Age and sex as predictors of biochemical activity in acromegaly: analysis of 1485 patients from the German Acromegaly Register.

OBJECTIVE: We evaluated the German Acromegaly Register for clinical variables associated with the initial biochemical activity of patients with acromegaly. DESIGN: Retrospective analysis of data in the registry. PATIENTS: A total of 1485 patients with acromegaly (males 45.6%, females 54.4%) were treated in 42 German endocrine centres until November 2005. Linear regression models were used to estimate the influence of various parameters on biochemical activity. RESULTS: Male patients with acromegaly were significantly younger at the time of diagnosis than female patients (41 vs. 47 years, P < 0.0001) and had significantly higher random GH levels than females (21 vs. 14 ng/ml, P < 0.005) and IGF-1 levels (773 vs. 679 ng/ml, P < 0.0001), respectively. Age at initial presentation turned out to be the most important independent risk factor associated with random GH levels, oral glucose tolerance test-suppressed GH levels, IGF-1 levels, body mass index (BMI), tumour size and prevalence of hypopituitarism. Sex was an independent risk factor for IGF-1 levels, BMI and prevalence of hypopituitarism. Tumour size was an independent risk factor for both GH and IGF-1 levels. CONCLUSIONS: In summary, initial biochemical activity of acromegaly is influenced by patient's age and to a lesser degree by patient's sex. Male patients are on an average 6 years younger than females.

Studies on the relationship between plasma free fatty acids and growth hormone secretion in man.

The influence of plasma free fatty acid (FFA) concentration on the secretion of human growth hormone (HGH) was investigated. (a) FFA depression was produced by means of a nicotinic acid (NA) infusion for either 1 or 5 hr in the presence of glucose-induced hyperglycemia. Controls received only saline. (b) FFA depression was also produced by a 90 min NA infusion and then rapid FFA elevation by a lipid-plus-heparin (lipid) infusion. This procedure was compared with a similar NA infusion not followed by lipid. (c) FFA elevation was produced either by a lipid or by a norepinephrine (NE) infusion and then HGH secretion was stimulated by insulin-induced hypoglycemia. Each subject in this group received both the lipid and the NE infusion on seperate days as well as two control tests (insulin alone and NE alone). Depression of FFA resulted in an increase of HGH with a lag period of approximately 2 hr. Maximal HGH rise after 1 hr NA infusion was 7.7+/-1.9 ng/ml and with 5 hr NA infusion 14.3+/-3.6 ng/ml (both significantly higher than during saline infusion, P < 0.025 and < 0.005 respectively) and occurred despite continuous hyperglycemia. Lipid infusion just before the expected HGH increase prevented the HGH response to FFA depression. HGH rise during insulin hypoglycemia (32.2+/-6.5 ng/ml) was significantly inhibited by prior FFA elevation whether achieved by lipid infusion (maximum HGH rise 11.4+/-1.6 ng/ml) or by NE infusion (maximum HGH rise 19.0+/-6.2 ng/ml). The results are suggestive of a negative feedback loop between plasma FFA and HGH secretion, of importance for subacute rather than acute changes in the plasma FFA concentration. FFA lack itself seems to be the signal for HGH release despite the lag period between FFA decrease and HGH increase. Glucose and FFA can at least not fully replace each other in their respective influence on HGH release.

The German Acromegaly Registry: description of the database and initial results.

UNLABELLED: Patient registries are valuable tools to study long-term morbidity and mortality of rare diseases. Acromegaly is rare (incidence 3-4/mill/year, prevalence 40-70/mill; approx. 300 new patients/yr and up to 5700 patients in Germany). Diagnostic and therapeutic possibilities have considerably improved, but treatment results remain often unsatisfactory. The main cause is residual disease activity after surgery, most importantly due to invasive macroadenomas. The German Acromegaly Registry is an initiative of the Pituitary Study Group of the German Endocrine Society (DGE). Formally established in January 2003 by the Board of the DGE, long-term financial support is guaranteed by an unrestricted grant from Novartis Pharma GmbH to the DGE. The registry cooperates closely with the United Kingdom and the Austrian registries. The aim of the German Acromegaly Registry is to establish a database of sufficient epidemiological strength in order to (1) document co-morbidity and mortality, (2) provide data on diagnostic and therapeutic procedures/effectiveness, (3) enable comparison of procedures in different national centres, (4) provide information for patient support groups/interaction with health care providers, (5) enable comparison with other national registries within Europe. The registry has at present 82 participating centres, and 42 have included patients (20 university clinics, 8 non-university hospitals, 14 centres in private practice). The database aims to include all acromegalic patients in Germany who are cared for and treated at present. Up to December 2005 1543 patients have been entered in a retrospective manner. Data collection is by external monitoring by highly trained study nurses who visit the individual centres. Inclusion is planned to continue at a rate of 500 per year. Starting in 2005 centres are revisited every 3 years at a rate of 500 per year (prospective phase of the registry). Quality of the data has been validated by an independent monitoring team which demonstrated high data concordance. CONCLUSIONS: Initial results of the German Acromegaly Registry show that it was possible to include a large number of patients within 3 years into the registry. Data quality has been validated and shown to be satisfactory. Therefore, the registry will be a useful tool to study long-term morbidity and mortality in a large series of patients.

Acromegaly and end-stage renal disease: a diagnostic challenge.

Chronic renal failure is associated with an impairment of the GH/IGF-I axis. We report the diagnostic challenges in a 72-yr-old female suffering from end-stage renal disease and presenting with clinical findings suggestive of acromegaly. GH was not suppressed during an oral glucose tolerance test, but rose paradoxically. However, serum IGF-I levels were within the normal range. IGF-binding proteins (IGFBP)-2 and -3 were markedly elevated and GH-binding protein (GHBP) was diminished. Clinical findings suspicious of acromegaly could be ascribed to pre-existing characteristics and consequences of end-stage renal disease. This suggested that the disturbances of the GH/IGF-I axis in our patient were due to chronic renal disease, rather than acromegaly. In the work-up for acromegaly, clinicians should be alerted to GH resistance in chronic renal failure.

Pattern of thyrotropin and thyroxine plasma concentrations during the 24-hour sleep-wake cycle in the male rhesus monkey.

The 24-h pattern of the plasma TSH concentration was investigated in five male rhesus monkeys prepared chronically with right atrial catheters and electroencephalogram (EEG) electrodes. The preparation allowed frequent blood sampling (every 15 min), TV monitoring, and EEG recording from the adjacent room for extended periods of time from undisturbed animals. In addition, nap deprivation, 5 h total sleep deprivation, and specific sleep stage deprivation experiments were performed in order to test their influence on the TSH pattern. T4 was also determined in approximately half of the profiles during undisturbed conditions. Both TSH and T4 patterns consisted of low amplitude, high frequency fluctuations which, however, did not exceed the assay variation. TSH showed superimposed higher amplitude spikes at unpredictable times (0-5/24-h). Intra- and interanimal variabilities of both TSH and T4 patterns were high. Power spectral maxima of the TSH time series indicated periodicities between 30-75 min which were not significant. No nyctohemeral difference in the TSH or T4 pattern or their mean concentrations was found, and there was no consistent pattern of a circadian cycle. Independent changes of average TSH and T4 concentrations were seen in 5 of the 16 profiles during undisturbed conditions, under which both hormones were determined. Cross-correlation analysis of the hormonal time series revealed no significant relation between TSH and T4 patterns. The deprivation procedures had no significant influence on the day or nighttime pattern of TSH. Cross-correlation analysis showed no relation between TSH and either activity during the day or sleep stages during the night. It is concluded that in the rhesus monkey, in contrast to man, TSH secretion shows no circadian variation and is not influenced by the sleep-wake cycle.

Dissociation of light onset and wake onset: effect on rhesus monkey growth hormone secretion.

Synchronization of GH-secretory episodes occurs at light onset in the rhesus monkey and is later lost during the 24-h day. The stimulus for this synchronization was studied in nine male adult monkeys prepared with chronic jugular catheters. In a first experiment, light onset was delayed by 2 h (from 0600 to 0800 h) on days 2-6 and returned to 0600 h on day 7. The animals were allowed to sleep on during the additional time of darkness. The early morning GH peak was immediately shifted to the new light-onset times, both after introduction of the delay and after its reversal. In a second experiment, the animals were awakened in darkness during a similar light-onset delay. Now the GH peaks constantly occurred at the time of awakening shortly after 0600 h, and no GH peak was seen after light onset at 0800 h. Neither experimental condition had an influence on the patterns of plasma PRL and cortisol. These results suggest that the early morning synchronization of the GH-secretory pattern in the rhesus monkey is triggered by awakening and not by light onset.

Pattern of plasma cortisol during the 24-hour sleep/wake cycle in the rhesus monkey.

The 24-h pattern of plasma cortisol and changes induced by alterations of the sleep/wake cycle were studied in 12 male rhesus monkeys. The chair-living animals were chronically prepared with a right atrial catheter and electroencephalogram electrodes. Hormone (blood samples every 15 min) and continuous activity/electroencephalogram profiles were obtained from the adjacent room for 96 h (4 animals), 24 h or various shorter periods of time. Plasma cortisol showed a circadian rhythm with a late evening minimum (1900-2100 h; approximately 60 micrograms/liter) and an early morning maximum (0400-0700 h; approximately 160 micrograms/liter). Superimposed were episodic fluctuations for which powerspectral analysis showed a weakly expressed 30- to 60-min periodicity in 24 of 27 24-h profiles. Cross-correlation analysis indicated no relation between cortisol on the one hand and daytime activity-arousal, nocturnal waking, slow wave sleep (SWS) or rapid eye movement sleep (REM), respectively. Five-hour total sleep deprivation, specific SWS-deprivation, and severe disruption of the REM-pattern provided no evidence for an immediate effect of sleep onset or sleep stages on the cortisol pattern. Cortisol rose significantly after termination of the 5-h deprivation, but the mechanism of this elevation remains to be determined. Cross-correlation analysis between the cortisol time series and those of GH, PRL, and TSH from already published data gave no evidence for a regular temporal relationship between the episodic patterns of these hormones.

Twenty-four-hour pattern of growth hormone secretion in the rhesus monkey: studies including alterations of the sleep/wake and sleep stage cycles.

The 24-h pattern of GH secretion and its possible relation to the sleep/wake cycle and to sleep stages were studied in 12 male rhesus monkeys. Blood samples were drawn every 15 min for 96 h, 24 h, or shorter periods of time through chronic right atrial catheters which extended through the wall into the adjacent room. In addition, activity rating (daytime) and determination of sleep stages from electroencephalogram recordings (nighttime) were done. GH profiles were obtained during undisturbed conditions and during deprivation of nap, 5 h total sleep, slow wave sleep (SWS), and rapid eye movement (REM) sleep. GH secretion was episodic, with peak concentrations often exceeding 20 ngeq/ml and nadirs mostly below 1 ngeq/ml. Autocorrelation analysis demonstrated a circadian and an ultradian rhythm during undisturbed conditions. However, the cycle length of the ultradian rhythm showed large inter- and intraindividual variations (from 3--6 h). Neither cross-correlation analysis between hormonal and activity/electroencephalogram sleep stage time series nor results of deprivation experiments produced evidence for a link between nap phases, the sleep/wake cycle, or the SWS/REM sleep stage cycle on the one hand and the GH secretory pattern on the other hand. However, while SWS deprivation was highly effective, REM deprivation did not substantially reduce total REM sleep time due to frequent entries into abortive REM sleep epochs. During the daytime, there was no significant correlation between activity/arousal and GH, but during the night, there was a significant positive correlation between stage waking and GH. A direct or indirect synchronizing effect of the matutinal light change is suggested by the pattern of the 24-h curve of mean GH concentrations during undisturbed conditions: a steep increase from very low concentrations at light onset, followed by a succession of nadirs and peaks at approximately 4.5-h intervals. However, the nadirs became progressively more shallow until there was no apparent periodicity during the night due to the loss of synchronization. It is concluded that GH in the rhesus monkey shows a circadian and an ultradian periodicity. However, in contrast to man, sleep and SWS are not important determinators of the 24-h GH pattern.

Dose-response study and long term effect of the somatostatin analog octreotide in patients with therapy-resistant acromegaly.

Twelve acromegalic patients in whom standard therapy was unsuccessful were evaluated with 24-h serum GH profiles (hourly sampling) and oral glucose tests (oGTT) while being treated with octreotide, a long-acting somatostatin analog. During a dose-response study (300, 600, and 1500 micrograms/day sc, for 4 weeks), serum GH decreased significantly after 300 micrograms/day in 8 of 12 patients [from 14.5 +/- 6.2 (+/- SE) to 4.9 +/- 1.9 micrograms/L]. Higher doses further reduced serum GH concentrations in 3 (600 micrograms/day) and 1 (1500 micrograms/day) patients, respectively. Four patients did not respond to any dose. Serum GH concentrations declined normally (GH nadir, less than 2 micrograms/L) after glucose ingestion in 4 of the 10 nondiabetic acromegalic patients. In 4 patients, including 2 of the initial nonresponders, serum GH further declined during long term treatment (12 and 18 months). In the latter 2 patients, serum insulin-like growth factor I (IGF-I) concentrations had decreased during the dose-response study despite the absence of measurable GH suppression. Eight patients attained normal serum IGF-I concentrations during treatment. Serum IGF-I and GH correlated significantly before, but not during, treatment. Retrospective comparison suggested that in 5 of 6 patients, serum GH was more effectively suppressed by octreotide than by bromocriptine. The 24-h serum octreotide concentration varied greatly among the patients. Although the 24-h serum octreotide and GH concentrations did not correlate with one another, the serum octreotide and IGF-I concentrations when the patients were receiving 300 micrograms/day tended to be negatively correlated (r = -0.496; P = 0.118). The 24-h serum insulin values decreased and those of glucose increased during treatment; after oral glucose, serum insulin was lower and glucose was higher. However, after 12 months of treatment, the 8-h serum insulin profile and peak serum insulin after oral glucose administration had returned to pretreatment values, while serum glucose remained abnormal. We conclude that 1) octreotide lowers serum GH in many, but not all, acromegalic patients resistant to other forms of treatment; 2) doses in excess of 300 micrograms/day should be tested in those patients in whom lower doses are ineffective; 3) serum IGF-I measurement may be a better indicator of treatment success than GH measurement; 4) octreotide concentrations do not correlate with GH suppression; and 5) deterioration of carbohydrate tolerance does occur but tends to improve during chronic treatment.

Octreotide long term treatment of acromegaly: effect of drug withdrawal on serum growth hormone/insulin-like growth factor-I concentrations and on serum gastrin/24-hour intragastric pH values.

We studied a possible persistence of low GH concentrations after drug withdrawal in eight acromegalic patients who had been receiving octreotide treatment continuously for 42 months. Since octreotide induces chronic active gastritis, intragastric pH and serum gastrin were also determined before and during drug withdrawal. Results were compared to the respective pretreatment (pre-Tx) values. GH and insulin-like growth factor-I (IGF-I) increased after 4 weeks of octreotide withdrawal to pre-Tx values (GH, 12-h profile, 4.5 +/- 0.6, 2.6 +/- 0.7, and 5.6 +/- 1.1 micrograms/L; IGF-I, three samples, 3.4 +/- 0.4, 0.8 +/- 0.1, and 2.5 +/- 1.0 IU x 10(3)/L; means +/- SE, pre-Tx, on and off octreotide). A reduced insulin and augmented glucose response to oral glucose during therapy normalized after octreotide withdrawal (insulin, 527 +/- 84, 289 +/- 62, and 733 +/- 110 pmol/L; glucose, 6.2 +/- 0.3, 8.5 +/- 0.4, and 6.8 +/- 0.2 mmol/L; pre-Tx, on and off octreotide, means +/- SE). During octreotide treatment, the median 24-h intragastric pH value was 2.8 (pre-Tx pH not determined), and the median serum gastrin concentration (areas under the curve of 12-h profiles) was 1275 +/- 153 ng/L.12 h (n = 7). During octreotide withdrawal, pH decreased to 1.4, while serum gastrin increased to a median of 2937 +/- 472 ng/L.12 h. We conclude that GH and IGF-I suppression by long term octreotide therapy does not persist after drug withdrawal, indicating a need for life-long treatment. Octreotide-induced insulin suppression and glucose elevation are reversible. A high gastric pH during treatment may facilitate the development of octreotide-related gastritis. The gastrin increase during octreotide withdrawal probably reflects a response to chronic active gastritis after release from octreotide-induced gastrin inhibition.

Growth hormone, glucagon, and insulin response to depression of plasma free fatty acids and the effect of glucose infusion.

It has previously been shown that nicotinic acid (NA)-induced depression of free fatty acids (FFA) stimulates the secretion of GH and glucagon. To evaluate this hormonal response further, we studied the influence of different doses of glucose administered by continuous iv infusion on the GH and glucagon increase during NA-induced FFA depression. In ten male non-obese volunteers, FFA depression by the infusion of NA (2.3 g over a period of 210 min) resulted in a late rise (from 150 min on) of GH (From 1.1 to 25.9 ng/ml) and an early increase (from 30 min on) of glucagon (from 71.7 to 138.2 pg/ml). When glucose was infused (approximately 60, 120 and 180 g, respectively, over a period of 270 min) during NA-induced FFA depression, the GH rise was reduced and delayed in relation to the amount of glucose infused, but could not be completely abolished (maximal GH concentration during the three NA-plus-glucose infusions: 16.5, 8.0 and 6.1 ng/ml, respectively). The glucagon rise was entirely reversed by the high glucose dose. Insulin did not rise during NA infusion alone. Its secretion in response to glucose infusion was not significantly influenced by FFA depression. Thus, during NA-induced FFA depression the secretion of two lipolytic hormones--GH and glucagon--is stimulated while the secretion of the lipogenetic hormone insulin remains low. Glucose has an inhibitory effect on the GH and glucagon response which, however, is different for each of the hormones.

Influence of ketone body infusion on plasma growth hormone and glucagon in man.

The influence of ketone body infusion on the serum GH and glucagon response to FFA depression and insulin hypoglycemia was investigated in 10 healthy men. Intravenous infusion of nicotinic acid induced suppression of both FFA and ketone bodies. This was accompanied by a delayed GH increase to 21.1 +/- 6.9 ng/ml (at 300 min). During an additional beta-hydroxybutyrate (OHB) infusion, FFA remained depressed, but ketone bodies were elevated, and the GH response was abolished (maximum 5.6 +/- 1.6 ng/ml). During infusion of OHB alone, FFA were suppressed. GH increased significantly, although less markedly than during suppression of both FFA and ketone bodies (to 9.3 +/- 3.1 ng/ml at 270 min). No GH rise occurred when both FFA and ketone bodies were kept elevated by the addition of a lipid infusion. The GH rise in response to insulin hypoglycemia was not changed by an OHB infusion (43.2 +/- 4.6 vs. 48.0 +/- 7.3 ng/ml). However, OHB increased the net GH output by significantly delaying the return to basal concentrations in the presence of a reduced FFA rebound. An effect of OHB infusion on the plasma glucagon concentration during all experiments was small, and its physiological significance is doubtful. These results confirm that FFA depression induces delayed GH secretion. They suggest that this is not wholly dependent on concomitant depression of ketone bodies. On the other hand, when ketone bodies are elevated, the GH response to FFA depression is diminished or absent. The net GH response to changes in lipid substrates probably depends on the concentration of both FFA and ketone bodies.

Gastrointestinal side-effects of octreotide during long-term treatment of acromegaly.

Gastrointestinal side-effects of prolonged therapy (greater than 2 yr) with the long-acting somatostatin analog octreotide were studied in 10 acromegalic patients. After 2 yr of therapy, 6 of 10 patients had newly developed gallstones, complicated by cholangitis and jaundice in 1. Serum vitamin B-12 concentrations declined in all 10 patients [from 380 +/- 32 to 172 +/- 21 pmol/L (mean +/- SE); P = 0.023] and became abnormally low in 4. Gastric biopsy specimens, obtained during gastroscopy (9 patients), showed moderate to severe active gastritis, with damage to the superficial and deeper layers of the mucosa in 9 of 9 and focal atrophy in 7 of 9 patients. Campylobacter pylori was found in the antral mucosa in 8 of 9 patients. Although information is lacking on similar studies in untreated acromegalic patients, we suggest that patients receiving chronic octreotide therapy be closely monitored for these and possible other side-effects related to gastrointestinal actions of octreotide.

Preoperative octreotide treatment of growth hormone-secreting and clinically nonfunctioning pituitary macroadenomas: effect on tumor volume and lack of correlation with immunohistochemistry and somatostatin receptor scintigraphy.

The factors that determine the hormone and volume responses of pituitary adenomas to the somatostatin analog octreotide are poorly understood. We, therefore, studied the correlation between 111indium-pentetreotide somatostatin receptor scintigraphy (SRS) and the clinical and immunohistochemical classification of pituitary adenomas, on the one hand, and hormone and volume responses, on the other hand. Ten patients with GH-secreting (6 females and 4 males; age, 31-67 yr) and 14 patients with clinically nonfunctioning (NF) macroadenomas (5 females and 9 males; age, 22-79 yr) were preoperatively treated with 300 micrograms/day octreotide, which was increased to 600 and 1500 micrograms/day at weekly intervals and then continued for at least 3 months until surgery. SRS was performed before therapy. A sellar magnetic resonance imaging scan was performed before therapy; 1, 2, and 3 weeks and 3 months after start of therapy; and after surgery. Acromegalics also had an 8-h GH profile, insulin-like growth factor-I determination, and a 100-g oral glucose load at these time points. An attempt was made to identify NF adenomas as gonadotroph adenomas using their LH, FSH, and alpha-subunit responses to TRH. In acromegalic patients, octreotide suppressed mean GH (8-h profile) and insulin-like growth factor-I concentrations from 34.9 +/- 9.7 to 8.1 +/- 3.6 micrograms/L and from 2122 +/- 1025 to 701 +/- 208 micrograms/L, respectively, after 3 months. Significant (26-85% decline) tumor shrinkage occurred in 5 of 10 patients, mainly within the first week. Tumor shrinkage and GH suppression were not correlated. Four of 7 patients had increased pituitary 111indium-pentetreotide uptake, but this did not predict GH suppression or tumor shrinkage. Of the NF adenomas, 2 responded with shrinkage (57% and 96% decline). Four of 12 adenomas had increased 111indium-pentetreotide uptake, but this did not correlate with tumor shrinkage (2 adenomas; 1 gonadotroph and 1 null cell adenoma), immunohistochemistry, or clinical classification. We conclude that preoperative octreotide therapy suppresses GH in most patients and reduces tumor volume in up to 50% of acromegalic patients. It also induces shrinkage in some NF adenomas, although less frequently. SRS does not predict shrinkage of either tumor type. Shrinkage does not correlate with clinical classification or immunohistological characteristics. Further studies are needed to identify the factors that determine the hormone and volume responses of pituitary adenomas to octreotide therapy.

Growth hormone, cortisol, and glucagon concentrations during plasma free fatty acid depression: different effects of nicotinic acid and an adenosine derivative (BM 11.189).

Two chemically unrelated inhibitors of lipolysis were used in order to differentiate between the effect of FFA depression and a possible FFA-unrelated drug effect, respectively, on the plasma concentrations of GH, cortisol, and glucagon. Saline infusion served as a control experiment. In eight healthy male volunteers, a similar FFA depression by either iv infusion of nicotinic acid (3-pyridine-carboxylic acid, NA) or oral intake of an adenosine derivative, N(6)-allyl-N(6)-cyclohexyl-adenosine (AD-D), was followed by a significant GH increase (to 22.1 +/- 6.2 and 9.6 +/- 2.9 ng/ml at 240 and 270 min, respectively). Due to the large scatter of the GH concentrations during NA infusion, these responses were not significantly different. No GH increase occurred when the FFA depression was prevented by addition of a lipid infusion. In contrast, plasma cortisol and glucagon both increased significantly (by 107.4 micrograms/liter at 270 min and by 48.4 pg/ml at 60 min, respectively) during NA- but not during AD-D-induced FFA depression. Addition of the lipid infusion abolished the cortisol increase during NA infusion but had no influence on basal cortisol concentrations during AD-D intake. It lowered glucagon to values slightly below basal concentrations when added to the NA infusion and more markedly during AD-D administration. The results provide evidence that 1) depression of plasma FFA per se stimulates the secretion of GH, and 2) the increase of cortisol and glucagon during NA infusion is probably unrelated to the FFA depression. Hence, the stimulatory effect of FFA lack on glucagon secretion needs to be reconsidered.

Plasma glucose and free fatty acids modulate the secretion of growth hormone, but not prolactin, in the rhesus and Java monkey.

In 11 freely moving rhesus and 5 Java monkeys the plasma GH, PRL, and cortisol responses to suppression and elevation of plasma glucose and FFA concentrations were studied. Blood was sampled and infusions given via chronic jugular catheters, extended via a swivel into the adjacent room. In the rhesus monkeys, the mean plasma GH concentration rose during insulin-induced hypoglycemia from 4.7 +/- 1.9 to 17.4 +/- 2.5 micrograms/L at 60 min (P less than 0.001), and the mean plasma cortisol concentration from 320 +/- 55 to 700 +/- 133 nmol/L at 90 min (P less than 0.001). The mean plasma PRL concentration (basal value, 5 +/- 2.3 micrograms/L) did not change significantly. During glucose-induced hyperglycemia, the mean plasma GH concentration oscillated between 2.0-5.2 micrograms/L from 60-360 min (no significant change). Large GH secretory episodes occurred during hyperglycemia in individual animals. During nicotinic acid-induced plasma FFA suppression, the mean plasma GH concentration increased from 3.7 +/- 0.6 to 17.9 +/- 2.3 micrograms/L at 270 min (P less than 0.001). During lipid-induced plasma FFA elevation, the mean plasma GH concentration decreased consistently from 6.5 +/- 1.0 micrograms/L to values between 1.3 +/- 0.2 and 2.6 +/- 0.6 micrograms/L from 60-360 min (P less than 0.01). Plasma PRL and cortisol concentrations were not affected by plasma FFA changes. Compared with the spontaneous plasma GH pattern in a previously studied group of rhesus monkeys, the mean plasma GH concentration was increased during hypoglycemia and plasma FFA suppression. It was strongly suppressed during plasma FFA elevation and slightly suppressed during hyperglycemia. Similar effects were observed in the Java monkeys, although hyperglycemia tests were not performed. We conclude the following. 1) In rhesus and Java monkeys, as in man, GH secretion is stimulated by plasma FFA suppression and is inhibited by plasma FFA elevation. In both species, acute hypoglycemia stimulates the secretion of GH and cortisol. 2) These nonhuman primates differ from man in that hyperglycemia only weakly inhibits GH secretion in the rhesus monkey, if at all (Java monkeys had no hyperglycemia tests), and in neither species does acute hypoglycemia stimulate the secretion of PRL. 3) Both primate species can serve as models for the metabolic modulation of GH secretion in man, although a suppressive effect of hyperglycemia remains to be proven.

Hypothalamic modulation of growth hormone secretion in the rhesus monkey: evidence from intracerebroventricular infusions of glucose, free fatty acid, and ketone bodies.

To evaluate the hypothalamus as a possible site of metabolic modulation of GH secretion, we studied the GH response to insulin hypoglycemia (IHG) and nicotinic acid (NA)-induced FFA depression in the absence and presence of third ventricular (ivt) infusions of glucose, oleic acid (Ol-Ac), or beta-hydroxybutyrate (beta OHB). Four rhesus monkeys had been prepared for chronic remote iv and ivt infusions as well as blood sampling from the adjacent room. Statistical evaluation used a two-way analysis of variance and individual comparisons with Tukey's Studentized range test. The GH response (area under the curve +/- SE) to IHG was significantly reduced by a concomitant ivt glucose infusion (control, 1.0 +/- 0.1; IHG, 12.1 +/- 3.3; IHG plus ivt glucose, 7.0 +/- 1.2 microgram/L.120 min). The GH response to FFA depression was significantly reduced by ivt Ol-Ac or beta OHB infusion (control, 6.0 +/- 1.0; NA, 51.5 +/- 4.1; Na plus Ol-Ac, 81.2 +/- 1.3; NA plus beta OHB, 38.6 +/- 3.5 microgram/L.300 min). Introcerebroventricular infusions of glucose, Ol-Ac, or beta OHB alone had no effect on plasma GH, glucose, FFA, or beta OHB concentrations. These results provide evidence for a hypothalamic site of metabolic modulation of GH secretion in the rhesus monkey. This does not exclude an additional effect directly at the pituitary gland.

Results of somatostatin receptor scintigraphy do not predict pituitary tumor volume- and hormone-response to ocreotide therapy and do not correlate with tumor histology.

The value of somatostatin receptor scintigraphy (SRS) to predict the effect of somatostatin analog therapy on pituitary adenomas is not clear, due to the use of different radiopharmaceuticals (123I-Tyr3-octreotide and 111In-pentetreotide) and the small number of patients in previous studies. We used 111In-pentetreotide scintigraphy in 49 patients in order to (i) correlate SRS results with basal tumor volume as well as volume- and hormone-response to 3 months of octreotide therapy (Oct-Tx). (ii) identify tumor remnants after incomplete surgery and (iii) evaluate any correlation with immuno histology. Twenty-five patients had a GH-secreting adenoma (GH-A, 15 prior to intended surgery, 10 with persistent/recurrent disease after previous therapy). Twenty-four patients had a clinically non-functioning adenoma (NF-A). For SRS, planar and single photon emission computer tomographic images (SPECT) were recorded 4 h and 24 h post injection. SRS grading was as follows: GO, no uptake: G1, uptake comparable to normal pituitary; G2, increased uptake: G3, very intense uptake. G2/3 was seen in 8/25 GH-A and in 12/24 NF-A. Pretreatment tumor volume (magnetic resonance imaging (MRI) tended to be related to 111In-pentetreotide uptake in GH-A with a tumor visible on MRI (G0/1 (n = 10) vs G2/3 (n = 8): 3.6 +/- 1.9 vs 10.5 +/- 6.5 cm3 (mean +/- S.E.), P = 0.051), but not in NF-A (G0/1 (n = 12) vs G2/3 (n = 12): 17.0 +/- 10.1 vs 14.3 +/- 3.6 cm3). SRS did not identify a tumor remnant in the 7 MRI-negative patients with persistent post-operative acromegaly. Basal GH (6-h profile) and IGF-1 in GH-A did not correlate with SRS results (G0/1 (n = 17) vs G2/3 (n = 8), GH: 32.3 +/- 18.2 vs 29.3 +/- 7.4 micrograms/l IGF-I: 851 +/- 80 vs 1038 +/- 153 micrograms/l). During Oct-Tx of GH-A neither tumor shrinkage nor GH suppression was related to SRS results. In 6 NF-A classified as gonadotropinomas (by their plasma glycoprotein hormone or alpha-subunit concentrations, basally and/or in response to TRH) 111In-pentetreotide uptake was not different from that of the non-gonadotropin/non-secreting adenomas. SRS results were not related to the immunohistological subtype in 22 GH-A (monohormonal mixed somatotrope/lactotrope, plurihormonal) or in 22 NF-A (null-cell adenomas, gonadotropinomas silent hormonal adenomas). We conclude that 111In-pentetreotide SRS reflects tumor volume poorly in GH-A and not at all in NF-A. It does not predict the effect of Oct-Tx on the volume of both GH-A and NF-A, nor on the GH concentration in GH-A. 111In-pentetreotide SRS is unable to identify post-operative tumor remnants not visible on MRI.

Effect of the somatostatin analog octreotide on gastric mucosal function and histology during 3 months of preoperative treatment in patients with acromegaly.

OBJECTIVE: To study the effects of the somatostatin analog octreotide on gastric mucosal function and histology during short-term (3 months) preoperative treatment in patients with acromegaly. DESIGN: Open design clinical study. METHODS: 10 patients were studied before treatment with octreotide (pre-tx), on day 1 of 300 microg octreotide/day (d300), after 1 week on 300 (w300), 600 (w600) or 1500 (wl500) microg octreotide/day, and after an additional 2.5 months on 1500 microg octreotide/day (M3). An 8h gastrin profile was obtained and ambulatory intragastric 23h pH-metry carried out at the indicated time points. Gastroscopy was performed at pre-tx and M3 and multiple mucosal biopsy specimens taken. RESULTS: The mean serum gastrin concentration at first declined during octreotide therapy to a nadir at w1500, then recovered despite ongoing therapy (probably in response to reduced gastric acidity) and was similar to pre-tx values at M3 (mean+/-S.E.: 87+/-26, 50+/-11 and 98+/-46ng/l for pre-tx, w1500 and M3 respectively; P<0.05, pre-tx vs w1500). Gastric acidity had also declined at d300(P<0.05, d300 vs pre-tx), then recovered (despite the increase in the octreotide dose), but declined again at M3 (mean pH (95% confidence interval): 2.4 (1.7-3.2), 3.3 (2.4-4.3), 2.6 (1.8-:3.5, n=8) and 2.9 (1.6-4.2, n=7) at pre-tx, d300, w1500 and M3 respectively). The gastrin concentration at M3, although similar to pre-tx values, remained inadequately low for the reduced gastric acidity. The reduction in gastric acidity was marked during the daytime (0900-2200 h; P<0.01, d300 vs pre-tx and P=0.028, M3 vs pre-tx). However, while the stimulated postprandial gastric acid secretion was reduced at d300 (P<0.01, d300 vs pre-tx) and at M3 (n=7; P=0.027, M3 vs pre-tx), fasting and preprandial acidity was not affected. During the night, gastric acidity was reduced from 2200 to 0300 h, but the reduction was less marked than during the daytime. Paradoxically, the physiological intermittent late nocturnal reduction in acidity ('pH peaks' (0300-0800 h)) was abolished rather than enhanced. No patient acquired new Helicobacter pylori infection. The mean gastritis scores for antrum and body (n=8, Sidney classification) increased marginally from 1.7 to 1.9 (chronicity) and from 0.7 to 0.9 (atrophy), while the activity score was slightly reduced from 1.2 to 1.0. CONCLUSIONS: Three months of preoperative octreotide treatment profoundly and persistently altered gastric mucosal function (gastrin suppression, reduced acidity), but caused only minor variations in the pre-existing gastritis scores.

Octreotide suppresses the incretin glucagon-like peptide (7-36) amide in patients with acromegaly or clinically nonfunctioning pituitary tumors and in healthy subjects.

OBJECTIVE: To study the effect of octreotide on glucagon-like peptide (7-36) amide (GLP-1) and insulin secretion in patients with pituitary tumors during preoperative treatment and in healthy subjects. DESIGN: Open design prospective clinical study. METHODS: Eighteen patients with pituitary macroadenomas (13 clinically nonfunctioning (NFA; 11/13 had GH insufficiency), 5 GH secreting (GHA)) received preoperative octreotide treatment: 3x100 microg/day s. c. for 3 months, and 3x500 microg/day s.c. for an additional 3 months. Seven healthy subjects received (for ethical reasons) only 3x100 microg/day for 10 days. A standardized meal (St-M) test, oral glucose test (oGTT) and i.v. glucose test (ivGTT) were done before octreotide therapy, on days 1, 2 and 3 (D1,2,3), after 3 months (M3) and 6 months (M6) of octreotide treatment in the patients, and before treatment, on D1,2,3 and on D8,9,10 of octreotide treatment in the healthy subjects. Serum GLP-1, insulin and GH as well as plasma glucose were determined for 180 min (oGTT, St-M) or 120 min (ivGTT). RESULTS: Pretreatment fasting GLP-1 concentrations as well as integrated responses (area under the curve 0-180 min) to oGTT and St-M were not significantly different between NFA, GHA and healthy subjects. During the oGTT, octreotide initially almost abolished the early (0-60 min) and diminished the late (60-180 min) GLP-1 and insulin responses in patients and healthy subjects. At M6 integrated insulin responses had significantly recovered, while the increase in GLP-1 response failed to reach significance (GLP-1: 56.5% of pretreatment at D2 versus 93.5% at M6 and 41.2 versus 63.1% in NFA and GHA respectively; insulin: 50.2 versus 71.2% and 35.5 versus 70. 4%). An escape of GLP-1 and insulin in healthy subjects (D2 versus D9) was not significant. Intestinal glucose absorption was apparently not reduced, since the early glucose rise was similar before and during octreotide treatment. During the St-M the GLP-1 and insulin responses were similarly suppressed by octreotide and recovered during ongoing treatment (GLP-1: 49.6% of pretreatment at D1 versus 79.0% at M6 in NFA and 46.9 versus 52.9% in GHA. Insulin: 27.6 versus 83.9% and 23.5 versus 54.4%). The escape was significant in NFA but not in GHA. In the healthy subjects the escape was already significant on D8 (GLP-1: 39.5% of pretreatment at D1 versus 68.3% at D8; insulin: 36.6 versus 53.8%). During the ivGTT GLP-1 did not increase. The early insulin response (0-30 min) was abolished by octreotide, followed by a reduced peak at 60 min. The reduction of the integrated insulin response during ivGTT was similar to that during oGTT. An insulin escape reached significance only for NFA (52. 6% of pretreatment at D3 versus 66.7% at M6). Glucose tolerance (KG value) deteriorated and did not improve during ongoing treatment. Octreotide suppressed the median GH concentration (8h profile) of the GHA patients from 10.3 microg/l (pretreatment) to 5.8, 6.3 and 3. 7 microg/l at D4, M3 and M6 with no escape. GH was 1.5 microg/l postoperatively. CONCLUSIONS: Octreotide abolishes the early and diminishes the late GLP-1 and insulin responses to oGTT and St-M in NFA and GHA patients and in healthy subjects. In contrast to GH, both hormones partially escape from suppression during ongoing therapy. During treatment with our conventional octreotide doses suppression of insulin secretion is maximal. Under these conditions an effect of the additional loss of GLP-1 is not apparent. Basal GLP-1 concentrations and integrated responses to oGTT and St-M were similar in healthy subjects and in patients with GH excess or GH insufficiency.