Cholinergic modulation of GH secretion in acromegalic patients before and after pituitary surgery

1992 â—½  
Vol 127 (6) â—½  
pp. 489-493 â—½  
Author(s):  
Leon Fiszlejder â—½  
Olga Penacini â—½  
Susana Ratz â—½  
Adriana Oneto â—½  
Maria Storani â—½  
...  
Keyword(s):  
Area Under The Curve â—½  
Pituitary Surgery â—½  
Normal Subjects â—½  
Physiological Control â—½  
Gh Secretion â—½  
Pathophysiological Role â—½  
Before And After â—½  
Transsphenoidal Adenomectomy â—½  
Ghrh Test

Cholinergic neurotransmission exerts a physiological control on GH secretion. Pirenzepine (Pz), an antagonist of muscarinic receptors, by enhancing hypothalamic somatostatin release, inhibits stimulated GH secretion in normal subjects but not in acromegalic patients. To address the hypothesis that a feedback effect of GH hypersecretion can be involved in this condition, GH responses to GHRH 1–29, 1 μg/kg iv, with and without administration of Pz, 40mg iv before tests, were investigated in eight acromegalic patients, before and 20–30 days after transsphenoidal adenomectomy. Pz diminished (p<0.001) the incremental area under the curve (AUC) of GH responses to GHRH in seven normal controls. In contrast, GHRH responsiveness in untreated acromegalic patients was not affected by Pz. Postoperative basal GH levels decreased by 62.4±14.9% (p<0.01). Pz inhibited GH responses to GHRH (p<0.01). Furthermore, a direct relationship (r = 0.73, p<0.01) between basal concentrations and the AUC of GH responses following Pz plus GHRH-test was found. The finding that muscarinic receptor activity recovered after the reduction of serum GH basal levels by pituitary surgery lends support to the proposed pathophysiological role of GH excess as a possible determinant factor in cholinergicsomatostatinergic dysfunction in acromegaly.

Influence of chronic naltrexone treatment on growth hormone secretion in normal subjects

1997 â—½  
pp. 631-634 â—½  
Author(s):  
P Villa â—½  
D Valle â—½  
L De Marinis â—½  
A Mancini â—½  
A Bianchi â—½  
...  
Keyword(s):  
Hormone Secretion â—½  
Growth Hormone Secretion â—½  
Normal Subjects â—½  
Molar Ratio â—½  
Normal Female â—½  
Gh Secretion â—½  
Igf I â—½  
Before And After â—½  
Ghrh Test â—½  
Igfbp 3

OBJECTIVE: To verify if a chronic opioid blockade could affect the GH/IGF-I axis. DESIGN: We have investigated the effects of naltrexone (NTX) treatment on GH response to GHRH in normal women. METHODS: GHRH test (50 micrograms i.v.) performed in seven normal female volunteers (age 25-38 years, with a body mass index ranging from 19.8 to 23.1 kg/m2) before and after 4-weeks NTX treatment (50 mg p.o. daily). RESULTS: Basal GH, IGF-I, insulin-like growth factor binding protein-3 (IGFBP-3) plasma levels and the IGF-I/IGFBP-3 molar ratio remained unaffected by NTX. NTX significantly reduced the GH peak values (15.52 +/- 3.59 vs 4.78 +/- 0.49 micrograms/l; P < 0.01), and GH area under curve (918.93 +/- 253.96 vs 401.09 +/- 79.63 micrograms/l; P < 0.01). CONCLUSIONS: This finding suggests that the long-term opioid receptor blockade has an inhibitory role on GHRH-induced GH secretion. A central influence on neurotransmitter control of GH might be hypothesised. The inhibition of stimulated GH release, without interference with the basal level, could indicate an enhanced somatostatin secretion and/or activity. Opioids could be involved only in the regulation of GH dynamics and not in basal secretion. Nevertheless, a direct involvement of opioids at the pituitary level, which could be modified by NTX, cannot be excluded.

Secretion of growth hormone-releasing hormone in patients with idiopathic pituitary dwarfism and acromegaly

1988 â—½  
Vol 117 (2) â—½  
pp. 273-281 â—½  
Author(s):  
Ryuichi Yamasaki â—½  
Haruhiko Saito â—½  
Kazuhito Kameyama â—½  
Eiji Hosoi â—½  
Shiro Saito
Keyword(s):  
Type I â—½  
Normal Children â—½  
Pituitary Dwarfism â—½  
Gh Secretion â—½  
Fasting Plasma â—½  
Pathophysiological Role â—½  
Plasma Gh â—½  
High Level â—½  
Normal Adults

Abstract. The plasma levels of immunoreactive-GHRH in patients with idiopathic pituitary dwarfism and acromegaly were studied in the basal state and during various tests by a sensitive and specific RIA. The fasting plasma GHRH level in 22 patients with idiopathic pituitary dwarfism was 6.3 ± 2.3 ng/l (mean ± sd), which was significantly lower than that in normal children (9.8 ± 2.8 ng/l, N = 21), and eight of them had undetectable concentrations (less than 4.0 ng/l). Little or no response of plasma GHRH to oral administration of L-dopa was observed in 7 of 10 pituitary dwarfs, and 3 of the 7 patients showed a response of plasma GH to iv administration of GHRH (1 μg/kg). These findings suggest that one of the causes of idiopathic pituitary dwarfism is insufficient GHRH release from the hypothalamus. The fasting plasma GHRH level in 14 patients with acromegaly and one patient with gigantism was 8.0 ± 3.9 ng/l, which was slightly lower than that in normal adults (10.4 ± 4.1 ng/l, N = 72). One acromegalic patient with multiple endocrine neoplasia type I had a high level of plasma GHRH (270 ng/l) with no change in response to L-dopa and TRH test. In 3 untreated patients with acromegaly L-dopa did not induce any response of plasma GHRH in spite of inconsistent GH release, and in 4 patients with acromegaly, TRH evoked no response of plasma GHRH in spite of a marked GH release, suggesting that the GH responses are not mediated by hypothalamic GHRH. These findings suggest that the measurement of plasma GHRH in response to L-dopa with a sensitive and specific RIA could be of use in clarifying the pathophysiological role of endogenous GHRH in patients with GH secretion disorders.

On the role of dopamine receptors in the central regulation of human TSH

1981 â—½  
Vol 98 (4) â—½  
pp. 521-527 â—½  
Author(s):  
G. Delitala â—½  
L. Devilla â—½  
A. Canessa â—½  
F. D'Asta
Keyword(s):  
Dopamine Receptors â—½  
Blood Brain Barrier â—½  
Median Eminence â—½  
Normal Subjects â—½  
Acute Administration â—½  
Central Regulation â—½  
Before And After â—½  
Tsh Secretion â—½  
Substituted Benzamides

Abstract. The effects of acute administration of haloperidol (4 mg im) and pimozide (4 mg orally) on TSH and Prl secretion were studied in normal and hypothyroid man. The TRH-induced TSH secretion before and after pre-medication with pimozide and domperidone, a peripheral dopamine (DA) blocker, was also evaluated in a group of normal subjects. Haloperidol and pimozide induced a marked increment in serum Prl; mean Prl levels were still significantly elevated 12 h following pimozide administration. A small but significant TSH increase was observed following haloperidol and pimozide in normal as well as hypothyroid subjects. Both domperidone and pimozide significantly enhanced TRH-induced TSH release. In another experiment 3 women with primary thyroid failure received an infusion of DA (4 (μg/kg/min for 4 h) with and without domperidone administration. TSH and Prl levels were suppressed by DA, but the effect was completely abolished by domperidone. The results suggest that psychotrophic drugs, such as haloperidol and pimozide, can, like substituted benzamides, stimulate TSH release in man. Since domperidone and DA do not cross the blood-brain-barrier and domperidone significantly enhanced the TSH response to TRH, the data also support the hypothesis that human TSH is regulated by DA at the hypothalamus (median eminence) and/or pituitary level.

Lowering of serum T3 and rise in reverse T3 induced by glucagon infusion in anaesthetized dogs

1987 â—½  
Vol 116 (1) â—½  
pp. 43-48 â—½  
Author(s):  
Udaya M. Kabadi â—½  
Lester Dragstedt
Keyword(s):  
Normal Saline â—½  
Normal Subjects â—½  
Reverse T3 â—½  
Significant Fall â—½  
Before And After â—½  
Serum T3 â—½  
Saline Administration â—½  
Glucagon Injection â—½  
Control Study

Abstract. We recently demonstrated that lowering of T3 and a rise in rT3 observed in non-thyroidal illnesses could be induced by glucagon infusion in normal subjects without altering T4, Free T4 (FT4) and T3 resin uptake (T3RU) values suggesting that altered T4 metabolism may be mainly responsible for those changes. To further assess the role of altered T4 metabolism in these changes during induction of hyperglucagonaemia, we studied glucose, T4, FT4, T3RU, T3, and rT3 concentrations before and after iv glucagon injection (0.5 mg) for up to 3 h in 6 anaesthetized dogs, since thyroxinebinding globulin (TBG) concentration is known to be extremely low in dogs. A control study was conducted with iv normal saline (0.5 ml) injection. T4, FT4 and T3RU remained unchanged during both studies. A significant fall was noted in T3 with glucagon (ΔT3, 0.23 ± 0.06 nmol/l vs 0 ± 0.03 nmol/l with normal saline; P < 0.01). rT3 rose markedly following glucagon infusion (ΔrT3, 0.04 ± 0.011 nmol/l vs −0.017 ± 0.006 nmol/l with normal saline; P < 0.01). Moreover, areas under the curves for T3 and rT3 were markedly increased during glucagon infusion when compared to saline administration (P < 0.01 for both comparisons). Therefore, this study suggests that changes in T3 and rT3 concentrations observed in non-thyroidal illnesses may be attributed to hyperglucagonaemia and may be secondary to altered T4 metabolism as reflected by lowered T3/T4 and increased rT3/T4 ratio.

Growth hormone (GH) release after administration of GH-releasing hormone in relation to endogenous 24-h GH secretion in short children

1989 â—½  
Vol 122 (1) â—½  
pp. 61-68 â—½  
Author(s):  
L. Gelander â—½  
K. Albertsson-Wikland
Keyword(s):  
Growth Hormone â—½  
Area Under The Curve â—½  
Tolerance Test â—½  
Insulin Tolerance Test â—½  
High Variability â—½  
Releasing Hormone â—½  
Gh Secretion â—½  
Insulin Tolerance â—½  
Short Children â—½  
Ghrh Test

ABSTRACT Endogenous GH secretion was measured every 20 min for 24 h in 36 short children. This was immediately followed by an i.v. injection of GH-releasing hormone (GHRH)(1–29)-NH2 (1 μg/kg), and GH was estimated every 15 min for the following 2 h. The aim was to determine whether endogenous pulsatile GH secretion had any relation to, or influence on, the GH release induced by GHRH. A high variability was found both in the 24-h GH secretion expressed as area under the curve above the baseline (0–1588 mU/l × 24 h) and the maximal GH response to GHRH (5–296 mU/l), as well as after an arginine–insulin tolerance test (4–59 mU/l). We found a positive correlation (correlation coefficient of Spearman (rs) = 0·49; P < 0·01) between the GH response to GHRH and the spontaneous GH secretion over a 24-h period, in spite of a negative correlation (rs = −0·80; P < 0·01) with the GH secretion during the preceeding 3 h. We conclude that the GH response to a GHRH test correlates with endogenous GH secretion in short children, and may be helpful in estimating the ability to release GH. It is important, however, to be aware of the influence of the spontaneous GH secretion during the 3 h immediately preceeding administration of GHRH. Journal of Endocrinology (1989) 122, 61–68

Continuous subcutaneous octreotide infusion markedly suppresses IGF-I levels whilst only partially suppressing GH secretion in diabetics with retinopathy

1989 â—½  
Vol 120 (2) â—½  
pp. 187-194 â—½  
Author(s):  
S. L. Hyer â—½  
P. S. Sharp â—½  
R. A. Brooks â—½  
J. M. Burrin â—½  
E. M. Kohner
Keyword(s):  
Normal Subjects â—½  
High Plasma â—½  
Prolonged Treatment â—½  
Somatostatin Analogue â—½  
Clinical Value â—½  
Gh Secretion â—½  
Treatment Regimens â—½  
Igf I â—½  
Before And After â—½  
Long Acting

Abstract. The response to GH releasing hormone (GHRH 1–29) and 24-h serum GH and IGF-I levels were measured in 9 insulin-dependent diabetics with retinopathy and 6 normal volunteers before and after different treatment regimens with octreotide, a long-acting somatostatin analogue. Octreotide, 50 μg by sc injection, completely suppressed GHRH-stimulated GH release in both groups. Thrice daily sc injections for up to 20 weeks were associated with variable plasma octreotide levels and failed completely to suppress GH secretion in either the patients or the normal controls. Three days of continuous sc pump infusion (500 μg/24-h) resulted in consistently high plasma octreotide levels and completely suppressed 24-h GH in 4 normal subjects, whilst treatment for up to 16 weeks only partially suppressed GH levels in 6 patients (AUC mU · l−1 · h−1;h 209 ± 81 vs 121 ± 82; P=0.01). Mean ± sd IGF-I levels (μg/l) in the patients (but not controls) were suppressed into the hypopituitary range by median 6 weeks (range 2–16) pump administration (203 ± 62 vs 60 ± 25; P= 0.02). Pump treatment achieved total GH suppression in normal subjects; diabetics with retinopathy seem more resistant to the GH suppressing effects of the drug. However, the reduction of serum IGF-I with prolonged treatment may be of clinical value in arresting the progress of diabetic retinopathy.

Growth hormone (GH) responsiveness to GHRH in normal adults is not affected by short-term gonadal blockade

1989 â—½  
Vol 120 (1) â—½  
pp. 31-36 â—½  
Author(s):  
L. Lima â—½  
V. Arce â—½  
N. Lois â—½  
C. Fraga â—½  
M.J. Lechuga â—½  
...  
Keyword(s):  
Gh Deficiency â—½  
Gonadal Steroids â—½  
Receptor Blockade â—½  
Testosterone Enanthate â—½  
Short Term â—½  
Gh Secretion â—½  
Before And After â—½  
Normal Men â—½  
Ghrh Test â—½  
Normal Adults

Abstract. The effects of changes in circulating gonadal steroids on GH secretion elicited by GHRH challenge (1 μg/kg) in normal adults volunteers (aged 18–24 years), were evaluated in 10 women and 10 men before and after gonadal blockade was achieved by a GnRH agonist (1500 μg/day by nasal spray for 40 days). To see if the effect of testosterone on GH secretion was dependent on its aromatization to estradiol (E2), GHRH tests were performed in 7 normal men prior to administration of testosterone enanthate (250 mg im), 8 days after this treatment had began, and again after E2 receptor blockade with tamoxifen (30 mg for 2 days plus 10 mg on the third day 2 h before the GHRH test, po) administered 8 days after testosterone enanthate. The study of the functional status of the somatotropes at the time of GHRH testing was made according to our previous postulate. Short-term gonadal blockade did not affect the parameters of GH response to GHRH in neither women nor men. Thus, the functional blockade of the gonads may be advisable as an adjunct therapy in the treatment of hypothalamic GH-deficiency during the peripubertal stage. In the other group of men, administration of testosterone enanthate significantly increased GHRH-elicited GH release, but this was reverted after E2 receptor blockade. Since the hypothalamic-somatotrope rhythm was altered by both these farmacological manipulations, it appears that testosterone acts on GH release mainly at the suprapituitary level, and that this action is secondary to its aromatization to E2

scholarly journals Markedly Reduced Expression of Platelet c-mpl Receptor in Essential Thrombocythemia

Blood â—½  
1997 â—½  
Vol 90 (10) â—½  
pp. 4031-4038 â—½  
Author(s):  
Yoko Horikawa â—½  
Itaru Matsumura â—½  
Koji Hashimoto â—½  
Masamichi Shiraga â—½  
Satoru Kosugi â—½  
...  
Keyword(s):  
Tyrosine Phosphorylation â—½  
Essential Thrombocythemia â—½  
Normal Subjects â—½  
Protein Tyrosine Phosphorylation â—½  
Hematopoietic Stem â—½  
Protein Tyrosine â—½  
Flow Cytometric â—½  
Pathophysiological Role â—½  
And Function

Abstract Thrombopoietin (TPO) is implicated as a primary regulator of megakaryopoiesis and thrombopoiesis through binding to the cytokine receptor c-Mpl (the product of the c-mpl proto-oncogene). In an effort to determine the pathophysiological role of TPO-c-Mpl system in essential thrombocythemia (ET), we have examined the levels of serum TPO and the expression and function of platelet c-Mpl in 17 patients with ET. In spite of extreme thrombocytosis, serum TPO levels were slightly elevated or within normal range in most, if not all, patients with ET (mean ± SD, 1.31 ± 1.64 fmol/mL), as compared with normal subjects (0.76 ± 0.21 fmol/mL). Flow cytometric and Western blot analyses revealed that the expression of platelet c-Mpl was strikingly reduced in all patients with ET. Furthermore, the expression of platelet c-mpl mRNA was found to be significantly decreased in the ET patients tested. In contrast, almost identical levels of GPIIb/IIIa protein and mRNA were expressed in platelets from ET patients and normal controls. In addition to expression level, activation state of platelet c-Mpl was investigated in ET patients. Immunoblotting with anti-phosphotyrosine antibody showed that no aberrant protein-tyrosine phosphorylation was observed in platelets of ET patients before treatment with TPO, and the levels of TPO-induced protein-tyrosine phosphorylation, including c-Mpl-tyrosyl phosphorylation, roughly paralleled those of c-Mpl expression, suggesting that c-Mpl–mediated signaling pathway was not constitutively activated in platelets of ET patients. These results suggested that the TPO-c-Mpl system may not be directly linked to pathogenesis of ET, and that gene(s) mutated in ET may be important in regulating the levels of c-mpl gene expression in addition to the growth and differentiation of multipotential hematopoietic stem cells.

scholarly journals The role of endogenous GHRH in arginine-, insulin-, clonidine- and l-dopa-induced GH release in normal subjects

2002 â—½  
Vol 146 (2) â—½  
pp. 197-202 â—½  
Author(s):  
K Hanew â—½  
A Utsumi
Keyword(s):  
Healthy Adult â—½  
Normal Subjects â—½  
Insulin Administration â—½  
Adult Males â—½  
Gh Secretion â—½  
Maximal Stimulation â—½  
Combined Administration â—½  
Serum Gh â—½  
Stimulation Of

OBJECTIVE: The role of endogenous GHRH in arginine-, insulin-, clonidine- and l-dopa-induced GH secretion was studied in man using a GHRH antagonist (GHRH-Ant). DESIGN: Ten healthy adult males were studied for serum GH responses to arginine or insulin singly, or sequentially 120 min after GHRH injection with or without combined administration of GHRH-Ant. Further, GHRH, clonidine or l-dopa were sequentially administered to these subjects 120 min after the GHRH injection. RESULTS: The combined administration of GHRH-Ant distinctly inhibited the arginine- and insulin-induced GH release. When these four agents were sequentially administered 120 min after GHRH injection, the GH responses to clonidine and l-dopa disappeared completely while clear responses were observed to arginine and insulin administration. These responses to arginine and insulin were also completely inhibited by the combined administration of GHRH-Ant. CONCLUSIONS: These results indicate that clonidine and l-dopa stimulate GH secretion mainly through the release of hypothalamic GHRH, and that arginine- and insulin-induced hypoglycaemia stimulate GH secretion mainly through the inhibition of hypothalamic somatostatin release. However, the presence of endogenous hypothalamic GHRH seems to be essential for the maximal stimulation of GH release induced by arginine and insulin.

Nasal Absorption of Growth Hormone in Normal Subjects: Studies with Four Different Formulations

1994 â—½  
Vol 28 (7-8) â—½  
pp. 845-848 â—½  
Author(s):  
Torben Laursen â—½  
Per Ovesen â—½  
Birgitte Grandjean â—½  
Sigrid Jensen â—½  
Jens Otto L. Jørgensen â—½  
...  
Keyword(s):  
Growth Hormone â—½  
Maximum Concentration â—½  
Relative Concentration â—½  
Elevated Serum â—½  
Area Under The Curve â—½  
Random Order â—½  
Normal Subjects â—½  
Nasal Symptom â—½  
Subcutaneous Injections â—½  
Gh Secretion

OBJECTIVE: Current growth hormone (GH) therapy with daily subcutaneous injections results in elevated serum concentrations of GH lasting for several hours, whereas physiologic GH secretion is characterized by a short-duration peak and low basal concentrations. A closer imitation of this pattern might be achieved by administering GH nasally. We studied the effect on the absorption of nasally administered human GH of increasing concentrations of the enhancer didecanoyl-L-α-phosphatidylcholine (DDPC). DESIGN: Four formulations of nasal GH containing the enhancer DDPC in the relative concentrations 0, 4,8, and 16% w/w were administered in random order. SETTING: Participants were admitted to the hospital during the four study periods. INTERVENTIONS: On four occasions the subjects received GH 6 IU (2 mg) in each nostril. Blood was sampled frequently for four hours. Anterior rhinoscopy was performed at 0 and 4 h. During the study the subjects completed a questionnaire to record nasal symptoms. PATIENTS: Sixteen healthy subjects were examined at 0800 h after an overnight fast. MAIN OUTCOME MEASURES: Bioavailability of a nasal preparation of human GH: area under the curve (AUC), the maximum concentration(Cmax), and the time to reach maximum concentration (tmax). Scores for each nasal symptom were recorded as were the total scores. RESULTS: AUC, Cmax, and tmax,. were not significantly affected by increasing the DDPC concentration from 0 to 4 percent or from 8 to 16 percent. AUC and Cmax, however, increased significantly when the concentration of DDPC was changed from 4 to 8 percent. Mean (±SD) AUC (μg·h/L) increased from 20.51 ± 10.53(4 percent)to 46.14 ± 34.59 (8 percent), (p<0.005). Mean (±SD) of Cmax (μg.L) increased from 11.11 ± 5.02 (4 percent) to 28.22 ± 20.85 (8 percent), (p=0.OO2). Mean (±SD) of tmax (min) was not significantly different on the four occasions(range 40.6 ± 36.4 to 61.0 ± 45.2 min, p=0.13). The symptom scores (range 17.56–21.5, maximum 360) were not significantly different (p=0.59). CONCLUSIONS: Increasing the relative concentration of the enhancer DDPC increases the absorption of nasally administered GH.

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