Effect of a single administration of somatostatin analogue (SMS 201-995) on GH, TSH and insulin secretion in patients with acromegaly

The effect of a long-acting somatostatin analogue SMS 201-995 on GH secretion was investigated. Eleven acromegalic patients received a single dose of 50 micrograms SMS 201-995 administered subcutaneously, and plasma GH, IGF-I, GRF, TSH, IRI and blood glucose were determined at regular intervals. Nine of 11 patients had elevated basal plasma GH levels above 5 ng/ml. In all patients, plasma GH levels fell immediately from 39.5 +/- 17.3 ng/ml (mean +/- SEM) to 4.3 +/- 1.6 ng/ml (P less than 0.05) with a maximal inhibition of 82.9 +/- 3.3% of the basal levels and the suppression persisted for about 6 h of the observation period. IGF-I and GRF levels were not apparently altered. TSH and IRI levels also rapidly fell. Blood glucose levels fell slightly by 0.5 h. Ten of 11 patients had pain at injection sites. Except for this, no side effects were observed. Our results show that the new somatostatin analogue SMS 201-995 may inhibit GH hypersecretion in acromegalic patients for significant periods, suggesting that this agent can be a useful clinical tool for the treatment of acromegaly.     

Effects of passive immunization of growth hormone-releasing hormone and somatostatin on growth hormone secretion under conditions of high somatostatin tone.

Pulsatile GH secretion decreases during food-deprivation in the rat. It has been hypothesized that this decrease is due to elevated hypothalamic somatostatin secretion. This is based on the observation that GH increases in food-deprived rats following removal of endogenous somatostatin using passive immunization techniques. Cognizant of the important stimulatory effects of growth hormone-releasing hormone (GHRH) on GH secretion, we sought to determine if this neuropeptide plays any role in mediating GH secretion in food-deprived rats. Male rats were prepared with indwelling venous catheters using sodium pentobarbital anesthesia seven days prior to experimentation. Animals were food-deprived for 72 h, after which control blood samples were drawn from -60 to 0 min. One group was then treated with normal rabbit serum (NRS), while a second group was treated with GHRH antiserum (GHRHab). At 55 min all animals received somatostatin antiserum (SSab). No animal exhibited any spontaneous GH peak during the one hour control period or in the subsequent one hour period following the administration of GHRHab or NRS. Absence of GH pulsatility during food-deprivation, coupled with no decrease in GH levels in food-deprived rats treated with GHRHab suggest that diminished GHRH pulsatility is likely during food-deprivation. Subsequent treatment of these animals with SSab resulted in an identical 2.5 fold increase in GH concentrations. This result suggests that GHRH is not involved in the GH rebound following somatostatin withdrawal in food-deprived rats.     

Effect of thyrotropin releasing hormone injection on blood growth hormone (GH), TSH and growth hormone releasing hormone (GHRH) concentrations in cancer patients

In order to investigate whether endogenous GHRH and somatostatin were involved in the mechanism of the paradoxical GH rise after TRH injection, changes in serum GH and plasma GHRH were examined before and after TRH injection in 12 cancer patients and changes in serum TSH and GH were similarly studied in 76 cancer patients including 31 GH-responders and 45 GH-nonresponders to TRH. TRH stimulated GH secretions without altering the circulating GHRH concentration in 4 of the 12 cancer patients. There was neither a significant correlation between the increase from the basal to maximum GH and GHRH after TRH injection in the 12 cancer patients nor a reciprocal relationship between the increase in GH and TSH after TRH injection in the 76 cancer patients. These findings suggested that the paradoxical GH rise after TRH injection in cancer patients was exerted by its direct action at the pituitary level, and not mediated through the hypothalamus.     

Effects of ingestion of glucose on GH and TSH secretion: evidence for stimulation of somatostatin release from the hypothalamus by acute hyperglycemia in normal man and its impairment in acromegalic patients

Ingestion of glucose is known to induce suppression of GH secretion in normal subjects and this phenomenon is often absent in acromegalic patients. To clarify the mechanism of GH suppression in acute hyperglycemia in normal subjects and disturbed GH response in acromegalic patients, the effects of acute hyperglycemia on plasma GH and TSH levels were examined in normal subjects and acromegalic patients. Plasma GH levels were significantly lowered 45-60 min after ingestion of 75 g glucose and elevated at 210 and 240 min in nine normal subjects. Plasma TSH levels were also significantly lowered between 45 and 120 min after ingestion; levels then gradually rose. Subcutaneous administration of 50 micrograms SMS 201-995, a long acting somatostatin analog, lowered plasma TSH levels in both normal subjects and acromegalic patients, and there was no significant difference in the degree of decrease in plasma TSH levels between the normal subjects and patients. These results, taken together with several reports that somatostatin suppresses TSH secretion as well as GH secretion, suggest that acute hyperglycemia stimulates somatostatin release from the hypothalamus, thus causing inhibition of GH and TSH secretion. However, in ten acromegalic patients, only two showed suppression of plasma GH levels to below 50% of basal level and the degree of suppression of TSH secretion was significantly less than in normal subjects in the glucose tolerance test. It is, therefore, suggested that somatostatin release in response to acute hyperglycemia is impaired in most acromegalic patients and that this abnormality may be one of causes for the absence of the normal GH response to acute hyperglycemia in this disorder.     

Involvement of central somatostatin in the alteration of GH secretion in starved rats

In order to determine the central or peripheral origin of the starvation-induced modifications of growth hormone (GH) and thyroid-stimulating hormone (TSH) secretions, the effects of starvation were studied in freely moving male rats with hypothalamo-hypophyseal disconnection. Five days after the disconnection GH secretion exhibited lower maximal values and higher trough levels and ultradian pulsatile secretion was lost as compared to controls. TSH levels were also decreased. The lesion did not modify pituitary somatostatin (SRIF) receptors as assessed by 125I-Tyr-O-D-Trp-8-SRIF binding or inhibition of adenylate cyclase activity. On the other hand, the growth hormone releasing factor (GRF) capacity to stimulate adenylate cyclase was strongly reduced by the lesion without modification of the affinity. Exposure to 72 h food deprivation decreased GH pulses and TSH levels in control rats but did not modify GH secretory profiles or TSH levels of lesioned rats. Plasma glucose and insulin levels were equally decreased after fasting in control and lesioned rats. Altogether, our results demonstrate that starvation-induced modifications of GH and TSH secretions are of central origin while glucose and insulin changes are peripherally triggered. They suggest that the hypothalamus is the only source of SRIF implicated in this effect.     

Pituitary and extrapituitary effects of somatostatin in normal man.

The effects of synthetic linear somatostatin on basal circulating levels on several pituitary and pancreatic hormones, and of glucose and free fatty acids (FFA) were studied in 6 normal men after an overnight fast. A priming intravenous infusion of 250 mug of somatostatin in 18 sec was followed by a constant infusion of 500 mug over a period of 60 min. A decrease in plasma values of GH, prolactin, TSH, insulin and glucagon and in blood glucose was observed during somatostatin infusion, while FFA levels increased progressively. Plasma IRI and blood glucose increased rapidly when the somatostatin infusion was stopped, while FFA decreased progressively; GH, prolactin, TSH and glucagon remained low as compared to basal levels for one hour after the end of the infusion, i.e. until the end of the experiment. A slight but significant increase of LH and ACTH was observed after the end of the infusion.     

Effect of pentobarbital and urethane on the release of hypothalamic somatostatin and pituitary growth hormone

Hypothalamic somatostatin release was investigated in the rat to elucidate the mechanism of anesthetic action on growth hormone (GH) release from the pituitary. Intraperitoneal injection of sodium pentobarbital (5 mg/100 gm B.W.) significantly elevated serum GH levels and increased hypothalamic somatostatin concentration from basal values of 0.98 +/- 0.01 to 1.21 +/- 0.06 ng/mg wet wt. In contrast, urethane (150 mg/100 gm B.W., IP) administration lowered serum GH levels and hypothalamic somatostatin concentration (0.64 +/- 0.04 ng/mg wet wt.). However, the mean concentration of pancreatic somatostatin showed no change in either case. In rats receiving passive immunization with 0.5 ml rabbit antiserum to somatostatin (SRIF-AS), serum GH levels were significantly increased (67.5 +/- 12.3 ng/ml) and did not differ from those in the group treated with normal rabbit serum (NRS) plus pentobarbital (101.3 +/- 18.5 ng/ml). However, serum GH levels in rats injected with SRIF-AS plus pentobarbital were increased to higher values than in rats given SRIF-AS alone. When urethane was administered to rats after passive immunization with SRIF-AS, urethane-induced suppression of serum GH levels was markedly inhibited (5.5 +/- 2.0 vs. 33.5 +/- 7.5 ng/ml). These results suggest a possibility that the changes in serum GH levels observed with pentobarbital or urethane administration may be induced at least in one part by somatostatin released from the hypothalamus.     

Effects of substance P and neurotensin on growth hormone and thyrotropin release in vivo and in vitro

Conscious ovariectomized (OVX) rats bearing a cannula implanted in the third ventricle were injected with 2 μl of 0.9% NaCl containing varying doses of substance P (SP) or neurotensin (NT) and plasma GH and TSH levels were measured by RIA in jugular blood samples drawn through an indwelling silastic catheter. Control injections of physiologic saline iv or into the third ventricle did not modify plasma hormone levels. Intraventricular injection of SP or NT at doses of either 0.5 or 2 μg elevated plasma GH concentrations within 5 min and they remained elevated for 60 min. Third ventricular injection of similar doses of SP or NT had no effect on plasma TSH. An intermediate dose of 1 μg of SP or NT given iv had no effect on plasma GH but NT elevated plasma TSH. Incubation of hemipituitaries from OVX rats with varying doses of SP or NT did not alter GH release into the medium but TSH release was enhanced with NT at doses of 100 or more ng/ml of medium. It is suggested that SP acts centrally to stimulate growth hormone-releasing factor (GRF) or to inhibit somatostatin release and thereby enhance GH release and that NT acts directly on the pituitary to stimulate TSH release.     

Treatment of acromegaly with long acting somatostatin analogue SMS 201-995

Ten acromegalic patients were treated with the somatostatin analogue SMS 201-995 (SMS) for 3-38 weeks in various doses and by different administration routines (thrice daily or multiple sc injection). Plasma GH daily profiles, plasma IGF-I, urinary GH, serum TSH, IRI and fasting blood glucose (FBG) concentrations were measured before and during SMS treatment. Plasma GH rapidly decreased within one hour in all patients and was suppressed for at least 4 h after a 50 micrograms sc injection of SMS in 8 patients. Multiple injections of 300-600 micrograms/day SMS (25-50 micrograms X 12) suppressed GH throughout the day. Plasma IGF-I was completely normalized in 4 patients, and, in all but one of the others, decreased markedly. Urinary GH decreased within the first week of treatment in all patients and normalization was obtained in 3 patients. Shrinkage of the pituitary tumor, as determined by CT or MRI, was observed in 7 of 9 patients. Other clinical improvements, such as diminution or complete disappearance of swelling of soft tissues, excessive perspiration, and headache, were observed in 7 of 8 patients. Changes in serum TSH, IRI and FBG were seen in 3-4 patients, but without any apparent clinical problems. In conclusion, SMS is a useful clinical tool for treatment of acromegaly, and a multiple sc injection method seems to be preferable.     

The effect of immunization against somatostatin on growth rates and growth hormone secretion in the chicken

The effect of both active passive immunization against somatostatin on growth rate and growth hormone levels was studied in chickens. Passive immunization against somatostatin by administration of antiserum had no effect on rate of growth of chickens and no persistent effect on circulating growth hormone (GH) levels. In acute experiments, administration of anti-somatostatin serum caused a marked elevation of GH levels in chickens at both 4 and 8 weeks of age, but the relative stimulation was greater in the older birds. Active immunization against somatostatin significantly stimulated growth rate in chickens, but was not shown to have a clear effect on circulating GH levels. These data suggest that somatostatin control over GH secretion may not be fully developed in the chicken at 4 weeks of age, but that immuno-neutralization of somatostatin can produce an increase rate of growth in chickens similar to that seen in mammals.     

Twenty-four-Hour Rhythms of Serum Acth,Prolactin, Growth Hormone,and Thyroid-Stimulating Hormone,and of Median-Eminence Norepinephrine,Dopamine, and Serotonin,in Rats Injected with Freund's Adjuvant

The effect of Freund's adjuvant injection on 24-h variation of circulating ACTH, prolactin, growth hormone (GH), and thyroid-stimulating hormone (TSH) levels, and of norepinephrine (NE) content, and dopamine (DA) and serotonin (5HT) turnover in median eminence, was examined in adult rats kept under light between 0800 and 2000 h daily. Groups of 6–10 animals Freund's complete adjuvant or its vehicle at 1 lOOh 3 days before sacrifice and were killed by decapitation at six different time intervals throughout a 24-h cycle. In rats injected with adjuvant's vehicle, serum ACTH and prolactin exhibited peak values around the light-dark transition (p < 0.0001 and < 0.04, respectively), while the maximum in TSH was found in the late afternoon (p < 0.0001, one-way ANOVA). GH levels did not vary on a 24-h basis. In Freund's adjuvant-injected rats, 24-h variations of TSH levels became blunted, while 24-h variations of prolactin and ACTH persisted. Freund's adjuvant augmented serum ACTH and prolactin levels, and decreased GH and TSH levels (p < 0.0007, factorial ANOVA). Median-eminence NE content, and turnover of DA, assessed by measuring dihydroxyphenylacetic acid, DOPAC/DA ratio, and of 5HT, assessed by measuring 5-hydroxyindoleacetic acid, HIAA/5HT ratio, varied on a 24-h basis in rats receiving adjuvant's vehicle (p < 0.02). Median-eminence NE content attained its maximum at 1600–2000 h, while maxima in DOPA/DA and HIAA/5HT ratios occurred at 0400 h. Injection with Freund's adjuvant reduced the amplitude of the daily variation of NE content, shifted the maximum of DOPAC/DA ratio toward the light-dark transition, and blunted the daily variation in HIAA/5HT ratio in median eminence. The administration at 1200 of the immunosuppressant drug cyclosporine (5 mg/kg, 5 days) restored the augmented ACTH and prolactin levels (p < 0.0001, factorial ANOVA) and depressed GH and TSH levels (p < 0.02) found in Freund's adjuvant-injected rats. Cyclosporine was also effective in restoring 24-h rhythmicity of serum ACTH and TSH, but not of prolactin, levels. Cyclosporine did not modify the effect of Freund's adjuvant on time-of-day changes of median-eminence NE content, but it was effective in counteracting the changes of DA and 5HT turnover found after immunization. The results are compatible with a significant effect of immune-mediated inflammatory response at an early phase after Freund's adjuvant injection on ACTH, GH, prolactin, and TSH release, which is partially sensitive to immunosuppression by cyclosporine. (Chronobiology International, 14(3), 253–265, 1997)     

Effects of a dopaminergic stimulant,amfonelic acid,on anterior pituitary hormone release in conscious rats

The response of plasma LH, Prolactin, GH and TSH levels to systematic administration of a specific central dopaminergic stimulant, amfonelic acid (AFA), by intravenous pulse injection in ovariectomized (OVX) and OVX estrogen-progesterone primed conscious rats has been evaluated. Intravenous injection of 0.2 mg/kg of AFA had no influence on plasma LH concentration until 60 min after injection when it was significantly elevated. Increasing the dose to 1 mg/kg reduced LH titers at 15 and 30 min with a return to preinjection levels by 60 min. AFA produced a dose-dependent decrease in plasma prolactin levels; the decrease occurred as early as 5 min after injection. AFA, both at 0.2 and 1 mg/kg doses, was effective in producing a sharp, dose-related rise in plasma GH levels. By contrast, TSH levels were significantly suppressed by both doses of AFA. Injection of the 1 mg/kg dose of AFA did not modify plasma LH levels in OVX-steroid-primed animals, white producing a comparable effect on plasma prolactin, GH and TSH levels to that observed in OVX animals. The present results indicate that endogenously released DA can have profound effects on pituitary hormone release, inhibiting PRL and TSH discharge, stimulating GH release and either inhibiting or stimulating LH release.     

Role of arginine vasopressin in control of ACTH and LH release during stress

To determine the role of arginine vasopressin (AVP) in stress-induced release of anterior pituitary hormones, AVP antiserum or normal rabbit serum (NRS) was micro-injected into the 3rd ventricle of freely-moving, ovariectomized (OVX) female rats. A single 3 microliter injection was given, and 24 hours later, the injection was repeated 30 min prior to application of ether stress for 1 min. Although AVP antiserum had no effect on basal plasma ACTH concentrations, the elevation of plasma ACTH induced by ether stress was lowered significantly. Plasma LH tended to increase following ether stress but not significantly so; however, plasma LH following stress was significantly lower in the AVP antiserum-treated group than in the group pre-treated with NRS. Ether stress lowered plasma growth hormone (GH) levels and this lowering was slightly but significantly antagonized by AVP antiserum. Ether stress also elevated plasma prolactin (Prl) levels but these changes were not significantly modified by the antiserum. To evaluate any direct action of AVP on pituitary hormone secretion, the peptide was incubated with dispersed anterior pituitary cells for 2 hours. A dose-related release of ACTH occurred in doses ranging from 10 ng (10 p mole)-10 micrograms/tube, but there was no effect of AVP on release of LH. The release of other anterior pituitary hormones was also not affected except for a significant stimulation of TSH release at a high dose of AVP. The results indicate that AVP is involved in induction of ACTH and LH release during stress. The inhibitory action of the AVP antiserum on ACTH release may be mediated intrahypothalamically by blocking the stimulatory action of AVP on corticotropin-releasing factor (CRF) neurons and/or also in part by direct blockade of the stimulatory action of vasopressin on the pituitary. The effects of vasopressin on LH release are presumably brought about by blockade of a stimulatory action of AVP on the LHRH neuronal terminals.     

Variety of GH and TSH responses to somatostatin in perfused rat pituitaries in vitro.

One male rat pituitary placed in a chamber was perifused with cyclic somatostatin (GIF) for 30 min. Either 160 nM or 1.6 muM GIF caused a decrease in the release of GH. The release of TSH was also decreased by 160 nM GIF, and paradoxically increased by 1.6 muM GIF. Increasing the dose of GIF to 16 muM resulted in an abrupt rise in the release of both GH and TSH during the perfusion; then the level of GH decreased to the nadir level followed by an elevation above the base line, while that of TSH promptly fell back toward the base line. The release of PRL was not clearly affected by 16 muM GIF. [Tyr8]-GIF did not have such stimulatory activities. These results indicate that GIF not only inhibits the release of GH and TSH, but also stimulates that of GH and TSH in this system, depending on its dose.     

Effects of intraventricular injection of gastrin on release of LH,prolactin, TSH and GH in conscious ovariectomized rats

Conscious ovariectomized (OVX) rats bearing a cannula implanted in the 3rd ventricle were injected with 2 μl of 0.9% NaCl containing varying doses of synthetic gastrin and plasma gonadotropin, GH and TSH levels were measured by RIA in jugular blood samples drawn through an indwelling silastic catheter. Control injections of saline iv or into the 3rd ventricle did not modify plasma hormone levels. Intraventricular injection of 1 or 5 μg gastrin produced significant suppression of plasma LH and prolactin (Prl) levels within 5 min of injection. Injection of 1 μg gastrin had no effect on plasma GH, but increasing the dose to 5 μg induced a progressive elevation, which reached peak levels at 60 min. By contrast, TSH levels were lowered by both doses of gastrin within 5 min of injection and the lowering persisted for 60 min. Intravenous injection of gastrin had no effect on plasma gonadotropin, GH and TSH, but induced an elevation in Prl levels. $\text{In}$$\text{vitro}$ incubation of hemipituitaries with gastrin failed to modify gonadotropin, GH or Prl but slightly inhibited TSH release at the highest dose of 5 μg gastrin. The results indicate that synthetic gastrin can alter pituitary hormone release in unrestrained OVX rats and implicate a hypothalamic site of action for the peptide to alter release of a gonadotropin, Prl and GH. Its effect on TSH release may be mediated both via hypothalamic neurons and by a direct action on pituitary thyrotrophs.     

The pituitary-thyroid axis in acromegaly

The pituitary-thyroid axis of 12 acromegalic patients was evaluated by measurement of the serum concentrations (total and free) of thyroxine (T4), triiodothyronine (T3) and reverse T3 (rT3) and thyrotropin (TSH), growth hormone (GH) and prolactin (PRL) before and after iv stimulation with thyrotropin releasing hormone (TRH). Using an ultrasensitive method of TSH measurement (IRMA) basal serum TSH levels of the patients (0.76, 0.07-1.90 mIU/l) were found slightly, but significantly (P less than 0.01), lower than in 40 healthy controls (1.40, 0.41-2.50 mIU/l). The total T4 levels (TT4) were also reduced (84, 69-106 nmol/l vs 100, 72-156 nmol/l, P less than 0.01) and significantly correlated (P less than 0.02, R = 0.69) to the TSH response to TRH, suggesting a slight central hypothyroidism. The acromegalics had, however, normal serum levels of TT3 (1.79, 1.23-2.52 nmol/l vs 1.74, 0.78-2.84 nmol/l, P greater than 0.10), but significantly decreased levels of TrT3 (0.173, 0.077-0.430 nmol/l vs 0.368, 0.154-0.584 nmol/l, P less than 0.01) compared to the controls. The serum concentration of the free iodothyronines (FT4, FT3, FrT3) showed similar differences between acromegalics and normal controls. All the acromegalics showed a rise of serum TSH, GH and PRL after TRH. Positive correlation (P less than 0.05, R = 0.59) was found between the TSH and GH responses, but not between these two parameters and the PRL response to TRH. These findings may be explained by the existence of a central suppression of the TSH and GH secretion in acromegalic subjects, possibly exerted by somatostatin. Euthyroidism might be maintained by an increased extrathyroidal conversion of T4 to T3.     

Effects of phorbol ester on GH, TSH and PRL release by superfused rat adenohypophysis

The present study was undertaken to examine the effects of 12-0-tetradecanoyl-phorbol-13-acetate (TPA), one of the potent tumor promoting agents, on GH, TSH and PRL release by rat adenohypophyseal dispersed cells and fragments, using a superfusion technique. TPA (10(-6) to 10(-5) M) stimulated GH release from acutely dispersed rat adenohypophyseal cells. Neither TSH nor PRL was affected, but both were increased by TRH in a dose-dependent fashion (10(-9) to 10(-7) M). In fragments, TPA (10(-8) to 10(-6) M) elicited a dose-related release of GH. Exposure of the fragments to 10(-6) M TPA for 5 min promptly caused a 5-fold increase in GH release which continued for at least 40 min after stopping the stimulation. The addition of somatostatin (SRIF) (10(-7) M) decreased basal GH release and abolished GH release induced by 10(-6) M TPA. In contrast to GH, neither TSH nor PRL release was affected by TPA, but both were stimulated by TRH. These results indicate 1) that GH release is more sensitive to stimulation with TPA in normal rat anterior pituitaries in vitro than the release of TSH and PRL, and 2) that SRIF abolishes TPA-induced GH release.     

The effect of cyproheptadine on plasma growth hormone (GH) and on somatostatin response to GH-releasing hormone in man

Cyproheptadine (CPH)--a putative serotonin antagonist--is known to inhibit growth hormone (GH) response to various pharmacological stimuli, as well as during sleep. To elucidate the possible site at which this drug takes effect, we examined plasma GH and somatostatin response to i.v. GHRH1-44 (1 microgram/kg body wt.) before and after CPH treatment in 10 healthy volunteers. The oral administration of CPH (8-12 mg daily for 5 days; total dose 56 mg) significantly curbed GH response to GHRH as expressed in peak plasma GH values (32.0 +/- 6.1 micrograms/l vs. 12.6 +/- 3.2 micrograms/l; P less than 0.01) and in integrated GH response area (2368 +/- 517 micrograms x l-1 x 2 h vs. 744 +/- 172 micrograms x l-1 x 2 h; P less than 0.01). Plasma somatostatin levels did not change in response to GHRH.     

Serum thyrotropin response to combined arginine and thyrotropin-releasing hormone administration provides evidence for an altered somatostatinergic tone in acromegaly.

The aim of this study was to evaluate plasma thyrotropin (TSH), prolactin (PRL) and growth hormone (GH) responses to the TSH-releasing hormone (TRH) test and to a combined arginine-TRH test (ATT-TRH) in 10 normal subjects and in 15 acromegalic patients. In controls, TSH responsiveness to TRH was enhanced by ATT (p less than 0.001). When considering the 15 acromegalic patients as a whole, no significant difference in TSH responses was detected during the two tests. However, patients without suppression of plasma GH levels after oral glucose load showed an increased TSH responsiveness to the ATT-TRH test if compared to TRH alone (p less than 0.025), while patients with partial suppression of plasma GH levels after glucose ingestion showed a decreased TSH responsiveness to ATT-TRH (p less than 0.05). No difference was recorded in PRL and GH responses, evaluated as area under the curve, during TRH or ATT-TRH tests in controls and in acromegalics. In conclusion, (1) normal subjects have an enhanced TSH response to the ATT-TRH test and (2) acromegalic patients without suppression of GH levels after oral glucose load show a TSH responsiveness to the ATT-TRH test similar to that of controls, while acromegalics with partial GH suppression after oral glucose load have a decreased TSH responsiveness to the ATT-TRH test. These data suggest that acromegaly is a heterogeneous disease as far as the somatostatinergic tone is concerned.     

Acute and Chronic Treatments with Citalopram Lower Somatostatin Levels in Rat Brain Striatum Through Different Mechanisms

Abstract: The suggestion that somatostatin is involved in the pathophysiology of obsessive-compulsive disorder and the evidence that selective serotonin reuptake inhibitors show significant antiobsessional effect prompted us to examine the effect of citalopram, a selective and potent serotonin reuptake inhibitor, on the somatostatinergic system in different brain regions of the rat. A single intraperitoneal injection of 10 mg/kg citalopram significantly reduced somatostatin levels in the striatum and nucleus accumbens after 4 but not 1, 8, or 24 h. No changes were found in hippocampus. In addition, we found that the K⁺-evoked overflow of somatostatin-like immunoreactivity from striatal slices was significantly increased 1 h after a single injection of citalopram and was still higher, although not significantly, 4 h after the drug injection. Levels of preprosomatostatin mRNA were unchanged in striatum and accumbens 1 and 4 h after a single drug administration. In rats treated with citalopram (10 mg/kg i.p.) twice daily for 14 days, the levels of somatostatin and its mRNA were significantly decreased in the striatum but not in other brain regions 24 h after the last dose. No change was found in the basal or K⁺-evoked overflow of somatostatin-like immunoreactivity at 1, 4, and 24 h after the last drug injection. These results suggest that acute and chronic treatment with citalopram reduces somatostatin levels in striatum by different mechanisms. Whereas a single dose of the drug reduces somatostatin levels by increasing the release of the peptide, repeated drug treatment reduces the biosynthesis of somatostatin.