propylthiouracil and Pituitary-Neoplasms

A 28 year-old woman in her first pregnancy was referred to the department of obstetrics and gynecology at 24 weeks of gestation because of pregnancy-induced hypertension.. Thyroid stimulating hormone (TSH), free T3 and free T4 were elevated. Antibody screening did not show antithyroid peroxidase (anti-TPO) antibodies and TSH receptor antibodies. Clinical findings were suspicious of TSH secreting pituitary tumour (TSH-om) or thyroid hormone resistance (RTH). In absence of clinical sings of elevated intracranial pressure magnetic resonance imaging (MR) was discussed but not carried out and planned after delivery. A visual-field defect was ruled out by orbital field evaluation.. Treatment with 3 × 50 mg propylthiouracil daily was initiated. However, normal fT3/fT4 titers could not be achieved. Serum levels were in the high normal ranges and TSH remained increased. The clinical situation of the patient improved resulting in a normal delivery at term. The healthy newborn was breast feed and MR imaging of the mother revealed a 5×8 mm tumor of the pituitary gland.. In pregnant women with pregnancy-induced hypertension thyroid diseases have to be ruled out. Rare causes of hyperthyreoidism are TSH secreting pituitary tumors or thyroid hormone resistance (RTH). Treatment of choice for hyperthyreoidism in pregnancy is propylthiouracil. Normal vaginal delivery and breast feeding are possible. Following delivery it is mandatory to determine an individual treatment strategy.

Topics: Adenoma; Antithyroid Agents; Female; Humans; Hyperpituitarism; Hyperthyroidism; Infant, Newborn; Magnetic Resonance Imaging; Pituitary Gland; Pituitary Neoplasms; Pregnancy; Pregnancy Complications, Neoplastic; Pregnancy Trimester, Second; Propylthiouracil; Rare Diseases; Thyroid Function Tests; Thyrotropin

We described a 39-yr-old asian female who was initially diagnosed with prolactinoma and presented with increase nervousness and weight loss. Laboratory evaluation revealed an inappropriately normal TSH level with elevated free T4, total T3, alpha-subunit and prolactin level. The alpha-subunit/TSH molar ratio was 4. MRI showed a macroadenoma extending to the suprasellar cistern. Treatment was begun with propylthiouracil and bromocriptine. After 5 months of therapy, she became pregnant. At 27 weeks of gestation, she developed headache and decreased visual acuity in her left eye. MRI showed a slightly increase in tumor size compressing the optic chaiasm. Transphenoid macroadenectomy was performed with immediate relief of the visual field abnormality. At 39 weeks gestation a baby with no malformations was delivered. This is the second case report of TSH secreting pituitary adenoma which was exarcerbated during pregnancy. In contrast to the first case, our case was managed with both surgical and medical approach. The judicious use of both medical and surgical therapy can result in a successful outcome to mother and fetus in a patient with TSH secreting pituitary adenoma.

Topics: Adenoma; Adult; Antithyroid Agents; Combined Modality Therapy; Female; Humans; Infant, Newborn; Magnetic Resonance Imaging; Pituitary Hormones; Pituitary Neoplasms; Pregnancy; Propylthiouracil; Thyrotropin

6-n-Propyl-2-thiouracil (6-PTU), the antithyroid agent, produces a time-, concentration-, and turnover-dependent inactivation of the NO synthetic capability of the neuronal nitric oxide synthase isoform irreversible by either arginine or (6R)-5,6,7,8-tetrahydro-L-biopterin. By contrast 6-PTU produces an inhibition of the cytokine-inducible and endothelial nitric oxide synthases fully reversible by arginine. The inactivation of neuronal nitric oxide synthase by 6-PTU follows first order kinetics, and is inhibited competitively by both arginine and (6R)-5,6,7,8-tetrahydro-L-biopterin, but is not accompanied by either a loss of heme-CO binding, heme fluorescence, or disassembly of dimeric structure. 2-Thiouracil behaves qualitatively identically to 6-PTU. Turnover-dependent inactivation of neuronal nitric oxide synthase by [2-14C]-2-thiouracil is accompanied by incorporation of radioactivity into the polypeptide chain. Ca2+-dependent NO formation by GH3 pituitary cells is inhibited by 6-PTU in a manner enhanced by depletion of either extracellular arginine or intracellular (6R)-5,6,7,8-tetrahydro-L-biopterin. These observations establish that 6-PTU is an alternate substrate, mechanism-based inactivator of the neuronal nitric oxide synthase isoform with the ability to suppress cellular NO formation.

Topics: Animals; Antithyroid Agents; Arginine; Biopterins; Calcium; Calmodulin; Carbon Monoxide; Carbon Radioisotopes; Citrulline; Enzyme Activation; Enzyme Inhibitors; Heme; Kinetics; Nitric Oxide; Nitric Oxide Synthase; Nitric Oxide Synthase Type I; Pituitary Neoplasms; Propylthiouracil; Rats; Thiouracil; Tumor Cells, Cultured

It is well known that estrogen (E2) induces progesterone receptor (PR) in the uterus and the mammary gland. In MtT/F84, a pituitary tumor, which was established in our laboratory and has been maintained with in vivo passages, we investigated the PR regulation by E2 in relation to the host's thyroidal status. The PR level in the tumor had increased five fold 48 h after an E2 injection. When the host rats were treated with propylthiouracil (PTU), an anti-thyroid drug, the induction of PR after an E2 injection was completely blocked. This result is consistent with our previous findings indicating that E2 responsiveness in the tumor may be under the control of thyroid hormones. The estrogen receptor (ER) level in the tumor treated with PTU was 15% of the control. This low ER level may account for the blocking of PR induction after an E2 injection. When the host animals were continuously treated with various doses of E2, the PR level in the tumor rose in correlation with the E2 doses. PTU administration, however, did not prevent long term induction of PR by continuous E2 treatment. Our findings suggest that PTU lower the ER level and suppresses the short term estrogenic actions such as PR induction after an E2 injection.

Topics: Animals; Antimetabolites; Antithyroid Agents; Cytosol; Dose-Response Relationship, Drug; Estrogens; Female; Neoplasm Transplantation; Neoplasms, Experimental; Pituitary Neoplasms; Propylthiouracil; Rats; Rats, Inbred F344; Receptors, Estrogen; Receptors, Progesterone

The current consensus is that iodothyronines down-regulate type II T4 monodeiodinase (5'-DII) by an extranuclear acceleration of enzyme inactivation. We have investigated 5'-DII regulation in cultured GC cells, in which thyroid hormone responses are mediated by nuclear thyroid receptor (TR). GC cells actively converted T4 to T3, independent of propylthiouracil and with a Km of 1.4 nM, which are characteristics of 5'-DII. When GC cells were incubated with 10 nM T3, the Km was not affected. However, the maximum velocity was significantly down-regulated by 10 nM T3, from 0.15 to 0.018 pmol/mg protein.min. Dose-response studies showed that a 50% reduction in enzyme activity was achieved with either 0.25 nM T3 or 12 nM rT3. Time-course studies showed that a 50% reduction in enzyme activity occurred after 40 min of incubation with 100 nM rT3 and after 160 min of incubation with 10 nM T3. The down-regulation of 5'-DII by physiological concentrations of T3 has the characteristics of an effect that is mediated by nuclear TR. Our studies, therefore, suggest that down-regulation of 5'-DII by these iodothyronines in GC cells may occur by different mechanisms: enzyme inactivation for rT3, in agreement with the current consensus, and decreased enzyme production for T3, probably mediated by TR.

Topics: Animals; Cells, Cultured; Dose-Response Relationship, Drug; Down-Regulation; Gene Expression Regulation, Enzymologic; Iodide Peroxidase; Iopanoic Acid; Neuroglia; Pituitary Neoplasms; Propylthiouracil; Rats; Time Factors; Triiodothyronine; Triiodothyronine, Reverse; Tumor Cells, Cultured

To investigate a possible effect of triiodothyronine (T3) on the regulation of estrogen receptor, estrogen dependent rat pituitary tumor, MtT/F84, was studied in rats which received surgical thyroidectomy (Tx) or were given propylthiouracil (PTU) and were supplemented with T3. In T3 loaded rats, the grafted tumor showed high estrogen receptor levels (160-200% of control), whereas low estrogen receptor levels (20-35% of control) were observed in the tumors grown in Tx and PTU treated rats. A single injection of T3 to Tx rats with MtT/F84 increased the estrogen receptor level in a time dependent manner and reached the maximal level at 6 h. In primary culture of MtT/F84 cells, T3 increased the specific 3H-estrogen binding to tumor cells in a dose dependent manner (165% of control by 10(-7)M T3) and also in a time dependent (maximum at 12 h) manner. These data suggest that T3 directly up-regulates the estrogen receptor level in MtT/F84 cells.

Topics: Animals; Dose-Response Relationship, Drug; Estradiol; Estrogens; Growth Hormone; In Vitro Techniques; Neoplasms, Hormone-Dependent; Pituitary Neoplasms; Prolactin; Propylthiouracil; Rats; Rats, Inbred F344; Receptors, Estrogen; Thyroidectomy; Time Factors; Triiodothyronine; Tumor Cells, Cultured; Up-Regulation

The activity of T4 5'-monodeiodinase (5'D) in the pituitary was measured in 12 patients with pituitary adenoma (3 patients with acromegaly, 2 with prolactinoma, 1 with Cushing's disease, 1 with TSH-producing tumor, and 5 with nonfunctioning tumor) and, as a control, in a patient who died of parotid cancer. The pituitaries, obtained at operation or autopsy, were homogenized in 0.1 mol/L potassium phosphate buffer, pH 7.0, and centrifuged at 800 x g. Supernatants were incubated with [125I]T4 and 20 mmol/L dithiothreitol (DTT) at 37C for 90 min. T4 5'-D was measured by the release of 125I- with the ion exchange method. The activity of T4 5'-D in the pituitaries from patients with prolactinoma and parotid cancer was dependent on protein concentration, incubation time, incubation temperature, and T4 concentration, and was labile to prior heating at 70 C for 30 min. T4 5'-D was not inhibited by 1 mmol/L propylthiouracil, but was inhibited 95% by 0.1 mmol/L iopanoic acid. The apparent Km and maximum velocity for T4 5'-D in homogenates of prolactinoma at 20 mmol/L DTT were 11 nmol/L and 1.54 pmol/mg protein.h, respectively. This reaction followed sequential-type reaction kinetics when the DTT concentration was varied. All other homogenates of pituitary tumors, except two nonfunctioning tumors, also demonstrated T4 5'-D activity. These results indicate that 1) the human pituitary express a low Km and PTU-insensitive T4 5'-D activity which is very similar to the type II enzyme activity in the rat pituitary; and 2) various types of pituitary tumor cells contain T4 5'-D activity.

Topics: Acromegaly; Adult; Dithiothreitol; Female; Humans; Iodide Peroxidase; Kinetics; Male; Middle Aged; Pituitary Gland, Anterior; Pituitary Neoplasms; Prolactin; Propylthiouracil

Previous studies in rats have shown that the ratio anterior pituitary nuclear L-triiodothyronine (T3) derived from intracellular deiodination of L-thyroxine [T3(T4)]/plasma T3(T4) is much greater than for exchangeable T3 [T3(T3)]. We have addressed the hypothesis that T3(T4) is either selectively accumulated or selectively retained by nuclei in comparison to exchangeable T3 [T3(T3)] in cultured GC cells. GC cells readily generated T3 from T4. When mean medium T3(T4) was experimentally maintained at a low percentage (less than 16%) of total medium T3, to mimic in vivo conditions, nuclear T3(T4) was 2-fold greater than nuclear T3(T3) and the nuclear: medium ratio for T3(T4) was 11-13-fold greater than for T3(T3). The t1/2 of release of nuclear T3(T4) and T3(T3) were indistinguishable from one another and both sources of T3 distributed similarly between the nuclear and cytosol compartments. Thus, in agreement with previous in vivo studies, T3(T4) is derived from cellular T4 and is a significant source of nuclear T3 in GC cells. No evidence for a separate nonexchangeable T3(T4) pool was found as the almost identical cellular distribution and release rates of T3(T4) and T3(T3) from nuclei suggest that T3(T4) generated in these pituitary tumor cells is fully exchangeable. Our findings suggest that the high concentration of T3(T4) in the nuclear fraction is the result of a high intracellular production rate of T3 from T4 relative to the rate of release of T3 from the cell.

Topics: Animals; Cell Nucleus; Cytosol; Half-Life; Iodide Peroxidase; Kinetics; Pituitary Gland, Anterior; Pituitary Neoplasms; Propylthiouracil; Rats; Thyroxine; Triiodothyronine; Tumor Cells, Cultured

Further examination of rat pituitary cell line GH3/C14 showed that at least the physiologic concentration of L-thyroxine was required for estrogen-dependent growth in vivo. Two L-thyroxine synthesis inhibitors, 6-n-propyl-2-thiouracil (propylthiouracil) and 1-methylimidazole-2-thiol (methimazole), were administered concurrently with estrogen to GH3/C14-inoculated hosts. Propylthiouracil administration to estrogen-treated males, intact females, and estrogen-treated ovariectomized females inhibited tumor formation by 93, greater than 95, and 68%, respectively, as compared to tumor formation in controls not treated with propylthiouracil. Methimazole treatment of estrogen-primed males and intact females inhibited tumor formation by 78 and 95%, respectively. Concentrations of total L-thyroxine and free L-thyroixine in sera from normal and inhibitor-treated hosts were depressed 70-80% by propylthiouracil and 60-70% by methimazole. Administration of either drug caused greater inhibition of tumor growth than of total body weight gain. In addition, the administration of a combination of L-thyroxine and L-triiodothyronine to male rats promoted tumor formation even in the absence of exogenous estrogen.

Topics: Animals; Body Weight; Castration; Cell Division; Cell Line; Estrogens; Female; Male; Methimazole; Neoplasms, Experimental; Ovary; Pituitary Neoplasms; Propylthiouracil; Rats; Rats, Inbred WF; Thyroxine

Topics: Animals; Female; Growth Hormone; Hydrocortisone; Hypothyroidism; Iodine Isotopes; Male; Neoplasms, Experimental; Pituitary Gland; Pituitary Neoplasms; Prolactin; Propylthiouracil; Radioimmunoassay; Rats; Thyroxine; Time Factors

Topics: Adenoma; Adenoma, Chromophobe; Child; Diagnostic Imaging; Drug Therapy; Hyperthyroidism; Intracranial Pressure; Pathology; Pituitary Neoplasms; Propylthiouracil; Radiography; Surgical Procedures, Operative; Visual Fields

Topics: Adrenal Glands; Amyloidosis; Animals; Antithyroid Agents; Castration; Iodine Isotopes; Kidney; Liver; Mice; Mice, Inbred C3H; Pathology; Pituitary Neoplasms; Propylthiouracil; Research; Spleen; Thiouracil; Thyroid Gland; Thyroid Hormones; Thyrotropin; Toxicology

Topics: Adrenalectomy; Adrenocorticotropic Hormone; Animals; Blood; Body Weight; Cortisone; Desoxycorticosterone; Dexamethasone; Female; Growth; Growth Hormone; Humans; Kidney; Lactotrophs; Liver; Mammary Glands, Animal; Neoplasm Transplantation; Organ Size; Ovary; Pharmacology; Pituitary Neoplasms; Prolactin; Propylthiouracil; Rats; Research; Spleen; Thymus Gland; Thyroidectomy; Thyroxine

Topics: Animals; Mice; Neoplasms; Neoplasms, Experimental; Pituitary Gland; Pituitary Neoplasms; Propylthiouracil; Thiouracil; Thyroid Gland; Thyroid Neoplasms