Clinical Significance of Radical Surgery in the Treatment of Silent Corticotroph Adenoma

OBJECTIVE: Silent corticotroph adenomas (SCA) are endocrine-inactive pituitary adenomas with positive immunohistochemistry staining for adrenocorticotropic hormone (ACTH). We investigated whether SCA-associated clinical profiles were more aggressive than hormonally negative adenomas (HNA). METHODS: Among 627 patients with pathologically proven endocrine-inactive pituitary adenomas between 2004 and 2013, positive immunohistochemistry revealed 55 SCAs and 411 HNAs. Surgical outcomes and radiological and endocrinological characteristics were compared. RESULTS: Strong female predominance was observed in the SCA group (p<0.001). Cavernous sinus invasion was identified in 22 (40%) SCA patients and 72 (17.6%) HNA patients (p<0.001). There were no differences in ACTH or cortisol levels between the two groups. The incidence of preoperative hypopituitarism and postoperative hormonal outcome did not differ between two groups. Total resection was achieved in 35 patients (63.7%) with SCA and 332 patients (80.8%) with HNA (p=0.007). When tumors were completely removed, recurrence rates were not statistically different between two groups (p=0.60). When complete resection was not achieved, tumors regrew from these remnants in seven patients (35.0%) with SCA and 12 patients (15.2%) with HNA (p=0.05). CONCLUSION: Total surgical resection for SCA is often challenging as these tumors frequently invade a cavernous sinus. Early remnant tumor intervention is justified, because untreated residual pituitary tumors regrow when patients were followed up for a long time. Prophylactic radiotherapy is not warranted for completely resected SCAs as tumor recurrence is uncommon.

Effects of Oxytocin on Cell Proliferation in a Corticotroph Adenoma Cell Line

BACKGROUND: Oxytocin (OXT) has been reported to act as a growth regulator in various tumor cells. However, there is a paucity of data on the influence of OXT on cell proliferation of corticotroph adenomas. This study aimed to examine whether OXT affects cell growth in pituitary tumor cell lines (AtT20 and GH3 cells) with a focus on corticotroph adenoma cells. METHODS: Reverse transcription polymerase chain reaction and enzyme-linked immunosorbent assay were conducted with AtT20 cells to confirm the effects of OXT on hormonal activity; flow cytometry was used to assess changes in the cell cycle after OXT treatment. Moreover, the impact of OXT on proliferating cell nuclear antigen (PCNA), nuclear factor κB, and mitogen-activated protein kinase signaling pathway was analyzed by Western blot. RESULTS: OXT treatment of 50 nM changed the gene expression of OXT receptor and pro-opiomelanocortin within a short time. In addition, OXT significantly reduced adrenocorticotropic hormone secretion within 1 hour. S and G2/M populations of AtT20 cells treated with OXT for 24 hours were significantly decreased compared to the control. Furthermore, OXT treatment decreased the protein levels of PCNA and phosphorylated extracellular-signal-regulated kinase (P-ERK) in AtT20 cells. CONCLUSION: Although the cytotoxic effect of OXT in AtT20 cells was not definite, OXT may blunt cell proliferation of corticotroph adenomas by altering the cell cycle or reducing PCNA and P-ERK levels. Further research is required to investigate the role of OXT as a potential therapeutic target in corticotroph adenomas.

Clinical Significance of Radical Surgery in the Treatment of Silent Corticotroph Adenoma

OBJECTIVE: Silent corticotroph adenomas (SCA) are endocrine-inactive pituitary adenomas with positive immunohistochemistry staining for adrenocorticotropic hormone (ACTH). We investigated whether SCA-associated clinical profiles were more aggressive than hormonally negative adenomas (HNA).METHODS: Among 627 patients with pathologically proven endocrine-inactive pituitary adenomas between 2004 and 2013, positive immunohistochemistry revealed 55 SCAs and 411 HNAs. Surgical outcomes and radiological and endocrinological characteristics were compared.RESULTS: Strong female predominance was observed in the SCA group (p<0.001). Cavernous sinus invasion was identified in 22 (40%) SCA patients and 72 (17.6%) HNA patients (p<0.001). There were no differences in ACTH or cortisol levels between the two groups. The incidence of preoperative hypopituitarism and postoperative hormonal outcome did not differ between two groups. Total resection was achieved in 35 patients (63.7%) with SCA and 332 patients (80.8%) with HNA (p=0.007). When tumors were completely removed, recurrence rates were not statistically different between two groups (p=0.60). When complete resection was not achieved, tumors regrew from these remnants in seven patients (35.0%) with SCA and 12 patients (15.2%) with HNA (p=0.05).CONCLUSION: Total surgical resection for SCA is often challenging as these tumors frequently invade a cavernous sinus. Early remnant tumor intervention is justified, because untreated residual pituitary tumors regrow when patients were followed up for a long time. Prophylactic radiotherapy is not warranted for completely resected SCAs as tumor recurrence is uncommon.

Germline mutation analysis of Tpit in Poodle dogs with ACTH-dependent hyperadrenocorticism / Análise de mutação germinativa do Tpit em cães da raça Poodle com hiperadrenocorticismo ACTH-dependente

There is a high incidence of pituitary-dependent hyperadrenocorticism (PDH) in Poodle dogs, with family members being affected by the disease, suggesting a genetic involvement. Tpit is an obligate transcription factor for the expression of pro-opiomelanocortingene and for corticotroph terminal differentiation. The aim of the present study was to screen the Tpit gene for germline mutations in Poodles with PDH. Fifty Poodle dogs (33 female, 8.71±2.8 years) with PDH and 50 healthy Poodle dogs (32 females, 9.4241 2.8 years) were studied. Genomic DNA was isolated from peripheral blood, amplified by PCR and submitted to automatic sequence. No mutation in the coding region of Tpit was found, whereas the new single nucleotide polymorphism p.S343G, in heterozygous state, was found in the same frequency in both PDH and control groups. We concluded that Tpit gain-of-function mutations are not involved in the etiology of PDH in Poodle dogs.

O hiperadrenocorticismo ACTH-dependente (HACAD) apresenta elevada incidência em cães da raça Poodle, sendo que membros da mesma família têm sido acometidos pela doença, sugerindo envolvimento genético. Tpit é um fator de transcrição obrigatório para a expressão do gene da pro-opiomelanocortina e para a diferenciação terminal dos corticotrofos. O objetivo deste trabalho foi pesquisar mutações germinativas no gene Tpit em Poodles com HACAD. Cinquenta cães da raça Poodle, 33 fêmeas, média de idade de 8,71±2,8 anos, com HACAD, e 50 cães Poodles saudáveis, 32 fêmeas, média de idade de 9,4±2,8 anos, foram estudados. Mutações na região codificadora do gene Tpit não foram identificadas. Foi observado um novo polimorfismo em heterozigose, p.S343G, com a mesma frequência no grupo de cães com HACAD e no grupo-controle. Conclui-se que a mutação ativadora no gene Tpit não está envolvida na patogênese do hiperadrenocorticismo ACTH-dependente em cães da raça Poodle.

Ultrastructural characterization of the pars distalis of the Indian female Sheath-tailed bat, Taphozous longimanus (Hardwicke) / Caracterización ultraestructural de la pars distalis del murciélago cola de vaina hembra indio, Taphozous longimanus (Hardwicke)

The present ultrastructural observations demonstrate the presence of six cell types in the pars distalis of non-pregnant and pregnant bats of Taphozous longimanus. In the pars distalis of T. longimanus, STH cells are round to oval with eccentrically placed nucleus, numerous secretory granules and well developed Golgi indicate a cell under vigorous synthetic activity while those filled with secretory granules with reduced Golgi complex suggest reserve or storage state of cells. LTH cell is characterized by the large secretory granules, dilated endoplasmic reticulum and numerous mitochondria in the cytoplasm which indicate that these cells are hypertrophied and synthetically very active during pregnancy. ACTH cells are found either singly or in groups and are elongated or angular with long cytoplasmic processes. The size and peripheral arrangement of secretory granules are characteristic of ACTH cell. TSH cells are distributed mostly towards the periphery of the pars distalis of T. longimanus. They are elongated, polygonal or triangular in shape. The secretory granules are small, electron dense, 150-200 nm in diameter. The rough endoplasmic reticulum is very well developed. In FSH, the secretory granules are small (200 to 400 nm) and less in number and are distributed towards the periphery of the cell. FSH cells show well developed mitochondria, Golgi and rough endoplasmic reticulum indicating active state of FSH during estrus and pregnancy. The hypertrophy of FSH and LH cells during pregnancy is associated with filigreed cytoplasmic pattern giving a bizarre appearance. At late pregnancy, FSH and LH cells are highly active and synthesize large quantities of hormone as indicated by the development of cell organelles.

Las observaciones ultraestructurales actuales demuestran la presencia de seis tipos de células en la pars distalis de murciélagos Taphozous longimanus preñadas y no preñadas. En la pars distalis del T. longimanus, las células STH son redondas u ovaladas con un núcleo excéntrico, numerosos gránulos de secreción y un Golgi bien desarrollado que indican una célula en actividad de síntesis vigorosa, mientras que las llenas de gránulos de secreción con un complejo de Golgi reducido sugieren un estado celular de reserva o almacenamiento. Las células LTH se caracterizan por grandes gránulos de secreción, el retículo endoplásmico dilatado y numerosas mitocondrias en el citoplasma, indicando que estas células están hipertrofiadas y con una actividad sintética muy activa durante el embarazo. Células de ACTH se encuentran de forma individual o en grupos, son alargadas o angulares, con largos procesos citoplásmicos. El tamaño y la disposición periférica de los gránulos de secreción de ACTH son característicos de la célula. Células de TSH se distribuyen principalmente hacia la periferia de la pars distalis del T. longimanus. Ellos son alargadas, poligonales o de forma triangular. Los gránulos de secreción son pequeños, electrodensos, de 150-200 nm de diámetro. El retículo endoplasmático rugoso está muy bien desarrollado. En células FSH, los gránulos de secreción son pequeños (200 a 400 nm), menores en número y se distribuyen hacia la periferia de la célula. Células FSH muestran mitocondrias bien desarrolladas, Golgi y retículo endoplasmático rugoso que indica el estado activo de la FSH durante el estro y la preñez. La hipertrofia de las células de FSH y LH durante la preñez se asocia con un patrón citoplasmático filigrana dando una extraña apariencia. Al final de la preñez, las células de FSH y LH son muy activas y sintetizan grandes cantidades de hormonas, como producto del desarrollo de las organelos celulares.

Adenoma corticotrópos silente de la glándula pituitaria / Silent corticotroph adenomas of the pituitary gland

Objetivos: En el presente trabajo se revisará nuestra serie de casos de Adenomas Corticotrópos silentes y revisar la literatura acerca de esta patología fascinante. Material y Método: Se revisaron las historias clínicas de 5 pacientes del Hospital Universitario Fundación Santa Fé de Bogotá en el periodo de enero de 1990 a enero de 2008, que se le realizó tratamiento para una masa sellar y se le realizó diagnóstico patológico de Adenoma Corticotrópos Silente. Discusión: Los adenomas de hipófisis corresponden entre el 17 por ciento de los tumores intracraneales. El 60 por ciento de estas lesiones se asocian a hipersecreción hormonal. Los adenomas corticotropos silentes son tumores hipofisarios que histológicamente muestran diferenciación corticotrópica con algún grado de secreción de ACTH pero sin la evidencia clínica de síndrome de Cushing. Conclusión: Aunque estos tumores sean clínicamente significativos y su histopatología fascinante, hay poca literatura y estudios clínicos con enfoque especial sobre estas lesiones. Estos tumores son muy importantes tenerlos en cuenta en la patología selar ya que su tratamiento requiere mayor dedicación y seguimiento a estos pacientes.

Objectives: In the present paper we want to review our series of silent corticotrofic adenomas and review the literature concerning this fascinating pathology. Material and Methods: we review the clinical history of 5 patients treated and diagnosed with Silent corticotrofic adenomas in University Hospital Fundacion Santa Fe de Bogota in the period of January 1990 till January 2008. Discussion: Pituitary adenomas count for 10 to 15 percent of intracranial tumors. In 60 percent of the cases there is a hormonal hypersecretory syndrome associated with these mass. Silent Corticotophic adenomas are pituitary tumors which histologically show a corticotrophic differentiation with secretion of ACTH but do not present with clinical evidence of Cushing disease. Although silent corticotophic adenomas are clinically significant and histologically fascinating there are only few clinical studies and medical literature with regard to these tumors. Conclusion: Although silent corticotophic adenomas are clinically significant and histologically fascinating there are only few clinical studies and medical literature with regard to these tumors. It is very important to take in regard this tumor in the pathology of the selar region since these patients demand a major dedication and a strict follow up.

Clinical and Hormonal Analysis of Five New Cases and Eight Previously Reported Cases of Isolated ACTCH Deficiency in Korea / 대한내분비학회지

Isolated ACTH deficiency is an uncommon disorder, which is defined by low cortisol production with low or normal plasma ACTH levels and no other pituitary abnormalities. We report five new cases of this disorder, and summarize the clinical and hormonal features of 8 previously reported cases in Korea plus 5 new cases. 1) The clinical manifestations of isolated ACTH deficiency are variable, non-specific and similar to those seen in adrenocortical insufficiency of any cause, the age of patients ranged from 21 to 66 years old with an average age of 46 years, and the male to female ratio was 10:3. 2) Hyponatremia and hypoglycemia were commmon laboratory findings, so the presence of unexplained hyponatremia or hypoglycemia should always warrant consideration of the diagnosis of isolated ACTH deficiency. 3) 3 of 13 patients accompanied by empty sella suggesting selective destruction of pituitary ACTH producing cells. 4) ACTH response to exogenous CRH or vasopressin was not elicited in all tested cases, suggesting pituitary disorders. 5) Most patients showed dramatic response with oral predinisone. In conclusion, when there are unexplained general weakness, fatigue, weight loss, nausea, vomiting, hypoglycemia, or hyponatremia, isolated ACTH deficiency should be excluded. Immunologic and pathologic studies, and hormonal evolution with glucocorticoid treatment are needed to understand the pathogenesis of isolated ACTH deficiency.

The Effect of Naloxone on the Reversal of Hypovolemic Shock in Rats / 대한마취과학회지

The effects of morphine in bringing sleep and an end to pain have been known from the beginning of recorded history. But the existence of endogenous opiates(endorphin) has been demonstrated only in the last decade. Endorphin bind to opiate receptors and exhibit potent opiate-like activity. In the corticotroph cells of the anterior lobe of pitultary, ACTH and beta-endorphin are synthesized simultaneously. There is a hypothalamic releasing factor which causes the secretion both beta-endorphin and ACTH, but ACTH and beta-endorphine are also released simultaneously by stress. Endorphins adversely affect the circulatory status and these effects are reversed by the intravenous injection of the narcotic antagonist, naloxone. The author studied Dirksen's hypothesis that endorphins may be involved in the pathophysiology of hemorrhagic shock. In this experiment, the author divided in the pathophysiology of hemorrhagic shock. In this experiment, the author divided laboratory animals into 3 groups and administered normal saline, salicylate or hyprocortisone, respectively. l. normal saline pretreated group. ll. salicylate pretreated group. lll. hydrocortisone pretreated group. Each group was then divided into 4 subgroups and treated as follows: 1) hypovolemic shock + normal saline. 2) hypovolemic shock + naloxone. 3) hypovolemic shock + hydrocortisone. 4) hypovolemic shock + PGE1. The following results were obtained: 1) MAP was significantly increased after naloxone and PGE1 adminitration in the normal saline pretreated group. 2) MAP was not changed in the salicylate pretreated group. 3) MAP was significantly increased after naloxone and PGE1 administration in the hydrocortisone pretreated group. 4) Pulse pressure was significantly increased after anloxone, hydrocortisone and PGE1 administration in the normal saline and hydrocortisone pretreated groups. From the above experiment, it may be inferred that endorphins and prostaglandin may play a role in the pathophysiology of hypovolemic shock.