Effect of ethyl alcohol on the TSH-receptor-cyclase system in thyroid and nonthyroid tissues.
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Adenylyl Cyclases↗
Biomedical subjects
O H Clark
Publications and source records attributed to O H Clark.
Decrease in serum uric acid level following parathyroidectomy in patients with primary hyperparathyroidism.
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Adenoma↗
Epidermal growth factor receptors in parathyroid tumors.
Hyperparathyroidism is caused by parathyroid adenomas, hyperplastic parathyroid glands, or rarely parathyroid carcinoma. Membrane receptors to epidermal growth factor (EGF), a growth-stimulating polypeptide, have been shown in other endocrine tissues such as thyroid, breast, and ovary, but not in parathyroid glands. Therefore we studied abnormal parathyroid glands from fourteen patients for the presence of EGF receptors. The binding of radioiodine-labeled EGF to the crude membrane fractions was studied using competitive inhibition with unlabeled EGF. In ten patients with solitary parathyroid adenomas, seven adenomas had no EGF binding, three had low affinity EGF binding with dissociation constants (Kd) of 28 to 148 nM and maximal specific binding (Bmax) of 285 to 1944 fmole/mg protein. In two patients with multiple adenomas, a high affinity EGF binding with Kd of 0.28 to 2.8 nM and Bmax of 6.7 to 43 fmole/mg protein was found. In one patient with hyperplastic parathyroid glands secondary to renal failure, a high affinity EGF binding with Kd of 1.7 nM and Bmax of 18 fmole/mg protein was found. In one patient with persistent hyperparathyroidism following a successful renal transplant (tertiary hyperparathyroidism), a low affinity EGF binding with Kd of 25 nM and Bmax of 219 fmole/mg protein was found. The binding of EGF did not correlate with the preoperative serum calcium or PTH levels. Thus, hyperplastic parathyroid glands (either primary or secondary) have high affinity EGF receptors whereas solitary parathyroid adenomas do not.
Adenoma↗
Parathyroid imaging: comparison of double-tracer (T1-201, Tc-99m) scintigraphy and high-resolution US.
Parathyroid scintigraphy using a double-tracer (T1-201, Tc-99m) subtraction technique depicted 17 of 23 (74%) parathyroid adenomas in patients with and without previous neck operations. High-resolution (10-MHz) ultrasound (US) depicted 18 (78%) of these adenomas. Average tumor size depicted by US was 17 X 10 X 8 mm (excluding a giant adenoma) and 19 X 10 X 9 mm by scintigraphy. Alone, neither modality was particularly sensitive in the depiction of primary hyperplasia of the parathyroid glands, but combined techniques were more effective than the use of a single modality. With both US and T1-201 scintigraphy, only two of 23 cases of parathyroid adenoma in the neck were missed, and none of the eight cases of secondary hyperplasia were missed. In 11 patients who had previously undergone neck surgery, parathyroid tumors were identified in eight by either US or double-tracer scintigraphy. Preoperative parathyroid imaging with double-tracer scintigraphy and high-resolution US is suggested for patients with hyperparathyroidism, particularly in those patients who have had previous parathyroid surgery.
Adenoma↗
MR imaging of the thyroid.
The thyroid gland was evaluated with MR imaging in six normal subjects and 32 patients with thyroid disease. The purpose was to evaluate signal characteristics of normal and diseased thyroid tissue; determine the contrast between normal and diseased tissue on T1- and T2-weighted images; compare relaxation times of normal thyroid, adenomas, and carcinoma; and assess the capability of MR for showing the extent of large thyroid masses. Adenomas and carcinomas were frequently isointense with normal thyroid tissue on T1-weighted images but had markedly higher intensity on T2-weighted images. The mean T1 (1202 +/- 717 msec) and T2 (118 +/- 48 msec) relaxation times of adenomas were markedly longer than the T1 (721 +/- 97 msec) and T2 (59 +/- 10 msec) times of normal thyroid tissue. Likewise, the T1 and T2 values of carcinomas were markedly prolonged compared with normal thyroid but the values overlapped with those of the adenomas. Sagittal and coronal images effectively depicted the extent of large goiters, adenomas, and carcinomas and indicated extension below the cervicothoracic junction. The marked prolongation of relaxation times associated with thyroid disease causes excellent contrast of lesions with normal thyroid and surrounding structures. The large field of view possible with coronal and sagittal images is useful for assessing extensive thyroid masses. These attributes indicate the potential clinical utility of MR for evaluating thyroid disease.
Adenoma↗
The effect of thyrotropin and cAMP on DNA synthesis and cell growth of human thyrocytes in monolayer culture.
Monolayer cultures of human thyrocytes from normal tissue (n = 10), and adenomas (n = 7), differentiated (n = 4), poorly differentiated (n = 2), and undifferentiated (n = 3) thyroid cancers were established to assess the significance of thyrotropin (TSH) and cAMP (adenosine 3',5'-cyclic monophosphate) on cell growth and DNA (deoxyribonucleic acid) synthesis. Cell growth of thyrocytes from normal and adenomatous tissues increased more rapidly (p less than 0.01) after TSH (0.1 IU/ml) was added but was unaffected by cAMP (10(-4) mol/L). In these cells, TSH also enhanced DNA synthesis twofold to twelvefold (p less than 0.01). The adenylate cyclase (AC) inhibitor, 2',3' dideoxyadenosine (ddA), increased DNA synthesis 1.3 to 6 times at a concentration of 2 X 10(-4) mol, whereas the membrane/passable cAMP analogue, dibutyryl-cAMP, and the AC stimulator, forskolin, failed to show any effect on DNA synthesis up to a concentration of 10(-5) mol/L (p less than NS). When administered simultaneously, TSH (1/2 maximum) and ddA (20 mumol) had no cumulative effect on DNA synthesis (p = NS). TSH stimulation in cancerous thyroid tissue (n = 11) demonstrated a lack of TSH response in seven of 11 monolayer cultures with no apparent correlation to cancer differentiation, patient age, or sex. Thus TSH was demonstrated to stimulate DNA synthesis and cell growth of human thyrocytes in monolayer cultures independent of the AC system. However, the TSH effect on cell growth and DNA synthesis was unpredictable in thyrocytes from cancerous tissues.
Adenoma↗
Parathyroid hormone: before and after parathyroidectomy.
The clinical value of measuring serum immunoreactive parathyroid hormone (iPTH) for the diagnosis of primary hyperparathyroidism is sometimes debated, and the clinical significance of an elevated postoperative serum iPTH level is unknown. Therefore we studied 141 consecutive patients with primary hyperparathyroidism before and after parathyroidectomy to determine the clinical value of measuring serum iPTH by a mid-region-specific radioimmunoassay. Eighty-eight percent of the patients with primary hyperparathyroidism had an absolute increase in the level of serum iPTH (greater than 40 microliter Eq/ml) before surgery, and the remaining patients had an inappropriately increased level of serum iPTH for the simultaneous serum calcium level. Preoperative serum iPTH level correlated positively with serum calcium level and parathyroid tumor size. Postoperative elevation of serum iPTH level was common (as high as 40%) and was associated with higher preoperative levels of blood urea nitrogen, serum creatinine, and alkaline phosphatase and larger tumors. An elevated postoperative serum iPTH level without hypercalcemia did not indicate a failed parathyroidectomy, whereas negative parathyroid exploration and postoperative hypercalcemia were the best predictors of persistent hyperparathyroidism. We conclude that preoperative serum iPTH measurement is a very sensitive diagnostic test for primary hyperparathyroidism, but postoperative serum iPTH measurement is not a good predictor for persistent or recurrent hyperparathyroidism.
Adult↗
Value of high resolution real-time ultrasonography in secondary hyperparathyroidism.
Thirty-two patients were treated surgically for symptomatic secondary or tertiary hyperparathyroidism, and 27 of these patients had high resolution (10 mHz) real-time ultrasonography before parathyroidectomy. This preoperative localization study identified one or more enlarged hyperplastic parathyroid glands in all but one patient who had not had a previous parathyroid operation, and in five of six patients who did have previous parathyroid operations. In both of the patients in whom no parathyroid glands were identified by ultrasonography the only abnormal enlarged parathyroid glands were those situated within the superior mediastinum. When large glands are not observed by ultrasonography in patients with severe secondary hyperparathyroidism, the glands are usually situated in the superior mediastinum, behind the trachea or esophagus, or deeply within the neck. The size of the parathyroid glands correlated positively with the serum parathyroid hormone level and with the severity of the secondary hyperparathyroidism. Thus, the preoperative identification of parathyroid glands by ultrasonography not only localizes the site of most hyperplastic parathyroid glands (70 percent of patients), but also detects those patients who have enlarged parathyroid glands, elevated serum parathyroid hormone levels, and severe secondary hyperparathyroidism. These are the patients who are thus unlikely to respond to further medical therapy.
Adenoma↗
Estrogen and thyroid-stimulating hormone (TSH) receptors in neoplastic and nonneoplastic human thyroid tissue.
Estrogen-binding receptors (ER) and thyroid-stimulating hormone (TSH) receptors were observed in the cytosol and in a membrane particulate fraction, respectively, in most neoplastic and nonneoplastic human thyroid tissues. Fourteen of 15 thyroid neoplasms and 6 of 15 nonneoplastic thyroid specimens had estrogen receptors (assuming the sensitivity of our estrogen receptor assay is 0.2 fmole/mg protein), and 14 of 15 thyroid neoplasms and 11 of 15 nonneoplastic thyroid specimens had a high affinity, low capacity TSH receptor. Neoplastic thyroid tissue had more ER (2.35 +/- 0.70/fmole/mg protein) than nonneoplastic thyroid tissue (0.57 +/- 0.181/fmole/mg protein) removed from the same patients (P less than 0.05). The Kd for ER did not differ in nonneoplastic (0.41 +/- 0.090 nM) and neoplastic (0.311 +/- 0.048 nM) thyroid tissue. The number of TSH receptors was comparable in neoplastic (0.609 +/- 0.191 pmole/mg protein) and in nonneoplastic (0.765 +/- 0.181 pmole/mg protein) thyroid tissue removed from the same patients who had the ER studies. The maximal adenylate cyclase response to TSH was greater in the neoplastic (147 +/- 26.9 pmole/mg protein/30 min) than in nonneoplastic thyroid tissue (32.8 +/- 6.69 pmole/mg protein/30 min) (P less than 0.001) suggesting a greater metabolic responsiveness of the neoplastic thyroid tissue to TSH. No correlation was evident, however, between the number of estrogen and TSH receptors in nonneoplastic and neoplastic thyroid tissue (r = 0.226). This study demonstrates that neoplastic human thyroid tissues have both estrogen receptors and TSH receptors. The neoplastic tissue also has a greater AC response to TSH than nonneoplastic thyroid tissue.
Adenocarcinoma↗
Binding of bovine thyrotropin to specific sites in thyroid tissue from control and hemithyroidectomized rats.
The binding of 125I-bovine thyrotropin to thyroid particulate fractions from sham-operated (control) and hemithyroidectomized rats was compared to determine if a change in either the number of bovine thyroid-stimulating hormone (bTSH) binding sites or their affinity for bTSH occurs in physiological situations that evoke changes in the intensity of thyroid stimulation. Following hemithyroidectomy serum TSH levels increase and the remnant thyroid lobe enlarges. Because of compensatory thyroid hypertrophy the concentration of TSH binding sites in the thyroid glands from hemithyroidectomized and control rats was related to particulate protein concentration, to the degree of thyroid cellularity as indicated by DNA concentration, and to the concentration of the plasma membrane markers, 5'-nucleotidase and magnesium-dependent ATPase. In each of four experiments, saturation studies revealed that the maximum specific binding of TSH per unit particulate protein and per thyroid lobe was greater in particulates from remnant than from control thyroid lobes. When related to DNA concentration, the concentration of TSH binding sites in remnant lobes was approximately twice that in control lobes. Because of an increase in plasma membrane markers per lobe after hemithyroidectomy, however, there was no difference in the number of TSH binding sites when related to the concentrations of the membrane marker enzymes in the particulate fractions. As judged from Scatchard analysis, the affinity of TSH binding was lower in remnant than in control lobes. This was partially but not completely due to the increased concentration of particulate protein in the remnant thyroid. These experiments demonstrate that the increase in serum TSH levels after hemithyroidectomy in the rat is associated with alterations in TSH receptor capacity and affinity.
5'-Nucleotidase↗
Surgery for thyroid disease.
Thyroidectomy is the keystone of management in most patients with thyroid cancer, and has unique advantages in many cases of hyperthyroidism. The role of thyroidectomy in these two conditions is considered, with specific discussion of indications, extent of operation, complications, and technique.
Carcinoma↗
Parathyroid aspiration biopsy under ultrasound guidance in the postoperative hyperparathyroid patient.
A 10-MHz high-resolution dedicated small parts scanner and a static 5-MHz digital scanner were used in the ultrasound (US) examination of 11 patients with hyperparathyroidism who had previously undergone surgery of the parathyroid (eight patients) or thyroid (three patients) gland. Using US localization, aspiration biopsies were performed successfully in nine patients: parathyroid disease was confirmed in seven patients and thyroid lesions in two. Inadequate aspirate was obtained in one patient; in another patient a biopsy was done successfully under CT guidance following a negative US examination. The authors conclude that high-resolution US is an effective tool for guiding the aspiration biopsy of nonpalpable parathyroid tumors in patients who have had neck surgery. They suggest modifications of the US equipment that would simplify the localization procedure.
Adenoma↗
Thyrotropin receptor-adenylate cyclase system in Hurthle cell neoplasms.
Hurthle cell neoplasms are though to arise from the follicular cells of the thyroid gland, although some studies suggest that they originate from the parafollicular cells. We studied tissue from five patients (three men and two women, aged 33-72 yr) with Hurthle cell neoplasms (four adenomas and one carcinoma) to determine whether Hurthle cell neoplasms have an intact TSH receptor-adenylate cyclase (AC) system and, if so, whether it differs in benign and malignant Hurthle cell and neoplasms. Binding of [125I]bovine (b) TSH and an AC response to TSH occurred in all four Hurthle cell adenomas. In three of these tumors, there was good binding and a relatively good correlation between the concentration of bTSH producing half-maximal inhibition of [125I]bTSH binding (4.8 mU/ml) and the TSH concentration causing half-maximal stimulation of AC (2.2 mU/ml). There was also a 2- to 5-fold increase in AC activity in response to bTSH (300 mU/ml), a value comparable to that which occurs in follicular thyroid neoplasms and differentiated thyroid cancers. In the fourth Hurthle cell adenoma, however, binding was low, the apparent Kd (170 mU/ml) and Km (20 mU/ml) were high, and there was only a 1.4-fold increase in AC activity in response to bTSH (300 mU/ml). In the one metastatic Hurthle cell carcinoma, there was no high affinity TSH binding or AC response to TSH. Thus, Hurthle cell neoplasms are of follicular cell origin, since benign Hurthle cell tumors have an intact TSH receptor-AC system. Malignant Hurthle cell neoplasms, like undifferentiated and medullary thyroid cancer, lack a functional TSH receptor.
Adenoma↗
Thyrotropin regulation of adenylate cyclase activity in human thyroid neoplasms.
Thyrotropin (TSH), stimulators of guanyl nucleotide regulatory protein, (sodium fluoride and guanyl-5'-yl-imido-diphosphate [Gpp(NH)p]) and a stimulator of the catalytic unit of adenylate cyclase (AC) (forskolin) were used to probe the TSH receptor-guanyl nucleotide regulatory protein-cyclase unit in normal and neoplastic thyroid tissue from 17 patients. Eleven of these patients had benign follicular adenomas and six patients had differentiated thyroid carcinomas. An 8000 X g particulate fraction that is rich in thyroid plasma membranes was prepared, and the activity of AC was determined by the conversion of alpha-32P-ATP to P32-cAMP. Thyroid neoplasms had a greater AC response to TSH than did normal thyroid tissue removed from the same patients (p less than 0.001). The AC response to NaF and Gpp(NH)p was greater in the neoplastic thyroid tissue, although in these experiments the increase was not significant. In contrast, the AC response to forskolin was comparable in normal (573 +/- 129) and neoplastic (526 +/- 132) thyroid tissue (mean +/- SEM). The effects of NaF, Gpp(NH)p, and forskolin on AC activity were additive with TSH when used at concentrations for optimal AC activity. Low concentrations of NaF and Gpp(NH)p stimulated AC activity whereas high concentrations of NaF and Gpp(NH)p assayed either together or separately inhibited AC activity. When forskolin and NaF were assayed together there was a greater than additive effect or potentiated effect on activity. Basal AC activity was increased in the presence of manganese (Mn+2) (2 mM) over magnesium (Mg+2) (2 mM) (p less than 0.001), whereas TSH-stimulated (p less than 0.01) and Gpp(NH)p-stimulated AC activity (p less than 0.05) were lower in the presence of Mn+2 than Mg+2. There was an excellent correlation between basal AC activity and AC activity in response to forskolin in both normal and neoplastic thyroid tissue, whereas there was no correlation between basal AC activity and TSH-stimulated AC activity in the thyroid neoplasms. These data suggest that the abnormality responsible for the greater AC response to TSH in neoplastic thyroid tissue is proximal to the catalytic unit of AC and most probably is due to an alteration in the guanyl nucleotide regulatory protein or in the coupling of the guanyl nucleotide regulatory protein to either the receptor or the catalytic unit of AC.(ABSTRACT TRUNCATED AT 400 WORDS)
Adenoma↗
Epidermal growth factor receptors in normal and neoplastic thyroid tissue.
Epidermal growth factor (EGF) stimulates DNA synthesis and proliferation of thyroid cells in culture and may have an important role in the regulation of normal and neoplastic thyroid cell growth. We therefore studied paired normal and neoplastic thyroid tissue from eight patients for the presence of EGF receptors using a radioreceptor assay. 125I EGF binds to a particulate membrane fraction from both normal and neoplastic thyroid tissue with high affinity (dissociation constant ranged from 0.5 to 16.7 nmol/L). The binding is saturable, and maximal binding is achieved within 40 minutes at 37 degrees C and pH 7.5. This EGF binding is specific since it is competitively inhibited by unlabeled EGF but not by other hormones (thyrotropin, insulin, glucagon, and transferrin). The binding of EGF to thyroid neoplasms is higher than the binding to normal thyroid tissue (p less than 0.05). Thyroid tumors with a poorer prognosis appear to have higher EGF binding compared with adjacent normal thyroid tissue than have tumors with a better prognosis. EGF may have a role in the regulation of normal and neoplastic thyroid cell growth. Characterization of EGF receptors may help predict the clinical course of patients with malignant thyroid neoplasms.
Adenoma↗
Localization studies in patients with persistent or recurrent hyperparathyroidism.
Preoperative localization studies are essential for patients who have undergone previous parathyroid operations. This is because the remaining parathyroid glands are more difficult to identify at operation because of increased scarring with loss of normal tissue planes and because the remaining abnormal parathyroid tissue is more likely to be situated in an ectopic position. This investigation concerns the accuracy of preoperative localization studies in 36 consecutive patients. All patients had symptoms and clinical and laboratory data diagnostic of primary (31 patients) or secondary (five patients) hyperparathyroidism. Ultrasonography was performed in all 36 patients; 18 (50%) were positive, 14 (39%) were negative, and four (11%) were false positive examinations. Eight of the negative study results occurred in patients with abnormal parathyroid glands situated in the mediastinum. Computerized tomography (CT) was performed in 25 patients. There was an equal number of positive (11; 44%) and negative (11; 44%) studies with three (12%) false positive test results. CT was helpful in identifying substernal lesions and other abnormal parathyroid glands situated in ectopic positions. Thallium chloride 201-technetium 99m pertechnetate scans were used in 22 patients. There was an equal number of positive (eight; 36%) and negative (eight; 36%) studies. Six patients (27%) had false positive scans. One or more of these noninvasive tests was positive in 27 of the 36 patients (75%). Highly selective venous catheterization for the measurement of immunoreactive parathyroid hormone concentrations localized the elusive parathyroid tumor in 12 of the 16 patients (75%) overall and in six of the nine patients (66%) whose tumors were not identified by other studies. One patient had both a false positive ultrasound and thallium chloride 201-technetium 99m pertechnetate scan. Preoperative localization studies were therefore very helpful for locating hyperfunctioning parathyroid glands in patients with recurrent or persistent hyperparathyroidism, and 75% of the tumors were identified by noninvasive studies. Seventy-five percent of the tumors not identified by noninvasive studies were localized by selective venous catheterization. Most tumors not identified by noninvasive studies were mediastinal or ectopic in position.
Adult↗
Hürthle cell neoplasms. Malignant potential.
We studied the records of patients with Hürthle cell neoplasms seen at the University of California at San Francisco, from 1943 to 1982, because of controversy concerning the malignant potential of these tumors. Of our 84 patients, 71 had Hürthle cell adenomas (HCAs), nine had Hürthle cell change in chronic thyroiditis, and four had Hürthle cell carcinomas. Coexisting papillary thyroid carcinoma occurred in three patients with HCA. Twelve patients with HCAs had multiple lesions, five of which were bilateral. Patients with HCA were followed up for 675 patient-years, 45 for four years or more (maximum duration, 36 years). There were no recurrences or deaths among the patients with benign Hürthle cell tumors. Thus, patients with HCA had a benign course, and histologic examination results accurately reflected malignant potential.
Adenoma↗
Mechanisms for increased adenylate cyclase responsiveness to TSH in neoplastic human thyroid tissue.
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Adenoma↗