Prolactin-secreting Tumors Research Articles

HERG K(+) currents in human prolactin-secreting adenoma cells.

To investigate the presence and possible function of ether-à-go-go-related gene (erg) K(+) channels in human lactotroph cells (HERG channels), primary cultures were prepared from human prolactinoma tissue. In almost all primary cultures, HERG currents could be recorded in identified prolactin cells using an external high-K(+) solution. The antiarrhythmic agent E-4031, a specific blocker of erg channels, served to isolate HERG currents as the drug-sensitive currents. In cells of two tumours tested, thyrotropin-releasing hormone significantly reduced the amplitude of the HERG currents. The potential dependence of HERG current availability and the deactivation kinetics differed significantly even between prolactin cells derived from one adenoma. For comparison, corresponding values were obtained for heterologously expressed rat erg1, erg2 and erg3 channels. The expression of the three HERG channel subunits was investigated in nine human adenomas using RT-PCR. Transcripts for HERG1 were present in all adenomas and although transcripts for HERG2 and HERG3 were also detected, their expression level was more variable. The results demonstrate the functional expression of HERG channels in human prolactin-secreting tumours and are compatible with a physiological role for these channels in the control of prolactin secretion, as has been shown in normal rat lactotroph cells.

Hormonal signal receptor mechanisms in neuroendocrinology

The role of sex hormones in the mechanisms of pituitary adenoma development has been investigated. The concentrations of estradiol and testosterone nuclear receptors were evaluated in adenohypophyseal tumors of different structure: prolactinomas, meningiomas, somatotropinomas, astrocytomas, neurinomas, and ependymomas. The concentrations of estrogen and androgen receptors are much higher in prolactin-secreting pituitary tumors than in somatotropinomas and other pituitary tumors examined.

Overexpression of vascular endothelial growth factor164 and its co-receptor neuropilin-1 in estrogen-induced rat pituitary tumors and GH3 rat pituitary tumor cells.

We have shown previously that the VEGF system plays a crucial role in regulation of tumor angiogenesis during the development of estrogen-induced prolactin-secreting pituitary tumors in Fisher 344 rats. Studies also suggested that both endothelial and non-endothelial cells expressed VEGF. However, several questions concerning the VEGF signals in regulation of estrogen-induced angiogenesis in rat pituitary remained unanswered. VEGF exists in a number of isoforms in human and rodent tissue (i.e., VEGF206h/205r, VEGF189h/188r, VEGF165h/164r, VEGF145h/144r and VEGF121) that differ in their molecular masses and biological activities. The VEGF isoforms bind with two tyrosine-kinase receptors, KDR/flk-1 and flt-1. In addition, VEGF165 binds with a newly identified co-receptor, neuropilin-1, which is expressed in human endothelial cells and several types of non-endothelial cells including tumor cells. The present study was undertaken to elucidate which isoforms of VEGF are predominantly expressed in normal Fisher 344 rat pituitaries, estrogen-induced prolactin secreting rat pituitary tumors and in prolactin secreting rat pituitary tumor cell line (GH3 cell line). To identify the isoform, RT-PCR with primer pairs derived from exon 1 and exon 8 of the VEGF gene, cloning, sequencing and Western blot analysis were performed. The status of neuropilin-1 in the rat pituitaries (normal and transformed) and GH3 pituitary tumor cell line has also been investigated using RT-PCR and Western blot analysis. These studies demonstrate that normal rat pituitaries, estrogen-induced rat pituitary tumors and GH3 pituitary tumor cells expressed VEGF164 and co-receptor, neuropilin-1. The VEGF164 was the predominant form in all of these cells. The VEGF164 and neuropilin-1 mRNA and protein levels were significantly higher in the estrogen-induced pituitary tumors and GH3 tumor cell line, as compared to normal pituitary. The data suggest that both VEGF164 and neuropilin-1 may actively participate in modulation of tumor angiogenesis and the development of pituitary tumors in Fisher 344 rats.

Clinical review 110: Diagnosis and treatment of pituitary tumors.

We are fortunate to have multiple safe and effective therapeutic options available for the treatment of pituitary tumors. These options include medical therapy, transsphenoidal surgery and radiotherapy. The treatment of choice depends on the type of pituitary tumor. The majority, of PRL-secreting tumors can be effectively treated with dopamine agonists. Transsphenoidal surgery is also an effective option for patients who are resistant to or intolerant of these drugs. Transsphenoidal surgery remains the treatment of choice for the majority of patients with GH, ACTH, and TSH-secreting tumors and for large nonsecreting tumors. Medical therapy with somatostatin analogs and/or dopamine agonists should be undertaken in patients with persistent elevations of GH and IGF-I levels; radiotherapy should be considered for patients with significant residual tumor in whom medical therapy is unsuccessful. Radiotherapy is also indicated for ACTH-secreting tumors not cured by surgery; medical therapy with ketoconazole and other adrenal enzyme inhibitors can be used as adjunctive therapy to lower cortisol levels. Postoperative radiotherapy for nonsecreting tumors is also an option if there is considerable residual tumor or evidence of tumor growth on follow-up MRI. Evaluation and treatment of hypopituitarism is an important part of the management of all patients with pituitary tumors. Patients also should be monitored for the development of new deficits, particularly after radiotherapy. The development of new medical therapies, such as GH antagonists, as well as refinements of surgical, radiotherapy, and imaging techniques should continue to improve our management of pituitary tumors.

Quantitative and functional expression of somatostatin receptor subtypes in human prolactinomas.

Recently, it was demonstrated that somatostatin analogs preferential for the SSTR5 subtype suppress PRL release from prolactinoma cell cultures by 30-40%. These data supported the idea of somatostatin receptor subtype-specific control of PRL secretion in such tumors. The present study examines the quantitative profile of SSTRs messenger ribonucleic acid (mRNA) in 10 PRL-secreting tumors and correlates the expression with the ability of native somatostatins (SS14 and SS28), SSTR2 preferential analogs (octreotide and BIM-23197), and the SSTR5 preferential analog BIM-23268 to suppress PRL secretion. RT-PCR quantitative analysis showed a large predominance of SSTR5 mRNA [5648 +/- 1918 pg/pg glyceraldehyde-3-phosphate dehydrogenase (GAPDH)] vs. SSTR2 mRNA (148 +/- 83 pg/pg GAPDH). The SSTR1 transcript was also highly expressed in prolactinomas (1296 +/- 669 pg/pg GAPDH). SSTR5 mRNA expression correlated with PRL inhibition induced by both SRIF14 and SRIF28. Among the different analogs tested, only BIM-23268 produced inhibition of PRL release similar to that achieved with the native peptides. Its EC50 for PRL suppression was 0.28 +/- 0.10 nmol/L. No additive effects on PRL suppression were achieved by cotreatment of the tumor cells with SSTR2 and SSTR5 preferential analogs. In the same tumor cell cultures, quinagolide, a potent dopamine agonist, produced a dose-dependent inhibition of PRL with an EC50 at least 10 times lower than that of BIM-23268. Coincubation of quinagolide and BIM-23268, particularly in tumor cells resistant to dopamine agonist treatment, did not produce additive effects on PRL suppression. In conclusion, prolactinomas have a specific pattern of SSTR subtype mRNA expression (SSTR5 and SSTR1). SSTR5 expression is correlated to PRL regulation. These inhibitory effects are superimposable, at a higher concentration, to those of the dopamine agonists, but are not additive, particularly in the adenomas resistant to dopaminergic suppression of PRL release.

Subclinical apoplexy in pituitary tumors

Acute pituitary apoplexy is a rare event, even in patients with pituitary macroadenomas. On the other hand, the presence of necrotic/hemorrhagic areas, especially in macroadenomas, seems to be more common than earlier reported in the CT period. After the introduction of MR in the presurgical workup of these patients, these apopleptic areas have been more easily diagnosed preoperatively. Forty consecutive patients with pituitary macroadenomas were studied with high-resolution 1.5 T T1 coronal, sagittal and axial slices over the sellar region. Special attention was paid in the detection of necrotic, cystic and hemorrhagic areas within these tumors. Ten patients had hemorrhagic/necrotic areas within their tumors, without any sign or symptom of acute apoplexy. These areas varied from small (2 mm) to very large (30 mm) ones. Seven patients had non-secreting tumors, 2 GH and 1 prolactin secreting tumors, which is the same profile of secretory pattern for the whole series (40 patients). The clinical picture included (other than that caused by endocrine secretion) slowly progressive (but not acute) visual loss (n = 8) and headache (n = 3). After surgical decompression of the surrounding structures and visual apparatus, which was facilitated by the presence of the necrotic areas, there was visual improvement in 6 patients and headache resolution in 2. The presence of asymptomatic apopletic areas in these macroadenomas and their absence in microadenomas as can be seen in the literature suggest that they are related more to the size of the tumor than to its endocrine secretion pattern. This is in agreement with a vascular insufficiency hypothesis in the pathogenesis of these lesions.

Growth factors in pituitary tumors.

Prolactin-secreting tumors are the most frequently occurring neoplasms in the human pituitary. Although the clinical syndrome associated with prolactinomas is well recognized the molecular and cellular mechanisms leading to cell transformation and development of these tumors remain elusive. In this paper we summarize recent evidence suggesting that both hypothalamic and intrapituitary defects can be involved in the development of prolactinomas. In particular alterations of the hypothalamo-pituitary dopaminergic transmission result in the dysregulation of the proliferative activity of lactotrope cells leading to tumor development. Similarly changes in the expression and activity of resident growth factors also play a role in pituitary tumorigenesis. In particular both overexpression of TGF alpha and loss of NGF production appear to be involved in the development and progression of prolactin-secreting tumors.

Growth factors in the pathogenesis of prolactin-secreting tumors.

Growth factors in the pathogenesis of prolactin-secreting tumors.

Pharmacological effects of BAM-1120, a novel ergoline derivative, on central dopaminergic functions in rats.

BAM-1120, an ergoline derivative, has been found to display a relatively high affinity for dopamine D2-like receptor subtypes in a preliminary binding study. This study investigated whether BAM-1120 acts as a dopamine receptor agonist on prolactin-secreting and motor functions. BAM-1120 suppressed hyperprolactinemia induced by pretreatment with reserpine or estradiol in female rats. Furthermore, BAM-1120 was able to shrink a prolactin-secreting pituitary tumor (prolactinoma) in the estradiol-treated female rats. BAM-1120 induced rotations contralateral to the lesion side in rats with unilateral 6-hydroxydopamine-induced lesions of nigrostriatal dopamine pathway at a dose that was at least 30-fold higher than that required for the inhibition of prolactin secretion. These findings suggest that BAM-1120 is characterized as a putative dopamine D2-like receptor agonist that possesses a preference of inhibiting prolactin secretion over activating motor behaviors.

Hormonal control of pituitary prolactin-secreting tumors.

Prolactin secreting adenomas (prolactinomas) are the most prevalent form of pituitary tumors in humans. Prolactinomas have been linked to estrogen exposure in humans and animals. However, the mechanism by which estrogen increases mitogenesis in lactotropes, as well as other estrogen responsive cells, is not well understood. Given the complex nature of steroid hormones and their wide array of actions, it seems plausible that there are multiple ways in which estrogen can exert its cell-transforming actions. Estrogen has a wide range of actions on cells depending on the cell type, receptor levels, and other factors present in the cell. A defect at any point could play a potential role in cell transformation. The source of such defects could be the result of any of a wide range of possibilities, including genetic predisposition, prolonged exposure to sufficient levels of the steroid hormone, or other insults to the cell which lead to altered responsiveness to estrogen in some way. This review discusses the recent advances that have been made in the area of understanding estrogen action in transformation of pituitary lactotropes.

P-5-622 - Surgical experience with giant and invasive pituitary tumors

This study reports the outcome of 70 patients who were treated by a consistent treatment plan of surgery and postoperative radiotherapy (RT) for pituitary macroadenomas in the modern era [computed tomographic scan or magnetic resonance imaging (MRI), dopamine agonist therapy (DA) added as indicated, and immunohistochemical staining]. Sixty-two patients underwent transsphenoidal surgery (vs. transcranial surgery) and 61 received 45-Gy25 fractions postoperatively (vs. other dose fractionation schemes). Twenty-four patients received DA for prolactin-secreting tumors. With a median follow-up of 8 years (range 2–15), 68 patients have experienced continuous control of their tumors. Most symptoms related to mass effect abated, while physiologic symptoms such as amenorrhea from markedly elevated prolactin levels tended to persist. Treatment-induced hypopituitarism occurred in 42% of the patients at risk. No patients in this series have died as a result of their pituitary tumor. No gross neuropsychologic dysfunction after treatment has been noted. While it is possible at this time with serial MRI to withhold postoperative RT and observe some patients who have had a “gross total” resection of a macroadenoma, the therapeutic ratio for surgery and adjuvant radiotherapy for patients with nonfunctional tumors as well as select patients with secretory macroadenomas is favorable.

Symptom resolution, tumor control, and side effects following postoperative radiotherapy for pituitary macroadenomas

This study reports the outcome of 70 patients who were treated by a consistent treatment plan of surgery and postoperative radiotherapy (RT) for pituitary macroadenomas in the modern era [computed tomographic scan or magnetic resonance imaging (MRI), dopamine agonist therapy (DA) added as indicated, and immunohistochemical staining]. Sixty-two patients underwent transsphenoidal surgery (vs. transcranial surgery) and 61 received 45-Gy 25 fractions postoperatively (vs. other dose fractionation schemes). Twenty-four patients received DA for prolactin-secreting tumors. With a median follow-up of 8 years (range 2–15), 68 patients have experienced continuous control of their tumors. Most symptoms related to mass effect abated, while physiologic symptoms such as amenorrhea from markedly elevated prolactin levels tended to persist. Treatment-induced hypopituitarism occurred in 42% of the patients at risk. No patients in this series have died as a result of their pituitary tumor. No gross neuropsychologic dysfunction after treatment has been noted. While it is possible at this time with serial MRI to withhold postoperative RT and observe some patients who have had a “gross total” resection of a macroadenoma, the therapeutic ratio for surgery and adjuvant radiotherapy for patients with nonfunctional tumors as well as select patients with secretory macroadenomas is favorable.

Intérêt de la radiochirurgie stéréotaxique dans les adénomes hypophysaires de l'enfant À propos de deux observations

The pituitary gland has been termed the ‘master gland’ because of the myriad of hormones that emanate from it that are vital for normal homeostasis as well as growth and development. Primary tumors of this region are frequent and account for up to 10% of intracranial tumors. Pituitary tumors are monoclonal in origin, and may arise from any of the different cell types of the pituitary gland. Hence, these tumors may be manifest by their hormonal secretions. This may lead to profound and striking physiological changes attributable, for example, to prolactin, growth hormone, or ACTH excess. The central location of the pituitary gland also leads to characteristic compressive symptoms. This review will explore the clinical presentations of growth hormone, ACTH, and prolactin secreting tumors as well as the non-secreting pituitary tumors. Advances in neuroimaging and neuropharmacology have resulted in changes in our treatment of these tumors. Treatment modalities including surgical, medical, and radiation therapy will be addressed. The treatment of choice is dictated by the type of tumor and the nature of the excessive hormonal expression. Outcomes and efficacy of treatment are discussed.

Dopamine infusion enhances the adrenocorticotropic hormone and Cortisol response to metoclopramide in hyperprolactinemic patients but not in normal subjects

Based on the facts that prolactin and adrenocorticotropic hormone (ACTH) each seem to influence the secretion of the other, that dopamine is the established inhibitory factor for prolactin secretion and negatively modulates ACTH release, and finally that alterations of the central dopaminergic tone have been postulated in tumorous hyperprolactinemia, we studied the effects of pharmacological manipulations of the dopaminergic system on ACTH and Cortisol secretion in patients bearing a prolactinoma and in normal subjects. Twenty-seven patients with a prolactin-secreting pituitary tumor and 12 healthy controls were submitted to three tests: (a) 4-h saline infusion; (b) 10 mg metoclopramide (MTC) as an intravenous bolus after a 2-h saline infusion; and (c) 4-h dopamine infusion at the dose of 0. 01 μg/kg/min with a 10-mg intravenous bolus of MTC given at the second hour of dopamine infusion. Administration of MTC, compared to saline, caused a moderate (not significant) plasma ACTH increase, and a significant Cortisol increase (p < 0.05), both in hyperprolactinemic and normal subjects, without statistically significant differences between the two groups. When MTC was administered during dopamine infusion, the ACTH and Cortisol elevation was significantly potentiated in prolactinoma patients while it was similar in magnitude to that recorded after MTC alone in control subjects. These findings support the concept of an inhibitory role exerted by dopamine and are compatible with a stimulatory influence exerted by prolactin on corticotropin-releasing hormone and ACTH secretion, and also favor the view of a reduced central dopaminergic tone in patients with tumorous hyperprolactinemia.

Effect of bromocriptine on the sensitivity of pituitary tumor cells to radiation.

GH3 cells, a PRL-secreting rat pituitary tumor cell line, are sensitive to bromocriptine, and provide a useful model for the present studies. GH3 cells, in the presence or absence of 2.5 x 10(-5) M bromocriptine, were irradiated at doses ranging from 0 to 10 Gy. After irradiation the bromocriptine was washed out, cells were seeded at a density of 10,000 cells/ml, and growth curves were obtained by counting the cell number at weekly intervals for 1 month. Cell growth was inhibited by the radiation in a dose-dependent fashion, with complete inhibition of cell growth by 9 Gy. However, no protection against radiation damage was afforded by bromocriptine. These results might suggest that the combined therapies of tumor shrinkage by bromocriptine and stereotactic irradiation of the sella might be a useful clinical therapeutic strategy, particularly in patients with large tumors, severe hyperprolactinemia, and pre-existing hypopituitarism.

Prolactin-secreting pituitary carcinoma with implants in the cheek pouch and metastases to the ovaries. A case report and literature review

Prolactin-secreting pituitary carcinomas are uncommon, locally destructive neoplasms that rarely metastasize outside the central nervous system. The authors report a case of a prolactin-secreting tumor that initially presented as the empty sella syndrome. Two recurrences along transsphenoidal surgery tracts in cheek pouches were followed by distant metastases later in the abdomen and pelvis. Only 10 previous cases of either extracranial or intracranial metastases from prolactin-secreting pituitary carcinomas have been reported. No metastases below the diaphragm have been reported previously. The patient's cheek pouch implants, lymph node metastases, ovarian metastases, and uterine metastases were studied with prolactin-specific immunohistochemistry. Long term treatment with bromocriptine, several debulking surgeries, extensive local radiation therapy (external beam and proton beam), and cytotoxic chemotherapy had little impact. Tamoxifen, however, may have slowed tumor growth. Tamoxifen may have efficacy in the treatment of prolactin-secreting pituitary carcinomas.

Pentobarbital anesthesia during the proestrous afternoon blocks lactotroph proliferation occurring on estrus in female rats.

Estradiol stimulates the synthesis and secretion of PRL and lactotroph proliferation, and its long-term administration induces PRL-secreting pituitary tumors. We examined changes in the number of proliferating lactotrophs throughout the estrous cycle in female rats and the involvement of the brain in the regulation of the lactotroph proliferation by anesthetizing with pentobarbital. Female rats revealing regular 4-day estrous cycles were injected ip with the thymidine analog 5-bromo-2'-deoxyuridine (BrdU) 3 h before decapitation to label DNA-replicating cells. Dispersed anterior pituitary cells obtained from these rats were stained for PRL and BrdU with a double labeling immunofluorescence technique. The rate of lactotroph proliferation was represented by the BrdU-labeling index (BrdU-labeled lactotrophs as a percentage of total lactotrophs counted). Lactotrophs from rats injected with BrdU at 1000 h showed a high BrdU-labeling index of 2.6% on estrus, whereas they showed almost undetectable levels of the BrdU-labeling index during the other stages of the estrous cycle. The anterior pituitary cells other than lactotrophs were scarcely labeled during any stages. The BrdU-labeling index began to rise by the midnight between proestrus and estrus, peaked between 0800 and 1200 h, and returned to undetectable levels by the midnight between estrus and diestrus I. Pentobarbital (35 mg/kg, i.p.) injected at 1345 h on proestrus, which was effective in blocking ovulation on estrus, eliminated completely the increase in the BrdU-labeling index as determined by BrdU injection at 1000 h on estrus. In contrast, the high BrdU-labeling index on estrus was partly suppressed to a level of 1.4% by pentobarbital injection at 0900 or 2100 h on proestrus. The rats injected with pentobarbital at 1345 h on proestrus did not show any increases in the BrdU-labeling index even after BrdU injection was delayed from 1000 to 1400 h on estrus. However, a high BrdU-labeling index of 3.7% was obtained in these animals when BrdU was injected at 1000 h on diestrus I. We conclude that 1) lactotrophs of cycling female rats proliferate selectively on the day of estrus; and 2) the proliferation of lactotrophs on estrus is not due to a direct action on the anterior pituitary of estradiol secreted from the ovaries but triggered by neural events occurring during the proestrous afternoon, which are closely related with the regulation of preovulatory surges of gonadotropin and PRL secretion.

Prolactin receptors in human pituitary adenomas

In the rat, prolactin receptors (PRL-R) have been identified in normal pituitary cells and in anterior pituitary tumours induced by oestradiol. No published data are available concerning PRL-R in the human pituitary. The aim of our study was therefore to detect the presence of PRL-R in the normal human pituitary gland and human pituitary adenomas. Evaluation of free and total PRL-R in the normal pituitary gland and different pituitary tumours characterized by immunocytochemical analysis. Twenty-six unselected patients (14 M, 12 F) who underwent surgery for pituitary adenoma (3 prolactinomas, 4 GH-PRL adenomas, 5 GH adenomas, 1 ACTH adenoma, 9 glycoprotein and/or alpha-subunit adenomas, 4 null cells adenomas) were studied. Nine pituitaries from subjects whose death was unrelated to brain and endocrine diseases, were also studied as a control group in the PRL binding studies. Free PRL-R in microsomal membranes were determined by in-vitro radioreceptor assay using 125I-labelled human PRL as ligand. Total PRL-R were also measured in the same membrane fractions by removing endogenous PRL bound to its receptors using 4 M MgCl2. Serum PRL levels were also evaluated in all patients before surgery using an IRMA method. Specific binding values for PRL (free PRL-R) were 0.39 +/- 0.03% (range 0-1.96%) in the pituitary adenomas. These binding values were identical to those observed in normal pituitaries (0.38 +/- 0.07%, range 0.1-0.78%). Elevated PRL binding (1.25% and 1.96%) was found in two patients with PRL secreting adenomas and very high serum PRL levels (5768 and 11240 mU/I. No PRL binding was shown in 4 patients. Treatment of membranes with 4 M MgCl2 increased the specific binding (total PRL-R) in both pituitary tumours (0.5 +/- 0.11%; P < 0.001) and normal pituitaries (0.47 +/- 0.07%; P < 0.02). Our data have demonstrated the presence of prolactin receptors in normal cadaveric pituitary and in most pituitary adenomas, irrespective of histological classification. In particular, elevated prolactin receptor levels were shown in PRL-secreting tumours from patients with markedly increased serum PRL levels. Our study may support several lines of experimental evidence for a specific functional role for PRL in the growth of some pituitary adenomas.

Estradiol Induces Vasoactive Intestinal Peptide and Prolactin Gene Expression in the Rat Anterior Pituitary Independently of Plasma Prolactin Levels

It is well established that estrogens are potent stimulators of prolactin (PRL) secretion. It has also been demonstrated that estradiol (E2) can increase the expression and the anterior pituitary levels of the vasoactive intestinal peptide (VIP), a peptide which also acts as a potent PRL-releasing factor. It thus remained unknown whether the effects on pituitary VIP were due to E2 itself or to E2-induced hyperprolactinemia (HPRL). In order to test this hypothesis, various plasma PRL levels were induced in rats either with ectopic pituitary grafts, PRL secreting tumours or E2 implants, and VIP mRNA expression in the anterior pituitary was measured by in situ hybridization and Northern blot analyses. Whereas decreases in VIP mRNA can be observed in pituitaries of rats with pure HPRL, a 6-fold increase in VIP mRNA can be seen in E2-treated rats. E2 increased both 1.0 and 1.7 Kb VIP mRNA species. The presence of the graft in E2-treated rats significantly reduced the increase in VIPmRNA observed following E2. The direct stimulation by E2 of VIP mRNA expression was further demonstrated by the fact that statistical analysis of the data indicated that both E2 and graft were acting independently of each other, and that a new selective antiestrogen, RU 58668, almost totally blocked the effect of E2. Moreover, under similar experimental conditions, pituitary PRL mRNA levels were reduced in the graft group and a marked up-regulation was observed similarly in both E2 and in E2 rats bearing ectopic grafts.(ABSTRACT TRUNCATED AT 250 WORDS)

Heterogenous in vivo and in vitro expression of basic fibroblast growth factor by human pituitary adenomas.

Basic fibroblast growth factor (bFGF) is a potent mitogenic and angiogenic factor that is known to regulate GH, PRL, and TSH secretion. Sequences within a bFGF gene family member have been detected in transforming DNA samples derived from human PRL-secreting tumors. Furthermore, elevated serum concentrations of bFGF have been noted in patients with multiple endocrine neoplasia-1. To further examine the significance of bFGF in sporadic human pituitary adenomas, we investigated the expression of bFGF by these tumors. Using an enzyme-linked immunoassay that recognizes all 16-24 kilodalton molecular mass forms of bFGF, we measured circulating serum concentrations in 21 patients with sporadic pituitary adenomas; they ranged from less than 0.5-84 pg/mL and declined following surgical adenomectomy. To confirm the pituitary source of this growth factor, we determined in vitro bFGF release from 43 adenomas (10 GH, 7 PRL, 10 ACTH, 14 gonadotrope adenomas/oncocytomas, and 2 silent subtype 3 adenomas). bFGF was present with wide variability (0.75-2100 pg/24 h.10(5) cells) in conditioned culture media of all adenomas examined. The adenohypophysial source of this growth factor was further demonstrated by the reverse hemolytic plaque assay. Variable bFGF messenger RNA expression was identified by the reverse-transcription polymerase chain reaction technique in 9 functional (2 PRL, 5 GH, 2 ACTH) and 7 nonfunctional (1 oncocytoma, 2 null cell, 2 gonadotrope, 2 Silent Subtype 3) adenomas examined. bFGF levels were unaltered in vitro following hypothalamic hormone stimulation/inhibition. The lack of a bFGF signal peptide sequence and hypothalamic hormone-independence suggest that secretion of this factor may be independent of pituitary hormone regulation. Immunocytochemistry failed to localize bFGF in tumors that released this factor in vitro, suggesting that storage of this peptide does not correlate with its synthesis and release. In conclusion, the heterogenous expression of bFGF suggests that it may play a specific and selective role in the tumorigenic process of some pituitary adenomas.