Criteria for the cure of acromegaly: comparison between basal growth hormone and somatomedin C plasma concentrations in active and non-active acromegalic patients

Fasting plasma growth hormone (GH) and somatomedin C (SmC) levels were compared as criteria for the cure of acromegaly in 7 untreated and 16 treated acromegalic patients studied 1 to 16 yr after pituitary surgery and/or radiotherapy. The patients without active disease presented a significant correlation between GH and SmC. Only when basal GH was lower than 2.5 ng/ml were SmC values within the normal range. The subjects with active acromegaly (both treated and untreated) presenting GH higher than 5 ng/ml did not show any correlation between GH and SmC levels.     

Serum type III procollagen propeptide levels in acromegalic patients

Serum type III procollagen propeptide (PIIIP) is a reliable index of tissue collagen synthesis. Since in acromegaly there is increased collagen production, we measured serum PIIIP in acromegalic patients before any treatment (basal), during medical treatment with the somatostatin analog SMS 201-995, and after pituitary adenomectomy. In all patients, serum GH and plasma somatomedin-C (SmC) levels were also measured. Basal serum PIIIP levels were significantly (P less than 0.01) higher in acromegalic patients (mean +/- SEM, 22.7 +/- 2.1 ng/ml) than in normal subjects (n = 30; 9.7 +/- 0.5 ng/ml), and they were significantly correlated with plasma SmC values (r = 0.31; P less than 0.05). A significant (P less than 0.01) reduction in PIIIP levels occurred in patients treated with SMS 201-995 or surgery (from 24.3 +/- 2.7 to 12.4 +/- 1 ng/ml) as well as in GH and SmC levels. The maximum percent decrease in serum PIIIP was significantly correlated with those in GH (r = 0.65; P less than 0.01) and SmC (r = 0.60; P less than 0.01). Serum PIIIP levels did not change in those patients in whom neither GH nor SmC were decreased by treatment. In conclusion, serum PIIIP levels are elevated in acromegalic patients, and they decline in parallel with GH and SmC during medical or surgical treatment. Serum PIIIP measurements may be useful in the evaluation of acromegalic patients to gain information on the biological activity of GH and in monitoring the course of the disease.     

Plasma insulin-like growth factor-I/somatomedin-C in acromegaly: correlation with the degree of growth hormone hypersecretion

We measured plasma insulin-like growth factor I/somatomedin-C (IGF-I/SmC) concentrations and mean 24-h GH secretion serially before and during therapy with the long-acting somatostatin analog SMS 201-995 in 21 patients with acromegaly. When mean plasma GH was elevated above 12.0 +/- 0.6 (+/- SE) micrograms/L, plasma IGF-I/SmC concentrations were uniformly high, but a decline of mean plasma GH below this value was accompanied by a linear decrease in IGF-I/SmC concentrations (r = 0.89; P less than 0.001). Even mildly abnormal mean GH concentrations (greater than 4.6 but less than 10 micrograms/L) were accompanied by high plasma IGF-I/SmC values. The log dose-response interrelation between mean 24-h plasma GH and IGF-I/SmC concentrations was linear (r = 0.86; P less than 0.001). We conclude that 1) an excellent log dose-response correlation between mean 24-h plasma GH and IGF-I/SmC concentrations is present in patients with acromegaly; 2) normalization of plasma IGF-I/SmC occurs only in patients with mean daily GH output within the normal range; and 3) determination of plasma IGF-I/SmC is an accurate indicator of normalcy of GH secretion and should be used in the diagnosis of active acromegaly as well as in monitoring the progress of therapy.     

Changes in plasma GH levels and clinical activity during bromocriptine therapy in acromegaly. The value of predictive tests

Twenty-seven patients with active acromegaly despite previous treatment by surgery and/or radiotherapy received bromocriptine in a dose of 10-20 mg daily for a period of 6-9 months. The results of chronic bromocriptine treatment were evaluated by measurement of plasma growth hormone (GH) levels during the day and by subjective and objective criteria of clinical activity. The results of chronic bromocriptine treatment were also compared with four biochemical criteria obtained before treatment e.g. basal plasma prolactin (Prl) levels and the plasma GH response to oral administration of 2.5 mg bromocriptine respectively iv administration of 200 micrograms TRH and 500 micrograms somatostatin. The main observations may be summarized as follows: 1) The mean pre-treatment GH levels during the day ranged from 6-207 mU/1. Hyperprolactinaemia was present in 6 patients. 2) During bromocriptine treatment mean plasma GH levels decreased to less than 50% in 11 patients (GH responders) whereas in 19 patients changes of mean plasma GH and of subjective criteria of clinical activity were concordant. 3) Glucose tolerance improved significantly (P less than 0.01) in 10 GH-responders and the urinary hydroxyproline/creatinine ratio decreased significantly (P less than 0.05) in 8 GH-responders. 4) Five out of 6 patients with hyperprolactinaemia belonged to the group of GH-responders. 5) A single dose of 2.5 mg bromocriptine induced a more than 50% decrease of plasma GH in 8 of 11 GH-responders and in 5 of 16 GH non-responders.(ABSTRACT TRUNCATED AT 250 WORDS)     

Somatotroph responsiveness to low dose dopamine infusion in normal subjects and acromegalic patients

We have investigated the effects of intravenous administration of a low dose of dopamine (DA) on plasma growth hormone (GH) concentrations in acromegalic patients and normal subjects with the aim of defining the somatotroph responsiveness to peripheral (i.e., outside the blood-brain barrier) specific dopaminergic stimuli. DA (0.02 micrograms/kg/min) was infused for 180 min into 12 acromegalic patients and 10 normal subjects. DA infusion discriminated between two groups of acromegalics. In group I (n = 7), the elevated plasma GH levels (64.1 +/- 29.9 ng/ml, mean basal value +/- SEM) decreased significantly (mean overall GH inhibition, 26% reduction from basal levels; range, 10-49), whereas in group II (n = 5) plasma GH levels (29.8 +/- 12.5 ng/ml) remained elevated (mean GH variation, 8% above baseline; range, 0-15). Plasma GH concentrations showed a significant rebound above baseline values after stopping DA infusion only in group I. In contrast, the responsiveness to TRH was not significantly different between the groups (percentage increase 767 +/- 317% in group I vs. 382 +/- 210% in group II) and they were also comparable with regard to sex, age, glucose tolerance, plasma prolactin (PRL) concentrations and adenoma size. However, the mean duration of the disease was significantly (p less than 0.02) longer in group I (12.8 +/- 2.6 years) than in group II (4.5 +/- 1.5 years). Further, 3 patients with previous radiotherapy for invasive adenomas were nonresponders to DA. In normal subjects, DA infusion had no significant effect on plasma GH levels. It is concluded that: somatotroph responsiveness to DA is not a constant feature of acromegaly.(ABSTRACT TRUNCATED AT 250 WORDS)     

The pulsatile GH secretion in acromegaly: Hypothalamic or pituitary origin?*

OBJECTIVE: We studied the effects of different modes of octreotide therapy on the pulsatile pattern of GH release in an attempt to define better its regulation by growth hormone-releasing hormone (GHRH) and somatostatin and its effects on IGF-I plasma levels in acromegaly. DESIGN: In six acromegalic patients not cured by previous treatment we compared the 24-hour GH secretion profiles under basal conditions with subcutaneous (s.c.) bolus injections of 100 micrograms octreotide every 8 hours and with continuous s.c. infusions of the same daily dose. Blood samples were taken every 10 minutes over 24 hours followed by a GHRH test (100 micrograms GHRH i.v.) with blood sampling every 15 minutes for another 2 hours. After a 4-week interval all patients were treated either by the bolus or continuous mode of octreotide application in a randomized cross-over design. On day 4 of treatment blood sampling and GHRH test were repeated. Octreotide treatment was withdrawn for another 4 weeks; all patients then received the alternate application mode and were measured under similar conditions. MEASUREMENTS: Serum GH and plasma IGF-I concentrations were analysed by serial array averaging. IGF-I levels were measured in two different assays with and without previous protein extraction. For GH pulse detection three different algorithms (Cluster, Pulsar, Desade) were applied. RESULTS: With both treatments, the initially elevated basal 24-hour mean serum GH concentrations (58.0 +/- 9.7 mU/l mean +/- SEM) decreased significantly (bolus: 11.5 +/- 4.9 mU/l, P < 0.001 vs basal; continuous infusion: 7.6 +/- 1.9 mU/l, P < 0.001 vs basal) after 4 days. GH suppression was significantly more pronounced following continuous infusion than bolus (P < 0.05). IGF-I plasma concentrations were lowered significantly (P < 0.05) with both forms of treatment which did not differ between themselves. Bolus and continuous infusion treatment significantly inhibited (P < 0.05) the amplitudes of pulsatile GH release, but did not change the pulse frequency. In two of the patients, GHRH stimulation did not increase GH serum levels suggesting a constitutive activation of adenylyl cyclase. CONCLUSION: Continuous subcutaneous octreotide treatment in acromegaly suppresses mean GH levels better than bolus injection. The number of GH pulses remains unaffected by both modes of treatment providing evidence against a somatostatinergic mechanism of pulsatile GH secretion in these patients. The unchanged frequency of pulsatile GH release in the patients unresponsive to exogenous GHRH indicates that this pattern might be independent of hypothalamic GHRH and somatostatin and suggests a pituitary-derived mechanism for GH pulse generation in acromegaly.     

Effect of oral administration of L-dopa on the plasma levels of growth hormone-releasing hormone (GHRH) in normal subjects and patients with various endocrine and metabolic diseases

The responses of plasma growth hormone-releasing hormone (GHRH) and growth hormone (GH) to oral administration of L-dopa were studied in normal subjects and patients with various endocrine and metabolic diseases to clarify the pathophysiological role of the GHRH-GH axis. In normal subjects, the plasma GHRH concentration was increased from the basal value of 9.8 +/- 1.4 pg/ml (mean +/- SE) to 34.8 +/- 3.1 pg/ml at 30 approximately 90 min after oral administration of 500 mg L-dopa, followed by a rise of GH release (plasma GH level from less than 1 ng/ml to 21.7 +/- 4.7 ng/ml) in most cases, indicating that L-dopa stimulates GH secretion via hypothalamic GHRH. On L-dopa administration, no apparent increases in both plasma GHRH and GH concentrations were observed in patients with hypothalamic hypopituitarism, whereas GHRH administration induced almost normal GH response. In patients with acromegaly, the plasma levels of GHRH remained stationary after the L-dopa administration and did not correlate with plasma GH levels. In subjects with simple obesity, the responses of plasma GHRH (peak 13.2 +/- 1.2 pg/ml) and GH (peak 4.3 +/- 1.7 ng/ml) to L-dopa were significantly lower than those in normal subjects (p less than 0.01). In patients with primary hypothyroidism, peak levels of plasma GHRH (12.6 +/- 1.3 pg/ml) and GH (2.4 +/- 0.6 ng/ml) were significantly lower than those in normal subjects (p less than 0.01). In patients with non-insulin dependent diabetes mellitus (NIDDM), the responses of GHRH and GH were divided into 2 groups; in the responder the peak values of GHRH and GH were 19.4 +/- 8.6 pg/ml and 12.2 +/- 1.4 ng/ml and in the low or non responder 14.7 +/- 1.5 pg/ml and 2.0 +/- 0.6 ng/ml, respectively. Between both groups, there was a significant difference in the values of fasting blood sugar and HbA1 and mean suffering period. These findings suggest that GH secretion evoked by the L-dopa administration is induced by GHRH released from the hypothalamus, and impairment of GH secretion associated with simple obesity, primary hypothyroidism, or NIDDM may be in part attributed to insufficiency of GHRH release from the hypothalamus, and indicate that L-dopa test is clinically useful for evaluating the ability of intrinsic GHRH release in such diseased states.     

GROWTH HORMONE RESPONSIVENESS TO HUMAN PANCREATIC GROWTH HORMONE RELEASING FACTOR IN ACROMEGALY: MODULATORY EFFECTS OF BASAL HORMONE LEVELS AND OF CONCOMITANT SOMATOSTATIN ADMINISTRATION

Human pancreatic growth hormone releasing factor 1-44 (hpGRF), 100 micrograms was administered as an i.v. bolus injection to eleven patients with acromegaly. The mean serum growth hormone (GH) levels rose (P less than 0.001) from 54 +/- 20 ng/ml to 215 +/- 126 ng/ml (+/- SEM) 20 min after the injection. Although the maximum response of GH levels was highly variable it correlated positively with the individual GH levels (P less than 0.01, Rs = +0.80). Thus the higher the GH levels, the greater the responsiveness to hpGRF. Administration of somatostatin (SRIF), 300 micrograms/h, lowered basal GH levels from 76 +/- 38 ng/ml to 13 +/- 5 ng/ml (P less than 0.01) after 1 h. hpGRF administration during concomitant SRIF infusion also led to highly variable growth hormone responses. The maximum GH responses again correlated positively with the GH level before hpGRF after 1 h of SRIF administration (P less than 0.05, Rs = +0.79). GH responses to hpGRF were completely blocked by SRIF in three out of four patients whose GH levels decreased to normal levels during SRIF infusion. Our data illustrate that the pituitary in acromegaly is normally responsive to both SRIF and hpGRF but at a higher setting of basal GH levels.     

A COMPARISON OF THE EFFECT OF LEVODOPA AND SOMATOSTATIN ON THE PLASMA LEVELS OF GROWTH HORMONE, INSULIN, GLUCAGON AND PROLACTIN IN ACROMEGALY

The acute suppressive effects of L-dopa and somatostatin (growth hormone release inhibiting hormone) on the elevated plasma GH concentrations of seven patients with acromegaly were compared. In addition the effects of the two agents on fasting concentrations of plasma glucose, insulin, glucagon and prolactin were studied. In six of the seven patients hourly samples for GH assay were taken from 08.00 to 20.00 hours on a control day. Synthetic cyclic somatostatin (100 mug) was infused intravenously in an albumin/saline solution over 75 min with a Harvard constant infusion pump. Levodopa 500 mg was given orally. Somatostatin infusion produced a reduction in plasma GH concentrations in six of seven patients (mean reduction 55%). L-Dopa produced a reduction in plasma GH concentrations in the same six patients (mean reduction 52%). The minimum GH concentrations achieved in the two tests were comparable and did not differ significantly from the minimum GH concentrations recorded during the 12 h control study. Mean plasma insulin and glucagon concentrations were also significantly reduced during the somatostatin infusion (P less than 0-025; P less than 0-05 respectively). Plasma glucose concentrations did not change. L-Dopa did not alter mean plasma glucose, insulin or glucagon values. Somatostatin did not alter prolactin values but L-Dopa suppressed basal values to less than 2 ng/ml in five patients. This study shows that the plasma GH change after the administration of L-dopa and somatostatin in acromegaly is comparable and confirms the pancreatic effects of somatostatin.     

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

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 microgram/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.(ABSTRACT TRUNCATED AT 250 WORDS)     

Pituitary adenocarcinoma in an acromegalic patient: response to bromocriptine and pituitary testing: a review of the literature on 36 cases of pituitary carcinoma

There are 36 reported cases of metastatic pituitary carcinoma and almost half (44%) of these were associated with syndromes of hormonal hypersecretion. The case of a 56-year-old acromegalic man with cervical lymphatic and spinal metastases from a primary pituitary carcinoma is described. Elevated basal levels of plasma growth hormone (GH) and insulin growth factor-1/Somatomedin C (IGF-1/SmC) were found. GH levels did not increase after TRH or LHRH administration but decreased after L-Dopa and glucose. Immunostaining of the metastatic tumor for GH and electron microscopy findings confirmed the diagnosis of pituitary GH-secreting carcinoma. Striking clinical improvement and a 46% decrease in plasma GH levels were observed with bromocriptine treatment, although IGF-1/SmC levels increased during therapy. The clinical course of most reported cases of pituitary adenocarcinoma has been one of progressive intracranial expansion of a pituitary neoplasm. In only 25% were metastatic lesions discovered antemortem, and disabling symptomatology caused by metastases was rare. Only four previously reported patients of 36 with pituitary carcinoma had acromegaly.     

EFFECT OF OCTAPEPTIDE SOMATOSTATIN ANALOGUE (SMS 201-995) ON PLASMA 7B2 (A NEUROENDOCRINE POLYPEPTIDE) LEVELS IN PATIENTS WITH ACROMEGALY

We studied the sequential changes of plasma levels of immunoreactive '7B2' (IR-7B2), a neuroendocrine polypeptide, after a subcutaneous injection of 50 micrograms of synthetic octapeptide somatostatin analogue (SMS 201-995) in seven patients with acromegaly due to GH-producing pituitary adenoma. Compared to the basal levels, mean plasma IR-7B2 and GH levels significantly decreased, until 5 and 10 h respectively after the administration of SMS 201-995. The mean (+/- SEM) nadir levels of plasma IR-7B2 and GH were 68.1 +/- 10.1 and 13.1 +/- 6.9%, respectively, compared to mean plasma levels before treatment (100%). Plasma IR-7B2 as well as GH levels did not change significantly when saline was administered subcutaneously to three acromegalic patients. In addition, plasma IR-7B2 levels did not change significantly after the administration of SMS 201-995 in normal subjects or in patients with primary hypothyroidism in whom SMS 201-995 induced a decrease of plasma TSH levels. These results strongly suggest that SMS 201-995 has an unequivocal suppressive effect on the synthesis and/or the secretion of 7B2 in human somatotroph adenoma cells.     

Effects of theophylline infusion on the growth hormone (GH) and prolactin response to GH-releasing hormone administration in acromegaly

Since theophylline has been shown to blunt the GH response to growth hormone-releasing hormone (GHRH) in normal subjects, we investigated whether the same effect of theophylline administration could be reproduced in patients with active acromegaly. Ten acromegalic patients received on two different days 100 micrograms GHRH iv alone and the same GHRH dose during a constant infusion of theophylline (3.56 mg/min), beginning 2 h before GHRH administration. In the whole group theophylline did not affect basal GH secretion significantly (from a mean of 44.6 +/- 14.4 at 0 min to 41.8 +/- 13.5 ng/ml at 120 min). However, the amount of GH released after GHRH stimulation was lower when theophylline was concomitantly infused (7525 +/- 3709 ng min/ml vs. 12038 +/- 6337 ng min/ml; p less than 0.05). The inhibitory effect of theophylline was not homogeneous, since either marked or minimal reductions of the GHRH-stimulated GH secretion occurred. Serum PRL levels increased after GHRH administration in 6 patients and theophylline infusion had no influence upon this response. Peak GHRH levels were not different in both studies (14.9 +/- 1.7 and 17.1 +/- 4.0 ng/ml, respectively). Free fatty acid levels rose progressively during theophylline administration (from 0.66 +/- 0.10 at 0 min to 1.04 +/- 0.10 mEq/l at 240 min) and were significantly higher than after GHRH stimulation alone from 180 min up to the end of the test. Our results demonstrate that in active acromegaly theophylline blunts the GH response to GHRH, though this effect is not uniformly seen in all patients.(ABSTRACT TRUNCATED AT 250 WORDS)     

The GH-releasing hormone (GHRH) test in acromegaly before and after adenomectomy

The GHRH test may represent a new tool in the study of GH dynamics in acromegaly. GH responsiveness to GHRH 1-40 (50 micrograms iv) has been studied in 21 acromegalic patients. Nineteen out of 21 had active disease. Five patients were also studied 1-12 months after neurosurgery. Two apparently cured acromegalics were studied 1-2 yr after surgery. GH secretion has been evaluated in all patients by means of TRH, bromocriptine and insulin hypoglycemia tests, too. GH response to GHRH has also been performed in 14 normal subjects. In acromegaly, GH responses after GHRH (p less than 0.01 vs placebo) were variable. The GH peak ranged from 8 to 445 ng/ml in patients with active disease. Maximum GH increase after GHRH (calculated as peak/basal value ratio) was significantly reduced in acromegaly (2.9 +/- 0.5 ng/ml; mean +/- SE) in comparison to controls (34.1 +/- 10.9 ng/ml; p less than 0.01). No significant differences in GH pattern after GHRH were found between untreated and previously treated patients with active disease. A significant correlation was found between GH basal levels and GH incremental area (p less than 0.05) and between GH basal and peak levels (p less than 0.01) after GHRH. A significant increase in PRL secretion was observed in acromegalic patients after GHRH (p less than 0.01 vs placebo). No discernable variation was found in the other pituitary hormones pattern after the peptide administration. A positive correlation was observed between GH increase after GHRH and insulin hypoglycemia (p less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)     

Primary hypothyroidism in dogs is associated with elevated GH release

The pulsatile secretion patterns of GH were investigated in seven beagle bitches by collecting blood samples every 10 min for 6 h during euthyroidism and 1.5 years after induction of primary hypothyroidism. Hypothyroidism was induced by surgical removal of the thyroid gland and subsequent destruction of any remnant thyroid tissue by oral administration of sodium [(131)I]iodide. Some of the physical changes observed in the dogs with primary hypothyroidism mimicked those of acromegaly. During both euthyroidism and hypothyroidism GH was secreted in a pulsatile fashion. The mean (+/-s.e.m. ) basal plasma GH concentration was significantly higher (P=0.003) in the hypothyroid state (4.1+/-1.6 microg/l) than in the euthyroid state (1.2+/-0.4 microg/l). Likewise, the mean area under the curve (AUC) for GH above the zero-level during hypothyroidism (27.0+/-10.0 microg/lx6 h) was significantly higher (P=0.004) than that during euthyroidism (11.7+/-2.0 microg/l x 6 h). The mean AUC for GH above the baseline was significantly lower (P=0.008) during hypothyroidism (2.4+/-0.8 microg/l x 6 h) than during euthyroidism (4.5+/-1.8 microg/lx6 h), whereas there was no significant difference in GH pulse frequency. The mean plasma IGF-I level was significantly higher (P<0.01) in the hypothyroid state (169+/-45 microg/l) than in the euthyroid (97+/-15 microg/l). The results of this study demonstrate that primary hypothyroidism in dogs is associated with elevated basal GH secretion and less GH secreted in pulses. This elevated GH secretion has endocrine significance as illustrated by elevated plasma IGF-I levels and some physical changes mimicking acromegaly. It is discussed that the increased GH release in hypothyroid dogs may be the result of the absence of a response element for thyroid hormone within the canine pituitary GH gene and alterations in supra-pituitary regulation.     

Pulsatile growth hormone secretion in patients with acromegaly and normal men: the effects of growth hormone-releasing hormone infusion

Twenty-four GH secretory patterns were studied before and during continuous infusions of GHRH in six patients with active acromegaly and in six normal adult men. GH release was episodic in both groups. Control subjects showed a normal diurnal variation in GH release, with the majority of GH released at night (2200-0800 h); mean levels were 1.5 +/- 0.4 (SE) ng/mL (day) and 4.2 +/- 0.8 ng/mL (night). Acromegalics had no diurnal variation in GH; levels were 45.3 +/- 13.7 ng/mL (day) and 39.8 +/- 12.2 ng/mL (night). Acromegalics demonstrated an increased frequency of GH pulses compared to normals (11.8 +/- 0.8 vs. 2.2 +/- 0.3/24 h). During continuous 24-h infusions of GHRH, the normal subjects continued to show a diurnal variation in GH release, but GH pulse frequency increased to a rate (11.7 +/- 1.4 pulses/24 h) very similar to that of the patients with acromegaly. In contrast, GHRH infusion did not alter the GH pulse frequency in the acromegalics. GHRH increased the mean levels of GH in both groups (patients 80.2 +/- 20.3 vs. 41.0 +/- 12.1 ng/mL, x +/- SE. P less than 0.05; controls 10.2 +/- 2.0 vs. 3.33 +/- 0.5 ng/mL, P less than 0.01). Some of the patients with acromegaly showed a progressive decline in GH levels during the infusion period, suggesting desensitization or exhaustion of releaseable stores; however, GH levels remained above basal values in all patients. After the 24-h GHRH infusions, the GH response to a bolus of GHRH was diminished in the normal subjects (2.1 +/- 0.9 vs. 16.8 +/- 5 ng/mL, x +/- SE; P less than 0.01) but not in the acromegalic patients (30.2 +/- 8.9 vs. 35.5 +/- 12.5 ng/mL; NS). These results indicate that GH release is episodic under basal conditions and during continuous GHRH infusion in both acromegalic and normal subjects, indicating the importance of other modulators of GH release, such as somatostatin, which may remain pulsatile even in acromegaly.     

Somatostatin, insulin and glucagon after arginine stimulation in active and treated acromegaly

Ten acromegalic patients, 28-71 years old, were compared with 10 normal controls, 21-39 years old. In another study, 7 patients with active acromegaly, 19-70 years old, were investigated before and 4-9 months following transsphenoidal adenectomy and radiation. They were all investigated following an arginine infusion (0.5 g/kg/20 min). Although the mean plasma somatostatin (somatotrophin release inhibiting factor (SRIF] was somewhat higher in acromegalic patients compared to normal controls (mean basal values 21 +/- 3.8 and 16.6 +/- 2.1 pmol/l, respectively), the difference was not significant. The patients had higher serum insulin (peak values 118 +/- 23.9 and 63 +/- 11.8 mU/l, respectively) and lower plasma glucagon (peak values 171 +/- 29.0 and 310 +/- 52.7 pmol/l, respectively). Plasma SRIF increased during arginine infusion, but the concentrations were similar before and following the operation (mean basal values 18.2 +/- 2.6 and 15.2 +/- 2.3 pmol/l, respectively). Serum insulin was significantly higher before the operation (peak values 154 +/- 38.8 and 91 +/- 24.9 mU/l, respectively). Plasma glucagon was similar before and after the operation (peak values 143 +/- 23.4 and 127 +/- 22.7 pmol/l, respectively). Plasma SRIF is similar in active acromegaly and normal controls, and in acromegaly before and following treatment, despite differences in serum growth hormone (GH), serum insulin and plasma glucagon. This points towards a modulating role for GH on plasma SRIF, possibly by affecting the other islet cell hormones.     

A long-term dose-response study of somatostatin analogue (SMS 201-995, octreotide) in resistant acromegaly

Ten acromegalic subjects were studied in a trial designed to ascertain the optimum dosage of the somatostatin analogue SMS 201-995 (octreotide) in active acromegaly. Twenty-four-hour growth hormone (GH) profiles were assessed monthly for 6 months and again after 1 year of continuous therapy. After basal assessment octreotide was administered subcutaneously at a dose of 100 micrograms three times a day throughout the first month. The dose was increased by 300 micrograms/day at monthly intervals to a maximum of 1500 micrograms/day, unless serum GH fell to within set criteria. Eight patients completed the trial. One patient withdrew because of intractable diarrhoea while another died of causes related to his acromegaly and we have no evidence that octreotide played any part in his death. Mean 24-h GH fell from a basal level of 34.3 +/- SEM 7.6 mU/l to 8.0 +/- 1.3 mU/l (P less than 0.05) after 6 months. At 1 month (300 micrograms/day) mean GH was 13.6 +/- 2.2 mU/l and at 2 months (600 micrograms/day) 10.8 +/- 2.2 mU/l (P less than 0.05 vs 300 micrograms/day dose), and at 5 months (1500 micrograms/day) 11.3 +/- 2.0 mU/l (all P less than 0.05 vs basal). Analysis of group means revealed no significant difference between any dose schedules above 600 micrograms/day. After 1 year the mean GH of the group (n = 8) was 7.5 +/- 1.3 mU/l (P less than 0.05 vs basal). Three patients developed a deterioration and one an improvement in their glucose tolerance and three developed asymptomatic gallstones during the year of therapy. In conclusion, octreotide lowered GH levels in acromegaly over a 1-year period. We found no evidence that routinely increasing the dose beyond 600 micrograms/day was helpful.     

Effects of growth hormone-releasing factor on growth hormone secretion in acromegaly

Twenty-nine patients with acromegaly (8 untreated and 21 previously treated in various ways) and 16 normal men were given iv bolus doses of human pancreatic tumor GH-releasing factor (hpGRF-40). Twenty-five of the 29 patients responded to hpGRF-40 with elevations of plasma GH. The magnitude of the responses varied widely. Responses of untreated patients were generally similar to those of the normal subjects. Previously treated patients had a significantly lower response than normal individuals [change in GH, 7.5 +/- 1.8 vs. 42.0 +/- 11.0 ng/ml (mean +/- SEM); P less than 0.01], and 4 patients who had received radiation therapy failed to respond to hpGRF-40. There was no significant correlation between the magnitude of the response and patients' age, sex, baseline GH levels, GH responsiveness of TRH, or GH suppression after oral glucose administration. Patients studied both pre- and postoperatively were responsive to hpGRF-40 at all times tested, but the magnitude of the response decreased after successful surgical removal of the adenoma. Thus, most patients with treated or untreated acromegaly respond to hpGRF-40, but their responses do not clearly distinguish them from normal subjects. GH-releasing hormone testing is unlikely to replace other endocrine tests available for the diagnosis and evaluation of acromegaly.     

Short term treatment of acromegaly with the somatostatin analog octreotide: the first double-blind randomized placebo-controlled study on its effects

Several studies suggest that the somatostatin analog octreotide, or SMS 201-995, may effectively reduce GH hypersecretion. However, no double blind, placebo-controlled study has substantiated these findings. We present the results of a randomized double blind 14-day clinical trial with octreotide in 20 patients with acromegaly. The drug was given sc every 8 h and to the initial dose (50 micrograms) was added another 50 micrograms every other day up to 200 micrograms. GH levels, calculated as the mean values of 12 observations at hourly intervals during 0700-1800 h, and insulin-like growth factor-I (IGF-I) levels were significantly reduced during octreotide treatment. Responses varied from a reduction of 97% of the basal mean GH level to no significant reduction in 2 of 10 patients. There was a good correlation between the reduction of GH and IGF-I levels. The main side-effects were gastrointestinal and well tolerated. We found a spontaneous variation of daily mean GH and IGF-I levels (at 0700 h) in the placebo group, ranging from approximately 150% to 50% of the GH and 120% to 80% of the IGF-I levels noted on day 0. In patients treated with octreotide, the occurrence of GH rises between administration times suggests that it may be desirable to give octreotide every 6 h in some patients.