EXOPHTHALMOS—Certain Endocrinological Aspects

The substance isolated from the anterior pituitary and responsible for the induction of thyroid hyperplasia in the tadpole (TSH) is not invariably found in increased amounts in the blood of patients with exophthalmos. The blood concentration of this substance is inversely related to the level of thyroid activity. Thyroid extract, pituitary irradiation and adrenocorticotropic hormone have not been shown conclusively to alter the course of exophthalmos.     

Thyroid hormone modulation of TRH precursor levels in rat hypothalamus, pituitary, thyroid and blood

In the present study we have examined the in vivo effects of thyroid hormones and TRH on tissue and blood levels of TRH and TRH-Gly (pGlu-His-Pro-Gly), a TRH precursor. Using specific radioimmunoassays (RIAs), we measured TRH immunoreactivity (TRH-IR) and TRH-Gly-IR concentrations in blood, hypothalamus, anterior and posterior pituitary, and thyroid in euthyroid, hypothyroid and thyroxine (T4)-treated 250 g male Sprague-Dawley rats. TRH-Gly-IR and TRH-IR were detected in all of these tissues. Highly significant positive correlations between whole blood TRH-Gly-IR levels and the corresponding serum TSH values (p less than 0.01), whole blood TRH-IR versus serum TSH (p less than 0.01) and whole blood TRH-Gly-IR versus whole blood TRH-IR (p less than 0.01) are consistent with cosecretion of TRH and TRH precursor peptides into the circulation. Euthyroid rats injected with TRH IP (1 microgram/100 g b.wt.) and hypothyroid rats had 4-fold higher whole blood TRH-Gly-IR levels compared to euthyroid controls (p less than 0.0005). Injection of TRH into euthyroid rats significantly increased the TRH-Gly-IR concentration in the hypothalamus, anterior and posterior pituitary and thyroid. The increase in blood TRH-Gly-IR following intravenous TRH may be due, in part, to partial saturation of TRH-degrading enzymes in blood and cell membranes. The ratio of TRH-Gly to TRH was significantly increased in the anterior pituitary by hypothyroidism and TRH injection, suggesting that thyroid hormones and TRH regulate the alpha-amidation of TRH-Gly to form TRH in this tissue. TRH-Gly levels of pooled pituitary and thyroid extracts quantitated by a combination of TRH-Gly RIA and high performance liquid chromatography (HPLC) revealed several-fold increases following incubation at 60 degrees C. Heating at this temperature may block the alpha-amidation activity in extra-hypothalamic tissues but not the "trypsin-like" enzymes which cleave prepro-TRH into TRH-Gly-immunoreactive peptides.     

Eye muscle antibodies in endocrine exophthalmos. Clinical and serological observations

Serum samples were obtained from 65 patients with endocrine exophthalmos class I-V. In 33/65 patients who were treated either with prednisone or with ciclosporin, blood was sampled before, during and after therapy. Antibodies against eye muscle were determined during the course of immunosuppressive therapy in order to have an objective parameter of the therapeutic effect. To ascertain the specificity of the reaction both eye and abdominal muscles were used as antigens in an ELISA system. Both IgG and IgM antibodies were detected. In 45/65 patients (71%) eye muscle antibodies were positive before starting therapy. Antibodies were mostly detected in patients with active disease. Patients with exophthalmos of recent onset always had IgM antibodies whereas patients with chronic exophthalmos were mostly IgG positive. Patients with relapse showed mostly IgG but also IgG and IgM positivity in 2 cases. In 58% of cases only IgG antibodies were found whereas in 34% both IgG and IgM were detected and in 8% only IgM antibodies. There was no association between antibodies directed against eye muscle and thyroid microsomal and thyroglobulin antibodies or with the state of thyroid function. Furthermore there was no correlation between exophthalmos classes and eye muscle antibody binding activity. The antibody level declined during therapy with prednisone or with ciclosporin but rose again 8-12 weeks after stopping the drug in patients with progressive disease.     

Neuropeptide control of thyroid blood flow and hormone secretion in the rat

The effects of peptide HI (PHI), neuropeptide Y (NPY), and substance P (SP) on thyroid blood flow and hormone levels were studied in anesthetized rats. Regional blood flows were determined using radioactive microspheres. No change in heart rate or mean left ventricular pressure occurred during these neuropeptide infusions (0.625 micrograms iv over 2 min). PHI treatment resulted in a four-fold increase in thyroid blood flow. Blood flows to the pancreas and salivary gland also increased during PHI treatment. Infusions of NPY or SP did not significantly alter thyroid blood flow. However, SP decreased blood flow to the spleen and small intestine. These neuropeptides had no effect on blood flows to the adrenal, kidney, brain, heart, and adipose tissues. Following PHI, NPY, and SP infusions, plasma triiodothyronine and thyroxine levels were not different from values in saline-treated rats. This study demonstrates that PHI, like vasoactive intestinal peptide, is a potent thyroidal vasodilator at a dose that does not affect circulating thyroid hormone secretion.     

Failure to demonstrate natriuretic activity in the posterior pituitary after immunoneutralization of the vasopressin content.

The attempt to demonstrate the presence of a natriuretic substance in the posterior pituitary after immunoneutralization of the AVP content failed. Rats infused i.v. AVP-immunoneutralized posterior pituitary extract did not respond by natriuresis to a saline infusion, in contrast to those infused untreated posterior pituitary extract. Thus, vasopressin seems to be the natriuretic substance in the posterior pituitary extract.     

Binding of an iodinated substance P analogue to cultured anterior pituitary prolactin- and luteinizing hormone-containing cells.

Several lines of anatomic, biochemical, and pharmacological evidence suggest that the neuropeptide substance P has a direct action on cells of the anterior pituitary lobe via a specific neurokinin-1 receptor. In the present study we confirmed this association by combining Bolton-Hunter iodinated substance P-receptor autoradiography with immunocytochemistry on cultured anterior pituitary cells. Radiolabeled substance P was bound to living cell cultures at 0 degrees C, and after a brief wash the cultures were fixed and processed immunocytochemically for prolactin and luteinizing hormone. A large proportion of cultured anterior pituitary cells possessed substance P binding sites. When receptor autoradiography was combined with immunocytochemistry, it was evident that both prolactin- and luteinizing hormone-immunoreactive cells were labeled with radiolabeled substance P. However, a small proportion of the radioligand-labeled cells were not stained by the immunocytochemical procedure, suggesting that additional cell types possess substance P receptors. The present study presents morphological evidence that substance P binds to prolactin- and luteinizing hormone-containing cells of the anterior pituitary lobe. Therefore, it is likely that substance P has a direct action on mammotrophs and gonadotrophs.     

The variable refractivity of the protein or polypeptide hormone-producing cells showing a unique luminescence in the dark-field microscope

Synopsis When cryostat sections of endocrine tissue were examined in a dark-field microscope, a brilliant granular luminescence was revealed in the endocrine cells thought to be concerned with protein or polypeptide hormone production. The sections were prepared from fresh materials either frozen in a cryostat chamber at –25°C, in dry ice-acetone, or fixed in formalin-calcium for 24 hr. The neurosecretory substance in the hypothalamus and the posterior lobe of the pituitary showed a blue luminescence; the acidophil cells of the anterior lobe of the pituitary, orange; basophil cells, green or blue; intermediate lobe cells, no luminescence; thyroid C cells, white-blue; pancreatic A cells, blue; B cells, orange; adrenomedullary cells, greenish blue; enterochromatin cells, green; and other endocrine cells in the gastrointestinal tract, blue or orange. After tearing and spreading the pituitary and hypothalamus with a pair of needles on a glass slide, and examining the teased specimen by dark-field microscopy, various cells of different luminescent colours became apparent in the anterior lobe of the pituitary, a blue fluorescent substance in the posterior lobe, and neurosecretory cell bodies in the hypothalamus. The different colours appear to be inherent in the granules of living tissues.     

Immunoreactive 7B2 concentrations in rats with various endocrine conditions

Changes in 7B2 immunoreactivity in the pituitary as well as in the other brain regions and gut after various endocrine situations were investigated. Gonadectomy and neonatal monosodium glutamate (MSG) treatment resulted in an appreciable increase in the pituitary 7B2 concentration, though 7B2 content in the MSG treated pituitary was not significantly different when calculation was performed on a per pituitary gland basis. The 7B2 concentration in the cerebellum, midbrain and cortex in thyroxine treated rats showed a significant increase, which might indicate possible thyroid hormone involvement in 7B2 metabolism in the brain. The pituitary 7B2 concentration during the estrous cycle did not change significantly. These results suggest that pituitary 7B2 may correlate to the pituitary gonadotropins and that brain 7B2 content may be modulated by thyroid hormones.     

Xenopus laevis FoxE1 is primarily expressed in the developing pituitary and thyroid

The members of the FoxE subfamily of Fox (forkhead) genes are expressed in the developing pituitary, thyroid and lens. Mammalian Foxe1 is expressed primarily in the developing pituitary and thyroid gland, Foxe3 is expressed in the developing lens, while Xenopus FoxE4 is expressed in the developing lens and thyroid. Here we report the identification of Xenopus FoxE1, a gene that is primarily expressed in the developing pituitary and thyroid.     

Effect of the isolated removal of the median eminence (ME) and pituitary stalk (PS) on the immunohistology and hormone release of the anterior pituitary gland grafted into the hypophysiotrophic area (HTA) and/or of the in situ pituitary gland.

Isolated removal of the median eminence (ME) and pituitary stalk (PS) of female rats was performed under visual control, using a new instrument to open up the 3rd ventricle. Atrophy of the uterus, the follicles and the intersitial tissue in the ovaries was accompanied by persistent corpora lutea and persistent diestrous vaginal smears in rats which had undergone a successful removal of ME and PS. No change was, however, detected in the weight of the thyroid and adrenal glands at the end of the six weeks experimental period. An adenohypophysis implanted in the place of the ME at the time of the surgery, could not prevent these changes. In animals, in which the removal of the ME was not complete, the changes of the gonadal system were less pronounced. Immunocytology of the pituitary LH-, FSH, TSH- and prolactin-cells in animals with completely removed ME and PS showed inactive LH- and FSH-cells both in the grafted and in situ pituitaries, while the TSH- and prolactin-cells appeared to be in a stimulated state. In animals with ME remnant, LH-RH axon terminals were localized only on the blood vessels of the remnant. The part of the pituitary graft in contact with these blood vessels, as well as some areas of the in situ pituitary gland, contained active LH cells as judged from their size and immunohistological appearance. Since in the absence of the ME, the hypophysiotrophic area is not able to exert its regulatory effect on the gonadotrophs of the pituitary implant in this area, the authors suggest that this effect is mediated by the blood circulation of the ME which is rich in releasing hormones and is drained toward both the anterior pituitary and the medial basal hypothalamus.     

The effect of propylthiouracil and temperature on avian thyroid activity.

High ambient temperatures cause a reduction in thyroid gland size of chickens but propylthiouracil (PTU) treatment produces an increase in gland size regardless of temperature. This increase in size after PTU treatment during high temperature is evident after 7 days of PTU treatment but not after 14 days of treatment. Cyclic AMP-dependent protein kinase is activated in the thyroid gland with PTU treatment during high temperatures with no alteration in activity in the pituitary. These results suggest that the pituitary is not activated by TRH during periods of high ambient temperature and the thyrotrophs may release TSH in direct response to lowered serum thyroid levels produced by PTU treatment.     

Pituitary metastasis of follicular thyroid carcinoma

OBJECTIVE: The case of a 60-year-old male patient with follicular thyroid cancer who developed a pituitary mass proved to be a metastasis from thyroid cancer. METHODS: Assessment with whole-body scan, ultrasound, computed tomography and thyroglobulin measurements. RESULTS: Despite surgery and repeated doses of radioiodine, the patient developed diplopia and ptosis of the right eyelid, along with increasing thyroglobulin levels. A pituitary mass was discovered, with no signs of pituitary deficiency. The mass was removed and found to consist of neoplastic cells immunohistochemically positive to thyroglobulin. CONCLUSIONS: Distant metastases may develop in cases of follicular thyroid carcinoma, even after repeated doses of (131)I. Metastatic follicular thyroid carcinoma to the pituitary is a rare entity.     

Role of the hypophysis in thyroid regeneration after partial thyroidectomy.

The role of the hypophysis in thyroid regeneration was investigated by measuring the mitotic activity of the thyroid remnant in hemithyroidectomized rats as well as the blood levels of thyroid hormone at various time-intervals after hemithyroidectomy. Mitotic activity underwent a significant increase to reach a peak (a 5- to 8- fold increase) 2 days after hemithyroidectomy. The thyroid hormone level in blood was lower than in controls. Histologically, the thyroid gland showed signs of an elevated rate of functional activity, as indicated by losses of colloid and cell hypertrophy. In a second approach, the mitotic activity of the thyroid remnant was estimated in hypophysectomized and in thyroxine treated rats. Both hypophysectomy and thyroxine injection prevented occurrence of the mitotic peak at 2 days. The regeneration of the thyroid after hemithyroidectomy, as it occurred in the present work, may be explained by a release of thyroid stimulating hormone from the pituitary, brought about by the low level of circulating thyroid hormone, itself resulting from a loss of thyroid tissue.     

Iodine-Induced Thyroid Blockade: Role of Selenium and Iodine in the Thyroid and Pituitary Glands

The purpose of this study was to determine the content of iodine and selenium in the thyroid and pituitary glands of rats under iodine-induced blockade of the thyroid gland. Electron probe microanalysis, wavelength-dispersive spectrometry, and point analysis were used in this investigation. We also determined the expression of sodium iodide symporter and caspase 32 in the thyroid and pituitary glands and the expression of thyroid-stimulating hormone in the pituitary. The samples for iodine analysis must be thoroughly dehydrated, and for this purpose, we developed a method that produced samples of constant mass with minimal loss of substrate (human thyroid gland was used for the investigation). Normal levels of iodine and selenium were found in the thyroid, pituitary, ovaries, testes hypothalamus, and pancreas of healthy rats. The levels of iodine and selenium in I- or Se-positive points and the percentage of positive points in most of these organs were similar to those of controls (basal level), except for the level of iodine in the thyroid gland and testes. Blockade of the thyroid gland changed the iodine level in iodine-positive points of the thyroid and the pituitary glands. On the sixth day of blockage, the iodine level in iodine-positive points of the thyroid gradually decreased to the basal level followed by an abrupt increase on the seventh day, implying a rebound effect. The opposite was found in the pituitary, in which the level of iodine in iodine-positive points increased during the first 6 days and then abruptly decreased on the seventh day. Expression of the thyroid-stimulating hormone in the pituitary decreased during the first 5 days but sharply increased on the sixth day, with a minimum level of iodine in the thyroid and maximum in the pituitary, before normalization of the iodine level in both glands preceding the rebound effect. The expression of sodium iodide symporter increased during the first 4 days of blockage and then decreased in both glands. The fluctuations of the thyroid-stimulating hormone in the pituitary gland reflected the changes of iodine in the thyroid gland more precisely than the changes of sodium iodide symporter. The selenium level in the selenium-positive points changed only in the pituitary, dropping to zero on the second and fifth day of the blockade. Simultaneously, the maximum induction of caspase 32 was observed in the pituitary gland. We believe that these results may help to clarify a role of the pituitary gland in the thyroid blockade.     

A circulating thyroid peroxidase-like substance in healthy human peripheral blood

Circulating thyroid peroxidase (TPO)-like substance in healthy human peripheral blood was studied to clarify the immunological role of TPO. By using a highly sensitive radioimmunoassay system combined with murine monoclonal antibodies, TPO-like substance was measurable in 6 out of 84 sera. Characterization of this circulating substance by gel filtration revealed that the molecular weight of a major peak corresponded to that of trypsinized TPO. From these findings it is possible that peripheral blood lymphocytes are exposed to a low level of TPO as well as to thyroglobulin.     

Changes in the cyclic nucleotides of rat thyroid, pituitary and plasma caused by methylthiouracil treatment.

Changes in the content of cyclic nucleotides (cAMP and cGMP) and related enzyme activities were observed in the rat thyroid, pituitary and plasma during the prolonged increase of endogenous TSH produced by treatment with methylthiouracil (MTU). Experiments were performed after 4 weeks treatment with MTU. The wet weight and cAMP content per wet weight of the thyroid increased 3 and 1.4 times respectively, but cGMP showed a slight decrease. Pituitary weight increased 1.3 times, but cAMP and cGMP content did not change. The cAMP level in plasma also increased about 1.3 times, but cGMP did not increase. The cAMP-phosphodiesterase activity in the thyroid, pituitary and plasma was increased 1.9, 1.4 and 1.3 times respectively after MTU treatment, while cGMP-phosphodiesterase showed no significant change. ATPase activity in the thyroid and pituitary was also increased more than 1.5 times after MTU treatment, while 5'-nucleotidase activitity decreased remarkably. These data indicate that the metabolism of the cyclic nucleotide system in the thyroid is stimulated by TSH.     

Surgical correction of exophthalmos secondary to Graves' disease

Graves' disease has been recorded in the medical literature for more than 150 years. Despite introduction of iodine into the diet, Graves' disease still remains the most important disorder of the thyroid gland. Clinically, Graves' disease is a multisystem disorder of unknown etiology characterized by the clinical triad of infiltrative pretibial dermopathy, thyroid glandular hyperplasia, and ophthalmopathy. Expansion of the bony orbital volume is an effective method of treating moderate to severe exophthalmos. Our experience with a simplified version of a three-wall orbital decompression to correct exophthalmos secondary to Graves' disease is presented.     

Effect of estrogen on the response of thyroid stimulating hormone to substance P in rats

The role of substance P (SP) in the control of thyroid stimulating hormone (TSH) release and the influence of gonadal steroid were investigated. Intravenous administration of SP failed to alter plasma levels of TSH in ovariectomized (OVX) rats, whereas SP induced a significant increase in plasma TSH in estradiol benzoate-primed (Eb-primed) OVX rats (P less than 0.001). Further, intravenously administered SP did not affect the plasma TSH concentration in normal male rats, but significantly increased it in Eb-primed castrated male rats (P less than 0.01). These data suggest possible roles for SP at the level of the hypothalamus and/or the pituitary gland in stimulating TSH secretion under the influence of estrogen.     

Pituitary-thyroid axis reaction after myocardial infarction.

Within the first 36 hours following myocardial infarction, serum total thyroxine (T4) levels were supranormal in most cases in contrast to normal thyrotropin values. After one week, T4 levels dropped to normal while TSH values rose significantly. These findings suggest that, in the acute phase of myocardial infarction, the secretion of thyroid hormones is increased, thereby inhibiting the pituitary thyrotropes. The stimulation of thyroid secretion might be due to the high levels of blood catecholamines generally found in patients with myocardial infarction.     

Acute effects of leptin on 5'-deiodinases are modulated by thyroid state of fed rats.

Leptin has been shown to modulate deiodinase type 1 (D1) and type 2 (D2) enzymes responsible for thyroxine (T4) to triiodothyronine (T3) conversion. Previously, it was demonstrated that a single injection of leptin in euthyroid fed rats rapidly increased liver, pituitary, and thyroid D1 activity, and simultaneously decreased brown adipose tissue (BAT) and hypothalamic D2 activity. We have now examined D1 and D2 activities, two hours after a single subcutaneous injection of leptin (8 microg/100 g BW) into hypo- and hyperthyroid rats. In hypothyroid rats, leptin did not modify pituitary, liver and thyroid D1, and thyroid D2 activity, while pituitary D2 was decreased by 41% (p<0.05) and hypothalamic D2 showed a 1.5-fold increase. In hyperthyroid rats, thyroid and pituitary D1, and pituitary and hypothalamic D2 were not affected by leptin injection, while liver D1 showed a 42% decrease (p<0.05). BAT D2 was decreased by leptin injection both in hypo- and hyperthyroid states (42 and 48% reduction, p<0.001). Serum TH and TSH showed the expected variations of hypo- and hyperthyroid state, and leptin had no effect. Serum insulin was lower in hypothyroid than in hyperthyroid rats and remained unchanged after leptin. Therefore, acute effects of leptin on D1 and D2 activity, expect for BAT D2, were abolished or modified by altered thyroid state, in a tissue-specific manner, showing an IN VIVO interplay of thyroid hormones and leptin in deiodinase regulation.