T3 levels in relation to prognostic factors in breast cancer: a population-based prospective cohort study.

BACKGROUND: The issue of a potential association between thyroid conditions/hormones and breast cancer has been studied extensively during the last decades but the results have been inconclusive and almost no studies have investigated breast cancer aggressiveness. We have previously found a positive association between prospectively measured levels of triiodothyronine (T3) and breast cancer incidence as well as breast cancer mortality. We now investigated prediagnostic T3 levels in relation to specific prognostic factors in breast cancer. METHODS: The Malmö Preventive Project is a population-based prospective cohort including 2185 women in whom T3 levels were measured at baseline. That is, total T3 levels were measured before a potential diagnosis of breast cancer. Mean follow-up was 23.3 years and 149 women in the study population were diagnosed with invasive breast cancer. Tumours were classified according to selected prognostic factors of breast cancer; i.e. grade, tumour size, lymph node metastasis, and hormonal receptor status. T3 was handled both as tertiles and as a continuous variable. A Cox's proportional hazards analysis yielded hazard ratios with 95% confidence intervals. All analyses were also restricted to postmenopausal women. RESULTS: Overall there was a statistically significant association between T3 and "all" breast cancers. The adjusted Hazard Ratio (HR) in the third tertile, as compared to the first, was (1.61:1.07-2.43). There was a statistically significant positive association between the third T3 tertile and large tumours, i.e. > 20 mm, (3.17:1.20-8.36) and the occurrence of lymph node metastases, (4.53:1.60-12.83). Other prognostic factors positively associated with T3 were negative oestrogen receptor (ER) status, (3.52:1.32-9.41) and negative progesterone receptor (PGR) status, (3.52:1.42-8.75). The analyses of T3 as a continuous variable and analysis restricted to postmenopausal women, confirmed the results but also showed an association with smaller tumours and in postmenopausal women a contemporary association with negative lymph nodes. CONCLUSIONS: This prospective study of serum T3 levels in relation to breast cancer aggressiveness is the first of its kind. We found statistically significant positive associations between higher prediagnostic T3 levels and larger tumours, occurrence of lymph node metastases, and negative ER and PGR status.

Triiodothyronine levels in relation to mortality from breast cancer and all causes: a population-based prospective cohort study.

OBJECTIVE: The potential association between thyroid hormones and breast cancer has been investigated in a large number of studies without conclusive results. This study investigated triiodothyronine (T3) levels in relation to breast cancer mortality in a population with no breast cancer patients at baseline. An additional aim was to study T3 levels in relation to mortality from other cancers and all-cause mortality. DESIGN AND METHODS: This was a population-based prospective cohort study including 2185 women in whom T3 levels were measured as part of a preventive health project, i.e. before diagnosis in women who later developed breast cancer. Mean follow-up was 24.1 years and record-linkage to The Swedish Cause-of-Death registry identified 471 women who died: 26 out of breast cancer and 182 from other cancers. Mortality was assessed using a Cox's analysis, yielding hazard ratios (HRs), with 95% confidence intervals. Analyses of T3 as a continuous variable were repeated for pre- and peri/postmenopausal women separately. RESULTS: T3 levels were positively associated with the risk of breast cancer-specific death in the age-adjusted analysis: HR for T3 as a continuous variable was 2.80 (1.26-6.25). However, the crude analysis did not reach statistical significance. Breast cancer mortality was even higher in postmenopausal women: 3.73 (1.69-8.22), but stratified analyses included few events. There were no statistically significant associations between T3 levels and deaths from other cancers, age-adjusted HR: 1.09 (0.72-1.65) or all-cause mortality (1.25:0.97-1.60). CONCLUSIONS: This study, the first of its kind on prospectively measured T3 levels, indicates that T3 levels are positively associated with breast cancer-specific mortality and that this is not related to a general effect on all-cause mortality.

Prospectively measured thyroid hormones and thyroid peroxidase antibodies in relation to breast cancer risk.

Thyroid hormones influence both normal breast cell differentiation and breast cancer cell proliferation and stimulate the angiogenesis of certain cancer forms. Several cross-sectional studies have measured thyroid hormones/autoantibodies in breast cancer ceases vs. controls, but it is difficult to determine the cause-effect direction in these studies. Only three prospective studies have reported on the subject so far. The aim of our study was to investigate prediagnostically measured levels of thyroid hormones, thyrotropin (TSH) and thyroid autoantibodies in relation to subsequent risk of breast cancer. The Malmoe Diet and Cancer study examined 17,035 women between 1991 and 1996. Blood samples were collected at baseline and free triiodothyronine (T3), free thyroxin (T4), TSH and thyroid peroxidase autoantibodies (TPO-Ab) levels were measured in 676 cases and 680 controls. Relative risks with 95% confidence intervals were assessed using a logistic regression analysis adjusted for potential confounders. Free T4 levels were positively associated with a high risk of breast cancer, and the OR for women with free T4 levels above vs. below the median was 1.40 (1.10-1.77). This association was most pronounced in overweight women (1.51:1.07-2.12). Women with high levels of TPO-Ab had a lower risk of breast cancer, but only the analysis of TPO-Ab as a continuous variable reached statistical significance. Free T4 was in our study positively associated with a high risk of breast cancer. This association was most pronounced in overweight/obese women. Women with a high level of TPO-Ab had a relatively low risk of breast cancer.

Prospectively measured triiodothyronine levels are positively associated with breast cancer risk in postmenopausal women.

INTRODUCTION: The potential association between hypo- and hyperthyroid disorders and breast cancer has been investigated in a large number of studies during the last decades without conclusive results. This prospective cohort study investigated prediagnostic levels of thyrotropin (TSH) and triiodothyronine (T3) in relation to breast cancer incidence in pre- and postmenopausal women. METHODS: In the Malmö Preventive Project, 2,696 women had T3 and/or TSH levels measured at baseline. During a mean follow-up of 19.3 years, 173 incident breast cancer cases were retrieved using record linkage with The Swedish Cancer Registry. Quartile cut-points for T3 and TSH were based on the distribution among all women in the study cohort. A Cox's proportional hazards analysis was used to estimate relative risks (RR), with a confidence interval (CI) of 95%. Trends over quartiles of T3 and TSH were calculated considering a P-value < 0.05 as statistically significant. All analyses were repeated for pre- and peri/postmenopausal women separately. RESULTS: Overall there was a statistically significant association between T3 and breast cancer risk, the adjusted RR in the fourth quartile, as compared to the first, was 1.87 (1.12 to 3.14). In postmenopausal women the RRs for the second, third and fourth quartiles, as compared to the first, were 3.26 (0.96 to 11.1), 5.53 (1.65 to 18.6) and 6.87 (2.09 to 22.6), (P-trend: < 0.001). There were no such associations in pre-menopausal women, and no statistically significant interaction between T3 and menopausal status. Also, no statistically significant association was seen between serum TSH and breast cancer. CONCLUSIONS: This is the first prospective study on T3 levels in relation to breast cancer risk. T3 levels in postmenopausal women were positively associated with the risk of breast cancer in a dose-response manner.

Levothyroxine treatment reduces thyroid size in children and adolescents with chronic autoimmune thyroiditis.

CONTEXT: The use of levothyroxine to reduce thyroid size in pediatric patients with goiter due to chronic autoimmune thyroiditis (AIT) remains controversial. In overtly hypothyroid patients, reductions in thyroid volume have been reported, whereas the effect in subclinically hypothyroid and euthyroid patients is less clear. OBJECTIVE: The objective of the study was to evaluate the effect of levothyroxine treatment on thyroid size (determined with thyroid ultrasonography) in children and adolescents with AIT. DESIGN AND SETTING: This study included patients with AIT treated at a university hospital outpatient clinic between 1987 and 2004. PATIENTS: Ninety children with AIT (73 girls and 17 boys, aged 6.1-17.7 yr) were included in the study. INTERVENTION: Intervention was treatment with levothyroxine for a median 2.8 yr (range 0.5-10.2). MAIN OUTCOME MEASURE: Change in thyroid volume sd score (SDS) during the study period was measured. RESULTS: Median thyroid volume SDS was reduced in patients euthyroid (-0.4 SDS, P < 0.001), subclinically hypothyroid (-1.4 SDS, P < 0.001), and overtly hypothyroid (-1.8 SDS, P < 0.002) at diagnosis of AIT. Both hypothyroid and euthyroid patients with goiter (thyroid volume > 2.0 SDS) at baseline reduced their median thyroid volume SDS (-1.6 and -0.9, respectively, P < 0.001). Hypothyroid patients without goiter also reduced median thyroid volume SDS (-1.2, P < 0.004), whereas no change was noticed in euthyroid children without goiter. CONCLUSIONS: Levothyroxine treatment is effective in reducing thyroid volume in pediatric patients and is suggested in treatment of goiter caused by AIT, especially in cases of hypothyroid, but also in euthyroid children.

Thyroid autoantibodies in cord blood sera from children and adolescents with autoimmune thyroiditis.

Autoimmune thyroid disease is common among women of childbearing age. Thyroid autoantibodies are predominantly of the immunoglobulin G (IgG)-type and pass the placental barrier from mother to child. Recent studies have suggested a pathogenetic role for transplacentally transmitted autoantibodies in the development of autoimmune disease. The aim of the present study was to investigate if children and adolescents with autoimmune thyroiditis (AIT) have been exposed to thyroid autoantibodies already in utero. Cord blood sera taken at delivery from 34 newborns who had developed AIT during childhood and adolescence, and sera from 31 of their mothers, were analyzed for the presence of autoantibodies against thyroid peroxidase (TPOAb) and thyroglobulin (TgAb), and compared to 233 randomly selected control children and their mothers. The prevalence of TPOAb in cord blood sera was elevated among the children and adolescents with AIT compared to controls (38% versus 14%; odds ratio [OR] 4.12, p < 0.001). An increased prevalence of TPOAb was also found among their mothers (29% versus 15%; OR 2.17, p < 0.048). No significant difference in the prevalence of TgAb was found either between children with AIT and the control children (18% versus 9%; OR 2.16, p < 0.15), or between their mothers and the control mothers (23% versus 12%; OR 2.17, p < 0.16). Most of the TPOAb-positive children had TPOAb-positive mothers, indicating the maternal origin of their TPOAb. In conclusion, a large proportion of children who later developed AIT had already been exposed to transplacentally transmitted TPOAb in utero. Whether these autoantibodies have any pathogenetic role in the development of AIT in offspring or if they simply mirror the inheritance of AIT, remains to be investigated.

Intrauterine exposure to maternal enterovirus infection as a risk factor for development of autoimmune thyroiditis during childhood and adolescence.

Maternal intrauterine enterovirus infection during pregnancy increases the risk for the offspring to develop type 1 diabetes mellitus. Type 1 diabetes mellitus and autoimmune thyroiditits (AIT) are closely linked. A common pathogenetic factor is possible. The objective of this study was to investigate a possible association between maternal enterovirus infection during pregnancy and the development of AIT in the offspring. Sera taken at delivery from 31 mothers whose children subsequently developed AIT was analyzed for immunoglobulin (Ig)A, IgG, and IgM antibodies against enterovirus, and compared to a control group comprising 233 randomly selected maternal sera. Of the mothers whose children developed AIT, 5 of 31 (16%) were enterovirus IgM-positive, compared to 17 of 233 (7%) in the control group (p = 0.16). The age at diagnosis of AIT was significantly lower in the group of children with IgM-positive mothers compared to children with IgM-negative mothers (p < 0.05). In addition, 3 children (60%) in the IgM-positive group were overtly hypothyroid at diagnosis of AIT, compared to no child (0%) in the IgM-negative group (p < 0.01). No significant differences were found in IgA and IgG antibody titers between the mothers whose children developed AIT and the control group. Although this study did not have enough power to reveal intrauterine exposure to maternal enterovirus infection during pregnancy as a risk factor for development of AIT during childhood and adolescence, it suggested an association with earlier onset of clinical disease in children to enterovirus IgM-seropositive mothers.