RESUMEN
Case 1 was a 51-year-old man diagnosed with thyrotropin (TSH)-secreting pituitary tumor. The octreotide loading test showed suppression of TSH secretion. Treatment with lanreotide preoperatively at 90 mg/month resulted in normalization of thyroid function. Three months after treatment initiation, tumor shrinkage was observed, and pituitary tumor resection was performed through transsphenoidal surgery. Case 2 was a 47-year-old woman in whom the octreotide loading test showed suppressed TSH secretion. Treatment with lanreotide preoperatively at 90 mg/month resulted in normalization of thyroid function. After six months of treatment, tumor reduction was observed, and transsphenoidal surgery was performed. In both cases, lanreotide administration before TSH-secreting pituitary tumor resection achieved normalization of thyroid function and tumor shrinkage. Treatment with lanreotide seems effective in patients who show TSH secretion suppression in the octreotide loading test.
Asunto(s)
Adenoma/tratamiento farmacológico , Péptidos Cíclicos/administración & dosificación , Neoplasias Hipofisarias/tratamiento farmacológico , Somatostatina/análogos & derivados , Tirotrofos/efectos de los fármacos , Adenoma/metabolismo , Adenoma/patología , Adenoma/cirugía , Terapia Combinada , Esquema de Medicación , Femenino , Humanos , Japón , Masculino , Persona de Mediana Edad , Neoplasias Hipofisarias/metabolismo , Neoplasias Hipofisarias/patología , Neoplasias Hipofisarias/cirugía , Periodo Preoperatorio , Somatostatina/administración & dosificación , Tirotrofos/metabolismo , Tirotrofos/patología , Tirotropina/metabolismo , Resultado del TratamientoRESUMEN
Rapid actions of triiodothyronine (T3) on thyrotropin (TSH) synthesis and secretion have been described in hypothyroid male rats. However, the molecular mechanisms remain unknown. TαT1 cells, a thyrotroph cell line, was used herein to characterize the possible non-genomic actions of T3 on the expression of alpha (Cga) and Tshb genes, and the posttranscriptional processing and translation of both transcripts. The involvement of αVß3 integrin was also assessed. T3 quickly reduced Tshb mRNA content, poly(A) tail length and its association with ribosomes. The effect of T3 on Tshb gene expression was detected even in the presence of a transcription inhibitor. The decrease in Tshb mRNA content and polyadenylation depend on T3 interaction with αVß3 integrin, while T3 reduced Cga mRNA content by transcriptional action. The translational rate of both transcripts was reduced by a mechanism, which does not depend on T3-αVß3 integrin interaction. Results indicate that, in parallel with the inhibitory transcriptional action in Cga and Tshb gene expression, T3 rapidly triggers additional posttranscriptional mechanisms, reducing the TSH synthesis. These non-genomic actions partially depend on T3-αVß3 integrin interaction at the plasma membrane of thyrotrophs and add new insights to the molecular mechanisms involved in T3 negative feedback loop.
Asunto(s)
Retroalimentación Fisiológica , Tirotropina de Subunidad beta/genética , Transcripción Genética/efectos de los fármacos , Triyodotironina/farmacología , Animales , Línea Celular , Supervivencia Celular/efectos de los fármacos , ADN/metabolismo , Hormonas Glicoproteicas de Subunidad alfa/genética , Hormonas Glicoproteicas de Subunidad alfa/metabolismo , Integrina alfaVbeta3/metabolismo , Poli A/metabolismo , Poliadenilación/efectos de los fármacos , Unión Proteica/efectos de los fármacos , ARN Mensajero/genética , ARN Mensajero/metabolismo , Ribosomas/metabolismo , Tirotrofos/efectos de los fármacos , Tirotrofos/metabolismo , Tirotropina de Subunidad beta/metabolismoRESUMEN
Low thyroid hormone (TH) conditions caused by a variety of prenatal and perinatal problems have been shown to alter postnatal regulatory thyrotropin (TSH) responsiveness to TH in humans and rodents. The mechanisms underlying this pituitary TH resistance remain unknown. Here we use the evolutionarily conserved zebrafish model to examine the effects of low TH on thyrotrope development and function. Zebrafish were exposed to the goitrogen 6-propyl-2-thiouracil (PTU) to block TH synthesis, and this led to an approximately 50% increase in thyrotrope numbers and an 8- to 10-fold increase in tshb mRNA abundance in 2-week-old larvae and 1-month-old juveniles. Thyrotrope numbers returned to normal 3 weeks after cessation of PTU treatment, demonstrating that these effects were reversible and revealing substantial plasticity in pituitary-thyroid axis regulation. Using a T4 challenge assay, we found that development under low-TH conditions did not affect the ability of T4 to suppress tshb mRNA levels despite the thyrotrope hyperplasia that resulted from temporary low-TH conditions. Together, these studies show that low developmental TH levels can lead to changes in thyrotrope number and function, providing a possible cellular mechanism underlying elevated TSH levels seen in neonates with either permanent or transient congenital hypothyroidism.
Asunto(s)
Hipófisis/efectos de los fármacos , Hipófisis/embriología , Hormonas Tiroideas/farmacología , Tirotrofos/efectos de los fármacos , Animales , Animales Modificados Genéticamente , Recuento de Células , Diferenciación Celular/efectos de los fármacos , Hipotiroidismo Congénito/complicaciones , Hipotiroidismo Congénito/embriología , Hipotiroidismo Congénito/genética , Hipotiroidismo Congénito/patología , Embrión no Mamífero , Regulación del Desarrollo de la Expresión Génica/efectos de los fármacos , Organogénesis/efectos de los fármacos , Hipófisis/citología , Hipófisis/patología , Propiltiouracilo/farmacología , Receptores de Hormona Tiroidea/genética , Receptores de Hormona Tiroidea/metabolismo , Tirotrofos/citología , Tirotrofos/fisiología , Tirotropina de Subunidad beta/genética , Pez Cebra/embriología , Pez Cebra/genéticaRESUMEN
Corticotrophin-releasing factor (CRF) regulates the hypothalamic-pituitary-adrenal axis response to stress through its type 1 receptor (CRF1 ) in the corticotrophs of the anterior pituitary. Although CRF1 mRNA expression has been confirmed in the rat pituitary, the distribution pattern of CRF1 protein in the pituitary has not been reported. Therefore, we generated an antiserum against the amino acid fragment corresponding to the 177-188 sequence of the first extracellular loop of the rat CRF1 . Using the antiserum, CRF1 -like immunoreactivity (CRF1 -LI) was detected in the anterior lobe cells of the rat pituitary where some of them expressed intense signals. CRF1 -LI also appeared in the intermediate lobe cells and on the fibre-like elements of the posterior lobe of the pituitary. Dual immunofluorescence labelling showed that corticotrophs exhibited the highest percentage of CRF1 (male: 27.1 ± 3.0%, female: 18.0 ± 3.0%), followed by lactotrophs (male: 6.7 ± 3.0%, female: 12.1 ± 1.3%), gonadotrophs (male: 2.6 ± 1.0%, female: 7.5 ± 0.5%), thyrotrophs (male: 2.9 ± 0.1%, female: 5.3 ± 1.2%) and somatotrophs (male: 1.1 ± 0.3%, female: 1.2 ± 0.5%). The percentage of CRF1 -LI-positive cells that were corticotrophs was significantly higher in male rats than in female rats, whereas CRF1 -LI-positive lactotrophs and gonadotrophs were significantly higher in female rats than in male rats. Almost all of the melanotrophs were positive for CRF1 in the intermediate lobe (98.9 ± 0.2%). CRF1 -LI and the percentage of CRF1 -LI in corticotrophs were decreased in the anterior pituitary, and the distribution patterns were altered from a diffuse to punctate one by adrenalectomy; the changes were restored by treatment with dexamethasone (100 µg/kg bw). These results suggest that CRF1 is involved in the modulation of the functions of the pituitary; moreover, protein expression and the distribution patterns of CRF1 are regulated by glucocorticoids in the rat anterior pituitary.
Asunto(s)
Adenohipófisis/metabolismo , Hipófisis/metabolismo , Receptores de Hormona Liberadora de Corticotropina/metabolismo , Adrenalectomía , Animales , Corticotrofos/efectos de los fármacos , Corticotrofos/metabolismo , Dexametasona/administración & dosificación , Femenino , Glucocorticoides/administración & dosificación , Gonadotrofos/efectos de los fármacos , Gonadotrofos/metabolismo , Inmunohistoquímica , Lactotrofos/efectos de los fármacos , Lactotrofos/metabolismo , Masculino , Hipófisis/efectos de los fármacos , Adenohipófisis/efectos de los fármacos , Cultivo Primario de Células , Ratas Wistar , Receptores de Hormona Liberadora de Corticotropina/inmunología , Somatotrofos/efectos de los fármacos , Somatotrofos/metabolismo , Tirotrofos/efectos de los fármacos , Tirotrofos/metabolismoRESUMEN
Human pluripotent stem cells (hPSCs) provide an unlimited cell source for regenerative medicine. Hormone-producing cells are particularly suitable for cell therapy, and hypopituitarism, a defect in pituitary gland function, represents a promising therapeutic target. Previous studies have derived pituitary lineages from mouse and human ESCs using 3D organoid cultures that mimic the complex events underlying pituitary gland development in vivo. Instead of relying on unknown cellular signals, we present a simple and efficient strategy to derive human pituitary lineages from hPSCs using monolayer culture conditions suitable for cell manufacturing. We demonstrate that purified placode cells can be directed into pituitary fates using defined signals. hPSC-derived pituitary cells show basal and stimulus-induced hormone release in vitro and engraftment and hormone release in vivo after transplantation into a murine model of hypopituitarism. This work lays the foundation for future cell therapy applications in patients with hypopituitarism.
Asunto(s)
Corticotrofos/metabolismo , Células Madre Embrionarias/metabolismo , Hipopituitarismo/terapia , Células Madre Pluripotentes/metabolismo , Tirotrofos/metabolismo , Hormona Adrenocorticotrópica/biosíntesis , Hormona Adrenocorticotrópica/metabolismo , Animales , Benzamidas/farmacología , Biomarcadores/metabolismo , Proteína Morfogenética Ósea 4/farmacología , Técnicas de Cultivo de Célula , Diferenciación Celular/efectos de los fármacos , Tratamiento Basado en Trasplante de Células y Tejidos , Corticotrofos/citología , Corticotrofos/efectos de los fármacos , Dioxoles/farmacología , Modelos Animales de Enfermedad , Células Madre Embrionarias/citología , Células Madre Embrionarias/efectos de los fármacos , Factores de Crecimiento de Fibroblastos/farmacología , Hormona Folículo Estimulante/biosíntesis , Hormona Folículo Estimulante/metabolismo , Factor de Transcripción GATA3/genética , Factor de Transcripción GATA3/metabolismo , Expresión Génica , Hormona del Crecimiento/biosíntesis , Hormona del Crecimiento/metabolismo , Proteínas de Homeodominio/genética , Proteínas de Homeodominio/metabolismo , Humanos , Hipopituitarismo/genética , Hipopituitarismo/metabolismo , Hipopituitarismo/patología , Péptidos y Proteínas de Señalización Intracelular/genética , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Ratones , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Hipófisis/metabolismo , Hipófisis/patología , Células Madre Pluripotentes/citología , Células Madre Pluripotentes/efectos de los fármacos , Proteínas Tirosina Fosfatasas/genética , Proteínas Tirosina Fosfatasas/metabolismo , Tirotrofos/citología , Tirotrofos/efectos de los fármacos , Factor de Transcripción AP-2/genética , Factor de Transcripción AP-2/metabolismo , Factores de Transcripción/genética , Factores de Transcripción/metabolismoRESUMEN
SCOPE: Fasting leads to a significant downregulation of the hypothalamus-pituitary-thyroid axis, and peroxisome proliferator-activated receptor (PPAR) α is a key transcription factor in mediating a magnitude of adaptive responses to fasting. In this study, we examined the role of PPARα in regulation of the hypothalamus-pituitary-thyroid axis. METHODS AND RESULTS: Thyroid-stimulating hormone ß-subunit (TSHß) mRNA abundance was being reduced in response to treatment of TαT1 cells with PPARα agonists (p < 0.05), indicating an inhibitory transcriptional regulation of TSHß by PPARα. As expected, fasting significantly downregulated TSHß mRNA expression in a two-factorial study with fed or fasted wild-type (WT) and PPARα knockout mice (p < 0.05). In contrast to the in vitro data, fasted PPARα knockout mice revealed lower mRNA concentrations of pituitary TSHß (-64%) and TSH-regulated thyroid genes, and lower plasma concentrations of thyroxine (T4, -25%), triiodothyronine (T3, -25%), free T4 (-60%), and free T3 (-35%) than fasted WT mice (p < 0.05). Those differences were not observed in fed mice. CONCLUSIONS: Data from thyrotrope cells revealed that PPARα could contribute to the fasting-associated downregulation of the TSHß mRNA expression. In a mouse model, fasting led to a significant reduction in TSHß mRNA level, but unexpectedly this effect was stronger in mice lacking PPARα than in WT mice.
Asunto(s)
Ayuno/fisiología , PPAR alfa/metabolismo , Tirotrofos/fisiología , Tirotropina de Subunidad beta/genética , Animales , Línea Celular , Ácidos Grasos no Esterificados/genética , Ácidos Grasos no Esterificados/metabolismo , Ácidos Fíbricos/farmacología , Regulación de la Expresión Génica/efectos de los fármacos , Humanos , Masculino , Ratones , Ratones Noqueados , Ratones Transgénicos , Neuroquinina B/análogos & derivados , Neuroquinina B/genética , PPAR alfa/agonistas , PPAR alfa/genética , Hipófisis/efectos de los fármacos , Hipófisis/metabolismo , Pirimidinas/farmacología , ARN Mensajero/metabolismo , Receptor alfa X Retinoide/genética , Receptores beta de Hormona Tiroidea/genética , Tirotrofos/citología , Tirotrofos/efectos de los fármacos , Tiroxina/sangre , Tiroxina/genética , Triyodotironina/sangre , Triyodotironina/genéticaRESUMEN
High intake of soybean phytoestrogens, isoflavones genistein (G) and daidzein (D), has been associated with health benefits. However, isoflavones were reported to affect adversely thyroid function in the presence of other goitrogenic factors. As the thyroid gland becomes functionally impaired with age, we examined whether supplementary doses of G or D would affect morphology and function of pituitary-thyroid axis in middle-aged male rats. Sixteen-month-old orchidectomized Wistar rats were treated with 10 mg/kg of either G or D, while the control sham-operated and orchidectomized group received just the vehicle for three weeks. The animals were fed soy-free diet with increased iodine content, and killed 24 h after the last treatment. Their pituitaries and thyroids were excised and prepared for further immunohistochemical and morphometric investigation. The concentrations of thyroid-stimulating hormone (TSH), total T(4) and T(3), in the serum were determined. In both isoflavone-treated groups, pituitary TSH-immunopositive cells had increased cellular volume and relative volume density (P < 0.05), as well as increased serum TSH levels (P < 0.05) in comparison to the controls; their thyroid tissue was characterized by increased volume of thyroglobulin-immunopositive epithelium (P < 0.05), epithelial height and index of activation rate (P < 0.05), while the volume of luminal colloid, and total serum T(4) and T(3) levels decreased (P < 0.05) in comparison to the controls. In conclusion, this study provides the first direct evidence that both G and D can induce microfollicular changes in the thyroid tissue and reduce the level of thyroid hormones in Orx middle-aged male rats, a model of andropause. This reduction consequently led to a feedback stimulation of pituitary TSH cells. The detected stimulatory effect was higher in the daidzein-treated rats.
Asunto(s)
Envejecimiento/efectos de los fármacos , Genisteína/farmacología , Isoflavonas/farmacología , Orquiectomía , Hipófisis/efectos de los fármacos , Glándula Tiroides/efectos de los fármacos , Envejecimiento/sangre , Animales , Peso Corporal/efectos de los fármacos , Tamaño del Núcleo Celular/efectos de los fármacos , Tamaño de la Célula/efectos de los fármacos , Genisteína/administración & dosificación , Inyecciones Subcutáneas , Isoflavonas/administración & dosificación , Masculino , Tamaño de los Órganos/efectos de los fármacos , Hipófisis/citología , Hipófisis/metabolismo , Ratas , Ratas Wistar , Glándula Tiroides/citología , Glándula Tiroides/metabolismo , Tirotrofos/citología , Tirotrofos/efectos de los fármacos , Tirotrofos/metabolismo , Tirotropina/sangre , Tiroxina/sangre , Triyodotironina/sangreRESUMEN
Mitotane therapy is associated with many side effects, including thyroid function perturbations mimicking central hypothyroidism, possibly due to laboratory test interference or pituitary direct effects of mitotane. We investigated whether increasing concentrations of mitotane in the therapeutic range might interfere with thyroid hormone assays and evaluated the effects of mitotane on a mouse TSH-producing pituitary cell line. TSH, free T(4), and free T(3) levels do not significantly change in sera from hypo-, hyper-, or euthyroid patients after addition of mitotane at concentrations in the therapeutic window. In the mouse TalphaT1 cell line, mitotane inhibits both TSH expression and secretion, blocks TSH response to TRH, and reduces cell viability, inducing apoptosis at concentrations in the therapeutic window. TRH is not capable of rescuing TalphaT1 cells from the inhibitory effects of mitotane on TSH expression and secretion, which appear after short time treatment and persist over time. Our results demonstrate that mitotane does not interfere with thyroid hormone laboratory tests but directly reduces both secretory activity and cell viability on pituitary TSH-secreting mouse cells. These data represent a possible explanation of the biochemical picture consistent with central hypothyroidism in patients undergoing mitotane therapy and open new perspectives on the direct pituitary effects of this drug.
Asunto(s)
Antineoplásicos Hormonales/farmacología , Antineoplásicos Hormonales/uso terapéutico , Mitotano/farmacología , Mitotano/uso terapéutico , Tirotrofos/efectos de los fármacos , Tirotrofos/metabolismo , Tirotropina/metabolismo , Animales , Antineoplásicos Hormonales/efectos adversos , Supervivencia Celular/efectos de los fármacos , Ensayo de Inmunoadsorción Enzimática , Humanos , Ratones , Mitotano/efectos adversos , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Tirotrofos/citología , Tirotropina/genética , Hormona Liberadora de Tirotropina/farmacología , Tiroxina/sangre , Triyodotironina/sangreRESUMEN
Glucocorticoids have an inhibitory influence on proliferation activity of the pituitary cells while stimulating apoptosis. Therefore, it was hypothesized that the synthetic glucocorticoid, dexamethasone (DX), has an inhibitory influence on the number of thyroid-stimulating hormone (TSH) cells during fetal development. The effects of maternal administration of DX on stereological parameters of TSH cells, and TSH serum concentration were investigated in 21-day-old rat fetuses. On day 16 of pregnancy, the experimental dams received 1.0 mg DX/kg b.w. subcutaneously, followed by 0.5 mg DX/kg b.w./day on days 17 and 18 of gestation. The control gravid females received the same volume of saline vehicle. TSH cells were stained immunocytochemically by the peroxidase-antiperoxidase (PAP) method. The fetal pituitary volumes were estimated using Cavalieri's principle. A physical disector counting technique in combination with the fractionator sampling method was used for estimation of pituitary TSH cell number. Cell and nuclear volumes were measured with a planar rotator. Maternal DX application was found to cause a significant decrease of pituitary volume and number of TSH cells per pituitary in 21-day-old fetuses in comparison with the control fetuses. TSH cell number expressed per body weight unit declined significantly after maternal DX administration. These results indicate an inhibitory DX influence on proliferative activity of precursors and likely differentiated TSH cells and increased apoptotic prevalence. The histological appearance, volume of TSH cells and TSH serum concentration suggest intensive synthetic activity in TSH cells of DX exposed fetuses.