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A three-month study of the effect of growth hormone (hGH) therapy (0.1 U/kg/day sc) on plasma levels of GH releasing hormone (GHRH), somatostatin and insulin-like growth factor I (IGF-I) and on the hGH responsiveness to exogenous GHRH was carried out in 32 prepubertal short-stature children with normal GH secretion. Blood samples were collected prior to initiation of therapy, and at 5, 30 and 90 days of onset of therapy, as well as 2 and 90 days after termination of therapy. The nonconventional hGH therapy induced an increase in serum IGF-I levels which lasted as long as therapy was continued. Plasma GHRH levels showed an early transitory decrease after five days of therapy, whereas plasma somatostatin levels were unaltered. A slight suppression in hGH responsiveness to exogenous GHRH was found at 2 but not at 90 days after termination of hGH therapy. It is concluded that nonconventional hGH treatment does not cause permanent changes in physiological hGH secretion.
The purpose of this study was to evaluate the contribution of endogenous GH-releasing hormone (GHRH) to exogenous GH-releasing hexapeptide (GHRP-6) activity, and to determine whether TRH or GnRH are endogenous analogs of GHRP-6. The activity of GHRP-6, a synthetic GH secretagogue, was significantly attenuated in rats administered GHRH antiserum or alpha-methyl-rho-tyrosine to reduce endogenous GHRH concentrations, and also in rats administered 5-50 micrograms/kg of [N-Ac-Tyr1,D-Arg2]-GRF 1-29 amide to block pituitary GHRH receptors. However, GHRP-6 activity was potentiated in rats administered 150 micrograms/kg [N-Ac-Tyr1,D-Arg2]-GRF 1-29 amide, presumably due to partial agonist activity of the GHRH receptor antagonist at the higher dose. These data show that endogenous GHRH contributes to full expression of exogenous GHRP-6 activity in vivo. Like TRH, a subthreshold dose of GHRP-6 was significantly more effective in hypothyroid rats than in euthyroid rats. However, suprathreshold doses of GHRP-6 were less effective in hypothyroid rats. Unlike TRH, GHRP-6 had no effect on GH and prolactin release from GH3 cells, and TRH and GnRH were poor competitors for 3H-GHRP-6 binding sites on pituitary membranes. A GnRH receptor antagonist did not block GHRP-6 activity in vivo, and GnRH administered alone or in combination with GHRP-6, did not stimulate GH release. The results of this study suggest that synergy between GHRH and GHRP-6 seen in pharmacological studies is physiologically relevant, and that TRH and GnRH are not endogenous analogs of GHRP-6.
The presence of immunoreactive adrenocorticotropin-releasing hormone (CRH), luteinizing hormone-releasing hormone (LHRH), growth hormone-releasing hormone (GHRH), and somatostatin has been investigated by immunohistochemistry in forty biopsies from breast cancer patients. All of these hypothalamic hormones were found in about 30% of the samples, seen in the cytoplasm or in the nuclei of the tumor cells. Positive immunostaining for the hypothalamic hormones was present in colloid, lobular, and infiltrating ductal carcinomas. There was not a clear relationship between occurrence of staining for the hypothalamic hormones and the histologic grade of tumors or the clinical stage of the disease. Immunoreactive LHRH was more frequently found in breast tumors with estrogen and progesterone receptors. On the other hand, preneoplastic breast lesions expressed mainly somatostatin, while immunoreactivity was absent in normal mammary tissue.
We administered two different growth hormone-releasing hormones (GHRH) to 20 short, prepubertal children who had spontaneous secretion of growth hormone (GH), assessed from 24-hour GH secretion profiles (72 sampling periods of 20 min). We compared one i.v. injection of 1 microgram/kg of GHRH 1-40 with that of GHRH 1-29 regarding serum concentrations of GH, prolactin, luteinizing hormone, follicle-stimulating hormone and IGF-I. The children were allocated to two groups without statistical randomization. Both groups were given both peptides, with at least 1 week in between. The first group started with GHRH 1-40, the other with GHRH 1-29. The peptides both induced an increased serum concentration of GH of the same magnitude: mean maximal peak of 89 +/- 12 mU/l after GHRH 1-40 and 94 +/- 10 mU/l after GHRH 1-29 (n.s.). The mean difference in maximum serum GH concentration in each child after injection was 52 +/- 9 mU/l, range 1-153 mU/l. GHRH 1-29 also induced a short-term, small increase in the concentrations of prolactin (p less than 0.05), luteinizing hormone (p less than 0.01) and follicle-stimulating hormone (p less than 0.05). We conclude that the shorter sequence GHRH 1-29, when given in a dose of 1 microgram/kg, gives a rise in serum concentration of GH similar to that after the native form GHRH 1-40.
The objective of this study was to determine the effect of a subtherapeutic level of chlortetracycline (CTC) fed to growing beef steers under conditions of limited and adequate dietary protein on plasma concentrations of GH, thyroid-stimulating hormone (TSH), and thyroid hormones before and after an injection of thyrotropin-releasing hormone (TRH) + GHRH. Young beef steers (n = 32; average BW = 285 kg) were assigned to a 2x2 factorial arrangement of treatments of either a 10 or 13% crude protein diet (70% concentrate, 15% wheat straw, and 15% cottonseed hulls) and either a corn meal carrier or carrier + 350 mg of CTC daily top dressed on the diet. Steers were fed ad libitum amounts of diet for 56 d, and a jugular catheter was then placed in each steer in four groups (two steers from each treatment combination per group) during four consecutive days (one group per day). Each steer was injected via the jugular catheter with 1.0 microg/kg BW TRH + .1 microg/kg BW GHRH in 10 mL of saline at 0800. Blood samples were collected at -30, -15, 0, 5, 10, 15, 20, 30, 45, 60, 120, 240, and 360 min after releasing hormone injection. Plasma samples were analyzed for GH, TSH, thyroxine (T4), and triiodothyronine (T3). After 84 d on trial, the steers were slaughtered and the pituitary and samples of liver were collected and analyzed for 5'-deiodinase activity. Feeding CTC attenuated the GH response to releasing hormone challenge by 26% for both area under the response curve (P<.03) and peak response (P<.10). Likewise, CTC attenuated the TSH response to releasing hormone challenge for area under the response curve by 16% (P<.10) and peak response by 33% (P<.02), and attenuated the T4 response for area under the curve by 12% (P<.08) and peak response by 14% (P<.04). Type II deiodinase activity in the pituitary was 36% less (P<.02) in CTC-fed steers than in steers not fed CTC. The results of this study are interpreted to suggest that feeding subtherapeutic levels of CTC to young growing beef cattle attenuates the release of GH and TSH in response to pituitary releasing hormones, suggesting a mechanism by which CTC may influence tissue deposition in cattle.
It has been reported that paradoxical GH responses to corticotropin-releasing hormone (CRH) occur in only few patients with acromegaly. However, we have observed such responses in 7 of 14 active acromegalic patients. Therefore, we have studied the GH responses to thyrotropin-releasing hormone (TRH) (500 micrograms, iv), gonadotropin-releasing hormone (LHRH) (100 micrograms, iv) and GH-releasing hormone (GHRH) (100 micrograms, iv) in these patients to examine the relationships between the GH responses to CRH and the responses to these hypothalamic hormones. Further, these patients received human CRH (1-41) NH2 (100 micrograms, iv) with or without dexamethasone (Dex) pretreatment (1 mg/100 ml saline, iv, from -30 to +30 min) to study the mechanism of CRH-induced GH secretion, and a perifusion experiment was performed using adenoma tissue obtained at surgery from one patient (10(-7) M CRH and TRH were added) to elucidate whether CRH acts directly at the pituitary level. Aberrant GH responses induced by CRH were found in 7 of 14 (50%) acromegalic patients (TRH responders: 10/13, 77%; LHRH responders: 2/9, 22%; GHRH responders: 10/12, 83%). In these patients, percent GH increment induced by CRH ranged from 81 to 144% (Mean +/- SE, 118 +/- 8%), and the GH peak (19 +/- 3 min) appeared as early as after TRH (23 +/- 4 min, N = 10).(ABSTRACT TRUNCATED AT 250 WORDS)
In vitro evidence suggests that calcium is involved in the release of anterior pituitary hormones. Therefore, we studied the effect of the slow calcium channel blocker or calcium antagonist nifedipine on the FSH and LH responses to LRH and the TSH and PRL responses to TRH in vivo. Nine normal male subjects were studied on two occasions, and nifedipine (20 mg, by mouth, or matching placebo) was administered in a randomized single blind manner. Blood pressure and heart rate were measured at 0 and 30 min. The patients then received TRH (200 micrograms) and LRH (100 micrograms) iv. Blood levels of FSH, LH, TSH, and PRL were measured by RIA at 0, 30, 50, 60, and 120 min. Nifedipine lowered diastolic blood pressure significantly (--12 +/- 8 mm Hg; P less than 0.005) and increased heart rate (+ 17 /*- 10 beats/min; P less than 0.005), but had no effect on either baseline hormone levels or the incremental response of any hormone to its secretagogue. In contrast to the results of previous studies with verapamil, nifedipine does not inhibit the release of pituitary hormones. More information is required on the precise intracellular actions of these drugs before they can be used to study the role of calcium in hormone release. Nifedipine, however, may be less likely to influence pituitary function than verapamil.
The responses of serum follicle-stimulating hormone (FSH) and luteinizing hormone (LH) to luteinizing hormone-releasing hormone (LH-RH) and the responses of prolactin (PRL) to thyrotropin-releasing hormone (TRH) and metoclopramide (MC) were measured in the late luteal phase of the cycle in 12 endurance runners and 11 control women and in 12 joggers and 7 control women. LH-RH (100 micrograms) and TRH (200 micrograms) were injected intravenously at the beginning of the test, and MC (10 mg) was injected 60 minutes later. Blood samples were obtained before and 20, 60, 80, and 120 minutes after the beginning of the test. Runners had significantly lower serum concentrations of estradiol and progesterone than control subjects, whereas the concentrations of FSH, LH, and PRL were similar at the beginning of the study. Compared with their controls, the runners had significantly lower FSH (P less than 0.05) and LH responses at 20 minutes (P less than 0.05) and lower LH responses at 80 minutes (P less than 0.01) to LH-RH and lower PRL responses to MC 20 minutes after MC injection (P less than 0.05). Joggers and their control subjects had similar LH, FSH, and PRL responses to these pharmacologic stimuli. It is concluded that decreased ovarian activity explains, at least partly, the lowered responses of FSH and LH to LH-RH and the lowered response of PRL to MC in endurance runners.
Abnormalities of hypothalamic-pituitary function in patients with anorexia nervosa (AN) have been reported previously. Since atypical responses to thyrotropin-releasing hormone (TRH) and luteinizing-hormone-releasing hormone (LHRH) have been observed in other disease states, hormonal responses to these hypothalamic peptides in 60 otherwise unstressed young women with anorexia nervosa were studied. Sixteen patients demonstrated a growth hormone (GH) response to TRH and 10 showed an increase in GH after LHRH. Five patients had an increase in cortisol after TRH, 2 of whom showed GH response, and 2 patients demonstrated a cortisol response to LHRH, 1 of whom had a GH response. Variable TSH responses to TRH were observed in the study but there was no correlation with the occurrence of GH or cortisol responses. GH responses to TRH and LHRH were typically not seen in the same patients, nor were they predictive of a cortisol response to the same stimulus. These data add to the evidence for an abnormal hypothalamic-pituitary regulation in AN.
OBJECTIVE: Several recent reports have demonstrated the expression of luteinizing hormone-releasing hormone receptors by human ovarian and endometrial cancers. Controversy persists on the relevance of this finding, in particular whether these receptors mediate direct antiproliferative effects of luteinizing hormone-releasing hormone analogues. We correlated the expression of luteinizing hormone-releasing hormone receptors by well-characterized ovarian and endometrial cancer cell lines with the ability of luteinizing hormone-releasing hormone analogues to reduce their proliferation and studied the autoregulation of luteinizing hormone-releasing hormone receptor expression by luteinizing hormone-releasing hormone agonist triptorelin and antagonist cetrorelix. The expression of luteinizing hormone-releasing hormone receptors was assessed in a series of specimens from primary ovarian and endometrial cancers. STUDY DESIGN: Luteinizing hormone-releasing hormone receptor expression was assessed by semiquantitative reverse transcriptase-polymerase chain reaction and radioligand binding assay. Antiproliferative effects were ascertained by proliferation assays in the absence or presence of luteinizing hormone-releasing hormone analogues. RESULTS: Ovarian (4/6 cell lines) and endometrial (5/6 cell lines) cancer cell lines expressed luteinizing hormone-releasing hormone receptors. The proliferation of these luteinizing hormone-releasing hormone receptor-positive cell lines was dose- and time-dependently reduced by agonistic and antagonistic luteinizing hormone-releasing hormone analogues. Luteinizing hormone-releasing hormone receptor density was reduced to 80% of controls (control, 100 %; P <.001) by luteinizing hormone-releasing hormone analogues. Seventy percent of primary ovarian cancers and 83% of primary endometrial cancers expressed luteinizing hormone-releasing hormone receptors. CONCLUSION: These findings suggest that luteinizing hormone-releasing hormone receptors that are expressed by human ovarian and endometrial cancer cell lines mediate direct antiproliferative effects of luteinizing hormone-releasing hormone analogues. Because most respective primary cancers expressed luteinizing hormone-releasing hormone receptors, these receptors might be used for novel antiproliferative therapeutic approaches and should be further evaluated.
The correlation between response of plasma GH to GHRH and the GHRH-induced stimulation of the intracellular adenylate cyclase (AC) activity in pituitary adenoma cell membranes in acromegalic patients was investigated. Each peak plasma GH level after iv administration of GHRH ranged from 1.1 to 13.8 times the basal level in 13 acromegalic patients. On the other hand, the maximal stimulation of intracellular AC activity (cAMP production) induced by GHRH varied from 1.4 to 6.4 times the control level in each GH-producing pituitary adenoma cell membrane. A significant positive correlation (r = 0.89, P less than 0.005) between plasma GH response to GHRH and intracellular cAMP production stimulated by GHRH was observed in nine of the acromegalic patients. In contrast, the response of plasma GH to GHRH was significantly blunted, despite a fairly large production of intracellular cAMP stimulated by GHRH, in the other four acromegalic patients. These results suggest that GHRH-induced GH release from GH-producing pituitary adenomas of patients with acromegaly may be regulated not only by GHRH receptor-adenylate cyclase system but also modified by several other factors including somatostatin and Sm-C.
The clinical significance of abnormal growth hormone (GH) secretion in response to thyrotropin-releasing hormone (TRH) and luteinizing hormone-releasing hormone (LHRH) was studied in 52 patients with acromegaly due to GH secreting pituitary adenomas treated by trans-sphenoidal microsurgery. The mean period of postoperative follow-up was 4.1 years. In 27 of the 36 patients who had abnormal GH responses to TRH or LHRH before surgery, basal GH levels normalized and abnormal GH responses disappeared immediately after surgery. Among the remaining nine patients, four had normal basal GH levels with abnormal GH responses and five showed persistently abnormal basal GH levels as well as abnormal GH responses. Recurrence requiring retreatment was not observed during follow-up in any of the 31 patients with normal postoperative basal GH levels, regardless of the GH response to TRH or LHRH. All five patients with abnormal basal GH and abnormal GH responses required additional treatment. Among the patients who underwent long-term postoperative TRH and LHRH testing, abnormal GH responses reappeared in three of 19 whose abnormal responses had disappeared immediately after surgery. The abnormal response disappeared spontaneously in two of three patients who had abnormal responses immediately after surgery. In four patients with both abnormal GH responses and abnormal basal GH levels immediately after surgery, abnormal GH responses persisted throughout the follow-up period. In addition, the abnormal GH responses appeared in two of 14 patients who had been nonresponsive before surgery. These results indicate that the postoperative GH response to TRH or to LHRH was not significantly related to the outcome.(ABSTRACT TRUNCATED AT 250 WORDS)
To study the role of peripheral immunoreactive growth hormone releasing hormone (ir-GHRH) concentrations and the GHRH test in the evaluation of growth hormone (GH) secretion in short stature, 46 children with a mean age of 9.4 years (range 1.6-16.3 years) and a mean relative height score of -3.2 SD (range -5.0-2.1 SD) were investigated. The children were divided into prepubertal (n = 35) and pubertal (n = 11) and the prepubertal children further into three groups based on their maximal GH responses to insulin-induced hypoglycaemia (IIH) and clonidine: (1) GH deficient subjects (maximal GH < 10 micrograms/l in both tests); (2) discordant responders (maximal GH < 10 micrograms/l in one test and > or = 10 micrograms/l in the other); and (3) normal responders (maximal GH > or = 10 micrograms/l in both tests). Peripheral ir-GHRH concentrations were measured during the IIH test by radioimmunoassay after purification of plasma samples on Sep-pak cartridges. Among the prepubertal children 10 fell into group 1, 16 into group 2 and 9 into group 3. Children in group 1 were older than those in group 3. There were no significant differences in relative heights and weights or absolute and relative growth velocities between the groups. Subjects in groups 1 and 2 had lower maximal GH responses to GHRH than those in group 3. There were no significant differences in the basal plasma ir-GHRH concentrations between the groups. Nine children (19.6%) had somatotrophs with a poor response to a single dose of exogenous GHRH (maximal GH < 10 micrograms/l).(ABSTRACT TRUNCATED AT 250 WORDS)
Adult male Sprague-Dawley rats averaging 300 g each were subjected to complete food removal for 7 days (acutely starved), 7 days complete food removal followed by 2 weeks of 1/4 ad libitum food intake (chronically strved), 7 days complete food removal and 2 weeks of 1/4 ad libitum intake followed by ad libitum feeding for 7 days (refed), or fed ad libitum throughout (controls). Serum LH, FSH, TSH, PRL, and GH levels were measured by radioimmunoassays for each group of rats. The in vivo response to the combination of synthetic LHRH and TRH also was tested in each group of rats. Circulating LH, TSH, GH, and PRL were significantly depressed in acutely and chronically starved rats, and FSH was lowered only in acutely starved rats. After 7 days of refeeding, serum levels of LH and FSH were significantly greater than in ad libitum fed controls, PRL returned to control levels, and TSH and GH increased but were still below control levels. After LHRH + TRH injection serum LH and TSH were increased significantly in all groups of rats, FSH and PRL rose in acutely but not in chronically starved rats, and GH was not elevated in any group. The increases in serum LH, FSH, TSH and prolactin in response to LHRH + TRH injection in acutely or chronically starved rats were equal to or greater than in the ad libitum fed controls. These data indicate that severe reductions in food intake result in decreased release of at least 5 anterior pituitary hormones, and this is due primarily to reduced hypothalamic stimulation rather than to inability of the pituitary to secrete hormones.
This study was designed to further investigate our postulate regarding the inhibitory role played by central alpha 2-adrenergic pathways on hypothalamic somatostatin (SS) release in rats. The growth hormone (GH) responses to exogenous GH-releasing factor (GRF; 3 micrograms/kg i.v.) or clonidine (CLO; 100 micrograms/kg i.v.), either given alone or in combination, were tested in 3-month-old male rats made GH-releasing hormone (GH-RH) deficient neonatally by administration of monosodium glutamate (MSG; 4 mg/g body weight s.c.). To prevent the presumable decrease in the pituitary GH content in these animals from leading to an erroneous interpretation of the results obtained, half of these rats were given GRF (MSG-GRF rats; 30 micrograms/kg s.c.) for 3 days immediately prior to GH testing. The other half of MSG-treated and non MSG-treated rats received saline during these days (MSG-S and controls, respectively). To establish the efficiency of GRF priming, the pituitary GH content was measured in other MSG-GRF, MSG-S, and control animals. The mean (+/- SEM) GH peaks in response to GRF challenge were significantly higher in controls than in MSG-GRF rats (125.2 +/- 28.5 vs. 67.5 +/- 19.4 micrograms/l; p < 0.05), while no significant GRF-induced GH release was observed in the MSG-S group. Most likely these results are related to the different pituitary GH content, significantly (p < 0.01) higher in controls than in MSG-GRF rats, and in the latter higher than in MSG-S animals (p < 0.05). CLO administration did not evoke a significant GH release in MSG rats, whether primed with GRF or not.(ABSTRACT TRUNCATED AT 250 WORDS)
Sixteen prepubertal children who were insufficient for growth hormone were treated with growth hormone releasing hormone (GHRH) 1-40 and GHRH 1-29 for a mean time of nine months (range 6-12 months) with each peptide. Eleven children received GHRH 1-40 in four subcutaneous nocturnal pulses (dose 4-8 micrograms/kg/day) and eight (three of whom were also treated with GHRH 1-40) received GHRH 1-29 twice daily (dose 8-16 micrograms/kg/day). Altogether 73% of the children receiving GHRH 1-40 and 63% receiving GHRH 1-29 showed a growth response. Double the daily dose of GHRH 1-29 was required to obtain equivalent growth response to pulsatile GHRH 1-40. A significant linear correlation was shown between growth hormone secretion and height velocity on GHRH 1-40 but not on GHRH 1-29 and there was a significant correlation between plasma GHRH and serum growth hormone concentrations during GHRH 1-40 administration. Response to conventional growth hormone treatment in a matched group of children was significantly better than the response after GHRH. A significant improvement in height velocity was observed in the children transferred to growth hormone replacement. Growth hormone remains the treatment of choice in growth hormone insufficiency. GHRH treatment may be of benefit in children with less severe growth hormone insufficiency in the presence of pulsatile endogenous growth hormone secretion.
The sites of localization of luteinizing hormone (LH), follicle-stimulating hormone (FSH), growth hormone (GH), adrenocorticotrophic hormone (ACTH) and prolactin (PRL) within placental tissues have been studied by an immunoperoxidase technique. The syncytiotrophoblast is the sole significant site of localization of LH, FSH, GH and ACTH; PRL is found both in syncytiotrophoblast and in decidual cells. It is highly probable that the sites of localization of these peptide hormones represents their sites of synthesis in the placenta and thus that the syncytiotrophoblast is the sole site of synthesis of LH, FSH, LH and ACTH. PRL appears to be synthesized both in syncytiotrophoblast and decidua, but the latter is probably not the major site of synthesis of this hormone. Whether these placental peptide hormones have any physiological role to play during pregnancy or whether the placental capacity to synthesize such hormones is an atavistic phenomenon of no functional importance is currently a moot point.