骨钙素与糖尿病及其大血管并发症危险因素的关系

骨钙素是由成骨细胞合成和特异性分泌的依赖维生素K的非胶原蛋白,其与糖代谢以及肥胖、肝脏脂肪沉积、代谢综合征等2型糖尿病及其大血管并发症的危险因素密切相关.骨钙素通过与G蛋白耦联受体C家族6组成员A(GPRC6A)结合,发挥其对代谢的保护作用.作为一种活性分子,GPRC6A可能成为糖尿病及其大血管并发症治疗的新靶点.     

肝炎肝硬化的骨钙素、甲状旁腺素、降钙素的变化及其临床意义

目的：为了解肝硬化骨病的形成机理。方法：本文采用放射免疫法对３５例肝炎肝硬化的血清进行了骨钙素、甲状旁腺素（ＰＴＨ）及降钙素（Ｃａｌｃｉｔｏｎｉｎ）的测定。结果：肝硬化患者的骨钙素（Ｇａｌ）明显高于正常对照（Ｐ＜０．０１），ＰＴＨ也高于正常，血钙低于正常，但均无统计学意义（Ｐ＜０．０５），各激素与血清白蛋白、凝血酶原时间及总胆红素之间无明显相关。按Ｃｈｉｌｄ分级，Ｃ级患者的Ｇａｌ及ＰＴＨ明显高于Ａ级及Ｂ级患者，而血钙浓度低于Ａ级及Ｂ级。结论：肝硬化对骨病的产生与所测三种激素的代谢紊乱有密切关系，由于钙离子吸收不良所致的低钙血症在致肝硬化骨病中可能起着相当重要的作用     

骨钙素对青春发育的作用

骨钙素影响睾酮的合成与分泌,因而亦会对男性青春发育的各方面产生影响,如性腺发育、精细胞凋亡及生长激增等,其在间质细胞上的相关受体及下游信号通路已得到了初步阐明.但尚未有证据支持骨钙素会对女性青春发育产生影响.同时,骨骼-睾丸正反馈系统的提出,对传统的下丘脑-垂体-性腺轴系统进行了补充,也为青春期相关疾病的研究和治疗提供了新的思路.     

Regulation of follicle-stimulating and luteinizing hormone receptor signaling by

Follicle-stimulating hormone receptor (FSHR) and luteinizing hormone receptor (LHR) belong to the super-family of G protein-coupled receptors (GPCR); GPCRs are negatively regulated by RGS ("regulators of G protein signaling") proteins. In this study we evaluated the effects of RGS3 and RGS10 on FSHR and LHR ligand binding and effector coupling. FSHR and LHR ligand binding were unchanged in the presence of RGS3 or RGS10. However, signaling by FSHR and LHR was diminished by RGS3 but not by RGS10. This constitutes the first demonstration of an interaction between RGS proteins and LH and FSH signaling pathways and identifies a mechanism for negative regulation of RGS3 on FSHR and LHR signaling.     

Influence of calcitonin treatment on the osteocalcin concentration in the algodystrophy of bone

Summary Algodystrophy (AD) attacks all tissues in the affected region and results in the rapid demineralization of bones. Osteocalcin (OC) and alkaline phosphatase (AP) are markers of bone turnover. Calcitonin is the treatment of choice of AD. Two groups of patients were studied: Group I (n=8)-acute stage of AD (before and during the calcitonin treatment), Group II (n=5)-late chronic stage of AD. In the acute stage of AD both OC level and AP activity were increased. They were normal in the chronic state of AD. During the calcitonin treatment OC level normalized after 14 days and then increased again. During the treatment, AP activity temporarily increased and then returned to the initial level. We confirm that an increased bone turnover is observed in the acute stage of AD. Discrepancy between OC level and AP activity reflects the local metabolic disturbances. Salmon calcitonin inhibits the algodystrophic process and probably contributes to the activation of the skeletal restoration.     

Reversion of the steroid-induced decrease of serum osteocalcin with sodium fluoride

Summary Osteopenia observed in corticotherapy is due, among other causes, to a decrease in bone formation as can be shown by a steroid-induced osteocalcin decrease. Although various treatments have been proposed there is no agreement as to which one is the best. Two such treatments, sodium fluoride and vitamin D administration increase osteocalcin levels. We treated a group of 12 patients under corticoid therapy (mean dose 16 mg per day) with 50 mg/day p.o. sodium fluoride, and determined osteocalcin levels before and two weeks after sodium fluoride treatment. Similarly, another group of 9 patients with a similar mean steroid dose was treated with 0.5 /day of 1(OH)₂D3 in order to assess the effect of this vitamin on osteocalcin and to determine which was the best treatment. Both groups were compared with respective control groups. A significant osteocalcin increase was observed in the control groups (p<0.001); similar significance was observed in the sodium fluoride group, whereas a lower significance (p<0.01) was observed in the vitamin D group. These results suggest that sodium fluoride could be more effective than vitamin D in the treatment of steroid-induced osteopenia.     

Regulation of pituitary gonadotropin-releasing hormone receptors by androgens in the male rabbit

The regulation of pituitary GnRH receptors was studied in adult male rabbits after castration and androgen replacement with testosterone (T) or 7 alpha-methyl-19-nortestosterone acetate (U-15,614; T analog) supplied by Silastic capsules implanted sc. Castration increased pituitary GnRH receptors significantly, from 99.3 to 329.5 fmol/mg protein within 4 weeks, without a change in the equilibrium association constant. Serum LH concentrations increased from 0.45 to maximum levels of 2.6 ng/ml by day 8 after orchiectomy; these levels persisted throughout the 4 weeks of study. Serum FSH reached maximum levels of 33.6 ng/ml 5 days after castration. T replacement with 250, 500, and 1000 micrograms/kg X day, prevented a postcastration rise in both pituitary GnRH receptor concentrations and gonadotropin secretion, while 100 micrograms/kg X day prevented an increase in GnRH receptors, but did not completely inhibit hypersecretion of gonadotropins. Administration of T analog at doses of 6.25 and 12.5 micrograms/kg X day partially suppressed the castration-induced increase in pituitary GnRH receptor concentrations, while 25, 50, and 100 micrograms/kg X day suppressed GnRH-binding sites to the levels found in intact controls in 15 of 16 rabbits. By contrast, none of the T analog doses was able to prevent completely LH and FSH hypersecretion. The fact that both T and T analog induced dose-dependent stimulation of prostate and seminal vesicle weights indicates that there are tissue-specific differences in the sensitivity to androgens. We conclude that in the male rabbit 1) pituitary GnRH receptors significantly increase after castration; 2) this increase may partially mediate the postcastration hypersecretion of LH and FSH; 3) castration-induced effects can be prevented by androgen replacement. These results are similar to those obtained in rats, where castration increases LHRH receptors, but contrast with results in mice and hamsters, where castration either reduces or does not change receptor levels. This indicates significant species differences in the response of pituitary GnRH receptor concentrations to elimination of the negative feedback effects of androgens.     

刚地弓形虫感染对雄性小鼠性激素分泌和睾丸激素受体的影响

目的探讨刚地弓形虫感染对雄性小鼠黄体生成素(LH)、睾酮(T)分泌的影响以及睾丸局部激素受体的改变。方法选用9~10周龄雄性BALB/c小鼠60只,随机分为正常对照组、刚地弓形虫感染组(腹腔分别注射刚地弓形虫速殖子2.5×103/只、5×103/只、1×104/只、2×104/只)及环磷酰胺阳性对照组。以放射免疫法检测小鼠血清LH、T以及睾丸局部T水平,并以免疫组织化学sABC法检测睾丸LH受体和T受体的变化。结果血清及睾丸局部T水平随攻虫剂量增加而明显降低,同时T受体表达代偿性增高(P<0.05),尤其在精母细胞;LH相对正常组无代偿性增高,LH受体亦无明显变化(P>0.05)。结论刚地弓形虫感染小鼠后可导致睾丸激素异常,使T降低并引起睾酮受体的代偿性表达增加,但对LH水平及LH受体表达影响不明显。     

慢性心力衰竭时性激素的变化及其意义

目的 :观察心力衰竭 (心衰 )时相关体液因子及性激素水平变化与心衰程度及类型的关系。方法 :本研究包括慢性心力衰竭组 ( 4 7例病人 ,术中男 2 6,女 2 1)和正常对照组 ( 5 3例健康人 ,其中男 2 4 ,女 2 9)。用放射免疫法测定男女心衰者与健康者血雌二醇 ( E2 )、睾酮 ( T)、醛固酮 ( Ald)水平。结果 :男女心衰患者 E2 、T平均值均较对照者高 ,但除男性 E2 差异有非常显著性意义 ( P <0 .0 1)外 ,余差异均无显著性意义。男性心衰者 E2 升高水平与 Ald明显升高结果相一致。结论 :雌激素与男性心衰关系密切 ,血浆 E2 浓度升高可能影响男性心衰发生发展过程 ,其含量变化与 Ald含量变化具有良好相关性 ,对于判断心衰病情及探索心衰发病机制具有一定的价值     

阻塞性睡眠呼吸暂停低通气综合征患者性激素水平的变化与分析

目的 探讨阻塞性睡眠呼吸暂停低通气综合征（OSAHS）男性患者性腺激素水平的变化及相互间的关系，为伴有性功能减退的OSAHS患者是否需要性激素替代治疗提供临床依据。方法 对男性OSAHS患者（OSAHS组）和对照组进行多导睡眠监测，应用美国强生全自动化学发光免疫分析系统测定血清促卵泡刺激素（follicular-sti mulating hormone，FSH）、黄体生成素（luteinizing hormone，LH）及睾酮（total testosterone，T）水平，分析其间的变化关系。结果 与对照组比较，OSAHS组患者FSH、LH[（4.10±1.61）U/L、（3.70±1.74）U/L]显著低于对照组[（11.68±3.33）U/L、（12.48±3.10）U/L；P均〈0.01]；T[（11.14±3.82）nmol/L]低于对照组[（13.15±1.36）nmol/L；P〈0.05]。血清LH水平与睡眠呼吸暂停低通气指数（AHI）呈显著负相关（r=-0.548，P〈0.01），与氧减〈90%的时间（min）和血氧饱和度〈90%时间占总监测数据的百分比（TS90%）呈负相关（r=-0.317，P〈0.05；r=-0.315，P〈0.05）；与LSpO2呈显著正相关（r=0.633，P〈0.01）。血清FSH水平与AHI呈显著负相关（r=-0.557，P〈0.01）；与LSpO2呈显著正相关（r=0.540，P〈0.01）。血清T与AHI和TS90%呈显著负相关（r=-0.468，P〈0.01；r=-0.442，P〈0.01）、与氧减〈90%的时间（min）呈负相关（r=-0.378，P〈0.05）；与LSpO2呈正相关（r=0.335，P〈0.05）。结论 OSAHS男性患者存在垂体-性腺轴激素分泌异常，反馈调节紊乱，并与AHI和夜间低氧相关。     

Regulation of luteinizing hormone secretion in male sheep by endogenous estrogen

Both androgens and estrogens are implicated in the regulation of gonadotropin secretion in the male. Three experiments were conducted to determine the physiological importance of estradiol (E2) in the feedback regulation of LH secretion in male sheep. In the first experiment, LH secretion in castrate rams (wethers) was shown to be susceptible to the picomolar concentrations of E2 found in intact rams. In the second experiment, aminoglutethimide (AG) was administered to testosterone-implanted wethers to block aromatization of testosterone and ascertain the possible consequences of E2 deprivation on testosterone-mediated LH suppression. AG had no apparent effect on serum testosterone, but reduced serum E2 by half and increased serum LH approximately 3-fold. These data suggest that aromatization of testosterone to E2 is a physiologically important step in the regulation of LH secretion in the ram and that aromatization occurs, at least in part, in peripheral tissues. The relative contributions of peripherally and centrally derived E2 in the regulation of LH remain uncertain. In the third experiment, immunoneutralization of endogenous E2 in intact rams by active immunization against E2 was shown to stimulate pulsatile LH secretion and elevate basal and mean LH concentrations. Associated with this LH response was a significant increase in serum testosterone, such that immunized rams exposed to a nonstimulatory 16-h light, 8-h dark photoperiod had testosterone concentrations equivalent to those of control rams exposed to a stimulatory 8-h light, 16-h dark photoperiod. Together, these findings emphasize the importance of E2 in the control of male reproduction and suggest the possibility of improving year-round reproductive performance of the domestic ram through E2 immunoneutralization.     

Effects of new multi-site hormone blockers on the fertility of male rats.

The effects on the fertility of adult male rats of six new synthetic steroids: I, 3-cyano-5alpha-androst-1-en-17-one; II, the 17beta-acetate form of I; III, 17beta-hydroxy-5beta-cyano-androstan-3-one; IV, 6-methylpregnenolone; V, 17beta-hydroxy-17alpha-ethynyl-5beta-cyano-19-norandrostan-3-one; and VI, 19-norspiroxenone (oestr-4-en-3-one-spiro-17alpha-2'-[tetrahydrofuran]) have been tested. After 6 weeks of treatment with daily doses of 5 mg (I, II, III), 15 mg (IV) or 10 mg (V, VI) only steroid VI blocked the completion of spermatogenesis and reduced the number of foetuses sired in at least five females/male. Steroid VI also diminished seminal vesicular, prostatic, testicular and epididymal weights. It inhibited the testicular enzymes, 3beta-hydroxysteroid dehydrogenase-delta4-5-3-oxosteroid isomerase system, 17alpha-hydroxylase, and C17-20 lyase markedly, but did not affect the adrenal dehydrogenase-isomerase system. It depressed, strikingly, testicular and serum levels of testosterone and 5alpha-dihydrotestosterone and reduced pituitary and serum levels of FSH and LH. Although marked depression of target organ weights also occurred with steroids II, IV and V, and reduction of androgen levels and LH in the circulation with III, IV and V, only VI was a potent blocker of male fertility with the exception of a slight block of the siring of viable foetuses by steroids IV and V. The major difference in site of action of steroid VI from the others was the depression of pituitary and serum levels of FSH along with a marked diminution of testicular content of both testosterone and 5alpha-dihydrotestosterone. 19-Norspiroxenone in the rat is a potent anti-oestrogen without inherent oestrogenicity and is anti-uterotrophic. Thus, VI may affect male fertility by virtue of its potent anti-oestrogenic action in the hypothalamus or testis.     

低铁环境对去势小鼠血清骨钙素及骨组织影响的初步研究

目的 观察去势小鼠在低铁环境下血清骨钙素及骨微结构的变化.方法 24只12周龄C57BL/6小鼠,体重(19.5±0.5)g分为假手术组(SHAM)、模型组(OVX)、低铁组(OVX+DFO),每组8只.低铁组于卵巢切除后第2天腹腔注射甲磺酸去铁胺(DFO),剂量为30 mg/kg,每周3次,共5周;模型组、假手术组均腹腔注射同等刹量0.9％生理盐水,共5周;第5 周末取血后处死小鼠并分离子宫、左侧股骨;ELISA试剂盒检测血清骨钙素、血清铁蛋白;分析天平称子宫重量;显微CT扫描股骨末端并取目标区进行三维重建,获取骨小梁、骨皮质三维结构图像,进行松质骨、皮质骨定量分析.结果 (1)血清骨钙素、血清铁蛋白:低铁组均显著低于模型组、假手术组(P＜0.01);(2)松质骨、皮质骨骨密度:低铁组均显著低于模型组、假手术组(P＜0.01),骨小梁厚度、骨小梁间隔低铁组显著增加(P＜0.01),骨小梁数量、骨体积分数低铁组显著降低(P＜0.01).结论 一定剂量的DFO(30 mg/kg)可以降低去势小鼠血清铁蛋白水平和骨组织形成指标.     

Regulation of luteinizing hormone pulse frequency and amplitude by testosterone in the adult male rat

Our objective was to gain a better understanding of the role of testosterone (T) in regulating the minute to minute dynamics of LH secretion in the adult male rat. To this end, we examined the patterns of blood LH levels in intact animals and evaluated the effect of small physiological doses of T on mean blood LH and FSH levels and on LH pulse frequency and amplitude in the castrate animal. The intact rat exhibited low frequency (period, approximately 145 min) and low amplitude (approximately 16 ng/ml) LH pulses. After castration, LH pulse frequency (period, approximately 20 min) and amplitude (approximately 118 ng/ml) increased dramatically over that of intact animals. T, administered to castrate rats through Silastic implants, caused a dose-dependent and parallel reduction in mean blood LH and FSH levels. The lowest T dose, which increased mean plasma T levels to 0.5 ng/ml above those of the sham-treated castrates, produced a significant reduction in LH pulse frequency, with a significant increase in pulse amplitude. The next highest T dose caused a reduction in pulse amplitude to a value significantly lower than that in the sham-treated castrates. The highest T dose, which produced steady state mean plasma T levels (approximately 1.6 ng/ml) less than the mean level of the intact group (approximately 2.2 ng/ml), caused a profound reduction in pulse frequency to lower than that of the intact group. These observations demonstrate that T can exert a complex, dose-dependent effect on LH secretory dynamics and imply that one important site of T-mediated negative feedback is the brain's LHRH pulse generator.     

Serum osteocalcin (bone Gla-protein) following corticosteroid therapy in postmenopausal women with rheumatoid arthritis. Comparison of the effect of prednisone and deflazacort

Summary In 28 postmenopausal women with rheumatoid arthritis, serum osteocalcin (OC) concentration decreased from 5.2±1.9 ng/ml to 3.0±1.6 ng/ml after 6 months therapy with corticosteroids (p<0.005). No differences, however, were found in a control group of 13 patients treated for 6 months with nonsteroidal anti-inflammatory drugs. In those patients with serial OC measurements, changes in serum OC were already evident within the first month of therapy. This suggests that a suppressed osteoblast function may be detectable early during corticosteroid therapy in rheumatoid arthritis. Fifteen patients treated with prednisone (5–25 mg once daily, mean 12.33 mg/day) showed a more marked decrease in serum OC than 13 patients treated with equivalent doses of deflazacort (p<0.005). Prednisone therapy at doses higher than 10 mg/day resulted in a severe suppression of OC values in most cases. The effect of deflazacort was, however, mild in the majority of patients treated with doses of up to 30 mg/day.     

雄激素对扩张型心肌病慢性心力衰竭雄性大鼠心肌细胞凋亡的影响

目的:探讨雄激素对扩张型心肌病慢性心力衰竭雄性大鼠心肌细胞凋亡的影响。方法:将74只雄性SD大鼠分为:正常对照组(A组)、心力衰竭组(B组)、睾丸切除加心力衰竭组(C组)、睾丸切除加心力衰竭加睾酮替代治疗组(D组)。通过超声心动图观察大鼠左室收缩功能的变化,应用放射免疫法检测大鼠血浆神经内分泌激素(睾酮)和肿瘤坏死因子-α水平,用凋亡原位检测方法(TUNEL法)检测心肌组织凋亡细胞,计算凋亡指数。结果:与B、C组比较,D组肿瘤坏死因子-α水平明显降低,心肌细胞凋亡指数减少,心功能也明显改善。结论:雄激素能抑制扩张型心肌病雄性大鼠心肌细胞的凋亡,从而保护了心功能,其作用的一个重要机制即是雄激素能拮抗肿瘤坏死因子-α的产生。     

Frailty in relation to variations in hormone levels of the hypothalamic-pituitary-testicular axis in older men: results from the European male aging study

OBJECTIVES: To explore the associations between frailty and reproductive axis hormones (as an important regulatory system) in middle aged and older men. DESIGN: Cross‐sectional. SETTING: The European Male Aging Study. PARTICIPANTS: Three thousand two hundred nineteen community‐dwelling European men aged 40 to 79. MEASUREMENTS: Interviewer‐assisted questionnaires to assess physical activity, health status, and mood were administered. Testosterone (T), luteinizing hormone (LH), follicle‐stimulating hormone (FSH), dehydroepiandrosterone sulfate (DHEAS), and sex hormone–binding globulin (SHBG) were measured in a fasting morning blood sample. Frailty was assessed as an index (FI) according to the number (out of 43 possible) of health deficits (symptoms, signs, and functional impairments). Relationships between FI and hormone levels (as outcomes) were explored using regression models. RESULTS: Mean FI was 0.12 ± 0.11 (range 0–0.67) was highest in the oldest group. After adjustment for confounders, higher levels of FI were significantly associated with lower levels of total T, free T, and DHEAS and higher levels of gonadotropins and SHBG; a 1‐standard deviation cross‐sectional increase in FI was associated with a regression coefficient of ?0.30 nmol/L (95% confidence interval (CI)=?0.53 to ?0.07) decrease in total T and 0.66 U/L (95% CI=0.48–0.83) increase in LH. CONCLUSIONS: The associations between high FI, high gonadotropins, and well‐maintained circulating T suggest that these changes are markers of aging‐related disruptions of multiple physiological regulation, of which alterations in pituitary–testicular function represent a sensitive marker rather than an underlying pathogenic mechanism for frailty.     

Embryonic gonadotropin-releasing hormone signaling is necessary for maturation of the male reproductive axis

Gonadotropin-releasing hormone (GnRH) signaling regulates reproductive physiology in mammals. GnRH is released by a subset of hypothalamic neurons and binds to GnRH receptor (GnRHR) on gonadotropes in the anterior pituitary gland to control production and secretion of gonadotropins that in turn regulate the activity of the gonads. Central control of reproduction is well understood in adult animals, but GnRH signaling has also been implicated in the development of the reproductive axis. To investigate the role of GnRH signaling during development, we selectively ablated GnRHR-expressing cells in mice. This genetic strategy permitted us to identify an essential stage in male reproductive axis development, which depends on embryonic GnRH signaling. Our experiments revealed a striking dichotomy in the gonadotrope population of the fetal anterior pituitary gland. We show that luteinizing hormone-expressing gonadotropes, but not follicle-stimulating hormone-expressing gonadotropes, express the GnRHR at embryonic day 16.75. Furthermore, we demonstrate that an embryonic increase in luteinizing hormone secretion is needed to promote development of follicle-stimulating hormone-expressing gonadotropes, which might be mediated by paracrine interactions within the pituitary. Moreover, migration of GnRH neurons into the hypothalamus appeared normal with appropriate axonal connections to the median eminence, providing genetic evidence against autocrine regulation of GnRH neurons. Surprisingly, genetic ablation of GnRHR expressing cells significantly increased the number of GnRH neurons in the anterior hypothalamus, suggesting an unexpected role of GnRH signaling in establishing the size of the GnRH neuronal population. Our experiments define a functional role of embryonic GnRH signaling.     

Reversal of chronic ethanol-induced testosterone suppression in peripubertal male rats by opiate blockade

Teenage drinking continues to be a significant problem in the U.S., as well as abroad. We have previously demonstrated that opiate blockade with naltrexone, a drug currently used in patients to diminish alcohol craving, prevented the fall in serum testosterone seen after acute ethanol (EtOH) exposure in young, peripubertal male rats. To follow-up on this reversal, a series of experiments was performed to determine if naltrexone would also prevent the testosterone suppression caused by chronic EtOH exposure. Peripubertal rats either 45 days old (mid-pubertal) or 55 days old (late pubertal) were fed an EtOH-containing liquid diet or pair-fed control diet for 14 days. Each animal was implanted with either a naltrexone containing or placebo pellet before starting the liquid diet. In each age group, EtOH alone significantly suppressed testosterone, whereas naltrexone prevented this fall, although it had no effect alone. Serum luteinizing hormone was also suppressed by EtOH; however, naltrexone did not abrogate this fall. In the 45-day-old animals, beta-luteinizing hormone mRNA levels rose significantly in the EtOH group, but not when naltrexone was coadministered with EtOH. There was no change in hypothalamic luteinizing hormone releasing hormone (LHRH) mRNA, pro-LHRH, or LHRH in any group at either age. Thus, naltrexone is able to partially prevent the EtOH-induced suppression of gonadal testosterone of young, adolescent male rats. This effect appears to be mediated directly at gonadal level, because hypothalamic and pituitary hormone changes were minor and nonsignificant.