REVIEW |
Correspondence to: R. Yoshiyuki Osamura, Dept. of Pathology, Tokai Univ. School of Medicine, Boseidai Isehara-city, Kanagawa 259-1193, Japan.
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Summary |
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Immunohistochemistry (IHC) and recently in situ hybridization (ISH) have elucidated various aspects of human pituitary adenomas, i.e., functional differentiation and classification, transcription factors and mechanism of hormone production, regulation of hormone secretion, and processing of prohormones. Recently, the use of tyramide (catalyzed signal amplification; TSA or CSA) and RT-PCR has been effective for detection of trivial amount of proteins (peptides) and mRNA, respectively. Immunomolecular histochemistry is expected to further clarify the function and biology of human pituitary adenomas. (J Histochem Cytochem 48:445458, 2000)
Key Words: pituitary adenoma, immunohistochemistry, in situ hybridization, transcription factor, nuclear receptor, steroid receptor, pituitary hormone, hypothalamic hormone
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Introduction |
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Human pituitary adenomas account for about 16.3% of intracranial neoplasms and are frequently treated by neurosurgical procedures usually removal by the transsphenoidal approach. The morphology of human pituitary adenomas was first studied by staining methods that was able to clarify different morphological appearances of adenomas according to their clinical function, i.e., hormone production. Classification of human pituitary adenomas has been profoundly assisted by immunohistochemistry (IHC) and, recently, by in situ hybridization (ISH). With the use of these techniques, human pituitary adenomas have been classified into prolactin (PRL)-secreting adenomas, growth hormone (GH)-secreting adenomas, adrenocorticotropic hormone (ACTH)-secreting adenomas, thyroid hormone-stimulating hormone (TSH)-secreting adenomas, gonadotropin (follicle-stimulating hormone, FSH; luteinizing hormone, LH)-secreting adenomas, and nonsecreting adenomas, which are more commonly designated as nonfunctioning adenomas. It is noteworthy that a significant proportion of nonfunctioning adenomas have been found to secrete gonadotropin subunit or ß (
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Functions of Human Pituitary Adenomas |
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Immunohistochemistry has greatly contributed to classification of functioning human pituitary adenomas. The functioning adenomas include GH-secreting adenomas, PRL-secreting adenomas, pro-opiomelanocortin (POMC)-secreting adenomas, TSH-secreting adenomas, and gonadotropin-secreting adenomas. Immunomolecular techniques have shown that GH-secreting adenomas, TSH-secreting adenomas, and gonadotropin-secreting adenomas are frequently multihormonal. Specifically, the GH-secreting adenomas (Fig 1 and Fig 2) are frequently positive for PRL, -subunit (SU), TSHß-SU, and FSHß-SU by IHC and ISH. TSH-secreting adenomas are frequently positive for GH and PRL as well as TSHß-SU and
-SU. Gonadotropin-secreting adenomas are frequently of the FSH-secreting type and sometimes also produce GH or ACTH. The multiple hormonality of the GH-secreting adenomas may be attributed to co-production of GH, PRL, and
-SU, as well as occasional FSHß-SU, by the same normal anterior GH cells that are classically categorized as acidophilic. This is a unique situation that could be elucidated only by IHC.
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The mechanisms of multihormone production are discussed from the standpoint of transcriptional factors. PRL-secreting adenomas are inevitably monohormonal, and POMC-secreting adenomas are often monohormonal. PRL-secreting adenomas have been successfully treated by bromocriptine (a dopamine agonist), although a few are resistant to this agent. Nonfunctioning adenomas are not infrequently positive for gonadotropin subunits, i.e., -SU and FSHß-SU, by IHC and ISH. The histogenesis and functional differentiation of this group of human pituitary adenomas have been debated with regard to their cell lineages (discussed below). Recently, some GH-secreting adenomas have been shown to secrete GHRH from the same cells that secrete GH, and both autocrine and paracrine mechanisms have been proposed for tumorigenesis and functional differentiation (see below). Most GH-secreting adenomas have many osmiophilic secretory granules in their cytoplasm and are designated as densely granulated adenomas. By light microscopic IHC, the tumor cells contain GH diffusely in the cytoplasm. A certain proportion of GH-secreting adenomas contain aggregated keratin filaments, which have been designated as "fibrous bodies" or "keratin bodies." In these tumors, the numbers of secretory granules are decreased, and they have therefore been designated as sparsely granulated adenomas. In contrast, most PRL-secreting adenomas contain few secretory granules and have been designated as sparsely granulated adenomas. They contain prominent Golgi complexes which have been shown by pre-embedding immunoelectron microscopy to contain PRL. These findings suggest rapid turnover of PRL in the tumor cells.
By postembedding immunoelectron microscopy, GH and PRL are localized to the secretory granules in GH-secreting adenomas and PRL-secreting adenomas, respectively. When bromocriptine treatment is effective, the tumor cells of PRL-secreting adenomas exhibit an increase in the numbers of secretory granules, indicating inhibition at the time of exocytosis. The rough endoplasmic reticula and Golgi saccules also become less prominent. For human pituitary adenomas, a variety of morphological and functional classifications have been proposed (-SU secretion. The classification of the tumor would therefore be as follows: GH-secreting adenoma; symptomatic (acromegaly); multihormonal (GH, PRL, TSH,
-SU) by IHC and ISH; macroadenoma; and densely granulated. Based on IHC and ISH techniques, this classification provides the clinical and morphological characteristics at a glance. By IHC and ISH analysis, nonfunctioning adenomas not infrequently reveal production of gonadotropin subunits. In these tumors, serum gonadotropin is usually not elevated. At present, it is debatable whether tumors that are positive for gonadotropin subunits should be classified as gonadotropin-secreting adenomas or nonfunctioning adenomas. The use of more sensitive amplification methods, such as tyramide (catalyzed) signal amplification (TSA or CSA), should increase the ability to detect gonadotropin subunits (
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Receptors in Human Pituitary Adenomas |
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The cells of the anterior pituitary are regulated by hypothalamic hormones and steroid hormones. The receptors corresponding to these hormones reside in the anterior pituitary cells and include the following: growth hormone-releasing hormone receptor (GHRH-R, also known as GRF-R); gonadotropin-releasing hormone receptor (GnRH-R); corticotropin-releasing hormone receptor(CRH-R); dopamine 2 receptor (D2R); estrogen receptor (ER). These receptors have been cloned. GHRH-R, GnRH-R and D2R are seven folded transmembranous proteins. ER, which include ER and ERß isoforms, is a nuclear protein that binds to estrogen at a DNA upstream site. ER has been detected by IHC and ISH on paraffin sections. D2R has been detected by ISH. For detection of GnRH-R and GHRH-R, present in the cell membrane in only trivial amounts, in situ RT-PCR has been used as a powerful tool to demonstrate specific mRNA (
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Experimental Models of Pituitary Adenomas |
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Experimental pituitary adenomas have been produced mainly in rodents. Classically, PRL-secreting tumors have induced by prolonged estrogen treatment. These tumors are a useful model for human PRL-secreting adenomas, especially from the aspect of functional and morphological changes induced by treatment with bromocriptine. They are also transplantable and have been established as cell lines (MtT series) (
Recently, the use of transgenic animals and gene-targeting knockout animals have produced pituitary adenomas (Fig 4a4k). In mice and rats, human GHRH transgenic techniques produced GH-secreting adenomas similar to those in human pituitary. The pituitary tumors in these transgenic animals are positive for GH, GHRH, PRL, and TSH. They also possess GHRH-R. The tumorigenic effect of GHRH through an autocrine/paracrine mechanism has been proposed. In these animals, a hyperplasiaadenoma sequence of GH cells has been shown (
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Transcription Factors and Mechanisms of Specific Hormone Production |
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As previously mentioned, human GH- and TSH-secreting adenomas are frequently multihormonal with a combination of GH, PRL, and TSH. For the functional differentiation of these tumor cells, the pituitary transcription factor (Pit-1) and its synergistic action with other factors have been a focus of research. IHC and ISH have strongly contributed to clarification of the functional roles of the transcription factors.
In 1988, Rosenfeld et al. and Karin et al. separately reported the presence of a pituitary transcription factor/growth hormone factor 1 (Pit-1/GHF-1) ( (wild-type), Pit-1ß (
In our immunohistochemical studies on human pituitary adenomas from 60 patients, we found Pit-1 immunoreactivity in the nuclei of all cases of GH- and TSH-secreting adenomas (
It is known that synergistic factors exist for Pit-1 in the functional differentiation of pituitary cell types: GH receptor (GHRH-R), estrogen receptor (ER), thyroxine receptor (TR), retinoic acid receptor (RAR), and retinoid X receptor (RXR) (Fig 5). GHRH-R is a member of the Gs-protein-coupled receptor family and is located on chromosome 7. This protein is transmembranous with seven folds, and its molecular weight is 4445 kD. Our ISH and RT-PCR studies showed that GHRH-R mRNA expression is common in GH- and TSH-secreting adenomas (Fig 4o and Fig 4p).
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ER belongs to the nuclear receptor superfamily and its ligand is estradiol (E2). ER is located on chromosome 17 on which many oncogenes and anti-oncogenes are also situated. The ER protein includes two isoforms, and ß, with 595 amino acid residues, and a molecular size of 65 kD. In normal human anterior pituitary, ER protein is found in the nuclei and ER mRNA is found in the cytoplasm of PRL-secreting cells. In PRL-secreting adenomas, Pit-1 mRNA and ER nuclear protein co-exist in the same tumor cells, which suggests a synergistic action of Pit-1 and ER (
RXRs are transcription factors that belong to the steroid/thyroid hormone receptor superfamily (, ß, and
. RXR
, ß, and
proteins consist of 446, 448, and 463 amino acid residues, respectively. RXRs bind to the hormone-responsive elements of specific genes and form homodimers (
and ß mRNAs are widely expressed (
mRNA is restricted to tissues such as skeletal muscle, heart, brain, and fetal pituitary (
was observed in all types of human anterior pituitary cells but RXR
was mainly localized in TSHß-, GH-, and
-SU-positive cells by double immunohistochemical staining. In all TSH-secreting adenomas, most adenoma cells showed Pit-1 mRNA in the cytoplasm and RXR
protein in the nuclei. Therefore, RXR
may promote the functional differentiation of TSH as indicated by the TSH-secreting adenomas.
Other Transcription Factors
Recently, several transcription factors relative to pituitary development have been discovered. Transcription factors transiently expressed during pituitary development include the prophet of Pit-1 (Prop-1) and Rpx/Hesx-1 (
Pituitary homeobox 1 (Ptx1) is a transcription factor first reported by
Recent investigations on cultured cells have shown that Ptx1 is involved not only with POMC transcription in corticotrophs but also with the transcription of other anterior pituitary hormones. T3-1 cells (gonadotroph precursor),
TSH cells (thyrotroph precursor), GHFT1.5 cells (somatolactotroph precursor), GH3 cells (a somatolactotrophic cell line), and TtT-97 cells (thyrotrophic tumor) These authors showed by Northern blotting that the Ptx1 mRNA level was higher in
T3-1,
TSH, and GHFT1.5 cells than in AtT-20 cells, indicating that Ptx1 may be actively expressed in pituitary cells other than corticotrophs. They also investigated cultured cells by Western blotting and showed that there was no discrepancy between Ptx1 protein expression and Ptx1 mRNA expression (
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SF-1/Ad4BP is a transcription factor that regulates the P-450 gene (
NeuroD1/ß2 is a transcription factor containing a helixloophelix heterodimer (
P-Lim/Lhx-3 mRNA initially appears in Rathke's pouch on e8.59, and it is known that four types of anterior pituitary cells, including -SU, are completely depleted in P-Lim/Lhx-3-deficient knockout mice (
-SU gene (
-SU, and P-Lim/Lhx-3 appears to be involved in
-SU transcription, as a co-factor of Ptx1 (
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Processing of Prohormones |
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It is well known that peptide hormones are produced as functionally inactive prohormones that are subjected to post-translational modification and then secreted as biologically active forms (MSH by PC2 (Fig 7).
MCH were localized to the same tumor cells in which PC1/3 and PC2 were expressed (
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Secretory Granule-related Proteins |
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Secretion is the phenomenon by which the cell synthesizes and concentrates bioactive substances and, after a certain period of storage, releases them in response to external stimulation. This process can be classified as constitutive secretion, or regulated secretion, depending on the involvement of secretory granules. In regulated secretion, secretory proteins are packaged in secretory granules, transferred to the plasma membrane, and then released in response to extracellular stimulation. This process is observed in neuropeptide and peptide hormone-secreting cells. The granin family, including chromogranins A and B (CgA and B), plays an important role in the packaging of these substances into secretory granules (
At present, well-known Ras oncogene products are believed to be low molecular weight GTP binding proteins that serve as a "switch" for signaling cell proliferation and differentiation. These Ras-related proteins, the Rab family, are considered to be involved in regulation of vesicular transport in the cell. At present, about 30 proteins have been identified in this family. Among these, Rab3 has been reported to be involved in the release of neurotransmitters from nerve cell synapses and in the exocytosis of secretory granules from endocrine cells, including those of the anterior pituitary (Fig 8). These functions of Rab3 were first proposed by
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In our study, the Rab3 protein was extensively expressed as the granular form in the cytoplasm of human anterior pituitary hormone-secreting cells. It was not expressed in S-100-positive FS cells, which do not contain secretory granules in their cytoplasm (
Four types of isoforms, Rab3A, 3B, 3C, and 3D, are known for Rab3 protein and these have homology of as high as 7785% (
At present, proteins that have been shown to be involved in exocytosis of secretory granules from endocrine cells include synaptotagmin, SNAP-25, syntaxin, and synaptobrevin/VAMP, in addition to the Rab3 isoform. Synaptotagmin possesses nine isoforms (
Received for publication July 6, 1999; accepted October 6, 1999.
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