EFFECT OF SMS 201–995, A LONG-ACTING SOMATOSTATIN ANALOGUE, ON THE SECRETION AND MORPHOLOGY OF A PITUITARY GROWTH HORMONE CELL ADENOMA

The present study reports the effects of SMS 201-995, a long-acting somatostatin analogue, on blood GH levels, glucose tolerance and tumour morphology in a 36-year-old, previously untreated acromegalic woman. Treatment (50 micrograms s.c., 8-hourly) resulted in marked suppression of GH concentration and an improvement in glucose tolerance. After 10 d of treatment, the tumour was removed by transsphenoidal surgery and studied by histology, immunohistochemistry, transmission electron microscopy and morphometry. Histologically, the tumour was an acidophilic adenoma which contained immunoreactive GH in many adenoma cells. By electron microscopy, the tumour was composed of densely granulated somatotrophs containing numerous large secretory granules and many lysosomes showing crinophagy. No cell necrosis or vascular impairment were evident. Using morphometry, the tumour was compared with 10 densely granulated somatotroph adenomas, removed from acromegalic patients not treated with somatostatin. The nuclear and cytoplasmic areas of the adenoma subjected to SMS 201-995 treatment were smaller, and the lysosomes occupied more of the cytoplasmic volume than those of controls. The nuclear/cytoplasmic ratio, cytoplasmic volume densities of endoplasmic reticulum, Golgi apparatus, mitochondria, secretory granules and secretory granule diameters were within the range of control adenomas. In vitro, treated adenoma cells secreted GH and retained responsiveness to both GRH stimulation and somatostatin suppression. The morphologic findings after SMS 201-995 treatment, are consistent with suppression of GH release. There is no evidence that somatostatin has any direct cytotoxic or vasotoxic effects. It appears that SMS 201-995 represents a potent and promising drug in the medical treatment of acromegaly, however, more work is needed to elucidate the mechanism of somatostatin suppression and to provide evidence for adenoma shrinkage.     

EFFECTIVE LONG-TERM TREATMENT OF ACROMEGALY WITH A LONG-ACTING SOMATOSTATIN ANALOGUE (SMS 201–995)

Nine acromegalic patients, six previously untreated, were studied before and after 3-15 months of treatment with a long-acting somatostatin analogue (SMS 201-995; 100 micrograms injected s.c. three times daily). During treatment, the mean (+/- SEM) 24-h GH concentration fell from 82 +/- 22 mIU/l to 33 +/- 7 mIU/l (P less than 0.001), and eight of the 9 patients showed a reduction of at least 50% in GH levels in the fasting state and/or during a glucose tolerance test. There was a significant 30% fall in serum concentrations of insulin-like growth factor (IGF-1) with SMS. All patients showed rapid clinical improvement, with diminished sweating and headaches, and reduction in skinfold thickness, hand volumes and finger size. Computer tomographic scanning of the pituitary in eight patients showed no change in the size of the pituitary tumour during treatment. The only side-effects of SMS noted were transient abdominal discomfort and loose stools in two patients on initiating therapy. Although fasting plasma glucose concentration did not change during treatment (5.4 +/- 0.3 vs 5.5 +/- 0.3 mmol/l), mean 24-h plasma glucose concentration was higher with SMS (6.6 +/- 0.5 mmol/l vs 6.0 +/- 0.4 mmol/l; P less than 0.02). Mean 24-h plasma insulin concentration fell from 87 +/- 11 mIU/l before treatment to 39 +/- 6 mIU/l during treatment (P less than 0.005). No change in other anterior pituitary hormones was observed. SMS appears to be a safe, rapidly effective, long-term treatment for certain patients with acromegaly.     

EFFECT OF SOMATOSTATIN ON ABNORMAL GROWTH HORMONE AND PROLACTIN SECRETION IN PATIENTS WITH THE CARCINOID SYNDROME

Growth hormone (GH) secretion has been studied in two patients with the carcinoid syndrome during glucose loading and growth hormone-release inhibiting hormone (GHRIH, somatostatin) infusion. Both patients had elevated fasting GH levels which were not suppressed by glucose; GH levels fell rapidly during GHRIH infusion. One patient also had hyperprolactinaemia with galactorrhoea and the prolactin (PRL) levels were unaltered by GHRIH. The association between carcinoid tumours and abnormalities of GH and PRL secretion is discussed.     

EFFECTS OF SOMATOSTATIN ANALOGUE SMS 201–995 IN NORMAL MAN

Long-acting somatostatin analogues may be of benefit in certain hypersecretory endocrine and gastrointestinal disorders. The 24 h hormonal and metabolic profiles of six normal male subjects receiving a twice daily subcutaneous injection of one such analogue SMS 201-995, 50 micrograms, has been compared to that obtained following placebo injection. Spontaneous daytime peaks of GH secretion were delayed until 1400 h following SMS 201-995 but nocturnal and total 24 h GH secretion were unaffected. The nocturnal rise in thyrotrophin was abolished by SMS 201-995 but thyroid function was unaffected. Insulin levels were suppressed following SMS 201-995 and the response to meals was inhibited. Glucose intolerance followed main meals. Glucagon levels were suppressed for up to 6 h. Circulating alanine levels were raised between 1200 h and 0600 h and there were intermittent elevations in lactate, pyruvate, glycerol and 3-hydroxybutyrate. Amino acid levels, including branched chain amino acids, were also increased. All six subjects suffered gastrointestinal side-effects. SMS 201-995, 50 micrograms, given twice daily shortly before meals does not suppress 24 h GH secretion, but demonstrates significant effects on metabolism and causes side effects in normal subjects.     

EFFECTS OF SOMATOSTATIN ANALOGUE SMS 201–995 IN NON-INSULIN-DEPENDENT DIABETES

The 24-h hormonal and metabolic profiles obtained in five non-insulin-dependent diabetics receiving twice daily s.c. injections of the long-acting somatostatin analogue SMS 201-995 (50 micrograms) have been compared with those obtained following placebo injection. Injections were given 30 min before breakfast and the evening meal. GH secretion was not suppressed by the analogue administered in this manner. Despite suppression of serum insulin levels following breakfast and the evening meal, blood glucose levels were similar during the two study periods with no evidence of worsening in diabetic control. Prolonged suppression of plasma glucagon levels was observed and the nocturnal elevation in serum TSH levels was abolished. Free T4 levels fell significantly following the analogue but total T3 levels were unaffected. Blood alanine levels were elevated throughout the study period following SMS 201-995 but changes in lactate, pyruvate, glycerol and 3-hydroxybutyrate were minor. All five subjects suffered gastrointestinal side-effects. SMS 201-995 (50 micrograms) given twice daily before meals does not cause a deterioration in metabolic control, does not suppress 24-h GH secretion and causes significant side-effects in patients with non-insulin-dependent diabetes mellitus.     

PHARMACOKINETICS OF THE LONG-ACTING SOMATOSTATIN ANALOGUE OCTREOTIDE (SMS 201-995) IN ACROMEGALY

A single-dose study was performed to examine the pharmacokinetics of subcutaneous octreotide in acromegalic patients and to investigate the relationship between growth hormone and the elimination half-life of the drug. Fourteen acromegalic patients (six men and eight women; age range 35-59 years) who had previously received conventional treatment were studied. Two subjects were on long-term octreotide which had been discontinued 72 h before the study. Octreotide 100 micrograms was administered subcutaneously and plasma samples taken every 10 min for 1 h and then hourly for up to 8 h. Growth hormone was measured at 0, 2 and 8 h. Octreotide was rapidly absorbed with a mean (+/- SEM) t1/2abs of 5.4 min (+/- 0.8) peaking at a mean plasma concentration of 3.4 nmol/l (+/- 0.2) in 27.4 min (+/- 3.7). The monoexponential elimination phase had a mean half-life of 110 min (+/- 9.6). The apparent volume of distribution was 29.4 1 (+/- 1.9) and total clearance was 172 ml/min (+/- 10.4). These results were similar to those obtained in normal volunteers. There was no simple relationship between the level of growth hormone and the half-life of octreotide. Growth hormone levels ranged from 2.5 to 34.0 mIU/l but were only greater than 10 mIU/l in three subjects. Further studies of octreotide pharmacokinetics are needed in untreated patients with acromegaly with raised growth hormone levels.     

INTERACTION BETWEEN GROWTH HORMONE RELEASING FACTOR (GRF) AND SOMATOSTATIN ANALOGUE (SMS 201–995) IN NORMAL SUBJECTS

Continuous infusion or pulsatile administration of growth hormone releasing factor leads to decreasing GH levels and GH responses in normal subjects. We have given 50 micrograms GRF 1-44 i.v. four times in 2-hourly intervals to five normal subjects. After 1 week the same protocol was repeated after s.c. administration of 50 micrograms of the synthetic octapeptide somatostatin (SMS 201-995). The GH response to the same GRF doses was higher after the initial GRF pulse and blunted to the following GRF pulses (pulse I: 37:0 +/- 11.2 ng/ml; Pulse II: 5.3 +/- 1.2 ng/ml; pulse III: 5.9 +/- 2.5 ng/ml; pulse IV: 5.9 +/- 3.2 ng/ml; mean +/- SE). When SMS 201-995 was given 60 min before pulsatile GRF administration, the GH secretion pattern was reversed (pulse I: 2.4 +/- 0.7 ng/ml; pulse II: 2.0 +/- 0.9 ng/ml; pulse III: 4.4 +/- 2.1 ng/ml; pulse IV: 11.4 +/- 3.6 ng/ml). Radioimmunoassayable GRF levels were not different before and after administration of SMS 201-995. The half time of disappearance was 8.6 +/- 0.4 min before and 8.0 +/- 0.5 min after SMS 201-995. Basal thyrotrophin and insulin levels, which remained constant over the 8 h period with GRF only, decreased significantly after SMS 201-995 administration. These findings are compatible with a limited releasable GH pool which is exhausted by chronic GRF stimulation but can be conserved by prior administration of the somatostatin analogue. Thus, when somatostatin bioactivity tapers off, there is recovery of GRF-stimulated GH secretion.     

CLINICAL AND BIOCHEMICAL EFFECTS OF INCREMENTAL DOSES OF THE LONG-ACTING SOMATOSTATIN ANALOGUE SMS 201-995 IN TEN ACROMEGALIC PATIENTS

Ten patients (seven women, three men) with active acromegaly, five previously treated and five newly diagnosed, were included in an open-label prospective trial of 3 daily subcutaneous injections of the long-acting somatostatin analogue SMS 201-995 (Sandostatin) at increasing doses in order to obtain maximum growth hormone (GH) suppression. Four patients had received surgery, radiotherapy or bromocriptine. SMS 201-995 doses were increased in a stepwise fashion from 100 μg every 8 h (three times daily) to 200, 300 and finally 500 μg three times daily at monthly intervals if mean serum GH values failed to decrease to undetectable levels in over 75% of the samples. The optimal dose was maintained for up to 28 months. Significant clinical improvement of headache, soft tissue swelling, facial features, hyperhidrosis and paraesthesia occurred in all patients. Mean 12-h GH levels were significantly suppressed in four patients and fell to normal values in four. Suppression of GH levels was not achieved in two patients. Comparison of the mean interindividual GH values shows that the optimal efficacious dose is 100 μg t. i. d. in 7/10 patients. Somatomedin-C (SM-C) was also significantly reduced to below 50% of pretreatment levels in nine patients in whom it was measured. The subsequent increments of SMS 201-995 up to 500 μg three times daily did not produce further clinically relevant GH or SM-C suppression. Pituitary tumour shrinkage occurred in five patients. Thyroid function remained normal. Impaired glucose tolerance occurred in four patients. Side-effects (diarrhoea, abdominal discomfort) were mild and transient. Asymptomatic gallstones occurred in three patients on 1500 μg/day and one patient on 600 μg/day after 6-12 months treatment. This dose-finding study shows that 100 μg three times daily SMS 201-995 is an effective therapy for most of the acromegalic patients we treated.     

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.     

RESISTANCE OF METASTATIC PANCREATIC ENDOCRINE TUMOURS AFTER LONG-TERM TREATMENT WITH THE SOMATOSTATIN ANALOGUE OCTREOTIDE (SMS 201–995)

Ten patients with metastatic pancreatic endocrine tumours were treated with the long-acting somatostatin analogue octreotide (SMS 201-995). Three patients showed no response, clinically or biochemically, and treatment was therefore withdrawn. The seven remaining patients continued treatment for a median period of 28 months (range 13-54 months). Treatment was initially effective, symptoms improved and the concentrations of tumour-related hormones were reduced. Worsening of symptoms and rising levels of tumour-related hormone concentrations occurred a median of 5 months (range 1-6 months) after the start of therapy and were initially reversed by increasing the dose of octreotide over a median of 10 months (range 6-16 months). However, after a median of 13 months (range 5-34 months) at the maximum dosage, symptoms recurred and were no longer responsive to a further increase in dosage of octreotide or other therapeutic measures. All patients died within a period of 5 months once this resistant phase of their illness had been reached.     

TREATMENT OF CUSHING''S SYNDROME WITH THE LONG-ACTING SOMATOSTATIN ANALOGUE SMS 201-995 (SANDOSTATIN)

Three patients with Cushing's disease and one patient with paraneoplastic hypercortisolism were treated for 24-49 days with the long-acting analogue of somatostatin, SMS 201-995, Sandoz (SMS), administered in increasing doses up to 400-1200 micrograms daily. In the three Cushing's patients during SMS treatment plasma ACTH displayed an initial rise and a subsequent decrease. The pattern of urinary free cortisol (UFC) tended to be opposite to that of ACTH. In one of these patients, UFC continued to decrease throughout the treatment, without becoming normal. In the patient with paraneoplastic hypercortisolism, SMS was associated with a progressive decrease, though not the normalization, of UFC and of ACTH and cortisol levels. The reciprocal changes of the ACTH and UFC levels observed in the three Cushing's patients receiving SMS suggest that the peptide may act temporarily by inhibiting glucocorticoid secretion. In view of the marked reduction of UFC recorded in 1 of the 3 Cushing's patients and in the patient with paraneoplastic Cushing's syndrome, administration of SMS seems worth trying in cases of ACTH-dependent hypercortisolism requiring medical treatment.     

THE EFFECT OF CALCITONIN ON GROWTH HORMONE SECRETION IN ACROMEGALY

To determine whether human calcitonin inhibits GH secretion in acromegaly, as previously described for healthy subjects, the effect of an i.v. bolus injection of calcitonin or saline on GH levels in patients with active acromegaly was studied and compared to that of an i.v. bolus injection of the synthetic somatostatin analogue, octreotide. After the injection of calcitonin, GH levels decreased by 46% of initial values, whereas octreotide reduced GH levels by 87% and saline had no significant effect. Administration of calcitonin to acromegalics did not cause the transient rise in plasma PRL and TSH levels seen in normal subjects. Octreotide induced a decrease in plasma PRL in three out of seven patients. It is concluded that human calcitonin suppresses GH secretion in acromegaly, but not to normal levels; moreover the effect is less than that found for octreotide. In addition, acromegalic patients did not exhibit the PRL and TSH-releasing activity of calcitonin found in normal subjects, while octreotide inhibited PRL secretion in some acromegalic patients.     

CONTINUOUS SUBCUTANEOUS PUMP INFUSION OF SOMATOSTATIN ANALOGUE SMS 201-995 VERSUS SUBCUTANEOUS INJECTION SCHEDULE IN ACROMEGALIC PATIENTS

Diurnal serum GH patterns were determined in 10 acromegalic patients before treatment, after 3 d continuous s.c. pump infusion and then after 3 d with three equal daily s.c. injections in both instances totalling 100 μg/24 h. Subcutaneous injections (33 μg) induced impressive suppression of serum GH lasting 3-6 h in eight patients followed by escape to pretreatment values before the next injection. In contrast, continuous infusion resulted in greater and more stable 24 h suppression to the levels reached at the nadir between injections. Suppression of mean 24 h serum GH below 5 ng/ml was achieved by pump treatment in four patients, while two patients had mean values between 5 rig/ml and 10 ng/ml. In four patients occasional or all levels were above 10 ng/ml (24 h average 12.4-102 ng/ml) implying either that adequate suppression by the SMS 201-995, was impossible during the 3 d pump infusion period, or that the dose administered was inadequate. Carbohydrate tolerance was unaffected in either regimen, indicating that reduction in insulin antagonistic hormones balanced inhibition of insulin release. Interestingly, and in contrast to somatostatin, SMS 201-995 did not inhibit TSH release. No untoward effects were observed at the moderate dosage and blood clinical chemistry was unchanged. Fairly constant diurnal serum SMS 201-995 values were obtained during pump infusion, while levels undulated inversely with serum GH during injection treatment. Average diurnal serum somatostatin-C immunoreactivity (all patients) decreased from 496 ± 129 (mean ± SD) to 385 ± 100 ng/ml ( P < 0 003) during pump treatment and did not decrease further during the following 3 d injection treatment (363 ± 76 ng/ml).     

THE HALF-LIFE OF EXOGENOUS GROWTH HORMONE AFTER SUPPRESSION OF ENDOGENOUS GROWTH HORMONE SECRETION WITH SOMATOSTATIN

We have estimated the half-life of serum growth hormone (GH) in six subjects on 14 occasions following an intravenous bolus injection of either 50 or 500 mU of biosynthetic human growth hormone (B-hGH) while endogenous GH secretion was suppressed by a continuous infusion of somatostatin. The disappearance curve of serum GH was mono-exponential and the mean half-life was 8.9 min (SD 1.5). This is less than previously reported and has important implications for the performance of GH profiles, which should be performed with 10-15 min sampling intervals, and the calculation of pituitary GH secretion rates.     

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.     

PREVENTION OF HYPOGLYCAEMIA IN A PATIENT WITH PANCREATIC MICROADENOMATOSIS BY A LONG-ACTING SOMATOSTATIN ANALOGUE SMS 201-995

Acute suppression of insulin secretion from pancreatic insulinomas by long-acting somatostatin analogue SMS 201-995 has been documented. We report the chronic use of the drug in a patient with persistent hypoglycaemia due to benign pancreatic microadenomatosis with satisfactory control of plasma glucose level and reduction of insulin production. There was no tachyphylaxis or untoward side-effect noted during the 6-month treatment period.     

IMMUNOCYTOCHEMICAL GROWTH HORMONE AND PROLACTIN IN PITUITARY ADENOMAS CAUSING ACROMEGALY AND THEIR RELATIONSHIP TO BASAL SERUM HORMONE LEVELS AND THE GROWTH RESPONSE TO THYROTROPHIN RELEASING HORMONE

Basal prolactin levels and the dynamics of growth hormone secretion in response to intravenous TRH in 34 untreated acromegalic patients were compared with immunocytochemical localization of growth hormone and prolactin in the adenoma cells. The serum prolactin level was elevated in 13 patients. All adenomas contained growth hormone detectable by immunocytochemistry. Twelve adenomas contained prolactin as well; of these only six were associated with hyperprolactinaemia. In six patients with a mixed adenoma the serum prolactin levels were in the normal range. In 17 patients the growth hormone value more than doubled after TRH. Eight of these patients had hyperprolactinaemia, and in only six did the adenomas contain immunoreactive prolactin; eight were associated neither with hyperprolactinaemia nor with positive immunostaining for prolactin. Eight adenomas had suprasellar extension, six of these were associated with hyperprolactinaemia. Of the seven adenomas with hyperprolactinaemia but no adenomatous prolactin immunoreactivity, four had supprasellar extension. In three patients hyperprolactinaemia was associated neither with prolactin immunoreactivity in the adenoma cells nor with suprasellar extension of the tumour. It is concluded that in acromegalics (1) there is no relation between hyperprolactinaemia, and the presence of prolactin in the adenoma cells; (2) the hyperprolactinaemia may be due either to adenomatous prolactin secretion or possibly suprasellar mass interference of hypothalamic control of normal prolactin cells; and (3) the presence of hyperprolactinaemia or immunocytochemically defined adenomatous prolactin does not correlate with the reactivity of the adenomatous growth hormone cells to TRH.     

GONADOTROPHIN, GROWTH HORMONE AND PROLACTIN SECRETION IN CHILDREN WITH PRIMARY HYPOTHYROIDISM

We have studied eight children with primary hypothyroidism (6F, 2M) aged 6.7 to 14.2 years. The girls were prepubertal and the boys had early normal pubertal development. Overnight secretion of LH, FSH, TSH, PRL and GH, and ovarian ultrasound morphology were assessed before and up to 9 months after commencing thyroxine treatment. Serum FSH concentrations in all the girls were increased above LH levels and severe hypothyroidism was associated with reduced GH secretion. These abnormalities reversed with thyroxine treatment. The boys had less severe hypothyroidism and did not demonstrate abnormal gonadotropin or GH secretion. We conclude that primary hypothyroidism in childhood is associated with widespread disturbance of pituitary function, including increased FSH secretion often without signs of early sexual maturation.     

A PRELIMINARY REPORT ON THE ROLE OF SOMATOSTATIN ANALOGUE (SMS 201-995) IN THE MANAGEMENT OF CHILDREN WITH TALL STATURE

We have studied the effect of somatostatin analogue (SMS 201-995) given as a subcutaneous injection on the growth and growth hormone secretion in seven tall children (two male; five female). SMS 201-995 was given in doses of 37.5 or 50 micrograms on a once or twice-daily regimen. Growth velocity decreased from a pretreatment median of 8.3 cm/year (range 5.5-12.2) to 3.0 cm/year (range 0.2-4.5) after 6 months treatment (Wilcoxon, P = 0.02). In three of the children therapy was discontinued for the next 6 months with restoration of growth rate to pretreatment values in two of the three. Growth hormone secretion decreased as a result of SMS 201-995 therapy although one child needed a twice-daily regimen to achieve long-term suppression. Final height measurements were reduced in four of five patients with an overall reduction between 1.1 and 6.3 cm and no change in the other. No effects of treatment on fasting glucose and insulin, glycosylated haemoglobin or serum thyroxine concentrations were observed. These preliminary studies suggest that SMS 201-995 may have a role in the management of the growth of tall children but the optimum mode of administration remains to be established.