Thyroid Function And Androgen Effects On Lipid Metabolism

[Objective]The first part Thyroid function and lipid metabolism Most studies found that hypothyroidism, subclinical hypothyroidism even high-normal range of thyroid stimulating hormone (TSH) levels can cause dyslipidemia. TSH was a very sensitive indicator of thyroid disease and was presumably related to the differences in the region, age, gender distribution, and other factors, so its reference value upper limit was still controversial; thyroid peroxidase antibody (TPOAb) as an important symbol of autoimmune thyroid disease, played an important role in the outcome of subclinical hypothyroidism, whether related to abnormal lipid metabolism were currently few studies. A cross-sectional study aimed to establish the TSH reference ranges for total population and two different age groups in eastern China, to investigate the prevalence of thyroid dysfunction, and to explore the relationship between cholesterol and other atherosclerotic disease risk factors with the TSH and TPOAb levels.The second part Androgen and lipid metabolismStudies have shown that testosterone levels decreased with increasing age participate in the development of abnormal lipid metabolism. Low testosterone levels in middle-aged men are related with total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C) levels increased and high-density lipoprotein cholesterol (HDL-C) decreased. After to lower testosterone levels in older men physiological dose testosterone supplements can be observed to improve lipid metabolism, and improves carotid intima-media thickness, brings cardiovascular benefits. However, the associated molecular mechanism of testosterone levels in the regulation of cholesterol metabolism is unclear. In this study, through the establishment of high-fat middle-aged male rats, testosterone supplementation after castration, set up the animal model to varying degrees of testosterone deficiency partially, simulate testosterone partial lack of different level in middle-aged and elderly men, observe changes in testosterone concentrations on lipid metabolism and atherosclerosis extent and possible molecular mechanisms.[Materials and Methods]First1. A cross-sectional study was conducted on 1806 adult subjects recruited from health check candidates (396 males and 1410 females; aged 35 to 87 years). We collected the following information:height, body weight, blood pressure, serum TSH, TPOAb, fasting plasma glucose (FPG), total cholesterol, triglyceride (TG) and high density lipoprotein cholesterol levels. This study aimed to establish the TSH reference ranges for total population and two different age groups, to investigate the prevalence of thyroid dysfunction, and to explore the relationship between cholesterol and other atherosclerotic disease risk factors with the TSH and TPOAb levels.2. Further subgroup analysis, research relationship between TPOAb positive with cholesterol, using TSH reference values (TSH 0.3-4.8mIU/L). We screened 1607 euthyroid subjects (aged 35 to 65 years old, male and female sex ratio was 1:3.7). All the subjects were divided into two groups, i.e., TPOAb-positive (n=205) and TPOAb-negative group (n= 1402) according to the level of TPOAb. Then grouped the subjects according to serum thyroid stimulating hormone (TSH) levels, i.e., low-normal, mid-range and high-normal TSH group (TSH 0.3-0.99 mlU/L,1.0-1.89 mlU/L and 1.9-4.80 mlU/L respectively). Each TSH group further subdivided into TPOAb-positive and TPOAb-negative subgroup. This study analyse influence of TPOAb and TSH levels on lipid profile in population of normal thyroid function.Second1. High-fat diet was reared for 50 SD male rats aged 10 months (equivalent to middle age men) for 6 weeks, and of which 47 survived, successfully established animal model of hyperlipidemia.2. In which 41 rats underwent castration randomly,6 sham castration as control group. After 12 days’adaptive feeding, ovariectomized rats survived 24, and then randomly divided into four groups:complete lack of testosterone group(n=6, injection of the corresponding amount ofmedical corn oil), low dose testosterone group (n=5, accepted 1mg/kg of testosterone propionate hypodermic injection), middle dose testosterone group(n=6, accepted 5mg/kg of testosterone propionate hypodermic injection) and high dose testosterone group(n=7, accepted 25mg/kg of testosterone propionate hypodermic injection). Control group was injected with a corresponding amount of medical corn oil. Testosterone supplemented for 8 weeks.3. Peripheral blood for detection of testosterone, blood lipid, blood glucose and insulin levels:to observe the effect of testosterone on the changes in the concentration of lipid metabolism.4. All rats were sacrificed, the liver tissue HE, oil red staining and masson staining to observe liver tissue infiltration of lipid and fibrosis.5. HE and Masson staining aorta, carotid artery blood vessel structure and observed morphological changes.6. Key genes involved in cholesterol metabolism screening (SIRT1, CETP, LCAT, LDLR, SOCS3, VCAM-1, HMGCR, ABCA1, CYP7A1, SR-BI and UGT1A1), RT-PCR method to identify where regulatory and well received testosterone the target influence cholesterol metabolism genes.7. Using Western Blot method to observe the effect of testosterone on the changes in concentration of testosterone which is well received by the regulation will affect cholesterol metabolism and protein levels of target genes, as well as some changes in the phosphorylation of key enzymes in the cholesterol metabolism.[Results]1. Clinical studies① The TSH reference range was 0.35-5.48 mlU/L for the total population,0.40-5.04 mlU/L for the<40 years old group, and 0.33-5.70 mlU/L for the>40 years old group. The upper limit of the TSH level increased with age and was higher in females than in males of the same age group.② The prevalence of subclinical hypothyroidism (with elevated TSH levels) was 1.88%. The prevalence of autoimmune subclinical hypothyroidism (with positive TPOAb and elevated TSH levels) was 1.22%. The positive TPOAb rate was 13.95% and the euthyroid with positive TPOAb rate was 12.13%. Both the positive TPOAb and euthyroid with positive TPOAb rates were higher in the females than in the males. The prevalence of positive TPOAb and euthyroid with positive TPOAb increased with age in the females’>40 year of age.③ Association of thyroid disorders with lipid metabolism:TC levels were higher in the euthyroid with positive TPOAb group than in the control group (P<0.05). TG, HDL-C and LDL-C levels did not change significantly than the control group (all P> 0.05). Lipid levels in remaining thyroid disease group-subclinical hypothyroidism, autoimmune subclinical hypothyroidism and positive and the control group were no significant difference (all P> 0.05).④Subgroup analysis found that, euthyroid population TPOAb-positive patients than TPOAb negative TPOAb, TC and HDL-C levels increased (all P<0.05), LDL-C tended to increase (P=0.053). After TSH reference range layered, in low-normal TSH levels, TPOAb positive patients than TPOAb negative, TC no statistical difference (P>0.05). In mid-range TSH levels, TPOAb-positive patients compared with TPOAb-negative subjects, TC tended to increase (P=0.121), the HDL-C levels were higher (P<0.05). In high-normal TSH levels, TPOAb-positive patients compared with TPOAb-negative subjects, TC levels were higher (P<0.05).2. Animal experiments①High-fat model successfully established:high-fat diet for 6 weeks, compared with before a high-fat diet, TC, TG, LDL-C were higher (all P< 0.01), HDL-C decreased (P<0.01).②Castrated and adding different concentration of testosterone, the changes in testosterone levels in rats:testosterone dose group and control group in the testosterone levels of similar (P>0.05), high dose group of testosterone is higher than the control group (P<0.05), the complete lack of testosterone group, low dose group were lower than the control group (all P<0.05).③Castrated and adding different concentration of testosterone, the indexes of blood lipids in rats:compared with control group, testosterone of high, middle dose group of TC, TG, HDL and LDL-C-C had no statistical difference (P>0.05), low dose group, the complete lack of group TC, LDL-C levels were elevated (P< 0.05), TG, HDL-C had no statistical difference (P> 0.05); Comparison between groups, high TC and LDL-C, middle dose group were less than complete lack of group (all P< 0.05), the levels of TG and HDL-C level no significant statistical differences (all P> 0.05); Groups of blood glucose and insulin levels no statistical difference (P> 0.05).④Liver histology changes (JEDA 801D morphological image analysis):each hepatocyte fatty degeneration situation (HE and oil red staining showed):testosterone high dose group, the control group, middle dose group, low dose group, the complete lack of group was mild, mild-to-moderate, moderate, moderately severe and severe steatosis. Groups of liver fibrosis (Masson staining showed):the complete lack of group, low dose group and middle dose group visible fibrosis, more than two groups did not see obvious fibrosis.⑤Large arteries morphological and structural changes (JEDA 80ID morphological image analysis):HE and Masson staining showed that groups of artery wall smooth muscle fiber components are reduced, and the collagen fiber has thickened, but no significant differences between groups.⑥RT-PCR and Western Blot experiments are in progress stage.[Conclusion]1. Eastern people TSH reference range 0.35-5.48 mIU/1, the JiaJian prevalence was 1.88%, autoimmune subclinical JiaJian prevalence was 1.22%, TPOAb positive rate was 13.95%, pure TPOAb positive normal levels (TSH) at a rate of 12.13%. In women, TPOAb positive rate and simple TPOAb positive rate increases with age and is higher than men,≥40 years of age is particularly evident.2. TPOAb system plays an important role in autoimmune thyroid disease, and TC metabolism; TPOAb positive, when TSH in the normal range of high value, TC level has already started to rise. We suggested that clinical doctors TPOAb positive patients, timely give lifestyle intervention and lipid adjusting treatment, and prevent the happening of the atherosclerosis development.3. Testosterone can be adjusted in middle-aged male rat peripheral blood TC and LDL-C level, high levels of testosterone can decrease TC and LDL-C, low levels of testosterone can make the TC and LDL-C rise. Testosterone deficiency can increase the liver ectopic fat deposition. To low testosterone levels of middle-aged and old male testosterone replacement therapy, can be of clinical benefit.