[Palliative treatment of brain metastases with gamma knife]. / Palliative Behandlung von Hirnmetastasen mit dem Gamma Knife.

The gamma knife is a stereotactic radiosurgery device which allows well defined, deep seated brain tumors or arteriovenous malformations with a maximal volume of about 25 ccm and a diameter not greater than 3.5 cm, to be treated in a single session under local anesthesia. The gamma knife offers an alternative treatment method to the classical approach of treating brain metastases by surgical excision and/or whole brain radiotherapy. The advantages of this technique are evident: the method is non-invasive, the treatment is carried out in a single session with a very short hospitalisation of two to three days, it is exempt from physical and psychical stress, the head does not need to be shaved and no hair loss occurs, a good quality of life is obtained for a reasonably prolonged survival time and it offers an economically favourable treatment method. Up to December 1999, over 30,000 patients suffering from brain metastases have been treated worldwide using the gamma knife. In Zürich, from September 1994 to December 2000 140 received this treatment. In the literature selection criteria may differ, and this may have determined some of differences in outcome. However, our results are comparable with those in the majority of publications with an average survival time of 263 days and a maximum survival of 1080 days. Good prognostic factors for survival and local control of brain metastases are a Karnofsky Performance Scale Score approaching 90 to 100, but not lower than 70, tumour volume, controlled primary cancer, and absence or stable extracranial metastases.

History of pituitary surgery from the technical aspect.

Transcranial and trans-sphenoidal pituitary surgery were developed independently with few exceptions by different groups of surgeons. The transcranial approaches, primarily the transfrontal-parasagittal and the frontotemporal along the sphenoid ridge, evolved without many variations within a short time span. The trans-sphenoidal exposures of the pituitary, on the contrary, underwent many modifications provoked by the fear of postoperative meningitis and the search for improved vision through the narrow alley leading to the target. Only Guiot in 1978 ended the extensive discussion by convincingly demonstrating that well-defined indications existed for each procedure. Improvement of diagnostic and surgical tools was a major factor for refining the surgical technique and improving the surgical results.

Octreotide may act as a radioprotective agent in acromegaly.

Clinical experience shows that an increasing number of patients undergoing radiation treatment for recurring acromegaly or acromegaly persisting after surgery are treated with octreotide. We, therefore, performed a follow-up study of patients undergoing stereotactic radiosurgery (Gamma Knife) to determine whether this medication has an influence on the ultimate result of radiation therapy in either a positive or negative sense. It has been suggested that the combination of radiation with antisecretory drugs may increase the effectiveness of radiation. A follow-up study of 31 patients suffering from recurrent acromegaly and acromegaly persisting after surgery, and who had been treated with stereotactic radiosurgery, showed that patients treated with octreotide at the time of radiation application simultaneously reached a normal level of growth hormone and insulin-like growth factor-I only after a significantly longer interval than patients who did not receive the drug. The two groups of patients did not demonstrate significant differences in the main clinical findings (age, sex, target volume, radiation dose, baseline growth hormone, and baseline insulin-like growth factor-I).

Gamma knife radiosurgery for prolactinomas.

OBJECT: In this retrospective investigation the authors examined the results of gamma knife radiosurgery (GKS) for tumor remnants after unsuccessful open surgery and medical treatment in 20 patients with prolactinomas. Particular attention is paid to a possible radioprotective action of dopamine agonists similar to the action of octreotide in acromegaly. METHODS: Twenty patients with prolactinomas were followed after GKS. Five patients were treated successfully; their prolactin (PRL) levels dropped into the normal range and dopaminergic drugs could be discontinued. Two spontaneous pregnancies were observed and 11 patients experienced improvement. Improvement was defined as normal PRL levels with the continued possibility of reduced medical treatment or a substantially reduced medical treatment dose with some degree of hyperprolactinemia maintained. The treatment failed in three patients who experienced no improvement. Patients treated with dopaminergic drugs during GKS did significantly less well in comparison with the untreated group when a cumulative distribution function (Kaplan-Meier estimate) was used. CONCLUSIONS: The results of GKS for prolactinomas in this investigation are better than the results published by others. This may be an effect of case selection because there were no "salvage cases" in our group of patients. Because a dopamine agonist seemed to induce radioprotection in this series, it is suggested that GKS be performed during an intermission in drug therapy when the dopamine agonist is discontinued.

17Beta-hydroxysteroid dehydrogenase type 1, 2, 3, and 4 expression and enzyme activity in human anterior pituitary adenomas.

17Beta-hydroxysteroid dehydrogenase (17betaHSD) isoforms reversibly catalyze the final step in the formation of estradiol (E2) from estrone (E1) and the formation of testosterone from androstenedione. We have investigated 17betaHSD type 1, 2, 3, and 4 gene expression and 17betaHSD estrogenic activity in human anterior pituitary adenomas. 17BetaHSD messenger ribonucleic acid (mRNA) expression was studied by RT-PCR in 42 pituitary tumors and 3 normal pituitaries, 17betaHSD activity was studied in 11 tumors and 17betaHSD type 1 was immunolocalized in vitro in 6 tumors. 17BetaHSD type 1 gene expression was detected in 34 of 42 adenomas in all tumor subtypes; 17betaHSD type 2 mRNA was detected in 18 of 42 adenomas, but not in prolactinomas; 17betaHSD type 3 mRNA was detected in 12 of 42 adenomas, but not in corticotropinomas; 17betaHSD type 4 was expressed in 20 of 42 adenomas by all adenoma subtypes. Reversible 17betaHSD activity was found in 9 of 11 adenomas, and 17betaHSD type 1 immunopositivity was cytoplasmically distributed in all 6 adenomas in vitro. All 4 17betaHSD isoforms are variably expressed in human anterior pituitary adenomas, which also show 17betaHSD enzyme activity, suggesting that 17betaHSD may play an important role in regulating the local cellular levels of estradiol.

Development of pituitary adenoma treatment--a critical essay.

The history of pituitary adenoma treatment shows, as in medicine in general, a succession of movements and counter movements. A large number of surgical techniques was proposed, but only very few survived the selection process. This selection was influenced not only by the general development of surgical techniques that also by the introduction of effective medical treatments and the arrival of new diagnostic methodology. We witness today a new selection mechanism besides the quality of the results--the economic pressure. Its importance may even increase in future because of progressing limitations of medical budgets. We subdivide the history of pituitary adenoma treatment into three main periods: the early period from Sir Victor Horsley to Norman Dott; the period of the reintroduction of the transphenoidal approach initiated by Gérard Guiot to the introduction of bromocriptine, the first effective antisecretory drug; and the period of refinement of the individual treatment methods still going on today. We present this history not so much in a retrospective way, by enumerating the single technical variations of surgical procedures but rather by presenting the momentary situations, as witnessed by our predecessors by presenting short extracts of contemporary texts to characterize the thinking in the past.

Stereotactic radiosurgery for recurrent surgically treated acromegaly: comparison with fractionated radiotherapy.

OBJECT: The authors tested the assumption that gamma knife radiosurgery is more effective than fractionated radiotherapy for the treatment of patients with acromegaly who have undergone unsuccessful resective surgery. Untreated and uncured acromegaly causes illness and death. Acromegalic patients in whom growth hormone and, particularly, insulin-like growth factor I are not normalized must undergo further treatment. METHODS: After unsuccessful operations, 16 patients suffering from recurrent and uncured acromegaly underwent stereotactic radiosurgery (25 Gy to the tumor margin, 50 Gy maximum), the outcome of which was compared with the result obtained in 50 patients who received fractionated radiotherapy (40 Gy). The cumulative distribution functions of the two groups (Kaplan-Meier estimate) differed significantly (p < 0.0001 in the log-rank test of Mantel). The mean time to simultaneous normalization of both parameters was 1.4 years in the group treated with the gamma knife and 7.1 years in the group treated with fractionated radiotherapy. CONCLUSIONS: The authors suggest the use of stereotactic radiosurgery as the preferred treatment for recurrent acromegaly resulting from unsuccessfully resected tumors.

Effect of cell density on hormonal secretion from human pituitary adenomas in vitro.

UNLABELLED: Cell density effects were investigated on tumorous hormonal secretion from 10 pituitary adenomas: 3 somatotrophinomas secreting GH and PRL; 7 gonadotrophinomas, 3 co-secreted both FSH and LH, all 7 secreted LH. Enzymatically dispersed tissue was plated out in 24-well plates at 5 x 10(5), 10(5), 5 x 10(4) and 10(4) cells/well in serum-free media. Media were collected weekly for 2 weeks. RESULTS: In 3 of 3 somatotrophinomas, GH and PRL secretion was higher (p < 0.05) at both week 1 and 2 from 10(4) cells/well, but similar at other cell densities. In all 3 gonadotrophinomas, the FSH secretory rate was highest at 5 x 10(5) cells/well which fell as cell density decreased. Conversely, in 7 of 7 gonadotrophinomas the LH secretory rate was highest at 10(4) cells/well (p < 0.01) which fell as cell density increased. CONCLUSION: These data suggest that paracrine factors may modulate tumorous GH, PRL, FSH and LH secretion, and show that FSH and LH secretion vary inversely as cell density increases.

[Gamma knife radiosurgery in neurosurgery]. / Das Gamma-Knife im Dienste der Neurochirurgie.

The gamma knife is a stereotactic radiosurgery device which allows well defined, deep seated brain tumors, or arteriovenous malformations having a diameter of less than 3 cm, to be treated in a single session under local anesthesia. This technique, which was first described over 40 years ago, has undergone major development in recent years and is the most commonly used method for radiosurgery worldwide. The principle relies on the over-lapping of narrow collimated beams from 201 cobalt-60 sources. The technique, which was introduced into Switzerland in September 1994, has rapidly gained recognition. 184 patients have been treated by 30 April 1997. An average follow-up period of 15 months is much too short for analysis of patients treated by radiosurgery. However, our series of benign tumors shows stabilization of volume in the first few months followed by a slow reduction of the tumor volume, in all but two cases. The gamma knife represents the treatment of choice for recurrent and unsuccessfully operated patients with endocrine active pituitary adenomas. With brain metastases, a rapid reduction in tumor volume is seen in the first few weeks in the majority of cases. The tumor volume may then remain stable or reduce further until complete disappearance. In the case of arteriovenous malformations complete obliteration of the nidus is not seen, on average, for 2-3 years. Individual patient follow-up studies illustrate these results. To date our results have shown zero morbidity and mortality. International statistics from 58,766 cases (as of December 1996) from 77 gamma knife centers demonstrate the value of this technique as a complement or, depending on the indication, an alternative to classical microsurgery.

Identification of proliferating human anterior pituitary adenoma cells in vitro.

A method to determine whether dispersed human anterior pituitary adenoma cells proliferate in mixed culture was developed. Fifteen pituitary adenomas were dispersed enzymatically to single cells, following which twelve were double immunostained after eight days. Proliferating cells were identified immunologically following one hour of bromo-deoxyuridine incorporation. Adenoma cells were subsequently identified with an anti-neuron-specific enolase antibody system. A time course of bromo-deoxyuridine labelling was performed on three nonfunctional adenomas over a four day period, with bromo-deoxyuridine being added to cultures at one hour, 24 hours and four days prior to immunostaining. Double immunolabelled cells were unambiguously identified by a dark brown nucleus surrounded by red cytoplasm. Eight out of 12 pituitary adenomas (two prolactinomas, three nonfunctional, three growth hormone secreting) showed an increased bromo-deoxyuridine labelling index (range 0.1%-1.4%). Bromo-deoxyuridine incorporation over four days showed an increase in bromo-deoxyuridine from 0.02%, 0.03% and 3.3% at one hour to 10.1%, 1.3% and 5.0% at four days, respectively, but evidence of mitosis was scant. This study shows that pituitary adenomas may proliferate in vitro and that this double immunostaining method may be used as an in vitro proliferation assay in a mixed cell population.

A comparison of proliferation indices in human anterior pituitary adenomas using formalin-fixed tissue and in vitro cell culture.

The authors compared detection methods for cell proliferation in human anterior pituitary adenomas using histological sections and dispersed cell culture. After tumor cells had been grown for 4 days in dispersed culture, bromodeoxyuridine (BUdR), proliferating cell nuclear antigen (PCNA), and Ki-67 were compared by double immunostaining and contrasted with single staining of PCNA and Ki-67 indices in the corresponding histological sections from 12 human pituitary adenomas. In vitro, the BUdR labeling index was positive in six of 12 tumors (range < 0.1-5.1%), 10 of 12 tumors were PCNA-positive (range < 0.1-100%), and Ki-67 was positive in 10 of 12 adenomas (range < 0.1-8%). In vitro, BUdR and Ki-67 gave similar proliferative indices for 10 of 12 adenomas. In vivo, the PCNA labeling index was positive in 12 of 12 adenomas (range 0.9-95%) and Ki-67 was positive in 11 of 12 adenomas (range < 0.1-2%). Tumors with a labeling index less than 0.1% were considered to be negative for proliferation. High PCNA values were found in vitro and in vivo, whereas Ki-67 labeling indices were similar in vitro and in vivo for nine of 12 adenomas. It is concluded that Ki-67 proliferative indices in vivo reflect those found in vitro, at least after 4 days in dispersed culture, but that PCNA overestimates pituitary adenoma proliferation in histological sections as well as in dispersed culture.

Cytokine expression in human anterior pituitary adenomas.

OBJECTIVE: There is increasing evidence for the role of cytokines in pituitary differentiated function and tumorigenesis, but the spectrum of cytokines found in the pituitary is unknown. Therefore profiles of cytokine expression were determined in different human anterior pituitary adenoma sub-types. DESIGN: The reverse transcriptase-linked polymerase chain reaction (PCR) was used to identify the presence of cytokine mRNA within human pituitary adenomas. PATIENTS: Seventeen pituitary adenoma biopsies removed at transsphenoidal surgery were examined: 4 somatotrophinomas, 7 non-functional adenomas, 4 prolactinomas, one case of Cushing's disease and one case of Nelson's syndrome. MEASUREMENTS: RNA was extracted from each adenoma biopsy and reverse transcribed into cDNA. This was specifically amplified in a PCR using oligonucleotide primers complementary to each cytokine. The cytokines investigated were interleukin (IL)-I alpha, IL-I beta, IL-2, IL-4, IL-5, IL-6, IL-7, IL-8, tumour necrosis factor (TNF)-alpha, TNF-beta and transforming growth factor (TGF)-beta 1, beta 2 and beta 3. The products of each PCR were visualized using agarose gel electrophoresis. RESULTS: All 17 adenomas expressed IL-8 transcripts, but no expression of IL-2, IL-5 or IL-7 was found. IL-6 was expressed in all 4 somatotrophinomas, 3 of 7 non-functional tumours, 2 of 4 prolactinomas and in the single case of Nelson's syndrome. At least one of the 3 isoforms of TGF-beta was found in all but 2 tumours; one prolactinoma and one non-functional adenoma. IL-1 alpha, IL-beta, IL-4, TNF-alpha and TNF-beta were expressed sporadically by individual adenomas. CONCLUSION: These data suggest that whilst IL-8 may be important, the local expression of the cytokines IL-2, IL-5 and IL-7 is not important in human anterior pituitary tumorigenesis.

External irradiation of macroinvasive pituitary adenomas with telecobalt: a retrospective study with long-term follow-up in patients irradiated with doses mostly of between 40-45 Gy.

PURPOSE: Published dose recommendations for radiotherapy in patients with pituitary macroadenomas vary. Therefore, we retrospectively analyzed the results in our patients from the treatment period 1973-1992. METHODS AND MATERIALS: From a total of 89 patients with macroinvasive adenomas, 66 received radiation therapy immediately following subtotal surgical removal (combined treatment modality), and 22 were irradiated as primary treatment or after surgical recurrence. Only one patient was reirradiated. The surgical interventions have been performed by the same surgeon. For the majority of patients (79 out of 89) with a mean follow-up of 8.1 years (0.5-19 years) the total tumor dose ranged between 40-45 Gy at a dose per fraction of 1.8-2.25 Gy. All patients had bilateral opposed fields with telecobalt. Eleven patients had an additional arc rotation. RESULTS: The 10-year progression-free survival for all 89 patients independent of treatment modality was 88.1%. The 10-year progression-free survival for patients treated by surgery and adjuvant radiation therapy (40-45 Gy at 1.8-2.25 Gy, 60 out of 79) was 90.3%, and for radiation therapy alone (40-45 Gy at 1.8-2.25 Gy, 19 out of 79), 100% (p = 0.32). The prognostic factors for progression-free survival were the subtype of adenoma, the presence of visual symptoms at the time of diagnosis, the suprasellar extension, and the initial hormone levels. The presence of infiltration of adenoma cells in the basal dura or in the mucosa of the sinus sphenoidalis do not represent prognostic factors showing the special biological behavior of pituitary adenomas. Signs of x-ray-induced cerebral necrosis have not been observed in any patient. Long-term visual complications developed in four patients. This could be due to scar formation in the treated region, which can compress the optic nerve and provoke disturbance similar to an empty-sella syndrome. The latter occurred prevalently years after treatment, even though surgical methods of sellar plugging were used. The incidence of hypopituitarism after combined treatment modality at time of last follow-up (irradiated between 40-45 Gy at 1.8-2.25 Gy) was low (36%, 21 out of 60). CONCLUSION: In patients with pituitary macroadenomas, radiotherapy with a total dose of 40-45 Gy at 1.8-2.25 Gy per fraction resulted in a high local tumor control without serious morbidity.

Effects of insulin-like growth factor-I on growth hormone and prolactin secretion and cell proliferation of human somatotrophinomas and prolactinomas in vitro.

OBJECTIVE: IGF-I inhibits GH secretion from normal and some tumorous pituitary tissue, and has been shown to be mitogenic for gonadotrophinoma cells in vitro. It is not known whether IGF-I affects somatotrophinoma cellular proliferation or the secretion of other hormones, such as PRL and alpha-subunit, which are often co-secreted by these tumours. We have therefore examined the effects of IGF-I on proliferation and hormonal secretion of human somatotrophinomas and prolactinomas in vitro. DESIGN: Pituitary adenoma tissue was dispersed to single cells in monolayer culture. The effects of 100 nM IGF-I on GH, PRL and alpha-subunit secretion were determined over 4-hour and over 4-day periods, and a 4-day dose-response study using 1-100 nM IGF-I was performed on two tumours. Adenoma cell S-phase proliferation was determined after bromodeoxyuridine incorporation for 1 hour after 4 days, using a double immunostaining method. RESULTS: Over 4 hours, 100 nM IGF-I had no effect on GH, PRL or alpha-subunit secretion in 7 tumours. Over 4 days, 100 nM IGF-I reduced GH secretion in 5/8 somatotrophinomas (range 17-84%, P < 0.05) compared to controls, with tumours responding to IGF-I having lower basal serum and in-vitro GH levels than tumours unaffected by IGF-I (P < 0.05). There was no effect on alpha-subunit secretion in any of the three tumours studied. PRL cosecretion was increased in 3/5 somatotrophinomas compared to control (20, 30 and 37%, P < 0.05), with tumours responding to IGF-I being associated with lower basal serum and in-vitro PRL levels than those tumours unaffected by IGF-I. IGF-I also increased PRL secretion in 2/2 prolactinomas (27 and 32%, P < 0.05) compared with control. GH was inhibited and PRL secretion was stimulated by 1 and 10 nM IGF-I in the two dose-response studies. The proliferative labelling index did not exceed 1.9% in any tumour and no proliferative effect was found with 100 nM IGF-I in any somatotrophinoma. CONCLUSION: IGF-I inhibited tumorous GH in 62% and stimulated PRL secretion in 71% of tumours over 4 days, without affecting alpha-subunit secretion or being mitogenic for somatotrophinoma cells in vitro. No hormonal effects were observed over short (4-hour) incubations. IGF-I may be a newly recognized factor directly stimulating tumorous PRL secretion.

Fibrin sealing of mucoperichondrial flaps in endonasal-transsphenoidal pituitary surgery: technical note.

We describe a simple technique that helps to avoid nasal septum perforations and the related complications after endonasal-transseptal transsphenoidal pituitary surgery. At the end of the Hirsch procedure, the mucoperichondrium is fixed to the septal cartilage with a thin layer of fibrin glue. Two silicone splints are applied to both sides of the septum and left in place for 2 days. The technique is very useful in preventing possible displacement of the mucoperichondrium, which may lead to compression and ischemia of the doubled mucosa between the septal cartilage and the silicone splints. A firm fixing of the margins of a mucoperichondrial laceration to the septal cartilage creates conditions for optimal healing and reduces nasal-packing time and nasal-splinting time. The technique is recommended for all patients with and without mucosal tears and is also recommended for the transsphenoidal reoperations.

The value of inferior petrosal sinus sampling in diagnosis and treatment of Cushing's disease.

OBJECTIVE: While microsurgical selective adenomectomy is the best method available at present for the treatment of Cushing's disease, its success depends to a large degree on precise preoperative intrapituitary microadenoma localization. This study compares the results of intrapituitary adenoma localization obtained with inferior petrosal sampling, computerized tomography and magnetic resonance imaging with the adenoma localization as found at surgery. DESIGN: The results of inferior petrosal sampling for intrapituitary localization of ACTH-producing pituitary adenomas were compared in a retrospective study with the results of computerized tomography, magnetic resonance imaging, surgical and pathological findings. Special attention was paid to the intersinus ACTH relation. PATIENTS: Thirty-eight patients (33 women and 5 men) of 11-68 years of age suffering from pituitary-dependent Cushing's disease were studied. Patients with ectopic ACTH-secreting tumours and recurrent pituitary adenomas were excluded. MEASUREMENTS: Blood samples were obtained simultaneously from both inferior petrosal sinuses and a peripheral vein before and 5, 10, 15 and 20 minutes after stimulation with 60 micrograms/m2 human corticotrophin-releasing hormone (hCRH). RESULTS: Of the adenomas in our series, 42% had a diameter of 3 mm or less. Only 6 of 20 adenomas examined by computerized tomography and 11 of 29 examined by magnetic resonance imaging were identified correctly. Inferior petrosal sinus sampling produced significantly better results, particularly when combined with a stimulation test with hCRH: for 29 of 38 adenomas examined, the location was predicted correctly with these techniques. Analysis of the intersinus adrenocorticotrophin concentration ratio showed that the best right-central-left discrimination was obtained with values of 1.3 and 1.4. CONCLUSIONS: We conclude that inferior petrosal sinus ACTH sampling after hCRH stimulation is the best method available for the intrapituitary localization of microadenomas causing Cushing's disease provided that the appropriate technique of blood sampling is used meticulously.

Differential effects of insulin-like growth factor 1 on the hormonal product and proliferation of glycoprotein-secreting human pituitary adenomas.

The effects of human recombinant insulin-like growth factor 1 (IGF-1) on the secretion, viability, and proliferation of dispersed human anterior pituitary adenomas secreting FSH, LH, and alpha-subunit (alpha-su) were examined in vitro over 4 h and 4 days. The acute effect of IGF-1 on secretion over 4 h was examined in four tumors secreting FSH, LH, and alpha-su. IGF-1 (100 nmol/L) reduced LH compared to control (100%) in one tumor (61%, P < 0.01), and three tumors remained unaffected. FSH and alpha-su secretion were insufficient to measure over 4 h. Nine tumors were studied over 4 days; relative to control, IGF-1 (100 nmol/L) increased FSH secretion in all seven tumors secreting FSH (28-266%, P < 0.05) and increased alpha-su secretion in all four tumors studied (36%, 63%, 91%, and 121%, P < 0.05). IGF-1 reduced LH secretion in four/nine tumors (13%, 23%, 32%, and 50%, P < 0.05). Dose response curves (1-100 nmol/L IGF-1) were performed on three tumors cosecreting FSH and LH. Stimulation of FSH was achieved with either 1 or 10 nmol/L IGF-1, a single tumor in which alpha-su was measured showed maximal stimulation at 10 nmol/L IGF-1, and one of three tumors showed LH inhibition with 100 nmol/L IGF-1. In situ viability of attached cells was assessed with fluorescein and propidium iodide in seven tumors. After 4 days' exposure to 100 nmol/L IGF-1, in situ viability was increased in five tumors (range 12-19%, 15 +/- 1.3% SEM, P < 0.05). The effects of IGF-1 on the adenoma cell proliferative S-phase fraction was determined in six tumors after 4 days of treatment using double immunostaining with bromodeoxyuridine incorporation for 1 h. In four/six adenomas that stained positive for bromodeoxyuridine in the controls (1-5.6%), the S-phase fraction was increased by 100 nmol/L IGF-1 [(range 2.1-10.6%, increase 90-220%) (P < 0.05)]. These results show that IGF-1 has differential effects on gonadotropins from human pituitary adenomas, stimulating intact FSH and alpha-su, inhibiting or being without effect on intact LH in vitro, and increasing both viability and number of tumorous glycoprotein-secreting cells entering into the S-phase of proliferation.

Basic fibroblastic growth factor stimulates prolactin secretion from human anterior pituitary adenomas without affecting adenoma cell proliferation.

The effects of human recombinant basic fibroblastic growth factor (bFGF) on the secretion and/or proliferation of 26 human anterior pituitary adenomas secreting PRL alone (6 tumors), PRL and GH (18 tumors), or GH alone (2 tumors) were examined. Secretory studies were performed over 4 h, 4 days, and 21 days, and proliferation studies over 4 days. The acute effect of bFGF on secretion over 4 h was examined in 10 tumors. bFGF (10 nmol/L) increased PRL compared to that in controls (100%) in 2 tumors (126% and 290%; P < 0.05) and PRL and GH in a third tumor (183% and 133%, respectively; P < 0.05), whereas 7 tumors remained unaffected. Fourteen tumors were studied over 4 days. bFGF (10 nmol/L) increased PRL secretion in 9 of 11 tumors (117-525%; P < 0.05) cosecreting PRL and GH and in all 3 tumors secreting PRL alone (156%, 183%, and 691%; P < 0.01). Dose-response curves with 0.1, 1, and 10 nmol/L bFGF in 2 of these tumors cosecreting GH and PRL showed that stimulation was achieved with all 3 concentrations. bFGF (10 nmol/L) stimulated GH secretion in 2 of 11 mixed tumors (159% and 196%, respectively; P < 0.05). In 2 tumors studied over 3 weeks, 5 nmol/L bFGF stimulated PRL secretion progressively without affecting GH secretion (106% and 207%; P < 0.05). Tissue proliferation was determined by double immunostaining after bromodeoxyuridine incorporation for 1 h in 7 tumors after 4 days. The labeling index did not exceed 1.2% in any tumor, and there was no effect of 10 nmol/L bFGF on the proliferation of adenoma cells. These results suggest that bFGF may have a paracrine role in the stimulatory regulation of PRL secretion in human pituitary adenomas, and these effects are most likely due to increased hormonal synthesis. An in vitro cell culture system can be used to study proliferative potential. However, bFGF is not mitogenic for human anterior pituitary adenomas secreting PRL and PRL plus GH in vitro.