Different responses of growth hormone secretion to guanfacine, bromocriptine, and thyrotropin-releasing hormone in acromegalic patients with pure growth hormone (GH)-containing and mixed GH/prolactin-containing pituitary adenomas

There is great variability in the GH secretory responses to different stimuli in patients with acromegaly. In the present study, we compared the effects on GH secretion of two compounds (bromocriptine and TRH), which presumably act directly at the pituitary level, with the effect of the centrally acting alpha-adrenergic agonist guanfacine in 14 untreated acromegalic patients. These in vivo responses of GH release were correlated with the results of immunocytochemical studies of the pituitary adenomas. In nine patients with pure GH-containing adenomas, GH secretion was suppressed by bromocriptine by more than 50% in one patient, while TRH stimulated GH release by more than 100% in another patient. Guanfacine (2 mg, orally) did not elicit a change in circulating GH levels in any of these nine patients. In the group of five patients with mixed GH/PRL-containing adenomas, however, bromocriptine suppressed GH levels by more than 50% in all patients, and TRH stimulated GH release by more than 100% in four of them. Guanfacine stimulated GH secretion significantly in four of these five patients. Guanfacine inhibited GH secretion significantly in five other acromegalic patients who had been treated 5-10 yr previously by external pituitary irradiation. We conclude that in acromegaly, the presence of PRL within the GH-secreting pituitary adenoma makes GH secretion more sensitive to bromocriptine and TRH, while normal sensitivity to hypothalamus-mediated stimulation (alpha-adrenergic agonist) is retained to some extent. In contrast, pure GH-secreting tumors responded little or not at all to bromocriptine, TRH, or guanfacine.     

Growth hormone and prolactin secretion by dispersed cell cultures of a normal human pituitary: effects of thyrotrophin releasing hormone, theophylline, somatostatin, and 2-bromo-alpha-ergocryptine

Growth hormone (GH) and prolactin (Prl) secretion by a normal human pituitary in dispersed cell culture has been investigated. Prl secretion was significantly stimulated after 0.5, 1, 2 and 4 h exposure to 1, 10, 100 and 1000 ng/ml thyrotrophin releasing hormone (TRH). Maximal effects were obtained with 10 ng/ml TRH at 2 h, higher doses being less effective. GH secretion was unchanged with the exception that 1 ng/ml TRH produced a small decrease at 4 h. GH and Prl secretion was significantly inhibited by incubation with 0.01, 0.1, 1 or 10 micrograms/ml 2-bromo-alpha-ergocryptine (bromocriptine). The inhibition persisted for a further 24 h after removal of bromocriptine. Theophylline (10(-2) M) significantly increased GH and Prl secretion during a 4 h incubation and this effect was blocked by co-incubation with 10 ng/ml somatostatin (SRIF). SRIF also inhibited basal GH and Prl secretion during 4 h and removal of SRIF and incubation for at further 4 h led to a rebound in GH and Prl secretion to levels greater than control. It is concluded that cell culture techniques previously applied to the study of hormone secretion by pituitary adenomas can be equally applied to the normal human pituitary.     

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.     

Somatostatin receptors in human growth hormone and prolactin-secreting pituitary adenomas

[125I-Tyr]Somatostatin [( 125I-Tyr]SRIH) binding was found in 11 GH-secreting pituitary adenomas [Kd = 0.46 +/- 0.15 (+/- SE) nM; maximum binding, 165 +/- 35 fmol/mg protein). This binding was specific, since it was displaced by somatostatin-14 (SRIH-14), N-Tyr-SRIH-14, and SRIH-28. In contrast, a number of peptides and drugs not structurally related to SRIH, such as bombesin, dopamine, LHRH, met-enkephalin, naloxone, neurotensin, secretin, substance P, TRH, or vasoactive intestinal peptide, did not affect [125I-Tyr]SRIH binding. [125I-Tyr]SRIH specific binding also was found in PRL-secreting pituitary adenomas. The kinetic characteristics of the specific binding were similar to those of GH-secreting adenomas. However, maximal binding was one quarter that of GH-secreting adenomas (37 +/- 9 fmol/mg protein). In contrast, nonsecreting (chromophobe) tumors were devoid of any specific binding. Finally, in acromegaly, the density of [125I-Tyr]SRIH-binding sites in the adenomas was negatively correlated with plasma GH levels before surgery (r = -0.80). This suggests that somatostatinergic control is involved in GH secretion in acromegalic patients.     

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.     

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.     

Preoperative growth hormone response to thyrotropin-releasing hormone and oral glucose tolerance test in acromegaly: a retrospective evaluation of 50 patients

The objective of this study was to investigate the relationship between growth hormone (GH) dynamic tests (thyrotropin-releasing hormone [TRH] test and oral glucose tolerance test [OGTT]), insulin-like growth factor-I (IGF-I) plasma values, tumor size, and clinical outcome in patients with GH-secreting pituitary adenomas. Furthermore, we investigated the potential prognostic utility of the above biochemical parameters in the follow-up of patients with acromegaly. We studied 50 acromegalic patients (18 males and 32 females; mean age, 40 years; range, 16 to 69) who underwent trans-sphenoidal removal of a GH-secreting pituitary adenoma from 1990 to 1994. Preoperatively, we evaluated (1) GH plasmatic levels after an oral glucose load (OGTT) (blood samples were drawn at -15, 0, 30, 60, 90, 120, 150, and 180 minutes after oral administration of 0.75 g/kg body weight [BW] of glucose), (2) GH plasma levels after a TRH test (200 microg as an intravenous [IV] bolus), and (3) basal IGF-I plasma levels after an overnight fast. From 3 to 12 months after surgery we evaluated (1) GH plasma values after an OGTT, and (2) basal plasma IGF-I, free triiodothyronine (FT(3)), free thyroxine (FT(4)), thyroid-stimulating hormone (TSH), and urinary free cortisol. The same tests were performed every year for 5 years. All of the patients were classified into 4 subgroups according to the system of Hardy and Vezina. Preoperatively, "controlled" patients (n = 29) had a GH paradoxical response to TRH (n = 28) and an unresponsiveness to OGTT (n = 29); 23 of them belonged to the I and II classes. Only 5 poorly controlled patients (n = 21) showed a preoperative paradoxical response to TRH and 9 had a preoperative GH partial inhibition after OGTT; 19 of them belonged to the III and IV classes. Our data suggest that in the preoperative period in acromegalic patients the simultaneous presence of a GH paradoxical response to TRH and lack of GH inhibition after OGTT is inversely related to the tumor size and therefore more likely to be restored to normal by surgical treatment.     

Effect of bromocriptine, somatostatin, and oestradiol-17 beta on hormone secretion and ultrastructure of human pituitary tumours in vitro

The effect of bromocriptine and somatostatin on hormone secretion and the ultrastructure of human pituitary adenomas was studied in vitro. Prolactin secretion was inhibited by bromocriptine in 3 out of 10 prolactin-secreting tumours and in explants from 2 normal pituitaries. GH secretion was reduced by bromocriptine in 4 out of 6 GH-secreting adenomas but was not affected by the drug in the incubations of normal pituitaries. Somatostatin inhibited GH secretion in 2 out of 5 pituitary adenomas and the effect was comparable with that of bromocriptine. Incubation of prolactin-secreting adenomas with oestradiol for as long as 24 days produced no change in hormone secretion. Examination of tumour explants by electron microscopy showed that somatostatin and bromocriptine produced accumulation of secretion granules but no changes in the secretory organelles. Long term bromocriptine treatment of "nude" athymic mice bearing xenografts of human pituitary adenomas suppressed hormone secretion and produced some increase in secretion granules but there were no morphological changes in the secretory organelles or other vital structures of the adenoma cells.     

PARENTERAL BROMOCRIPTINE IN THE TREATMENT OF HORMONALLY ACTIVE PITUITARY TUMOURS

Eleven patients with PRL and three with GH-secreting pituitary adenomas were treated with a single intramuscular injection of 50 mg of bromocriptine retard (Parlodel, LA (long-acting)). There was a marked PRL suppression in 9 prolactinoma patients, in four for a period of at least 6 weeks. In one patient with acromegaly GH plasma levels decreased into the normal range. The size of the pituitary adenoma diminished considerably, as shown by CT scan, in three out of the 9 responding patients with prolactinoma and in the above acromegalic patient. Visual fields normalized within 14 d in one patient with a PRL-secreting macroadenoma and bitemporal hemianopsia who also had CT scan-documented shrinkage of the tumour. There were no side-effects except slight hypotension in two and local tenderness at the injection site in one patient; these symptoms disappeared without treatment. It is concluded that bromocriptine retard is a safe and effective therapeutic tool for shrinking hormonally active pituitary tumours in selected patients. Due to its good tolerance and the rapid hormonal and clinical improvement it may be also considered as the best therapeutic approach to initiate the treatment of PRL- and/or GH-secreting pituitary tumours.     

In vitro effect of dopamine and L-dopa on prolactin and growth hormone release from human pituitary adenomas.

To determine the site of action of dopaminergic drugs on human PRL and GH release from pituitary adenomas, five PRL-and five GH-secreting adenomas were incubated with and without dopamine and L-dopa. Bromocriptine was also tested in order to compare its effect to that of the other drugs. In all of the experiments except one, a decrease of PRL, which was often statistically significant, was observed. When pooling the results of the PRL-secreting adenomas, the mean levels of PRL with dopamine, L-dopa, and bromocriptine were, respectively, 49%, 55%, and 60% of the control levels. In the GH-secreting adenomas, they were 60%, 67%, and 55% of that of the control. For GH, a decrease of the release was observed in four out of five GH-secreting adenomas. When pooling the results from these tumors, the mean levels of GH with dopamine, L-dopa, and bromocriptine were, respectively, 63%, 76%, and 64% of the control levels. In one case, a significant increase of GH was observed with the three dopaminergic drugs. This study produced the following conclusions. 1) Dopamine acts directly on PRL and GH release from human pituitary adenomas; in vitro, L-dopa effects are similar (its action probably occurs after conversion to catecholamines). These observations strongly suggest the presence of dopaminergic membrane receptors on human lactotroph and somatotroph adenomatous pituitary cells. 2) In vitro hormonal results are in good agreement with in vivo dynamic tests using L-dopa and bromocriptine. 3) The paradoxical effect of dopaminergic drugs on GH secretion in acromegalic patients may be attributed to modified dopamine membrane receptors. However, the paradoxical response is not a constant feature in acromegaly, and its mechanism needs further investigations.     

Prevalence of Gs alpha mutations in Korean patients with pituitary adenomas

The reported frequencies of Gs alpha mutations (gsp mutations) in growth hormone (GH)-secreting pituitary adenomas are variable (ranging from 4.4 to 43%), and the presence of these mutations in the other pituitary adenomas is still a matter of controversy. Previous clinical and biochemical analyses of patients with GH-secreting pituitary adenomas and gsp mutations produced conflicting results and did not demonstrate obvious characteristics. Therefore, we investigated the prevalence of gsp mutations in Korean patients with pituitary adenomas and elucidated the characteristics of these patients. Forty-four GH-secreting adenomas, 7 prolactin (PRL)-secreting adenomas and 32 clinically non-functioning adenomas were examined for the presence of point mutations in codon 201 and 227 of the Gs alpha gene using a nested PCR and direct sequencing of DNA extracted from fresh tissue or paraffin-embedded pituitary adenoma samples. Seven of the 44 GH-secreting pituitary adenomas had point mutations at codon 201 or 227; of these, five mutations were in codon 201 and two were in codon 227. In patients with gsp mutations, mean tumor size was significantly smaller than in patients without gsp mutations (15.9+/-8.7 mm vs. 24.9+/-14.9 mm, P<0.05). Age, sex, basal GH levels, GH response to oral glucose loading, GH response to octreotide and surgical outcome were not different in the two groups. One of the 32 clinically non-functioning pituitary adenomas had a point mutation at codon 201; none of the seven prolactinomas had these mutations. These results show that gsp mutations are not rare in Korean acromegalic patients and mean tumor size is significantly smaller in acromegalic patients with gsp mutations. Our results also confirm the low frequency of gsp mutations in clinically non-functioning pituitary adenomas and the absence of gsp mutations in prolactinoma.     

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.     

Characterization of growth hormone-releasing hormone receptors in pituitary adenomas from patients with acromegaly

GHRH receptors in pituitary adenoma cell membranes from five patients with acromegaly were characterized using [125I] [His1,Nle27]GHRH-(1-32)NH2 ([125I]GHRHa) as a ligand. Specific binding of [125I]GHRHa to adenoma cell membranes was maximal within 20 min at 24 C, remained stable for 60 min, and was reversible in the presence of 500 nmol/L human GHRH-(1-44)NH2 (hGHRH). The specific binding increased linearly with 10-160 micrograms cell membrane protein. This binding was inhibited by 10(-11)-10(-6) mol/L hGHRH in a dose-dependent manner, with an ID50 of 0.20 nmol/L, but not by 10(-7) mol/L vasoactive intestinal peptide, glucagon, somatostatin-14, somatostatin-28, TRH, LHRH, and CRH. The specific binding of [125I]GHRHa to the membranes was saturable, and Scatchard analysis of the data revealed an apparent single class of high affinity GHRH receptors in five adenomas from acromegalic patients; the mean dissociation constant was 0.30 +/- 0.07 (+/- SE) nmol/L, and the mean maximal binding capacity was 26.7 +/- 7.0 (+/- SE) fmol/mg protein. In three nonfunctioning pituitary adenomas, GHRH receptors were not detected. The plasma GH response to hGHRH (100 micrograms) injection was studied in four acromegalic patients before surgery. Plasma GH levels increased variably in response to hGHRH injection in all four patients. However, there was no correlation between the characteristics of the tumor GHRH receptors and plasma GH responsiveness in these patients. We conclude that pituitary GH-secreting adenomas have specific GHRH receptors. Exogenously administered GHRH presumably acts via these receptors, but the variations in plasma GH responsiveness to hGHRH in these patients cannot be directly related to the variations in binding characteristics of the GHRH receptors on the GH-secreting adenoma cells.     

Long-term in-vitro treatment of human growth hormone (GH)-secreting pituitary adenoma cells with octreotide causes accumulation of intracellular GH and GH mRNA levels

OBJECTIVE: We studied the effects of long-term in-vitro exposure of human GH secreting pituitary adenoma cells to octreotide on GH release, intracellular GH concentrations and GH messenger ribonucleic acid (mRNA) levels. DESIGN: Human GH-secreting pituitary adenoma cells were cultured for periods from 4 days up to 3 weeks without or with octreotide (10 nM) and/or bromocriptine (10 nM). The effects of these drugs were measured on GH release, intracellular GH concentrations and intracellular GH mRNA levels. PATIENTS: Thirteen patients with GH-secreting pituitary adenomas were studied. Twelve patients were untreated, one had been pretreated with octreotide (12 weeks, 3 x 100 micrograms daily). MEASUREMENTS: GH, PRL, alpha-subunit and IGF-I concentrations in plasma, media and cell extracts were determined by immunoradiometric or radioimmuno-assays. GH mRNA levels were determined by automatic quantification of grain numbers in individual adenoma cells. RESULTS: Incubation of the adenoma cells for 4 days with 10 nM octreotide induced a dose-dependent inhibition of GH release and a parallel increase (increase varying between 124 and 617% of control) in the intracellular GH levels was observed in six of seven adenomas. In addition, bromocriptine, when effective in inhibiting GH release by the adenomas, also induced an increase in intracellular GH levels. Even after 3 weeks of exposure to 10 nM octreotide in vitro there was a statistically significant increase in intracellular GH levels (between 191 and 923% of control). Withdrawal of octreotide after 6 days of incubation resulted in a lowering of intracellular GH levels to control values, showing that the octreotide-induced increase in intracellular GH is reversible. In a 96-hour incubation with 10 nM octreotide, GH mRNA levels were increased in two, and slightly decreased in one of the three adenomas tested. This effect was time dependent in that there was no significant effect of 10 nM octreotide on GH mRNA levels in a 24-hour incubation. CONCLUSIONS: (1) Long-term in-vitro exposure of GH-adenoma cells to octreotide causes an increase in intracellular GH levels in the majority of the adenomas, probably because of an increase in GH mRNA levels in the adenoma cells; and (2) this considerable increase in intracellular GH levels may be one of the explanations for the relatively poor effect of octreotide on tumour shrinkage in patients with GH-secreting pituitary adenomas.     

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

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

The effect of thyrotropin-releasing hormone (TRH) and somatostatin (GHRIH) on growth hormone and prolactin secretion in vitro and in vivo in the domestic fowl (Gallus domesticus).

The effects of thyrotropin-releasing hormone (TRH) on growth hormone (GH) and prolactin (Prl) secretion have been investigated in vitro and in vivo in domestic fowl. In both conscious and anaesthetized immature chickens the administration (i.v.) of TRH (2.5 and 25 microgram/kg) significantly increased the concentration of plasma GH. The simultaneous administration of somatostatin (GHRIH), 2.5 microgram/kg, to conscious birds significantly reduced the magnitude of the GH response to TRH treatment, but had no effect on the basal levels of plasma GH. The repeated injection of TRH (10 microgram/kg) every 20 min over a 100-min period failed to maintain the concentration of plasma GH at a high level. Prl secretion was not stimulated in any of these experiments, and in anaesthetized birds TRH (2.5 and 25 microgram/kg) treatment was followed by a depression in the level of plasma Prl. The effects of TRH and GHRIH on GH secretion by an in vitro dispersed pituitary cell suspension system were very similar to the in vivo studies. TRH stimulated Prl release in vitro, in contrast to the in vivo studies, and the response was dose related. GHRIH had no effect on the basal release of Prl in vitro but significantly inhibited the response to TRH treatment.     

Glycoprotein hormone alpha-subunit secretion in patients with pituitary adenomas: influence of TRH, LRH and bromocriptine

Twelve patients with pituitary adenomas and increased serum concentration of the glycoprotein hormone alpha-subunit were studied. Eight patients were acromegalic and one had a FSH producing tumour. The adenomas in 9 patients had undergone subtotal operative removal and/or external irradiation but no patient was studied within 3 months of these treatments. Many of the acromegalic patients, with moderately elevated alpha-levels, showed marked increases in alpha-concentration after TRH and/or LRH, compared with controls. The non-acromegalic patients, with the highest alpha-levels, showed poor responses to releasing hormones. These results suggest that excessive alpha-subunit secretion in acromegalic patients is often under hypothalamic control whereas in non-acromegalic patients it is often autonomous. Seven patients, 4 with acromegaly, were then given oral bromocriptine, 5 mg over 3 h. There was a significant fall in log mean alpha-level at 4 and 5 h (P less than 0.02). Six patients took bromocriptine for 1--2 months. Log mean alpha-concentration was significantly reduced at the end of treatment (P less than 0.02) and then recovered to basal levels after stopping treatment for one week. alpha-Subunit hypersecretion in some patients with pituitary adenomas is therefore modulated by dopaminergic control mechanisms.     

Secretion of glycoprotein hormone alpha-subunit by pituitary tumors

Serum glycoprotein hormone alpha-subunit levels were determined in 165 patients with pituitary adenomas. Elevated serum alpha-subunit levels were found in 17 patients (acromegaly, 5 of 58; prolactinoma, 6 of 56; nonfunctioning adenoma, 5 of 32; and ACTH-producing adenoma, 1 of 19), most of whom had normal serum TSH and gonadotropin levels. When TRH (0.5 mg) was injected iv in the 6 prolactinoma patients with elevated serum alpha-subunit levels, serum PRL and alpha-subunit levels increased in only 1 patient. Four acromegalic patients with high serum alpha-subunit levels received TRH; serum GH and alpha-subunit increased in 1 patient and did not change in 2, and only serum GH increased in the remaining patient. Oral administration of bromocriptine (5 mg), on the other hand, consistently decreased serum alpha-subunit and PRL levels in 2 patients with prolactinoma and alpha-subunit and GH levels in 1 acromegalic patient. When serum from 3 patients was subjected to Sephadex G-100 gel filtration, immunoreactive alpha-subunit eluted in a single peak, which emerged in fractions corresponding to [125I]TSH alpha. Concanavalin A (Con A) affinity chromatography revealed that the major portion of immunoreactive alpha-subunit was retained to Con A. A pituitary adenoma removed at surgery from a patient with acromegaly was studied in monolayer cell culture. Secretion of both alpha-subunit and GH from cultured adenoma cells was stimulated by TRH and suppressed by dopamine in a dose-dependent manner. Immunohistochemistry of the pituitary adenomas removed from patients with prolactinoma and acromegaly who had high serum alpha-subunit levels demonstrated alpha-subunit-containing cells as well as PRL- or GH-containing cells. These results suggest that elaboration of glycoprotein hormone alpha-subunit occurs without concurrent production of glycoprotein hormones in a substantial number of patients with pituitary adenomas and that alpha-subunit responses to stimuli in such adenomas are generally parallel with those of the concomitantly produced hormones.