Pituitary blastoma: a unique embryonal tumor.

Pituitary blastoma, a recently described tumor of the neonatal pituitary, exhibits differentiation to Rathke epithelium and adenohypophysial cells of folliculostellate and secretory type, a reflection of arrested pituitary development and unchecked proliferation (Scheithauer et al. in Acta Neuropathol 116(6):657-666, 2008). Herein, we report the pathologic features of three additional cases, all ACTH-producing. One involved a 9-month-old male presenting with progressive right ophthalmoplegia, MRI findings of a large suprasellar mass with cavernous sinus invasion, and elevated plasma ACTH levels. The second was nonfunctioning and occurred in a 13-month-old female with right third nerve palsy. The third had been previously published as a "pituitary adenoma" in a 2-year-old female (Min et al. in Pathol Int 57(9):600-605, 2007). The subtotally resected tumors were subject to histochemical, immunohistochemical and, in two cases, ultrastructural study. Histologically, the complex tumors consisted of glands of varying from rosettes to glandular structures resembling Rathke epithelium, small undifferentiated-appearing cells (blastema), and large secretory cells. Mucin-producing goblet cells were noted in case 3. Cell proliferation was high in two cases and low in case 3. Immunoreactivity of the secretory cells included synaptophysin, chromogranin, various keratins and, to a lesser extent, ACTH and beta endorphin. MGMT immunolabeling was 40-60%. Mitotic activity was moderate to high in cases 1 and 2 and was low in case 3. The same was true for MIB-1 labeling. Germ cell markers were lacking in all cases. One tumor ultrastructurally consisted of three cell populations including (a) small, polyhedral, primitive-appearing cells (blastema) with scant cytoplasm, abundant glycogen and few organelles, (b) folliculostellate cells and (c) large corticotroph cells containing rough endoplasmic reticulum, golgi membranes, spherical, 150-400 nm secretory granules and occasional perinuclear, intermediate filament bundles. A second example (case 3) lacked a blastema and glandular component. The clinical and morphologic features of our three cases were those of pituitary blastoma. The finding of cellular elements of adenohypophysial development is consistent with a diagnosis of pituitary blastoma and aligns it with blastomas of other organs. It also suggests an underlying specific genetic abnormality. Marked variations in cellular proliferative activity suggest blastomas occur in low- and higher-grade form. Variable MGMT reactivity suggests an incomplete response to temozolomide therapy. Literature regarding similar morphologically complex, infantile, Cushing disease-associated lesions is briefly reviewed.

Silent subtype 3 pituitary adenoma: a clinicopathologic analysis of the Mayo Clinic experience.

BACKGROUND: Macroadenomas represent 50% of pituitary tumours and are often (30%) nonfunctioning. Their immunophenotype suggests differentiation toward a specific pituitary cell line. A substantial proportion of tumours with particularly aggressive behaviour are so called 'silent subtype 3 adenoma'. Its diagnosis requires ultrastructural confirmation. Although once included among silent corticotroph adenomas, this aggressive, morphologically distinctive tumour is now recognized as a major form of plurihormonal adenoma and, in fact, some patients might present with clinical hormonal excess. The cytogenesis and pathobiology of silent subtype 3 adenomas is unsettled. OBJECTIVE: We undertook a systematic clinicopathologic examination of the Mayo Clinic experience with this poorly understood tumour. DESIGN: This retrospective, single institution study found 27 confirmed examples of silent subtype 3 adenoma, a frequency of 0.9% of adenomas. Despite histologic and immunophenotypic variation, their ultrastructural features were diagnostic and the sole basis for case inclusion. RESULTS: The study group was comprised of 16 men (59%) and 11 women (41%); two patients (7%) had definitive diagnosis of multiple endocrine neoplasia type 1 (MEN1). Three tumours (11%) were discovered incidentally. Nine patients each (38%) presented with headaches or visual field loss. Endocrine hyperfunction was noted in eight cases (30%), including GH excess in five (19%) and clinically significant PRL elevation in three (11%). Hypogonadism was noted in 17 cases (63%) and growth arrest in one (4%). All tumours were macroadenomas; 16 (60%) showed radiographic evidence of invasion. Most tumours were plurihormonal, featuring immunoreactivity for PRL (17), GH (15), TSH (16) or ACTH (3); only one lesion was immunonegative. Although a gross total resection was achieved in 19 cases (70%), re-operation for recurrence(s) was required in seven of these (37%). Follow-up (mean, 69 months) showed a high (59%) rate of persistent or recurrent of tumour. Overall, 14 patients (54%) underwent radiotherapy after surgical treatment: three patients (12%) for substantial residual tumour, eight (31%) as adjuvant therapy and three (12%) for tumour regrowth. CONCLUSION: Silent subtype 3 adenoma, a plurihormonal tumour, is rare and aggressive in nature. This adenoma must be considered in the differential of often clinically nonfunctioning but plurihormonal adenomas featuring variable cytologic atypia. Electron microscopy is required for confirmation of the diagnosis. The cytogenesis of silent subtype 3 adenoma remains unsettled.

Specific endocrine tissue marker defined by a monoclonal antibody.

One of two mouse monoclonal antibodies (LK2H10) produced by hybridoma technology against a human endocrine tumor (pheochromocytoma) demonstrated specific immunoreactivity for 69 normal and neoplastic endocrine and tissues known to contain secretory granules. This immunoreactivity was specific, since other normal tissues, tumors from endocrine cells without granules, and tumors from other nonendocrine tissues were negative when tested with antibody LK2H10. The antibody reacted with human fetal adrenal medulla and human pancreatic endocrine cells and with adrenal medullary cells from monkeys and pigs. The antigen detected by antibody LK2H10 is associated with cytoplasmic secretory granules, has an estimated molecular weight of 68,000, and may be related to human chromogranin.

Plurihormonal gonadotroph cell pituitary adenoma: report of a unique case.

OBJECTIVE AND IMPORTANCE: Pituitary adenomas producing primarily FSH and to a lesser extent GH, LH, alpha-subunit, TSH and PRL without clinical or laboratory evidence of increased hormone release have not previously been reported. Our aim was to obtain some insight into the possible cytogenesis of this unusual tumor. CLINICAL PRESENTATION: A 65-year-old woman presented with headaches. Magnetic resonance imaging (MRI) demonstrated a sellar mass. Pituitary hormone assays showed normal blood levels. The tumor was removed by the transsphenoidal approach. RESULT: By light microscopy, the adenoma was chromophobic, weakly PAS-positive, and immunoreactive mainly for FSH (85%) and to a lesser extent for GH (30%), LH (15%), alpha-subunit (3%), TSH (2%), and PRL (1%). Although double immunostaining showed hormone reactivities to be localized largely in separate distinct cells, the tumor was ultrastructurally monomorphous, i.e., consisted of a single-cell type, resembling gonadotrophs. CONCLUSION: The cytogenesis of plurihormonal pituitary adenomas is not fully understood. Further investigations are required to clarify the basis for their plurihormonality despite an ultrastructural gonadotroph phenotype.

Pituitary corticotroph hyperplasia preceding adenoma in a patient with Nelson's syndrome.

We report the case of a 42-year-old woman with Cushing's disease and Nelson's syndrome. When she was 17 years old, transsphenoidal surgery was performed. A detailed morphologic study demonstrated nodular hyperplasia of corticotroph cells but no adenoma. Following a long-lasting remission (14 years), Cushing's disease recurred. After an unsuccessful second transsphenoidal surgery, Cushing's disease persisted and both adrenals were removed (at the age of 34). Subsequently the patient developed Nelson's syndrome. The pituitary tumor proved to be a corticotroph adenoma; it was removed by the transsphenoidal approach (at the age of 42). Although in most patients Cushing's disease is due to an ACTH-secreting pituitary corticotroph adenoma which precedes the manifestation of Nelson's syndrome, our case indicates not only that corticotroph hyperplasia may cause Cushing's disease but that it may exist before the development of Nelson's syndrome after the removal of both adrenals. Our study supports the view that protracted stimulation of corticotrophs resulting from the elimination of the negative inhibitory feedback effect by corticosteroids plays a role in adenoma initiation.

Effects of diethylstilbestrol and propylthiouracil on the rat pituitary. An immunohistochemical and ultrastructural study.

The effects of diethylstilbestrol [(DES) CAS: 56-53-1] and propylthiouracil [(PTU) CAS: 51-52-5] on the pituitary glands of female weanling F344 rats were studied by immunohistochemistry and electron microscopy. Six weeks of PTU treatment resulted in a significant increase in pituitary gland weight and in the percentage of pituitary prolactin (PRL) cells. The percentage of thyroid-stimulating hormone (TSH) cells was slightly increased in PTU-treated rats. DES treatment produced a thirteenfold increase in pituitary gland weight and a significant increase in the percentage of PRL cells as well as in serum PRL levels. Combined PTU-DES treatment increased pituitary gland weight and serum PRL levels, but this increase was less than that observed with only DES treatment. A relative decrease in the percentage of TSH cells was seen after both DES and PTU-DES treatment. Ultrastructural immunohistochemical studies showed two types of PRL cells in the pituitary of all groups. Classical PRL cells with granule diameters of 150-800 nm were most abundant in DES-treated groups, whereas cells with smaller granules, 100-350 nm in diameter, were equally prominent in control groups and after PTU treatment. The results of this study show that while PTU causes a slight increase in pituitary gland weight and in PRL cell numbers, it inhibits estrogen-induced PRL cell hyperplasia. This model can be used to study the effects of PTU on pituitary PRL cell morphology and on the regulation of PRL cell hyperplasia.

Analysis of prolactin and growth hormone production in hyperplastic and neoplastic rat pituitary tissues by the hemolytic plaque assay.

The reverse hemolytic plaque assay (RHPA) was used to detect hormone release from cultured normal, hyperplastic, and neoplastic rat pituitary cells. Hyperplastic pituitary cells were produced by s.c. diethylstilbestrol (DES) treatment (10 mg in Silastic tubes) for 3, 6, and 9 weeks. Neoplastic pituitary cells from rats with MtT/W15 transplantable tumors treated with DES for 3 weeks were also analyzed. Aliquots of the same cells were also analyzed by immunocytochemical staining. DES treatment resulted in an increase in prolactin (PRL)-producing cells in hyperplastic pituitaries compared to untreated pituitaries after 9 weeks of treatment by the RHPA [61.2 +/- 5.2 (SE) versus 32 +/- 3.0] and by immunocytochemical staining [70.9 +/- 2.4 versus 36 +/- 1.4]. The percentage of mammosomatotropic cells decreased from 11.3 +/- 3.8 to 4.2 +/- 2.6% in pituitary cells from these same groups of animals. After 3 weeks of DES treatment in rats with MtT/W15 tumor, there was an increase in growth hormone (GH)-producing cells and a decrease in PRL-producing cells when analyzed by the RHPA (control: percentage of GH, 36.3 +/- 6.2; percentage of PRL, 39.0 +/- 1.6 versus DES-treated tumors: percentage of GH of 68.2 +/- 1.9; and percentage of PRL, 3.2 +/- 1.8%). The percentage of mammosomatotropic cells declined from 12.4 +/- 2.3 to 0.77 +/- 2.4%. A combined procedure of RHPA followed by immunocytochemical staining on the same slides also revealed a decline in mammosomatotropic cells after chronic DES treatment in hyperplastic and neoplastic MtT/W15 tumor cells. These results show that DES has different effects on PRL and GH secretion and storage in hyperplastic pituitary and in the MtT/W15 pituitary tumor cells.

Effects of estradiol on prolactin and growth hormone messenger RNAs in cultured normal and neoplastic (MtT/W15 and GH3) rat pituitary cells.

The effects of 17 beta-estradiol (E17 beta) on prolactin (PRL) cell proliferation and on the expression of PRL and growth hormone (GH) proteins and mRNAs were analyzed in cultured pituitary cells by immunocytochemistry, in situ hybridization, and Northern blot hybridization studies. Three different cell cultures were used: (a) normal pituitary cells; (b) GH3 tumor cell line; and (c) MtT/W15, a transplantable PRL and GH-producing pituitary tumor. E17 beta (10(-7) M) caused a significant increase in PRL cell proliferation in normal pituitary [3.9 +/- 0.4 versus 7.7 +/- 0.9% (SEM) of immunostained PRL cells with thymidine incorporation] [P less than 0.01] but produced a significant decrease in PRL cell proliferation in MtT/W15 primary cell cultures [6.7 +/- 1.0 versus 3.7 +/- 0.8%] [P less than 0.05]. PRL mRNA was significantly increased in normal pituitary and in GH3 tumor cells by E17 beta treatment. There was a significant decrease in PRL mRNA and an increase in GH mRNA expression in cultured MtT/W15 tumor cells by immunocytochemistry and in situ hybridization analyses. The percentage of cells producing both PRL and GH or mammosomatotropic cells analyzed by two different techniques declined after one week in culture in normal pituitary cells and in cultured MtT/W15 tumor cells after E17 beta treatment. These results show that E17 beta has a direct stimulatory effect on normal pituitary and GH3 cells and a direct inhibitory effect on MtT/W15 tumor cells with respect to cell proliferation and PRL hormone and mRNA expression.

Prevention of trauma-induced cochlear fibrosis using intracochlear application of anti-inflammatory and antiproliferative drugs.

Cochlear fibrosis is a common finding following cochlear implantation. Evidence suggests that cochlear fibrosis could be triggered by inflammation and epithelial-to-mesenchymal cell transition (EMT). In this study, we investigate the mechanisms of cochlear fibrosis and the risk/benefit ratio of local administration of the anti-inflammatory drug dexamethasone (DEX) and antimitotic drug aracytine (Ara-C). Cochlear fibrosis was evaluated in cochlear fibrosis models of rat cochlear slices in vitro and in KLH-induced immune labyrinthitis and platinum wire cochlear implantation-induced fibrosis in vivo. Cochleae were invaded with tissue containing fibroblastic cells expressing α-SMA (alpha smooth muscle actin), which along with collagen I, fibronectin, and laminin in the extracellular matrix, suggests the involvement of a fibrotic process triggered by EMT in vitro and in vivo. After perilymphatic injection of an adenoviral vector expressing GFP in vivo, we demonstrated that the fibroblastic cells derived from the mesothelial cells of the scalae tympani and vestibuli. Activation of inflammatory and EMT pathways was further assessed by ELISA analysis of the expression of IL-1ß and TGF-ß1. Both markers were elevated in vitro and in vivo, and DEX and Ara-C were able to reduce IL-1ß and TGF-ß1 production. After 5days of culture in vitro, quantification of calcein-positive cells revealed that Ara-C was 30-fold more efficient in preventing fibrosis, and provoked less sensory hair cell loss, than DEX. In KLH-induced immune labyrinthitis and platinum wire-implanted models, Ara-C was more efficient in preventing proliferation of fibrosis with less side effects on hair cells and neurons than DEX. In conclusion, DEX and Ara-C both prevent fibrosis in the cochlea. Analysis of the risk/benefit ratio favors the use of Ara-C for preventing cochlear fibrosis.

Ectopic bioactive luteinizing hormone secretion by a pancreatic endocrine tumor, manifested as luteinized granulosa-thecal cell tumor of the ovaries.

Endocrine pancreatic tumors are rare neoplasms consisting of multipotent cells capable of secreting various bioactive substances causing characteristic clinical syndromes. Ovarian stromal hyperthecosis is characterized by varying degrees of luteinized stromal cell proliferation after sustained LH and/or human chorionic gonadotropin stimulation, clinically manifested by symptoms/signs of virilization resembling the polycystic ovary syndrome (PCOS). We report a case of ectopic bioactive LH production from a pancreatic endocrine tumor in a 33-yr-old woman with rapidly developing symptoms/signs of hyperandrogenism and markedly elevated serum androgen and LH levels leading to hyperthecosis and bilateral luteinized granulosa-thecal cell tumors of the ovaries. Although the patient was initially thought to have either severe PCOS or an LH-secreting pituitary tumor, an LH-producing pancreatic endocrine tumor bearing somatostatin receptors was demonstrated on scintigraphy with [111In]octreotide and abdominal imaging. Symptoms and signs of hyperandrogenism resolved after the resection of the tumor. Immunohistochemistry, in situ hybridization, and electron microscopy studies confirmed LH synthesis by the tumor cell. Although extremely rare, ectopic LH production from nonpituitary endocrine tumors should be considered in the differential diagnosis of hyperandrogenism, particularly when associated with highly elevated serum LH levels.

p27(kip1) protein expression correlates with survival in myxoid and round-cell liposarcoma.

PURPOSE: The p27(kip1) protein (p27) is a cyclin-dependent kinase inhibitor that has been shown to be an independent prognostic factor in a variety of human neoplasms. Low expression of p27 tends to occur in more aggressive neoplasms. The role of p27 as an independent prognostic factor in the spectrum of myxoid and round-cell liposarcomas has not been examined. MATERIALS AND METHODS: Forty-seven cases of myxoid and round-cell liposarcomas were examined. Clinicopathologic features and immunohistochemical expression of p27 and Ki-67 antigen were studied in all cases. Survival analysis was performed using the log-rank test and the Cox multivariate regression model. RESULTS: The male:female ratio was 1. 4:1, and the mean age at diagnosis was 45 years. The tumors were located in the lower extremities (94%) and retroperitoneum (6%). The median tumor size was 13.5 cm. The median follow-up was 6.3 years, and the overall 5- and 10-year survival rates were 76% and 67%, respectively. Low expression of p27 was identified in 34 cases (72%) and correlated with decreased metastasis-free (P =.026) and overall survival (P =.008). In a multivariate analysis, only round-cell differentiation and low expression of p27 independently predicted decreased metastasis-free and overall survival. CONCLUSION: p27 expression predicts the clinical behavior of myxoid and round-cell liposarcomas, even in neoplasms with few or no round-cell differentiation.

Obesity is associated with a decreased leptin transport across the blood-brain barrier in rats.

Leptin exerts important effects on the regulation of food intake and energy expenditure by acting in the brain. Leptin is secreted by adipocytes into the bloodstream and must gain access to specific regions in the brain involved in regulating energy balance. Its action is mediated by interaction with a receptor that is mainly expressed in the hypothalamus but is also present in other cerebral areas. To reach these target areas, leptin most likely needs to cross the blood-brain barrier (BBB). In this study, we compared the permeability of leptin at the BBB in homozygous lean (FA/FA), high-fat diet-induced (HFD) obese rats (FA/FA rats on a highfat diet), and genetically obese fa/fa Zucker rats by quantifying the permeability coefficient surface area (PS) product after correction for the residual plasma volume (Vp) occupied by leptin in the vessel bed of different brain regions. The intravenous bolus injection technique was used in the cannulated brachial vein and artery using leptin radioiodinated with 2 isotopes of iodine (125I and 131I) to separately determine the PS and Vp values. The PS for leptin at the BBB in lean FA/FA rats ranged from 11.0 +/- 1.6 at the cortex to 14.8 +/- 1.4 x 10(-6) ml x g(-1) x ml(-1) at the posterior hypothalamus. The PS for leptin in HFD obese FA/FA and obese fa/fa rats ranged from 3.0- to 4.0-fold lower than in lean FA/FA rats. The Vp values were not significantly different among the 3 groups studied. SDS-PAGE analysis of the radioiodinated leptin after 60 min of uptake revealed intact protein in the 8 different brain regions. Plasma leptin levels were significantly higher in both obese rat groups compared with those in lean FA/FA rats. Leptin levels in cerebrospinal fluid were not significantly different among the 3 groups of rats. These findings strongly suggest that the leptin receptor (OB-R) in the BBB can be easily saturated. Saturation of the BBB OB-R in obese individuals would explain the defect in leptin transport into the brain described in this study.

The cell cycle inhibitors p21WAF1 and p27KIP1 are associated with survival in patients treated by salvage prostatectomy after radiation therapy.

We evaluated p27KIP1 and p21WAF1 expression in 52 patients treated by salvage radical prostatectomy and bilateral pelvic lymphadenectomy for biopsy-proven locally persistent or recurrent prostate cancer after external beam radiation therapy. We defined low and high expression based on the median value observed in our sample. Five-year distant metastasis-free survival and cancer-specific survival were 71 and 82%, respectively, for patients with low expression of p21 (< or =5%), compared with 94 and 100%, respectively, for those with high expression of p21 (>5%; P = 0.02 and 0.01, respectively). Five-year distant metastasis-free survival and cancer-specific survival were 71 and 82%, respectively, for patients with low expression of p27 (<50%), compared with 88 and 96%, respectively, for those with high expression of p27 (> or =50%; P = 0.06 and 0.01, respectively). These findings indicate that p21 and p27 expression levels are significant predictors of survival for patients selected for salvage prostatectomy for recurrent prostate cancer.

Prognostic indicators in an aggressive pituitary Crooke's cell adenoma.

OBJECTIVE: To investigate prognostic indicators in an aggressive Crooke's cell adenoma of the pituitary. METHODS: The surgically removed tumor was studied by histology, immunohistochemistry and transmission electron microscopy. RESULTS: An aggressive invasive sellar tumor removed by repeated surgeries from a 43-year-old woman with pituitary related Cushing's disease was classified as a Crooke's cell adenoma of the pituitary. The application of several cell proliferation markers confirmed the aggressive nature of the tumor. CONCLUSIONS: The investigation of the present case provides additional evidence that pituitary Crooke's cell adenomas may possess aggressive behavior.

Targeted ablation of pituitary gonadotropes in transgenic mice.

LH, FSH, and TSH are heterodimeric glycoprotein hormones composed of a common alpha-subunit and unique beta-subunits. The alpha-subunit is produced in two distinct specialized cell types of the pituitary gland: gonadotropes, which synthesize LH and FSH, and thyrotropes, which synthesize TSH. We have demonstrated that 313 base pairs of the bovine-alpha subunit promoter direct expression of diphtheria toxin A chain specifically to the gonadotropes in transgenic mice. Animals carrying this transgene generally exhibit reproductive failure and lack of gonadal differentiation, consistent with gonadotrope ablation. Lack of gonadotrope activity was verified by RIA and immunohistochemical staining for LH. The phenotype of these transgenic mice is nearly identical to mice homozygous for the spontaneous mutation, hpg, which is due to a deletion in the gene encoding GnRH. Thyrotrope function was judged normal based on overall growth of the animals, appearance of their thyroids, T4 levels measured by RIA, and immunohistochemical staining for TSH. The ablation of gonadotropes but not thyrotropes suggests that separate cis-acting elements are necessary for expression of the alpha-subunit gene in these two cell types. Pituitary content of ACTH and GH was apparently normal, while PRL synthesis and storage were reduced. Thus, in a pituitary almost completely devoid of gonadotropes, most other pituitary functions were normal. This suggests that most pituitary cells are able to differentiate independently of terminal gonadotrope differentiation and can function in the absence of paracrine signaling provided by gonadotropes.

Enhancer-mediated high level expression of mouse pituitary glycoprotein hormone alpha-subunit transgene in thyrotropes, gonadotropes, and developing pituitary gland.

The pituitary hormones LH, FSH, and TSH are heterodimers composed of a common alpha-subunit and unique beta-subunits. We demonstrate that 4.6, 2.7, 1.49 or 0.48 kilobases (kb) mouse alpha-subunit 5'-flanking sequences are sufficient for transgene expression in both gonadotropes and thyrotropes but not in inappropriate pituitary cells. In contrast, transgenes with bovine or human alpha-subunit flanking sequences have been shown to confer reporter gene expression only to gonadotrope cells, suggesting that the elements regulating cell-specific expression may differ between species. Equal levels of reporter gene expression were conferred by 5.0 and 0.48 kb in transiently transfected thyrotrope tumor-derived cells. In contrast, in transgenic mice, high level expression was only obtained with 4.6 kb 5'-flanking sequences, indicating the presence of an enhancer element between 4.6 and 2.7 kb. The 4.6 kb of 5'-flanking sequences are sufficient for both hormonal and developmental regulation of transgene expression. Mice rendered hypothyroid by radiothyroidectomy had significantly higher levels of transgene expression than either hyperthyroid or euthyroid animals. The temporal and spatial pattern of transgene expression in Rathke's pouch paralleled that of the endogenous gene; the onset of transgene expression occurred by embryonic day 9.5. Low level expression of both the transgene and the endogenous alpha-subunit gene were detected in some unexpected peripheral sites, such as the embryonic extraocular and olfactory regions, suggesting that alpha-subunit may have a more diverse role in development than previously considered.

Thyroid hormone-responsive pituitary hyperplasia independent of somatostatin receptor 2.

Mice homozygous for the targeted disruption of the glycoprotein hormone alpha-subunit (alphaGsu) display hypertrophy and hyperplasia of the anterior pituitary thyrotropes. Thyrotrope hyperplasia results in tumors in aged alphaGsu(-/-) mice. These adenomatous pituitaries can grow independently as intrascapular transplants in hypothyroid mice, suggesting that they have progressed beyond simple hyperplasia. We used magnetic resonance imaging to follow the growth and regression of thyrotrope adenomatous hyperplasia in response to thyroid hormone treatment and discovered that the tumors retain thyroid hormone responsiveness. Somatostatin (SMST) and its diverse receptors have been implicated in cell proliferation and tumorigenesis. To test the involvement of SMST receptor 2 (SMSTR2) in pituitary tumor progression and thyroid hormone responsiveness in alphaGsu(-/-) mutants, we generated Smstr2(-/-), alphaGsu(-/-) mice. Smstr2(-/-), alphaGsu(-/-) mice develop hyperplasia of thyrotropes, similar to alphaGsu(-/-) mutants, demonstrating that SMSTR2 is dispensable for the development of pituitary adenomatous hyperplasia. Thyrotrope hyperplasia in Smstr2(-/-), alphaGsu(-/-) mice regresses in response to T4 treatment, suggesting that SMSTR2 is not required in the T4 feedback loop regulating TSH secretion.

The pituitary in klinefelter syndrome.

BACKGROUND: Klinefelter syndrome is a genetically determined primary gonadal defect characterized by the XXY karyotype. The testes are small, blood testosterone levels are low, and blood gonadotropin levels are elevated. Pituitary changes in patients with Klinefelter syndrome have not been evaluated in detail. DESIGN: The first patient, a 76-yr-old man, was operated for a large sellar mass. The second and third patients, a 62- and a 52-yr-old man, respectively, died of cardiac failure. Both the latter pituitaries were normal-sized and removed at autopsy. The diagnosis of Klinefelter syndrome was confirmed by genetic testing in all three cases. The formalin-fixed and paraffin-embedded pituitaries of three patients were evaluated for adenohypophysial hormone immunoreactivity. For immunohistochemistry, the streptavidin- biotin-peroxidase (ABC) complex method was applied. RESULTS: In case 1, histology and immunohistochemistry revealed an oncocytic gonadotroph macroadenoma immunoreactive for FSH and alpha subunit. No pituitary gland was evident. The pituitary of case 2 featured hyperplasia of gonadotrophs, some with features of "gonadal deficiency cells," and a microadenoma immunoreactive for GH. The pituitary of case 3 similarly showed hyperplasia of gonadotrophs and the formation of gonadal deficiency cells. CONCLUSION: Protracted stimulation of gonadotrophs due to lack of androgen feedback might have been a factor in the formation of the gonadotroph adenoma in case 1 and in the development of gonadotroph hyperplasia in cases 2 and 3. The clinically silent GH microadenoma of case 2 was regarded as an incidental finding.

The pituitary in Turner syndrome.

Although Turner syndrome is not uncommon, studies of the pituitary in this condition are few. We undertook a histochemical and immunohistochemical study of four cases. As expected, "gonadal failure cells" were seen, but without recognizable gonadotroph hyperplasia. No gonadotroph adenomas were encountered. Instead, three silent corticotroph microadenomas were seen; their etiology remains unexplained. The question of whether the simultaneous occurrence of Turner syndrome and silent corticotroph adenoma is causal or incidental cannot be answered on the basis of the study of our material. Because these two diseases are rare, an etiologic association has to be considered. For example, it is possible that (a) protracted stimulation of gonadotrophs leads to transdifferentiation to corticotrophs, a hypothesis supported by the fact that normal and neoplastic gonadotrophs can contain ACTH and that some corticotroph adenomas produce LH and/or alpha subunit, (b) corticotrophs develop gonadotropin-releasing hormone (GnRH) receptors and undergo neoplastic transformation when exposed to continuous elevation of GnRH, FSH, and/or LH levels, and (c) the genetic defect in Turner syndrome promotes the formation of corticotroph adenomas.