Sex difference in human mevalonate metabolism.

Two pathways of mevalonate metabolism have been demonstrated: the major (sterol) pathway leads to cholesterol synthesis, whereas the second shunts mevalonate away from sterol production and ultimately results in its oxidation to CO2. Previous studies have demonstrated that the female rat metabolizes circulating mevalonate by the shunt pathway at twice the rate of the male, whereas the male rat converts significantly more circulating mevalonate to cholesterol than the female. The present study extends these observations to humans. Six men and five premenopausal women with normal renal function were injected with R,S-[5-14C]mevalonate, and 14CO2 expired in the breath of the subjects was monitored continuously with an ionization chamber. On an average, the female subjects expired 16.5% and the males 9.8% of the injected R-[5-14C]mevalonate (P less than 0.001). No differences were observed in the plasma and erythrocyte [14C]cholesterol levels. These data demonstrate, in human beings, a sex difference in mevalonate metabolism. The overall impact of the greater mevalonate shunt activity on cholesterol balance in women is unknown.     

Studies of the In Vivo Metabolism of Mevalonic Acid in the Normal Rat

Studies were performed to examine synthesis, tissue localization, and metabolism of mevalonic acid in normal rats. Circulating mevalonate was found to have a rapid turnover phase of 5 min and a slower phase of 40-50 min. Under in vitro conditions the synthesis of mevalonate is carried out most actively by the liver and only to a minor extent by the other tissues studied. The most unexpected finding of this study was that both in vivo and in vitro the kidneys rather than the liver are the primary site of the metabolism of circulating mevalonate. Whereas mevalonate in the liver is rapidly transformed to cholesterol, the major products of mevalonate metabolism in the renal tissues during the same time period are squalene and lanosterol. Exogenous in contrast to circulating mevalonate is metabolized primarily in the intestine.     

Role of the kidneys in the metabolism of plasma mevalonate. Studies in humans and in rhesus monkeys.

Studies were carried out in humans and in rhesus monkeys to determine the role of the kidneys in the metabolism of circulating mevalonic acid (MVA). Following intravenous infusion of [14C]MVA and [3H]cholesterol, there was a rapid appearance of [14C]squalene in the kidneys that exhibited a significantly longer half-life than plasma or hepatic squalene. In man and in rhesus monkeys there was a rapid equilibration between newly synthesized cholesterol from MVA and exogenously administered cholesterol in all tissues except the kidneys, where the specific activity ratio of newly synthesized to exogenous cholesterol was significantly higher. Estimates of the quantitative metabolism of intravenously infused radiolabeled MVA in the monkey demonstrated that 23% was excreted in the urine, 67% metabolized to cholesterol (58% in nonrenal tissues and 9% in the kidneys), and 10% catabolized to CO2 and nonsteroid products. Measurements of MVA metabolism in anephric and uninephric patients demonstrate that, in the absence of renal uptake of MVA, exogenous and newly synthesized cholesterol achieve almost instantaneous equilibrium in the plasma; whereas in control subjects with normal renal function, this equilibration required at least 21 d for the two cholesterol decay curves to become parallel. These results suggest that the kidneys are solely responsible for the observed disequilibrium between newly synthesized and exogenous cholesterol; we suggest that this was due to the delayed release of newly synthesized cholesterol from the kidneys into the plasma compartment following intravenous infusion with radiolabeled MVA. The data document the importance of the kidneys in the metabolism of circulating MVA. However, calculation of the quantitative significance of this pathway in relation to whole body MVA metabolism indicates that renal metabolism of MVA accounts for approximately 0.1% of daily MVA turnover, and that alterations in this pathway due to any form of renal pathology would not result in significant changes in hepatic or whole body sterol synthesis rates. We urge caution in the use of radiolabeled MVA in long-term kinetic studies of sterol metabolism because our data show that the plasma compartment of MVA is not necessarily in isotopic equilibrium with tissue MVA.     

乙型糖尿病患者甲状腺激素及自身抗体异常的临床分析

目的：通过分析乙型糖尿病患者和健康对照组甲状腺激素及自身抗体的异常情况,探讨乙型糖尿病和甲状腺疾病的关系。方法对396例乙型糖尿病患者及411例健康体检者（对照组）测定其血清促甲状腺激素（TSH）、游离三碘甲状腺原氨酸（FT3）、游离甲状腺素（FT4）水平,同时测定其抗甲状腺球蛋白抗体（TGAb）及抗甲状腺过氧化物酶抗体（TPOAb）。结果在健康对照组中,甲状腺激素异常发病率为7．5％,其中男性为5．5％,女性为9．4％,女性亚甲减患病率为4．7％,高于男性亚甲减患病率的1．5％,差异有统计学意义（P ＜0．05）;健康对照组中 TPOAb 阳性率为10．2％,TGAb 阳性率为6．6％。在乙型糖尿病（T2DM）患者中,甲状腺激素异常发病率为16．2％,男性为12．3％,女性为20．5％,其中女性亚甲减患病率为9．2％高于男性4．3％,差异有统计学意义（P ＜0．01）,T2DM 患者亚甲减占甲状腺功能异常发生率的40．6％;TPOAb 阳性率为15．2％,TGAb阳性率为7．1％。结论乙型糖尿病患者中甲状腺疾病患病率较健康对照组明显增加,以女性亚甲减为主;对糖尿病患者进行甲状腺自身抗体筛查及定期监测 FT3、FT4、TSH,对糖尿病患者的病情的评估、预后的判断和指导治疗具有重要的临床意义。     

Depression in primary hypothyroidism masquerading as inadequate or excessive L-thyroxine consumption

Depression may occasionally be a presenting feature of primary hypothyroidism but the influence of psychological illness upon L-thyroxine compliance in hypothyroidism has not been specifically addressed. We report six patients with primary hypothyroidism in whom repeated thyroid function tests implied that they were not taking their L-thyroxine as prescribed. The eventual recognition of underlying depression and its treatment led to appropriate treatment with thyroxine as evidenced by clinical euthyroidism and normal thyroid function tests.     

舒尼替尼致转移性肾细胞癌患者甲状腺功能异常的临床分析

目的 总结接受舒尼替尼治疗的转移性肾细胞癌患者的甲状腺功能变化规律,评价舒尼替尼对甲状腺功能的影响.方法 前瞻性收集北京大学第一医院泌尿外科2008 年6 月至2010 年4 月37 例转移性肾细胞癌接受舒尼替尼治疗的患者的临床资料,其中22 例患者于基线及每个治疗周期第28 天进行甲状腺功能检测.对甲状腺功能异常发生情况进行分析.结果 22 例患者接受舒尼替尼的中位治疗时间为7 个周期(10.5 个月),共18 例(81.8%)患者出现甲状腺功能减低,其中亚临床甲状腺功能减低14 例(63.6%),临床甲状腺功能减低4 例(18.2%),予左旋甲状腺素片替代治疗;6 例(27.3%)患者出现一过性亚临床甲状腺毒症后转为甲状腺功能减退,无持续甲状腺功能亢进患者.甲状腺功能减低的风险随舒尼替尼用药时间延长而增加,出现甲状腺功能减退的中位时间为3 个周期(1 ～7个周期).治疗3 个周期内,50.0%(11/22 例)的患者出现甲状腺功能减退;4 ～6个周期时,约72.7%(16/22 例)患者出现甲状腺功能减退.结论 舒尼替尼致甲状腺功能减退的发生率较高,程度可较严重,应引起临床重视.舒尼替尼相关性甲状腺功能减退可以用激素替代进行治疗,因此应避免舒尼替尼减量或停药.     

Lipid metabolism and functional status of the kidney in hypothyroid patients depending on the phase of disease

AIM: To evaluate renal function in correlation with lipid metabolism parameters in patients with primary hypothyroidism (HT) in compensation and decompensation. MATERIAL AND METHODS: 45 HT patients' examination included study of blood creatinine, urea, cholesterol, triglycerides, high and low density lipoproteins, urinary microalbumin, thyroid hormones and thyrotropin, beta 2-microglobulin levels, glomerular filtration rate (GFR), renal functional reserve (RFR). Also, Zimnitsky test and ultrasound investigation of the kidneys were made. RESULTS: It was found that renal dysfunction in decompensated HT is characterized by normal renal concentration function, high intraglomerular pressure (low GFR and RFR), high concentration of beta 2-microglobulin in blood. Severe HT runs with negative correlation between GFR and total blood cholesterol, LDL. Albuminuria and low RFR in decompensated HT and marked hyperlipidemia suggest development of glomerulopathy related to abnormal physicochemical processes in glomerular endothelium. CONCLUSION: Patients with decompensated HT have apparant glomerular dysfunction and disturbances in lipid metabolism. Hyperlipidemia in HT is a factor of renal damage.     

Sex differences in the control of plasma concentrations and urinary excretion of glycine betaine in patients attending a lipid disorders clinic

OBJECTIVES: To find whether the control of betaine metabolism differs between male and female patients and identify the effects of insulin and other hormones. DESIGN AND METHODS: Data from non-diabetic lipid clinic patients (82 female symbol and 76 male symbol) were re-analyzed by sex. Data on insulin, thyroid hormones and leptin were included in models to identify factors affecting the circulation and excretion of betaine and its metabolites. RESULTS: Different factors influenced plasma concentrations and urinary excretion of betaine, dimethylglycine and homocysteine in males and females. In males, apolipoprotein B (negative), thyroid stimulating hormone (positive) and insulin (negative) predicted circulating betaine, consistent with betaine-homocysteine methyltransferase mediated control. In females, insulin positively predicted plasma dimethylglycine. Urinary betaine excretion positively predicted circulating homocysteine in males (p<0.001), whereas dimethylglycine excretion (also indicating betaine loss) was a stronger positive predictor (p<0.001) in females. Carnitine affected betaine homeostasis. CONCLUSIONS: Betaine metabolism is under endocrine control, and studies should use sex stratified groups.     

Estimation of thyroxine and triiodothyronine distribution and of the conversion rate of thyroxine to triiodothyronine in man.

Studies on peripheral metabolism of simultaneously administered 125-I-labeled L-thyroxine ([125-I]T4) and 131-I labeled L-trilodothyronine ([131-I]T3) were performed in five normal subjects, in four patients with untreated hypothyroidism, and in 3 hypothyroid patients made euthyroid by the administration of T4. The fractional turnover rate (lambda 03) of thyroid hormones irreversibly leaving the site of degradation and the volumes of pool 1 (serum V1) of pool (interstitial fluid, V2), and of pool 3 (all tissues, V3)were obtained by using a three-compartment analysis. In addition to the turnover studies, the ratios for the in vivo T4 to T3 conversion were determined by paper chromatographic study in sera obtained 4, 7, and 10 daysafter the injection. The rate (K12) of the extrathyroidal conversion of T4 to T3 was also estimated by the compartment analysis. The T3 distribution volume (V3) of pool 3, in which T3 is utilized and degraded, was about 60% of totaldistribution volume (V=V1+V2+V3) in normal subjects, whereas only about 25% of the extrathyroidal T4 pool was in the intracellular compartment, indicating that T3 is predominantly an intracellular hormone..     

Steroids, sex hormone-binding globulin, homocysteine, selected hormones and markers of lipid and carbohydrate metabolism in patients with severe hypothyroidism and their changes following thyroid hormone supplementation.

Laboratory markers of thyroid function, selected steroid hormones, sex hormone-binding globulin (SHBG), homocysteine, prolactin, major markers of lipid- and glucose metabolism and of insular-growth hormone axes were investigated in fasting sera from 16 female patients with severe hypothyroidism after thyroidectomy because of thyroid cancer. The results obtained in severe hypothyroidism within 5-6 weeks after withdrawal of thyroid substitution therapy before control scintigraphy were compared with those obtained after correction of thyroid function. Elevated levels of homocysteine and prolactin in hypothyroidism significantly decreased after correction, while SHBG concentration increased. Correction of thyroid function led to significant changes of growth hormone and immunoglobulin F1 (decrease and increase, respectively), while insulin and proinsulin increased only insignificantly. Elevated levels of total cholesterol and triglycerides in hypothyroidism were normalized, along with a significant increase in high density lipoprotein (HDL)-cholesterol. As revealed by correlation and factor analyses, different relationships characterizing both states were found in hypothyroidism and after correction of thyroid function. A strong inverse relationship between homocysteine and free thyroid hormones confirms the effect of thyroid hormones on homocysteine metabolism. No such inverse relation was found in euthyroid state, however. Similarly, in hypothyroidism only, dehydroepiandrosterone sulfate correlated positively with immunoglobulin F1 and homocysteine and negatively with thyroid hormones and SHBG.     

Altered thyroidal responsivity to thyrotropin induced by circulating thyroid hormones. A "short-loop" regulatory mechanism?

We studied the effect of thyroid hormone administration on responsivity of murine thyroid to exogenous thyrotropin (TSH) in order to explore the possibility that the thyroid gland might be directly inhibited by its own hormones. In the rat both L-thyroxine (T4) and 3,5,3'-L-triiodothyronine (T3) pretreatment inhibited TSH-induced thyroidal ornithine decarboxylase (ODC) activity in vivo in a dose-related manner (half-maximal inhibition, 1.7 mug/rat and 0.6 mug/rat, respectively). Other structurally related compounds exhibited the following inhibitory potencies compared to T4: T3, 283%; triiodothyroacetic acid, 40%; D-T4, 18%; 3,5-L-diiodothyronine, 9%. Monoiodotyrosine, diiodotyrosine, and iodide were not inhibitory. The full inhibitory effect of T4 or T3 was observed when thyroid hormone was administered from 96 to 12 h before TSH and was also seen in hypophysectomized animals. Pretreatment with T4 or T3 in divided doses over 2 1/2 days inhibited TSH-induced increase in [1-14C]glucose oxidation to 14C02 and [3H] leucine incorporation into protein in rat thyroid. In the mouse T4 or T3 pretreatment (0.25-25 mug daily) caused dose-related inhibition of both thyroidal ODC activity and 131I release induced by TSH in vivo. In mice on a low-iodine diet (LID) but not in animals on a regular diet (RD) NaI pretreatment also blunted TSH-induced thyroidal ODC activation and 131I release. When LID or RD mice were pretreated with 12.5-125 mug of T4 or T3 over 2 1/2 days, TSH-induced in vitro stimulation of thyroid cyclic 3',5'-adenosine monophosphate formation was inhibited in a dose-related manner; NaI pretreatment was inhibitory in the LID mouse only. Prior administration of exogenous TSH blunted the activation of thyroid ODC and thyroid hormone release induced by subsequent TSH administration in rat and mouse. These studies indicate altered thyroid responsivity to TSH under the influence of circulating thyroid hormones and suggest the existence of a "short-loop" negative feedback regulating thyroid function.     

Thyroid function tests, serum lipids and gender interrelations in a middle-aged population.

OBJECTIVE: To study the value of screening for thyroid function in a screening program for hyperlipidaemia. DESIGN: A screening study in primary health care. SETTING: All individuals in a defined rural area, S?der?kra, Sweden, aged 40-59 years were invited to a screening programme at the local primary health care centre. PARTICIPANTS: 782 individuals were invited for screening. Blood samples were obtained from 88% of the invited males and from 92% of the females. MAIN OUTCOME MEASURES: Thyroid function tests (thyroid stimulating hormone (TSH) and free T4), serum lipids (total-cholesterol, HDL-cholesterol, LDL-cholesterol and s-triglycerides), b-glucose and body anthropometry (body mass index and waist to hip circumference) were measured. RESULTS: 0.57% of males and 1.13% of females showed evidence of hypothyroidism as defined by a TSH value greater than 3.75 mU/l of those with s-cholesterol concentration above 7 mmol/l. In addition, higher TSH values in females were associated with higher s-cholesterol, s-LDL-cholesterol and s-triglycerides. CONCLUSION: It seems appropriate to screen for hypothyroidism in females with s-cholesterol above 7.0 mmol/l.     

原发性甲状腺功能减退症与血脂代谢的相关性研究

目的：探讨不同程度甲状腺功能减退症和病程对血脂的影响,并观察甲状腺功能减退症患者激素替代治疗后血脂谱的动态变化。方法收集甲状腺功能减退症患者97例,亚临床甲状腺功能减退症32例,中度甲状腺功能减退症28例,重度甲状腺功能减退症37例和31例健康体检者。分别在初诊和激素替代治疗1个月后检测各组血清游离三碘甲状腺原氨酸（FT3）、游离甲状腺素（FT4）、促甲状腺激素（TSH）、总胆固醇（TC）、甘油三酯（TG）、高密度脂蛋白胆固醇（HDL-C）、低密度脂蛋白胆固醇（LDL-C）、载脂蛋白A（ApoA）、载脂蛋白B（ApoB）、脂蛋白（a）[Lp（a）]。通过病史回顾对病程估计的方法确定病程时间。结果不同程度的甲状腺功能减退症对血脂影响不同,重度甲状腺功能减退症组血脂各项均升高,中度甲状腺功能减退症组除TG与HDL-C外均升高,亚甲状腺功能减退症组ApoA与Lp（a）升高。血脂各项与FT3和FT4呈负相关,与TSH呈正相关。甲状腺功能减退症患者激素替代治疗1个月后血脂各项除 Lp（a）外其余基本恢复正常。结论甲状腺功能减退症可引起血脂增高,随甲状腺功能减退症程度加重及病程延长,血脂升高越明显,经激素替代治疗后,甲状腺功能减退症病情好转血脂逐渐恢复,血脂可先于甲状腺功能恢复正常。     

PRIMARY HYPOTHYROIDISM WITH HYPER-PROLACTINAEMIA AND PITUITARY ENLARGEMENT MIMICKING A PITUITARY MACROADENOMA

Hyperprolactinaemia can occur in patients with hypothyroidism. A 32-year-old woman with primary hypothyroidism presented with amenorrhoea and galactorrhoea of two years' duration. She had hyperprolactinaemia, low basal morning cortisol levels and evidence of a pituitary macroadenoma on magnetic resonance imaging. Therapy with L-thyroxine resulted in induction of regular menses, resolution of galactorrhoea, normalisation of hormone levels and disappearance of the image of pituitary macroadenoma. It seems that enlargement of the pituitary due to thyrotroph and/or lactotroph cell hyperplasia secondary to hypothyroidism is responsible for this ‘pseudotumour’ image on radiological study. Recovery of her low basal cortisol values during treatment could also be explained by the dissolution of the pressure effect of enlarged pituitary in addition to the regression of hypothyroidism. In subjects with primary hypothyroidism and hyperprolactinaemia and pituitary enlargement, thyroid hormone replacement should be a first line treatment preceding pituitary surgery and bromocriptine use.     

Hypothyroidism: an update

Hypothyroidism is a clinical disorder commonly encountered by the primary care physician. Untreated hypothyroidism can contribute to hypertension, dyslipidemia, infertility, cognitive impairment, and neuromuscular dysfunction. Data derived from the National Health and Nutrition Examination Survey suggest that about one in 300 persons in the United States has hypothyroidism. The prevalence increases with age, and is higher in females than in males. Hypothyroidism may occur as a result of primary gland failure or insufficient thyroid gland stimulation by the hypothalamus or pituitary gland. Autoimmune thyroid disease is the most common etiology of hypothyroidism in the United States. Clinical symptoms of hypothyroidism are nonspecific and may be subtle, especially in older persons. The best laboratory assessment of thyroid function is a serum thyroid-stimulating hormone test. There is no evidence that screening asymptomatic adults improves outcomes. In the majority of patients, alleviation of symptoms can be accomplished through oral administration of synthetic levothyroxine, and most patients will require lifelong therapy. Combination triiodothyronine/thyroxine therapy has no advantages over thyroxine monotherapy and is not recommended. Among patients with subclinical hypothyroidism, those at greater risk of progressing to clinical disease, and who may be considered for therapy, include patients with thyroid-stimulating hormone levels greater than 10 mIU per L and those who have elevated thyroid peroxidase antibody titers.     

Depression in Primary Hypothyroidism Masquerading as Inadequate or Excessive L-Thyroxine Consumption

Depression may occasionally be a presenting feature of primaryhypothyroidism but the influence of psychological illness uponL-thyroxine compliance in hypothyroidism has not been specificallyaddressed. We report six patients with primary hypothyroidismin whom repeated thyroid function tests implied that they werenot taking their L-thyroxine as prescribed. The eventual recognitionof underlying depression and its treatment led to appropriatetreatment with thyroxine as evidenced by clinical euthyroidismand normal thyroid function tests.     

调查来宾市人口甲状腺功能性疾病的患病情况

目的 研究来宾市人口不同性别、年龄甲状腺功能性患病情况.方法 采用横断面研究方法,回顾性分析本院甲状腺检查的38 798例患者的资料.结果 女性在年龄的11～20、21～30、31～40、41～50岁中甲状腺功能亢进所占的比例分别为:70%、71%、57%、67%;女性在年龄为11～20、21～30、31～40、41～50岁中甲状腺功能减退所占的比例分别为:76%、77%、56%、71%;男女比例差异有统计学意义.结论 女性和男性激素分泌的差异导致男女在甲状腺疾病方面发病率的差异.     

Targeting the mevalonate cascade as a new therapeutic approach in heart disease,cancer and pulmonary disease

The cholesterol biosynthesis pathway, also known as the mevalonate (MVA) pathway, is an essential cellular pathway that is involved in diverse cell functions. The enzyme 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase (HMGCR) is the rate-limiting step in cholesterol biosynthesis and catalyzes the conversion of HMG-CoA to MVA.     

Myocardial adenyl cyclase: activation by thyroid hormones and evidence for two adenyl cyclase systems

The mechanism responsible for the hyperdynamic circulatory state in hyperthyroidism has not been defined. Although certain cardiac manifestations resemble those caused by excessive adrenergic stimulation, recent evidence suggests that thyroid hormone exerts an effect on the heart that is independent of the adrenergic system. Since the inotropic and chronotropic effects of norepinephrine appear to be mediated by activation of adenyl cyclase, the possibility that thyroxine and triiodothyronine are also capable of activating adenyl cyclase was examined in the particulate fraction of cat heart homogenates.L-thyroxine and L-triiodothyronine increased the conversion of adenosine triphosphate-(32)P (ATP-(32)P) to cyclic 3',5'-adenosine monophosphate-(32)P (3',5'-AMP-(32)P) by 60 and 45% respectively (P < 0.01). A variety of compounds structurally related to the thyroid hormones, but devoid of thyromimetic activity did not activate adenyl cyclase: these included 3,5-diiodo-L-thyronine, L-thyronine, 3,5-diiodotyrosine, monoiodotyrosine, and tyrosine. D-thyroxine activated adenyl cyclase and half maximal activity was identical to that of the L-isomer. Although the beta adrenergic blocking agent propranolol abolished norepinephrine-induced activation of adenyl cyclase, it failed to alter activation caused by thyroxine. When maximal concentrations of L-thyroxine (5 x 10(-6) moles/liter) and norepinephrine (5 x 10(-5) moles/liter) were incubated together, an additive effect on cyclic 3',5'-AMP production resulted.THIS INVESTIGATION DEMONSTRATES: (a) thyroid hormone is capable of activating myocardial adenyl cyclase in vitro and (b) this effect is not mediated by the beta adrenergic receptor. Moreover, the additive effects of norepinephrine and thyroxine suggest that at least two separate adenyl cyclase systems are present in the heart, one responsive to norepinephrine, the other to thyroid hormone.These findings are compatible with the hypothesis that the cardiac manifestations of the hyperthyroid state may, in part, be caused by the direct activation of myocardial adenyl cyclase by thyroid hormone.