A COMPARISON BETWEEN THE EFFECTS OF SMS 201–995, BROMOCRIPTINE AND A COMBINATION OF BOTH DRUGS ON HORMONE RELEASE BY THE CULTURED PITUITARY TUMOUR CELLS OF ACROMEGALIC PATIENTS

The in-vivo reaction of the plasma GH concentration to the administration of the somatostatin analogue SMS 201-995, bromocriptine and their combination were compared with the in-vitro effects of both compounds and their combination on GH release and the GH tumour cell content of 9 acromegalic patients. Exposure of cultured GH-secreting pituitary tumour cells for 4-96 h to SMS 201-995 showed a variable, but in all instances during longer incubations statistically significant inhibition of GH release, which paralleled the sensitivity of GH secretion to the drug in vivo. This inhibitory effect on GH release was in two of the eight tumours accompanied by a decrease in the GH tumour cell content after 24-72 h of culture. These changes either reflect an inhibition of GH synthesis and/or an increase in intracellular breakdown (crinophagy) of GH and might be the basis for the tumour shrinkage which has been observed in about half of the acromegalic patients during long-term SMS 201-995 therapy. The inhibitory effects of bromocriptine on GH secretion were antagonized by haloperidol, while the inhibitory effect of SMS 201-995 was not affected by the dopamine receptor antagonist. This suggests that the effects of SMS 201-995 and bromocriptine are mediated via separate mechanisms involving different receptors. Additive but no potentiating inhibitory effects of both drugs on GH release were observed in a group of six patients in vivo and in three of six tumours in vitro.     

A CLOSE CORRELATION BETWEEN THE INHIBITORY EFFECTS OF INSULIN-LIKE GROWTH FACTOR-I AND SMS 201-995 ON GROWTH HORMONE RELEASE BY ACROMEGALIC PITUITARY TUMOURS IN VITRO AND IN VIVO

In the present study we compared the in-vitro effects of IGF-I and SMS 201-995 on GH release by cultured tumour cells obtained from seven acromegalic patients with the preoperative in-vivo GH dynamics, including the acute response to 50 micrograms SMS 201-995 subcutaneously. IGF-I and SMS 201-995 inhibited GH release during a 24 h incubation in four and five of the seven tumour cell preparations, respectively. The inhibitory effect of SMS 201-995 was greater than that exerted by IGF-I (P less than 0.01). There was a close correlation between the in-vitro inhibitory effects of IGF-I and SMS 201-995 (P less than 0.01). In addition, the acute inhibitory effect of 50 micrograms SMS 201-995 on circulating GH levels in vivo correlated with the inhibitory effects in vitro of both SMS 201-995 (P less than 0.01) and IGF-I (P less than 0.05). The inhibitory effects of IGF-I and SMS 201-995 on GH release in vitro were shown to be additive in two of four tumours. There was no relation between the in-vitro effects of IGF-I and/or SMS 201-995 and several in-vivo parameters, including fluctuations in GH levels, sleep-induced GH release, a paradoxical increase of GH in response to TRH, and the circulating IGF-I and PRL levels. In conclusion: (1) there is a close correlation between the sensitivity of GH release by cultured human adenoma cells to IGF-I and SMS 201-995. (2) There is also a close correlation between the in-vivo inhibitory effect on GH release of SMS 201-995 and the in-vitro inhibitory effects of both SMS 201-995 and IGF-I. (3) A subgroup of acromegalic patients harbour pituitary tumours in which the qualitative regulation of hormone secretion is similar to that of normal GH secretion.     

THE SENSITIVITY OF GROWTH HORMONE AND PROLACTIN SECRETION TO THE SOMATOSTATIN ANALOGUE SMS 201–995 IN PATIENTS WITH PROLACTINOMAS AND ACROMEGALY

The somatostatin analogue SMS 201-995 has recently been shown to be effective in suppressing GH secretion in most acromegalic patients. In the present study it was investigated whether PRL release in prolactinoma and acromegalic patients might also be sensitive to SMS 201-995 and whether co-secretion of PRL in acromegaly plays a role in determining the sensitivity of GH secretion to SMS 201-995. The s.c. administration of 50 micrograms SMS 201-995 did not affect high plasma PRL levels in four microprolactinoma patients. Therapy of one of these patients for 3 d with 50 micrograms three times a day also did not affect PRL levels. The single administration of 50 micrograms SMS 201-995 in 22 acromegalic patients lowered plasma GH levels for 2-6 h to less than 5 micrograms/l in 14 patients and to less than 50% of control values in 16 patients. In 18 of these 22 patients the immunohistochemical picture of the pituitary tumour was known. Eleven patients had pure GH-containing tumours and in seven patients there were mixed GH/PRL-containing tumours. In two of these latter patients there was evidence for GH and PRL being secreted by the same tumour cells. The sensitivity of GH secretion to SMS 201-995 did not differ between the patients with pure GH or mixed GH/PRL-containing adenomas. Plasma PRL levels were not affected by SMS 201-995 in the patients with pure GH-secreting tumours, but were significantly suppressed in four of the seven patients with mixed GH/PRL containing tumours. Chronic treatment for 16 weeks of one patient with a mixed GH/PRL-containing tumour with SMS 201-995 (100 micrograms three times a day) resulted in normalization of both the increased GH and PRL levels. It is concluded that SMS 201-995 does not affect tumorous PRL secretion in patients with pure prolactinomas. In acromegalic patients with mixed GH/PRL-containing tumours PRL secretion in some patients is sensitive to SMS 201-995, making these patients good candidates for chronic treatment with the analogue. The simultaneous presence of PRL in the GH-secreting pituitary tumour or the presence of hyperprolactinaemia in acromegalics does not play a role in the sensitivity of GH secretion to the somatostatin analogue.     

GLYCOPROTEIN HORMONE ALPHA-SUBUNIT AND PROLACTIN RELEASE BY CULTURED PITUITARY ADENOMA CELLS FROM ACROMEGALIC PATIENTS: CORRELATION WITH GH RELEASE

In-vitro data of pituitary adenoma cells from 28 acromegalic patients were evaluated. In addition to GH, PRL was produced by 16 adenomas (57%) and alpha-subunit by 15 adenomas (54%) while there was a significantly higher incidence of tumours producing PRL and alpha-subunit simultaneously. From 26 pituitary adenomas enough cells were obtained in order to perform secretion studies. Percentage basal hormone release (medium: (medium + intracellular hormone)) x 100% of GH and alpha-subunit by 11 adenomas showed a close correlation while such a correlation for GH and PRL was present only in a subgroup of 10 of 13 adenomas. The responses of GH and alpha-subunit release to 10nM SMS201-995, 10nM bromocriptine, 100 nM TRH and 10nM GHRH were closely related in that a response or an absent response of GH release to the four secretagogues was virtually always attended with a response or an absent response respectively of alpha-subunit release. Such a relationship was less evident with respect to the effects of SMS201-995, bromocriptine. TRH and GHRH on GH and PRL release. We conclude that basal and secretagogue-induced alpha-subunit release by cultured pituitary adenoma cells from acromegalic patients closely follows the pattern of GH release while such a relationship for GH and PRL is present only in a subgroup of the adenomas secreting GH and PRL simultaneously.     

Studies on the mechanism of action of the inhibitory effect of the somatostatin analog SMS 201-995 on the growth of the prolactin/adrenocorticotropin-secreting pituitary tumor 7315a

The somatostatin analog SMS 201-995 (2 X 6 or 2 X 20 micrograms daily for 30 days) inhibited the growth of the PRL/ACTH-secreting pituitary tumor 7315a by 36% and 48%, respectively. A biphasic curve of the inhibitory effect of the SMS analog on tumor growth was recognized: the actual tumor growth inhibitory effect occurred during the first 15 days, after which the tumors grew in parallel with the control tumors despite SMS 201-995 treatment. At the end of the 30-day SMS 201-995 treatment, plasma GH and plasma somatomedin-C levels were similar to those in the control tumor-bearing rats. Separate experiments in normal rats showed that tachyphylaxis of the GH-secretion inhibitory effects of three different doses of SMS 201-995 occurred within 6-10 days. No specific somatostatin-14 or SMS 201-995 receptors were present on well grown, untreated 7315a pituitary tumors. However, PRL and ACTH secretion by cultured cells prepared from the 7315a tumor was inhibited by SMS 201-995. Pretreatment of the cultured cells with dexamethasone made PRL secretion by these tumor cells insensitive to SMS 201-995. These studies suggest that several factors played a role in the mechanism of action of the tumor growth-inhibitory actions of SMS 201-995. Twice daily administration of the somatostatin analog rapidly (within 6-10 days) induces tachyphylaxis of the GH-inhibitory effect. From 10 days after implantation the PRL/ACTH-secreting pituitary tumor causes adrenal hyperplasia and increased plasma corticosterone concentrations. Exposure of the 7315a tumor to high glucocorticosteroid levels probably decreases the number of somatostatin receptors, diminishing the possible direct antitumor effect of SMS 201-995.     

Long term treatment with the somatostatin analog SMS 201-995 in a patient with a thyrotropin- and growth hormone-secreting pituitary adenoma

A patient with a mixed pituitary tumor secreting TSH and GH was treated, starting 3 months after partial adenomectomy, with the somatostatin analog SMS 201-995 for 8 months. Somatostatin itself inhibited TSH, GH, and alpha-subunit release by the tumor both in vivo and in vitro. Long term treatment with twice daily sc injections of SMS 201-995 resulted in decreased TSH secretion and lower serum thyroid hormone levels. However, euthyroidism was achieved only when the patient was treated with three daily 200-micrograms injections of SMS 201-995. After 30 weeks of SMS 201-995 therapy, TSH secretion increased, while GH secretion remained suppressed. After withdrawal for 6 months, SMS 201-995 (100 micrograms, sc, twice daily) again completely inhibited TSH secretion. SMS 201-995 did not alter the volume of the residual adenomatous tissue. We conclude that SMS 201-995 may be a valuable therapeutic agent for the management of patients with a thyrotroph adenoma. However, desensitization may occur during long term treatment.     

Regulation of galanin gene expression in the rat anterior pituitary gland by the somatostatin analog SMS 201-995.

In addition to inducing pituitary tumors in rats, estrogen (E2) markedly increases galanin and PRL gene expression. We previously showed that galanin secretion from pituitary cells in vitro is inhibited by dopamine and somatostatin and stimulated by TRH. The objectives of these in vivo studies were to assess whether the long-acting somatostatin analog SMS 201-995 alters 1) immunoreactive galanin or PRL levels in the anterior pituitary, neurointermediate lobe, hypothalamus, or plasma, 2) pituitary galanin and PRL mRNA levels, and 3) the development of E2-induced pituitary tumors. Ovariectomized Fischer 344 rats were implanted with E2-filled or empty Silastic capsules and treated with or without SMS 201-995 (1.5 mg) via Alzet miniosmotic pumps. Two or 6 weeks later, immunoreactive galanin and PRL levels were determined by RIA. In ovariectomized rats, the somatostatin analog lowered the anterior pituitary content of galanin by 50%, but had no effect on PRL concentrations. E2 increased galanin and PRL levels in the anterior pituitary by 220- and 4-fold, respectively. Concomitant E2 and SMS 201-995 treatment further increased galanin and PRL in the anterior pituitary by 60-80%, but decreased plasma galanin and PRL levels. Likewise, the administration of SMS 201-995 for 2 and 6 weeks inhibited the E2-induced growth of the anterior pituitary. Galanin and PRL mRNA levels were quantified by solution hybridization. Galanin mRNA levels were reduced to undetectable levels in ovariectomized rats treated with SMS 201-995. Furthermore, a 10-fold increase in galanin mRNA levels seen in the presence of E2 was inhibited 80% by SMS 201-995. PRL mRNA levels in E2-treated rats were unchanged by SMS 201-995. We conclude that SMS 201-995 1) lowers plasma galanin and PRL levels in E2-treated rats, 2) elevates the anterior pituitary contents of galanin and PRL in E2-exposed rats, probably through decreased secretion of the hormones, and 3) reduces galanin mRNA levels in E2-treated and untreated ovariectomized rats. Overall, these results establish the differential regulation of galanin and PRL gene expression in vivo by SMS 201-995. Moreover, the data demonstrate that somatostatin receptor agonists may have therapeutic potential for some prolactinomas.     

In vitro and in vivo herpetic vector-mediated gene transfer in the pituitary gland: impact on hormone secretion

OBJECTIVE: Herpes simplex virus type 1 (HSV-1)-derived vectors are known to be effective tools to deliver transgenes into normal and neoplastic anterior pituitary (AP) cells in vitro. Our objective was to assess the in vitro and in vivo effects of tsK/beta-gal, a temperature-sensitive HSV-1-derived vector harbouring the E. coli beta-galactosidase gene, on AP hormone secretion as well as on transgene expression in rat AP tumours (hyperplastic prolactinomas). DESIGN: The impact of vector infection on prolactin (PRL) and GH release was determined in vitro in normal and hyperplastic (lactotrophic) dispersed AP cells exposed for 24 h to tsK/beta-gal as well as in vivo in ectopic AP grafts. In some oestrogen-induced prolactinoma-carrying rats, vector suspension was stereotaxically injected into the glands to assess transgene expression in vivo. METHODS: GH and PRL release was measured by specific RIAs. In vivo transgene expression was assessed by immunohistochemistry for beta-galactosidase and enzymohistochemistry (5-bromo-4-chloro-3-indolyl-beta-d-galactopyranoside). Ectopic pituitary grafts and stereotaxic surgery were performed following standard procedures. RESULTS: At a multiplicity of infection of 0.5, the vector induced a 30 and 22% fall in PRL and GH release respectively in normal AP cells, whereas the corresponding hormone release inhibition for hyperplastic AP cells was 41 and 33% for PRL and GH respectively. In ectopic pituitary grafts, the effect of vector infection on hormone secretion was assessed by measuring serum PRL levels in the host rats every 5 days for 4 weeks post-grafting. In the pituitary-grafted rats that received the viral vector, serum PRL failed to increase to the levels achieved in control-grafted animals. Finally, pituitary tumours stereotaxically injected with tsK/beta-gal showed widespread expression of the beta-galactosidase transgene around the injection areas. CONCLUSIONS: The results reported here have implications for basic studies using gene transfer to pituitary gland as well as potential gene therapy approaches to pituitary diseases.     

Effects of two novel dopaminergic drugs, CV 205-502 and CQP 201-403, on prolactin and growth hormone secretion by human pituitary tumours in vitro

Two novel dopaminergic drugs, designated CV 205-502 and CQP 201-403 have recently been developed by Sandoz Pharmaceuticals Ltd (Basle, Switzerland). The effects of these drugs on PRL and GH secretion by normal rat and tumorous human pituitary cells in vitro have been investigated. Low doses of both CV 205-502 and CQP 201-403 immediately and profoundly suppressed PRL secretion, which failed to recover up to 7 h after removal of the drugs. Similarly, CQP 201-403 significantly suppressed basal GH secretion by human pituitary somatotropic tumours in culture, and both drugs significantly reduced the stimulatory effect of GHRH. These effects are more potent and longer acting than the previously described in vitro effects of bromocriptine. It is concluded that CV 205-502 and CQP 201-403 hold potential for the treatment of patients with hyperprolactinaemia and, possibly, also in patients with acromegaly.     

Atypical McCune-Albright syndrome associated with growth hormone-prolactin pituitary adenoma: natural history, long-term follow-up, and SMS 201-995--bromocriptine combined treatment results.

A 35-yr-old woman is described as having atypical McCune-Albright syndrome, associated with acromegaly and hyperprolactinemia due to pituitary adenoma. The patient did not present sexual precocity, but primary amenorrhea. After transphenoidal adenomectomy, the GH plasma levels returned to normal, whereas the PRL values decreased; bromocriptine therapy normalized PRL levels and induced ovulatory menses. After 4 uneventful yr the patient developed relapse of active acromegaly that did not recover after a second neurosurgical exploration. Bromocriptine treatment maintained normal PRL levels but did not significantly reduce GH ones; the association with long-acting somatostatin analog SMS 201-995 by continuous sc pump infusion induced definitive control of GH and somatomedin-C secretion. These results suggest an additive inhibitory effect on GH secretion exerted by the two drugs.     

The sensitivity of growth hormone secretion to medical treatment in acromegalic patients: influence of age and sex

OBJECTIVE: We investigated the relationship between age, sex, pituitary tumour volume, serum GH, PRL and IGF-I levels with the responsiveness of GH to TRH, bromocriptine and octreotide in patients with acromegaly. DESIGN: We performed a retrospective study. Correlations were determined between all variables using univariate regression analysis. PATIENTS: One hundred previously untreated acromegalic patients were studied (60 males (age 23-76; mean 49 years) and 40 females (age 25-83; mean 51 years)). MEASUREMENTS: We studied tumour volume, fasting morning circulating levels of GH, PRL and IGF-I, mean 24-hour circulating GH levels and the acute GH responses to TRH, bromocriptine and octreotide. RESULTS: Tumour size was related to serum and mean 24-hour GH levels, but not to IGF-I. Circulating IGF-I and GH levels were related only for the group of patients whose fasting and unsuppressed GH level was 80 mU/l (40 micrograms/l) or less. Older patients tended to have lower circulating GH and IGF-I levels. There was a close similarity in the responsiveness of tumorous GH secretion to TRH, bromocriptine and octreotide. An elevated serum PRL level predicted a stronger inhibitory response of bromocriptine on GH. The sensitivity of GH release to octreotide was highest in elderly (especially male) acromegalics, as well as in patients with lower IGF-I levels. CONCLUSIONS: Hormone secretion by GH secreting pituitary tumours, as well as circulating IGF-I levels, tend to be lower in elderly patients. These tumours are more sensitive to octreotide, especially in elderly male patients. This suggests that octreotide might be used especially successfully as a primary medical therapy in elderly, male acromegalics.     

A randomized study of SMS 201-995 versus bromocriptine treatment in acromegaly: clinical and biochemical effects

Twenty-six acromegalic patients were randomized to treatment with either SMS 201-995 or bromocriptine in increasing doses and were investigated before treatment, after 2, 4, and 8 weeks of treatment, and 2 weeks after discontinuation of treatment. There were two dropouts from the bromocriptine group and one from the SMS 201-995 group. Amelioration of clinical signs and symptoms was seen in both groups during treatment. After 8 weeks mean 12-h GH concentrations had declined from 13.8 +/- 5.2 to 2.9 +/- 4.4 (mean +/- SEM) in SMS 201-995-treated and from 18.8 +/- 7.5 to 5.4 +/- 1.2 micrograms/L in bromocriptine-treated patients. Somatomedin-C concentrations fell from 3.04 +/- 0.36 to 1.43 +/- 0.36 in SMS 201-995-treated and from 2.93 +/- 0.40 to 2.13 +/- 0.27 U/mL in bromocriptine-treated patients. Size reduction of the pituitary tumor was seen in one patient receiving bromocriptine. Gastrointestinal glucose absorption was delayed, and insulin secretion suppressed during treatment with SMS 201-995. Hemoglobin-A1 concentrations remained unchanged in SMS 201-995-treated patients, but declined in the bromocriptine group. Side-effects were common, but usually tolerable, with both treatments. It is concluded that both drugs are of benefit in the treatment of acromegaly.     

Effect of somatostatin analog (SMS 201-995) onin vivo intestinal fluid transport in rats

Somatostatin analog, SMS 201-995, effectively inhibits the release of hormones from gastrointestinal endocrine tumors and reduces hormonally mediated diarrheas. Its clinical efficacy in nonhormonally mediated diarrhea is limited, despite a potent antisecretory and proabsorptive effect in vitro. The effect of serosal addition of SMS 201-995 on in vitro short-circuit current responses in rat intestine is dependent upon chloride and more marked in colon and ileum than jejunum. In contrast, in vivo loop studies demonstrated that systemic administration of SMS 201-995 for five consecutive days produced a paradoxical decrease in basal colonic fluid absorption with no effect in jejunum or ileum. Furthermore, systemically administered SMS 201-995 did not alter cholera toxin-stimulated intestinal secretion. We conclude that despite a previously identified intestinal antisecretory and proabsorptive effect of SMS 201-995 in vitro, this effect is not seen in vivo and may explain the limited use of SMS 201-995 as an antidiarrhoeal agent in nonhormonally mediated diarrhoea.     

Effects of gonadotropin-releasing hormone and its agonists on prolactin secretion from normal and tumorous pituitary cells

Previous studies on the effect of gonadotropin-releasing hormone (LHRH) agonist on prolactin (PRL) secretion from normal and tumorous pituitary cells have not been conclusive as to the mechanism of action of these agonists. In this study the short-term administration of a LHRH agonist did not affect circulating PRL levels, but depleted the PRL content of the pituitary gland by 24, 49 and 73% after 2, 3 and 4 days, respectively, in normal female rats and by 75% after 4 days in normal male rats. This effect of the agonist could not be attributed to changes in the sex steroid environment: although plasma 17 beta-estradiol concentrations were significantly suppressed in female rats, circulating testosterone levels had not changed yet in the male rats. Interestingly, the pituitary luteinizing hormone (LH) content was depleted already from day 2 of LHRH agonist administration onwards, while the follicle-stimulating hormone (FSH) content of the pituitary glands had not changed even after 4 days. Culture studies with pituitary cells from normal adult male and female rats for 4-7 days did not reveal a direct effect of synthetic LHRH or an agonist on PRL release. Chronic systemic administration of a LHRH agonist greatly inhibited the growth of the transplantable PRL-secreting rat pituitary tumor 7315a in female rats, while circulating PRL levels were also suppressed. However, no direct effect of the LHRH agonist was observed on PRL release from a tumor cell clone, derived from the 7315a tumor, and no LHRH-binding sites were detectable on the tumor.(ABSTRACT TRUNCATED AT 250 WORDS)     

Treatment of acromegaly with the long-acting somatostatin analog SMS 201-995

Current treatment of acromegaly (surgery, radiation, and bromocriptine) is often unsatisfactory, and a sizeable proportion of patients with this disease continue to have GH hypersecretion after all therapeutic modalities have been exhausted. Fifteen patients with active acromegaly (8 previously treated and 7 newly diagnosed) were treated with the long-acting somatostatin analog SMS 201-995 (Sandoz; 50-250 micrograms, sc, every 6-8 h for up to 21 months). The mean daily plasma GH concentration was significantly suppressed in 13 patients, and it became normal in 10. Two patients, however, did not have GH suppression by SMS 201-995 treatment alone; in 1, a significant decline in mean daily GH was achieved after the addition of bromocriptine. As expected, suppression of GH secretion was associated with normalization of plasma somatomedin-C values and significant clinical improvement. Plasma GH responses to synthetic GHRH-(1-44) and TRH were either abolished or blunted by SMS 201-995. Thyroid function remained normal, and glucose tolerance did not change. Significant shrinkage of pituitary tumors occurred in 7 previously untreated and 2 previously treated patients. Side-effects were minimal. SMS 201-995 is an effective agent for the treatment of acromegaly. Further studies are necessary to establish guidelines for identification of non-responders and to examine the effect of preoperative tumor shrinkage on subsequent surgical outcome.     

Mechanism of serotonin effects on prolactin and growth hormone secretion in domestic fowl

Brain serotonin levels were increased in immature chickens by ip injection of pargyline (75 mg/kg) and clorgyline (5 mg/kg) and by L-tryptophan (100 mg/kg) and imipramine (10 mg/kg) treatment. These treatments increased the circulating prolactin level and reduced the concentration of plasma growth hormone (GH). Treatment with para-chlorophenylalanine (PCPA, 100 mg/kg) reduced the brain serotonin content and the level of plasma prolactin. Treatment with these drugs in vivo similarly affected the basal level of prolactin release from pituitary glands in vitro, although it did not affect the basal level of GH release. The in vitro responsiveness of the pituitary gland to hypothalamic stimuli eliciting prolactin secretion was increased by in vivo pargyline and combined tryptophan: imipramine treatment but reduced by PCPA administration. The in vitro GH response to hypothalamic stimulation was reduced after the in vivo injection of pargyline, clorgyline and tryptophan: imipramine. The hypothalami from clorgyline and tryptophan: imipramine treated birds induced a greater stimulation of in vitro prolactin secretion from control pituitary glands than hypothalami from controls birds, whereas the GH releasing activity was reduced. These results suggest that serotonin stimulates prolactin secretion in chickens by increasing pituitary responsiveness to hypothalamic releasing factors and by increasing the prolactin releasing activity of the hypothalamus. Serotonin appears to suppress GH secretion by reducing pituitary sensitivity to releasing factors and by reducing hypothalamic GH releasing activity.     

A comparison among the growth hormone-lowering effects in acromegaly of the somatostatin analog SMS 201-995, bromocriptine, and the combination of both drugs

The acute GH inhibitory effects of 50 micrograms SMS 201-995, a somatostatin analog, and 2.5 mg bromocriptine were compared in 17 acromegalic patients. SMS 201-995 suppressed plasma GH levels after 2-6 h to 5 micrograms/liter or less in 10 of these 17 patients, while bromocriptine did the same in only 5 of them. There was much variation in the responsiveness to both drugs in these patients, but the GH-lowering effect of 50 micrograms SMS 201-995 was significantly greater than that of 2.5 mg bromocriptine. SMS 201-995 and bromocriptine together significantly suppressed plasma GH levels in 2 of 3 acromegalic patients who were insensitive to both compounds when tested separately. We conclude that most acromegalic patients respond better to SMS 201-995, while a few patients are more sensitive to the GH-lowering effect of bromocriptine. In addition, the combination of SMS 201-995 and bromocriptine can be of value in a few acromegalic patients who do not respond to either drug alone.     

Does SMS 201-995 normalize growth hormone secretion in acromegaly? GH day profiles and GH concentrations after oral glucose loading

GH secretion in acromegaly was studied in 8 patients before and during treatment with SMS 201-995, a somatostatin analogue, 100 micrograms twice daily, by evaluating GH day profiles and GH suppressibility after oral glucose tolerance tests (OGTT). Normalization of GH secretion, estimated by OGTT, was only observed in the three patients who had a decrease in plasma GH to less than 2 micrograms/l after SMS 201-995 injection, and who had the lowest mean plasma GH levels during the day and the largest percent decline of mean plasma GH levels. We conclude that real normalization of GH secretion during SMS 201-995 therapy only occurs in a subset of patients. The data illustrate that the applicability of the generally held cut-off value of 5 micrograms/l, between normal and abnormal plasma GH, has to be reconsidered in the case of chronic intermittent subcutaneous therapy with SMS 201-995.     

Reduction of pituitary size by the somatostatin analogue SMS 201-995 in a patient with an islet cell tumour secreting growth hormone releasing factor

Acromegaly is rarely caused by the ectopic secretion of growth hormone releasing factor (GRF) from peripheral neuroendocrine tumours. We evaluated the ability of a recently developed somatostatin analogue (SMS 201-995, Sandoz) to reduce hormone levels and pituitary size in a young woman with acromegaly and Zollinger-Ellison syndrome secondary to a metastatic pancreatic islet cell tumour secreting GRF and gastrin. Gastrin, GRF, and growth hormone (GH) levels declined dramatically following the initiation of therapy with the analogue by continuous iv infusion. Although intermittent sc therapy was not effective in suppressing hormone levels, continuous sc infusion of SMS 201-995 has provided good control of both GRF and GH levels for nine months. Moreover, treatment with SMS 201-995 was associated with a substantial reduction in pituitary enlargement and an improvement in her gastric symptoms. Continuous sc infusion of SMS 201-995 may be useful in treating enlarged pituitaries resistant to other modes of therapy.     

Inhibitory effect of the somatostatin analog octreotide on rat pituitary tumor cell (GH3) proliferation in vitro

The effects of somatostatin-14 (SS-14) and the somatostatin-analog octreotide (SMS 201-995, Sandostatin) on proliferation of GH3 pituitary tumor cells were investigated in vitro. SMS 201-995 exerted a significant, but transient, inhibition on GH3 cell growth which reached a maximum at 24 h and was no longer detectable at 48 h. The concentration that evoked the strongest inhibitory effect was 10 nM SMS 201-995, while lower and higher doses resulted in a less pronounced effect. The inhibitory effect SMS 201-995 exerted on cell proliferation was associated with a dose- and time-related reduction in both c-myc and c-fos mRNA levels. SS-14 had no noteworthy influence on either cell proliferation or c-myc and c-fos protooncogene expression. These data demonstrate that SS-analogs transiently inhibit pituitary tumor cell proliferation in vitro.