Muscarinic receptor activity change after prolonged treatment with growth hormone and somatostatin

1. The effect of 10-day treatment with growth hormone (GH) (1 mg/kg body weight day) and somatostatin (SRIF) (0.25 mg/kg body weight day) subcutaneously on the activity of muscarinic (M) receptors in rat hypothalamic, pituitary and cerebral cortical membrane fractions was studied using (3H)quinuclidinyl benzylate [(3H)QNB] as radioligand. 2. The administration of GH and SRIF significantly decreased the M-receptor binding affinity in the hypothalamus. 3. In the pituitary the M-receptor affinity was increased after both GH and SRIF treatment. 4. In the hypothalamus and the pituitary the binding capacity of muscarinic receptors was unchanged. 5. In the cerebral cortex the chronical GH injection induced an increase in the number of antagonist binding sites and a decrease of their affinity, while the similar SRIF treatment led to an increase of the binding affinity without any change of M-receptor capacity. 6. These results indicate that GH and SRIF selectively and region-specifically modulate muscarinic receptor binding affinity and capacity and provide new insight into the feedback regulatory mechanisms of GH secretion.     

Feeding reduces activity of growth hormone-releasing hormone and somatostatin neurons

Secretion of growth hormone (GH) is synchronized among castrate male cattle (steers) around feeding when access to feed is restricted to a 2-hr period each day. Typically, concentrations of GH increase before and decrease after feeding. Our objectives were to determine whether i) concentrations of GH decrease in blood after start of feeding; ii) activity of immunoreactive growth hormone-releasing hormone (GHRH-ir) neurons decreases in the arcuate nucleus (ARC) after feeding; iii) activity of immunoreactive somatostatin (SS-ir) neurons in the periventricular nucleus (PeVN) and ARC increase after feeding; and iv) GHRH stimulates release of GH to a similar magnitude at 0900 and at 1300 hr, in steers fed between 1000 and 1200 hr. Blood samples were collected at 20-min intervals from 0700 to 1300 hr. Groups of steers were euthanized at 0700, 0900, 1100, and 1300 hr (n = 5 per group). Dual-label immunohistochemistry was performed on free-floating sections of hypothalami using antibodies directed against Fos and Fos-related antigens (Fos/FRA) as a marker of neuronal activity in immunoreactive GHRH and SS neurons. Concentrations of GH were high before and decreased after feeding. The percentage of SS-ir neurons containing Fos/FRA-ir in the PeVN was 50% lower (P<0.01) at 1100 hr and 36% lower (P<0.05) at 1300 hr than at 0900 hr. There was no change in percentage of SS-ir neurons containing Fos/FRA-ir in the ARC. The percentage of GHRH-ir neurons containing Fos/FRA-ir in the ARC was 66% lower (P<0.05) at 1100 hr and 65% lower (P<0.05) at 1300 hr than at 0700 hr. In contrast, the number of GHRH-ir neurons increased from 0700 to 1300 hr. GHRH-induced release of GH was suppressed at 1300 hr compared with 0900 hr. In conclusion, reduced basal and GHRH-induced secretion of GH after feeding was associated with decreased activity of GHRH neurons in the ARC and decreased activity of SS neurons in the PeVN.     

Developmental correlation between hypothalamic somatostatin and hypophysial growth hormone

Summary The objective of the present study was to determine, by means of immunocytochemistry, the age in fetal development at which GH is first detectable in the pituitary gland and somatostatin in the median eminence, and to correlate temporally the development of these two hormones throughout the remainder of pregnancy. Mice were studied at 15–19 days of gestation with the peroxidase-antiperoxidase (PAP) technique of Sternberger. Somatotropes in the pars distalis were initially detected at 16 days of gestation and by 17 days they were a prominent component of the parenchymal cell population of the hypophysis. These cells were ovoid and distributed uniformly throughout the pars distalis; many were located adjacent to sinusoidal capillaries. Their number and staining intensity increased by 19 days. Somatostatin was not consistently observed in the median eminence until 19 days of gestation. Reaction product indicative of the presence of somatostatin in presumptive nerve endings was located on the ventral surface of the median eminence and in the external lamina of the infundibulum in proximity to the superficial portal capillaries. Results of the present investigation support the concept that the potential for neuroendocrine control of GH secretion exists in the mouse by the end of fetal development. Several hypotheses concerning the temporal relationship between the appearance of somatostatin in the hypothalamus and of GH in the anterior pituitary gland are discussed.Supported by a Biomedical Research Support Grant (NIH RR 5417). Appreciation is extended to the National Pituitary Agency, NIAMDD for the following radioiodination-grade hormones: hGH, rPRL, rTSH, rFSH and hCG     

Growth hormone stimulates hypothalamic somatostatin.

Hypothalamic somatostatin concentration is increased in normal rats treated with growth hormone. Somatostatin is reduced in the median eminence of hypophysectomized rats but restored to normal following growth hormone administration. These results suggest that growth hormone exerts a positive feedback effect on hypothalamic somatostatin mechanism by which it may regulate its own secretion.     

Insulin sensitivity in adults with growth hormone deficiency and effect of growth hormone treatment

Adult growth hormone deficiency (GHD) is a multifactorial disorder in which pituitary dysfunction associated with pituitary adenomas or their treatment plays a major role. The introduction of recombinant growth hormone (GH) for the treatment of GHD has opened up new treatment avenues but has also raised concerns about possible untoward long-term metabolic effects of GH, such as the potential effect of GH on insulin sensitivity and a deterioration in glucose tolerance. Research has shown that GH induces insulin resistance by the stimulation of lipolysis and a concomitant switch from oxidation of glucose to oxidation of lipids, during both acute and chronic treatment. However, although this is a consistent effect of GH therapy, it does not mean per se that it leads to abnormal glucose tolerance and diabetes mellitus. This article discusses this and other potential long-term metabolic effects of GH, and raises a number of questions to be addressed by future research.     

Absence of catch-down growth in Russell-Silver syndrome after short-term growth hormone treatment

We describe 3 children with Russell-Silver syndrome without growth hormone insufficiency who were treated with growth hormone for 2, 3. 7 and 6 years, showing a rapid growth acceleration. After cessation of growth hormone treatment, they grew at a normal rate without 'catch-down' growth. It may be possible that short intra-uterine growth retardation (IUGR) children with dysmorphic features respond to growth hormone therapy differently from non-dysmorphic IUGR short children. Short-term growth hormone treatment for children with Russell-Silver syndrome may avoid side effects and diminish costs.     

Effects of prolonged treatment with diltiazem on pituitary secretion of luteinizing hormone, follicle-stimulating hormone, thyrotropin and prolactin.

In previous studies it has been observed that acute administration or short-term treatment with calcium channel blockers can influence the secretion of some pituitary hormones. In this study, we have examined the effect of the long-term administration of diltiazem on luteinizing-hormone (LH), follicle-stimulating hormone (FSH), thyrotropin (TSH) and prolactin (PRL) levels under basal conditions and after gonadotropin-releasing hormone (GnRH)/thyrotropin-releasing-hormone (TRH) stimulation in 12 subjects affected by cardiovascular diseases who were treated with diltiazem (60 mg 3 times/day per os) for more than 6 months and in 12 healthy volunteers of the same age. The basal levels of the studied hormones were similar in the two groups. In both the treated patients and the control subjects, a statistically significant increase (p < 0.01) in LH, FSH, TSH and PRL levels was observed after GnRH/TRH administration. Comparing the respective areas under the LH, FSH, TSH and PRL response curves between the two groups did not present any statistically significant difference. These findings indicate that long-term therapy with diltiazem does not alter pituitary hormone secretion.     

Final height after growth hormone therapy in peripubertal boys with a subnormal integrated concentration of growth hormone.

The aim of this study was to test the effect of growth hormone (GH) therapy on final height in peripubertal boys with idiopathic short stature in whom a subnormal integrated concentration of GH (< 3.2 micrograms/l) was found. Twenty-eight peripubertal children were studied. Height was below 2 SD for age, growth velocity was < 4.5 cm/year, bone age was more than 2 SD below mean for age and GH response to provocative tests was more than 10 micrograms/l. Eleven subjects (group B) were treated with recombinant GH 0.75 unit/kg/week, divided into 3 weekly doses for 2 years, and then the same weekly dose divided into daily injections was administered until final height was attained. Seventeen untreated children (group A) who were followed until cessation of growth served as controls. The GH-treated patients reached their target heights (-2.1 +/- 0.5, mean +/- SD in SDS) and predicted heights (-1.8 +/- 0.8) determined by the Bayley and Pinneau method, while the final heights of the untreated patients were significantly lower than their target heights and their predicted final heights (-2.7 +/- 0.7, -1.8 +/- 1.0 and -2.7 +/- 0.7, respectively). The main effect of GH was observed during the 1st year of treatment when height velocity was significantly higher in the GH-treated group than in the untreated one (9.3 +/- 2.1 vs. 5.3 +/- 1.1, respectively, p < 0.001). The high cost of the treatment in this specific age group should be weighed against the results.     

Twenty-four hour rhythms of hypothalamic corticotropin-releasing hormone, thyrotropin-releasing hormone, growth hormone-releasing hormone and somatostatin in rats injected with Freund's adjuvant

The effect of Freund's adjuvant injection on 24-hour variation of hypothalamic corticotropin-releasing hormone (CRH), thyrotropin-releasing hormone (TRH), GH-releasing hormone (GRH) and somatostatin levels was examined in adult rats kept under light between 0800 and 2000 h daily. Groups of rats receiving Freund's complete adjuvant or its vehicle 3 days before sacrifice were killed at six different time intervals throughout a 24-hour cycle. In the median eminence, adjuvant vehicle-injected rats exhibited significant 24-hour variations for the four hormones examined, with maxima at noon. These 24-hour rhythms were inhibited or suppressed by Freund's adjuvant injection. In the anterior hypothalamus of adjuvant vehicle-treated rats, CRH content peaked at 1600 h, while two peaks were found for TRH and GRH levels, i.e., at 2400-0400 h and 1600 h. Freund's adjuvant injection suppressed 24-hour rhythm of anterior hypothalamic CRH, TRH and GRH content and uncovered a peak in anterior hypothalamic somatostatin levels at 0400 h. In the medial hypothalamus of adjuvant vehicle-treated rats, significant 24-hour variations were detectable for TRH (peaks at 1600 and 2400 h) and somatostatin (peak at 2400 h) which disappeared after Freund's adjuvant injection. In the posterior hypothalamus of adjuvant vehicle-treated rats, two peaks were apparent for CRH, TRH and somatostatin levels, i.e. at 1600 h and 2400-0400 h, this hormonal profile remaining unmodified after Freund's adjuvant administration. The administration of the immunosuppressant drug cyclosporine (5 mg/kg, 5 days) impaired the depressing effect of Freund's adjuvant injection on CRH, TRH and somatostatin content in median eminence, but not that on GRH. In the anterior hypothalamus, cyclosporine generally prevented the effect of immunization on hormone levels an revealed a second maximum in TRH at 0400 h. Cyclosporine also restored 24-hour variations in TRH and somatostatin levels of medial hypothalamus of Freund's adjuvant-injected rats but was unable to modify them in the posterior hypothalamus. The results further support the existence of a significant effect of immune-mediated inflammatory response at an early phase after Freund's adjuvant injection on hypothalamic levels which was partially sensitive to immunosuppression by cyclosporine.     

Interaction of human pancreatic growth hormone-releasing factor, thyrotropin-releasing hormone, and somatostatin on growth hormone release in chickens

The effects of synthetic somatostatin (SRIF) on serum growth hormone (GH) concentrations stimulated by exogenous administration of synthetic thyrotropin-releasing hormone (TRH) and/or human pancreatic GH-releasing factor (hpGRF) were investigated in 4-week-old cockerels. In addition, the additive effects of TRH and hpGRF on serum GH were examined. TRH and hpGRF, when given in combination intravenously, produced an additive effect on serum GH concentration that peaked 10 min after the injection. The somatostatin did not significantly affect basal GH concentrations when given alone, but did significantly decrease the magnitude of the GH response to hpGRF. In contrast, SRIF did not significantly decrease the stimulatory effects of TRH on GH release. These results suggest that TRH and hpGRF are potent GH releasers in vivo and that their stimulating effects on GH release are additive, suggesting different mechanisms for their stimulation. The results obtained from the combination studies suggest that the main site of the stimulatory action of hpGRF is at the pituitary, and that SRIF significantly inhibited the rise in serum GH induced by a synthetic hpGRF, but not that induced by TRH.     

Pine needle growth and fine structure after prolonged acid rain treatment in the subarctic

The growth and morphology of Scots pine needles were studied in a long-term acid rain experiment in the far north of Finnish Lapland. Pine trees 5 m tall of age 50–70 years were exposed, by spraying the foliage and soil from a height of 2 m, to either clean water (IC) or acidified water over the period 1985–1992, the acidification site being divided into sub-areas in which the precipitation contained two levels of either sulphuric (Sm, Sh) or nitric (Nm, Nh) acid, or both (SNm, SNh). The treatments with medium and high sulphate-S over eight consecutive years yielded a total sulphur deposition of 3·4 and 17·1 gm⁻², respectively, and those with medium and high nitrate-N a total nitrogen deposition of 1·1 and 5·9 g m⁻². Needles were collected for light and electron microscopy, growth measurements and morphometry. Growth in branch height had decreased by about 40% after 6 years of SNm or SNh treatment, and needle growth by 15% in the SNh trees as compared with the irrigated control trees (IC), although decreases were statistically significant only with respect to the non-irrigated control trees (DC). Growth of branches and needles was slightly better in the Nh treatment than in the IC group. The areas of the whole needle, the mesophyll and the phloem decreased in response to SNh treatment as compared with IC or DC, and a statistically significant decrease of about 30–40% was seen in the area of the xylem in comparison with DC. Cellular damage was observed following the acid treatments, especially with a high acid load. The damage was manifested in collapse of the cellular compartments, increases in lipid accumulations and swelling or disorganization of the protoplast. Increased vacuolization of the cytoplasm, plasmalemma irregularities and chilling-type damage to the mitochondria were also observed.