Starvation induces a partial failure of triiodothyronie to inhibit the thyrotropin response to thyrotropin-releasing hormone

During starvation the response of TSH to TRH decreases in many subjects. This could be due to an increased sensitivity to TSH secretion to circulating thyroid hormones. To study this hypothesis, 13 subjects were starved twice for 2-day periods. After both starvation periods, a standard TRH test (200 micrograms TRH, iv) was performed; during 1 starvation period 15 micrograms T3 were injected iv 24 h before the TRH test. The TRH tests were also performed while on normal nourishment, once without pretreatment and once 24 h after the iv injection of 15 micrograms T3. The spontaneous decrease of the TSH response to TRH was seen in 10 of 13 subjects. In these 10 subjects it decreased from 18.0 +/- 1.9 to 9.7 +/- 1.2 microU/ml (mean +/- SEM; P < 0.001). The additional inhibition of the TRH test with T3 was small compared with the one observed under normal conditions. In starvation, T3 decreased the maximal TSH response from 9.7 +/- 1.2 to 8.4 +/- 1 microU/ml (P = NS), while during the control period the maximal TSH response fell from 18.0 +/- 1.9 to 11.4 +/- 1.3 microU/ml (P < 0.001). These data indicate a diminished effectiveness of T3 in inhibiting TSH secretion and are consistent with the hypothesis of a more generalized resistance of target organs to T3 during starvation in man.     

Effect of estrogens on thyroid function. I. Alterations in rhesus plasma thyrotropin and its kinetics.

The circulating levels of TSH, its metabolism, and its response to synthetic TRH were studied in five euthyroid menstruating rhesus monkeys before and during treatment with estradiol monobenzoate (E2B, 50 microgram/kg BW/day sc). The pre-E2B treatment mean plasma TSH level was 1.4 +/- 0.12 (SE) microunit/ml. A significant increase in mean plasma TSH (P less than 0.01) to 1.54 +/- 0.29 microunit/ml was observed as early as 48 h after intiation of E2B treatment; it continued to rise progressively to day 28 when it plateaued around a mean concentration of 3 microunit/ml. It normalized within 10 days after cessation of E2B therapy. After iv TRH (5 microgram/kg BW), a consistent rise in plasma TSH was observed before and on days 11 and 56 of E2B therapy. The peak TSH level and maximum rise over the basal level (deltaTSH) during the three tests were not significantly different. During E2B therapy there were remarkable changes in TSH kinetics. These alterations included a significant decrease (P less than 0.01) in metabolic clearance rate, contraction of the distribution space, and expansion of the extrapituitary TSH pool, but there was no appreciable change in TSH production rate. Although a definite trend towards the above alterations was discernible on day 17 of treatment, they were well established by day 66. These data suggest that the estrogen-induced rise in circulating TSH was caused mainly by decreased degradation and not by increased production.     

Apomorpine inhibits the prolactin but not the TSH response to thyrotropin releasing hormone.

Pretreatment of normal subjects with apomorphine, a dopamine receptor agonist, resulted in significant impairment of the subsequent prolactin (PRL) response to thyrotropin releasing hormone (TRH). The mean maximal increment of PRL was 27.9+/-2.4 ng/ml after TRH alone, and 11.9+/-3.0 ng/ml (P less than 0.001) after apomorphine plus TRH. In contrast, the.thyrotropin (TSH) response to TRH was unaffected by apomorphine (10.5+/-2.9 vs. 9.5+/-1.8 muU/ml, P greater than 0.5). These results demonstrate that dopaminergic effects are capable of inhibiting PRL responses to TRH, probably via a direct effect on the lactotrope cell. They also suggest that dopaminergic influences are not important in the regulation of TSH secretion.     

Response to thyrotropin releasing hormone: an objective criterion for the adequacy of thyrotropin suppression therapy.

Most serum thyrotropin (TSH) assays do not adequately discriminate between normal values and absent TSH. We therefore evaluated the TSH response to thyrotropin releasing hormone (TRH) as a criterion for the adequacy of TSH suppression therapy. Twenty-six outpatients with various thyroid disorders (cancer, 10; nodules, 9; miscellaneous, 4; hypothyroidism after 131I therapy for Graves' disease, 3) were studied. Using the frequent sampling technique (samples every 20 min) in two normal volunteers and one untreated patient who was TRH-responsive, we first confirmed the observation that TSH secretion occurred episodically throughout the 24-h period. In contrast, serum TSH was undetectable (less than 0.6 micronU/ml) throughout the 24-h period in 5 patients on TSH suppression therapy who were TRH-unresponsive and one who had a minimal response to TRH. Thus, TRH-unresponsive patients did not secrete measurable amounts of TSH throughout the 24-h period. To suppress TSH secretion, all patients were treated with L-thyroxine (T4) at doses which resulted in undetectable TSH values in random plasma samples. TRH tests were carried out only when random TSH concentrations were less than 0.6 micronU/ml. Seven of the twenty-six patients (27%) including two with thyroid cancer were TRH-responsive indicating a potential for TSH secretion. In these seven, the T4 dose was adjusted until they were TRH-unresponsive. The mean change in T4 dose of these 7 patients was 20+/-10 (SD) microng/day and this resulted in a mean increase of 1.5+/-1.1 microng/dl for T4 and 20+/-20 ng/dl for T3. For all patients, the mean T4 dose required for TSH suppression was 172+/-53 microng/day or 2.6+/-0.8 microng per day per kg body weight. Twenty-three of 26 patients required between 100-200 microng/day and the remaining 3, 250-300 microng/day. The T4 dose required to suppress TSH resulted in normal serum concentrations of T4. 9.1+/-2.0 MICRONG/DL, AND T3, 136.7+/-33.6 NG/DL. These T4 doses did not produce a rapid heart rate, either awake or asleep, arrhythmias, or electrocardiographic abnormalties as assessed by 24-h Holter monitor tracings in 11 patients. Our results thus show that the T4 dose which results in an unresponsive TRH test ensures that serum TSH will remain undetectable (less than 0.6 micronU/ml) throughout the 24-h period. An unresponsive TRH test, therefore, appears to be a very useful and reliable index of TSH suppression.     

Are fasting-induced effects on thyrotropin and prolactin secretion mediated by dopamine?

To investigate whether total caloric deprivation influences TSH and/or PRL responsiveness, seven healthy volunteers fasted overnight (8 h) and were injected iv with a small dose (25 micrograms) of TRH and 30 min later with 40 mg cimetidine (CIM). This combined TRH-CIM test was repeated in the same individuals after a fasting period of 56 h. The TRH-stimulated mean maximal TSH increment fell from 5.1 +/- 1.2 to 1.2 +/- 0.6 microU/ml (P less than 0.01) during fasting. In contrast, both the TRH- and CIM-induced PRL responses were unaffected. To exclude methodologic errors on this reduced TSH responsiveness, an additional four normal subjects fasted for 56 h and then were given TRH alone. Two days later the TRH test was repeated after a fasting period of only 8 h. This experimental design also resulted in a significantly lower TSH response after the longer fasting period than after the shorter period, thus demonstrating that prolonged fasting inhibits TSH responsiveness regardless of whether the starvation period precedes or follows the TRH injection, and regardless of whether the pituitary thyrotrophs are stimulated with TRH plus CIM, or with TRH alone. In an additional seven healthy subjects injected with TRH plus CIM before and after a fasting period of 56 h, a dopamine D-2 receptor blocking agent, metoclopramide (MET), was given orally 90 min before the second TRH-CIM load. This priming with MET failed to restore normal TSH responsiveness in the fasting subjects, thus indicating that the suppressed TSH secretion could not have been mediated through dopamine D-2 receptors. However, since oral pretreatment with MET completely abolished the CIM-elicited PRL response in the fasting subjects, it is reasonable to assume that CIM stimulates PRL release via a reduced dopaminergic inhibition of the pituitary lactotrophs.     

Circadian and pulsatile thyrotropin secretion in euthyroid man under the influence of thyroid hormone and glucocorticoid administration

The inhibitory action of thyroid hormones (TH) and glucocorticoids on circadian and pulsatile TSH secretion was investigated in groups of five normal men by sampling blood every 10 min for 24 h (start, 1750 h). Serum TSH was measured by a sensitive immunoradiometric assay. Continuous infusion of 50 micrograms T3 or 250 micrograms T4 for 8 h (1900-0300 h) significantly suppressed serum TSH levels (T3, P less than 0.025; T4, P less than 0.05; by paired t test). Administration of 3 g sodium ipodate 7 h before TH infusion did not alter the TSH response to T3, but T4-dependent suppression was abolished. Pulsatile TSH secretion [basally, 5.8 +/- 1.3 (+/- SD) pulses/24 h, as analyzed by the PULSAR program; 6.8 +/- 1.9 by the Cluster program] was not significantly altered by any of the experimental conditions. The additional finding of blunting of the TSH response to TRH after TH alone or ipodate and T3 suggests a predominantly pituitary feedback action of TH exerted via conversion of T4 to T3. In contrast, bolus injections of 4 mg dexamethasone (dex) at 1900 and 2200 h abolished TSH pulses for at least 6 h (PULSAR, 6.6 +/- 1.6 pulses/24 h basally vs. 3.6 +/- 3.0 under dex; Cluster, 7.0 +/- 2.7 pulses/24 h basally vs. 1.6 +/- 1.6 under dex). Dex administration also resulted in a prompt, sustained, and significant suppression of basal TSH (P less than 0.0005). Together with a normal serum TSH response to TRH (in separate experiments 1, 9, and 19 h after dex administration), these data suggest that glucocorticoid feedback occurs at a suprapituitary level.     

Blunted nocturnal TSH surge does not indicate central hypothyroidism in patients after pituitary surgery.

The thyrotropin-releasing hormone stimulation test (TRH test) is commonly used as part of the endocrine evaluation after pituitary surgery. However, some patients with a normal thyrotropin (TSH) response to TRH after pituitary surgery develop central hypothyroidism during follow-up. On the other hand, hypothyroidism does not necessarily ensue in patients with a blunted TSH response. As TSH is secreted in a pulsatile fashion with maximum secretion in the early morning, we investigated whether measurement of the nocturnal TSH surge is useful for predicting development of thyrotropic function after pituitary surgery. Serum TSH concentrations were measured at hourly intervals from 16.00 h to 06.00 h in 13 healthy volunteers and in 10 patients within 2 weeks after pituitary surgery. A standard TRH test using i.v. injection of 200 microg synthetic TRH was performed the next morning. Three and six months later thyroid function was reassessed in all patients by measuring thyroid hormones and TSH. Healthy volunteers showed a clear nocturnal TSH surge from a nadir of 0.55 +/- 0.27 microIU/ml at 18.00 h to a peak concentration of 1.82 +/- 0.97 microU/ml at 06.00 h (p = 0.0015). DeltaTSH during TRH test was 6.31 +/- 2.27 microIU/ml. In contrast, following pituitary surgery, patients invariably showed a blunted nocturnal increase in TSH concentration, which was 0.27 +/- 0.20 microIU/ml at 18.00 h and 0.33 +/- 0.26 microIU/ml at 06.00 h (p = 0.044). DeltaTSH during TRH test was 1.99 +/- 2.51 microIU/ml and was subnormal in 8 out of 10 patients. Levothyroxine supplementation was initiated in two of these patients, because free T4 levels were also subnormal and clinical hypothyroidism was present. In the remaining patients with subnormal TRH response, no case of central hypothyroidism was identified at the follow-up visits after 3 and 6 months. We conclude from these data that both nocturnal TSH surge and TRH test are subnormal after pituitary surgery and do not indicate that central hypothyroidism will develop.     

Reduced thyroid function after thyrotropin stimulation.

The course of serum T4 and T3 return to baseline after TSH stimulation was studied in two groups at six normal subjects over 28 days after im bovine TSH (b TSH; 0.15 U/kg). In the first group of six subjects, serum bTSH rose from undetectable levels to a mean peak of 5.6 +/- 0.5 ng/ml (mean +/- SE) at 2 h, and fell below detectable levels by 24 h with a t1/2 of 7 +/- 1 h. T4 rose to a peak 59 +/- 10% above basal levels within 24 h, returned to basal levels on day 7, then dropped below basal levels on days 9-24, with a nadir of -16 +/- 4% on day 14. Free T4 paralleled T4 levels. T3 rose to a peak 104 +/- 28% above basal at 24 h, then fell faster than T4, reaching basal levels by day 4. During the period of low T4, T3 was at or below basal levels. Human TSH (h TSH) concentration dropped when T4 and T3 rose, but did not rise above basal levels when T4 and T3 fell below basal levels. Neither a T3 elevation nor an increased percentage of free T4 was present during the time of reduced T4 levels. The same pattern of thyroidal response was seen in the second group of six subjects. In this second group, hTSH response to repeated TRH challenge was studied. During the period of reduced T4 and T3, hTSH response to TRH was diminished. On day 28, T4, T3, hTSH, and hTSH response to TRH returned to basal levels. We conclude that the brief elevation of T4 and T3 after bTSH stimulation exerts a suppressive effect on the pituitary which extends beyond the period of elevated thyroid hormone levels, and that delay in pituitary recovery is the mechanism of the decreased thyroid function after acute bTSH stimulation.     

Combined pituitary stimulation test: interactions of hypothalamic releasing hormones in man

The use of hypothalamic releasing hormones for the clinical assessment of anterior pituitary function is both simple and free of severe side effects. Tests with the recently discovered substances GRF and CRF as well as with combinations of several releasing hormones are therefore used in many clinics. A reliable interpretation of such combined tests, however, is only possible when positive or negative interactions between these releasing hormones are known. After a rest of 2 h to reach basal cortisol levels, 7 groups of 5 male volunteers each received an iv bolus injection consisting of either: A): GRF (100 micrograms) + CRF (50 micrograms) + TRH (200 micrograms) + LHRH (100 micrograms), B): CRF + TRH, C): GRF + TRH, D): LHRH + TRH, E): TRH, F): GRF, G): CRF. During the following 2 h, GH, TSH, cortisol, LH, FSH and prolactin were measured every 15 min. The TSH response after the injection of all 4 releasing hormones was significantly higher (delta TSH = 16.5 +/- 2.0 microU/ml, x +/- SE) compared to the injection of TRH alone (delta TSH = 9.3 +/- 1.4 microU/ml; p less than 0.025). This increment in TSH secretion was confirmed when 2 groups of 5 female volunteers were studied with the TRH-test (delta TSH = 9.9 +/- 1.8 microU/ml) or the combination of all four releasing hormones (delta TSH = 16.8 +/- 2.9 microU/ml; p less than 0.05). This exaggerated TSH-response to TRH was demonstrated to be entirely due to simultaneous administration of GRF, whereas CRF and LHRH in combination with TRH had no additional effect on TSH release.(ABSTRACT TRUNCATED AT 250 WORDS)     

Dopamine affects basal and augmented pituitary hormone secretion.

Although the role of the neurotransmitter, dopamine (DA), in the regulation of PRL has been well documented, controversy exists regarding its participation in the regulation of the other pituitary hormones. Consequently, we infused DA into six healthy male subjects (ages 19-32) and studied its effects on both basal pituitary hormone levels and augmented hormonal release induced by insulin hypoglycemia (ITT), TRH, and gonadotropin-releasing hormone (GnRH). DA alone produced a modest though significant increase in GH concentration from 2.2 +/- 0.5 to 11.9 +/- 3.7 ng/ml (P less than 0.05) by 60 min, but the peak incremental GH response to ITT was significantly inhibited by DA (43.5 +/- 5.0 vs. 16.3 +/- 3.3 ng/ml; P less than 0.01). PRL concentrations fell during the DA infusion (20.4 +/- 3.0 to 10.6 +/- 1.5 ng/ml; P less than 0.02) at 235 min, and the PRL responses to both ITT and TRH were completely abolished. Although the basal LH and FSH concentrations were unaffected by DA, the incremental LH response to GnRH was inhibited (45.5 +/- 10.6 to 24.4 +/- 5.4 mIU/ml; P less than 0.05), while the FSH response was unchanged. DA significantly reduced the basal TSH concentration from 3.9 +/- 0.2 to 2.5 +/- 0.2 micro U/ml (P less than 0.01) at 230 min and blunted the peak incremental TSH response to TRH (6.0 +/- 1.5 vs. 2.9 +/- 0.9 microU/ml; P less than 0.01). DA had no effect on basal cortisol levels, the cortisol response to ITT, basal plasma glucose, or the degree of hypoglycemia after ITT. Our data provide new evidence that DA has an inhibitory as well as a stimulatory role in the regulation of GH secretion in normal humans. It inhibits centrally as well as peripherally mediated PRL secretion and blunts the LH response to GnRH. In addition, DA lowers both basal and TRH-mediated TSH release, confirming the reports of other investigators.     

Dynamics of thyrotropin-releasing hormone-induced thyrotropin and prolactin secretion by acutely dispersed rat adenohypophyseal cells. Evidence for 'all-or-none' secretion by heterogeneous secretory units, each with a specific response threshold

We have examined the dynamics of thyrotropin-releasing hormone (TRH)-stimulated secretion of prolactin (PRL) and thyrotropin-stimulating hormone (TSH) using enzymatically dispersed rat adenohypophyseal cells suspended in a perfusion chamber with a volume of 0.2 ml to minimize mixing and dilution. One-min exposure to 3-300 nM TRH, the effective dose range, elicited immediate pulses of PRL and TSH secretion with dose-dependent amplitudes. At all TRH concentrations, following a brief burst of secretion lasting less than 1 min, release of both hormones declined precipitously. Increasing the duration of stimulation up to 30 min with half-maximal TRH concentrations did not alter the dynamics of the initial response and was ineffective in maintaining the initial amplitude of secretion. This phenomenon could not be attributed to exhaustion of readily releasable intracellular PRL and TSH, since an increment in TRH concentration elicited a second pulse of hormone secretion with temporal response characteristics identical to the first. The amplitude of the second pulse was dependent on both the initial concentration of TRH and the magnitude of the increment in TRH concentration. With a stepwise increase in TRH concentration during continuous perfusion, the sum of PRL or TSH secreted from all bursts of secretory activity approximated that achieved with a single exposure to the highest concentration of TRH employed. The high-amplitude secretory response to a given concentration of TRH was restored after an 8-min perfusion with medium alone.(ABSTRACT TRUNCATED AT 250 WORDS)     

The influence of long-term low dose thyrotropin-releasing hormone infusions on serum thyrotropin and prolactin concentrations in man

The purpose of the present study was to evaluate in man the relative thyrotroph and lactotroph response to a 48-h low dose constant TRH infusion. Before, during, and after the 75 ng/min TRH constant infusion, serum samples were obtained every 4 h in six euthyroid ambulating male subjects for measurements of TSH, PRL, T4, and T3. The TSH response, employing a specific and sensitive human TSH RIA, demonstrated a significant rise from the mean basal pre-TRH value of 2.35 +/- 0.64 microU/ml (+/- SEM) to 3.68 +/- 0.80 (P < 0.005) during the TRH infusion; this value fell below the basal level to 1.79 +/- 0.47 (P < 0.05) post infusion. Serum T4 values were increased above basal both during (P < 0.025) and after (P < 0.025) TRH infusion, whereas serum T3 values were not significantly changed throughout the entire study period. The daily TSH nocturnal surge was augmented in both absolute and relative terms during the first 24 h or the TRH infusion, unchanged during the second 24 h of infusion, and inhibited during the first postinfusion day. Other than a minimal increase in serum PRL during the first few hours of the infusion, no significant alteration in the mean basal concentration or circadian pattern of PRL secretion was evident during or after the low dose TRH infusion. These findings would indicate that 1) near-physiological stimulation of the pituitary with TRH produces a greater stimulation of TSH release than of PRL release and 2) the factor or factors producing the circadian TSH surge may not be mediated through fluctuations in endogenous TRH.     

The paradoxical response of growth hormone (GH) to thyrotropin-releasing hormone (TRH) in constitutionally tall children involves a cholinergic pathway

To investigate whether or not a cholinergic pathway is involved in the paradoxical response of GH to TRH in constitutionally tall children, we studied 8 healthy prepubertal children aged 4 2/12-7 10/12 yr, whose heights were over the 95th percentile of the NCHS tables. We defined as "paradoxical" a GH increment greater than 5 ng/ml in response to TRH. Five out of 8 children showed a paradoxical response of GH to TRH (mean GH peak after TRH of 10.7 +/- 1.1 ng/ml). Pretreatment with atropine (0.01 mg/kg IM 30 min prior to the TRH administration) abolished the TRH induced GH rise (peak GH after TRH of 1.5 +/- 1.0 ng/ml, p less than 0.01) but did not modify the TSH response (peak TSH after TRH: basal conditions 8.7 +/- 0.8 microU/ml, post atropine: 9.5 +/- 1.4 microU/ml, p greater than 0.05). Our results demonstrate that a cholinergic pathway is involved in the paradoxical response of GH to TRH in constitutionally tall children.     

The effects of endogenous opioids and cortisol on thyrotropin and prolactin secretion in patients with Addison's disease.

This study assessed the controversial role of endogenous opioids and cortisol in the regulation of TSH and PRL secretion in humans. Seven euthyroid male patients with Addison's disease were studied four times, with an interval of 1-3 months, as follows: 1) during normocortisolism [graduated infusion of hydrocortisone, 0.4 mg/kg, over 19.5 h]; 2) normocortisolism and coadministration of naloxone, at 25 microg/kg x h during the last 6.5 h; 3) hypocortisolism (24 h withdrawal of hydrocortisone, followed by 19.5 h saline infusion); and 4) hypocortisolism plus naloxone administration. The TSH and PRL levels were measured every 15 min, from 0800-1530 h. A TRH test was performed at 1300 h and 1400 h (10 microg and 200 microg of TRH, respectively). The mean TSH level increased significantly during hypocortisolism, compared with normocortisolism (1.78 +/- 0.04 vs. 0.84 +/- 0.02 mU/L; P < 0.001). The administration of naloxone suppressed the TSH levels during hypo- and normocortisolism (1.78 +/- 0.04 vs. 1.50 +/- 0.03 and 0.84 +/- 0.02 vs. 0.61 +/- 0.02 mU/L, respectively; P < 0.001). During hypocortisolism, the TSH responses to small and high doses of TRH were significantly higher than during normocortisolism (P < 0.02). Naloxone had no effect on the TSH responses to TRH, neither during hypo- nor during normocortisolism. The mean PRL level increased significantly during hypocortisolism, compared with normocortisolism (5.8 +/- 0.4 vs. 3.6 +/- 0.2 microg/L; P < 0.001), and naloxone induced an increase in PRL levels both during hypo- and normocortisolism (7.1 +/- 0.7 vs. 4.7 +/- 0.5 microg/L, respectively; P < 0.01). The PRL responses to TRH were similar during hypo- and normocortisolism and without any change during opioid receptor blockade. In conclusion, cortisol suppressed basal TSH and PRL secretion and reduced the sensitivity of the thyrotrophs to TRH, without affecting the PRL response to TRH. Our results suggest that endogenous opioids act at the hypothalamic level to stimulate TSH secretion and to suppress the PRL secretion, but these results argue against an essential role of endogenous opioids in the physiological regulation of TSH and PRL secretion in humans.     

The comparative effect of T4 and T3 on the TSH response to TRH in young adult men.

The effect of graded increments of chronically administered oral T4 or T3 on the TSH response to TRH was studied in normal young adult men. The TSH response was assessed in the baseline state and after each increment of each hormone (two weeks at each dose level) using both 30 mug and 500 mug doses of TRH. Each thyroid hormone caused a dose-related decrease in the TSH response to TRH; thus the TSH response could be used as a bioassay for the biologic activity of the thyroid hormones in man. The dose of thyroid hormone that caused a 50% suppression of the TSH response, or the SD50, was not different with either 30 mug or 500 mug of TRH indicating that thyroid hormone suppression of the TSH response is not more easily detected with a small dose of TRH. The mean SD50 for T4 was 115 mug/day, for T3 stopped 2 h before testing the mean SD50 was 29 mug/day, and for T3 stopped 24 h before testing it was 45 mug/day. Using the average SD50 for the two T3 regimens (37 mug/day), the calculated relative potency indicates that oral T3 is 3.3 times as potent as oral T4, a value in reasonable agreement with the value previously estimated with a calorigenic end-point. The mean dose of T4 needed to decrease the TSH response to TRH to below the normal range (max delta TSH of 2 muU/ml) was 150 mug/day; this value is probably more appropriate than the SD50 in the treatment of patients with primary hypothyroidism or goiter and was about the same (160 mug/day) using a peak TSH after TRH of 3 muU/ml as an end-point. Estimation of the SD50 in each subject showed a 2- to 3-fold range with all regimens of thyroid hormones; similarly there was a 2-fold in the dose of T4 needed to suppress the TSH response to TRH to below the normal range. Further, the difference in the mean SD50 for the two T3 regimens indicates that a single daily dose of oral T3 does not exert a constant biologic effect throughout the day. Thus, because of individual variation and, in the case of T3, because of changing activity during the day a given dose of thyroid hormone may have a widely varying biologic effect. There was also a 3-fold range in the relative potency of T3 to T4 in the four subjects treated with both hormones. This suggests that the therapeutic administration of a fixed ratio fo T3 to T4 may have a variable effect from patient to patient. Finally, the serum T4 rose while the serum T3 did not at a dose of T4 that abolished the TSH response to TRH, indicating that circulating T4 is a determinant of TSH secretion in normal man.     

TSH secretion in Cushing's syndrome: relation to glucocorticoid excess, diabetes, goitre, and the 'sick euthyroid syndrome'

Thyrotrophin (TSH) secretion was studied in 63 patients with Cushing's syndrome (53 patients with pituitary dependent Cushing's disease, eight with adrenocortical tumours, and two with the ectopic ACTH syndrome). Prior to treatment, TSH response to 200 micrograms of TRH intravenously was significantly decreased compared to controls; TSH response was 'flat' (increment less than 2 mU/l) in 34 patients (54%). Patients with a flat response to TRH had significantly higher morning and midnight cortisol levels than patients with a TSH response of 2 mU/l and more; this was not due to differences in serum thyroid hormone levels. Basal TSH, TSH increment after TRH, and stimulated TSH value, but not serum triiodothyronine, were correlated with cortisol measurements (0800 h serum cortisol, midnight cortisol, and urinary free corticoid excretion). After exclusion of 40 patients with additional disease (severe systemic disease, diabetes mellitus, or goitre), cortisol-TSH correlations were even more pronounced (r = -0.73 for midnight cortisol and stimulated TSH levels), while in the patients with additional complications, these correlations were slight or absent. Successful treatment in 20 patients was associated with a rise in thyroid hormone levels and the TSH response to TRH. These results indicate that (1) the corticoid excess but not serum T3 is the principal factor regulating TSH secretion in Cushing's syndrome, (2) a totally flat response to TRH is rare, and (3) TSH suppression and lower than normal serum thyroid hormone levels are reversible after treatment. Since factors like severe systemic disease, diabetes mellitus and goitre also affect TSH secretion, they tend to obscure the statistically significant correlations between cortisol excess and TSH secretion.     

Effects of phenobarbital on hypothalamic-pituitary-thyroid axis in the rat

It has been reported that phenobarbital (PB) increases the peripheral clearance of T4 and T3 and decreases serum T4 and T3 concentrations in the rat, but serum TSH remains unchanged. To explore a possible direct effect of PB on TSH secretion at the hypothalamic-pituitary level, adult male rats were given PB 100 mg/kg or vehicle IP for 10 days. No difference in their thyroid weights was observed. In the PB-treated group serum T4 was decreased (PB, 3 +/- 0.2 micrograms/dl vs. control, 3.8 +/- 0.1 micrograms/dl, mean +/- SE, p less than .002), as was serum T3 (PB, 51 +/- 6 ng/dl vs. control, 70 +/- 5 ng/dl, p less than .05), but serum TSH remained unchanged. Pituitary TSH and hypothalamic TRH contents also were unchanged. Further studies were carried out similarly in the thyroidectomized hypothyroid rat to eliminate the effect of PB on serum T4 and T3 levels. PB or vehicle were started two days after thyroidectomy. By postoperative day 12, TSH levels in the PB-treated rats were lower than in the controls (PB, 697 +/- 62 microU/ml vs. control, 891 +/- 53 microU/ml, p less than .05). Pituitary TSH and hypothalamic TRH contents again were similar in both groups. When TRH (500 ng/kg body weight, IV) was given, the increment in serum TSH at 10 minutes was significantly lower in the PB group (PB, 53 +/- 26 microU/ml vs. control, 131 +/- 18 microU/ml, p less than .05).(ABSTRACT TRUNCATED AT 250 WORDS)     

BROMOCRIPTINE SUPPRESSES THE THYROTROPHIN RESPONSE TO THYROTROPHIN RELEASING HORMONE DURING HUMAN PREGNANCY

Thyrotrophin (TSH) responses to 200 microgram of intravenous thyrotrophin releasing hormone (TRH) were measured in fifteen healthy women in normal early pregnancy before and at the end of a bromocriptine treatment of 5.0-7.5 mg daily for 1-2 weeks. Bromocriptine did not change the basal levels of TSH, triiodothyronine (T3) and thyroxine (T4) during pregnancy. Before the start of bromocriptine, TRH caused a significant TSH elevation from 12.8 +/- 0.5 muu/ml (mean +/- SE) to 21.2 +/- 1.9 muu/ml after 20 min. During bromocriptine intake, TRH caused a TSH elevation from 11.9 +/- 0.4 muu/ml to only 15.5 +/- 1.1 muu/ml which is significantly less (P less than 0.001) than before bromocriptine. Similarly, the mean maximal TSH increment of 8.4 +/- 1.5 muu/ml before bromocriptine was greater (P less than 0.001) than that of 3.8 +/- 60 muu/ml during bromocriptine intake. When women were retested with TRH before and during bromocriptine after legal abortion, bromocriptine did not change the basal levels of TSH, T3 and T4 or the TSH response to TRH. Therefore, the TSH inhibition caused by bromocriptine is specifically related to the pregnancy itself, but the mechanism for this inhibition remains unknown.     

The effect of iodized oil on the TSH response to TRH in endemic goiter patients.

The TSH and T3 response to synthetic TRH was evaluated in 4 groups of patients: normal controls and goitrous subjects from the urban area of Sao Paulo (urinary iodine excretion: 172.2 +/- 48.3 mug I/g creatinine) and nongoitrous and goitrous subjects from the endemic areas of Sao Bento (urinary iodine excretion: 53.8 +/- 17.1 mug I/g). Plasma T4 and T3 were within our normal range in all groups of patients. The mean plasma TSH was significantly higher (5.2 +/- 3.3 muU/ml) in goitrous subjects living in Sao Bento as compared to normal control groups both in urban or endemic areas, and after TRH these patients had an exaggerated and sustained TSH response with a significantly higher peak level (21.1 +/- 7.9 muU/ml). T3 concentration rose in all subjects following TRH and all patients from the Sao Bento endemic areas had a significantly higher proportionate increase in plasma T3 at 120 min. After an injection of iodized oil basal plasma TSH returned to the normal range in the goitrous subjects from Sao Bento. The mean peak TSH response to TRH was 9.1 +/- 3.8 muU/ml at 3 months after the iodized oil injection, and only at 6 months after the iodized oil TSH response was significantly reduced (peak level: 6.1 +/- 2.4 muU/ml). It is confirmed that plasma TSH levels are increased in endemic goitrous patients but not in normal controls living in the same endemic area and it is suggested that the pituitary threshold for inhibition of secretion of TSH by T4 and T3 has been reset in these goitrous subjects to achieve a persistently higher secretion rate of TSH.     

Persistent pituitary resistance to thyroid hormone in congenital versus later-onset hypothyroidism

The pituitary and peripheral responses to L-T4 and L-T3 therapy were studied in 12 patients with congenital goitrous hypothyroidism, in 10 patients with an ectopic thyroid and onset of hypothyroidism at 3-8 years of age, and in 6 patients with adult-onset hypothyroidism, after they had had their chronic thyroid hormone replacement therapy discontinued for 30 days. They were first treated with increasing L-T4 (0.1, 0.2 and 0.4 mg daily) followed by L-T3 (0.05 and 0.2 mg daily) after stopping thyroid medication for another month. Ten normal subjects were treated identically. In normal individuals the peak TSH, alpha, and TSH-beta response to TRH was significantly decreased with 0.1 mg L-T4 or 0.05 mg L-T3 daily and was suppressed with 0.2 and 0.4 mg L-T4 or 0.2 mg L-T3 daily; serum cholesterol and triglyceride decreased significantly with 0.2 or 0.4 mg L-T4 or 0.2 mg L-T3 daily; testosterone-estradiol binding globulin (TeBG) increased significantly at the same doses. In congenitally hypothyroid patients receiving 0.2 mg L-T4 daily, the mean peak TSH after TRH was 24 +/- 17 microU/ml, whereas in patients with an ectopic thyroid or adult-onset hypothyroidism the peak TSH was significantly less at 5.9 +/- 8.8 and 5.5 +/- 5.7 microU/ml, respectively. Only at the highest doses of L-T4 (0.4 mg/day) or L-T3 (0.2 mg/day) was the TSH response to TRH suppressed in the congenitally hypothyroid group. The alpha and TSH-beta subunit levels followed those of TSH.(ABSTRACT TRUNCATED AT 250 WORDS)