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The Journal of Clinical Endocrinology & Metabolism Vol. 82, No. 8 2731-2737
Copyright © 1997 by The Endocrine Society

Endocrinological Oncology

A Growth Hormone-Releasing Hormone-Producing Pancreatic Islet Cell Tumor Metastasized to the Pituitary Is Associated with Pituitary Somatotroph Hyperplasia and Acromegaly

Naoko Sanno, Akira Teramoto, R. Yoshiyuki Osamura, Shigeru Genka, Hideki Katakami, Long Jin, Ricardo V. Lloyd and Kalman Kovacs

Department of Neurosurgery, Nippon Medical School (N.S., A.T.), 1-1-5 Sendagi, Bunkyo-ku, Tokyo 113, Japan; Department of Pathology, Tokai University School of Medicine (N.S., R.Y.O.), Boseidai, Isehara-city Kanagawa 259-11, Japan; Department of Neurosurgery, Yokohama Shin Midori Hospital (S.G.), Kanagawa, Japan; Department of Internal Medicine, Miyazaki Medical College (H.K.), Miyazaki, Japan; Department of Laboratory Medicine and Pathology, Mayo Clinic and Mayo Foundation (L.J., R.V.L.), Rochester Minnesota 55905; Department of Pathology, St. Michael’s Hospital (K.K.), Toronto, Ontario, M5B 1W8 Canada

Address all correspondence and requests for reprints to: Naoko Sanno, Department of Neurosurgery, Nippon Medical School, 1-1-5, Sendagi Bunkyo-ku, Tokyo 113, Japan.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
The functional and morphological changes in the pituitary gland caused by a GHRH-producing pancreatic islet cell tumor that metastasized to the pituitary and caused somatotroph hyperplasia are described. A 52- yr-old woman presented with loss of visual acuity, diabetes insipidus, and acromegaly caused by a GHRH-producing endocrine carcinoma metastasized to the pituitary. The serum GHRH, GH, and insulin-like growth factor I levels of the patient were elevated. Immunohistochemical and in situ hybridization study revealed GHRH immunoreactivity and GHRH messenger RNA (mRNA) in the metastatic tumor cells. The anterior pituitary showed hyperplasia of somatotroph cells with intact acinar structure that did not contain an adenoma, determined by light microscopy using silver impregnation. Electron microscopy revealed hyperplastic characteristics of densely granulated somatotrophs. In situ hybridization documented strong signals for GH mRNA and pituitary-specific transcriptional factor Pit-1 mRNA in the hyperplastic somatotrophs. A weak signal for GHRH receptor mRNA was detected in these somatotrophs. However, using in situ RT-PCR, GHRH receptor mRNA was more conclusively observed in most of the somatotrophs. The excessive production of GHRH by metastatic tumor may have resulted in somatotroph hyperplasia by the synergistic effects of Pit-1 and GHRH receptor. It can be concluded that the pathogenesis of pituitary adenoma formation is primarily mediated by other factors than hypothalamic hormone.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
ACROMEGALY is most often caused by a GH-producing pituitary adenoma; however, on very rare occasions, ectopic GHRH-producing tumors may result in the acromegaly (1). Approximately 50 cases have been described in the literature (2), and the majority of these neoplasms have been pancreatic, pulmonary, or gastrointestinal endocrine tumors. The morphological features of the pituitary have been analyzed in only 12 patients of those ectopic GHRH-producing tumors (2- 6). Most of them had hyperplasia of somatotrophs, while one adenoma (7) and one adenoma-like transformation (8) have been reported. GH-producing pituitary adenomas in patients with hypothalamic GHRH-producing gangliocytoma (9) or in GHRH transgenic mice lend support to the view that prolonged stimulation might induce neoplastic formation (10, 11, 12). Even if those findings are taken into consideration, the role of hypothalamic hormones on pituitary tumorigenesis is still controversial.

In this report, we describe the morphological features of the pituitary in an individual with a GHRH-producing pancreatic tumor metastasis to the pituitary using immunomolecular histochemical techniques. The interaction between GHRH-receptor (GHRH-R) and pituitary-specific transcriptional factor (Pit-1) in cultured rat pituitary cells has been suggested previously (13). We investigated GH, GHRH, GHRH-R, and Pit-1 messenger RNA (mRNA) expression in the hyperplastic pituitary cells using in situ hybridization and in situ RT-PCR combined with immunohistochemistry. The aim of our study was to clarify the morphological features of the pituitary caused by the production of excess GHRH by the metastatic tumor in the pituitary. The role of hypothalamic hormone on pituitary tumorigenesis is discussed from a molecular and immunohistochemical perspective.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Case report

A 52-yr-old woman was referred because of loss of left visual acuity. She presented with acromegalic features in face, hands, and feet; polyuria; and polydipsia. Endocrinological examination showed elevated serum GH 14 ng/mL (normal < 5 ng/mL) and insulin growth factor I levels of 3.20 U/mL (normal >1.88 U/mL), respectively. Serum GH responded paradoxically to glucose tolerance test and TRH stimulation test. Serum TSH, PRL, and other anterior pituitary hormones were within normal ranges. Her plasma GHRH, measured by enzyme immunoassay, was elevated to 1145 pg/mL (normal 4–12 pg/mL). Computerized tomography scans and magnetic resonance images showed a mass over 1 cm in diameter in the pituitary fossa. Histological examination of the tumor from a biopsy demonstrated numerous degenerated small cells with nuclear pleomorphism consistent with the diagnosis of metastatic carcinoma. The patient died of cachexia caused by multiple metastases. Postmortem examination revealed that the primary tumor was in the pancreas with widespread metastases in the anterior pituitary and pituitary stalk, parietal and occipital lobes, cerebellum, parietal bone, thyroid, lung, liver, both adrenal glands, both ovaries, subcutaneous tissue, and lymph nodes. The pancreatic tumor measured 16.5 x 7.0 x 6.0 cm in size and weighed 260 g. The detailed clinical course of this patient has been reported by Genka et al. (14).

Light- and electron-microscopic studies

Tissues from surgery and autopsy were fixed in 10% formalin for 18 h and embedded in paraffin. Serial sections were prepared and stained with hematoxylin and eosin and Grimelius’ silver method. For immunohistoheistry, avidin-biotin peroxidase complex method was applied with catalyzed signal amplification (15).

The following antibodies were used: anti-GH (dilution 1:800), anti-PRL (1:600), anti-ACTH (1:800) polyclonal antibodies (from Dako, Glostrup, Denmark), anti-FSH-ß (1:200), anti-LH-ß (1:100), anti-TSH-ß (1:2000), and anti-{alpha}-subunit of glycoprotein polyclonal antibody (1:200) (from National Institute for Diabetes of Digestive and Kidney Disease, Pituitary Hormone Program, Bethesda, MD). Antineuron-specific enolase (1:100), somatostatin (1:100), glucagon (1:200), vasoactive intestinal peptide (1:500), {alpha}-fetoprotein (1:200), calcitonin (1:200) polyclonal antibodies (Dako), and chromogranin-A (1:50) monoclonal antibody (LK2H10, Class IgG1, Immunon, Pittsburgh, PA) were also applied. The avidin-biotin peroxidase complex method was performed as reported previously (14). The catalyzed signal amplification method (15) was performed to localize GHRH in the tumor using polyclonal antibody for human GHRH peptide 44 diluted 1:20,000. Serial sections were used when comparing the reactivities with the other antibodies. Double immunostaining method was also applied using 3-3'diaminobenzidine (DAB) and alkaline phosphatase-conjugated second antibody (Amersham Life Sciences, Arlington Heights, IL) (16).

Formalin-fixed, paraffin-embedded tissues from a normal human pituitary, a GH-secreting pituitary adenoma and adenomatous pituitaries of rats transgenic for human GHRH served as controls for immunohistochemistry, in situ hybridization, and in situ RT-PCR.

For electron microscopic examination, a section of paraffin-embedded tissue was dewaxed and embedded in Quetol (WakoPure Chemicals, Tokyo, Japan) by inverted gelatin capsule method. Ultrathin sections were stained with uranyl acetate and lead citrate and investigated by JOEL 1200 EX electron microscope.

Oligonucleotide primers and probes for in situ hybridization, RT-PCR, and in situ RT-PCR

The oligonucleotide primers and hybridization probes were synthesized by a DNA oligonucleotide synthesizer. The sequence of hybridization probes for GH, PRL, and Pit-1 mRNA were GGC GCG GAG CAT AGC GTT GTC, GGC TTG CTC CTT GTC TTC GGG, and GAG CCA TGC ACA GCT GCC AGG GCC TCC CCA AC, respectively (17). The hybridization probes for GHRH were GHRH-1: GTA GCT GTT GGT GAA GAT GGC ATC TGC ATA and GHRH-44: AGC CGT GCC CTT GCT CCT CGC TCT TGG TTG, which correspond to human GHRH amino acids 1–10 and 34–44 (18). The primer pair for human GHRH-R were (GenBank: S799912) GHRH-R sense primer: ACG ACA CCT CCC CCT ACT GG and GHRH-R antisense primer: CAA CAA TGA AGC CCT GGA A, which correspond to nucleotides 875–894 and 1146–1166, respectively. GHRH-R hybridization probe was nucleotides 919–948: AAA AAG CCC AAA GTT CAC CCC GAC CGA GAG G, located internal to the PCR products.

Solution RT-PCR

To confirm the specificity of primer sets and hybridization for in situ RT-PCR, solution PCR was performed using extracted total RNA from a GH-secreting adenoma. Total RNA extraction was performed by the single-step method with a Trizol reagent kit (Life Technologies, Gaithersburg, MD) (19). First-strand complementary DNA was prepared from total RNA by using a first-strand synthesis kit (Stratagene, La Jolla, CA). The RT reaction was performed in a final volume of 50 mL with 5 mg total RNA, 300 ng antisense primer, 1x RT buffer, 1.0 mM each deoxyribonucleotide (dATP, dCTP, dTTP, and dGTP), 40 U RNase inhibitor, and 50 U Moloney murine leukemia virus reverse transcriptase at 37 C for 60 min. PCR was performed in 100 mL final reaction volumes containing 5 mL RT reaction product as template DNA corresponding to complementary DNA synthesized from 500 ng total RNA, 1x PCR buffer (Promega, Madison, WI), 1.5 mM MgCl2, 0.2 mM of each deoxynucleotide (Boehringer Mannheim, Indianapolis, IN), 300 ng of each sense and antisense primer for GHRH-R, and 2.5 U Taq DNA polymerase (Promega). Programmable temperature cycling (Perkin-Elmer/Cetus 480, Norwalk, CT) was performed with the following cycle profile: 95 C for 5 min, followed by 94 C for 1 min, and 60 C for 1 min. A 20-mL aliquot of PCR product was analyzed by gel electrophoresis using a 2% agarose gel and stained with ethidium bromide. The separated PCR products were transferred to nylon membrane filters, and Southern hybridization with a single internal probe that hybridized to regions within the amplified sequences was performed. Hybridization was performed with 1x 106 cpm/mL [33P]dATP-labeled probe at 42 C for 18 h. Autoradiography was performed at -70 C with Kodak Omat-AR film (Eastman Kodak, Rochester, NY) with intensifying screens.

In situ hybridization

The probes for the detection of GH, PRL, Pit-1, GHRH, and GHRH-R mRNA were labeled with Biotin-dUTP (Boehringer Mannheim) by terminal deoxyribonucleotidyl transferase reaction. The in situ hybridization procedure was performed as described previously (20, 21). The sections were hybridized with 1 ng/mL of the specific probe at 42 C for 18 h. After hybridization, signal detection was performed using streptoavidin-biotin (Dako), then the reaction product was visualized by nitroblue tetrazolium salt and 5-bromo-4 chrolo-3 indolyl phosphate (NBT-BCIP, Sigma Chemical, St. Louis, MO). Control experiments were carried out using sense probes, which have a complementary sequence to the antisense probe. For the simultaneous detection of genes and hormones, in situ hybridization followed by indirect immunohistochemistry was also performed on the same section (22).

In situ RT-PCR

The in situ RT-PCR technique was performed by a three-step protocol as previously described (23). The same GHRH-R primers and probes used for solution RT-PCR were employed for in situ RT-PCR. Briefly, tissue sections were digested with 2 mg/mL proteinase K at 37 C for 15 min and subsequently inactivated by heating to 80 C in PBS for 10 min. Then the RT reaction was performed on the slides for 2 h at 42 C. The PCR amplification was performed on the block of the thermocycler (Omni Slide; Hybaid, Middlesex, UK) in the following steps: an initial denaturing step of 95 C for 5 min, 20 cycles of 94 C for 2 min, 60 C for 1.5 min, and 72C for 1.5 min, and final extension at 72 C for 10 min. After PCR reaction, tissues were fixed with 4% paraformaldehyde for 5 min, followed by incubation in ethanol, and rinsed in 2x SSC. Slides were incubated with hybridization solution with labeled probe overnight at 42 C. Signal detection was performed as above. For the positive controls, in situ RT-PCR using tissues of somatotroph adenoma of human GHRH transgenic rat and human GH-producing adenoma was also performed. Other control experiments performed included: 1) omission of reverse transcriptase or Taq polymerase; 2) omission of PCR primers; 3) pretreatment with RNase (Sigma) 100 mg/mL in PBS at 37 C for 2 h before RT; and 4) analyzing the amplified products in solution from the in situ RT-PCR by gel electrophoresis and Southern hybridization.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
By light microscopy, carcinoma was identified surrounded by nontumorous adenohypophysis. The tumor was well demarcated with fibrous capsule from nontumorous anterior pituitary, however, when analyzing the the serial section, we found that tumor cells had invaded to the nontumorous pituitary and the pituitary stalk (Fig. 1Go).



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  		Figure 1. A, Hematoxylin and eosin-stained section show well-demarchated metastatic tumor (right) and anterior pituitary with hyperplastic eosinophilic cells. Acinar structure is somewhat irregular. Magnification, x150. B, Immunohistochemical staining shows GH immunoreactivity in hyperplastic eosinophilic cells, whereas metastatic tumor is immunonegative. Magnification, x150.

 
The pancreatic carcinoma was composed of monotonous round cells with a large number of bizarre, multinucleated giant cells and spindle cells. Immunohistochemically, the tumor was immunoreactive for GHRH, neuron-specific enolase and chromogranin A as reported previously (14). Based on those findings, the diagnose of a pancreatic endocrine carcinoma was made. The metastatic tumor in the pituitary had similar pathological features. The tumor contained numerous small cells showing nuclear pleomorphism. Immunohistochemistry revealed immunoreactivity for GHRH, chromogranin A, neuron-specific enolase and somatostatin. No immunoreactivity was expressed for carcinoembryonic antigen, gastrin, vasoactive intestinal peptide, calcitonin, and {alpha}-feto protein. By in situ hybridization, a strong signal for both GHRH 1 probe and GHRH 44 probe was observed in the cytoplasm of many tumor cells (Fig. 2Go).



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  		Figure 2. A, Immunostaining for GHRH in metastatic tumor. Many tumor cells are immunoreactive for GHRH by catalyzed signal amplification method. Magnification, x300. B, In situ hybridization using biotinylated oligonucleotide probe specific for GHRH peptides 34–44 shows a positive signal for GHRH mRNA in tumor cells. Magnification, x300.

 
In the nontumorous anterior pituitary, no adenoma was found. Acidophilic cell hyperplasia was identified in all areas of the nontumorous pituitary. The Grimelius’ silver stain demonstrated the preservation of the reticulin fiber network, however, partial destruction of the enlarged acinar architecture was seen (Fig. 3Go).



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  		Figure 3. A, Grimelius’ silver stain shows somatotroph hyperplasia. Acinar structure in anterior pituitary is preserved and several acini are irregular and expanded. Magnification, x200. B, Electron micrograph of anterior pituitary shows that hyperplastic cells are densely granulated somatotrophs. G, Golgi apparatus; SG, secretory granule. Magnification, x8000.

 
By immunohistochemistry, the acidophilic cells were GH-immunoreactive. Other cell types containing PRL, ACTH, TSH-ß, FSH-ß, LH-ß, and the {alpha}-subunit of glycoprotein hormones were also recognized among GH-immunopositive cells. By the double immunostaining method, colocalization between GH and PRL immunoreactivity in the same cells was rarely noted. By electron microscopy, the hyperplastic cells contained numerous granules of approximately 200–300 nm. Those findings are compatible with hyperplasia of densely granulated type somatotrophs (Fig. 3Go).

In situ hybridization revealed a strong signal for GH mRNA in the cytoplasm of most of the hyperplastic somatotrophs. Signal for PRL mRNA was found only in scattered cells. Pit-1 mRNA was noted in most of hyperplastic somatotrophs (Fig. 4Go). Combined in situ hybridization and immunohistochemistry for Pit-1 mRNA and GH protein revealed that expression of Pit-1 mRNA was observed not only in GH immunoreactive cells but also in other cell types.



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  		Figure 4. A, In situ hybridization for GH mRNA reveals strong signal in many anterior pituitary cells. Magnification, x300. B, Combined in situ hybridization and immunohistochemistry for GH mRNA and GH protein. Signal for GH mRNA is visualized as purple staining with NBT-BCIP, and immunoreactivity for GH protein is visualized as brown staining with DAB. More cells expressed GH mRNA than GH protein. Colocalization of mRNA and protein in same cells are indicated by arrows. Magnification, x300. C, In situ hybridization for pituitary specific transcriptional factor Pit-1 reveals overexpression of Pit-1 mRNA in many hyperplastic cells. Magnification, x300. D, Combined in situ hybridization and immunohistochemistry for Pit-1 mRNA and GH protein. Signal for Pit-1 mRNA is visualized as purple staining, and immunoreactivity for GH protein is demonstrated as brown staining. Many cells expressed Pit-1 mRNA that was colocalized with GH protein. Magnification, x400.

 
In situ hybridization showed weak signal for GHRH-R mRNA in scattered cells. Solution PCR study was performed using total RNA from fresh-frozen tissue of a GH-secreting adenoma before in situ RT-PCR study for GHRH-R mRNA. The expected 293- and 893-bp bands, which are the reported sizes of alternative splicing GHRH-R (24), were detected by electrophoresis of the RT-PCR products. Southern blot analysis using a P33-labeled probe revealed hybridization signal for both PCR products (Fig. 5Go).



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  		Figure 5. Solution RT-PCR for detection of GHRH receptor mRNA in a GH-secreting pituitary adenoma. Expected 293- and 893-bp bands were detected using same primers for the in situ RT-PCR. Bottom, Southern hybridization with a probe internal to amplified product from primers labeled with 33P shows GHRH receptor bands.

 
In situ RT-PCR study using tissues of a GH-secreting pituitary adenoma and adenomatous pituitary of rats transgenic for human GHRH as positive controls, demonstrated strong signal amplification for GHRH-R mRNA after 20 cycles of PCR (not shown). The same procedure performed on the section of the pituitary revealed strong signal for GHRH-R mRNA in the hyperplastic somatotrophs (Fig. 6Go), whereas the metastatic tumor tissue on the consecutive section shown no signal for GHRH-R mRNA. Control studies performed on consecutive sections omitting RT, PCR primers, and Taq polymerase showed no signal amplification. Combined immunohistochemistry after in situ RT-PCR revealed GHRH-R mRNA expression in the cytoplasm of many GH-immunoreactive cells (Fig. 6Go).



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  		Figure 6. Expression of GHRH-R mRNA in pituitary of patient by in situ RT-PCR. Signals were detected with an oligonucleotide probe labeled with biotin and visualized with NBT-BCIP. A, A strong positive signal for GHRH mRNA is detected in some cells in pituitary. B, Omission of PCR primers resulted in negative signal for GHRH-R mRNA. Magnification, x300). C, Expression of GHRH-R mRNA (purple) detected by in situ RT-PCR followed by immunohistochemical detection for GH protein (brown) with DAB. Colocalization of GHRH-R mRNA in GH immunoreactive cells is indicated by arrows. Magnification, x400.

 

   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
Acromegaly is most often caused by a GH-secreting pituitary adenoma. Approximately 50 cases of ectopic GHRH-producing tumor with acromegaly have been reported, including pancreatic tumors; pulmonary endocrine tumors; and tumors from the jejunum, cecum, retroperitoneum, and adrenal gland (2). In our case, GHRH immunoreactivity and GHRH mRNA expression in the metastatic carcinoma indicated that ectopic production of GHRH was responsible for the elevated serum GHRH, GH, and insulin growth factor I, and acromegaly. Because the metastatic tumor invaded to the pituitary stalk in addition to the anterior pituitary, the patients presented with diabetes insipidus.

Immunohistochemical examination of the pituitary gland of ectopic GHRH-producing tumors has been reported in only 12 cases in the literature (2, 3, 4, 5, 6, 7, 8). Only one patient had pituitary adenoma containing both GH and PRL (5) and another patient had adenoma-like areas in the hyperplastic pituitary (8). Two adenomas of one patient with gigantism were composed of somatotroph cells and null cells (7). In the other cases, the pituitaries had diffuse and/or nodular hyperplasia of somatotrophs (2, 4, 6). It is often difficult to distinguish adenoma from hyperplasia in the pituitary gland (4). In our case, because the normal acinar structure of the pituitary was preserved, we made the diagnosis of hyperplasia rather than adenoma.

Pit-1 mRNA was demonstrated in the hyperplastic somatotrophs by in situ hybridization. The pituitary-specific transcription factor Pit-1, which was first described as a nuclear binding protein of rat GH and PRL cells, has known to selectively activate GH, PRL, and TSH transcription in somatotrophs, lactotrophs, and thyrotrophs (25, 26, 27). Several investigators have reported Pit-1 transcript and protein expression in human pituitary adenomas (28, 29, 30). Whether Pit-1 is associated with abnormal cell proliferation in the development of pituitary adenomas is controversial. Pelligrini et al. (28) observed overexpression of Pit-1 mRNA in PRL- and GH-secreting adenomas by RT-PCR. A recent study using antisense oligonucleotide analysis indicated that Pit-1 was involved in proliferation in the rat pituitary cell line (31). It has been suggested that Pit-1 has a role in differentiation of pituitary adenomas, however, some additional factors may be required for development of pituitary adenomas (29, 30).

GHRH modulates cellular cAMP levels through GHRH-R, and because both the GH and Pit-1 genes contain cAMP response element, GHRH stimulates GH and Pit-1 production (32, 33). Pit-1-dependent expression of GHRH-R mediating pituitary cell growth in dwarf mice has been reported (34). Hence, the effects of GHRH on somatotrophs include Pit-1 stimulation, with GHRH and Pit-1 acting either independently or in combination to stimulate expression of the GH gene. In our case, it is conceivable that GHRH stimulated Pit-1 mRNA transcription via GHRH-R, and subsequently Pit-1 acted synergistically with GHRH on GH transcription and somatotroph cell proliferation resulting in somatotroph hyperplasia.

A signal for GHRH-R mRNA was observed only weakly by in situ hybridization, and required the more-sensitive technique of in situ RT-PCR to demonstrate a signal clearly. In our case, it is possible that physiological down-regulation of GHRH-R may result in a weak signal in the face of the elevated levels of GHRH. In our studies, appropriate controls, including solution RT-PCR in a somatotroph cell adenoma; a pituitary of a rat transgenic for human GHRH as positive tissue control; a GHRH-producing tumor on the same section as a negative tissue control; and omission of RT, Taq polymerase, and primer sets in PCR reaction served as negative controls for PCR for the confirmation of the specific amplification.

Recently, the evidence of intrinsic hypothalamic hormone and hypothalamic hormone receptors in the pituitary and pituitary adenomas has been demonstrated by various investigators (35, 36, 37), which suggests that hypothalamic hormones play an paracrine/autocrine role in tumor formation (35). In somatotroph adenomas with GHRH-producing gangliocytomas, GHRH-immunoreactive ganglion cells are found, and local paracrine/autocrine function has been suggested (38).

Although human pituitary adenomas have been shown to be monoclonal in origin (39, 40), it is still not known whether hypothalamic hormones have a role in tumorigenesis in human pituitary adenomas. Data have accumulated to show that hypothalamaic hormones stimulate cell proliferation in the anterior pituitary (36, 37).

In multiple endocrine neoplasia syndromes, genetic changes are known to play a major role in the pathogenesis of pituitary adenomas (38). The three previous reports with adenoma formation secondary to GHRH-producing tumors have been associated with multiple endocrine neoplasia type 1 (5, 7, 8). G-protein, a mutation in a significant percentage of GH-secreting adenomas, has been implicated in the pathogenesis of this type of adenoma (41). The roles of oncogenes such as c-fos (42); growth factors such as fibroblast growth factor, epidermal growth factor, and transforming growth factor; and hormone receptors have been claimed to have important roles in pituitary tumor formation (43). It has been proposed that pituitary tumors can produce a number of substances that may have secretory, differentiating, and proliferative functions (36).

Despite extremely high local levels of hypothalamic releasing hormone, adenoma formation did not occur in our patient. This study provides further evidence that although hypothalamic hormone excess may be important in cellular proliferation, the pathogenesis of pituitary adenoma formation may be mediated by other factors including new oncogenes and suppressor genes that are as yet uncharacterized.

Received March 18, 1997.

Revised May 9, 1997.

Accepted May 15, 1997.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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