Balancing the benefits and harms of thyroid cancer surveillance in survivors of Childhood, adolescent and young adult cancer: Recommendations from the international Late Effects of Childhood Cancer Guideline Harmonization Group in collaboration with the PanCareSurFup Consortium.

Radiation exposure to the thyroid gland during treatment of childhood, adolescent and young adult cancer (CAYAC) may cause differentiated thyroid cancer (DTC). Surveillance recommendations for DTC vary considerably, causing uncertainty about optimum screening practices. The International Late Effects of Childhood Cancer Guideline Harmonization Group, in collaboration with the PanCareSurFup Consortium, developed consensus recommendations for thyroid cancer surveillance in CAYAC survivors. These recommendations were developed by an international multidisciplinary panel that included 33 experts in relevant medical specialties who used a consistent and transparent process. Recommendations were graded according to the strength of underlying evidence and potential benefit gained by early detection and appropriate management. Of the two available surveillance strategies, thyroid ultrasound and neck palpation, neither was shown to be superior. Consequently, a decision aid was formulated to guide the health care provider in counseling the survivor. The recommendations highlight the need for shared decision making regarding whether to undergo surveillance for DTC and in the choice of surveillance modality.

Direct release of parathyroid hormone fragments from functioning bovine parathyroid glands in vitro.

To determine the origin of circulating parathyroid hormone fragments, hormonal peptides released from bovine parathyroid tissue in a physiologically responsive in vitro "perifusion" system were analyzed by gel exclusion chromatography and region-specific radioimmunoassays. When exposed to low Ca++, the tissue released large quantities of intact hormone (parathyroid hormone 1--84) as well as amino- and carboxyl-terminal fragments. Fragments of the hormone were also released when the tissue was exposed to high Ca++, but the carboxyl fragments comprised a much greater proportion of the hormonal peptides released. Control experiments indicated that fragmentation of the hormone occurred within the gland and not after it was secreted. These experiments provide direct evidence, therefore, that release of fragments from the parathyroid gland may contribute to the immunologic heterogeneity of the hormone in the circulation.

Thyroid abnormalities associated with protracted childhood exposure to 131I from atmospheric emissions from the Mayak weapons facility in Russia.

Between 1948 and 1960, the Mayak nuclear weapons facility in Ozyorsk, Russia discharged relatively high levels of radionuclides, primarily (131)I, into the atmosphere, resulting in appreciable exposure to the residents of Ozyorsk. To evaluate the association between thyroid diseases and childhood exposure to radioiodines, we screened 894 Ozyorsk residents born between 1952 and 1953. The study population was comprised of 581 exposed individuals living in Ozyorsk during the years of heaviest exposure and 313 nonexposed individuals who moved to Ozyorsk when radiation exposure from Mayak largely had ended. The screening protocol included a patient interview, palpation of the thyroid, cervical lymph nodes and salivary glands, an ultrasound examination, and measurement of fT4, TSH and TPOAb. Twenty-eight percent of the study group was diagnosed with a thyroid abnormality. The prevalence of nodular disease was significantly higher in the exposed group (20.7%) compared with the nonexposed (14.4%) group (relative risk = 1.4, 95% CI = 1.1; 1.9). Risks were larger for solitary nodules and for nodules > or = 10 mm in diameter. Expansion of the study to increase the number of persons screened as well as detailed dose estimation would offer an unique opportunity to evaluate thyroid disease in relation to chronic exposure to radioiodines during childhood.

Thyroid nodularity and chromosome aberrations among women in areas of high background radiation in China.

Thyroid nodularity following continuous low-dose radiation exposure in China was determined in 1,001 women aged 50-65 years who resided in areas of high background radiation (330 mR/yr) their entire lives, and in 1,005 comparison subjects exposed to normal levels of radiation (114 mR/yr). Cumulative doses to the thyroid were estimated to be of the order of 14 cGy and 5 cGy, respectively. Personal interviews and physical examinations were conducted, and measurements were made of serum thyroid hormone levels, urinary iodine concentrations, and chromosome aberrations in circulating lymphocytes. For all nodular disease, the prevalences in the high background and control areas were 9.5% and 9.3%, respectively. For single nodules, the prevalences were 7.4% in the high background area and 6.6% in the control area (prevalence ratio = 1.13; 95% confidence interval = 0.82-1.55). There were no differences found in serum levels of thyroid hormones. Women in the high background region, however, had significantly lower concentrations of urinary iodine and significantly higher frequencies of stable and unstable chromosome aberrations. Increased intake of allium vegetables such as garlic and onions was associated with a decreased risk of nodular disease, which seems consistent with experimental studies suggesting that allium compounds can inhibit tumor growth and proliferation. The prevalence of mild diffuse goiter was higher in the high background radiation region, perhaps related to a low dietary intake of iodine. These data suggest that continuous exposure to low-level radiation throughout life is unlikely to appreciably increase the risk of thyroid cancer. However, such exposure may cause chromosomal damage.

Thyrotropin increases the iodine content of rat circulating thyroglobulin as measured by equilibrium density gradient centrifugation.

In previous work we demonstrated that circulating thyroglobulin contains very little or no iodine. We have now characterized circulating thyroglobulin following administration of thyrotropin (TSH) to determine whether its iodine content remains low or increases after stimulation. The iodine content of circulating thyroglobulin was estimated from its density determined by equilibrium density gradient (isopycnic) centrifugation. TSH stimulated thyroglobulin from 182 +/- 28 ng/ml to 571 +/- 83 ng/ml at 8-14 h. Circulating thyroglobulin in the basal state had a density consistent with very little or no iodine. Its density increased following TSH to a maximum at 8-14 h which was nearly the same as the density of thyroglobulin extracted directly from the thyroid. To determine whether selective peripheral metabolism, based on the degree of iodination, could account for the density shift, purified rat thyroid thyroglobulin was injected into thyroidectomized rats. The density of thyroglobulin remained unchanged for 25 h during which time it was metabolized by more than 97%. Therefore, selective metabolism of thyroglobulin based on iodine content did not occur. We conclude that TSH causes a marked increase in the iodine content of circulating thyroglobulin. It is most likely that in the basal state circulating thyroglobulin comes from selective release of poorly iodinated molecules, while after TSH, it comes from release of previously synthesized, iodinated and stored molecules.

Dimeric ("big") human placental lactogen. Immunological and biological activity.

Dimeric ("big") human placental lactogen has been isolated in near homogeneous form from placental tissue. It consists of a disulfide-linked (stable) form and a noncovalently associated (unstable) form of the native hormone. The two forms were separated by exposure to denaturing conditions and resolution by gel exclusion chromatography. Both forms retained immunological activity, ability to bind mammary membranes, and ability to induce mammary N-acetyllactosamine synthetase in vitro. On a molar basis, stable dimeric placental lactogen was more active than placental lactogen in the radioimmunoassay indicating that the immunological determinants on both monomeric units could bind to antibody. On a molar basis, stable dimeric placental lactogen was equally active with monomeric placental lactogen in competing for mammary gland membrane binding sites, indicating that only one active site in the molecule could interact with the membrane at a time. Stable dimeric placental lactogen was also active in an in vitro bioassay using the induction of N-acetyllactosamine synthetase. It is concluded that dimer formation does not alter the biologically active portion of the placental lactogen molecule. Since the carboxyl-terminal region (residues 182-191) is involved in the interchain disulfide bonds of dimeric placental lactogen, this portion of the molecule is probably not necessary for its biological activity.

Radioiodine-induced thyroid cancer: Studies in the aftermath of the accident at Chernobyl.

While a great deal is known about the relationship between external radiation exposure and thyroid cancer, much less is known about the oncogenic effects of internal radiation exposure from isotopes of iodine. The accident at the Chernobyl nuclear power plant released massive quantities of radioiodine isotopes into the atmosphere. The large number of ensuing thyroid cancers in exposed children leaves little doubt that these malignancies have occurred as a result of the accident. However, carefully planned epidemiological studies are needed to confirm that these are due predominantly to I-131 exposure, to determine the dose-response relationship, to monitor for continuing effects and to evaluate other contributing factors. Preliminary evidence indicates that there is a distinct pattern of somatic genetic changes in the thyroid cancers from the Chernobyl area.

Multiple schwannomas and meningiomas associated with irradiation in childhood.

OBJECTIVE: To determine the pattern of neural tumors (schwannomas, vestibular schwannomas [acoustic neuromas], and meningiomas) that developed in 3013 people who received radiation treatment with x-ray beam therapy for benign conditions of the head and neck area before their 16th birthday. METHODS: The surgical and pathology reports and pathology slides were reviewed for all neural tumors in the cohort. Patients with more than 1 neural tumor were compared with those with 1 neural tumor and those with no neural tumors. RESULTS: There were 7 patients with multiple neural tumors and 63 with single neural tumors. The distribution of tumors in these 2 groups differed. The group with multiple tumors had more spinal nerve root schwannomas, while the group with single tumors had more cranial nerve schwannomas. Six of the 7 patients did not meet the diagnostic criteria for neurofibromatosis type 2. CONCLUSIONS: Our findings suggest that host factors that increase susceptibility to radiation may be involved in the development of the multiple neural tumors. Clinically, patients with multiple neural tumors who do not meet the diagnostic criteria for neurofibromatosis type 2 should be questioned about radiation exposure. If exposure is confirmed, then screening for other radiation-related tumors should be initiated.

Differential incorporation of sulfate into the chondroitin chain and complex carbohydrate chains of human thyroglobulin: studies in normal and neoplastic thyroid tissue.

Human thyroglobulin (TG) is one of a growing number of glycoproteins that are known to contain sulfate. Among these TG is unusual because it contains sulfate on both its asparagine-linked complex carbohydrate units and its single chondroitin 6-SO4 unit. We incubated tissue fragments prepared from normal and neoplastic thyroid tissue with [35S]sulfate to study the incorporation of sulfate into these two types of carbohydrate acceptor sites. Incubation conditions (0.1 mM sulfate for 16 h) were selected that maintained linear incorporation of [35S]sulfate and retention of more than 90% of iodinated TG in the tissue. Enzyme susceptibility was used to determine incorporation into the complex carbohydrate units (endoglycosidase-F) and the chondroitin 6-SO4 unit (chondroitin ABC lyase). In a representative experiment, 29.8% of the incorporated sulfate was found in the chondroitin 6-SO4 unit during the first hour of incubation. This increased progressively to 72.5% in the chondroitin unit during the incubation period from 8-16 h. A reciprocal decrease occurred in the proportion of sulfate incorporated into the complex carbohydrate units. TG released into the medium and retained in the tissue had the same ratio of sulfate in the two types of carbohydrate units. Neoplastic thyroid tissue incorporated more [35S]sulfate into TG than normal thyroid tissue from the same patient. Neoplastic and normal tissue differed further in the ratios of sulfate incorporated into the two types of carbohydrate units. We conclude that the incorporation of sulfate into the two types of sulfate-containing carbohydrate units of TG does not occur in a fixed ratio and that this differential incorporation of sulfate does not appear to be related to its release from the tissue.

Inhibition of chondroitin sulfate incorporation into human thyroglobulin by p-nitrophenyl-beta-D-xylopyranoside.

Human thyroglobulin (TG) is unique among glycoproteins and TGs of other species in having a chondroitin sulfate chain. We studied the effects of p-nitrophenol-beta-D-xylopyranoside (PNXP), an inhibitor of chondroitin sulfate incorporation into core protein of proteoglycans, on the synthesis of human TG. Fragments of normal thyroid tissue from two patients were preincubated for 1 h with PNXP before adding [35S] sulfate and [3H]leucine. TG was purified by ammonium sulfate precipitation, sucrose gradient centrifugation, and CsCl equilibrium density gradient centrifugation. Chondroitin ABC lyase released 38-42% of the [35S]sulfate from control TG, synthesized in the absence of inhibitor, demonstrating the presence of chondroitin sulfate units. In the samples incubated with increasing concentrations of PNXP (0.2 and 1 mM), the fraction of [35S] sulfate released by ABC lyase decreased progressively (14-23% and 8-11%, respectively). This confirms that, as in chondroitin sulfate proteoglycans, chondroitin sulfate synthesis in TG is initiated by the transfer of a galactose unit, by galactosyltransferase, to a xylosyl-serine in the TG peptide backbone. This step is prevented by PNXP, which is a competitive acceptor of galactose. The density of TG synthesized in the presence of PNXP was determined by CsCl equilibrium density centrifugation. [3H] leucine-labeled TG from the samples incubated with PNXP was less dense than [3H]leucine-labeled TG from the control specimen. The newly synthesized TG was less dense either because of the lack of the chondroitin sulfate chain or because further processing of the TG was impaired. To differentiate these possibilities, we treated control, [3H]leucine-labeled TG with chondroitin ABC lyase and compared its density to that of [3H] leucine-labeled TG synthesized in the presence of 1 mM PNXP. The decrease in density produced by PNXP was greater than the decrease brought about by chondroitin ABC lyase (4.3-5.2 x 10(-3) and 2.4-2.8 x 10(-3) g/cm3, respectively). Therefore, the density contributed by the chondroitin chain was insufficient to account for the entire density shift seen with PNXP. We conclude that 1) chondroitin sulfate synthesis is initiated by the transfer of a galactosyl unit to xylosyl-serine in the TG peptide backbone; and 2) inhibition of this step decreases the density of TG by preventing the addition of the chondroitin chain and interfering with the further processing of TG.

Dystroglycan is present in rat thyroid and rat thyroid cells and responds to thyrotropin.

Dystroglycan is a high affinity laminin-binding glycoprotein originally described as a member of the dystrophin-associated glycoprotein complex in muscle. We have demonstrated the presence of dystroglycan in the thyroid using immunocytochemistry, immunoblots, ligand binding assays, and relative quantitative RT-PCR. In intact rat thyroid glands, antibodies against the alpha (extracellular, laminin-binding subunit) and beta (cytoplasmic/membrane bound) portions of the dystroglycan protein reacted at basolateral membranes where they colocalized with laminin. Western-blotted protein from the Fischer rat thyroid cell line FRTL-5 reacted with both the alpha- and beta-dystroglycan antibodies. The alpha-dystroglycan-reactive band colocalized with laminin-binding activity, and the protein and binding activity were decreased by TSH. In contrast, in the culture medium of these cells, alpha-dystroglycan was increased by TSH. The beta-dystroglycan antibody recognized the full-length 43-kDa band and an approximately 30-kDa truncated form. The truncated form was reduced in cells cultured with TSH, whereas the full-length form was not significantly diminished by TSH. Immunofluorescence of FRTL-5 cells in the absence of TSH showed a colocalization of dystroglycan and laminin. This was disrupted by the addition of TSH and was correlated to morphological changes. PCR amplification of complementary DNA with primer pairs from alpha- and beta-dystroglycan produced appropriately sized bands, whose sequence had identical protein-coding sequences and more than 96% nucleotide homology to mouse dystroglycan sequences. Relative quantitative RT-PCR of beta-dystroglycan messenger RNA showed reduced expression in cells cultured with TSH. We conclude that dystroglycan is present in rat thyroid and in FRTL5 rat thyroid cells and that TSH reduces its expression.

Identification of "big" human placental lactogen in placenta and serum.

Because of increasing evidence for the heterogeneity of polypeptide hormones, studies of the molecular species of human placental lactogen (hPL) were initiated. When extracts of freshly delivered human placentas were passed over Sephadex G-100 in 0.05M ammonium carbonate, three immunoreactive peaks were detected. In addition to a peak corresponding to native hPL (Kav = 0.39) and one in the void volume, a consistent peak which eluted before hPL (Kav = 0.20) was present. The latter represented 2-25% of total hormonal activity and could be rerun without significant conversion to hPL. In 8M urea, the peak continued to behave as a large molecular weight form on both Sephadex chromatography and on polyacrylamide disc gel electrophoresis. Extraction procedures at both neutral and alkaline pH produced similar quantities of the larger material. [125I]iodo-hPL was not converted to the larger form by the conditions of extraction or analysis. These properties are consistent with a larger molecular weight, non-aggregated form of hPL. In comparison with the native hormone, the idsplacement curves for the larger form were parallel in radioimmunoassay studies. Sera obtained from pregnant women during various stages of gestation also showed consistent evidence for a large molecular weight form of the hormone. These observations provide direct evidence, both in placental tissue and in serum for "big" hPL.

Abnormal properties of thyroglobulin in mice with inherited congenital goiter (cog/cog).

A recessive autosomal mutation (cog) in mice that results in congenital goiter was recently described. Since the mutation has been linked to the thyroglobulin (TG) gene, we have studied the immunological and physical properties of TG in cog/cog mice. +/Cog mice, which are phenotypically normal, were used as controls. In a mouse TG RIA the displacement curve produced by cog/cog thyroid extract was not parallel to normal murine TG, and at maximum displacement 15.4% of the tracer was still bound to the antibody. Extract from +/cog thyroid tissue produced parallel and complete displacement. Sucrose density gradient velocity centrifugation followed by RIA was used to determine the sedimentation properties of cog/cog TG. An abnormal pattern was obtained; a small peak in the 3-8S area and a broad, poorly defined peak at 12S and extending to above 27S were present. By comparison, +/cog thyroids had sharp peaks at 19S and 27S. These findings suggest that normal TG contains some immunological determinants that are absent, and some that are altered, in cog/cog TG. They also indicate that the association of 12S subunits to form 19S TG in cog/cog mice is weak and abnormal. Thyroid tissue was labeled with Na125I in vivo and with [35S] methionine in vitro. In cog/cog mice iodine was incorporated predominantly into albumin and other non-TG proteins. However, by polyacrylamide gradient gel electrophoresis, distinct 125I-labeled bands comigrating with normal TG were present. The bands migrating with TG were also precipitable with anti-TG antiserum. In +/cog mice TG was the predominant iodinated molecule. With [35S]methionine labeling, cog/cog and +/cog thyroids formed TG with the same electrophoretic mobilities. These data indicate the cog/cog thyroids synthesize TG of normal, or very nearly normal, size. The immunological and sedimentation properties of this TG are abnormal, supporting the possibility that the cog mutation is in the TG gene.

Anionic carbohydrate groups of human thyroglobulin containing both phosphate and sulfate.

We showed previously that human thyroglobulin (hTG) contains anionic complex carbohydrate units with up to four sulfate groups, some containing both sulfate and sialic acid. Recent reports indicate that the carbohydrate units of hTG may also contain phosphate, but these reports are not all in accord. The purpose of this study was to confirm the presence of phosphate on the carbohydrate units of hTG and to determine whether phosphate coexists with other acidic moieties, such as sulfate and sialic acid, on the same carbohydrate units. Alkaline phosphatase and acid hydrolysis were used to detect phosphate on the sulfated carbohydrate units of hTG derived from normal and neoplastic tissues. Thyroid fragments from two patients were incubated for 16 h in [35S]sulfate-containing medium, and hTG was purified. Complex carbohydrates were released from hTG with endoglycosidase-F and analyzed at pH 2.2 on a HPLC ion exchange column. Sulfate-containing peaks were monitored by radioactivity, and sialic acid-containing ones were identified by their reduced charge after neuraminidase or acid treatment. None of the sulfate-labeled carbohydrate peaks shifted after alkaline phosphatase treatment alone, indicating that none of them contained phosphomonoesters. Several of the sulfate-labeled peaks shifted after acid hydrolysis, some to positions of decreased charge, due to removal of sialic acid, and some to positions of increased charge, suggesting the presence of phosphodiesters. The latter was confirmed by the observation that some of the newly formed peaks were susceptible to alkaline phosphatase digestion. Thus, acid hydrolysis converted phosphodiesters into alkaline phosphatase-susceptible phosphomonoesters, most likely mannose-6-phosphate. We conclude that some anionic complex carbohydrate units of hTG contain exclusively sulfate, while others contain combinations of sulfate, sialic acid, and phosphodiesters. Phosphodiesters are present in the sulfated carbohydrate units of hTG from normal as well as neoplastic thyroid tissue.

Metabolic labeling of human thyroglobulin with [35S]sulfate: incorporation into chondroitin 6-sulfate and endoglycosidase-F-susceptible carbohydrate units.

To study the incorporation of sulfate into thyroglobulin, human thyroid tissue was incubated with [35S]sulfate. Labeled thyroglobulin was purified by ammonium sulfate precipitation, gel exclusion chromatography, and equilibrium density gradient centrifugation, the last of these specifically to remove proteoglycans. [35S]Sulfate was found in thyroglobulin with low density, indicating that sulfate was incorporated into newly synthesized molecules before their iodination. Chondroitin ABC lyase and chondroitin AC lyase released equal amounts of [35S]sulfate, demonstrating the presence of chondroitin units, and TLC showed this to be predominantly chondroitin 6-sulfate. Additional [35S]sulfate was released by endoglycosidase-F (Endo-F), but not by Endo-H. The Endo-F-sensitive sulfate-labeled complex carbohydrate units were heterogeneous, one fraction passing through a Concanavalin-A-Sepharose column without delay and another fraction showing weak affinity for the lectin. More than 90% of the incorporated [35S]sulfate was accounted for by the chondroitin ABC lyase and Endo-F-sensitive fractions. Thus, human thyroglobulin contains sulfate in at least three types of carbohydrate units, 1) chondroitin 6-sulfate units, 2) complex units with no affinity for Concanavalin-A (tri- or tetraantennary forms), and 3) complex units with weak affinity for Concanavalin-A (biantennary forms).

Differences between circulating and tissue thyroglobulin in rats.

The mechanism whereby thyroglobulin (TG) reaches the circulation can involve either the release of newly synthesized TG or the release of colloid-stored TG from the thyroid gland. To distinguish between these possibilities, we have compared the properties of circulating and glandular TG in normal and thyroidectomized thyroid tumor-bearing rats. Circulating TG had the properties of poorly iodinated molecules; it was more susceptible to dissociation into subunits and had a lower density, the latter determined by equilibrium centrifugation in concentrated RbCl. The density of circulating TG was the same as that of glandular TG from propylthiouracil-treated rats, suggesting that circulating TG was nearly or completely devoid of iodine. Circulating TG bound to Concanavalin A-Sepharose and had a normal MCR, indicating that mannose was present and galactose was not in terminal positions, both properties of glandular TG. Since previous studies suggest that these properties cannot arise from differential clearance of TG molecules in the periphery, these data suggest that the TG in the circulation may arise from the direct release of poorly iodinated newly synthesized TG from the thyroid.

Anionic complex-carbohydrate units of human thyroglobulin.

Human thyroglobulin (hTG) contains sulfate in chondroitin 6-sulfate chains and in complex carbohydrates. In this study the sulfate-containing complex carbohydrates were characterized by the number of sulfate and sialic acid residues that they contain. Samples of normal and nodular thyroid tissue were incubated for 16 h in [35S]sulfate-containing medium, and hTG was purified from the tissues and the media. Complex carbohydrates were enzymatically removed from hTG. Subsequent analysis on an HPLC anion exchange column at pH 2.2 separated the carbohydrate units according to their number of negative charges. Sulfate-containing peaks were monitored by radioactivity, and sialic acid-containing peaks were identified by their shift to lower charge after treatment with neuraminidase. Peaks corresponding to sialic acid-free carbohydrate units with one to four sulfates were identified. Also, carbohydrate units with two and three negative charges containing both sulfate and sialic acid were present. In the nodular tissue of one patient there were more sulfated units with higher charge, especially units containing sialic acid. In this patient the proportion of sulfated polyvalent units with sialic acid was 22.4% for normal and 64.6% for nodular tissue. No difference in the composition of the charged units between the tissues and their corresponding media was seen, making it unlikely that the sulfate-containing carbohydrates play a role in hTG release. It is concluded that hTG contains complex carbohydrate units with up to four sulfate groups and units with both sulfate and sialic acid. In some patients, the sulfate-containing anionic carbohydrate units of hTG from normal and nodular thyroid tissue are different.

Radioimmunoassay of human thyroglobulin: effect of antithyroglobulin autoantibodies.

This study was designed to investigate quantitatively the interference of thyroglobulin autoantibodies in the RIA of human thyroglobulin (hTG). Anti-hTG autoantibodies were combined with purified hTG to produce samples with known antibody titers and hTG concentrations. These samples were analyzed in the RIA. By using anti-human globulin serum it was first shown that immune complexes formed between labeled hTG and human anti-hTG. It was then shown that the most important factor in determining the direction of the interference was the specificity of the precipitating (second) antiserum with respect to these immune complexes. When the precipitating antiserum was specific, i.e. did not recognize human antibodies, the immune complexes remained in the supernatant and the measured hTG concentration was falsely elevated. When the precipitating antiserum cross-reacted with human antibodies, the direction of the interference depended on the sample volume. At small volumes there was false depression while at large volumes there was false elevation of apparent hTG levels, depending on the capacity of the precipitating antiserum to combine with human antibodies. Anti-hTG titers far below those detected by the tanned-red cell hemagglutination test had very large effects, to the point where measurements of hTG could not be made, when a cross-reactive precipitating antiserum was used. Therefore, the procedure which investigators have used until now, to exclude samples with anti-hTG hemagglutination titers above an arbitrary limit, is not adequate. It is necessary, until methods are developed which avoid the problem of autoantibody interference, to characterize each assay to determine the limits of anti-hTG that can be tolerated. The factors which influence anti-hTG interference in the hTG RIA are 1) the specificity of the precipitating antiserum, 2) the sample volume, 3) the maximum tracer binding, and 4) the anti-hTG titer.

Iodine content of serum thyroglobulin in normal individuals and patients with thyroid tumors.

We indirectly estimated the iodine content of serum thyroglobulin (TG) in normal individuals and patients with benign and malignant thyroid tumors. Because insufficient TG is present in the serum to perform chemical determinations, equilibrium density centrifugation was used to determine its density, a measure of TG iodine content. In five patients undergoing thyroidectomy, serum TG was compared to TG extracted from the nodules and TG from the surrounding normal thyroid tissue. The iodine content of the tumor TG was much less than that of normal TG in four of the five patients. In patients with benign and malignant nodules, the iodine content of serum TG was lower than that of normal TG, and it was similar in patients with benign and malignant disease. In normal individuals, serum TG was also poor in iodine, similar to the serum TG from the patients, and in the same position as TG with virtually no iodine. These findings are in accord with our report that serum TG in rats is nearly completely devoid of iodine. TG could enter the circulation either by secretion of newly synthesized TG or release of stored TG from the thyroid. The findings show that serum TG in normal individuals does not result from the release of preexisting TG. More likely, it arises from the secretion of poorly iodinated, newly synthesized molecules. Since the elevated serum TG found in patients with nodules also is poor in iodine, it must come directly from the tumor rather than from destruction of surrounding normal thyroid tissue.

Pathological hyperprolactinemia suppresses hot flashes in menopausal women.

Hyperprolactinemia impairs pituitary-gonadal function in young women, but its effect in menopausal women is not known. The purpose of this report is to describe the effect of hyperprolactinemia on gonadotropin secretion and hot flashes in menopausal women before and after treatment with a dopamine agonist. We studied two such women with prolactinomas. Both had plasma LH and FSH levels in the range found in premenopausal women and no hot flashes. Treatment with bromocriptine was associated with normalization of plasma PRL levels, elevation of plasma gonadotropin levels, and the onset of menopausal hot flashes in both patients. We conclude that hyperprolactinemia can inhibit the augmented gonadotropin secretion that occurs in postmenopausal women and prevent hot flashes.