Benign thyroid diseases and the risk of death from breast cancer.

A survey of the causes of death among women with benign thyroid disease was conducted to assess the risk of breast cancer mortality in thyroid patients. The study population was all women diagnosed with one of several types of thyroid disease at the Massachusetts General Hospital Thyroid Clinic from 1925 to 1974. A population-based comparison group was matched to the Clinic patients for age and socioeconomic status, resulting in a total of 9,520 matched pairs. A search of the Massachusetts mortality records located death certificates for 10.9% (1,039) of the Thyroid Clinic patients and 10.5% (995) of the comparison women. Cancer was the cause of death in 21% (218) of the Thyroid Clinic patients and 24% (239) of the comparison women. Fewer patients than comparison women died from cancers of the digestive organs (30.2 vs. 45.5%), but more patients died from thyroid cancer (3.7 vs. 0%), lymphatic and hematopoietic cancers (11.5 vs. 4.2%), and cancers of other sites (8.3 vs. 3.8%). Breast cancer deaths accounted for 21.6% of cancer deaths in the patients and 22.2% of cancer deaths in the comparison women. When specific thyroid diagnoses were considered, the percent of all deaths due to breast cancer ranged from 1.9 to 5.6%, compared to 5.3% in the comparison women. Of the diagnostic groups studied, patients with Hashimoto's thyroiditis had the lowest percent of deaths due to breast cancer, while those with nontoxic nodular goiter had the highest.

Cancer mortality in women with thyroid disease.

A retrospective follow-up study of 7338 women with either nontoxic nodular goiter, thyroid adenoma, hyperthyroidism, hypothyroidism, Hashimoto's thyroiditis, or no thyroid disease was conducted. All women patients at the Massachusetts General Hospital Thyroid Clinic who were seen between 1925 and 1974 and who were treated for a minimum of 1 year were traced. A total of 2231 women (30.4%) were dead and 2012 women (27.4%) were alive as of December 31, 1978. Partial follow-up information was available for the remaining 3095 women (42.2%). The average length of follow-up was 15.2 years. When losses to follow-up were withdrawn at the time of their loss, the standardized mortality ratios (SMR) for all causes of death were 1.2 [95% confidence interval (CI), 1.1-1.3] for women with nontoxic nodular goiter, 1.2 (95% CI 1.0-1.3) for those with thyroid adenoma, 1.4 (95% CI 1.3-1.5) for women with hyperthyroidism, 1.5 (95% CI 1.3-1.7) for hypothyroid women, 1.2 (95% CI 0.9-1.5) for those with Hashimoto's thyroiditis, and 1.5 (95% CI 1.4-1.6) for those without thyroid disease. For deaths from all cancers, the standardized mortality ratios were 1.5 (95% CI 1.2-1.8) for women with nontoxic nodular goiter, 1.5 (95% CI 1.1-1.9) for those with thyroid adenoma, 1.2 (95% CI 1.0-1.4) for women with hyperthyroidism, 1.0 (95% CI 0.7-1.4) for the hypothyroid women, 1.2 (95% CI 0.7-2.1) for those with Hashimoto's thyroiditis, and 1.3 (95% CI 1.0-1.5) for those women without thyroid disease. When specific cancer sites were studied, excess numbers of deaths were observed from breast cancer in women with nontoxic nodular goiter (SMR = 1.6, 95% CI 1.0-2.6) and from lymphatic and hematopoietic cancer in women with nontoxic nodular goiter (SMR = 2.4, 95% CI 1.2-4.3) and thyroid adenoma (SMR = 2.7, 95% CI 1.1-5.2). An increase in thyroid cancer risk was observed in women with thyroid adenoma (SMR = 11.7, 95% CI 1.3-42.1) but was based on only two deaths. In hyperthyroid women, statistically significant increases in the number of deaths were observed from pancreatic cancer (SMR = 2.6, 95% CI 1.4-4.3) and respiratory cancer (SMR = 2.2, 95% CI 1.3-3.5), but not breast cancer (SMR = 1.3, 95% CI 0.8-1.8). When the data were stratified by the time between the onset of thyroid symptoms and death, a nonsignificant excess number of cancer deaths was observed in hyperthyroid women who died 20 or more years after their symptoms began.(ABSTRACT TRUNCATED AT 400 WORDS)

Radioactive iodine therapy and breast cancer. A follow-up study of hyperthyroid women.

A follow-up study of 1,762 hyperthyroid women who were treated at the Massachusetts General Hospital Thyroid Unit between 1946 and 1964 was conducted. The average length of follow-up was 17.2 years. A 1978 mailing address or a death certificate was located for 92% of the women, and 88% of 1,058 living patients responded to a mail questionnaire. The standardized mortality ratio (SMR) for all causes of death was 1.3 (95% confidence interval (CI) 1.2-1.4). The standardized mortality ratios for all malignant neoplasms and for breast cancer were 0.9 (95% CI 0.7-1.1) and 1.3 (95% CI 0.8-1.9), respectively. More deaths than expected were observed from endocrine and metabolic diseases (SMR = 1.8, 95% CI 1.2-2.7), circulatory system diseases (SMR = 1.4, 95% CI 1.3-1.6), and respiratory system diseases (SMR = 1.9, 95% CI 1.3-2.6). The standardized incidence ratios (SIR) for all malignant neoplasms and for breast cancer were 0.9 (95% CI 0.8-1.1) and 1.2 (95% CI 0.9-1.5), respectively. A nonsignificant excess breast cancer risk was observed 10 years after the onset of thyroid symptoms and was present at the end of 30 years of observation. A statistically significant excess number of pancreatic cancer cases (SIR = 2.0, 95% CI 1.0-3.7) and a nonsignificant excess of brain cancer cases (SIR = 2.3, 95% CI 0.7-5.3) were observed. Eighty per cent of the women were treated with radioactive iodine. When age at treatment and year of treatment were controlled, women who were ever treated with radioactive iodine had a standardized rate ratio for breast cancer of 1.9 (95% CI 0.9-4.1), compared with those who were never treated with radioactive iodine. Women who developed hypothyroidism as a result of their treatment for hyperthyroidism did not have an increased risk of developing breast cancer (SIR = 1.1, 95% CI 0.8-1.6).

Rat thyroid peroxidase (TPO) biosynthesis in vitro: studies using antiserum to porcine TPO.

Using partially purified trypsin-solubilized porcine thyroid peroxidase (TPO), an antiserum was developed which inhibited enzyme activity in vitro, and which cross-reacted with partially purified rat TPO. Using rat thyroid minces, this antiserum was utilized to detect radiolabeled TPO in vitro. Newly synthesized rat TPO was observed in the presence of TSH (10 mU/ml), an effect which was completely blocked by co-incubation with cycloheximide. TPO biosynthesis was detected within 6 h of incubation, consistent within a rapid effect of TSH on thyroidal protein biosynthesis.

Antineutrophil autoantibodies in Graves' disease. Implications of thyrotropin binding to neutrophils.

The hyperthyroidism of Graves' disease may be caused by autoantibodies to thyrotropin (TSH) receptors. We have found that patients with this disease have autoantibodies to neutrophils as well, which can be displaced by TSH. Using a radiochemical opsonic assay, we found serum antibodies against homologous neutrophils in 6 of 11 Graves' patients. With a staphylococcal protein A-binding assay, we detected circulating antibodies to homologous neutrophils in 10 of 20 patients, while finding cell-bound antibody on autologous neutrophils in 7 of 8 (including 2 with negative serum tests). Use of human 125I-TSH in a radioligand binding assay revealed that TSH bound to neutrophils rapidly (maximum binding within 10 min at 22 degrees C, pH 7.4), specifically (less than 20% nonspecific binding), and reversibly. Adding TSH to the radiochemical assay resulted in a dose-dependent inhibition of opsonic antibody activity in serum from patients with Graves' disease. In contrast, TSH did not inhibit antibody activity of serum from patients with immune neutropenia not associated with thyroid disease. Our findings suggest a basis for the association of Graves' disease with neutropenia. Furthermore, the discovery of such antineutrophil antibodies in Graves' disease permits detection of cell-bound antibody when free antibody is not present.

Methimazole pharmacology in man: studies using a newly developed radioimmunoassay for methimazole.

A RIA for the antithyroid drug methimazole [1-methyl-2-mercaptoimidazole (MMI)] has been developed. A MMI derivative, 5-COOH-MMI, was conjugated to porcine thyroglobulin, and antibodies to the conjugate were raised in rabbits. [35S]MMI was used as the tracer. At a final antibody dilution of 1:100, the assay could detect MMI in amounts as low as 2.5 ng. The putative MMI metabolites 3-methyl-2-thiohydantoin and 1-methylimidazole had minor cross-reactivities of 2.1% and 0.5%, respectively. There was no effect of serum proteins on MMI immunoactivity. MMI was given orally to normal subjects (n = 6), hyperthyroid patients (n = 5), patients with hepatic cirrhosis (n = 4), and normal lactating women (n = 4). After a single dose of 60 mg, peak MMI levels were similar in the normal subjects and the hyperthyroid patients (approximately 1.5 micrograms/ml). Patients with hepatic cirrhosis had similar peak MMI serum levels [1.31 +/- 0.3 (+/- SEM) micrograms/ml], but the half-time of MMI disappearance from serum was significantly prolonged compared with the normal value (21.2 vs. 6.0 h; P less than 0.001). The lactating women received 40 mg MMI as a single dose. Over the next 8 h, mean MMI levels in serum and milk were nearly identical, with a mean serum to milk ratio of 1.03 +/- 0.16. A total of 70.0 +/- 6.0 micrograms MMI was excreted in the milk over the 8-h time period. This amount of MMI could affect neonatal thyroid function.

Methimazole pharmacology in the rat: studies using a newly developed radioimmunoassay for methimazole.

Methimazole [1-methyl-2-mercaptoimidazole (MMI)] was given to normal male rats in their drinking water in concentrations ranging from 0.0001-0.05% for either 1 week or 1 month. Serum MMI levels in the rats ranged from 0.008-19.6 micrograms/ml, and were similar after 1 week and 1 month of treatment. Serum MMI was linearly related to the MMI concentration in the drinking water (r = 0.98, P less than 0.001). In contrast, intrathyroid MMI content plateaued with increasing MMI concentrations in the water, and was linearly related to the logarithm of the MMI concentration. At the highest MMI concentration (0.05%), thyroid MMI contents were similar in the 1-week and 1-month groups (approximately 1 X 10(-4) M). Surprisingly, at lower MMI concentrations, thyroid MMI content was significantly higher in the 1-week group than the 1-month group. Thyroid function was inhibited by MMI with similar depression of serum T4 or T3 after 1 week or 1 month of MMI treatment. Although the MMI concentration for 50% suppression of thyroid PBI was 0.003% in both groups, thyroid MMI content at this MMI concentration was 97 microM after 1 week but only 15 microM after 1 month. The continued thyroid-inhibiting activity of MMI at 1 month, despite a striking decrease in thyroid MMI content, may relate to intrathyroid iodide depletion, which was more severe after 1 month (thyroid 127I = 40 microM) than after 1 week (thyroid 127I = 140 microM) or in controls (470 microM). Rats were given 0.05% MMI for either 1 week or 1 month, and the drug was then withdrawn. In the 1-week group, serum MMI disappeared biexponentially, with a rapidly declining phase (t1/2 = 3.2 h) and a second, slower disappearance phase (t1/2 = 47.7 h). Similar findings were noted after 1 month of treatment. The disappearance of thyroid MMI was also biexponential after 1 week, but this variable could not be evaluated after 1 month because thyroid MMI fell rapidly to undetectable levels. There was a highly significant correlation in the 1-week group between the disappearance of MMI from the thyroid and the recovery of thyroid function as assessed by thyroid PBI (r = 0.81, P less than 0.01). Despite the very rapid disappearance of MMI from the thyroid after 1 month of treatment, the recovery time of thyroid PBI was significantly longer than after 1 week of treatment (2.1 days vs. 1.4 days for 50% recovery, P less than 0.01).(ABSTRACT TRUNCATED AT 400 WORDS)

Propylthiouracil (PTU) pharmacology in the rat. I. Serum and thyroid PTU measurements by radioimmunoassay.

We have developed a highly sensitive and specific RIA for propylthiouracil (PTU) which uses 125I-labeled PTU as the radioactive ligand. At a final antibody dilution of 1:10,000, the detection limit for PTU was 100 pg; cross-reactivity with circulating, urinary, and intrathyroid PTU metabolites was negligible. Using this assay, serum and thyroid PTU levels were determined after short term (1 week) and long term (1 month) PTU treatment at doses of 0.0001-0.05%. Serum PTU was a linear function of the PTU dose (r = 0.99; P less than 0.001), whereas thyroid PTU was a linear function of the logarithm of the PTU dose (r = 0.99; P less than 0.001). Serum PTU levels were higher after 1 month of treatment than after administration for 1 week, probably because steady state conditions were not achieved after 1 week. At several doses, thyroid PTU levels were also higher after 1 month of treatment, but the differences were not as striking as those seen in the serum levels. The pharmacokinetic data are consistent with a multicompartmental model for PTU distribution. The logarithmic relationship between thyroid PTU and PTU dose suggests a saturable uptake mechanism for PTU by the thyroid; inhibition of thyroid PTU uptake by PTU itself could also explain these observations.

Propylthiouracil (PTU) pharmacology in the rat. II. Effects of PTU on thyroid function.

Using a sensitive and specific RIA for propylthiouracil (PTU), we examined the effects of short term (1 week) and long term (1 month) PTU treatment on thyroid function in the rat, and correlated changes in thyroid function with serum and thyroid PTU levels. After 1 week, dose-dependent decreases in thyroid PBI, serum T4, and serum T3 were observed, with concomitant elevations in the serum rT3 to T4 ratio and serum TSH. Fifty percent suppression of thyroid PBI occurred at a PTU concentration in the drinking water of 0.0005% (ED50), with concomitant serum and thyroid PTU levels of 0.3 micrograms/ml and 300 ng/thyroid, respectively. After 1 month of PTU, serum T4 values were lower than after 1 week of treatment for all PTU concentrations, but values for the other thyroid functional variables were similar to those in the 1 week group at comparable PTU dosage. The PTU dose-response curve for thyroid PBI was similar to that seen after 1 week of treatment, with an ED50 of 0.0004%. After discontinuation of PTU treatment, PTU disappeared from serum in a biexponential fashion, with an early rapid distribution phase (t 1/2 = approximately 4 h) and a second slower elimination phase (t 1/2 = approximately 2.6 days). In the thyroid, an initial increase in PTU content was seen up to 18 h after PTU withdrawal; thereafter, thyroid PTU declined linearly, with a t 1/2 of 1.4 days in both groups. After PTU withdrawal, thyroid PBI recovered with a t 1/2 of 1.09 days after 1 week on PTU, but recovery was prolonged (t 1/2 = 2.8 days) after 1 month of treatment. Log thyroid PTU and log thyroid PBI were linearly related after PTU withdrawal (r = 0.97; P less than 0.001) after 1 week but not after 1 month. Serum T4 and serum T3 remained below control values for 2 days, but then rapidly normalized, with T3 values rising transiently above the control value. This rebound occurred at a time when PTU was still present within the thyroid, before thyroid PBI had returned to baseline. These data indicate a close inverse relationship between PTU dose and both thyroid hormone biosynthesis and peripheral T4 deiodination. In addition, short and long term PTU treatments have quantitatively similar effects on thyroid function, although recovery of thyroid function is prolonged after long term treatment. The biexponential disappearance of PTU from the serum is compatible with a two-compartment model of PTU distribution. The early increase in thyroid PTU after drug withdrawal is suggestive of an inhibitory effect of PTU upon its own uptake by the thyroid, whereas the faster disappearance of PTU from the thyroid than from serum is consistent with intrathyroid drug metabolism.

Use of adjunctive potassium iodide after radioactive iodine (131I) treatment of Graves' hyperthyroidism.

One hundred and nineteen patients with Graves' hyperthyroidism who were treated with 131I alone or 131I followed by potassium iodide (131I + KI) were studied retrospectively. Patients in both groups who required only a single dose of 131I for successful treatment of hyperthyroidism had similar age, gland size, 24-h radioactive iodine uptake, pretreatment serum T4 concentrations, and radioactive iodine treatment dose. Seven weeks after 131I, mean serum T4 concentrations were 12.3 +/- 6.1 micrograms/dl (mean +/- SD) in patients who received 131I alone and 8.0 +/- 3.9 micrograms/dl in patients who received 131I + KI (p less than 0.001). Sixty percent of the patients who received 131I + KI and remained euthyroid 1 yr after 131I treatment developed documented transient hypothyroidism while receiving KI (serum T4, 1.4 +/- 0.9 micrograms/dl). Patients with transient hypothyroidism receiving KI had larger estimated thyroid gland weights when hypothyroid than patients whose hypothyroidism was permanent (32 +/- 6 vs. 16 +/- 11 g; P less than 0.001). The overall incidence of hypothyroidism 1 yr after treatment with 131I was 58% in each of the two groups. Sixteen percent of each group were not successfully treated by a single dose of 131I and required further therapy. Adjunctive KI effectively treated thyrotoxicosis more rapidly than 131I alone without adversely affecting outcome at 1 yr; however, patients taking KI more often develop transient hypothyroidism.

Androgen and oestrogen dynamics in hyperthyroidism.

Using constant infusions of [3H]testosterone and [14C]oestradiol or [3H]androstenedione and [14C]oestrone the dynamics of androgen and oestrogen metabolism and production in patients with hyperthyroidism were measured. The metabolic clearance rates of testosterone and oestradiol were decreased but those of androstenedione and oestrone were within the normal range. The conversion ratios of testosterone to androstenedione and of testosterone to dihydrotestosterone (DHT) were decreased whereas those of androstenedione to testosterone and androstenedione to DHT were increased. These changes could be explained by increased serum levels of sex hormone binding globulin which binds testosterone and DHT but not androstenedione. The fraction of androstenedione infused into and measured as oestrone in the blood was normal in seven out of nine subjects and the fraction of testosterone infused and measured as oestradiol was normal in all nine subjects. The production rates of testosterone and oestradiol were in the normal range but the production rates of androstenedione and oestrone were raised in half the subjects.

The effect of thyroid hormones on prolactin secretion by cultured bovine pituitary cells.

The effect of thyroid hormones and thyrotropin releasing hormone (TRH) on prolactin (PRL) secretion has been studied using a primary calf anterior pituitary cell culture system. After mechanical and enzymatic dispersion, cultured pituitary cells were preincubated with T3 or T4 for 48 hr prior to a 24 hr experimental incubation. T3 stimulated the release of PRL into the medium in a dose-related fashion, with an ED50 of 3 nM; at 10 nM T3, a maximal 52 +/- 5% stimulation (p less than 0.001) was observed. T4 at 100 nM stimulated medium PRL 27 +/- 10% (p less than 0.05); the ED50 for T4 was 20 nM. Neither T3 nor T4 affected intracellular PRL content. The stimulation of medium PRL by T3 was observed in medium containing 10% euthyroid as well as 10% charcoal-stripped hypothyroid calf serum. The relative stimulation by TRH of PRL release into the medium was significantly diminished by 10 nM T3 in euthyroid and stripped hypothyroid serum medium, but only as a consequence of the stimulation of basal medium PRL by T3; there was no change in maximal TRH-stimulated PRL release. In medium supplemented with unstripped hypothyroid serum, however, T3 did decrease absolute TRH-stimulated PRL release.

Cardiac function in mild and severe primary hypothyroidism.

One hundred patients with mild to severe primary hypothyroidism have been analyzed for abnormalities in left ventricular performance utilizing noninvasive techniques. These studies have revealed significant abnormalities in cardiac function which correlated inversely with serum T4 levels. The abnormalities in cardiac function were completely reversible with thyroid hormone therapy. Even in patients with mild subclinical hypothyroidism, significant changes in left ventricular performance were achieved by doses of thyroid hormone which normalized TSH secretion. Therapy with either L-T4 or L-T3 resulted in normal cardiac function though L-T3 produced normal cardiac function on lower doses than were necessary to normalize TSH secretion. These studies are intended to provide new information on the optimal treatment of hypothyroidism.

Peripheral responses to thyroid hormone before and after L-thyroxine therapy in patients with subclinical hypothyroidism.

Twenty patients with serum levels of T4 and T3 within the normal range but with elevated serum concentrations of TSH were evaluated before and after treatment with L-T4. This therapy increased serum T4 (5.5 +/- 1.1 to 8.8 +/- 1.8 microgram/dl) and T3 (116 +/- 20 to 137 +/- 28 ng/dl) levels. Cardiac systolic time intervals (STI) were significantly (P less than 0.01) reduced by this therapy. The preejection period (123 +/- 18 to 114 +/- 14 msec; n = 12), the change in preejection period (+17 +/- 17 to +6 +/- 15 msec; n = 12), the ratio of preejection period to left ventricular ejection time (0.412 +/- 0.068 to 0.357 +/- 0.063 msec; n = 12), and the interval from the Q wave of the electrocardiogram to the pulse wave arrival time at the brachial artery (224 +/- 10 to 200 +/- 13 msec; n = 10) were consistently reduced. Cardiac STI were significantly correlated with serum TSH and T4 levels, but not with serum T3 levels. Normalization of serum TSH levels was associated with changes in QKd measurements even in those patients with minimal elevations in serum TSH. These studies demonstrate that patients having the combination of elevated TSH but T4 and T3 levels in the normal range have alterations in STI which can be changed significantly by L-T4 in doses which normalize TSH secretion. These data suggest that such patients have a mild form of primary hypothyroidism.

Nucleotide sequence of the mRNA encoding the pre-alpha-subunit of mouse thyrotropin.

We have constructed and cloned in bacteria recombinant DNA molecules containing DNA sequences coding for the precursor of the alpha subunit of thyrotropin (pre-TSH-alpha). Double-stranded DNA complementary to total poly(A)+RNA derived from a mouse pituitary thyrotropic tumor was prepared enzymatically, inserted into the Pst I site of the plasmid pBR322 by using poly(dC).poly(dG) homopolymeric extensions, and cloned in Escherichia coli chi 1776. Cloned cDNAs encoding pre-TSH-alpha were identified by their hybridization to pre-TSH-alpha mRNA as determined by cell-free translations of hybrid-selected and hybrid-arrested RNA. The nucleotide sequences of two cDNAs (510 and 480 base pairs) were determined with chemical methods and corresponded to much of the region coding for the alpha subunit and the 3' untranslated region of pre-TSH-alpha mRNA. The sequence of the 5' end of the mRNA was determined from cDNA synthesized by using total mRNA as template and a restriction enzyme DNA fragment as primer. Together these sequences represented greater than 90% of the coding and noncoding regions of full-length pre-TSH-alpha mRNA, which was determined to be 800 bases long. The amino acid sequence of the pre-TSH-alpha deduced from the nucleotide sequence showed a NH2-terminal leader sequence of 24 amino acids followed by the 96-amino-acid sequence of the apoprotein of TSH-alpha. There is greater than 90% homology in the amino acid sequences among the murine, ruminant, and porcine alpha subunits and 75-80% homology among the murine, equine, and human alpha subunits. Several regions of the sequence remain absolutely conserved among all species, suggesting that these particular regions are essential for the biological function of the subunit. The successful cloning of the alpha subunit of TSH will permit further studies of the organization of the genes coding for the glycoprotein hormone subunits and the regulation of their expression.

The effect of amoxapine and imipramine on serum prolactin levels.

The effect of traditional tricyclic antidepressants on serum prolactin levels is controversial. In a five-week double-blind study of depressed outpatients, imipramine hydrochloride therapy did not lead to any significant change in serum prolactin levels. In contrast, amoxapine, a new antidepressant, produced significant elevations in serum prolactin levels in female and in male patients. Amoxapine may block dopamine receptors in central tuberoinfundibular pathways, which would account for its prolactin-elevating activity. On the other hand, imipramine and other traditional tricyclic antidepressants do not affect dopamine transmission, do not raise serum prolactin levels, and are not effective antipsychotic drugs.