Increase of thyrotropin response to thyrotropin-releasing hormone (TRH) and TRH release in rats during pregnancy

Regulation of thyrotropin (TSH) release by thyrotropin releasing hormone (TRH) in the anterior pituitary gland (AP) of pregnant rats was studied. The pregnant (day 7, 14, and 21) and diestrous rats were decapitated. AP was divided into 2 halves, and then incubated with Locke's solution at 37 degrees C for 30 min following a preincubation. After replacing with media, APs were incubated with Locke's solution containing 0, or 10 nM TRH for 30 min. Both basal and TRH-stimulated media were collected at the end of incubation. Medial basal hypothalamus (MBH) was incubated with Locke's medium at 37 degrees C for 30 min. Concentrations of TSH in medium and plasma samples as well as the cyclic 3':5' adenosine monophosphate (cAMP) content in APs and the levels of TRH in MBH medium were measured by radioimmunoassay. The levels of plasma TSH were higher in pregnant rats of day 21 than in diestrous rats. The spontaneous release of TSH in vitro was unaltered by pregnancy. TRH increased the release of TSH by AP, which was higher in pregnant than in diestrous rats. Maternal serum concentration of total T3 was decreased during the pregnancy. The basal release of hypothalamic TRH in vitro was greater in late pregnant rats than in diestrous rats. After TRH stimulation, the increase of the content of pituitary cAMP was greater in late pregnant rats than in diestrus animals. These results suggest that the greater secretion of TSH in pregnant rats is in part due to an increase of spontaneous release of TRH by MBH and a decrease of plasma thyroid hormones. Moreover, the higher level of plasma TSH in rats during late pregnancy is associated with the greater response of pituitary cAMP and TSH to TRH.     

Long-term treatment of acromegaly with bromocryptine: postprandial HGH levels and response to TRH and glucose administration.

Fourteen patients with acromegaly were treated with bromocryptine (CB 154, Sandoz), 4 X 2.5 mg, for periods of up to eleven months. One patient did not tolerate the drug, ten of the remaining thirteen experienced considerable clinical improvement. There was a dose-dependent suppression of plasma growth hormone levels, but growth hormone response to TRH injection and to glucose administration was still present during therapy although reduced. TSH response to TRH was not significantly altered. The suppressive power of bromocryptine on growth hormone appears to be related to the mechanism by which TRH stimulates growth hormone secretion in acromegaly, but long-term administration of this drug may be successful in spite of an absent response to TRH in some cases. Bromocryptine appears to be a safe and effective drug for the treatment of acromegaly.     

Provocation of a paradoxical growth hormone response to corticotropin-releasing hormone by pretreatment with metoclopramide in patients with acromegaly and normal subjects

Two of 7 patients with acromegaly and one of 7 normal subjects exhibited a paradoxical rise in growth hormone (GH) to human corticotropin-releasing hormone (CRH) when pretreated with metoclopramide, although CRH alone did not induce an increase in GH. In one of these two patients with acromegaly, the GH increase to metoclopramide alone also reached the criteria of a paradoxical response. These two acromegalic patients showed a GH increase to metoclopramide pretreatment before and up to two months after surgery. In another acromegalic patient, whose GH level remained high 5 months after surgery, metoclopramide induced an increase in GH level, while in a patient who had an above-normal GH level 18 months after surgery, the resumption of physiological GH secretion after surgery was evidenced by a postoperative absence of a GH response to metoclopramide. It is suggested from these results that the GH response to metoclopramide and the metoclopramide-provoked GH response to CRH in patients with acromegaly result from the secretion of GH from nonadenomatous cells of the pituitary.     

Growth hormone releasing hormone-sensitive adenylate cyclase activity in growth hormone-producing pituitary adenoma: correlation to the response of plasma growth hormone to growth hormone releasing hormone in patients with acromegaly

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.     

Abnormalities of growth hormone release in response to human pancreatic growth hormone releasing factor (GRF (1-44) ) in acromegaly and hypopituitarism.

Human pancreatic growth hormone releasing factor (GRF (1-44)) is the parent molecule of several peptides recently extracted from pancreatic tumours associated with acromegaly. A study was conducted to examine its effects on the release of growth hormone in normal volunteers and in patients with hypopituitarism and acromegaly. GRF (1-44) dose dependently stimulated the release of growth hormone in normal people and produced no appreciable side effect. This response was grossly impaired in patients with hypopituitarism and, although similar to the growth hormone response to hypoglycaemia, was of quicker onset and a more sensitive test of residual growth hormone function. Patients with acromegaly appeared to fall into (a) those with a normal response to GRF, whose growth hormone suppressed significantly with oral glucose, and (b) those who had an exaggerated response to GRF (1-44), whose growth hormone had not suppressed previously after oral glucose. Present methods for testing growth hormone deficiency entail using the insulin stress test, which is time consuming, unpleasant, and sometimes dangerous. A single intravenous injection of GRF now offers the possibility of an easier, safer, and more reliable routine test for growth hormone deficiency. It has the further advantage of being free of side effects and readily performed in outpatients. Hence it seems likely to become the standard test and take the place of the insulin stress test.     

Effect of TRH on growth hormone (GH) release induced with ACTH]

We examined 14 volunteers subjects sound and exempt from en docrine disease. The rapid injection of 0,25 mg of ACTH (Synacten) was followed by a distinct increase of plasma Hormone (GH) within 30 or 60 min in 12 of 14 normal volunteers. The test were the 12 "responders after previous subministration of 200 g of TRH and the GH response was totally abolished.     

Endogenous opiates modulate release of growth hormone in response to electroacupuncture

The effect of electroacupuncture on serum growth hormone levels was investigated in 5 normal subjects and in 10 patients with chronic musculoskeletal pain. Serum growth hormone did not change in the normal subjects but there was an approximate 5-fold increase in the chronic pain subjects. This effect was partially inhibited by prior administration of the opiate antagonist naloxone, suggesting that the rise in growth hormone was mediated via release of central nervous system opioids.     

Thyrotropin-releasing hormone (TRH) does not suppress growth hormone response to L-dopa in insulin-dependent diabetes mellitus.

Thyrotropin-releasing hormone (TRH) blunts growth hormone (GH) response to various stimuli in normal subjects. We were interested if similar inhibitory effect of TRH could be demonstrated in diabetes mellitus where GH is abnormally regulated. In this study we compared the effect of TRH on GH response to L-dopa in normal and diabetic subjects. TRH 0.2 mg iv blunted GH response to L-dopa 0.5 g p.o. in normal subjects with peak GH values 13.1 and 7.3 micrograms/l, p < 0.05. In the diabetics no inhibitory effect of TRH was demonstrated and GH was even paradoxically increased after TRH: 14.9 and 21.9 micrograms/l, p = NS. Lack of inhibitory effect of TRH was more pronounced in patients with proliferative retinopathy. It is concluded that TRH has no inhibitory effect on L-dopa-induced GH response in diabetic subjects. This finding provides further evidence for disturbed GH regulation in diabetes mellitus.     

Gel filtration studies of serum growth hormone in acromegaly following bromocriptine administration.

Sera of 7 patients with active acromegaly were fractionated by Sephadex G-100 chromatography and the effects of bromocriptine on the concentrations of total growth hormone (hGH) and its different molecular forms studied. Three immunoreactive peaks were observed, corresponding to molecular weights of about 20,000 ('little hGH'), 40,000 ('big hGH'), and more than 100,000 ('big big hGH') Following bromocriptine administration, there was significantly more reduction of 'little hGH' than of 'big big hGH'. Careful interpretation of these changes is required in view of the possible influences of sample storage and handling on hGH heterogeneity. We suggest that either bromocriptine acts differentially on the release of 'little' and 'big big hGH', or that these components differ in their metabolic half-life. However, even the suppression of 'little hGH' is insufficient to explain the clinical response of the disease to bromocriptine.     

Episodic and TRH induced growth hormone release in primary hypothyroidism of man and rat.

In 27 hypothyroid subjects studied over 20 to 120 minutes, the concentration of serum growth hormone (GH) was variable with the amplitude and frequency of the secretory patterns similar to those reported by others for normal individuals. Serum GH, after the administration of thyrotropin releasing hormone (TRH) did not differ from values observed as spontaneous surges, in contrast to a consistent increase in thyrotropin and prolactin. Episodic secretion of GH persisted in thyroidectomized rats and did not differ significantly from that present in intact controls. It is concluded that episodic GH secretion is not abolished in primary hypothyroidism and that TRH is not a constant GH secretagogue in human subjects with hypothyroidism.     

Effect of deflazacort on growth hormone response to insulin tolerance test.

Deflazacort (DF) has been claimed to be provided with a reduced distribution into the central nervous system, therefore it is conceivable that this glucocorticoid holds a lower inhibitory effect on GH secretion. To test this hypothesis we studied the GH response to insulin tolerance test (ITT) in two matched groups of patients given equivalent doses of DF and prednisone (PN). The serum glucose changes induced by ITT were similar in the two groups and in control subjects; the mean increase in plasma GH, in particular the peak and the area under the curve (delta AUC), were not different in control subjects and DF-treated patients (25 +/- 12.5 ng/ml and 1790 +/- 904 ng/ml/min versus 27.7 +/- 21.5 ng/ml and 1578 +/- 1242 ng/ml/min) but were significantly reduced in PN-treated patients (8.8 +/- 9.7 ng/ml and 431.6 +/- 451 ng/ml/min). Our study demonstrates that DF does not interfere with the GH response to ITT as PN does.     

Bed rest suppresses bioassayable growth hormone release in response to muscle activity

McCall, G. E., C. Goulet, R. E. Grindeland, J. A. Hodgson,A. J. Bigbee, and V. R. Edgerton. Bed rest suppresses bioassayable growth hormone release in response to muscle activity.J. Appl. Physiol. 83(6):2086-2090, 1997.Hormonal responses to muscle activity werestudied in eight men before (13 or 12 and 8 or 7 days), during (2 or 3, 8 or 9, and 13 or 14 days) and after (+2 or +3 and +10 or +11 days) 17 days of bed rest. Muscle activity consisted of a series of unilateral isometric plantar flexions, including 4 maximal voluntary contractions (MVCs), 48 contractions at30% MVC, and 12 contractions at 80% MVC, all performed at a 4:1-swork-to-rest ratio. Blood was collected before and immediately aftermuscle activity to measure plasma growth hormone by radioimmunoassay (IGH) and by bioassay (BGH) of tibia epiphyseal cartilage growth inhypophysectomized rats. Plasma IGH was unchanged by muscle activitybefore, during, or after bed rest. Before bed rest, muscle activityincreased (P < 0.05) BGH by 66% at13 or 12 days (2,146 ± 192 to 3,565 ± 197 µg/l)and by 92% at 8 or 7 days (2,162 ± 159 to 4,161 ± 204 µg/l). After 2 or 3 days of bed rest, there was no responseof BGH to the muscle activity, a pattern that persisted through 8 or 9 days of bed rest. However, after 13 or 14 days of bed rest, plasmaconcentration of BGH was significantly lower after than before muscleactivity (2,594 ± 211 to 2,085 ± 109 µg/l). After completionof bed rest, muscle activity increased BGH by 31% at 2 or 3 days(1,807 ± 117 to 2,379 ± 473 µg/l;P < 0.05), and by 10 or 11 days theBGH response was similar to that before bed rest (1,881 ± 75 to4,160 ± 315 µg/l; P < 0.05). These data demonstrate that the ambulatory state of an individual canhave a major impact on the release of BGH, but not IGH, in response toa single bout of muscle activity.

     

Bioassayable growth hormone release in rats in response to a single bout of treadmill exercise.

Plasma growth hormone (GH) measured by immunoassay [immunoassayable GH (IGH)] and by tibial bioassay [bioassayable GH (BGH)] increases in humans in response to exercise. In rats, however, IGH does not change in response to exercise. The objective of this study was to determine the BGH response to an acute exercise bout in rats. The rats ran on a treadmill at a rate of 27 m/min for 15 min, after which plasma and pituitary hormones, including IGH and BGH, and plasma metabolites were measured. Plasma and pituitary IGH were unchanged from control groups after the acute exercise bout, whereas plasma BGH was increased by 300% and pituitary BGH was decreased by 50%. Plasma thyroxine and corticosterone levels were significantly increased after a single exercise bout, but plasma testosterone, 3,5, 3'-triiodothyronine, glucose, lactate, and triglyceride concentrations were unchanged. Given previous results from in situ nerve stimulation studies (Gosselink KL, Grindeland RE, Roy RR, Zhong H, Bigbee AJ, Grossman EJ, and Edgerton VR. J Appl Physiol 84: 1425-1430, 1998), these in vivo results are consistent with the rapid BGH response during exercise being induced by the activation of muscle afferents.     

Factors influencing the growth hormone response to growth hormone-releasing hormone in children with idiopathic growth hormone deficiency

OBJECTIVE: To evaluate the factors influencing the growth hormone (GH) response to GH-releasing hormone (GHRH) test in idiopathic GH deficiency. METHODS: 28 patients aged 4.9 +/- 0.7 years with certain GH deficiency were given GHRH (2 microg/kg). RESULTS: The GH peak after GHRH was correlated negatively with age at evaluation (r = -0.37, p < 0.05) and body mass index (r = -0.44, p = 0.02), and positively with anterior pituitary height (r = 0.47, p = 0.02), GH peak after non-GHRH stimulation (r = 0.78, p < 0.0001) and spontaneous GH peak (r = 0.82, p = 0.007). It was lower in the patients aged >5 years than in the youngest (p = 0.04), but it was similar in the patients with and without features suggesting a hypothalamic origin. CONCLUSION: The GH response to GHRH test cannot be used to differentiate between hypothalamic and pituitary forms of idiopathic GH deficiency, probably because the GH response decreases after the first 5 years of life, whatever the origin of the deficiency.