Search

Background: Radiation induces time-dependent loss of anterior pituitary function, attributed to damage of the pituitary gland and hypothalamic centres. The development of growth hormone deficiency (GHD) in irradiated acromegaly patients is not well defined., Objective: Detailed analysis of spontaneous 24-h GH and prolactin (PRL) secretion in relation to other pituitary functions and serum IGF-I concentrations in an attempt to find criteria for GHD in acromegalic patients with a GH response < 3 microg/l during the insulin tolerance test (ITT)., Design: Plasma hormone profiles obtained by 10 min sampling for 24 h in postoperatively irradiated acromegalic patients, compared with patients cured by surgery only and matched healthy controls., Setting/participants: University setting. Fifteen subjects in each group., Outcome Measures: GH and PRL secretory parameters quantified by deconvolution, cluster, cosinor and approximate entropy (ApEn) analyses, IGF-I concentrations., Results: Irradiation attenuated pulsatile secretion of GH and PRL, but total PRL secretion was unchanged. GH and PRL secretory regularity were diminished. Circadian timing remained intact. Pulsatile GH secretion and IGF-I were correlated (R = 0.30, P = 0.04). Criteria of pulsatile GH secretion = 12 microg/l/24 h and ApEn = 0.800 separated 12 of 15 irradiated patients from all others., Conclusion: Irradiated acromegaly patients with a subnormal GH response to ITT have very limited spontaneous GH secretion, with specific attenuation of the size of GH bursts and a highly irregular pattern, but with retained diurnal properties. These patients are thus likely GH-deficient and might benefit from GH replacement.

Six GH adenomas and three prolactinomas were investigated by light- and electron-microscopic morphological and immunocytochemical methods and the effect of vasoactive intestinal polypeptide (VIP) on growth hormone (GH) and prolactin (PRL) secretion was tested in vitro. The tumour cells of the acromegalic patients revealed both GH and PRL immunoreactivity while prolactinomas showed only PRL activity. All the adenomas stained immunocytochemically also for VIP. By electron microscopy, the tumours included two densely and two sparsely granulated GH, two mixed GH/PRL, and three sparsely granulated PRL adenomas. The dissociated cells were explanted, and cultured in vitro. The cultures in micro test plates were treated with VIP at different concentrations between 10(-5)-10(-12) M. GH and PRL contents in the culture media were measured by radioimmunoassay. GH release was significantly stimulated by VIP in a dose-dependent manner over the whole concentration range, while VIP was effective on the PRL release only at 10(-6)-10(-7) M concentration. The cells of a mixed adenoma were grown in Petri dishes and used for ultrastructural and immunocytochemical studies. The cytoplasmic structure of the cells treated with VIP corresponded to that of active hormone-secreting cells with large ergastoplasmic fields and Golgi zones containing secretory granules. Massive exocytotic events were encountered mainly in the GH-type cells. GH and PRL double immunocytochemistry showed the predominance of GH cells, many of them containing low amounts of PRL as well. Cells predominantly containing PRL were spread among them, they also might contain GH as well. Some of the cells contained only a single immunoreactive hormone. The intensity of gold labelling of the secretory granules appeared higher in the VIP-treated cells than in the untreated control ones which showed a cytoplasmic structure characteristic of glandular cells with low secretory activity. As all the adenoma cells both contained and reacted to VIP, our results are in agreement with an autocrine or paracrine effect of this peptide. The fine structure of the cells in the cultures treated with VIP supply an additional argument to the assumption that VIP may serve as a growth factor for these cell types.

The purpose of this study was to detect in vitro growth hormone (GH) and prolactin (PRL) secretion from adenomas clinically associated with GH or PRL hypersecretion. The reverse hemolytic plaque assay (RHPA) was applied in order to reveal possible differences among various morphologic adenoma types, and to examine the inhibitory effects of octreotide on GH release as well. The 20 surgically resected pituitary adenomas studied included 15 from acromegalic patients and 5 from patients with hyperprolactinemia. All adenomas were diagnosed by histology, immunocytochemistry and electron microscopy. Among tumors associated with acromegaly, 5 were densely granulated (DG), 5 were sparsely granulated (SG) somatotroph (SM) adenomas, 2 were mammosomatotroph (MSM) and 3 mixed somatotroph-lactotroph cell (mixed SM-LT) adenomas; tumors causing hyperprolactinemia included 4 lactotroph (LT) adenomas and 1 mixed SM-LT adenoma. GH release assessed by the RHPA corresponded to in vivo hormone secretion and to tissue immunoreactivity. Statistical analysis showed significant differences among all morphologic types of SM adenomas, exclusive of SG-SM adenomas compared to mixed SM-LT adenomas. The mean plaque size in DG-SM and MSM adenomas was significantly greater than that of SG-SM and mixed SM-LT adenomas, indicating higher GH secretion by the former two types during the same incubation time. PRL secretion was documented in 2 mixed SM-LT adenomas. Plaques for PRL, but not for GH were formed in all LT adenomas. In all SM and LT adenomas, cells producing large plaques represented a minority of the plaque-forming cell population, however, they accounted for the largest part of the total plaque area, thus the largest part of hormone secretion. Octreotide effects on GH release were studied in 6 adenomas by the RHPA. Octreotide treatment induced a rapid and significant reduction in GH secretion by SM cells in vitro, with a selective effect on high-secreting cells.

In order to gain insight into the neuroendocrine mechanism underlying the paradoxical GH response to TRH in acromegalic patients, we have investigated the effect of an infusion of Naloxone (Nal, 1.6 mg/hr for two hours), on a TRH test performed both in responder (n = 9) and non-responder (n = 5) acromegalic patients. The response of GH, PRL and TSH to TRH injection were evaluated. NAL did not exert significant variations in the GH response, even if different patterns of GH response during NAL were observed in the group of TRH-responder patients. Similarly, TRH-induced PRL response was not significantly affected by the infusion of an opiate antagonist. On the contrary, a significant inhibition of the TSH response was observed in the group of TRH-responder patients (delta TSH after TRH 4.76 +/- 1.11 microU/ml, after NAL + TRH 2.81 +/- 0.99 microU/ml, p < 0.05). No significant effects were observed in the TRH non-responder patients (delta TSH after TRH 4.58 +/- 1.44 microU/ml, after NAL + TRH 6.26 +/- 3.27 microU/ml). The differences observed in the two groups of patients could be ascribed to a different endogenous somatostatinergic tone and could furnish a prognostic indication in acromegalic patients.

The aim of the study was to evaluate the interrelation between the levels of growth hormone (GH), prolactin (PRL), somatomedin-C (Sm-C) and melatonin determined at 3 h intervals over a 24 h period (8.00, 11.00, 14.00, 17.00, 20.00, 23.00, 2.00 and 5.00) in 8 acromegalic patients after radiotherapy. The circadian rhythms and the interrelation between hormone and Sm-C levels were evaluated using Halberg's cosinor method and the correlation analysis, respectively. We observed a total abolition of melatonin rhythm with significantly lower nocturnal values in all patients which could be due to earlier radiotherapy.

Altogether 25 patients with acromegaly, 19 patients with prolactinomas, and 6 patients with nonfunctioning hypophyseal tumors (NHT) were investigated. Dopaminergic regulation of PRL, STH, TSH, LH and FSH was investigated with sulpiride (an antagonist of peripheral action) in all the patients. In acromegaly, irrespective of the presence of hyperprolactinemia, one can observe dysfunction of the central dopaminergic system (DAE) and DAE-regulation of adenohypophyseal hormones. Signs of disordered hormonal DAE-regulation are disorder of the normal ejection of PRL and pathological ejection of TSH in response to administration of DA antagonists. The results of investigations revealed both an enhanced tone of the DAE-system and insufficiency of DAE-control of hormonal secretion in patients with different hypophyseal tumors and other neuroendocrine diseases.

The role of dopaminergic agents (DA) in the regulation of growth hormone (GH) secretion was investigated in patients with untreated acromegaly. TRH (0.5 mg iv), bromocriptine (Br) (2.5 mg orally) or L-Dopa (500 mg orally) loading tests were performed, and serum levels of TSH, GH and prolactin (PRL) were measured. Patients were defined as responders to TRH when peak TSH level after TRH test was higher than 5 microU/ml. Br or L-Dopa was considered to be effective when serum GH or PRL levels were suppressed more than 50% of the basal value. The patients were classified into large adenoma group with suprasellar extension or cisternal herniation (L group, n = 7) and intrasellar small adenoma group (S group, n = 11) which was further divided into TRH responder (Sr group, n = 4) and TRH non-responder with suppressed TSH (Ss group, n = 7). Br was effective in 7 or 100% of 7 patients in the Ss group but only in one or 25% of 4 patients in the Sr group. Br was also effective in 5 or 71% of 7 patients in the L group, although most of them were responders to TRH. Percent inhibition of serum GH levels by Br was significantly higher in the Ss group (82.3 +/- 12.3%, p less than 0.001) and in the L group (64.7 +/- 20.5%, p less than 0.05) compared with that in the Sr group (29.3 +/- 21.6%). Suppression of serum GH level by L-Dopa was also observed in the Ss group. In contrast to the difference in the response of GH, serum PRL level was equally suppressed by Br or L-Dopa in each group. Suppression of TSH by administration of exogenous T4 had no effect on the GH suppression effect of Br in the Sr group. Considering the dual effects of DA to enhance growth hormone-releasing hormone (GHRH) secretion in the hypothalamus and to suppress GH secretion in the pituitary gland, these findings suggest that the paradoxical effect of DA to suppress serum GH level is observed when the hypothalamo-pituitary axis is disturbed mechanically by large adenoma in the L group or functionally in the Ss group probably due to enhanced secretion of somatostatin which suppresses TSH secretion and impairs the effect of GHRH.

We have investigated the relationship between the plasma PRL concentrations of 98 untreated acromegalic patients and the GH levels during basal and dynamic conditions. Hyperprolactinaemia was present in 27 patients. In patients with marked hyperprolactinaemia (PRL greater than 80 ng/ml or greater than 1600 mU/l), basal plasma PRL and the TRH-induced response correlated with basal plasma GH (correlation coefficients of 0.9, P less than 0.001 and 0.74, P less than 0.02, respectively). The PRL response to TRH also correlated with GH response to TRH (r = 0.38, P less than 0.01). In contrast, in patients with moderately elevated PRL (20 to 80 ng/ml), and in those with normal plasma PRL (less than 20 ng/ml or less than 400 mU/l), no such correlations were found. Immunostaining for PRL was positive in 24 out of 25 adenomas of patients with hyperprolactinaemia, while no PRL was found in the tumour tissue of 10 normoprolactinaemic patients. In conclusion, our data suggest the existence of two populations of acromegalic patients with hyperprolactinaemia, one group with correlations between GH and PRL secretion, and the other without.

The results are presented of the treatment of 31 females with different hypothalamic-hypophyseal abnormalities: persisting lactorrhea-amenorrhea syndrome, acromegaly, hypothalamic syndrome, lactorrhea syndrome without amenorrhea. The effect of parlodel acute load on STH and the blood serum prolactin content was studied. It was concluded, that parlodel acute load produces a marked decrease in the prolactin level 2 hours after the drug injection both in the patients with an originally elevated prolactin level, and in the subjects, having the prolactin level within normal. Significant changes in the STH level were not observed 2 hours after parlodel load.

The effect of dopamine on thyrotropin (TSH) and prolactin (PRL) levels was studied in 5 normal subjects, 7 women with galactorrhea, 9 acromegalics and 4 patients with primary hypothyroidism. Dopamine infused at the rate of 280 micrograms/min produced significant decrease in plasma TSH and PRL levels in all four groups, though a lower fall in TSH was noted in acromegalics. A similar reduction in PRL was also noted after 28 micrograms/min dopamine. Phentolamine infusion (0.5 mg/min) had no effect on PRL response to dopamine. These results indicate that a dopaminergic stimulation led to an inhibition of TSH and PRL secretion. Since the high polarity of dopamine impedes its passage through the blood-brain barrier, its site of action should be outside this barrier, probably in the pituitary.

Dependence of lactorrhea on the basic blood level of somatotropic hormone (STH), prolactin (PL), folliculostimulating hormone (FSH), and luteinizing hormone (LH) was studied in 62 patients with an active phase of acromegaly, untreated, and in 41 with inactive phase of the disease following radiation therapy. Thyrotropic hormone (TTH), PL, and STH secretion (basic and after intravenous injection of 200 micrograms of thyroliberin) was determined in 20 patients with active and in 6--with inactive acromegaly following radiation therapy. In patients with active acromegaly the percentage of lactorrhea in women constituted 60 and in men--9.5, and with inactive acromegaly (after radiation therapy) it was 13.3 and 0, respectively. Basic PL level was significantly elevated in both groups of patients. The principle role in the pathologenesis of lactorrhea in acromegaly proved to be played by increased PL secretion. Under the effect of thyroliberin PL secretion was significantly elevated in comparison with control in 15 patients with active acromegaly and in all cases at the stage of remission. Basic TTH level and this level after thyroliberlin stimulation was within the normal range. In 4 patients with lactorrhea the absence of TTH secretion was combined with unresponsiveness of PL secretion, this suggesting the presence of tumour growth. STH secretion was independent of lactorrhea both under basic conditions and after thyroliberin stimulation.

Plasma from a 69-year-old acromegalic woman with hyperprolactinemia (350-570 ng/ml) was chromatographed on dextran gel. Three components of immunoactive prolactin were observed. Component I eluted with an apparent molecular weight (MWapp) of greater than 100,000, Component II with MWapp of 45,000 and Component III with MWapp of 21,500 daltons (indistinguishable from monomeric pituitary prolactin). Components I and II comprised more than 70% of the total circulating prolactin. All components had similar activities in immunoassays and in receptor assays. Components II and III maintained their elution positions on re-chromatography. Component I whether frozen or stored at 4 C eluted in the position of Component II on rechromatography, suggesting that Component I is a loosely-bound oligomer of Components II or III, or Component III loosely-bound to another constituent of plasma. The gel chromatography pattern for immunoactive growth hormone was indistinguishable from that of other acromegalic patients.

Plasma levels of growth hormone (GH) and prolactin (PRL) were measured in twelve acromegalic patients after acute administration of an ergoline derivative (methergoline) which has been proposed as a specific serotoninergic blocking agent. The administration of methergoline (4 mg p.o.) was followed by a significant decrease in plasma GH and PRL concentrations. The administration to the same subjects of CB 154 (2.5 mg p.o.), a known stimulator of dopaminergic receptors, led to results almost superimposable to those obtained with methergoline although the suppressive effect of CB 154 on GH and PRL levels was more sustained. Also on the ground of results obtained in these patients with the use of cyproheptadine, phentolamine, or pimozide, we have concluded that methergoline inhibition of GH and PRL release is, in acromegalic patients, most probably due to a dopaminergic mechanism of action.

The serum TSH and prolactin responses to dopamine receptor blockade (domperidone 10 mg i.v.) were measured in eight acromegalic subjects and seven normal controls. The serum TSH response was exaggerated in acromegalics when compared to controls (sum of the increments 12.2 +/- 2.8 mU/l and 4.0 +/- 1.2 mU/l respectively P less than 0.05), whereas the serum prolactin response was blunted (sum of the increments 5029 +/- 1377 mU/l and 14 673 +/- 2889 mU/l respectively P less than 0.01). Dopamine receptor blockade did not significantly alter basal growth hormone levels in either group. To ascertain whether this response was merely a reflection of high circulating growth hormone levels six normal controls were pretreated for 24 h with either intramuscular growth hormone (three injections of 4 IU) or an equivalent volume of saline before the administration of domperidone (10 mg i.v.). The serum TSH and prolactin responses were not affected by prior growth hormone treatment. The opposite TSH and prolactin responses to dopamine blockade do not allow any firm conclusions to be made about the level of hypothalamic dopamine activity in acromegaly.

An in vitro technique for continuous perifusion of human pituitary has been developed to study the effect of dopamine on hormone release. Pituitary tissue was obtained from 2 patients with prolactinomas, 3 patients with acromegaly and 2 patients with disseminated malignancy whose pituitaries were normal. During perifusion prolactin release was reversibly inhibited from both normal and adenomatous glands, confirming the direct effect of dopamine on the pituitary. Rebound secretion following inhibition suggested that dopamine acted upon hormone release rather than synthesis under these conditions. Growth hormone (GH) release in vivo is stimulated by levodopa in normal subjects but inhibited in acromegaly. In vitro, however, we have demonstrated inhibition of GH release by dopamine, regardless of whether the pituitary was normal or adenomatous. This finding does not support the view that dopamine receptors are acquired by tumour cells as a result of adenomatous dedifferentiation. It is suggested that the paradoxical GH response to levodopa in acromegaly can be explained by a dual action of dopamine at hypothalamic and pituitary levels. According to this hypothesis GH release is stimulated by a hypothalamic effect, whereas inhibition occurs at pituitary level. The net effect of these opposing stimuli in vivo may depend upon the sensitivity of dopamine receptors at the prevailing concentration of GH.

In six acromegalite patients oral administration of 4 mg of metergoline, an antiserotonin agent, produced a fall in plasma growth hormone (GH) and prolactin (PRL) concentrations. In the same patients this inhibitory effect was observed after administration of dopaminergic drugs, L-Dopa and 2-Br-alpha-ergocryptine. Both GH and PRL levels remained suppressed during a 6 day course of treatmnt with metergoline. These results are consistent with the hypothesis that the inhibitory effect of netergoline on GH and PRL release is determined by inactivation of serotonin receptors in the hypothalamus or at the pituitary.

The basal PRL levels and after estimulation with synthetic TRH were evaluated in 12 patients with active acromegaly, and in 12 normal individuals. None of the patients had galactorrhea and 5 of them had tumoral supra-sellar extension. Basal hyperprolactinemia was detected in 66% of the patients. After TRH stimulation, only 4 patients exhibited a percentual increment greater than 100% over the PRL basal value. PRL response to TRH was negative in 8 patients. The high PRL levels can be explained by the parallel production of GH and PRL by the tumoral cells, nevertheless a disturbance of the normal hypothalamic control cannot be excluded.

Metoclopramide (DA-antagonist, M) tests were performed in 21 patients with acromegaly and in controls; the levels of adrenohypophyseal hormones were determined before and after drug administration. Irrespective of the basal level of prolactin (P) all the patients demonstrated a decrease in stimulated P secretion which was more noticeable in patients with hyperprolactinemia. The hyperergic response of TSH to M administration was observed in some of the patients with acromegaly. Such a response indicated an elevated tone of the dopaminergic (DA) system. The results obtained were suggestive of dysfunction of DA regulation of P secretion in all the patients with acromegaly.

The 24-h PRL and LH hormone profiles were analysed of 16 cured male acromegalic patients who had undergone selective transsphenoidal surgery 4-9 years previously. Eight of these patients also underwent pituitary irradiation. Blood samples were taken at 20-min intervals; the PRL and LH data were analysed with the cluster program. ARIMA modelling, cross-correlation techniques, Fourier analysis, and cosinor analysis. About 10-11 PRL and LH peaks were demonstrated for both non-irradiated and irradiated patients. The absolute heights of PRL pulses and the mean valley levels were significantly greater for irradiated patients than for non-irradiated patients, but the increment in amplitude did not differ. A significant diurnal rhythm for PRL was found for all non-irradiated patients but for only one irradiated patient. LH pulse area and amplitude were lower in the group of irradiated patients. The incremental responses of LH and PRL to GnRH and TRH, respectively, were lower in irradiated patients than in non-irradiated patients. During the night (0200-0800 h) the number of PRL pulses decreased in non-irradiated patients but not in irradiated patients. Pulse nadirs and amplitudes increased during the evening and night in non-irradiated patients but were constant in irradiated subjects. Bivariate modelling of the data for 14 patients revealed significant cross-correlations between LH and PRL pulses in nine subjects. This study demonstrates that the pulsatile secretion of PRL and LH in treated acromegalics is basically normal. Additional radiation therapy, however, may lead to damage of the hypothalamus, as reflected by the absence of a circadian PRL rhythm. A direct influence on the pituitary by radiation is indicated by the decreased magnitude of LH pulses and the diminished response of LH and PRL after injection of GnRH and TRH, respectively.

Ten patients with active acromegaly were studied. In 9 plasma GH levels failed to suppress after glucose (OGTT), in 8 an increase in serum GH occurred after thyrotropin releasing hormone (TRH). After L-Dopa, 4 patients showed no change in serum GH, 3 exhibited a decrease and in 3 an increase in serum hGH occurred. With a combined insulin (ITT) and arginine (ATT) test, 2 patients exhibited an increase in hGH, and in 6 no change occurred. Fasting serum GH concentration was less than 11 ng/ml in 5 patients. Basal prolactin (hPRL) levels were normal in all patients including two with galactorrhea. L-Dopa suppressed and TRH stimulated hPRL secretion in all, but the responses which were seen were subnormal. Hydrocortisone infusion in two acromegalics did not affect the prolactin induced increase after TRH but blunted the GH increase after TRH.

The plasma GH, PRL, TSH, and dopamine (DA) responses to an infusion of L-dopa were examined in six acromegalic patients before and after pretreatment with carbidopa, a drug which inhibits the peripheral conversion of L-dopa to DA. Carbidopa neither modified baseline DA nor induced changes in baseline GH, PRL, or TSH levels. The drug instead markedly reduced the L-dopa-induced DA rise, an effect which was concomitant to a striking reduction of the suppressive effect of L-dopa on plasma GH and a partial inhibition of the suppressive effect of L-dopa on plasma PRL. TSH levels did not change either after L-dopa alone or L-dopa plus carbidopa. These data demonstrate that in "responder" acromegalics, L-dopa inhibits GH secretion through its peripheral conversion to DA and not via activation of central DA neurotransmission. For the effect of L-dopa on PRL secretion, in addition to a peripheral dopaminergic component, a central component cannot be disregarded.

An acromegalic patient with galactorrhea was treated with an ergot alkaloid, 2-Br-alpha-ergocryptine (CB-154). Serum prolactin decreased rapidly to normal level by CB-154 and the complete cessation of galactorrhea was noted. The inhibitory effect of CB-154 On growth hormone (GH) release was also noted, but slight. The mechanism of inhibitory action of CB-154 on both prolactin and GH secretion was discussed in connection with the experimental model of pituitary tumors, in which both hormones were produced by a single type of tumor cells. The discontinuation of CB-154 treatment was associated with the return of both prolactin and GH levels to the initial high values with resumption of galactorrhea.

An extensive hypothalamic neurotransmitter impairment has been proposed in acromegaly. However, at the moment, the hypothalamic GABAergic system has been little investigated in this disorder. Since GABA has been shown to modulate growth hormone (GH) and prolactin (PRL) secretion in human subjects, it seemed reasonable to investigate hypothalamic GABAergic functioning through the assessment of basal GH and PRL responses to pharmacological activation of this system. 800 mg of sodium valproate (SV), a drug with GABA facilitating properties, were administered orally to 7 acromegalic patients and 9 healthy volunteers. Blood samples were collected before and after the drug administration for the measurement of plasma GH and PRL levels. SV induced a clear-cut rise in basal GH and a decrease in basal PRL in healthy subjects, but it did not induce any change in the basal levels of these hormones in acromegalics. These results suggest that the response of GH and PRL to SV in acromegaly is qualitatively different from normal controls.

The effects of ergot alkaloids (mainly bromocriptine) on the secretion of GH and PRL in normal subjects and in pathological conditions (i.e. acromegaly and hyperprolactinemic states) are discussed. In the normal subjects, bromocriptine releases GH whereas in about 50% of acromegalics it causes a marked and long-lasting inhibition of the hormone secretion. PRL release is reduced by the drug both in normal subjects and in hyperprolactinemic states. Physiopathological studies in the humans indicate that, according to the experimental data, bromocriptine inhibits GH release in acromegaly and PRL secretion through a dopaminergic mechanism of action playing at the pituitary level. Data are reported on the effectiveness of bromocriptine in the medical treatment of acromegaly and of hyperprolactinemic states.

The effect of somatostatin on the thyrotropin (TSH), prolactin, growth hormone (GH) and insulin responses to the combined administration of thyrotropin releasing hormone (TRH) and arginine was studied in six healthy subjects, three hypothyroid patients and three acromegalic patients. Similar inhibition by somatostatin of the TSH and insulin responses was observed in the three groups. While the tetradecapeptide had no significant effect on the prolactin response in the healthy and acromegalic subjects, it caused an unexpected inhibition of the prolactin response in two of the hypothyroid subjects. Contrary to the findings in the healthy and hypothyroid subjects, somatostatin did not inhibit the GH response in the acromegalic patients. Normal inhibition by somatostatin of the insulin response, followed by a rebound in insulin secretion, was observed in all subjects. These preliminary data indicate increased sensitivity of the prolactin-secreting cells to somatostatin in hypothyroidism and suggest that decreased responsiveness of the somatotrophs to somatostatin could play a role in the pathogenesis of acromegaly.

The effect of an iv injection of growth hormone releasing factor (GRF) on Prl secretion in healthy volunteers and patients with active acromegaly was investigated. Thirteen normal subjects received 100 micrograms GRF 1-44, and 19 acromegalics received 100 micrograms GRF 1-44. Nine normals and 9 patients were given the diluent only and served as placebo control. In healthy volunteers GRF did not affect Prl secretion significantly when compared to placebo, whereas in acromegalics Prl levels after GRF were higher than after placebo. We have divided acromegalics in Prl-responders to GRF (n = 11) and Prl-non-responders (n = 8) using the criterion of strict parallelism between GH and Prl secretion after GRF. In cases with no GH response to GRF a clear increase of Prl levels with the maximum 15-30 min after GRF was also regarded as a Prl response. Acromegalic Prl-responders and Prl-non-responders did not significantly differ in age, sex, previous therapy, and basal GH and Prl levels. However, Prl-non-responders had a significantly reduced response of both GH and Prl to TRH (GH: 147.3 +/- 16.0 vs 590.1 +/- 127.8%; mean +/- SE; Prl: 159.4 +/- 32.6 vs 504.9 +/- 109.3%). It is concluded that 50 or 100 micrograms GRF does not affect Prl secretion in normal subjects. In contrast, in acromegaly GRF leads to Prl secretion in more than half of all patients.

The degree of autonomy in prolactin secreting pituitary adenomas and also prolactin secretory reserve in cases with suspected functional galactorrhea syndrome was evaluated with the use of metoclopramide, TRH and L-DOPA. It was found that in patients with pituitary adenoma the basal prolactin (PRL) level often exceeded 150 micrograms/l and the response to stimulation with TRH and/or metoclopramide was markedly diminished or even nonexistent, while the response to L-DOPA was usually retained. In patients with galactorrhoea and/or amenorrhoea, with normal skull X-ray the basal PRL level was either normal or moderately raised but the response to stimulation was various; mostly it was excessive, it was sometimes normal, but in some other cases it was markedly diminished as in patients with adenoma. In the author's opinion the so-called "functional disorder" of prolactin secretion is mainly hyperresponsiveness to stimulation, whereas the basal PRL level in those cases is usually normal or only intermittently raised. In the cases with a moderate hyperprolactinaemia, especially if it appears to be constant, and the response to stimulation is diminished or none at all, we suspect a pituitary microadenoma. Finally, there are rare cases of galactorrhoea with normal basal PRL and normal response to stimulation, in which the sensitivity of the mammary PRL receptor is probably increased. We suggest therefore that the above mentioned PRL stimulation tests may help in distinguishing between tumoural and functional hyperprolactinaemia.

In an attempt to evaluate the effect of LRH on GH and PRL secretion, LRH in a dose of 100 micrograms was injected iv to 22 patients with active acromegaly. A definite increase in both serum GH and PRL levels was observed in one patient, while four other subjects responded to LRH to secret either GH or PRL. The effectiveness of LRH on GH and PRL release was not correlated with the age or sex of patients, the basal levels of serum GH or PRL, the GH response to TRH administration, or the increase in serum gonadotropin concentrations after LRH injection. In three patients, this LRH-induced GH and PRL release was completely blocked by pretreatment with 2-bromo-alpha-ergocriptine (CB154). The results suggest that elevations of GH and PRL after LRH occur rather sporadically in acromegalic patients and that the action of LRH on GH release is occasioned by a different mechanism from that of TRH.

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.