Graves' disease (GD) is an autoimmune thyroid disease. Multiple genetic factors are believed to be involved in its pathogenesis, but the factors are largely unknown, except for sex (female disease preponderance) and the role of human leukocyte antigen (HLA) genes on chromosome 6. To understand the mechanisms underlying the development of GD, a search for non-HLA-linked genes is crucial, and we tested several candidate genes, including the CTLA-4 gene on chromosome 2q33. CTLA-4 molecules may either facilitate or down-regulate the second signal to T-cells, which is provided by the interaction between the two accessory molecules CD28 and B7. One hundred and thirty-three Caucasian patients (26 males) with GD and 85 local controls were included in this study. Polymerase chain reaction was used to amplify DNA containing the (AT)n repeat within the 3'-untranslated region of exon 3 of the CTLA-4 gene. The 5'-forward primer was radiolabeled, and amplified products were resolved on 5-7% sequencing gels. All subjects were previously typed for HLA class II alleles. Twenty-one alleles were observed with sizes ranging from 88-134 basepairs. In the association analysis, the genotype frequencies between GD patients and controls differed significantly (P = 0.012), and the difference was attributable to a higher frequency of the 106-basepair allele among patients (relative risk, 2.82). When the patients were subdivided with respect to sex and HLA, the phenotype frequencies of allele 106 was higher in the female patients with protective HLA specificities (DQA1*0201 positive/DQA1*0501 negative) than in those with susceptible HLA specificities (DQA1*0201 negative/DQA1*0501 positive; 81.8% vs. 45.5%; P = 0.026). The CTLA-4 gene or a closely associated gene (including CD28) confers susceptibility to GD. This association may be more important in female patients with protective HLA specificities, who otherwise would be at low risk of developing the disease.

Our aim was to assess testicular function in patients treated with high-dose radioiodine. Luteinizing hormone (LH), follicle-stimulating hormone (FSH), and testosterone levels were determined in 52 men with thyroid carcinoma before and 6, 12, and 18 months after radioiodine therapy (3.7-5.5 GBq 131 I; mean, 4.25 GBq 131 I) (group 1) and were also determined before and 18 months after the last radioiodine therapy in 22 patients who received high cumulative activities (13-27.7 GBq; mean, 20.3 GBq 131 I) (group 2). FSH levels were increased 6 months after therapy in all patients of group 1, while a decline was observed after 12 months, with 37 of 52 (71%) subjects presenting normal values. FSH values returned to normal after 18 months in all patients. In group 2, 12 of 22 (54.5%) patients presented elevated FSH and 8 (66%) of these individuals had oligospermia. Six months after radioiodine, increased LH levels were observed in only 5 of 52 (9.6%) patients of group 1, which returned to normal after 12 months, and in 5 of 22 (22%) of group 2. All patients showed normal testosterone levels. We conclude that 131 I therapy may cause impairment of testicular function. A generally transient increase in FSH is highly common but is usually reversed within 18 months. Oligospermia was common (one third) after high cumulative 131 I activities. Becausee we did not perform a spermiogram before therapy, we cannot state that high cumulative 131 I activities cause permanent infertility. We recommend the routine use of sperm banks in the cases of men who still wish to have children and who will undergo therapy with 131 I activities of 14 GBq or more or in the case of patients with pelvic metastases. 667

Radioiodine causes transitory alterations in ovarian function even in younger women and after a mean activity of 4.2 GBq (115 mCi).

Patients who have undergone thyroidectomy for thyroid carcinoma are frequently subjected to periods of induced severe hypothyroidism in preparation for 131I whole body scanning and measurement of serum TG. These two tests are crucial in evaluating the patient's clinical status and determining administration of 131I or other necessary treatment. Severe hypothyroidism produces fatigue, weight gain, depression, inability to carry out usual activities, and occasionally significant illness. We compared the efficacy of inducing moderate hypothyroidism by cutting replacement therapy in half, to a standard method. In the standard preparation, patients substituted triiodothyronine for thyroxine replacement over a 3-week period, and then omitted hormone therapy for 3 weeks. For the subsequent scan, 6 to 12 months later, the thyroxine dosage was cut in half. TSH levels were assessed 4 weeks later, and if adequately elevated, whole body scanning was conducted at the end of the fifth week. Pulse, weight, clinical symptoms, thyroid hormone levels, and some clinical chemistries were evaluated prior to each scan, and some of the tests were also carried out during the interval between scans. Moderate hypothyroidism induced by the half-dose protocol induced TSH elevations above the target level (25-30 microU/mL) at 5 weeks in most patients. Typically TSH of 15 microU/mL in the previous week predicted adequate elevation of TSH at the time of scan. Half dose therapy can be prolonged, if necessary, especially in patients who begin with extreme suppression of TSH, or if a higher TSH is desired. Pulse, weight gain, and cholesterol were significantly different in the two protocols, and the patient's subjective evaluation of hypothyroid symptoms was significantly reduced. Reduction of thyroxine replacement dosage to half the usual amount, in patients with thyroid cancer, allows after 5 weeks in most patients sufficient elevation of TSH for whole body scanning and measurement of TG levels. This simple and economical procedure drastically reduces symptomatology of hypothyroidism and makes this key procedure much more tolerable to patients.

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