4 < 0.7 ng/dl (group III) or euthyroid FT4>0.8 ng/dl (group II2).II1, n=9,Δ TSHn:50.3±15.3%, deficient in 7/9 (77%), TRH test was abnormal in 5/9 (56%); 112, n=24, Δ TSHn: 110.9±21.5%, deficient in 9/24 (37.5%),. TRH test abnormal in 10/24 (62.5%). The TSHn was found deficient in 77% of patients with central hypothyroidism, normal in mild hypothyroidism but absent in overt hypothyroidism. We conclude thatΔTSHn did not provide a complete discrimination between euthyroidism and central hypothyroidism. The ΔTSHn plays and important role in the pathophysiology of central hypothyroidism but many others factors may be implicated.

19 HYPOTHALAMIC-PITUITARY. THYROID ABNORMALITIES IN RENAL TRANSPLANT CHILDREN BEFORE AND AFTER DEFLAZACORT THERAPY

In chronic renal failure we found central hypothyroidism (J Pediatric 1991; 118: 873), so we attempted to study thyroid hormone leveles, TSH/TRH response and the circadian TSH pattern in 9 children (9-16 years old) after renal transplantation (Tx), before and a year after substitution of methylprednisione (MP) with D. D is an oxazoline compound derived from prednisolone with similar antiinflammatory actions but fewer side effects. Renal fuction remained stable. Mean concentrations of T3 (2.3 ± 0.3 vs 2.3 ± 0.4 nmol/L), total T4 (112 ± 26 vs 110 ± 19 nmol/L) and basal TSH (3.4 ± 0.8 vs 2.8 0.9 mU/L) were normal; mean free T4 (13.4 ± 3.5 vs 14.2 ± 2.4 pmol/L) was low (p<0.01). Five patients on MP and 5 on D had deficient TSH increment to TRH; 3 out of patients on MP and 1 out of 5 on D had a nocturnal TSH surge below the normal range (47% - 300%). The association of low free T4, deficient TSH/TRH response and impaired nocturnal TSH surge, support the hypothesis that some renal transplant patients have central hypothyroidism. The circadian TSH pattern seems to improve on D therapy.

Persistence of the circadian thyrotropin rhythm under constant conditions and after light-induced shifts of circadian phase.

TSH levels in human, which normally peak in the late evening, are augmented by sleep deprivation. Based on prior research, we postulated that TSH secretion is governed by both sleep and circadian processes. However, environmental and behavioral factors known to affect each of those processes were not controlled in prior investigations. Therefore, we evaluated TSH secretory patterns in three different conditions: 1) entrainment to the 24-h day, 2) a constant routine designed to unmask the endogenous component of circadian rhythmicity, and 3) before and after a light-induced phase shift of the circadian timing system. We found that TSH levels rose over the 4-5 h preceding sleep during entrainment, followed by a precipitous drop at sleep onset. When subjects remained awake on a constant routine, TSH levels remained elevated throughout the nighttime hours. Subjects kept awake for 2 consecutive nights on constant routine showed two distinct cycles of nocturnal TSH secretion, despite increasing sleep deprivation. Both the TSH and body temperature rhythms were substantially shifted, by an equivalent amount, in response to three consecutive nightly exposures to bright light. These data demonstrate that both the output of the human circadian pacemaker and the inhibitory effect of sleep contribute to the regulation of TSH secretion. Under normal conditions, the inhibitory effect of sleep on TSH secretion opposes the nocturnal peak in the circadian TSH drive.

Pulsatile thyrotropin secretion in patients with Cushing's syndrome

Pulsatile and circadian thyrotropin (TSH) secretion were studied in 16 healthy controls and in three patients with Cushing's syndrome who were studied twice (before and after treatment). Blood was sampled every 10 minutes over 24 hours for TSH (immunoradiometric assay [IRMA]). Mean 24-hour TSH in Cushing's syndrome was lower than in controls (0.4 ± 0.2 v 1.7 ± 0.7 mU/L, P < .001), related to a lower mean 24-hour TSH pulse amplitude (Desade: 0.16 ± 0.15 v 0.44 ± 0.20 mU/L, P < .001; Cluster: 0.17 ± 0.14 v 0.39 ± 0.20 mU/L, P < .001; mean ± SD). TSH pulse frequency was unchanged with approximately 10 pulses 24 h . The nocturnal TSH surge was diminished relative to controls (median-0, range-−0.03 to 0.2 mU/L v 0.9 and 0.3 to 2.5 mU/L, respectively), related to a loss of the usual nocturnal increase in TSH pulse amplitude, but not of TSH pulse frequency. In the eucorticoid state, there was an increase of mean 24-hour TSH to 1.3 ± 0.8 mU/L ( P < .001) under normalization of the mean 24-hour TSH pulse amplitude. The nocturnal TSH surge also increased (median, 0.21; range, 0.15 to 0.4 mU/L) under restoration of the usual nocturnal increase in TSH pulse amplitude. In conclusion, Cushing's syndrome is associated with a decrease of mean 24-hour plasma TSH, related to a decrease of TSH pulse amplitude (not of TSH pulse frequency). The nocturnal TSH surge is decreased in Cushing's syndrome associated with a loss of the usual nocturnal increase of TSH pulse amplitude. The changes in pulsatile TSH release disappear upon restoration of the eucorticoid state.

Effects of naloxone infusions on pulsatile thyrotropin secretion.

Endogenous opioids are known to modulate the secretion of some anterior pituitary hormones, but they are not thought to have significant effects on TSH secretion. However, dynamic TSH secretion has not been characterized during naloxone infusions. Therefore, we measured TSH levels every 15 min over 24 h in nine healthy young men at baseline and during infusions of naloxone at 2 mg/h. A TRH test was performed after each study. TSH pulses were located by Cluster analysis. Naloxone infusions decreased 24-h mean TSH levels by 28%, from 1.68 +/- 0.20 to 1.21 +/- 0.19 mU/L. Mean daytime TSH levels did not change, but nocturnal TSH levels were decreased by 39%, from 2.21 +/- 0.30 to 1.35 +/- 0.21 mU/L. There were no changes in TSH pulse frequency, but naloxone infusions decreased 24-h TSH pulse amplitude by 32%, from 2.02 +/- 0.26 to 1.37 +/- 0.21 mU/L. Daytime TSH pulse amplitude was relatively unaffected (1.27 +/- 0.15 vs. 1.16 +/- 0.21 mU/L), whereas nocturnal TSH pulse amplitude was decreased by 42%, from 2.72 +/- 0.40 to 1.57 +/- 0.23 mU/L. TSH responses to acute TRH administration were decreased after naloxone infusions (12.38 +/- 1.93 vs. 9.17 +/- 1.36 mU/L). Serum T3 levels fell by 21% during naloxone infusions, from 1.9 +/- 0.1 to 1.5 +/- 0.1 nmol/L, whereas other thyroid hormone levels and cortisol levels were unchanged. These findings suggest that endogenous opioids have significant stimulatory effects on TSH secretion, predominantly during the nocturnal TSH surge.

Pulsatile secretion of thyrotropin in children.

To examine pulsatile TSH secretion, serum TSH was determined every 30 min for 24 h in eight short normal prepubertal children (3 males and 5 females, age 4.0-12.6 yr). All children exhibited a clear circadian pattern of TSH secretion. Pulsatile TSH secretion was identified in all subjects with a mean (+/- SD) TSH pulse frequency of 6.9 +/- 1.2 pulses/24 h. The group mean TSH pulse amplitude was 1.4 +/- 0.3 mU/L. Mean TSH concentration was higher during the night hours (2.1 +/- 0.8 mU/L) than during the day hours (1.3 +/- 0.4 mU/L, p < 0.005), and significantly more pulses were detected during the night (mean 4.7 +/- 1.4) than during the day hours (2.1 +/- 0.6, p < 0.005). On average, 62 to 68% of the peaks were detected in the night hours. Mean TSH pulse amplitude during the night hours was not significantly different from that during the day hours. Our findings indicate that, as previously shown in adults, a pulsatile pattern of TSH secretion is present in children. In our study group, the nocturnal TSH surge is associated with an increase in pulse frequency but not amplitude.

Effects of hydrocortisone on pulsatile pituitary glycoprotein secretion.

During states of stress, hypothalamic-pituitary-thyroid and hypothalamic-pituitary-gonadal function can be suppressed. One putative mediator of this stress response may be glucocorticoids, which have widespread effects on thyroid and gonadal function. To characterize dynamic pituitary glycoprotein secretion during glucocorticoid administration, 24-h TSH, LH, FSH, and alpha-subunit pulses were measured in 10 healthy young subjects on 3 occasions: 1) at baseline, 2) during infusions of 100 mg hydrocortisone (HC) over 24 h, and 3) during infusions of 300 mg HC over 24 h. These HC infusions led to serum cortisol levels similar to the endogenous cortisol levels seen in moderate and severe stress. Both HC infusions had profound rapid effects on TSH levels, decreasing TSH pulse amplitude by 60% and abolishing the nocturnal TSH surge. However, TSH pulse frequency was unaltered. In contrast, HC infusions did not change mean or pulsatile LH, FSH, or alpha-subunit secretion. These results suggest that stress levels of cortisol acutely suppress TSH secretion at the pituitary level, with little effect on the TSH pulse generator. On the other hand, the effects of stress and/or hypercortisolism on the gonadal axis may require higher cortisol levels, more prolonged exposure, or other mediators of the stress response.

Thyroid and Adrenal Dysfunction in Abstinent Alcoholic Men: Locus of Disturbance

Certain neuroendocrine abnormalities (e.g., blunted plasma adrenocorticotropic hormone [ACTH] response to corticotropin-releasing hormone [CRH] administration and blunted serum TSH response to thyrotropin-releasing hormone [TRH] administration) are common in alcoholic patients. It was the objective of this study to evaluate whether they are centrally mediated: that is, whether they are secondary to increased activity of CRH and/or TRH neurons. We evaluated the nocturnal secretion (2200 hours to 1000 hours, q 15 min) of plasma ACTH, serum cortisol, and serum TSH, and their responses to the combined administration of CRH and TRH, in 28 acutely abstinent alcoholic (age range: 32 to 57 years; mean: 42.4 years) and 19 normal men (age range: 21 to 52 years; mean: 32.1 years). To assess the validity of administering CRH and TRH simultaneously, we gave 10 additional abstinent alcoholic men (age range: 36 to 53 years; mean: 45.8 years), in random order and at least 4 days apart, either CRH, TRH, placebo, or CRH plus TRH. Nocturnal ACTH, cortisol, and TSH secretion, as well as cortisol and TSH responses after CRH plus TRH administration, were similar in alcoholic and normal men. However, ACTH peak responses to CRH plus TRH were reduced in the alcoholic men (p < 0.05). The ACTH, but not cortisol, response was greater after combined CRH plus TRH administration than after CRH alone (p < .002). The blunted ACTH response does not appear to be the result of increased endogenous CRH activity, because all parameters of nocturnal ACTH pulsatility were normal in the alcoholics. It rather appears to be secondary to an intrinsic defect in the CRH responsiveness of the pituitary corticotroph, possibly due to genetic vulnerability or to the toxic effects of prolonged alcohol abuse.

Pulsatile thyrotropin secretion in nonthyroidal illness.

Pulsatile and nocturnal TSH secretion was investigated in 16 healthy controls (group A) and 21 patients with nonthyroidal illness (NTI; group B). Ten patients had normal plasma T3 and T4 values (group B1), and 11 patients had decreased plasma T3 with normal or low plasma T4 (group B2). Mean 24-h TSH secretion in NTI patients was higher than that in controls (3.1 +/- 0.7 vs. 1.7 +/- 0.7 mU/L; P < 0.01; mean +/- SD). This was associated with an increased TSH pulse amplitude in NTI patients relative to controls [Desade, 0.79 +/- 0.46 vs. 0.44 +/- 0.20 mU/L (P < 0.01); Cluster, 0.64 +/- 0.42 vs. 0.39 +/- 0.20 mU/L (P < 0.05)]. There was no difference in TSH pulse amplitude between subgroups B1 and B2. TSH pulse frequency was not different between NTI patients and controls (approximately 10 pulses/24 h). The mean 24-h TSH concentration was significantly related to the mean 24-h TSH pulse amplitude but not to the mean 24-h TSH pulse frequency. The absolute nocturnal TSH surge in NTI patients was lower than that in controls (0.6 +/- 0.6 vs. 1.0 +/- 0.6 mU/L; P < 0.05). The lower nocturnal TSH surge in patients with decreased plasma T3 (group B2) was associated with a loss of the usual nocturnal increase of TSH pulse amplitude; the usual nocturnal increase in TSH pulse frequency was preserved. This was also observed in the six patients (two in group B1 and four in group B2) in whom the nocturnal TSH surge was completely absent. The changes in nocturnal TSH secretion in NTI resemble those found in central hypothyroidism, suggesting that features of central hypothyroidism are involved in the euthyroid sick syndrome.

Pulsatile thyrotropin release in patients with untreated pituitary disease.

Pulsatile and nocturnal TSH secretion was investigated in 16 healthy controls (group A) and 19 patients with untreated pituitary disease [7 were euthyroid without suprasellar extension (group B), 6 were euthyroid with suprasellar extension (group C) of pituitary lesions, and 6 were hypothyroid with or without suprasellar extension (group D)]. Pulse analysis was performed using Desade and Cluster algorithms. No changes were observed among groups A-D in mean 24-h TSH pulse amplitude [values given as mean +/- SD; Desade, 0.4 +/- 0.2 vs. 0.7 +/- 0.4 vs. 0.6 +/- 0.4 vs. 0.5 +/- 0.2 mU/L (P = NS); Cluster, 0.4 +/- 0.2 vs. 0.7 +/- 0.4 vs. 0.5 +/- 0.3 vs. 0.4 +/- 0.2 mU/L (P = NS)] or in the mean 24-h TSH pulse frequency (approximately 10 pulses/24 h). The mean 24-h TSH concentration was highly correlated to the mean 24-h TSH pulse amplitude in controls (r = 0.93; P < 0.001) and patients (r = 0.63; P < 0.01), but not to the mean 24-h TSH pulse frequency. The nocturnal TSH surge was similar in controls and euthyroid patients without suprasellar extension (group A, 1.0 +/- 0.6; group B, 1.3 +/- 1.3 mU/L; P = NS), but was decreased in euthyroid patients with suprasellar extension (group C, 0.3 +/- 1.0 mU/L; P < 0.05) and hypothyroid patients (group D, 0.4 +/- 0.4 mU/L; P < 0.05). The decreased nocturnal TSH surge was associated with a loss of the usual nocturnal increase in TSH pulse amplitude, whereas the usual nocturnal increase in TSH pulse frequency was maintained. In conclusion, 1) mean 24-h TSH pulse amplitude and frequency are unchanged in untreated patients with pituitary disease; and 2) patients with central hypothyroidism as well as euthyroid patients with suprasellar extension of pituitary lesions had a decreased nocturnal TSH surge associated with a loss of the usual nocturnal increase in TSH amplitude, but not TSH pulse frequency.

THYROID FUNCTION IN NON-GH-DEFICIENT SHORT CHILDREN DURING A PLACEBO-CONTROLLED DOUBLE-BLIND TRIAL OF GH THERAPY

Growth hormone (GH) therapy has been reported to cause changes in thyroid function in GH deficiency including decreases in T4 and TSH and an increase in T3. We sought to determine if GH therapy alters thyroid function in non-GH-deficient short children. Twenty-two children (19 boys) were followed for 12 months while receiving either GH (Humatrope, Eli Lilly) 0.074mg/kg t.i.w. s.c. (n=10) or placebo (n=12). Total T4, free T4, T3 and TSH were measured every 3 months and in 13 children also at 1 and 2 months. A TRH test and nocturnal TSH surge were performed at baseline and 6 months in 19. There were no significant clinical differences at baseline between the placebo and GH groups. The results below are mean (SD). There were no significant differences between the two groups in any of the above measurements or in TSH response to TRH or in nocturnal TSH surge. We conclude that GH therapy over 12 months does not alter thyroid function significantly in non-GH-deficient children.