Pituitary adenomas in acromegaly: Comparison of different adenoma types with clinical data

Adenoma tissues from 309 patients with active acromegaly was examined by routine light microscopy and immunohistochemistry, and selectively by electron microscopy. All adenomas were immunoreactive for growth hormone. Eighty-seven adenomas were monohormonal (28%), 58 were bihormonal (immunoreactive for growth hormone and prolactin) (19%), and 157 adenomas were plurihormonal (51%), with positivity for glyco-proteins and/or their α-subunit as well. The mean tumor size was significantly greater in monohormonal adenomas than in other adenoma types. There was no difference in invasiveness among the various adenoma types. Younger patients showed invasive tumor growth more often. Patients with densely granulated GH cell adenomas had a significantly longer duration of symptoms compared to patients with other adenoma types. More than half of the patients with sparsely granulated GH cell adenomas had a duration of less than 5 yr. There was no correlation between duration of symptoms and tumor size. The preoperative mean GH level was significantly higher in patients with sparsely granulated GH cell adenomas than in those with mixed GH/PRL cell adenomas. The preoperative mean PRL level was significantly higher in patients with bihormonal adenomas than in those with plurihormonal adenomas. There was an inverse correlation between age and preoperative GH and PRL levels. No linear correlation was found between preoperative basal GH and PRL levels. Monohormonal adenomas presented more often with suprasellar and/or parasellar extension than other adenoma types. Our data suggest a positive correlation between tumor extension and preoperative GH and PRL levels. Patients with plurihormonal adenomas were significantly older than patients with sparsely granulated GH cell adenomas and mixed GH/PRL cell adenomas. No significant difference was found between the various adenoma types and the extent of surgical removal, which depends on the degree of invasiveness, tumor size, and extrasellar tumor extension.     

垂体生长激素细胞腺瘤的电镜及免疫电镜观察

24 cases of growth hormone(GH)-producing pituitary adenomas were studied with electron microscopy and immunoelectron microscopy by protein A-gold complex, 6 cases were identified as densely granulated GH adenoma and 15 cases as sparsely granulated GH adenoma, among which 4 cases were proved by immunoelectron microscopy to be containing granules with prolactin(PRL) activity simultaneously. Intracytoplasmic fibrous bodies were often seen in the sparsely granulated cells anyhow, not all those cells with fibrous bodies possess the secretory granules with GH activity, and fibrous bodies were also detected in some PRL cells of certain mixed type adenoma. This suggests that fibrous bodies might not be the specific morphological feature of pituitary growth hormone cell adenomas.     

Growth hormone (GH) and prolactin (PRL) gene expression and immunoreactivity in GH- and PRL-producing human pituitary adenomas

Summary Growth hormone(GH)-producing pituitary adenomas are morphologically heterogeneous and frequently contain not only GH immunoreactivity but also variable numbers of prolactin (PRL) immunopositive cells. Paraffin sections of 59 surgically removed GH- and/or PRL-producing adenomas classified by histology, immunocytochemistry (ICC) and electron microscopy were studied using in situ hybridization (ISH) for GH and PRL mRNA and combined with ICC for the coded hormones. Somatotroph adenomas (10 densely and 10 sparsely granulated tumours) and mammosomatotroph adenomas (10 cases) contained both GH mRNA and GH immunoreactivity. In 4 densely and 4 sparsely granulated somatotroph adenomas and 4 mammosomatotroph adenomas, only GH mRNA and its product were found. In 28 cases (6 densely and 6 sparsely granulated somatotroph adenomas, 10 mixed somatotrophlactotroph adenomas and 6 mammosomatotroph adenomas) both GH and PRL mRNA were present, although no PRL immunoreactivity was not in 2 densely granulated somatotroph adenomas. In these cases, ISH for PRL mRNA combined with GH immunostaining revealed the presence of variable numbers of mammosomatotrophs. In 9 acidophil stem cell adenomas only PRL mRNA and its product were found; one tumour expressed both GH and PRL mRNA and their products. Nine lactotroph adenomas contained only PRL mRNA and PRL immunoreactivity. The results show that GH and/or PRL mRNA content could not be correlated with ICC for coded proteins and ultrastructural features. The mammosomatotrophs were more numerous using ISH when compared with ICC. Somatotroph, mammosomatotroph and mixed adenomas are closely related and they can be considered to represent one basic tumour type originating in a cell committed to GH production. This may undergo clonal differentiation towards a mammosomatotroph and further to the lactotroph line. The results also indicate that lactotroph adenomas arise in a cell committed to PRL production. Acidophil stem cell adenomas seem to be more closely related to lactotroph cells than somatotroph.     

Mixed growth hormone and prolactin-secreting human pituitary adenomas: a pathologic, immunocytochemical, ultrastructural, and immunoelectron microscopic study

A study of 30 adenomas from patients with signs of growth hormone (GH) and prolactin (PRL) hypersecretion revealed the presence of mammosomatotroph cells (MSC) containing both hormones in all cases. Although the number of immunostained cells varied from case to case, in 14 of 25 tumors, all stained cells were MSC. Nine tumors had the ultrastructural appearance of densely granulated growth hormone adenomas, while 11 cases resembled sparsely granulated growth hormone adenomas with frequent fibrous bodies. Exocytosis was present in six of these 11 cases, a feature unusual for pure growth hormone adenomas. Nine tumors consisted of a mixture of cells with the morphology of GH and PRL cells. In the four cases examined, immunoelectron microscopy using double immunolabeling with protein A-gold particles revealed the presence of secretory granules containing both hormones in some tumor cells recognized as mammosomatotroph cells.     

Effects of somatostatin on somatotroph adenomas of the human pituitary: An in vitro functional and morphological study

The effects of somatostatin or the somatostatin analog SMS 201–995 were studied on 4 densely granulated somatotroph adenomas and 4 sparsely granulated somatotroph adenomas in vitro. Release of growth hormone (GH) into culture media during incubation with somatostatin or SMS 201 -995 were measured by radioimmunoassay, and light-microscopical and ultrastructural morphometric parameters were compared with those of cultured control somatotroph adenoma cells of the same tumor. In all tumors except for 1 densely granulated somatotroph adenoma, somatostatin or SMS 201–995 decreased GH release into culture media in 24- and 2-hour incubations. After 48-hour incubation with somatostatin or SMS 201–995, there was no change in cell size or secretory granule diameter. One densely granulated adenoma showed decreased cytoplasmic volume density (CVD) of Golgi apparatus and secretory granules, and a sparsely granulated adenoma had reduced CVD of endoplasmic reticulum. All the tumors that responded with decreased GH release exhibited increased CVD of lysosomes after incubation with somatostatin or SMS 201–995. These results indicate that both densely and sparsely granulated somatotroph adenomas respond to somatostatin inhibition and, furthermore, that inhibition of hormone release is associated with accumulation of lysosomes, suggesting lysosomal degradation of stored hormone. Hospital 20 Nov. (ISSSTE) Coyoacan y Felix Cuevas, Colonia del Valle and (Dept Patologia) y Hospital de Especialidades (C.M.N., IMSS) Cuauhtemoc y Dr. Marquez, Mexico City (IF).     

Definition and differential diagnosis of chromophobe pituitary adenomas: light and electron microscopic studies]

Introduction: Chromophobe adenomas have been defined by the absence of secretory granules in them. But this definition has become doubtful since a granulation could be electron microscopically demonstrated. Hence we studied a collection of more than 100 surgically removed pituitary adenomas in order to find precise morphological criteria for the differential diagnosis of chromophobe adenomas, specially from the sparsely granulated chromophilic tumors. Furthermore we tried to find relations between the amount and type of granulation of the tumor cells and the clinical endocrine hyperfunction. Material and methods: 108 unselected pituitary tumors were studied by light and electron microscopic methods. For histology the tissue was fixed in Helly's fluid or in buffered formalin. The paraffin wax sections were stained with haematoxylin-eosin, PAS, gallocyanin-chrome alum, carmoisine L-orange G-wool green, Herlant's tetrachrome method, and performic acid-alcian blue-PAS-orange G. For electron microscopy small pieces of the tumor were fixed in buffered glutaraldehyde, postfixed in osmium tetroxide, and embedded in epon 812. Sections were stained with toluidine blue for light microscopy. Thin sections were stained with uranyl acetate and lead citrate. Electron microscopical pictures with a primary magnification of 4000 were semi-quantitatively judged for the content and the extent of rough endoplasmic reticulum, Golgi complexes, secretory granules, lysosomes, and mitochondria by a grading with 6 degrees. Results. With special stains and the electron microscope 46 adenomas could be identified which consisted only of slightly granulated or agranular cells but not of densely granulated cells. These were defined as chromophobe adenomas. Oncocytic adenomas were regarded as another tumor type and were not included. One half of the chromophobe adenomas showed ultrastructurally well developed protein-synthesizing organellas. The diameter of the secretory granules amounts up to 500 mum. One quarter had many autolysosomes or lipid droplets. On the other hand, 18 adenomas of our collection exhibited moderate acidophilic granulation with only a few denser or fully granulated cells. These were designated as sparsely granulated acidophilic adenomas. They were rich in organelles. 89% of them showed a well developed rough endoplasmic reticulum and large Golgi complexes as signs of high endocrine activity. The secretory granules had diameters between 200 and 600 upsilonm. The autolysosomes were for the most part small and rare. The 20 fully granulated acidophilic adenomas could be easily recognized and are not discussed in this paper. The sparsely granulated mucoid cell-adenomas were easily identified by a positive PAS-reaction. Discussion: From our studies we conclude that chromophobe adenomas exhibit only sparse granulation and no denser or fully granulated tumor cell...     

Pathology of growth hormone-producing tumors of the human pituitary

This paper reviews the morphologic features of growth hormone-producing tumors of the human pituitary. These tumors are associated with elevated blood growth hormone levels and acromegaly or gigantism and can be classified into the following morphologically distinct entities by the combined application of histology, immunocytology, and electron microscopy: densely granulated growth hormone cell adenoma; sparsely granulated growth hormone cell adenoma; mixed growth hormone cell- prolactin cell-adenoma; acidophil stem cell adenoma; mammosomatotroph cell adenoma; growth hormone cell carcinoma; plurihormonal adenoma with growth hormone production.     

In vitro studies of human pituitary adenomas

The application of morphologic and tissue culture techniques to the study of human pituitary adenomas allows further investigation of structure-function correlations. Using these methods, we have documented morphometric differences between densely and sparsely granulated somatotroph adenomas but the release of growth hormone in vitro and responses to adenohypophysial hormones/drugs do not correlate with tumor type. The morphologic and functional alterations in somatotroph adenomas exposed to SMS 201-995 appear to be reversible in vitro. Incubation of lactotroph adenomas with bromocriptine for 3 days directly reduces tumor cell size, cytoplasmic volume and cytoplasmic volume densities of endoplasmic reticulum and Golgi regions; these changes are similar to the effects of longterm bromocriptine therapy in vivo. Tissue culture studies of gonadotroph adenomas of men confirm that gonadotropin-releasing hormone (GnRH) stimulates gonadotropin release by tumor cells and yields morphologic evidence of increased hormone synthesis whereas these tumors have variable sensitivity to gonadal steroids; structural changes in tumor cells correlate with hormone release after stimulation, suggesting that morphologic parameters may reflect the hormonal milieu of these adenomas. Null cell adenomas and oncocytomas release small quantities of glycoprotein hormones, predominantly gonadotropins in vitro and there are no functional differences between these 2 tumor types; gonadotropin release responds to GnRH stimulation and, paradoxically, to other adenohypophysiotropic hormones, but such stimulation does not result in secretion of other adenohypophysial hormones by these tumors.     

Hypophysentumoren

Pituitary adenomas must be clearly differentiated from other tumors of the sellar region (especially meningiomas, granular cell tumors, chordomas and germinomas), which may look very similar. The sub-classification of adenomas depends on the methods used, in particular the immunostaining for pituitary hormones. This sub-classification is not necessary in every case, but must be performed if unusual findings are observed during surgery or if surgery is unsuccessful and radiation or drug-therapy is planned. Special structures and non-immunohistochemical stainings are very helpful for typing adenomas. We differentiated monohormonal densely or sparsely granulated GH-cell adenomas, monohormonal sparsely or very rarely densely granulated prolactin cell adenomas, monohormonal densely or sparsely ACTH-cell adenomas, monohormonal TSH-cell adenomas and FSH/LH cell adenomas from bihormonal adenomas of mammosomatotroph or GH/prolactin cell type or of the acidophil stem cell adenoma type. The number of plurihormonal adenomas decreased with the use of improved monoclonal antibodies. Clinically inactive adenomas are classified as null cell adenomas, oncocytic adenomas or FSH/LH-cell adenomas. These appear as subtypes of one entity deriving from the gonadotroph cell type. Craniopharyngiomas are classified into adamantinous and papillary types, which are not only structurally but also clinically different. If adamantinous craniopharyngiomas show very strongly regressive changes, immunostaining for keratin may be necessary to identify the squamous epithelia for the demonstration of craniopharyngioma.     

Histopathological analyses of silent pituitary somatotroph adenomas using immunohistochemistry, in situ hybridization and confocal laser scanning microscopic observation

To characterize the morphological and functional aspects of silent somatotroph adenomas with paradoxical responses of GH in TRH or GnRH provocation tests, which are considered to be a useful strategy for endocrinological identification of silent somatotroph adenomas, we examined three silent somatotroph adenomas histopathologically. The adenomas were investigated by immunohistochemistry, including the highly sensitive catalyzed signal amplification system, the non-radioisotopic in situ hybridization method, and confocal laser scanning microscopy. GH production and GH-immunopositive secretory granules in the adenoma cells were demonstrated histopathologically, and the adenomas were interpreted as being densely granulated somatotroph adenomas. Endocrinological identification of silent somatotroph adenomas in combination with paradoxical responses of GH in TRH or GnRH provocation tests may elucidate the increasing number of silent somatotroph adenomas that have been regarded as mammotroph or clinically inactive adenomas. One should be aware of the differences between the previously reported silent somatotroph adenomas, most of which are sparsely granulated somatotroph adenomas, a somatotroph adenomas with paradoxical and the silent somatotroph adenomas, most of which are sparsely granulated somatotroph adenomas, and the silent somatotroph adenomas with paradoxical responses of GH in TRH or GnRH provocation tests, which are densely granulated somatotroph adenomas.     

An Atypical Acidophil Cell Line Tumor Showing Focal Differentiation Toward Both Growth Hormone and Prolactin Cells

We report a case of giant pituitary adenoma in a child. Computerized tomography (CT) scan revealed a suprasellar extension tumor mass with hydrocephalus. There was no clinical evidence of acromegaly, gigantism, and other hormonal symptoms. Endocrinologic studies showed within normal value of serum growth hormone (GH: 4.2 ng/mL) and slightly increased levels of prolactin (PRL: 78 ng/mL) and other pituitary hormone values were within normal range. On suppression test by bromocryptin, both GH and PRL levels were reduced. Histopathological findings revealed that the tumor consisted of predominantly chromophobic and partly eosinophilic adenoma cells. Immunohistochemical staining detected GH and PRL in a small number of distinctly different adenoma cells, respectively. Nonradioactivein situ hybridization (ISH) also showed GH and PRL mRNA expression in identical immunopositive cells. Electron microscopy (EM) demonstrated adenoma cells with moderate or small numbers of two types of dense granules and without fibrous body which are characteristic of sparsely granulated GH-cell adenomas. The adenoma does not fit into any classification but may be an atypical acidophil cell line tumor showing focal differentiation toward both GH and PRL cells.     

Pituitary Adenomas that Show a Faint GH-Immunoreactivity but Lack Fibrous Body: Pit-1 Adenoma with Endocrinologically Low Activity

Growth hormone (GH)-producing pituitary adenomas have been classified into densely and sparsely granulated adenomas. The latter are chromophobic with weak GH-positivity and characteristically possess fibrous body (FB), aggregation of cytokeratin filaments. We report eight cases of unusual chromophobic adenomas. GH-immunoreactivity was detected in most adenoma cells in five cases and scattered in three cases. However, it appeared much weaker than that seen in ordinary GH-producing adenomas because of spotty immunoreactivity. Although intracytoplasmic organelles were well-developed, secretory granules were small and sparse. FB was not identified in any cases. Thyroid-stimulating hormone was positive in four cases. Pit-1 protein was positive in all eight cases. A weak labeling with GH probe was detected in two of two cases examined by in situ hybridization. Acromegalic features were evident in four cases, while mild or absent in four cases. GH levels were below 5 μg/l in four cases and 5–10 μg/l in the remaining cases. Macroadenomas and invasive adenomas were seen in seven and six cases, respectively.     

Localization of insulin-like growth factor-II mRNA in human pituitary adenomas

Insulin-like growth factors (IGFs) have been reported to promote cell proliferation in many tumours, but their contribution to pituitary adenoma development and growth has not been characterized. We report the presence of insulin-like growth factor II (IGF-II) mRNA in pituitary adenomas using in situ hybridization (ISH). The intensity of IGF-II hybridization signal was correlated with adenoma type, and the presence of Ki-67. Among the 109 adenomas examined, 55 (50.4%) were positive for IGF-II mRNA. All acidophil stem cell, functioning corticotrophic and plurihormonal adenomas contained the message; a high incidence of signal was found among sparsely (7/8) and densely (4/6) granulated growth hormone (GH) cell adenomas, mixed GH cell–prolactin (PRL) cell adenomas (6/7), thyrotrophic (4/6) and null-cell (6/7) adenomas. Less frequently, IGF-II mRNA was localized in mammosomatotrophic, silent subtype 3, gonadotrophic, and oncocytic adenomas, whereas all sparsely granulated PRL cell adenomas and silent corticotrophic adenomas of subtypes 1 and 2 were negative. The MIB-1 labelling index was significantly higher in adenomas with a moderate to intense IGF-II signal than in adenomas with weak or no signal. The results suggest that IGF-II, when highly expressed, may have a role in pituitary adenoma proliferation.     

Ultrastructural Morphology of Folliculo-Stellate Cells in Human Pituitary Adenomas

Fifty-six pituitary adenomas were studied by electron microscopy in a search for the presence of folliculo-stellate cells (FSCs) with the aim of evaluating their prevalence and ultrastructural morphology. FSCs were scattered in two adenomas (one oncocytoma and one densely granulated GH cell adenoma) and were numerous in a sparsely granulated GH cell adenoma; their overall prevalence was 5.4%. Ultrastructural examination of the three neoplasms revealed that FSCs were hypertrophic element with abundant cytoplasm and organelles (in contrast to FSCs of the normal pituitary) and no obvious signs of neoplastic transformation. Junctional complexes between FSCs were similar to those described in the normal gland. Numerous follicular structures were lined by FSCs. FSCs in pituitary adenomas are probably nonneoplastic, reactive cells showing signs of hyperactivity, similar to FSCs found during pituitary hypersecretion and in estrogen-induced tumor.     

Alpha and beta subunits of glycoprotein hormones in argyrophil pituitary tumors with small granule cells

A group of 33 functionless pituitary tumors with small argyrophil groups (SAG) were collected from a series of 200 pituitary adenomas (16.5% of all adenomas). Histologically, the tumors showed an unusually high frequency of trabecular patterns, perivascular pseudo-rosettes, and oncocytoid transformation. Immunoreactivity for glycoprotein hormone alpha-chain was found in more or less numerous cells of 20 cases (64.5% of SAG tumors). Thirteen of these cases also showed specific beta-chain immunoreactivity, especially for follicle-stimulating hormone (FSH) beta-chain, which was present in 11 tumors. Various admixtures of immature, oncocytic, sparsely granulated, and densely granulated cells were observed ultrastructurally, with prevalence of the latter cell variants in tumors showing immunoreactive cells and prevalence of the former cell variants in tumors lacking immunoreactive cells. It is suggested that some relationship may exist between SAG cell (glycoprotein hormone precursor cells?) tumors--or at least part of them--and glycoprotein hormone cell lines. Anyway, whatever their origin and interpretation, SAG cell tumors seem to represent a distinct clinicopathologic entity.     

Ultrastructure,immunohistochemistry and hormone release of pituitary adenomas in relation to prolactin production

Summary Fifteen cases of pituitary adenoma, 14 of which were associated with hyperprolactinemia, were studied by observation and granule morphometry of electron micrographs, immunohistochemistry and sequential observation of in vitro release with regard to hormone production, storage and secretion. Adenoma cells of 6 cases with marked elevation of plasma prolactin were sparsely granulated, showed characteristic ultrastrucures including the presence of small secretory granules, well developed Golgi and rough membranes, misplaced exocytosis, and positive or negative immunostaining for prolactin. These adenomas also showed vigorous release of the hormone into the circulation and/or culture medium. In vitro studies showed that negative immunostaining of adenoma cells did not preclude the production and secretion of the hormone. One densely granulated adenoma containing cells with numerous lactotroph type granules showed moderate release of prolactin into the circulation. In an acromegalic case associated with both high plasma growth hormone and prolactin, some cells were shown by immunohistochemistry to store both hormones. There were 4 adenomas which could not be shown to produce, store and secrete prolactin by any method available.Abbreviations Used in this Paper ACTH adrenocorticotropic hormone - -MSH -melanocyte stimulating hormone - hGH human growth hormone - hPRL human prolactin - LH luteinizing hormone - FSH follicle stimulating hormone - TSH thyroid stimulating hormone - TRH Thyrotropin-releasing hormone This work was supported in part by Grants-in-Aid for Cancer Research (No. 50-14) and for Specific Diseases (Disorder of Hypothalamic and Pituitary System) from the Ministry of Health and Welfare, and for Cancer Research (No. 401034) from the Ministry of Education, Science and Culture, Japan     

Octreotide Effect on Growth Hormone and Somatostatin Subtype 2 Receptor mRNAs of the Human Pituitary Somatotroph Adenomas

Octreotide, a somatostatin analog used to treat acromegalic patients harboring a pituitary tumor, acts via somatostatin subtype 2 receptor (SSTR2) and causes significant decrease of circulating GH levels and sometimes mild to moderate tumor shrinkage. To further elucidate the mechanism of octreotide action, we studied GH and SSTR2 mRNAs by in situ hybridization in densely and sparsely granulated somatotroph adenomas removed by surgery from 14 treated and 14 untreated patients. Only in densely granulated adenomas were the GH and SSTR2 mRNA signals mildly decreased relative to untreated matched adenomas. The decrease of GH mRNA in densely granulated somatotroph adenomas suggests that they may have a more favorable response to octreotide therapy than sparsely granulated tumors.     

Utility of Pit-1 Immunostaining in Distinguishing Pituitary Adenomas of Primitive Differentiation from Null Cell Adenomas

Pit-1 immunostaining is not routinely used in the characterization of pituitary adenomas, and its utility in distinguishing adenomas dedicated towards the lactotroph, somatotroph, and thyrotroph lineage from null cell adenomas warrants further evaluation. Pituitary adenomas that were negative for expression of a basic panel of hormonal markers (ACTH, prolactin, and growth hormone) were further evaluated for TSH, SF-1, and Pit-1 expression using a tissue microarray. Among the 147 identified pituitary adenomas that were negative for ACTH, prolactin, growth hormone, and TSH, expression of SF-1 was present in 68 cases (46%). Of the remaining 72 cases with sufficient tissue for further analysis, four were Pit-1 positive (6% of the adenomas negative for ACTH, prolactin, growth hormone, TSH, and SF-1); the remaining 68 were potentially null cell adenomas. Two of the Pit-1-positive adenomas displayed a paranuclear CAM 5.2 staining pattern suggestive of a sparsely granulated somatotroph adenoma; however, only one case contained fibrous bodies within a majority of the adenoma cells. Our data suggests that Pit-1 can be utilized as a second tier immunostain in cases of clinically non-functioning adenomas that are immunonegative for ACTH, prolactin, growth hormone, TSH, and SF-1 in order to further segregate rare cases of Pit-1-positive adenomas from null cell adenomas. Pit-1 immunostaining can recognize rare cases of sparsely granulated somatotroph adenomas that appear immunonegative for growth hormone, as well as rare cases of other Pit-1-positive adenomas that are negative for Pit-1 lineage hormones. Overall, pituitary adenomas of the Pit-1 lineage that do not produce prolactin, growth hormone, or TSH are rare, with only four cases identified in the current study.     

Silent somatotroph adenomas of the human pituitary. A morphologic study of three cases including immunocytochemistry, electron microscopy, in vitro examination, and in situ hybridization.

Pituitary adenomas, removed surgically from three women with normal or slightly elevated serum growth hormone levels and no evidence of acromegaly, were studied. The tumor cells were shown by electron microscopy to correspond to sparsely granulated somatotrophs but immunocytochemistry showed that they contained no, moderate, or little growth hormone. Two tumors examined in vitro secreted small amounts of growth hormone in the tissue culture medium initially with a spontaneous rise after several days, and responded to growth hormone-releasing hormone stimulation with increased growth hormone release. In situ hybridization demonstrated growth hormone mRNA expression in adenoma cells. Clinically silent somatotroph adenomas represent a hitherto undescribed entity; electron microscopy shows that they consist of somatotrophs, and express growth hormone mRNA but do not secrete growth hormone in amounts needed to raise substantially serum growth hormone levels and cause acromegaly. Further work is required to clarify the mechanisms accounting for the lack of clinical and biochemical evidence of hormone excess associated with these tumors.