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J Bohm, VM Kosma, M Eskelinen, S Hollmen, M Niskanen, H Tulla, E Alhava, and L Niskanen

OBJECTIVE: Although in most cases differentiated thyroid carcinoma (DTC) responds to surgery and radioiodine (RaI) therapy, some patients will have recurrence and eventually cancer-related death. However, although various prognostic factors of DTC have been identified (e.g. staging, suppressed thyrotropin), none of the previous studies have assessed simultaneously their role in multivariate analysis. DESIGN AND METHODS: In this retrospective population-based study, we reviewed the clinicopathological data of 254 DTC patients treated in eastern Finland during the years 1976-1995, for clinical characteristics, primary treatment, follow-up and cancer recurrence. Tumor stage was based on pathological tumor-node-metastasis (pTNM) classification, and histopathological specimens were re-evaluated. RESULTS: DTC recurrence occurred in 33 patients (13%). In univariate analyses, the predictors of recurrence were older age (>60 years, P<0.05), follicular tumor type (P<0.01), pTNM classification system (P<0.05) and post-ablative radioiodine uptake outside the neck (P<0.05). Non-suppressed serum thyrotropin (TSH) and elevated serum thyroglobulin (>3 microg/l) measured one year after operation were both related to tumor recurrence (P<0.05 and P<0.001 respectively). In multivariate analysis the independent predictors for recurrence were both elevated thyroglobulin (P<0.001) and non-suppressed TSH (P<0.05) independent of histology, pTNM stage and RaI uptake. Adjusted risk ratio for recurrence of DTC for unsuppressed thyrotropin was 2.3, for elevated thyroglobulin 14.0 and, if both conditions were present, the risk ratio increased to 45.1. CONCLUSION: Our results suggest that both non-suppressed serum TSH and elevated serum thyroglobulin are related to an increased risk of DTC recurrence independent of tumor type and pTNM stage.

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DE Laaksonen, L Niskanen, K Punnonen, K Nyyssonen, TP Tuomainen, R Salonen, R Rauramaa, and JT Salonen

OBJECTIVE: Mild hypoandrogenism in men is associated with features of the metabolic syndrome, but the association with the metabolic syndrome itself using an accepted definition has not been described. DESIGN: Men with the metabolic syndrome were identified and testosterone and sex hormone-binding globulin (SHBG) levels were determined in a population-based cohort of 1896 non-diabetic middle-aged Finnish men. RESULTS: Calculated free testosterone and SHBG were 11% and 18% lower (P<0.001) in men with the metabolic syndrome (n=345, World Health Organisation definition). After categorisation by tertiles and adjusting for age and body mass index, total and free testosterone and SHBG were inversely associated with concentrations of insulin, glucose, triglycerides, C-reactive protein (CRP) and CRP-adjusted ferritin and positively associated with high-density lipoprotein cholesterol. Men with free testosterone levels in the lowest third were 2.7 (95% confidence interval (CI) 2.0-3.7) times more likely to have the metabolic syndrome in age-adjusted analyses, and 1.7 (95% CI 1.2-2.4) times more likely even after further adjusting for body mass index. Exclusion of men with cardiovascular disease did not alter the association. The inverse association of SHBG with the metabolic syndrome was somewhat stronger. CONCLUSIONS: Low testosterone and SHBG levels were strongly associated not only with components of the metabolic syndrome, but also with the metabolic syndrome itself, independently of body mass index. Furthermore, sex hormones were associated with inflammation and body iron stores. Even in the absence of late-stage consequences such as diabetes and cardiovascular disease, subtle derangements in sex hormones are present in the metabolic syndrome, and may contribute to its pathogenesis.

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IK Vauhkonen, LK Niskanen, L Mykkanen, SM Haffner, MI Uusitupa, and M Laakso

OBJECTIVE: The purpose of this work was to study whether there are differences in plasma proinsulin levels and proinsulin-to-specific insulin ratio in the offspring of patients with different phenotypes of type II diabetes. DESIGN: Eleven glucose-tolerant offspring of type II diabetic patients with deficient insulin secretion phenotype (IS group), nine glucose-tolerant offspring of patients with insulin-resistant phenotype (IR group), and fourteen healthy control subjects without a family history of diabetes were studied. METHODS: Plasma specific insulin, plasma proinsulin, and plasma C-peptide levels were measured during a 2-h oral glucose tolerance test and during hyperglycemic clamp. RESULTS: Plasma proinsulin levels during the oral glucose tolerance test and the hyperglycemic clamp did not differ among the study groups. The IR group had a lower fasting plasma proinsulin-to-specific insulin ratio (10.3+/-1.7%) than the control group (15.4+/-1.4%; P<0.05) and the IS group (18.6+/-2.7%; P<0.05). Furthermore, the IR group had lower plasma proinsulin-to-specific insulin ratio at 30, 60 and 90 min after the oral glucose load than the IS group. However, there were no significant differences in proinsulin-to-C-peptide ratio during the oral glucose tolerance test among the study groups. In stepwise multiple regression analysis, hepatic specific insulin extraction in the fasting state (beta =0.65; P<0.001) and fasting blood glucose (beta =0.32; P<0.05) together explained 52% of the variation in fasting plasma proinsulin-to-specific insulin ratio. CONCLUSIONS: Hyperproinsulinemia is not a characteristic finding in glucose-tolerant offspring of type II diabetic probands with deficient insulin secretion or insulin-resistant phenotype. The differences in proinsulin-to-specific insulin ratios were most likely explained by different hepatic extraction among the study groups.

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AM Heikkinen, MT Tuppurainen, L Niskanen, M Komulainen, I Penttila, and S Saarikoski

OBJECTIVE: The positive short-term effects of postmenopausal hormone replacement therapy (HRT) on serum lipids are well known, but it has been suggested that they vanish with time. Cholecalciferol (vitamin D3) is widely used to prevent postmenopausal osteoporosis but the influence of vitamin D3 on serum lipids is poorly known. The long-term effects of HRT and vitamin D3 on the concentrations of serum lipids were studied in a population-based prospective 3-year study. DESIGN AND METHODS: 464 women were randomized into four treatment groups: (i) HRT (sequential combination of 2 mg estradiol valerate and 1 mg cyproterone acetate), (ii) Vit D3 (vitamin D3 300 IU/day), (iii) HRT+Vit D3 (both as above), (iv) placebo (calcium lactate 500 mg/day). RESULTS: 320 women completed the study. After three years of treatment, serum concentrations of low density lipoprotein (LDL) cholesterol decreased in the HRT group (10.1%, P<0.001) and the HRT+Vit D3 group (5.9%, P=0.005), increased in the Vit D3 group (4.1%, P=0.035) but remained unchanged in the placebo group. The concentrations of total cholesterol decreased by 5.8% in the HRT group (P<0.001) and by 3.3% in the HRT+Vit D3 group (P=0.023), but did not change in the other two groups. Serum concentrations of high density lipoprotein (HDL) cholesterol decreased in the Vit D3 group (5.2%, P=0.001), HRT+Vit D3 group (3.7%, P=0.046), and the placebo group (4.5%, P=0.006) but did not change significantly in the HRT group. The HDL/LDL ratio increased in the HRT group (10.5%, P=0.006) and decreased in the Vit D3 group (10.5%, P<0.001) whereas no changes occurred in the other two groups. In addition, serum triglycerides increased similarly in all groups (14.0-18.8%, P<0.05-0.001). CONCLUSIONS: Our results confirm the positive long-term effect of HRT with sequential estradiol valerate and cyproterone acetate on serum lipid concentrations. In addition, the results suggest that vitamin D3 supplementation may have unfavorable effects on lipids in postmenopausal women. Pure vitamin D3 treatment was associated with increased serum LDL cholesterol. Furthermore, the beneficial effects of HRT on serum LDL cholesterol content were reduced when estradiol valerate was combined with vitamin D3. However, the relevance of these associations to cardiovascular morbidity remains to be established.

Free access

I Vauhkonen, L Niskanen, S Haffner, S Kainulainen, M Uusitupa, and M Laakso

OBJECTIVE: To investigate whether there are differences in serum leptin levels between the offspring of non-insulin-dependent diabetes mellitus (NIDDM) patients representing different phenotypes of NIDDM, and furthermore to investigate the role of different fat tissue (subcutaneous fat area (SCFAT) and intra-abdominal fat area (IAFAT)) and insulin sensitivity on serum leptin levels. DESIGN: Twenty non-diabetic offspring of NIDDM patients with insulin secretion deficient phenotype (IS-group), 18 non-diabetic offspring of NIDDM patients with insulin resistant phenotype (IR-group) and 14 healthy control subjects without a family history of diabetes were studied. METHODS: Serum leptin levels were measured by RIA. SCFAT and IAFAT were measured by computed tomography. the total fat mass (TFM) by bioelectrical impedance and the whole body glucose uptake (WBGU) by the euglycemic hyperinsulinemic clamp technique. RESULTS: Subjects of the control group (P = 0.003) and the IS-group (P<0.001) had lower serum leptin levels than subjects of the IR-group even after adjustment for gender (P<0.001). TFM (P = 0.009), fasting plasma insulin (P = 0.003) and for IAFAT (P<0.001). The differences weakened after adjustments for SCFAT (P = 0.028) or WBGU (P = 0.040) and disappeared after adjustment for both SCFAT and WBGU (P = 0.058). In the stepwise multiple regression analyses SCFAT. WBGU and gender explained 58% of the variation of serum leptin levels whereas IAFAT failed to be a significant determinant of serum leptin levels. CONCLUSIONS: The higher serum leptin levels in the IR-group was markedly, but not solely, explained by lower rates of WBGU and higher SCFAT. SCFAT was shown to be a more important determinant of serum leptin levels than IAFAT among these study groups.

Free access

O Vierimaa, T M L Ebeling, S Kytölä, R Bloigu, E Eloranta, J Salmi, E Korpi-Hyövälti, L Niskanen, A Orvola, E Elovaara, A Gynther, T Sane, M Välimäki, J Ignatius, J Leisti, and P I Salmela

Objective: The existence of genotype–phenotype correlation in multiple endocrine neoplasia type 1 (MEN1) is controversial. Two founder mutations of the MEN1 gene in Northern Finland gave us an opportunity to compare clinical features among heterozygotes of different mutations.

Design and methods: Study cohort included 82 MEN1 heterozygotes who were tested for MEN1 during the years 1982–2001. Medical records were reviewed for manifestations of MEN1, other tumours and cause of death by the end of August 2003. Logistic regression analysis was used in evaluating the impact of age, gender and mutational status of affected heterozygotes on the likelihood of developing manifestations of MEN1.

Results: Founder mutations 1466del12 and 1657insC were found in 39 and 29 individuals, and D418N, G156R and R527X mutations in 9, 3 and 2 individuals respectively. Except for pituitary adenoma and nonfunctional pancreatic tumour (NFPT), age was a risk factor for all the disease manifestations. For NFPT, frameshift/nonsense mutations (1657insC, R527X) gave an odds ratio (OR) of 3.26 (95% confidence intervals (CI), 1.27–8.33; P = 0.014) compared with in-frame/missense mutations (1466del12, D418N, G156R); including the founder mutation carriers (n = 68) only, the 1657insC mutation gave an OR of 3.56 (CI, 1.29–9.83; P = 0.015). For gastrinoma, in-frame/missense mutations predicted the risk with an OR of 6.77 (CI, 1.31–35.0; P = 0.022), and in the founder mutations group the 1466del12 mutation gave an OR of 15.09 (CI, 1.73–131.9, P = 0.014).

Conclusions: In this study population, NFPT was more common in the frameshift/nonsense or 1657insC mutation carriers, whereas gastrinoma was more common in the in-frame/missense or 1466del12 mutation carriers.