EFFECT OF DOPAMINE AND A DOPAMINE D-1 RECEPTOR AGONIST ON PULSATILE THYROTROPHIN SECRETION IN NORMAL WOMEN

The inhibitory effect of a pharmacological dose of dopamine and the specific dopamine D-1 receptor agonist fenoldopam on basal and pulsatile TSH secretion was investigated in normal women. The TSH response to fenoldopam and subsequent releasing hormone administration was also studied. Six women received placebo or dopamine infusion (4.0 micrograms/kg min) for 17 h. After 9 h, blood samples were collected every 10 min between 0800 and 1600 h for measurement of TSH. Eight women received 8-h (0900-1700 h) infusions of either fenoldopam (0.5 micrograms/kg min) or placebo. After 7 h of infusion 10 micrograms TRH, 5 micrograms GnRH and 25 micrograms CRF was given i.v. Blood samples were collected every 10 min. Dopamine infusion as well as fenoldopam infusion significantly reduced both mean basal TSH secretion and TSH pulse frequency compared with corresponding control infusions (P less than 0.05). However, while the effect on TSH pulsatility was comparable (P greater than 0.05), the percentage decrease in basal TSH levels after 16 h of dopamine infusion was 51 +/- 16% (mean +/- SD) and after 7 h of fenoldopam infusion 19 +/- 12% (P less than 0.05). Neither of the drugs affected TSH pulse amplitude and fenoldopam did not influence TRH-stimulated TSH release (P greater than 0.05). The results suggest that dopamine D-1 receptors are involved in modulation of TSH pulsatility probably at the hypothalamic level. It is argued that dopaminergic inhibition of basal TSH secretion and TSH pulsatility is predominantly regulated through dopamine D-2 receptors at the pituitary level, and through D-1 receptors at the hypothalamic level, respectively.     

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.     

Physiological regulation of circadian and pulsatile thyrotropin secretion in normal man and woman

The circadian and pulsatile TSH secretion profiles were investigated in 5 females at the time of menstruation and 21 healthy males by sampling blood every 10 min for 24 h. Computer-assisted analysis, i.e. the Cluster and Desade programs, revealed means of 9.9 +/- 1.7 (Cluster) and 11.4 +/- 3.9 (Desade) pulses/24 h. More than 50% of the TSH pulses were detected between 2000-0400 h. Male and female subjects showed no significant difference in the basal mean and pulsatile secretion of TSH or in the TSH response to TRH (200 micrograms). Repetition of the TSH secretion analysis in 4 healthy subjects after 1, 2, and 6 months (2 subjects) revealed a significantly better cross-correlation within than between individuals (P less than 0.0001). We modulate the circadian TSH secretion pattern by acute sleep withdrawal or prolonged sleep after a night of sleep withdrawal in six healthy male volunteers. Sleep withdrawal augmented the nightly TSH secretion (mean serum TSH, 2.1 +/- 1.3 mU/L; mean TSH in sleep, 1.3 +/- 0.5 mU/L; P less than 0.05), whereas sleep after sleep withdrawal almost completely suppressed the circadian variation (mean TSH, 1.1 +/- 0.7 mU/L; P less than 0.01). This modulation is due to a significant decrease in pulse amplitude, but not to an alteration in the frequency or temporal distribution of TSH pulses.     

Comparison of the effects of pulsatile and continuous TRH infusion on TSH release in men

Pulsatile secretion of hypothalamic releasing factors modulates the release of pituitary hormones. To compare the effects of pulsatile and continuous administration of TRH on TSH secretion, we studied six healthy euthyroid 20- to 38-year-old men by obtaining blood samples every 20 minutes for 12 hours (8 AM to 8 PM) during five days of study. TRH was administered according to the following schedule: day 1 (no TRH, control); day 2 and subsequent day 3 (20 micrograms IV bolus of TRH every 96 minutes); 6 to 17 days rest; then consecutive days 4 and 5 (continuous infusion of 20 micrograms TRH/96 minutes) for 12 hours on and 12 hours off. The highest mean serum TSH levels occurred on the first day of pulsatile TRH. Serum TSH on pulsatile days 1 and 2 and continuous day 1 was significantly greater than on the control day. Similarly, the mean TSH on each day of pulsatile TRH was greater than the mean TSH on the corresponding days of continuous TRH administration. The highest serum T4 and T3 levels were observed on pulsatile day 2, suggesting that the decrease in serum TSH on this day was due to thyroid hormone negative feedback at the pituitary. The mean T4 and T3 values on continuous day 1 and 2 did not differ significantly, suggesting that other factors, including "down-regulation" of the pituitary TRH receptors by the continuous TRH infusion may be involved in the further decline of TSH levels on continuous day 2. We conclude that pulsatile TRH infusion releases more TSH, T3, and T4 than the corresponding amount of TRH administered continuously.(ABSTRACT TRUNCATED AT 250 WORDS)     

Acute hyperglycemia and activation of the beta-adrenergic system do not exhibit synergistic inhibitory actions on thyrotropin-releasing hormone (TRH)-induced thyroid stimulating hormone (TSH) secretion

Thyrotropin-releasing hormone (TRH)-stimulated thyroid stimulating hormone (TSH) response in normal subjects is suppressed by oral glucose administration. Pharmacologic studies indicate that this suppressive action of glucose is mediated by an increase in hypothalamic somatostatin (SRIH) tone. Since activation of the beta-adrenergic system also suppresses basal TSH secretion by enhancing SRIH release we sought to determine whether isoproterenol alters the suppression of TRH-induced TSH response induced by the stimulation of glucose. Four tests were performed in seven healthy young men: Test 1: 200 microg TRH (iv) at 0 min; Test 2: 100 g oral glucose at -30 min and TRH at 0 min; Test 3: TRH at 0 min with isoproterenol (0.012 microg/kg, iv) infused continuously; Test 4: oral glucose at -30 min, TRH at 0 min with isoproterenol infused continuously. Pretreatment with glucose significantly suppressed TRH-induced TSH secretion. Isoproterenol infusion also suppressed the TRH-induced TSH secretion, but it did not enhance the inhibitory action of glucose on TSH secretion. The degree of suppression induced by glucose was significantly higher than that achieved by isoproterenol. These data suggest that combined administration of glucose and isoproterenol does not exhibit synergistic inhibitory actions on TRH-stimulated TSH secretion, and that the glucose-TRH test could be used for the evaluation of the hypothalamic somatostatinergic activity.     

Human pituitary chronoendocrinology: repetitive stimulation with LRH/TRH at different times of the day

To determine whether human pituitary is characterized by a circadian periodicity in response to repetitive injection of hypothalamic hormones, 8 healthy subjects were challenged iv with a triple stimulation with 50 micrograms of LRH and 100 micrograms of TRH in a single bolus at 0, 90 and 180 min, receiving the first pulse of hypothalamic hormones either at 02.00 h (02.00 h test) or at 09.00 h (09.00 h test). In addition, a placebo was injected instead of LRH/TRH to evaluate the spontaneous hormonal changes during the 02.00 h test. The LH, FSH, Prl and TSH basal levels were similar in the two phases studied. The mean LH, FSH and TSH peaks after each injection of LRH/TRH were similar among them. The mean Prl peak responses to the third pulse of LRH/TRH, in both the 02.00 h and the 09.00 h tests, were lower (P less than 0.05) than those after the first pulse of LRH/TRH. Placebo did not significantly change circulating LH, FSH, Prl or TSH during nocturnal sampling. The mean LH, FSH and Prl levels after LRH/TRH during the 02.00 h test were similar to those during the 09.00 h test. The mean TSH levels 15 min after the second and third pulses of LRH/TRH during the 02.00 h test were higher (P less than 0.05) than those of the 09.00 h test. Thus, thyrotropes responsiveness to pulsatile stimulation with LRH/TRH is greater during the night than in the morning, while LH, FSH and Prl responses remain constant at the two phases studied.     

Anterolateral hypothalamic deafferentation inhibits histamine-induced prolactin secretion and potentiates TRH-induced thyrotropin secretion in male rats

We studied the effect of histamine on serum prolactin and thyrotropin (TSH) levels in male rats with anterolateral hypothalamic deafferentation of hypothalamic connections or anterolateral cut (ALC). The success of ALC was confirmed by immunohistochemistry of somatostatin (SRIF) in the medial basal hypothalamus. ALC did not affect basal prolactin or TSH levels. Thyrotropin-releasing hormone (TRH, 200 ng/rat, i.p.) did not affect prolactin secretion either in sham-operated or ALC rats. In sham-operated rats intracerebroventricularly administered histamine increased significantly prolactin levels. Hypothalamic deafferentation abolished the effect of histamine on prolactin levels. TRH increased significantly serum TSH levels both in sham-operated controls and ALC rats. In the latter, however, the TSH-secretory response to TRH was significantly (p less than 0.05) larger compared to the controls. Intracerebroventricularly infused histamine (2 micrograms/rat) did not change the TRH-induced TSH secretion in either group of rats. These results show that (1) the effect of histamine on prolactin secretion is mediated through nerve tracts which are destroyed by ALC, and (2) cutting of afferent TRH (through sensitization) and SRIF fibers (through lacking inhibition) entering medial basal hypothalamus may both contribute to the enhanced TSH response to exogenous TRH.     

Decreased basal and stimulated thyrotropin secretion in healthy elderly men

To delineate the effects of aging on basal and stimulated TSH secretion, we studied the 24-h profile of plasma TSH levels and the TSH response to TRH stimulation (200 micrograms TRH, iv) in eight healthy elderly men, aged 67-84 yr, and eight normal young men, aged 20-27 yr. Subjects with thyroid antibodies against microsomal or thyroglobulin antigens were excluded. During the 24-h study, blood was sampled at 15-min intervals. TSH levels were measured by an ultrasensitive immunoradiometric assay. Sleep was polygraphically monitored, and circadian and pulsatile TSH variations were quantified using specifically designed computer algorithms. In older men, the 24-h mean TSH concentration was approximately 50% lower than that in young men (0.78 +/- 0.37 vs. 1.43 +/- 0.41 microU/mL; P less than 0.01), but basal T3 levels were only slightly lower (93 +/- 12 vs. 115 +/- 16 ng/dL; P less than 0.02), while basal T4 levels were normal. The normal diurnal variation of TSH levels, with a nocturnal acrophase and an afternoon nadir, as well as the pulsatile nature of TSH release were preserved in elderly men. When expressed in microunits per mL, the amplitude of these temporal variations was reduced in elderly men compared to that in younger subjects. However, when expressed in relation to the mean TSH levels, the amplitudes of diurnal and pulsatile variations were similar in both groups of subjects. TRH-induced TSH secretion was lower in old than in young men (area under the curve, 15.9 +/- 6.3 microU/mL.10 min in elderly men vs. 42.0 +/- 16.6 microU/mL.10 min in young men; P less than 0.002). However, the TRH-induced elevations of T3 and T4 were of similar magnitude in both groups. These results indicate that in healthy elderly men, the overall 24-h TSH secretion is decreased, and the pituitary is less responsive to stimulation by TRH. However, the chronobiological modulation is preserved. These alterations could reflect an adaptative mechanism to the reduced need for thyroid hormones in old age. The thyroid keeps an intact capacity to respond to acute increases in TSH concentrations.     

Effects of dopamine and somatostatin on pulsatile pituitary glycoprotein secretion.

The hypothalamic factors dopamine (DA) and somatostatin (SRIH) inhibit pituitary glycoprotein secretion, but little is known regarding the effects of these factors on glycoprotein pulses. To address this question, 12 healthy volunteers underwent frequent blood sampling over 12 h at baseline and during 12-h infusions of DA and/or SRIH. TSH, LH, FSH, and alpha-subunit (alpha) levels were measured in all samples, and hormone pulses were located by Cluster analysis. Both DA and SRIH suppressed TSH pulse amplitude by 70%, while SRIH decreased TSH pulse frequency as well. Both infusions decreased LH pulse amplitude by 30-35%, but had no effect on pulse frequency. In contrast, neither infusion significantly altered FSH pulse parameters, although mean FSH levels declined 15%. DA had no effect on pulsatile alpha secretion, while SRIH decreased alpha pulse frequency. Serum thyroid hormone levels declined during both infusions, but there were no major changes in serum sex steroid levels. Thus, the hypothalamic inhibitory factors DA and SRIH had divergent effects on glycoprotein hormone pulses. The major effects on pulse amplitude, rather than frequency, imply that these factors do not play major roles in the generation of glycoprotein pulses, although SRIH may directly affect the TSH and alpha pulse generators.     

EFFECT OF FENOLDOPAM, A DOPAMINE D-1 RECEPTOR AGONIST, ON PITUITARY, GONADAL AND THYROID HORMONE SECRETION

The influence of fenoldopam, a dopamine (DA) D-1 receptor agonist, on basal and GnRH/TRH stimulated PRL, GH, LH, TSH, testosterone and thyroid hormone secretion was studied in nine normal men. All men received 4-h infusions of either 0.9% saline or fenoldopam at an infusion rate of 0.5 microgram/kg min, 12-16 ml/h, adjusted according to weight. After 3 h of infusion, 50 micrograms GnRH and 100 micrograms TRH was given i.v. Blood samples were collected every 15 min from 1 h before to 1 h after the infusion for a total of 6 h for measurements of PRL, LH, FSH, GH, TSH, testosterone, T4 and T3. The median PRL concentration increased significantly (P less than 0.01) to 128%, range 87-287, of preinfusion levels, compared to the decline during control infusion (85%, 78-114). Basal TSH levels declined significantly to 71% (60-91) during fenoldopam compared with 82% (65-115) during control infusion (P less than 0.05). Basal LH, FSH, GH and thyroid hormones were similar during fenoldopam and control infusions (P greater than 0.05). The LH response to GnRH/TRH was significantly (P less than 0.02) increased by fenoldopam infusion. Basal and stimulated testosterone concentration was lower during fenoldopam (P less than 0.01) infusion compared with control. Other hormones were similar after GnRH/TRH stimulation during fenoldopam and saline infusions. These results suggest that DA D-1 receptors are involved in the modulation of pituitary hormone secretion. We suggest that the effect of fenoldopam on PRL and TSH is mainly at the hypothalamic level. Regarding the effect on LH concentrations, an additional direct effect of fenoldopam on testosterone regulation can not be excluded.     

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.     

Arginine stimulates growth hormone secretion by suppressing endogenous somatostatin secretion

To determine how arginine (Arg) stimulates GH secretion, we investigated its interaction with GHRH in vivo and in vitro. Six normal men were studied on four occasions: 1) Arg-TRH, 30 g arginine were administered in 500 mL saline in 30 min, followed by an injection of 200 micrograms TRH; 2) GHRH-Arg-TRH, 100 micrograms GHRH-(1-44) were given iv as a bolus immediately before the Arg infusion, followed by 200 micrograms TRH, iv; 3) GHRH test, 100 micrograms GHRH were given as an iv bolus; and 4) TRH test, 200 micrograms TRH were given iv as a bolus dose. Blood samples were collected at 15-min intervals for 30 min before and 120 min after the start of each infusion. Anterior pituitary cells from rats were coincubated with Arg (3, 6, 15, 30, and 60 mg/mL) and GHRH (0.05, 1, 5, and 10 nmol/L) for a period of 3 h. Rat GH was measured in the medium. After Arg-TRH the mean serum GH concentration increased significantly from 0.6 to 23.3 +/- 7.3 (+/- SE) micrograms/L at 60 min. TRH increased serum TSH and PRL significantly (maximum TSH, 11.1 +/- 1.8 mU/L; maximum PRL, 74.6 +/- 8.4 micrograms/L). After GHRH-Arg-TRH, the maximal serum GH level was significantly higher (72.7 +/- 13.4 micrograms/L) than that after Arg-TRH alone, whereas serum TSH and PRL increased to comparable levels (TSH, 10.2 +/- 3.0 mU/L; PRL, 64.4 +/- 13.6 micrograms/L). GHRH alone increased serum GH to 44.9 +/- 9.8 micrograms/L, significantly less than when GHRH, Arg, and TRH were given. TRH alone increased serum TSH to 6.6 +/- 0.6 mU/L, significantly less than the TSH response to Arg-TRH. The PRL increase after TRH only also was lower (47.2 +/- 6.8 micrograms/L) than the PRL response after Arg-TRH. In vitro Arg had no effect on basal and GHRH-stimulated GH secretion. Our results indicate that Arg administered with GHRH led to higher serum GH levels than did a maximally stimulatory dose of GHRH or Arg alone. The serum TSH response to Arg-TRH also was greater than that to TRH alone. We conclude that the stimulatory effects of Arg are mediated by suppression of endogenous somatostatin secretion.     

The role of glucocorticoids in the regulation of thyrotropin

The potentially inhibitory action of endogenous or exogenous synthetic glucocorticoids on TSH secretion was investigated. Pulsatile and circadian TSH and cortisol rhythms were measured in healthy subjects (12 rhythms), but no correlation between the hormones could be detected. Acute stimulation of endogenous cortisol secretion by CRH tests (1 microgram/kg of ovine CRH) at 20.00 h in 9 healthy volunteers did not significantly alter the nightly increase in TSH. Chronic elevation of endogenous cortisol serum levels in patients with Cushing's disease revealed a heterogeneous pattern. In 2 patients serum TSH and thyroid hormone levels showed a normal 24-h rhythm, whereas the other 2 patients had low TSH serum levels. Acute treatment of 9 healthy volunteers with 0.5, 1 or 2 mg dexamethasone po at 23.00 h resulted in a significant dose-dependent suppression of mean basal TSH levels 9h later. Treatment with 30 mg of prednisone for 1 week in 7 patients with Crohn's disease did not influence basal TSH. The TSH response to TRH was only temporarily suppressed on day 3, but not on day 7 of treatment. The results suggest than under physiological conditions glucocorticoids have no regulatory influence on pulsatile and circadian TSH secretion.     

Corticotropin-releasing hormone inhibition of paradoxical growth hormone response to thyrotropin-releasing hormone in insulin-dependent diabetics.

A paradoxical growth hormone (GH) response to thyrotropin-releasing hormone (TRH) has been observed in type 1 diabetic patients and was hypothetically attributed to a reduced hypothalamic somatostatin tone. We have previously reported that corticotropin-releasing hormone (CRH) inhibits GH response to growth hormone-releasing hormone (GHRH) in normal subjects, possibly by an increased release of somatostatin. To study the effect of CRH on anomalous GH response to TRH, we tested with TRH (200 micrograms intravenously [IV]) and CRH (100 micrograms IV) + TRH (200 micrograms IV) 13 patients (six males and seven women) affected by insulin-dependent diabetes mellitus. A paradoxical GH response to TRH was observed in seven of 13 patients, one man and six women. In these subjects, the simultaneous administration of CRH and TRH significantly reduced the GH response to TRH, as assessed by both the maximal GH mean peak +/- SE (2.18 +/- 0.67 v 9.2 +/- 1.26 micrograms/L, P less than 0.005) and the area under the curve (AUC) +/- SE (187 +/- 32 v 567 +/- 35 micrograms.min/L, P less than .001). CRH had no effect on TRH-induced thyroid-stimulating hormone (TSH) release. Our data demonstrate that the paradoxical GH response to TRH in patients with type 1 diabetes mellitus is blocked by CRH administration. This CRH action may be due to an enhanced somatostatin release. Our data also show that exogenous CRH has no effect on TSH response to TRH, thus suggesting the existence of separate pathways in the neuroregulation of GH and TSH secretion.     

Dopaminergic control of circadian and pulsatile pituitary thyrotropin release in women

Dopamine (DA) inhibits pituitary TSH release, but its role as a regulator of circadian and pulsatile TSH secretion is not clear. Accordingly, we studied the 24-h TSH secretory patterns in seven normal women in the early follicular phase of their cycles before and during DA receptor blockade by metoclopramide (MCP). Serum TSH was measured by a highly sensitive (0.05 mU/L) RIA at 15-min intervals for 48 h during sequential 24-h saline and 24-h MCP infusions (30 micrograms/kg.h). Sleep was confirmed by electroencephalogram between 2300-0700 h. All women had a nocturnal rise of TSH, independent of sleep, which began in the late afternoon and reached a peak (acrophase) after midnight during the saline infusion. This circadian periodicity was composed of a series of TSH pulses with greater magnitude and frequency during nocturnal hours. Infusion of MCP had no effect on pulse frequency, but the pulse amplitude increased (P less than 0.05), especially at night. As a consequence, the circadian excursion of TSH, as assessed by cosinor function, was exaggerated. The mean acrophase amplitude and mesor levels increased (P less than 0.05), but the nadir and acrophase times did not change. These findings suggest that DA is an inhibitor of TSH pulse amplitude throughout the 24-h biological clock. By inference, the neuroendocrine mechanism(s) that underlies the nocturnal increase in TSH secretion is not due to decreased dopaminergic inhibition.     

Effects of vasoactive intestinal polypeptide, TRH, and dopamine on prolactin secretion in estrogen-primed postmenopausal women

Prolactin secretion is influenced by at least three important hypothalamic neurotransmitters: TRH, vasoactive intestinal polypeptide and dopamine. The purpose of this study was to determine whether, in estradiol-primed postmenopausal women, the PRL response to TRH, vasoactive intestinal polypeptide, and dopamine differed. Ten postmenopausal women were studied during treatment with estradiol benzoate at a dose of 0.625 mg per day during 15 days. TRH (200 micrograms iv), saline infusion, vasoactive intestinal polypeptide (75 micrograms infused iv during 15 min), coadministration of vasoactive intestinal polypeptide and TRH, and dopamine (4 micrograms.kg-1.min-1 iv for 3 h) were administered for 5 consecutive days before and during the last 5 days of estradiol benzoate treatment. Before estradiol benzoate administration, the PRL, response to TRH was significantly greater than that of vasoactive intestinal polypeptide. Estradiol benzoate treatment increased significantly the PRL release induced by TRH (p less than 0.01), but did not modify the response to vasoactive intestinal polypeptide. At the end of estradiol benzoate treatment, the maximal increase in PRL after the combined (vasoactive intestinal polypeptide + TRH) test was greater than that obtained with TRH alone and occurred earlier (p less than 0.04). Dopamine suppressed PRL secretion to a similar extent after estradiol benzoate treatment.(ABSTRACT TRUNCATED AT 250 WORDS)     

Different prolactin, thyrotropin, and thyroxine responses after prolonged intermittent or continuous infusions of thyrotropin-releasing hormone in rhesus monkeys

Serum PRL, TSH, and T4 secretion during prolonged continuous or intermittent iv infusions of TRH were studied in 14 adult ovariectomized rhesus monkeys (Macaca mulatta). For 9 days, TRH was administered intermittently at 0.33 or 3.3 micrograms/min for 6 of every 60 min and continuously at 0.33 micrograms/min. With both modes, the PRL levels and responsiveness to TRH simulation peaked on day 1 and then fell to levels that were still higher than the preinfusion values; levels for the intermittently treated group on days 3-9 were 2- to 4-fold above prestimulation levels and significantly (P less than 0.01) higher than levels for the continuously treated group. Elevated basal levels and PRL responses to TRH pulses were similar during the 0.33 and 3.3 micrograms/min pulses of the 9-day treatment period. For both TRH modes, TSH levels were elevated significantly (P less than 0.001) on day 1 [this increase was higher with continuous infusion (P less than 0.001)] and then fell to preinfusion levels by day 3. Serum T4 also increased during both continuous and intermittent TRH stimulations. However, serum T4 levels were significantly lower (P less than 0.01) after intermittent TRH (both 0.33 and 3.3 micrograms/min) than after continuous (0.33 micrograms) TRH (8 +/- 1.1 and 10 +/- 1.8 micrograms T4/dl vs. 18 +/- 3.1 micrograms, respectively). These PRL and T4 responses were replicated when the mode of administering 0.33 micrograms/min TRH was reversed after 9 days. An iv bolus of TRH (20 micrograms) after 9 days of continuous or intermittent TRH infusion caused significant release of PRL and TSH, an indication that neither mode of administration resulted in pituitary depletion of releasable hormone. We have concluded that intermittent TRH is more effective in elevating serum PRL, and continuous TRH is more effective in raising TSH and T4 levels. Thus, the manner of TRH secretion by the hypothalamus may determine its relative physiological importance in the stimulation of lactotropes and thyrotropes.     

Histamine-induced paradoxical growth hormone response to thyrotropin-releasing hormone in normal men

GH responses to TRH occur in patients with certain diseases, such as acromegaly, severe liver disease, uremia, and mental disorders, and presumably reflect disruption of normal hypothalamic control of GH secretion. Since histamine (HA) inhibits hypothalamic stimulation of GH secretion, we investigated the combined effect of HA receptor activation and TRH administration on GH secretion in normal men. Eight men were given 4-h infusions of the following: saline, HA, HA plus mepyramine (Me; and H1-antagonist), HA plus cimetidine (C; an H2-antagonist), and C alone. TRH (200 micrograms) was injected iv 2 h after the start of each infusion. HA alone or in combination with either antagonist had no effect on basal or TRH-stimulated TSH secretion and no effect on basal GH secretion. However, when TRH was injected during H1 stimulation by HA plus C, GH secretion increased significantly [from 0.7 +/- 0.1 to 7.1 +/- 1.8 (+/- SEM) ng/ml; P less than 0.01] in seven of eight subjects. This GH response was reproducible and did not occur when saline was administered instead of TRH. A smaller and delayed GH response to TRH occurred during infusions of HA alone (from 0.8 +/- 0.1 to 4.9 +/- 1.0 ng/ml; P less than 0.05). No effect of TRH on GH secretion occurred during the infusion of saline (1.2 +/- 0.3 ng/ml), HA plus Me (0.9 +/- 0.1 ng/ml), or C (2.2 +/- 1.0 ng/ml). There was a significant increase in GH secretion after cessation of the infusions of HA (from 3.4 +/- 1.1 to 7.5 +/- 2.2 ng/ml) and HA plus Me (from 0.8 +/- 0.1 to 5.1 +/- 1.8 ng/ml). This rebound in GH secretion might indicate an inhibitory effect of TRH during H2-receptor stimulation. This concept is supported by the significantly smaller GH response to TRH during HA infusion than during HA plus C infusion (P less than 0.01). The study indicates that H1-receptor stimulation induces a stimulatory effect of TRH on GH secretion in normal men and that H2-receptor stimulation possibly induces an inhibitory effect of TRH on GH secretion.     

The pulsatile GH secretion in acromegaly: Hypothalamic or pituitary origin?*

OBJECTIVE: We studied the effects of different modes of octreotide therapy on the pulsatile pattern of GH release in an attempt to define better its regulation by growth hormone-releasing hormone (GHRH) and somatostatin and its effects on IGF-I plasma levels in acromegaly. DESIGN: In six acromegalic patients not cured by previous treatment we compared the 24-hour GH secretion profiles under basal conditions with subcutaneous (s.c.) bolus injections of 100 micrograms octreotide every 8 hours and with continuous s.c. infusions of the same daily dose. Blood samples were taken every 10 minutes over 24 hours followed by a GHRH test (100 micrograms GHRH i.v.) with blood sampling every 15 minutes for another 2 hours. After a 4-week interval all patients were treated either by the bolus or continuous mode of octreotide application in a randomized cross-over design. On day 4 of treatment blood sampling and GHRH test were repeated. Octreotide treatment was withdrawn for another 4 weeks; all patients then received the alternate application mode and were measured under similar conditions. MEASUREMENTS: Serum GH and plasma IGF-I concentrations were analysed by serial array averaging. IGF-I levels were measured in two different assays with and without previous protein extraction. For GH pulse detection three different algorithms (Cluster, Pulsar, Desade) were applied. RESULTS: With both treatments, the initially elevated basal 24-hour mean serum GH concentrations (58.0 +/- 9.7 mU/l mean +/- SEM) decreased significantly (bolus: 11.5 +/- 4.9 mU/l, P < 0.001 vs basal; continuous infusion: 7.6 +/- 1.9 mU/l, P < 0.001 vs basal) after 4 days. GH suppression was significantly more pronounced following continuous infusion than bolus (P < 0.05). IGF-I plasma concentrations were lowered significantly (P < 0.05) with both forms of treatment which did not differ between themselves. Bolus and continuous infusion treatment significantly inhibited (P < 0.05) the amplitudes of pulsatile GH release, but did not change the pulse frequency. In two of the patients, GHRH stimulation did not increase GH serum levels suggesting a constitutive activation of adenylyl cyclase. CONCLUSION: Continuous subcutaneous octreotide treatment in acromegaly suppresses mean GH levels better than bolus injection. The number of GH pulses remains unaffected by both modes of treatment providing evidence against a somatostatinergic mechanism of pulsatile GH secretion in these patients. The unchanged frequency of pulsatile GH release in the patients unresponsive to exogenous GHRH indicates that this pattern might be independent of hypothalamic GHRH and somatostatin and suggests a pituitary-derived mechanism for GH pulse generation in acromegaly.     

SUBCUTANEOUS GROWTH HORMONE-RELEASING HORMONE AUGMENTS PULSATILE NOCTURNAL GH RELEASE IN GH-INSUFFICIENT CHILDREN, BUT MAY ALSO RAISE BASAL GH SECRETION

Growth hormone-releasing hormone (GHRH) when given s.c. to GH-insufficient children either as pulses, or once or twice daily, promotes linear growth. These treatment regimens, however, are not ideal as they require frequent drug administration and a significant proportion of patients do not show improved growth. We have now investigated the GH response to a nocturnal s.c. infusion of GHRH (1-29)NH2, at two dosages, 5 and 10 micrograms/kg/h, in a group of five GH-insufficient children. The s.c. infusion of GHRH between 2100 h and 0600 h augmented nocturnal pulsatile GH release in all five children. There was a dose-dependent response for the GH area under the curve (AUC), and mean total GH concentration. The AUC for GH was significantly greater after the 10 than 5 micrograms/kg/h GHRH which in turn was greater than that after placebo; mean (SD) AUC: 14816 (3978), 8125 (1931), 3032 (1582) mU min/l respectively (P less than 0.01 and P less than 0.05). There was no significant change in the number of GH pulses during the 9-h infusions when the subjects were infused with GHRH 10 or 5 micrograms/kg/h compared to placebo, and they occurred at similar times although the number of pulses tended to be greater after GHRH; the mean (SD) numbers of GH pulses were 5.0 (0.7), 3.8 (0.8), 3.2 (0.8), respectively. There was however a significant rise in the mean baseline GH concentration in all patients during the infusion of GHRH 10 micrograms/kg/h compared to placebo, but not with 5 micrograms/kg/h. Thus, GHRH(1-29)NH2 given s.c. augmented nocturnal pulsatile GH release in GH-insufficient children but it also increased baseline GH secretion. These results suggest that a sustained release preparation of GHRH could be a potential treatment for GH-insufficient children, and that a dose of 5 micrograms/kg/h would promote pulsatile GH release, but that at higher dosage it may also raise basal GH secretion.