Somatotroph Hyperplasia Research Articles

Pancreatic GHRHomas in Patients with or without Multiple Endocrine Neoplasia Type 1 (MEN 1) : An Analysis of 36 Reported Cases.

Pancreatic GHRHomas (pGHRHomas) with acromegaly have unique conditions, harboring the existence of multiple endocrine neoplasia type 1 (MEN 1). Moreover, pituitary lesions are affected by both protracted ectopic GHRH and loss of menin function. Of significance is the clarification of clinicopathological aspects of pGHRHomas in patients with or without MEN 1. From 1977-2016, thirty-six patients with pGHRHomas were reported. Twenty-two out of 36 patients (61%) had pGHRHomas with MEN 1 and 14 patients did not. The former had a tendency of male predominance, benign tumor behavior and fewer metastasis rather than the latter. The latter is a single pGHRHoma accompanied by pituitary enlargement with somatotroph hyperplasia (hyperplasia) caused by protracted ectopic GHRH. Nine patients with MEN 1 underwent transsphenoidal surgery (TSS). The hyperplasia associated with various pituitary adenomas (PAs) including three GH-related adenomas was observed in seven subjects (32%). In these patients, the resection of their pGHRHomas was feasible. Furthermore, all patients with acromegaly due to pGHRHomas without MEN 1 had non-TSS, whereas approximately 70% of those with MEN 1 had unnecessary TSS. The association with hyperplasia and various PAs suggested that formation of the three GH-related adenomas may be induced by the foundations of MEN 1 gene mutations. J. Med. Invest. 71 : 1-8, February, 2024.

Acromegaly in a Young Women With Pituitary Hyperplasia Secondary to a Neuroendocrine Tumor

Acromegaly is rarely due to an excess of the GH-releasing hormone (GHRH) and pituitary hyperplasia on histology should alert to its presence. Clinical Case: A 35-year-old was referred to surgery with a confirmed diagnosis of symptomatic acromegaly. Her GH failed to suppress during an oral glucose tolerance test (OGTT), her IGF-1 and prolactin was high. Her serum calcium was normal and her chromogranin B was high. MRI scan suggested microadenoma. Her surgery was deferred because of Covid 19, and she was treated with somatostatin analog (SSA). She finally had surgery in July. The histology and immunocytochemistry suggested pituitary hyperplasia with diffuse positivity for chromogranin and synaptophysin. GH was positive in the majority of the cells with many cells positive for Prolactin and ACTH. FSH and LH were positive in scattered cells with patchy positivity of TSH. A solitary nodule was noted in her neck during an examination. We arranged to look for conditions associated with pituitary hyperplasia resulting in GHRH production, including the genetic tests for inherited conditions. Her calcitonin level was normal. She had an ultrasound scan guided fine needle aspiration of the thyroid nodule, this showed Thy3f oncocytic nodule with no features of medullary thyroid carcinoma. She had an NMGa68DOTATATE whole body PET CTand the scan showed a large DOTATAE avid mass from the right adrenal gland compatible with Pheochromocytoma. Her 24 hours total urinary metadrenaline and normetadrenalin was high. Her genetic test for MEN1, CDKN1B, and MEN2 are negative. We have requested the GHRH measurement. After a pituitary surgery, her GH suppressed adequately on OGTT. Her IGF-1 and prolactin is low and her hypogonadism is resolved. Conclusion: Excess production GHRH can result from neuroendocrine tumors of the lung, pancreas, thyroid (medullary thyroid cancer), or pheochromocytomas and hypothalamic gangliocytomas.Several familial syndromes, multiple endocrine neoplasia type 1 (MEN1) and 4 (MEN4), familial isolated pituitary adenoma (FIPA), Carney complex, and sporadic germline mosaic disorder McCune-Albright disease predispose to pituitary hyperplasia. GHRH acromegaly should be suspected in a patient with biochemical/clinical features of acromegaly in the presence of co-existing neuroendocrine tumors when there is diffuse pituitary enlargement on imaging or resolution of acromegaly after the surgical resection of the primary neuroendocrine tumour or persistent acromegaly after surgery if there is histological evidence of somatotroph hyperplasia.

Prkar1a haploinsufficiency ameliorates the growth hormone excess phenotype in Aip-deficient mice.

Mutations of the regulatory subunit (PRKAR1A) of the cyclic adenosine monophosphate (cAMP)-dependent protein kinase (PKA), leading to activation of the PKA pathway, are the genetic cause of Carney complex which is frequently accompanied by somatotroph tumors. Aryl hydrocarbon receptor-interacting protein (AIP) mutations lead to somatotroph tumorigenesis in mice and humans. The mechanisms of AIP-dependent pituitary tumorigenesis are still under investigation and evidence points to a connection between the AIP and PKA pathways. In this study, we explore the combined effects of Aip and Prkar1a deficiency on mouse phenotype and, specifically, pituitary histopathology. Aip+/- mice were compared with double heterozygous Aip+/-, Prkar1a+/- mice. The phenotype (including histopathology and serological studies) was recorded at 3, 6, 9 and 12months of age. Detailed pituitary histological and immunohistochemical studies were performed at 12months. Twelve-month old Aip+/- mice demonstrated phenotypic and biochemical evidence of GH excess including significantly elevated insulin-like growth factor 1 levels, larger weight and body length, higher hemoglobin and cholesterol levels and a higher frequency of growth plate thickening in comparison to Aip+/, Prkar1a+/- mice. Pituitary histopathology did not uncover any pituitary adenomas or somatotroph hyperplasia in either group. These results demonstrate a slow progression from elevated GH release to the formation of overt somatotropinomas in Aip+/- mice; the acromegalic phenotype of these mice is surprisingly ameliorated in Aip+/-, Prkar1a+/- mice. This highlights the complexities of interaction between the AIP and PKA pathway. Specifically targeting GH secretion rather than somatotroph proliferation may be an advantage in the medical treatment of AIP-dependent human acromegaly.

SAT-LB48 Novel Genetic Variant of Carney Complex With Acromegaly

Objective: To describe an uncommon case of Carney complex with acromegaly secondary to pituitary microadenoma with a novel genetic variant. Background: Carney complex (CNC) is a rare autosomal dominant syndrome characterized by myxomas, pigmented skin and mucosal lesions, as well as multiple endocrine tumors. The etiology is an inactivating mutation of the regulatory subunit type 1A of the cAMP-dependent protein kinase (PRKAR1A). Recently, additional CNC pathologic variants in PRKACA and PRKACB have been identified.[1] Elevated growth hormone (GH) and IGF-1 levels are sometimes seen in patients with CNC, thought to be secondary to somatotroph hyperplasia. However, less than one fifth of patients with CNC have clinical acromegaly. [2] Case: Here we describe a 35-year-old female diagnosed with atrial myxoma after presenting with fatigue in her 20s. After her fatigue failed to resolve following surgical excision, further investigation revealed an ovarian tumor. The patient sought care in Mexico where she underwent radiation for presumed ovarian malignancy. Review of the ovarian lesion biopsy at a university hospital later revealed benign melanocyte proliferation. She subsequently developed amenorrhea and hirsutism which prompted referral to endocrinology. Evaluation revealed coarse facial features, large hands, elevated IGF-1, and positive GH suppression test leading to a diagnosis of acromegaly. Gene sequencing revealed a novel pathologic variant of PRKAR1A consistent with CNC. MRI brain was originally negative for pituitary lesions; however follow up imaging after our visit with the patient showed a hypoenhancing lesion concerning for a pituitary microadenoma. Neurosurgical evaluation is underway. Discussion: Acromegaly with a pituitary adenoma is uncommon in patients with CNC. However, clinicians should have high suspicion for the disease in patients with CNC and other endocrine neoplasia disorders. The diagnosis has many deleterious consequences if not treated early. Additionally, this case represents a novel pathologic variant of PRKAR1A that has not previously been identified in Carney complex.

SUN-322 Worsening of Carcinoid Syndrome during Lutetium Therapy in a Patient with Bronchial Carcinoid and Acromegaly

Introduction: Neuroendocrine tumors (NET) are uncommon, particularly when affecting the lungs having an incidence of 0.2 to 2 per 100,000. However, they represent 1-2% of all lung malignancies and up to 30% of all NET. In the context of Multiple Endocrine Neoplasia type 1 (MEN1), bronchial carcinoid account for 2% of tumors and have also been reported in MEN4. Case: A 22 year-old male presented with an incapacitating headache after a dental extraction. Brain MRI showed a 3.3x2.4x1.4 cm lesion, suggestive of pituitary apoplexy. Of note, he had a normal brain MRI performed 20 months before due to mental confusion. He complained of abdominal cramps and diarrhea that started six months before, and had an unexplained weight loss of 10 kg during the last two months. He exhibited mild acromegalic features. On pre-operative evaluation, a routine chest X-ray was performed that showed a central lesion in inferior left pulmonary lobe (ILL). A CT scan revealed a 4.5x4.0x3.5 cm lesion in ILL. On biochemical assessment, he had panhypopituitarism with basal GH levels of 2.05 ng/mL and IGF-I of 823 ng/mL (normal range 99-289). He was submitted to transsphenoidal surgery and the histopathological analysis revealed a somatotropinoma and not somatotroph hyperplasia. A bronchoscopy showed a vegetative and hypervascularized lesion, obstructing the left bronchial segment, compatible with bronchial carcinoid. 18F-FDG PET CT and 68Ga-DOTATOC PET CT scans revealed discrete increase in glycolytic metabolism and significant increase of SSTR expression in the ILL lesion, hepatic lesions and multiple bone lesions consistent with a well differentiated metastatic bronchial carcinoid. At baseline, chromogranin A level was 17,906 ng/mL (normal range 25-140), serotonin 806.8mcg/L (normal range 30-200) and urinary 5-hydroxyindolacetic acid 19.3 mg/24h (normal range 2.0-9.0). MEN1 sequencing was negative for mutations. In the post-operative evaluation, IGF-I level fell to 474 and GH was 2.48. Pegvisomant and octreotide LAR were started with normalization of IGF-I levels. Peptide receptor radionuclide therapy (PRRT) was initiated with lutetium worsening dramatically his abdominal pain, which resolved after rescue subcutaneous octreotide and reintroduction of octreotide LAR. Since the second cycle, octreotide LAR has been given after 177Lu dose. BNP levels are within normal range and the patient has a normal echocardiography. Conclusion: The patient has two NET that can be part of a yet undiagnosed syndrome. Well-differentiated NET may synthesize humoral factors that can cause carcinoid syndrome. Excessive circulating serotonin levels may lead to carcinoid heart disease, diarrhea and cramping. During PRRT, hormone-related crisis can occur as a severe side effect. Therefore, octreotide LAR should not be stopped during Lutetium therapy.

Mild pituitary phenotype in 3- and 12-month-old Aip-deficient male mice.

Germline mutations in the aryl hydrocarbon receptor-interacting protein (AIP) gene predispose humans to pituitary adenomas, particularly of the somatotroph lineage. Mice with global heterozygous inactivation of Aip (Aip(+/-)) also develop pituitary adenomas but differ from AIP-mutated patients by the high penetrance of pituitary disease. The endocrine phenotype of these mice is unknown. The aim of this study was to determine the endocrine phenotype of Aip(+/-) mice by assessing the somatic growth, ultradian pattern of GH secretion and IGF1 concentrations of longitudinally followed male mice at 3 and 12 months of age. As the early stages of pituitary tumorigenesis are controversial, we also studied the pituitary histology and somatotroph cell proliferation in these mice. Aip(+/-) mice did not develop gigantism but exhibited a leaner phenotype than wild-type mice. Analysis of GH pulsatility by deconvolution in 12-month-old Aip(+/-) mice showed a mild increase in total GH secretion, a conserved GH pulsatility pattern, but a normal IGF1 concentration. No pituitary adenomas were detected up to 12 months of age. An increased ex vivo response to GHRH of pituitary explants from 3-month-old Aip(+/-) mice, together with areas of enlarged acini identified on reticulin staining in the pituitary of some Aip(+/-) mice, was suggestive of somatotroph hyperplasia. Global heterozygous Aip deficiency in mice is accompanied by subtle increase in GH secretion, which does not result in gigantism. The absence of pituitary adenomas in 12-month-old Aip(+/-) mice in our experimental conditions demonstrates the important phenotypic variability of this congenic mouse model.

SomaticGNASMutation Causes Widespread and Diffuse Pituitary Disease in Acromegalic Patients with McCune-Albright Syndrome

Context:McCune-Albright syndrome (MAS) is caused by sporadic mutations of the GNAS. Patients exhibit features of acromegaly. In most patients, GH-secreting pituitary adenomas have been held responsible for this presentation. However, surgical adenomectomy rarely eliminates excess GH production.Objective:The aim of this study was to elucidate pituitary pathology in patients with MAS and to explain the basis of failure of adenomectomy to eliminate GH hypersecretion.Design and Setting:We conducted a case series at the National Institutes of Health.Intervention(s):Interventions included medical therapy and transsphenoidal surgery.Patients and Main Outcome Measures:We studied clinical and imaging features and the histology and molecular features of the pituitary of four acromegalic MAS patients.Results:We identified widespread and diffuse pituitary gland disease. The primary pathological changes were characterized by hyperplastic and neoplastic change, associated with overrepresentation of somatotroph cells in structurally intact tissue areas. Genetic analysis of multiple microdissected samples of any type of histological area consistently revealed identical GNAS mutations in individual patients. The only patient with remission after surgery received complete hypophysectomy in addition to removal of multiple GH-secreting tumors.Conclusions:These findings indicate developmental effects of GNAS mutation on the entire anterior pituitary gland. The pituitary of individual cases contains a spectrum of changes with regions of normal appearing gland, hyperplasia, and areas of fully developed adenoma formation, as well as transitional stages between these entities. The primary change underlying acromegaly in MAS patients is somatotroph hyperplasia involving the entire pituitary gland, with or without development of somatotroph adenoma. Thus, successful clinical management, whether it is medical, surgical, or via irradiation, must target the entire pituitary, not just the adenomas evident on imaging.

Pituitary Tumors and Hyperplasia in Multiple Endocrine Neoplasia Type 1 Syndrome (MEN1): A Case-Control Study in a Series of 77 Patients Versus 2509 Non-MEN1 Patients

Patients affected by the multiple endocrine neoplasia type I syndrome (MEN1) display a high incidence of pituitary adenomas, though it is still unknown whether these pituitary tumors have specific pathologic features that would distinguish them from sporadic pituitary adenomas. Pituitary tissue specimens of 77 MEN1 patients from the GTE (Groupe d'étude des Tumeurs Endocrines) register were compared with unselected 2509 non-MEN1 sporadic pituitary tumors and also to a control subgroup of 296 cases, where 1 MEN1 tumor was matched with 4 sporadic tumors of the same hormonal immunoprofile. Sex, age, size, and invasiveness of tumors, and menin gene mutations were documented. Histologic analysis took into account 33 items, including immunocytochemical data, the proliferative marker Ki-67, and an examination of the juxtatumoral pituitary. MEN1 tumors were significantly larger and more often invasive by histology. MEN1 patients with large pituitary tumors (grade IV) were younger than non-MEN1 patients. MEN1 tumors had no other characteristic histologic features and no predominance of any one hormone producing subtype. However, plurihormonal adenomas versus monohormonal and nonimmunoreactive adenomas were more frequent in MEN1 tumors (39%) than in the control non-MEN1 group (P = 0.001). Especially, the growth hormone and prolactin plurihormonality with unusual association with follicle-stimulating hormone, luteinizing hormone, or adrenocorticotropic hormone was more frequent in MEN1 tumors. In addition, multiple adenomas were significantly more frequent (4% vs. 0.1%; P < 0.0001), especially prolactin-adrenocorticotropic hormone. Somatotroph hyperplasia, with or without a microadenoma was found in only 3 MEN1 patients, with growth hormone-releasing hormone hypersecretion by a pancreatic tumor in 2 of them. All types of mutation were observed, including frameshifts, nonsenses, missenses, and 1 case of germline MEN1 encompassing large deletion, strongly suggesting the absence of any phenotype-genotype correlation.

Acromegaly Secondary to Growth Hormone-releasing Hormone Secreted by an Incidentally Discovered Pheochromocytoma

Ectopic growth hormone-releasing hormone (GHRH)-secreting tumors are rare and cause acromegaly with somatotroph hyperplasia. We report a case of acromegaly secondary to GHRH secretion by an incidentally discovered pheochromocytoma in a normotensive patient. A 23-year-old man presented with signs and symptoms of acromegaly. Laboratory evaluation confirmed the diagnosis and magnetic resonance imaging (MRI) revealed a sellar mass which was thought to be a macroadenoma and surgically resected. The patient was not cured and medical treatment was indicated. An abdominal ultrasound performed before initiation of medical treatment showed a solid/cystic lesion superiorly to the right kidney. An abdominal MRI confirmed an adrenal tumor. Hormonal workup of the adrenal incidentaloma revealed elevated urinary catecholamine and total metanephrines findings strongly suggestive of a pheochromocytoma. Acromegaly was then suspected to be due to ectopic secretion of GHRH by the tumor. Patient underwent surgical resection and histopathologic examination confirmed a pheochromocytoma which stained positively for GHRH. Also, review of the pituitary specimen confirmed somatotrophic hyperplasia. Genetic analysis of the ret proto-oncogene showed no mutation. Pituitary MRI was repeated 10 months after pheochromocytoma resection and revealed a slightly enlarged pituitary and partial empty sella. The diagnosis of acromegaly caused by ectopic production of GHRH is a challenging task. A careful histopathological examination of the surgically excised pituitary tissue has a key role to arouse the suspicion and guide the investigation of a secondary cause of acromegaly.

The dependence receptor Ret induces apoptosis in somatotrophs through a Pit-1/p53 pathway, preventing tumor growth

Somatotrophs are the only pituitary cells that express Ret, GFRalpha1 and GDNF. This study investigated the effects of Ret in a somatotroph cell line, in primary pituitary cultures and in Ret KO mice. Ret regulates somatotroph numbers by inducing Pit-1 overexpression, leading to increased p53 expression and apoptosis, both of which can be prevented with Ret or Pit-1 siRNA. The Pit-1 overexpression is mediated by sustained activation of PKCdelta, JNK, c/EBPalpha and CREB induced by a complex of Ret, caspase 3 and PKCdelta. In the presence of GDNF, Akt is activated, and the Pit-1 overexpression and resulting apoptosis are blocked. The adenopituitary of Ret KO mice is larger than normal, showing Pit-1 and somatotroph hyperplasia. In normal animals, activation of the Ret/Pit-1/p53 pathway by retroviral introduction of Ret blocked tumor growth in vivo. Thus, somatotrophs have an intrinsic mechanism for controlling Pit-1/GH production through an apoptotic/survival pathway. Ret might be of value for treatment of pituitary adenomas.

Acromegaly and Somatotroph Hyperplasia with Adenomatous Transformation Due to Pituitary Metastasis of a Growth Hormone-Releasing Hormone-Secreting Pulmonary Endocrine Carcinoma

GHRH excess from extracranial endocrine tumors is known to cause somatotroph hyperplasia and acromegaly. Hypothalamic gangliocytomas producing GHRH are also known to be associated with pituitary adenomas causing acromegaly. The objective of this study was to describe a case of acromegaly due to a pulmonary GHRH-secreting endocrine carcinoma with metastasis to the pituitary gland and to look at the peculiar histological features of this case. The patient was a 44-yr-old woman who was diagnosed with a biopsy-proven metastatic pulmonary endocrine tumor during pregnancy. After delivery, she underwent radiation and chemotherapy for pulmonary and skeletal metastases. Her disease was clinically stable for 7 yr until she developed bitemporal hemianopia. She had symptoms and signs of acromegaly. Imaging, biochemical, and histological studies were performed. Magnetic resonance imaging (MRI) of the brain confirmed the presence of a 2.6-cm lesion within the sella turcica extending above the sella and compressing the optic chiasm. Endocrine studies showed elevated serum levels of GH, prolactin, alpha-subunit of glycoprotein hormones, IGF-I, chromogranin A, and GHRH. The patient underwent uneventful transsphenoidal resection of the sellar tumor. Postoperatively, she noted an improvement in symptoms of acromegaly. Histological examination confirmed metastatic endocrine carcinoma to the pituitary, and immunohistochemistry localized GHRH to the tumor cells. The adjacent pituitary exhibited somatotroph hyperplasia with abundant reactivity for GH and alpha-subunit. In addition, there was focal neoplastic transformation to a sparsely granulated somatotroph phenotype with fibrous bodies. This is the first report of a GHRH-producing endocrine tumor metastasizing to the pituitary and causing local hyperstimulation with somatotroph hyperplasia and adenomatous transformation.

Reversible Transdifferentiation: Interconversion of Somatotrophs and Lactotrophs in Pituitary Hyperplasia

Previous studies conclusively demonstrated transformation of somatotrophs into bihormonal mammosomatotrophs in gestational lactotroph hyperplasia during pregnancy. Similar transdifferentiation of somatotrophs into thyrotrophs through bihormonal intermediate thryrosomatotrophs was documented during thyrotroph hyperplasia in both rodent and human pituitaries in hypothyroidism. The cessation of the stimulation resulted in reversal of the process in both conditions. The conversion of lactotrophs into somatotrophs was suggested but not documented previously in the human gland. The present study was undertaken to investigate cases of somatotroph hyperplasia by transmission electron microscopy, immunoelectron microscopy using double immunogold labeling for growth hormone and prolactin, as well as combined immunocytochemistry and in situ hybridization. Adenohypophysial tissue was removed from a 38-year-old man and a 29-year-old woman with longstanding acromegaly due to ectopic overproduction of growth hormone–releasing hormone (GRH) by bronchial carcinoid tumors. For comparison, two pituitary biopsies were studied: one from a 38-year old woman with idiopathic lactotroph hyperplasia and one from a 14-year-old boy with secondary lactotroph hyperplasia due to a suprasellar craniopharyngioma. In the patients with somatotroph hyperplasia, the prevailing cell type was the hyperplastic somatotroph joined by mammosomatotroph deriving from lactotrophs, whereas monohormonal lactotrophs were rare. The predominance of mammosomatotrophs and active lactotrophs was documented in the patient with idiopathic lactotroph hyperplasia, whereas the case of the patient with secondary lactotroph hyperplasia was characterized by monohormonal lactotrophs and somatotrophs, but mammosomatotrophs were rare. That finding in the pituitary of the boy suggests that participation of mammosomatotrophs in lactotroph hyperplasia is not unconditional. Our findings conclusively demonstrate conversion of lactotrophs into mammosomatotrophs during somatotroph hyperplasia, providing further evidence for the potential of reversible transdifferentiation between somatotrophs and lactotrophs in response to functional demand.

Pituitary hyperplasia.

Comprehensive article summarizing more than 25 years of experience with pituitary hyperplasia in surgical material. Morphologic forms of hyperplasia--diffuse and nodular--are defined and, for comparison, the normal morphology, frequency and intraglandular distribution of cell types are briefly reviewed. All cell types can give rise to hyperplasia, although their frequency, extent and clinical importance widely vary. Somatotroph hyperplasia is rare; it is limited to cases of GHRH overproduction by extrapituitary endocrine neoplasms and sporadic examples of gigantism. Prolactin cells display the highest propensity for non-neoplastic proliferation. Physiologic hyperplasia occurs in pregnancy and lactation. Pathological hyperplasia is mostly secondary to other, neoplastic or non-neoplastic, space occupying processes. Idiopathic lactotroph hyperplasia is very rare. The much-disputed corticotroph hyperplasia is infrequent cause of pituitary dependent Cushing's disease. Despite difficulties of diagnosis in fragmented biopsies, several well-documented cases prove the existence of corticotroph hyperplasia which is nearly always nodular. Thyrotroph hyperplasia, secondary to hypothyroidism, a treatable condition, is not expected to occur in surgical material, yet several cases have been identified. Operated lesions are massive nodular leading to significant pituitary enlargement thereby mimicking TSH- or PRL-producing adenoma. Hyperprolactinemia is a frequent concomitant of severe thyrotroph hyperplasia. Gonadotroph hyperplasia and proliferation of pars intermedia derived POMC cells are not likely to occur in surgical material and have no clinical significance. Adenoma formation may rarely be associated with any type of pituitary hyperplasia.

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

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.

Galanin gene expression in radiothyroidectomy-induced thyrotroph adenomas.

Galanin gene expression is markedly increased in the anterior pituitary glands of estrogen-treated rats (lactotroph hyperplasia) as well as human growth hormone-releasing hormone transgenic mice (somatotroph hyperplasia). The objective of this study was to examine galanin in a mouse model of thyrotroph adenoma formation. Male mice were radiothyroidectomized by use of iodine-131 (131I), and galanin peptide levels were assessed in the hypothalamic-pituitary axis. Immunoreactive galanin concentrations in the anterior pituitaries of 131I-treated mice were decreased 80% at 3, 6, 9, and 12 mo after radiothyroidectomy. Galanin peptide levels in the hypothalamus were decreased 20-25% at these times. Treatment with either estradiol or 3,3',5-triiodo-L-thyronine increased galanin peptide concentrations in the anterior pituitaries of 131I-treated mice, but neither treatment restored galanin concentrations. Galanin mRNA levels were decreased > 80% 1 yr after radiothyroidectomy. We conclude that, unlike animal models of lactotroph and somatotroph hyperplasia, galanin gene expression is suppressed throughout the development of thyrotroph adenomas, suggesting that galanin does not have a stimulatory role in the proliferation of thyrotrophs. Moreover, these data show that thyroid hormones are important positive regulators of galanin gene expression in the mouse and that estrogen may stimulate galanin gene expression in the absence of thyroid hormones.

Somatotroph hyperplasia without pituitary adenoma associated with a long standing growth hormone-releasing hormone-producing bronchial carcinoid

Somatotroph hyperplasia without pituitary adenoma associated with a long standing growth hormone-releasing hormone-producing bronchial carcinoid

Pituitary Gigantism

Pituitary gigantism is a rare condition whose association with McCune-Albright syndrome suggests that mutations in a-subunit of a Gs protein are an important cause of this condition. In addition to somatotroph adenoma, it is now recognized that somatotroph hyperplasia can also result from increased levels of growth hormone-releasing hormone. Transgenic rats with hypersomatotrophism are prone to renal and hepatic pathology.

Morphology of adenohypophysial tumors in mice transgenic for vasopressin-SV40 hybrid oncogene.

Transgenic mice for the promoter sequence of bovine arginine vasopressin (AVP) gene fused to large SV40 T-antigen coding sequence develop pituitary tumors and insulin-producing pancreatic tumors. In order to establish the cellular composition of the pituitary tumors, histological, immunocytochemical, in situ hybridization, and electron microscopic technics were applied. Pituitary anterior lobe tumors were identified in 10 out of 14 glands examined. In 2 of these cases, intermediate lobe tumors were also found. The anterior lobe tumors contained a variable number of GH immunoreactive cells. In situ hybridization performed in 7 cases revealed a diffuse distribution of GH messenger RNA over all tumor cells. Ultrastructurally, the tumors contained undifferentiated cells with very small secretory granules and rare cells showing some resemblance to somatotrophs. The results indicate that these pituitary tumors are composed of undifferentiated somatotrophs. The presence of a few PRL immunoreactive cells in four tumors and scattered TSH immunoreactive cells in two tumors supports the view that somatotrophs have the potential to produce PRL and TSH. The intermediate lobe tumors were immunoreactive for ACTH and intensely positive for POMC mRNA. In the nontumorous adenohypophyses, no hyperplasia of any cell type was noted. Several GH immunoreactive cells exhibited pleomorphic, giant nuclei and mitoses. In conclusion, the majority of transgenic mice for AVP/large T-antigen develop pituitary tumors originating in and composed of somatotrophs. Less frequently, intermediary lobe tumors were present as well. AVP/SV40 transgenic mice provide a unique experimental model for somatotroph tumors that are neither preceded by, nor associated with somatotroph hyperplasia.

Growth Hormone-Releasing Hormone-Producing Tumors: Clinical, Biochemical, and Morphological Manifestations*

This paper has reviewed current knowledge of clinical, biochemical, and morphological manifestations of extracranial GRH-producing tumors. Excessive GRH release stimulates pituitary somatotrophs causing elevation of blood GH levels and acromegaly. In some patients with GRH-containing tumor, blood GH concentrations are normal and no acromegaly develops. GRH-producing tumors associated with acromegaly are rare. Based on a critical analysis of the literature, 30 tumors are accepted as definitive. They possess unique features: occurrence in young age, female preponderance, foregut derivation, benign biological behavior, small secretory granules, and frequent association with MEN type I syndrome. The pancreas and lung are common primary sites. GRH-containing tumors unassociated with acromegaly include those of gut and thymus, small cell carcinoma of lung, and medullary carcinoma of thyroid. Several tumors are plurihormonal. In contrast to somatotroph adenoma seen in patients with classical acromegaly, the hypophysial lesion represents somatotroph hyperplasia in acromegalic patients with GRH-producing tumor. This finding indicates that GRH not only increases somatotroph secretory activity but causes somatotroph proliferation. Studies of GRH-producing tumors are of fundamental importance in obtaining a deeper insight into endocrine activity of pituitary somatotrophs and the pathogenesis of GH-secreting pituitary adenomas associated with acromegaly; the importance of GRH in the etiology of acromegaly is still unresolved. The relationship between GRH-secreting tumors and MEN type I syndrome is controversial; further studies are required to elucidate whether they represent two distinct entities or whether GRH-producing tumors accompanied by acromegaly are only forme fruste manifestations of MEN type I syndrome.