Effects Of Cholesterol-lowing Therapy With Simvastatin On Sexual Hormones And Thyroid Hormaones In Rabbits

Recent studies suggest that inflammation-proliferative response of vascular wall after local injury is the main pathological mechanism of the development of atherosclerosis. Low-density lipoprotein cholesterol (LDL-C), especially oxidized LDL-C (oxLDL-C) plays an important role in it. Many multi-center prospective randomized controlled clinical trials confirmed that intensive lipid-lowering therapy with statins in patients with coronary heart disease reduced the rates of cardiac death, acute myocardial infarction, stroke and other cardiovascular end point events. So the clinical guidelines emphasis that intensive lipid-lowering therapy must be included in the treatments and secondary preventions for the patients at high risk or very high risk of coronary heart disease. "The Guideline for Prevention and Treatment of Chinese Adult Dyslipidemia 2007" recommended that the target level of LDL-C should be below 2.07mmol/L for the patients at very high risk (including the patients with acute coronary syndrome or ischemic cardiovascular disease plus diabetes mellitus), while the LDL-C levels in the patients with high or moderate risk factors were also significantly lower than normal range. Therefore, intensive lipid-lowering therapy with statins has become an integral part of treatments for all of the patients with coronary heart disease.However, cholesterol is the important structural material for many tissues and organs, and a precursor substance or raw material of many important physiological endocrine hormones such as sexual hormones (estrogen, progesterone and testosterone), glucocorticoid, mineralocorticoid, and thyroid hormones. There is complex interaction relationship between these hormones and cholesterol metabolism. The synthesis of these hormones depends on cholesterol while these hormones can affect cholesterol metabolism. For example, Estrogen can significantly decrease the levels of cholesterol, triglyceride (TG), LDL-C but increase the level of high-density lipoprotein cholesterol (HDL-C), and inhibit the oxidative modification of LDL-C and the absorption of LDL in arteries walls. In recent years a large number of studies have shown that physiological levels of endogenous plasma (free or bioavailable) testosterone were positively correlated to the levels of HDL-C and apolipoprotein AI, but negatively correlated to the levels of cholesterol, TG, LDL-C and lipoprotein. When the plasma testosterone level decreases, the level of HDL-C decreases and the levels of LDL-C, LDL-C/HDL-C and free fatty acids rise, cholesterol synthesis increases, and the initiation and progression of atherosclerosis is promoted.Sexual hormones can affect a variety of factors in the process of atherosclerosis. The migration and proliferation of vascular smooth muscle cells (VSMC) is one of the pathophysiological mechanisms of atherosclerosis. Though testosterone has no effect on the proliferation and migration of VSMCs, it can increase the expression of androgen receptor gene of VSMCs and result in the inhibition of atherosclerosis. As a role in the anti-inflammatory, testosterone can inhibit the expression of vascular cell adhesion molecule (VCAM-Ⅰ) and nuclear factor-B (NF-B) induced by tumor necrosis factor-α(TNF-α). In addition, there is interaction between statins and sexual hormones. Bonapace found that statins can reversibly inhibit the mitogenic factors in promoting the role of VSMCs proliferation, while the 17G estradiol reversed the statin-induced G1 cell proliferation in quiescent and promote cell proliferation.There is complex relationship and interaction between sexual hormones and statins during the process of atherosclerosis. General theoretically, the decrease of LDL-C by statins therapy reduces the raw material for steroid synthesis and results in decrease of steroid hormone synthesis. Therefore, it is clinical significant to declare if there is any effects of intensive lowering-cholesterol therapy with statins on the synthesis and secreation of sexual hormones.In addition to sex hormones, the similar interaction may also exist between statins, cholesterol and thyroid hormones.Therefore, this study is designed to investigate the effects of intensive lowering-cholesterol therapy with different dose of Simvastatin on the sexual hormones and thyroid hormones in the New Zealand white rabbits.ObjectiveTo investigate the effects of lipid-lowering therapy with different dose of Simvastatin on serum testosterone, estradiol, free tetraiodothyronine(FT4), free triiodothyronine (FT3) and thyrotropic-stimulating hormone (TSH) in New Zealand rabbits.Subjects and methodsSubjectsTotally 18 New Zealand White rabbits (9 male and 9 female), weighted 1.7±0.3kg and aged 6±1 months and bought from the Guangdong Animal Experimental Centre, were employed to undergo this experiment. MethodsThe 18 rabbits were equally randomized into 3 groups. A dose of 20mg/Kg/d of Simvastatin is given in group A while 40mg/Kg/d in group B and no Simvastatin in group C The levels of serum LDL-C, testosterone, estradiol, FT3, FT4 and thyrotropic-stimulating hormone at the baseline and the tenth month of the treatment. To avoid the inaccuracy of hormones levels caused by the physiological fluctuations in different times of day, morning fasting blood samples were collected from the ear veins. The first 2ml of blood was abandonded. Amount of 3 ml blood sample was centrifug in 3000 rpm for twice to obtain the supernatant. Enzymatic oxidation was used to detect LDL-C level while enzyme-linked immunosorbent assay was employed to measure the levels of testosterone, estradiol, and promote the thyroid hormones. Comparison of statistical methods using balanced ANOVA test, LSD and linear correlation analysis,.A P<0.05 was considered statistically significant.ResultsThere were no significant differences in the weights of the rabbits between the three groups before the treatment as well as after the treatment (P> 0.05). The baseline of LDL-C was not significantly different between the three groups (P> 0.05). However, the LDL-C level was statistically lower in group B (0.54±0.07mmol/L) than in group A (0.75±0.06 mmol/L, P< 0.05) and group C (1.25±0.21 mmol/L, P< 0.05).Before the treatment, the baselines of testosterone and estradiol were not remarkably different between the three groups even in the male and female subgroups (P> 0.05). After the treatment, there were no significant differences in the testosterone level of male rabbits and the estradiol levels of female rabbits between the three groups (P> 0.05). However, the testosterone level of female rabbits was remarkable lower in group B (1.04±0.20 ng/ml) than in group A (1.54±0.36 ng/ml, P< 0.05) and group C (1.68±0.25 ng/ml, P< 0.05) when there was no statistical difference between group A and group C (P> 0.05). There were no significant differences in the estradiol levels of female rabbits between the three groups after the treatment (P> 0.05) when the estradiol level of male rabbits was remarkable lower in group A (22.14±1.76 pg/ml) and in group B(21.37±2.79 pg/ml) than in group C(30.06±2.19 pg/ml, P< 0.05).The levels of TSH, FT3 and FT4 were not significantly different between the three groups before and after the treatment (P> 0.05).The linear correlation analysis showed that there were significantly positive correlated between testosterone (r-0.413, P< 0.05) or estradiol (r= 0.367, P< 0.05) and LDL-C. But there were no significant correlations between thyroid hormones and LDL-C..ConclusionsIntensive lipid-lowering therapy with high dose Simvastatin may decrease the estrogen level in male rabbits and the testosterone level in female rabbits while LDL-C was significantly reduced. However, the thyroid function was not impacted within this dose range.