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.

The association between the IGF-I axis, thyroid hormones and cortical bone in patients with mild primary hyperparathyroidism.

OBJECTIVES: Primary hyperparathyroidism (PHPT) is associated with low bone mineral density (BMD) and increased risk of osteoporotic fractures. This study investigated whether the IGF-I axis and thyroid hormones are associated with BMD and osteoporotic fractures before and after parathyroidectomy (PTX). MATERIALS AND METHODS: Forty-five patients with mild PHPT were examined before and 1 year after PTX. Circulating concentrations of IGF-1, IGFBP-3, and thyroid hormones were measured and related to BMD in hip and lumbar (L:2-L:4) spine. RESULTS: Serum IGFBP-3 concentration decreased 1 year after PTX (p < 0.01), whereas serum IGF-1 and thyroid hormone concentrations were unchanged. Serum IGF1 concentration correlated positively with IGFBP-3 concentration (p < 0.0001) and BMD in the femoral neck (p < 0.05), both pre- and postoperatively. Serum IGFBP-3 concentration correlated positively with BMD in the femoral neck postoperatively (p < 0.05). Serum TSH correlated positively, and free thyroxine (T4) negatively, with all measures of hip BMD at baseline. Patients suffering from previous osteoporotic fractures before inclusion had lower serum TSH concentration compared to patients without fractures (p < 0.01). CONCLUSION: Serum IGFBP-3 concentration decreased after successful PTX in patients with mild PHPT, while serum IGF1 and thyroid hormone concentrations were unchanged. Both the IGF-I axis and thyroid hormones associated with cortical bone as serum IGF-1 and IGFBP-3 concentrations correlated positively, and free T4 negatively with hip BMD. Moreover, serum TSH concentration was reduced in patients with previous osteoporotic fractures.

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.

Adrenergic and cardiac dysfunction in primary hyperparathyroidism.

OBJECTIVE: Primary hyperparathyroidism (PHPT) is associated with cardiovascular morbidity and premature death, but the underlying mechanisms are incompletely understood. The aim of this study was to investigate whether adrenergic dysfunction may be a contributing factor. PATIENTS AND METHODS: Forty-nine patients with mild PHPT (serum calcium 2·7 ± 0·1 mM) and 48 control subjects, matched for age and sex, were examined; patients within 1 month before parathyroidectomy (PTX) and 6 months postoperatively; control subjects at inclusion. Heart rate variability (HRV) was analysed in 24-h electrocardiograms, and plasma concentrations of epinephrine and norepinephrine were measured at rest and immediately after standardized physical tests. RESULTS: At baseline, the patients showed, compared to the controls, reduced stress-related increase of circulating epinephrine (P < 0·05) and norepinephrine (P < 0·05). No significant change was observed 6 months after PTX. At baseline, there were no significant differences between patients and controls in HRV or heart rate, but 6 months after curative PTX, the patients showed significantly reduced HRV in both frequency and time domain, and their maximum and average heart rate had decreased (P = 0·011 and P = 0·018, respectively). The patients with the highest preoperative levels of circulating parathyroid hormone showed the greatest changes in heart rate and HRV postoperatively. CONCLUSIONS: This study demonstrates a previously unknown impairment of catecholamine response to physical stress in PHPT along with changes of HRV, also indicating adrenergic dysfunction. These factors should be considered in the ongoing controversy regarding the management of patients with mild 'asymptomatic' PHPT.

Factors influencing insulin sensitivity in patients with mild primary hyperparathyroidism before and after parathyroidectomy.

OBJECTIVES: Primary hyperparathyroidism (PHPT) is associated with cardiovascular disease. The aims of this study were to investigate lipid and glucose metabolism in mild PHPT, and to identify whether insulin sensitivity correlates with circulating levels of adiponectin, SHBG, and osteocalcin before and after parathyroidectomy (PTX). MATERIALS AND METHODS: Forty-five patients with PHPT were examined before and 1 year after PTX. Circulating levels of triglycerides, total cholesterol, HDL-cholesterol, insulin, glucose, adiponectin, SHBG, osteocalcin, and erythropoietin were measured. RESULTS: At baseline, the mean serum levels of total cholesterol, LDL-cholesterol and triglycerides were above the upper reference limit or in the upper normal range, and insulin sensitivity was reduced as assessed using the HOMA index. One year after parathyroidectomy, serum lipids as well as HOMA index and erythropoietin were unchanged while adiponectin had increased (p < 0.05), and SHBG and osteocalcin had decreased (p < 0.05 and p < 0.0001, respectively). HOMA index correlated negatively with circulating levels of adiponectin, SHBG and osteocalcin. In multiple regression analysis SHBG was the most important predictor of insulin sensitivity, both pre- and postoperatively. CONCLUSION: Untreated mild PHPT is associated with a moderate derangement of lipid and glucose metabolism. As previously shown in population-based cohorts, insulin sensitivity is positively associated with circulating concentrations of adiponectin, SHBG and osteocalcin. One year after PTX, the mean level of adiponectin was increased, but the levels of SHBG and osteocalcin had decreased and the levels of serum lipids and the insulin sensitivity remained unchanged as compared with baseline.

Increased markers of inflammation and endothelial dysfunction in patients with mild primary hyperparathyroidism.

OBJECTIVES: The association between primary hyperparathyroidism (PHPT) and cardiovascular disease is incompletely understood. The aims of this study were to evaluate how cardiac function and markers of inflammation and endothelial dysfunction correlate in patients with mild PHPT, and how these markers are influenced by surgical cure of the parathyroid disease (PTX). MATERIAL AND METHODS: Forty-five patients with PHPT were examined before and 1 year after PTX. Serum/plasma concentrations of calcium, PTH, highly sensitive C-reactive protein (CRP), interleukin-6 (IL-6), vascular adhesion molecule-1 (VCAM1), E-selectin, and NT-proBNP were measured as well as erythrocyte sedimentation rate (ESR) and creatinine clearance. Cardiac function was evaluated by equilibrium radionuclide angiography. RESULTS: The baseline serum level of IL-6 correlated negatively with baseline parameters of cardiac function (exercise capacity, p < 0.001, left ventricular ejection fraction at exercise, p < 0.01). The mean serum concentrations of IL-6 and CRP and the ESR had increased 1 year after PTX (p < 0.001, p < 0.01, and p < 0.001, respectively) in parallel with a decrease in cardiac function and an increase in circulating NT-proBNP. The mean serum level of VCAM1 was above the upper normal range at baseline and had not changed significantly 1 year after PTX. CONCLUSION: Patients with mild PHPT and normal renal function displayed signs of subclinical inflammation and endothelial dysfunction. One year after PTX, the inflammatory markers were increased in parallel with a subclinical decrease in cardiac function. Further studies are warranted to clarify the natural course and clinical implications of these changes.

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.

Serum levels of vitamin D, PTH and calcium and breast cancer risk-a prospective nested case-control study.

Previous studies indicate that calcium and its regulating hormones, i.e., parathyroid hormone (PTH) and vitamin D, might affect breast cancer risk. Evidence also suggests that this relationship could be influenced by menopausal status and BMI. We examined breast cancer risk related to prediagnostic serum levels of vitamin D (25OHD(2) and 25OHD(3)), PTH and calcium using a nested case-control design within the Malmö Diet and Cancer Study. There were 764 incident breast cancer cases, and 764 controls were selected by incidence density matching, using age as the underlying time scale, matching on calendar time at inclusion, menopausal status and age at inclusion. Using logistic regression analysis, odds ratios (OR) with 95% confidence intervals were calculated for breast cancer risk in different quartiles of the analyzed factors. All analyses were adjusted for risk factors for breast cancer, and for levels of albumin, creatinine and phosphate. Analyses were repeated stratified for BMI and menopausal status, and for low vs. high levels of 25OHD(3), PTH and calcium. There was a weak, nonsignificant inverse association between breast cancer risk and 25OHD(3), and the OR for the 2nd, 3rd and 4th quartiles, as compared to the first, were 0.84 (0.60-1.15), 0.84 (0.60-1.17) and 0.93 (0.66-1.33). Serum calcium was positively associated with breast cancer in premenopausal women (OR for the 4th quartile = 3.10:1.33-7.22 and p for quartile trend = 0.04), and in women with BMI > 25 (OR for the 4th quartile = 1.94:1.12-3.37 and p for trend < 0.01). There was no association between baseline serum PTH and breast cancer risk.

Reproductive history, lifestyle factors and season as determinants for serum calcium concentrations in women.

OBJECTIVE: Serum calcium concentrations have been associated with the risk of malignant disease, especially breast cancer. Thus, determinants of serum calcium concentrations, with special regard to risk factors of breast cancer, are of great interest. MATERIAL AND METHODS: Previous studies have either been small or they have not focused on reproductive factors. The present study examined serum calcium concentrations in relation to reproductive history, selected lifestyle factors and screening season in a large population-based cohort study comprising 8,114 women. ANOVA followed by the Bonferroni t-test were used for comparison of means, and logistic regression and multiple regression analysis were used to test associations. RESULTS: Serum calcium concentrations were lower in hormone replacement therapy users versus non-users (2.321 mmol/L versus 2.364; p<0.001) and in users of oral contraceptives versus non-users (2.304 versus 2.348; p<0.001). They were higher in peri-/postmenopausal versus premenopausal women (2.357 versus 2.319; p<0.001). Overweight and obese women had higher mean calcium concentrations (2.350 and 2.355) than women with body mass index between 20 and 25 (2.342; p<0.001). Serum calcium concentrations were higher in spring and autumn than in winter (2.352 and 2.353 versus 2.343; p = 0.002). Both younger (40-45 years) (2.334; p = 0.001) and older age groups (>55 years) (2.363; p<0.001) had higher mean calcium concentrations compared to those of women aged 45-50 years (2.320), even when adjusting for menopausal status, suggesting that age has an independent influence on calcium concentrations. CONCLUSIONS: It is concluded that reproductive factors such as menopausal status, use of oral contraceptives or hormone-replacement therapy, and age, BMI and season are associated with serum calcium concentrations.

Variation in the adiponutrin gene influences its expression and associates with obesity.

Adiponutrin is one of three recently identified adipocyte lipases. Surprisingly, these proteins also retain transacylase activity, a hitherto unknown pathway of triacylglycerol synthesis in the adipocytes. This may enable them to participate in both anabolic and catabolic processes. The adiponutrin gene (ADPN) is downregulated by fasting and upregulated by refeeding, suggesting a role in lipogenesis. Experiments in human adipocytes confirmed that the gene is upregulated in response to insulin in a glucose-dependent fashion. Obese subjects had increased levels of subcutaneous and visceral abdominal adipose tissue ADPN mRNA. Visceral ADPN mRNA expression was correlated to measures of insulin sensitivity (fasting insulin and homeostasis model assessment). We also studied genetic variation in ADPN and its relation to obesity, lipolysis, and mRNA expression. Two ADPN polymorphisms showed association with obesity. Carriers of the obesity-associated variants showed a lesser increase in the levels of adipose tissue ADPN mRNA and an increased basal lipolysis. Our results suggest that obese subjects that are insulin resistant and/or carriers of the obesity-associated ADPN alleles fail to upregulate the gene and that upregulation of adiponutrin may be an appropriate response to orchestrate energy excess.

Thyrostimulin (a TSH-like Hormone) expression in orbital and thyroid tissue.

OBJECTIVE: To investigate gene expression of thyrostimulin in orbital and thyroid tissue from patients with and without Graves' disease. DESIGN: Real-time reverse transcriptase polymerase chain reaction (RT-PCR) was used for detection of thyrostimulin gene expression in intraorbital adipose tissue from patients with severe ophthalmopathy and thyroid healthy controls in addition to thyrostimulin expression in normal thyroid tissue, multinodular goiter tissue, and Graves' thyroid tissue. MAIN OUTCOME: In intraorbital tissue, thyrostimulin expression was identified in both patients and controls with fluorescence intensities varying between 0.23 and 0.88 in patients and 0.29 and 8.9 in controls before treatment with DNase. The signal of thyrostimulin was weak or absent in intraorbital adipose tissue from patients with ophthalmopathy and thyroid healthy controls after treatment of samples with DNase. This was in contrast to the expression of the thyroid-stimulating hormone (TSH) receptor and the housekeeping gene cyclophilin A that were detected both before and after DNase treatment. Similar results were found when analyzing human and rat thyroid tissue. CONCLUSIONS: Neither did we demonstrate gene expression of thyrostimulin in intraorbital adipose tissue or in thyroid tissue, nor could we confirm earlier findings in rat thyroid tissue. Whether thyrostimulin is a regulator of thyroid function has to be further investigated in future studies.

Early parathyroidectomy increases bone mineral density in patients with mild primary hyperparathyroidism: a prospective and randomized study.

BACKGROUND: There is an ongoing controversy regarding how to take care of patients with mild primary hyperparathyroidism (PHPT) and how to grade their disease activity in terms of bone parameters. This prospective and randomized study was undertaken to evaluate skeletal effects of delayed surgical treatment in such patients. METHODS: Fifty patients with mild PHPT (serum calcium, 2.55 to 2.95 mmol/L; 10.2 to 11.8 mg/dL) were randomized to parathyroidectomy either at diagnosis or 1 year later. Hip and spine bone mineral density (BMD, determined by dual energy x-ray absorptiometry), bone alkaline phosphatase in serum, osteocalcin and beta-CrossLaps in plasma, and calcium in urine were measured in all patients at inclusion in the study and 1 and 2 years later. RESULTS: The skeletal effects of mild PHPT varied with anatomy and time of exposure. Parathyroidectomy decreased all biochemical bone markers ( P < .0001) and increased lumbar spine BMD ( P < .05) equally in both groups, even in patients without overt osteoporosis, whereas hip BMD was increased ( P < .05) in the early intervention group only. CONCLUSION: Prolonged exposure to mild and seemingly stable PHPT is a risk factor for hip fractures, which adds to other reasons for surgical treatment of this condition without delay regardless of serum calcium levels.

Cardiac dysfunction in mild primary hyperparathyroidism assessed by radionuclide angiography and echocardiography before and after parathyroidectomy.

BACKGROUND: Primary hyperparathyroidism (PHPT) is associated with increased cardiovascular morbidity for reasons that are incompletely understood. The present study was undertaken to evaluate the effects of parathyroidectomy on cardiac function especially in patients with mild PHPT. METHODS; Fifty patients with mild PHPT (serum calcium, 2.55 to 2.95 mmol/L) were randomized to parathyroidectomy either directly (group A) or after 1 year of observation (group B). Equilibrium radionuclide angiography (ERNA) at rest and at exercise was performed in addition to echocardiography on all patients at inclusion in the study and 1 and 2 years later. RESULTS: Left ventricular mass index was larger (P <.05) in group B compared with group A after 2 years and showed significant correlation to the serum concentration of parathyroid hormone (but not serum calcium) after 1 year. ERNA showed transient subclinical changes in both systolic and diastolic function parameters after parathyroidectomy (decrease of left ventricular ejection fraction and peak filling rate, with return to preoperative levels within 1 year). CONCLUSIONS: Combined evaluation by ERNA and echocardiography has shown previously unknown aspects of parathyroid/myocardial interaction, which is consistent with an inotropic influence exerted by parathyroid hormone, and is in favor of early surgical treatment for PHPT irrespective of serum calcium levels.

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.

Effect of successful parathyroidectomy on 24-hour ambulatory blood pressure in patients with primary hyperparathyroidism.

OBJECTIVE: The pathogenesis of hypertension in patients with primary hyperparathyroidism (PHPT) is unclear, and the prevailing opinion is that parathyroidectomy does not affect the blood pressure (BP). Most previous studies have been based on BP measurements at rest in a clinical setting. The aim of this study was to get additional information by 24-hour ambulatory measurements. DESIGN AND PATIENTS: Forty-nine consecutive patients with PHPT (age 63+/-12 years, 44 women) were examined before and 6 months after curative parathyroid surgery. MEASUREMENTS: Serum concentrations of calcium and PTH, and 24-hour ambulatory mean, minimum, and maximum systolic (S) and diastolic BP, and mean arterial BP. RESULTS: On average, the patients showed no BP change after parathyroidectomy. However, those with a history of hypertension (n=20) showed generally increased BP values after parathyroidectomy, with significantly increased minimum and average SBP (P=0.02 and P=0.04, respectively), whereas patients without a history of hypertension (n=29) showed unchanged or slightly reduced BP values after parathyroidectomy, with significantly decreased maximum SBP (P=0.04). Serum concentrations of PTH and calcium were not significantly related to any of the BP variables measured. CONCLUSIONS: The novel finding that patients with both PHPT and hypertension may show increased BP after parathyroidectomy warrants intensified BP control postoperatively in these patients, and motivates early treatment of PHPT in order to prevent the development of complicating hypertension.

Serum calcium and tumour aggressiveness in breast cancer: a prospective study of 7847 women.

Experimental, epidemiological and clinical studies suggest that calcium and/or its regulating hormones affect breast cancer risk. There has been no prospective cohort study investigating serum calcium levels and breast cancer aggressiveness, as determined by tumour histology and stage. Dichotomized prediagnostic serum calcium levels were investigated in relation to breast cancer aggressiveness as determined by grade (mitotic frequency, tubule formation, nuclear atypia) and stage (tumour size and axillary lymph node status). Cox's proportional hazards analysis and heterogeneity analysis were used to investigate the associations between low/high calcium and grade/stage in a prospective cohort study of 7847 women, out of whom 462 women were diagnosed with incident breast cancer during a mean follow-up of 17.2 years. All analyses were stratified for body mass index and menopausal status. Prediagnostic serum calcium levels in premenopausal women were positively associated with increased tumour aggressiveness as determined by a higher risk of nodal metastasis; relative risk (RR) for calcium above median as compared with calcium below median was 1.88 with a 95% confidence interval (CI) of 1.04-3.38. In overweight women, prediagnostic serum calcium levels were also associated with tumour aggressiveness, as determined by both a higher risk of nodal metastasis [RR (95% CI) 1.69 (0.95-3.02)] and severe nuclear atypia [RR (95% CI) 2.06 (1.10-3.86)]. Results also indicate that, in overweight women, calcium is positively associated with worse grade as determined by tubule formation and mitotic frequency. In conclusion, prediagnostic serum calcium levels are positively associated with increased tumour aggressiveness in premenopausal and/or overweight women.

Serum calcium and breast cancer risk: results from a prospective cohort study of 7,847 women.

Experimental and epidemiological studies suggest that calcium-regulating hormones--parathyroid hormone (PTH) and vitamin D--may be associated with breast cancer risk. No prospective cohort study has investigated the association between pre-diagnostic calcium levels and subsequent risk of breast cancer. We have examined this in a cohort of 7,847 women where serum calcium levels and established risk factors for breast cancer had been assessed at baseline. During a mean follow-up of 17.8 years, 437 incident breast cancer cases were diagnosed. Incidence of breast cancer was calculated in different quartiles of serum calcium levels and a Cox's proportional hazards analysis was used to obtain corresponding relative risks (RR), with a 95% confidence interval (CI), adjusted for potential confounders. In premenopausal women, serum calcium levels were inversely associated with breast cancer risk in a dose-response manner. The adjusted RR (95% CI) of breast cancer was in the 2nd calcium quartile 0.91 (0.65-1.30), in the 3rd quartile 0.89 (0.60-1.31), and in the 4th quartile 0.56 (0.32-0.98), as compared to the 1st calcium quartile. In postmenopausal overweight women (BMI > 25), breast cancer risk was higher in calcium quartiles 2-4 as compared to the 1st quartile. Our findings may have implications for primary prevention of breast cancer and for the management of asymptomatic primary hyperparathyroidism.

Increase of bioavailable testosterone is associated with gain in bone mineral density after cure of primary hyperparathyroidism in postmenopausal women.

OBJECTIVE: The recovery of bone mineral density (BMD) after surgical cure of primary hyperparathyroidism (PHPT) seems to be multifactorial and not just dependent on declining PTH. The aim of the present study was to evaluate the role of sex steroids in this context. DESIGN AND PATIENTS: Thirty-six postmenopausal women with PHPT were examined before and 1 year after curative parathyroidectomy. Their mean age at inclusion in the study was 71.7 +/- 1.1 years (range 54-83). BMD was measured in hip and lumbar spine using dual energy X-ray absorptiometry. No patient received any replacement therapy with sex hormones or treatment with corticosteroids, oestrogen receptor modulators or bisphosphonates. MEASUREMENTS: Serum concentrations of oestradiol, testosterone, androstenedione, dehydroepiandrosterone sulphate, SHBG, PTH and calcium. RESULTS: Postoperative increase of free (bioavailable) testosterone was positively correlated to the change of BMD in the hip (P < 0.01), whereas the change of PTH in serum correlated to the change of BMD in the lumbar spine (P < 0.05). Multiple regression analysis showed that bioavailable testosterone was the most important determinant of change in BMD in both spine and hip (femoral neck: P < 0.05; Ward's triangle: P < 0.001; trochanter: P < 0.01; lumbar spine: P < 0.05). The increase of bioavailable testosterone after curative parathyroidectomy was related to declining SHBG. CONCLUSIONS: An increase of bioavailable testosterone following surgical cure of PHPT is related to improvement of hip and lumbar spine BMD in postmenopausal women. This previously unknown hormonal interaction may also be important to other aspects of hyperparathyroidism.