scholarly journals Selective Loss of Somatostatin Receptor 2 in Octreotide-Resistant Growth Hormone-Secreting Adenomas

2008 ◽  
Vol 93 (4) ◽  
pp. 1203-1210 ◽  
Author(s):  
Ursula Plöckinger ◽  
Susann Albrecht ◽  
Christian Mawrin ◽  
Wolfgang Saeger ◽  
Michael Buchfelder ◽  
...  
Keyword(s):  
Growth Hormone ◽  
Maximum Dose ◽  
Somatostatin Receptor ◽  
Somatostatin Analogs ◽  
Gh Secretion ◽  
Selective Loss ◽  
Octreotide Treatment ◽  
Group A ◽  
Group B ◽  
Growth Hormone Secreting Adenomas

Abstract Objective: The somatostatin analog octreotide preferentially binds to somatostatin receptor (sst) 2A and to a lesser extent to sst5. Although sst2A and sst5 mRNAs are consistently expressed in GH-secreting adenomas, octreotide controls GH secretion only in 65% of acromegalic patients. Hence, we investigated the immunocytochemical expression of sst in a large group of somatotroph tumors. Methods: Acromegalic patients, cared for in a university referral center, were either operated on without pretreatment (group A, n = 14) or pretreated with octreotide [median (minimum-maximum): dose 1250 (300–1500) μg/d for 5.6 (3–9) months] before surgery (group B, n = 20). In group B octreotide reduced GH secretion by more than 50% in 14 patients (70%) (GH responders). Six patients with less than 50% GH suppression were considered GH nonresponders. We used a panel of extensively characterized antibodies to determine the immunocytochemical sst status in somatotroph adenomas and compared their expression between the groups. Results: All group A tumors demonstrated immunoreactive sst2A, and all but one had sst5. A similar pattern was found in the GH responders of group B. In contrast, none of the GH nonresponders exhibited detectable sst2A (sst2A: GH responders vs. GH nonresponders, P < 0.0001), whereas sst5 was found in 70%. sst1 and sst3 were detected in 85 and 24% of all cases, independent of previous octreotide treatment. Conclusions: Our findings suggest that octreotide resistance in GH-secreting adenomas occurs due to a selective loss of sst2A. The persistent expression of sst1 and sst5 receptors suggests that these tumors are potential targets for pan-somatostatin analogs.

Effects of exogenous growth hormone pretreatment on the pituitary growth hormone response to growth hormone-releasing hormone alone or in combination with pyridostigmine in Type I diabetic patients

1991 ◽  
Vol 125 (5) ◽  
pp. 510-517 ◽  
Author(s):  
Andrea Giustina ◽  
Simonetta Bossoni ◽  
Corrado Bodini ◽  
Antonino Cimino ◽  
Giuseppe Pizzocolo ◽  
...  
Keyword(s):  
Growth Hormone ◽  
Blood Glucose ◽  
Normal Subjects ◽  
Diabetic Patients ◽  
Type I ◽  
Gh Secretion ◽  
Glucose Levels ◽  
Group A ◽  
Group B ◽  
And Control

Abstract. We evaluated the effects of iv pretreatment with exogenous GH on the GH response to GHRH either alone or in combination with pyridostigmine in 14 Type I diabetic patients and 6 normal subjects. All the subjects received an iv bolus injection of biosynthetic human GH, 2 IU; 2 h later they received either a. pyridostigmine, 120 mg orally, or b. placebo, 2 tablets orally, followed 1 h later by iv injection of GHRH(1-29) NH2, 100 μg. In normal subjects the median GH peak after GH+GHRH was 1.8, range 1.2-6.9 μg/l. Pyridostigmine enhanced the GH response to GHRH in all subjects. The median GH peak after pyridostigmine+ GH+GHRH was 32.7, range 19.8-42.1 μg/l (p<0.001 vs GHRH alone). Seven diabetic subjects had median GH peaks after GH+GHRH >6.9 μg/l (the maximum GH peak after GH+GHRH in normal subjects) (group A: median GH peak 35.7, range 21.7-55 μg/l). The other diabetic subjects had GH peak lower than 6.9 μg/l (group B: median GH peak 4.4, range 2.1-6.5 μg/l). Pyridostigmine significantly increased the GH response to GHRH in group B patients (median GH peak 29.3, range 15.7-93.4 μg/l, p<0.001 vs GH+GHRH alone), but not in group A patients (median GH peak 39.9, range 21.9-64.9 μg/l). Group A diabetic patients were younger and had higher HbA1c and blood glucose levels than group B patients. In those diabetic patients with an exaggerated GH response to GH+GHRH, pyridostigmine failed to cause the increase in GH secretion observed in diabetic and control subjects with no responses to GH+GHRH. It can be suggested that elevated 24-h GH levels in some Type I diabetic patients may be due to decreased somatostatinergic tone which in turn causes altered autoregulation of GH secretion. We hypothesize that this finding is a consequence of a reset of the hypothalamic control of GH secretion caused by a chronically elevated blood glucose level in this subpopulation.

scholarly journals Dopamine receptor subtype 2 and somatostatin receptor subtype 5 expression influences somatostatin analogs effects on human somatotroph pituitary adenomas in vitro

2005 ◽  
Vol 35 (2) ◽  
pp. 333-341 ◽  
Author(s):  
M C Zatelli ◽  
D Piccin ◽  
F Tagliati ◽  
A Bottoni ◽  
M R Ambrosio ◽  
...  
Keyword(s):  
Growth Hormone ◽  
Primary Culture ◽  
Pituitary Adenomas ◽  
Somatostatin Receptor ◽  
Somatostatin Analogs ◽  
Receptor Subtype ◽  
Inhibitory Effects ◽  
Gh Secretion ◽  
Secretion Inhibition

Dopamine (DA) and somatostatin (SRIF) receptor agonists inhibit growth hormone (GH) secretion by pituitary adenomas. We investigated DA subtype 2 receptor (DR2) and SRIF receptor (sst) subtypes 2 and 5 expression in 25 GH-secreting pituitary adenomas and tested in primary culture the effects on GH and prolactin (PRL) secretion of sst agonists selectively interacting with sst2 (BIM-23120), sst5 (BIM-23206), and sst2 and sst5 (BIM-23244). All adenomas expressed sst2; eight adenomas expressed both sst5 and DR2, eight sst5 but not DR2, and eight DR2 but not sst5. One tissue lacked expression of DR2 and sst5. GH secretion was inhibited by BIM-23120 in all samples, while it was reduced by BIM-23206 only in adenomas not expressing DR2. BIM-23120’s inhibitory effects correlated with sst2 and DR2 expression, whereas DR2 expression correlated inversely with BIM-23206 inhibitory effects on GH secretion. In seven mixed GH-/PRL-secreting pituitary adenomas, PRL secretion was inhibited in sst5-expressing tumors by BIM-23206, but not by BIM-23120. BIM-23244 reduced PRL secretion only in adenomas expressing sst2, sst5 and DR2. sst5 and DR2 expression correlated directly with BIM23206 inhibitory effects on PRL secretion. Our results suggest that adenomas expressing DR2 are less likely to respond to clinically available SRIF analogs in terms of GH secretion inhibition. Therefore, drugs interacting also with DR2 might better control secretion of pituitary adenomas.

scholarly journals Ghrelin Receptor (GHS-R1a) and Its Constitutive Activity in Somatotroph Adenomas: A New Co-targeting Therapy Using GHS-R1a Inverse Agonists and Somatostatin Analogs

2014 ◽  
Vol 99 (12) ◽  
pp. E2463-E2471 ◽  
Author(s):  
Yves Mear ◽  
Marie-Pierre Blanchard ◽  
Céline Defilles ◽  
Thierry Brue ◽  
Dominique Figarella-Branger ◽  
...  
Keyword(s):  
Somatostatin Receptor ◽  
Somatostatin Analogs ◽  
Inverse Agonist ◽  
Receptor Subtype ◽  
Dependent Manner ◽  
Constitutive Activity ◽  
Targeting Therapy ◽  
Ghrelin Receptor ◽  
Gh Secretion

Context: The ghrelin receptor GHS-R1a is highly expressed in human somatotroph adenomas and exhibits unusually high basal signaling activity. In humans, the suppression of this constitutive activity by mutation induces a short stature. Objective: Using a GHS-R1a inverse agonist, modified substance P (MSP), we explored the role of GHS-R1a constitutive activity in GH hypersecretion from somatotroph adenomas and as a putative therapeutic target. Design: The effects of MSP were assessed on GH secretion from 19 human somatotroph tumors in vitro. Moreover, these effects were compared with those of octreotide (somatostatin receptor subtype 2 [sst2] agonist) and with the combination of both drugs. Expression and localization of GHS-R1a and sst2 were studied. Results: For all tumors, MSP inhibited GH secretion in a dose-dependent manner from 13 to 64%. Moreover, MSP enhanced octreotide-induced GH inhibition. For five tumors, the effects of combined MSP plus octreotide treatment were significantly higher than the sum of effects of each drug alone. MSP increased the membrane localization of GHS-R1a and of microdomains colocalizing sst2-GHS-R1a, highlighting the cooperation between the two drugs. Conclusions: The GHS-R1a inverse agonist could open new therapeutic options for acromegalic patients, particularly patients partially sensitive to octreotide whose GH secretion is not completely controlled by the sst2 agonist.

THERAPEUTICAL DOSES OF SALBUTAMOL INHIBIT THE SOMATOTROPIC RESPONSIVENESS TO GROWTH HORMONE-RELEASING HORMONE IN ASTHMATIC CHILDREN

PEDIATRICS ◽  
1994 ◽  
Vol 94 (2) ◽  
pp. 262-263
Author(s):  
Hemalini Mehta ◽  
Robert F. Lemanske
Keyword(s):  
Growth Hormone ◽  
Systemic Disease ◽  
Forced Expiratory Volume ◽  
Growth Hormone Releasing Hormone ◽  
Assay Sensitivity ◽  
Releasing Hormone ◽  
Children With Asthma ◽  
Group A ◽  
Study Population ◽  
Group B

Purpose of the Study. To determine the effects of therapeutic β2 agonists (specifically salbutamol) on growth hormone (GH) response to growth hormone releasing hormone (GHRH) in children with asthma. Study Population. Fifteen prepubertal children with asthma, ages 6-11 (average age of 9) with normal or normal short stature were studied. Those with an endocrine abnormality, nutritional deficiency, psychological deprivation, or other systemic disease were excluded. Only those children with known bronchial asthma, who showed a 15% decrease of the 1-second forced expiratory volume (FEV1) with methacholine challenge were included. All patients were asymptomatic, and had not experienced an asthma exacerbation, respiratory infection or allergen exposure in the month preceding the study. No child was on medications. Methods. Subjects were divided into two groups. Both groups had baseline GH response to GHRH determined. After an overnight fast, GH levels were obtained the following morning at -60, 0, and then every 15 minutes until 120 minutes after GHRH administration. Two days following this, Group A received salbutamol (0.125 mg/kg) orally at -60 minutes and GH response to GHRH was remeasured. Group B received aerosolized salbutamol (2 mg over 15 minutes) (details of administration were not specified by the authors). All serum GH levels were measured in duplicate by immunoradiometric assay (sensitivity of 0.1 µg/L). Findings. Basal GH levels were similar in both groups. Orally administered salbutamol (Group A) markedly inhibited GH response to GHRH (peak of 3.7 ± 0.6 vs. 18.6 ± 4.7 g/L). Inhaled salbutamol (Group B), although blunting the GHRH-induced GH response, did so to a lesser extent (peak of 20.0 ± 7.5 vs. 35.8 ± 9.4 g/L, P &lt; .02).

Urinary Growth Hormone Measurements in Children with Renal Insufficiency

1993 ◽  
Vol 30 (6) ◽  
pp. 540-544
Author(s):  
G Turner ◽  
A Skinner ◽  
J S Woodhead
Keyword(s):  
Growth Hormone ◽  
Renal Insufficiency ◽  
Causative Factor ◽  
Plasma Creatinine ◽  
Tubular Dysfunction ◽  
Control Subjects ◽  
Significant Difference ◽  
Proximal Tubular ◽  
Group A ◽  
Group B

It has been reported that intrinsic renal factors could affect urinary growth hormone (UGH) measurements. We compared UGH excretion in 21 children aged 4–16 years, with various degrees of renal insufficiency, with that in 10 control subjects aged 5–13 years. We found 100- to 1000-fold elevations in UGH in children with plasma creatinine concentrations > 120 μmol/L (Group A) compared with patients with plasma creatinine concentrations < 120 μmol/L (Group B) and control subjects. UGH excretion (μU) in the three groups was as follows: group A 804–8556 (median 2649); group B 1·0–85 (median 7·5); and controls 2·6–7·3 (median 4·0). Elevated urinary β2-microglobulin levels (μg) were also observed in group A patients: 875–15 400 (median 11 637) as compared with group B, 1·0–104 (median 32) and controls, 3–18·7 (median 8·0). There was no significant difference in albumin excretion between groups A and B though six patients in group B with nephrotic syndrome (NS) excreted significantly more albumin (P < 0·05) than the other 15 patients investigated. Our data show that abnormalities of renal function have a profound effect on growth hormone excretion and we suggest proximal tubular dysfunction as the causative factor. We conclude that UGH measurements do not provide a reliable means of assessment of hypothalamo-pituitary function in patients with renal insufficiency.

scholarly journals Blood asymmetric dimethylarginine and nitrite/nitrate concentrations in short-stature children born small for gestational age with and without growth hormone therapy

2017 ◽  
Vol 46 (2) ◽  
pp. 761-772 ◽  
Author(s):  
Hironori Nagasaka ◽  
Ichiro Morioka ◽  
Mayuko Takuwa ◽  
Mariko Nakacho ◽  
Mayumi Yoshida ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Growth Hormone ◽  
Asymmetric Dimethylarginine ◽  
Therapy Group ◽  
Adma Level ◽  
Gh Therapy ◽  
Normal Children ◽  
Group A ◽  
Group B ◽  
Nitrite Nitrate

Objective To investigate the basal amino acid metabolism and impact of growth hormone (GH) therapy in short-stature children born small for gestational age (short SGA children). Methods In this age-matched case-control study, the basal blood levels of amino acids, asymmetric dimethylarginine (ADMA), and nitrite/nitrate (NOx) were compared between 24 short SGA children and 25 age-matched normal children. Changes in these parameters were assessed for 12 months in 12 short SGA children initiating GH therapy (Group A) and 12 age-matched short SGA children without GH therapy (Group B). Results The arginine levels were significantly lower in the short SGA than in normal children. The ADMA levels were significantly higher and NOx levels were significantly lower in the short SGA than normal children. In Group A, the ADMA level was significantly lower and NOx level was significantly higher at 6 months than at baseline. At 12 months, the ADMA level in Group A began to increase, but the NOx level remained the same. Group B showed no significant changes. Conclusions This study is the first to show that ADMA is promoted and nitric oxide is suppressed in short SGA children and that GH therapy affects the production of ADMA and nitric oxide.

Transient impairment or delay of urinary trihydroxypregnanone (THS) response to metyrapone in boys with delayed adolescence and in patients with isolated growth hormone deficiency

1982 ◽  
Vol 99 (2) ◽  
pp. 166-173 ◽  
Author(s):  
M. Zachmann ◽  
D. Tassinari ◽  
W. Sorgo ◽  
G. U. Exner ◽  
B. Kempken ◽  
...  
Keyword(s):  
Growth Hormone ◽  
Single Dose ◽  
Growth Hormone Deficiency ◽  
Bone Age ◽  
Urine Samples ◽  
Hormone Deficiency ◽  
Cortisol Response ◽  
Transient Impairment ◽  
Group A ◽  
Group B

Abstract. Twentythree boys with delayed adolescence (age 15.7 ± 2.0, bone age 12.4 ± 2.1 years) were studied. Their cortisol response to insulin was normal. After oral metyrapone (500 mg/m2 by mouth) one to three consecutive 12 h urine samples were collected for analysis of THS. Thirtyseven tests with 37 first, 21 second, and 11 third samples were carried out. The results could be divided into two main groups: 25 tests (group A) were subnormal in the first sample, 12 of them with a very weak (40 ± 8 μg/m2/12 h) and 13 with an insufficient (191 ± 16 μg/m2/12 h) THS response. Values in the second and third sample were higher, indicating a dealyed response. In 12 tests (group B), the results were normal (1016 ± 143 μg/m2/12 h) in the first and lower in the second and third samples. In three patients with repeated tests, there was improvement with increasing bone age. The THS-responses to metyrapone did not correlate with those of growth hormone, gonadotrophins, and TSH to stimuli. It is concluded that the THS-response to a single dose of metyrapone may be temporarily insufficient or delayed in delayed adolescence. We interpret this finding as showing transiently reduced or slow hypothalamic responsiveness.

The relationship between naldemedine administration and the maximum dose of oral opioids.

2020 ◽  
Vol 38 (4_suppl) ◽  
pp. 818-818
Author(s):  
Shinya Kajiura ◽  
Shingo Chikaoka ◽  
Ayaka Kadota ◽  
Sakie Fukai ◽  
Takako Matsushita ◽  
...  
Keyword(s):  
Maximum Dose ◽  
Median Dose ◽  
Patients With Cancer ◽  
Day Range ◽  
Opioid Receptor Antagonists ◽  
Significant Difference ◽  
Group A ◽  
Starting Date ◽  
Group B ◽  
The Relationship

818 Background: Opioid-induced constipation (OIC) is the most common side effect of opioid therapy. Laxatives are usually used as a first-line treatment for OIC. Treatment options for OIC are switching to other opioids associated with less frequent OIC, such as Fentanyl. Naldemedine is an orally active peripherally acting µ-opioid receptor antagonists that was approved in Japan from 2017 for management of cancer-related OIC. The aim of this study is to investigate the relationship between Naldemedine administration and the maximum dose of oral Oxycodone which is the most frequently used oral opioids at our hospital. Methods: During June 2017 and December 2018, a total of 217 patients with cancer-related pain received Oxycodone at our institution. The first group of the patients concurrently received Naldemedine 0.2 mg daily (group A, n = 101), and the second group didn’t receive it (group B, n = 116) for cancer-related OIC reduction. We compared the maximum Oxycodone dose between two groups by medical record retrospectively. Results: The median age of group A was 69 y.o. (range 20-87 y.o.), and the median age of group B was 67 y.o. (range 27-88y.o.). There was no significant difference in common patient background between group A and B. The median dose of maximum Oxycodone dose of group A was 40 mg/day (range 10-480 mg/day), and that of group B was 20 mg/day (range 10-320 mg/day). There was a significant difference in the median dose of maximum Oxycodone between group A and B (Mann-Whitney U test, P < 0.0001). In Group A, the administration was started in 31 patient Naldemedine and Oxycodone at the same time. As for 70 remaining patients, the administration was started when they had constipation after oxycodone was administrated. In those patients, the median days was 19 days from the Oxycodone administration starting date to the Naldemedine administration starting date. Conclusions: Naldemedine administration in patients with cancer-related OIC may increase the maximum dose of oral Oxycodone.

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