Recidiva de macroadenoma hipofisario posterior a tratamiento estándar / Pituitary macroadenoma relapse after standard treatment

RESUMEN Introducción: la acromegalia es una patología de larga evolución y compromiso multisistémico, originada por un aumento en la liberación de hormona de crecimiento luego del cierre metafisario de los huesos largos. Su diagnóstico es complejo y suele presentarse entre la quinta y sexta década de la vida. El tratamiento incluye la resección quirúrgica y manejo mediante quimioterapia y radioterapia, así como control endocrino fármacológico. La enfermedad presenta una tasa de recidiva comprendida entre el 2 a 14%. Presentación de caso: paciente femenina de 67 años de edad con diagnóstico de acromegalia hace 15 años, quien luego de ser sometida a tratamiento estándar, presenta manifestaciones clínicas progresivas y compatibles con una función hipofisaria activa. Conclusiones: la paciente en efecto presentó recidiva de la enfermedad con persistencia del tumor benigno, debido a la interrupción del tratamiento y el insuficiente seguimiento del caso; por tanto, es fundamental el seguimiento estricto en el paciente que recibe manejo quirúrgico y tratamiento farmacológico por parte del equipo de salud. MÉD.UIS. 2017;30(2):89-93.

ABSTRACT Introduction: acromegaly is a disease of long evolution and multisystemic involvement, caused by an increased release of growth hormone after the metaphyseal closure of long bones. Diagnosis is often difficult and usually occurs between the fifth and sixth decade of life. The treatment is based on surgical resection, chemotherapy and radiotherapy, as on endocrine control by drugs. The disease has a low recurrence rate of from 2 to 14%. Case presentation: a 67 year old female patient with a diagnosis of acromegaly 15 years ago, who, after being subjected to standard treatment, presents progressive and clinical manifestations compatible with an active pituitary function. Conclusions: the patient relapsed effect of the disease with persistency of the benign tumor, due to the discontinuation of treatment and insufficient monitoring of the case; therefore strict monitoring is essential in patients receiving pharmacological therapy and surgical management by the health team. MÉD.UIS. 2017;30(2):89-93.

Ultrastructural changes in lactotrophs and somatotrophs of alloxan-induced diabetic rats and the possible protective effect of alpha-lipoic acid

Alteration in the cellular composition of the anterior pituitary gland could be involved in both prolactin and growth hormone disturbances in cases of poorly controlled diabetes. This study was conducted to investigate the ultrastructural changes in both somatotrophs and lactotrophs of diabetic rats and to investigate the possible protective effect of alpha-lipoic acid. Thirty adult male rats were randomly divided into three equal groups: group A [control], group B [alloxan-induced diabetic rats], and group C [alloxan-induced diabetic rats that received alpha-lipoic acid]. In rats of groups B and C, diabetes was induced by a single intraperitoneal injection of alloxan monohydrate. In animals of group C, alpha-lipoic acid was given intraperitoneally during the period of the experiment. Twelve weeks after induction of diabetes, specimens of the pituitary gland were processed for transmission electron microscopic examination and a morphometric study was conducted. Somatotrophs of diabetic rats showed condensed nuclei, dilated Golgi saccules, and dilated rough endoplasmic reticulum cisternae. Further, some lactotrophs showed corrugated or condensed nuclei, dilated Golgi saccules, and relatively fewer granules. In both somatotrophs and lactotrophs of diabetic rats, the number of cytoplasmic granules was significantly decreased as compared with that of control rats. In addition, a significant increase in the percentage of empty granules to the total number of granules was recorded. However, the total number of granules and the percentage of empty granules to the total number in both somatotrophs and lactotrophs were significantly reduced in diabetic rats treated with alpha-lipoic acid as compared with untreated diabetic rats. The spectrum of changes in lactotrophs and somatotrophs of uncontrolled diabetic rats was found to be corrected by alpha-lipoic acid and therefore alpha-lipoic acid is recommended as a form of adjuvant therapy for diabetes

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.

Activin inhibits the promoter activity of human growth hormone gene in rat pituitary GH3 cells / 生理学报

The present study was aimed at investigating the effect of activin on the activity of human growth hormone (hGH) gene promoter in rat pituitary GH3 cells and the underlying molecular mechanism. The method of luciferase reporter gene was used. We firstly established a stable GH3 cell line which contains hGH gene promoter (-484 to 30 bp) and luciferase reporter gene by transfecting pGL3-484-Luc2 luciferase expression plasmid into GH3 cells using Lipofectamine transfection reagent. After treating these cells with activin or activin plus various signaling transduction activators, the concentration of GH in the medium and lysate of GH3 cells and luciferase activities in GH3 cells were measured. The results showed that activin (5 nmol/L, 50 nmol/L) decreased the secretion and synthesis of GH. The amounts of GH content in GH3 lysate and medium treated with 50 nmol/L activin were 82% and 59% of the control, respectively. Furthermore, activin (5, 50 nmol/L) reduced the luciferase expression in stable GH3 cells, with the expression being 77% and 69% of the control (P<0.001). Among the activators of intracellular signaling transduction pathways, mitogen-activated protein kinases kinase (MAPKK/MEK) activators C(6) ceramide (1 micromol/L) abolished completely the inhibitory effect of activin. Western blot analysis further confirmed the inhibition of phosphorylated MEK in GH3 cells. The inhibitory effect of activin was abrogated following the deletion of the fragment from -132 to -66 bp within the hGH gene promoter. These results indicate that activin decreases the activity of hGH gene promoter in rat pituitary GH3 cells. The intracellular MEK dependent signaling pathway and the promoter sequence that spans the -132 to -66 bp fragment of hGH gene are involved in the inhibitory effect of activin.

[Effect of morphine on the number of adenohypophysis acidophil cells in male rat]

The influence of morphine on pituitary secretion through micrimu receptors has been nearly known. It is also reported that morphine has an effect on cell proliferation. In the present study we investigated the effect of morphine on the proliferation of acidophil cells of adenohypophysis in male rat. This study has been carried out on 14 adult male Wistar rats divided into two groups of morphine dependent and control. The animals in morphine-dependent group were addicted through consumption of morphine for 21 days. After controlling withdrawal syndrome signs, serum prolactin level was determined by Elisa method. In the next step after anesthetizing animals and performing cardiac perfusion, the hypophysis was removed and fixed at 10% formalin. After processing, staining was done by routine immuno-histochemistry method and the number of mammotropes and somatotropes in morphine-dependent and control groups were compared. Mean prolactin production in dependent group as compared with control group showed significant increase. There was a significant increase in the ratio of mammotropes to acidophil cells and a significant decrease in the ratio of somototrops to acidophil cells in morphine-dependent group compared to the control group [P<0.05]. Morphine dependency may lead to increase in the percentage of prolactin secreting cells and serum prolactin level and decrease of growth hormone secreting cells

Mek and p38 MAPK-dependant pathways are involoved in the positive effect of interleukin-6 on human growth hormone gene expression in rat MtT/S somatotroph cells / 中国医学科学杂志(英文版)

<p><b>OBJECTIVE</b>To investigate the effect of interleukin-6 (IL-6) on the human growth hormone (hGH) gene expression in a rat somatotropic pituitary cell line MtT/S.</p><p><b>METHODS</b>The plasmids containing various lengths of hGH gene 5'-promoter fragments were constructed. Stably transfected MtT/S cells were created by cotransfecting the above plasmids and pcDNA3. 1(+) with DMRIE-C transfection reagent After the administration of these cells with IL-6 and/or various inhibitors of signaling transduction pathways, the luciferase activities in MtT/S cells lysis were assayed to demonstrate the effects of IL-6 on hGH gene promoter activity and possibly involved mechanism.</p><p><b>RESULTS</b>The 10(3) U/mL IL-6 stimulated GH secretion and synthesis, and promoted the 5'-promoter activity of GH gene in stably transfected MtT/SGL cells with the action of 1.69 times above the control. Among inhibitors of signaling transduction pathways, mitogen-activated protein kinase kinase (MAPKK/MEK) inhibitor PD98059 (40 micromol/L) and p38 mitogen-activated protein kinase (MAPK) inhibitor SB203580 (5 micromol/L) completely blocked the stimulatory effect of IL-6. Western blot analysis further confirmed the activation of phosphorylated MEK and p38 MAPK in MtT/SGL cells. Neither over-expression of Pit-1 nor inhibition of Pit-1 expression affected IL-6 induction of hGH promoter activity. A series of deletion constructs of hGH promoter were created to identify the DNA sequence that mediated the effect of IL-6. The results showed that the stimulatory effect of IL-6 was abolished following deletion of the -196 to - 132 bp fragment.</p><p><b>CONCLUSIONS</b>IL-6 promotes GH secretion and synthesis by rat MtT/S somatotroph cells. The stimulatory effect of IL-6 on hGH gene promoter appears to require the activation of MEK and p38 MAPK, and a fragment of promoter sequence that spans the - 196 to - 132 bp of the gene, but may be unlinked with Pit-1 protein.</p>

Effect of interleukin-1 beta on growth hormone gene expression and its possible molecular mechanism in rat MtT/S somatotroph cells / 中国医学科学杂志(英文版)

<p><b>OBJECTIVE</b>To elucidate the effect of interleukin-1 beta (IL-1 beta) on human growth hormone (hGH) gene expression in a rat somatotropic pituitary cell line MtT/S.</p><p><b>METHODS</b>Stably transfected MtT/S cells were firstly established by transfecting 484-Luc1 plasmid which contained hGH gene promoter -484 to +30 bp and luciferase reporter gene. The effect of IL-1 beta on hGH gene expression was determined by assaying the luciferase activities. RT-PCR method was also used to determine whether IL-1 recepor mRNA was expressed in MtT/S cells.</p><p><b>RESULTS</b>The 10(3) U/mL IL-1 beta stimulated secretion and synthesis of GH, and promoted the 5'-promoter activity of GH gene in stably transfected MtT/SGL cells with the action of 1.38 times above the control. Among inhibitors of signaling transduction pathways, mitogen-activated protein kinase kinase (MAPKK/MEK) inhibitor PD98059 (40 micromol/L) and p38 mitogen-activated protein kinase (MAPK) inhibitor SB203580 (5 micromol/L) completely blocked the stimulatory effect of IL-1 beta, and phosphatidylinositol-3-kinase (PI3-K) inhibitor LY294002 partly abolished the effect of IL-1 beta. Western blot analysis further confirmed the activation of phosphorylated MEK and p38 MAPK in MtT/SGL cells. Neither over-expression of Pit-1 nor inhibition of Pit-1 expression affected induction of hGH promoter activity by IL-1 beta. A series of deletion constructs of hGH promoter were created to identify the DNA sequence that mediated the effect of IL-1 beta, and results showed that the stimulatory effect of IL-1 beta was abolished following deletion of the -196 to -132 bp fragment.</p><p><b>CONCLUSIONS</b>IL-1 beta promotes GH secretion and synthesis in rat MtT/S somatotroph cells. The stimulatory effect of IL-1 beta on hGH gene promoter appears to require the activation of MEK, p38 MAPK, PI3-K, and a fragment of promoter sequence that spans the -196 to -132 bp of the gene, but it may be unlinked with Pit-1 protein.</p>

Current Research on the Structure and Function of the Growth Hormone Releasing Hormone Receptor / 대한내분비학회지

Growth hormone releasing hormone receptor (GHRH-R) is a family B1 G-protein coupled receptor found predominantly on pituitary somatotrophs. In the adults it is required for the normal synthesis and release of growth hormone (GH) from the pituitary. During development it is required for the normal proliferation and maturation of somatotrophs within the pituitary. Mutations of this receptor in mouse and man are associated with GH deficiency, short stature and pituitary hypoplasia. This signaling system plays important roles in growth and development, metabolism of muscle and fat, and is implicated in the regulation of cardiac and immune function, wound healing, tumor growth and the aging process. Current areas of active research discussed here include: studiesof the structure of the receptor binding site and its interaction with GHRH, alternative splice variants of the GHRH-R which appear to promote tumor proliferation, truncated receptor isoforms that act as dominant negative inhibitors of wild type receptor, and the unclear physiologic role of the GHRH system in birds and fishes.

Expression of Metallothionein-1, 2 in Folliculostellate Cells of Rat Anterior Pituitary Gland / 대한해부학회지

Metallothionein (MT) family, intracellular zinc binding proteins, has been suggested to play an important regulatory role in zinc metabolism. The present study utilized light and confocal microscopic methods to investigate the expression pattern of MT-1, 2 and to determine the distribution and extent of colocalization of MT-1, 2 relative to subpopulations of S100 positive folliculostellate (FS) cells and somatotrophs in normal rat anterior pituitary. By light microscopy, MT-1, 2 immunoreactivity was observed both in pars intermedia and pars distalis of anterior pituitary. Confocal microscopy revealed that most MT immunoreactivity was colocalized in S100 positive FS cells, not in somatotrophs. This is the first report that FS cells in pars distalis contain MT-1, 2. These results suggest that MT family may be involved in regulation of hypophyseal endocrine functions and can be used as new markers of FS cells.

A Case of Isolated Familial Somatotropinoma / 대한내분비학회지

The familial occurrence of a pituitary adenoma associated with multiple endocrine neoplasia (MEN) type 1 or Carney complex is a well-recognized entity. However, an isolated familial somatotropinoma is a rare inherited disease, which is characterized by clustering of a somatotrophic adenoma and acromegaly or gigantism in a family, but without other manifestations of MEN type 1, with only 68 cases, in 28 families, described in the literature. The mode of inheritance is autosomal dominant, with incomplete penetration, but the genetic background of these pituitary adenomas remains unknown. A family exists where both the father and son were affected. Endocrinological investigations confirmed hypersecretion of GH and IGF-1, and the pituitary adenomas were identified by magnetic resonance image in both cases. There was no symptom of MEN type 1 or other form of endocrine dysfunction. Herein is reported a case of an isolated familial somatotropinoma in Korea, with a review of the literature

A Case of Isolated Familial Somatotropinoma / 대한내분비학회지

The familial occurrence of a pituitary adenoma associated with multiple endocrine neoplasia (MEN) type 1 or Carney complex is a well-recognized entity. However, an isolated familial somatotropinoma is a rare inherited disease, which is characterized by clustering of a somatotrophic adenoma and acromegaly or gigantism in a family, but without other manifestations of MEN type 1, with only 68 cases, in 28 families, described in the literature. The mode of inheritance is autosomal dominant, with incomplete penetration, but the genetic background of these pituitary adenomas remains unknown. A family exists where both the father and son were affected. Endocrinological investigations confirmed hypersecretion of GH and IGF-1, and the pituitary adenomas were identified by magnetic resonance image in both cases. There was no symptom of MEN type 1 or other form of endocrine dysfunction. Herein is reported a case of an isolated familial somatotropinoma in Korea, with a review of the literature

The Effect of T3 on Thyroid Hormone Receptor Dynamics in Thyroid Hormone Response Element of Chicken Lysozyme Silencer / 대한내분비학회지

BACKGROUND: The regulation of gene transcription can be controlled by both positive (enhancer) and negative (silencer) regulatory sequences. Several enhancer and silencer elements have been described in the 5' region of the chicken lysozyme gene. The silencer located at -2.4 kb upstream of the chicken lysozyme gene is composed of two separate modules (F1 and F2) that can function as silencers by themselves, but also show synergistic repression after multimerization. The F1 module is bound by a protein termed NeP1 and F2 module, a F2 thyroid hormone response element (F2-TRE), and can be bound by the thyroid hormone receptor (TR). F2-TRE has an inverted palindromic structure, with high affinity to TR. Although many current reported results have tried to explain the regulatory mechanism of chicken lysozyme gene expression due to the thyroid hormone, there have been few studies that clarify the TR dynamics in the F2-TRE of the chicken lysozyme gene, either with or without exposure of the thyroid hormone. Here, the changes in the TR binding patterns in the F2-TRE of the chicken lysozyme gene are described, both before and after T3 stimulation over time. METHODS: Using the stably transfected rat pituitary somatotroph tumor cell line, GC8 cells, with the F2-TRE inserted 5' to the thymidine kinase (TK) promoter, together with a mouse TRalpha- expressing plasmid, a chromatin immunoprecipitation (ChIP) technique was employed to reveal the TR-TRE interaction before and after T3 stimulation. Following the cross-linking and sonication of the cells, the immunoprecipitation was performed overnight, at 4 degrees C, with TRalpha1, TRbeta1 and TRbeta2 antibodies, respectively. The binding patterns and amounts of TRalpha1, TRbeta1 and TRbeta2 to the F2-TRE, before and after 12 hours of 100 nM T3 stimulation, were analyzed using conventional and quantitative real-time polymerase chain reactions (RQ-PCR). The ChIP technique was used to give a basal value for 20 minutes and 1, 2, 4, 6, 8 and 12 hours after the 100 nM T3 stimulation, and RQ-PCR was then performed. Western blot with TRalpha1, TRbeta1 and TRbeta2 antibodies were also performed. RESULTS: After 12 hours of 100 nM T3 stimulation of the GC8 cells, the TRalpha1 and TRbeta2 binding to the F2-TRE increased, but the TR 1 binding to the F2-TRE decreased, by conventional PCR. Although all the TR isoforms were bound to the F2-TRE by RQ-PCR, the TR 1 binding to the F2-TRE, after 12 hours of 100 nM T3 stimulation, was significantly increased (1.01-->2.73, delta=+170.3%, p2.98, delta=+17.8%). The TRbeta1 binding was significantly decreased compared with that of the basal level (4.59-->2.06, delta=-55.1%, p7.77, delta=-4.4%). The binding patterns and amounts of TRalpha1, TRbeta1 and TRbeta2, both before and after the 100 nM T3 stimulation, were also identified over time. While the TRbeta1 bindings to the F2-TRE after 1 hour of 100 nM T3 stimulation were acutely reduced, those of the TRalpha1 at 20 minutes and 6 hours were increased. The TRbeta2 bindings showed a maximal increase at 20 minutes. The directions of the TR binding patterns, between the before and after 2 hours of 100 nM T3 stimulation, were identical to those for between 4 and 6 hours of T3 stimulation. There was no significant difference in the TR bindings to the F2-TRE in relation to the amounts (1.5 vs. 4.5 microliter) of TR antibodies used during the ChIP assays. The Western blots showed no significant change of the levels of each TR isoform proteins, either before or after 12 hours of exposure to 100 nM T3. CONCLUSION: These results show the dynamic binding patterns of the TR isoforms to the F2-TRE of the chicken lysozyme gene, both before and after T3 stimulation, over time. Further investigation, however, will be needed to clarify the mechanisms of our observations. The ChIP technique may then be used to reveal the dynamic models of the cofactors, as well as TR isoforms, in the TR-regulated transcription machinery.

Gene Expression of Somatostatin Receptor (Subtype 2 & 5), Gi2 alpha and Pit-1 in GH-secreting Pituitary Adenomas / 대한내분비학회지

BACKGROUND: Mutation of Gs protein subunit (gsp oncogene), detected in about 30~40% of growth hormone (GH)-secreting pituitary tumors, is associated with an increased long-acting somatostatin analog octreotide sensitivity. However, the mRNA expression of somatostatin receptor (sst) was not changed in the GH-secreting pituitary tumor, regardless of whether they were gsp oncogene positive or negative. This suggests that the expression of genes coding for Gi2 alpha , Pit-1 and the other factors involved in the regulation of secretory activity in somatotrophs is likely to be altered in gsp oncogene positive tumors. We observed the impact of the gsp oncogene on the expression of the genes coding for Gi2 alpha, Pit-1 and sst (2&5) in GH-secreting pituitary tumors. METHODS: The GH response to octreotide was examined in 13 acromegalic patients before transsphenoidal adenomectomy. Genomic DNA and RNA were extracted from fresh frozen tumor tissues. PCR was performed to amplify and sequence the region between codon 184 and 251 that includes exons 8 and 9 of the Gs gene. Sst2, sst5, Gi2 alpha and Pit-1 mRNA levels were measured by semi-quantitative RT-PCR. RESULTS: Sst2 and sst5 mRNA transcripts were detected in all tumors (7 gsp +, 6 gsp-). The amount of sst transcripts varied considerably varied between the tumors. There were no significant differences in sex, age, tumor size, grade or basal GH levels. Pit-1 and sst2 mRNA levels were not different. In contrast, Gi2 alpha mRNA levels were significantly higher in gsp (+) while sst5 mRNA levels were higher in gsp (-). CONCLUSION: These data suggests that gsp oncogene may increase Gi2 alpha levels but decrease sst5 mRNA levels. However, Pit-1 and sst2 mRNA expression may not be affected by gsp oncogene. The increased expression of the Gi2 alpha gene might be an inhibitory compensatory response to the action of gsp oncogene.

Morphological evidence of mitotic activity of mammotrophs and somatotrophs in monolayer cultured rat anterior pituitaries / 대한해부학회지

No abstract available.