Kisspeptins 对下丘脑-垂体-性腺轴作用机制新进展

近年来,Kisspeptins 的发现使人们对调控青春期和生殖的神经内分泌轴有了新的认识。Kisspeptins 不仅是促进 GnRH 分泌的上游因子,而且调控下丘脑-垂体-卵巢轴,主要表现在促性腺激素分泌的调节、青春期的启动以及生殖功能的调控等方面。 通过对健康人群及生殖内分泌紊乱患者的观察,发现 Kisspeptins 可以刺激 GnRH 分泌,后者诱导 LH 分泌,而且增强 LH 的脉冲频率。这些研究表明 Kisspeptins 将成为生殖内分泌研究的热点,并为生殖内分泌疾病提供新的治疗策略。目前许多动物试验研究证明 Kisspeptins 在以下几个方面也存在潜在的作用,如卵巢的功能的调节、胚胎植入及胎盘的形成。本文将集中收集关于 Kisspeptins 调控 GnRH 的脉冲式分泌的现有的依据,特别是青春期启动及生殖内分泌方面。     

抗早熟Ⅱ号对青春期大鼠长骨干骺端胰岛素样生长因子1及其受体基因表达的影响

目的观察抗早熟Ⅱ号对青春期大鼠长骨干骺端胰岛素样生长因子1(IGF1)及胰岛素样生长因子1受体(IGF1蛳R)基因表达的影响,探讨抗早熟Ⅱ号对长骨干骺端骨生长的作用机理。方法将青春期SD雌性大白鼠分为2组,对照组喂饲生理盐水1个月,实验组喂饲抗早熟Ⅱ号中药合剂1个月,采用实时荧光RT蛳PCR定量检测技术检测大鼠长骨干骺端IGF1mRNA及IGF1蛳RmRNA表达水平。结果实验组长骨干骺端IGF1基因表达水平较对照组显著下调(t=10.268,P<0.05);两组间IGF1蛳R基因表达水平差异无统计学意义(t=0.110,P=0.914)。结论抗早熟Ⅱ号通过使长骨干骺端软骨细胞IGF1的基因表达水平下调,从而抑制长骨生长,延缓骨骼成熟。     

加减知柏地黄丸对特发性中枢性性早熟患者骨相关指标的影响

目的 探讨特发性中枢性性早熟女童骨相关指标异常的规律及加减知柏地黄丸治疗的效果.方法 对不同年龄水平的性早熟女童进行N-MID骨钙素片段(N-MID OCT)、Ⅲ型前胶原氨基末端前肽(PⅢNP)和胃促生长素(Ghrelin)含量的测定,将各项指标与正常同龄儿作比较,以探讨患儿骨骼发育异常的规律.其中60例患儿随机单盲分成两组,分配无差异,经加减知柏地黄丸治疗和亮丙瑞林西药对照组治疗,病情缓解后观察骨相关指标.结果 治疗组与对照组治疗前后比较差异无统计学意义(P＞0.05),治疗组治疗前N-MID OCT、PⅢNP、Ghrelin分别为(110.51±11.16)、(31.73±0.30)、(2.73±0.04),治疗6个月,N-MID OCT、PⅢNP分别为(92.22±3.80)和(29.46±0.88),都出现下降,差异均有统计学意义(均P＜ 0.01),Ghrelin为(2.74±0.03),差异无统计学意义(P＞0.05),治疗1年,N-MID OCT、PⅢNP分别为(61.49±4.64)和(23.14±1.47),均下降Ghrelin为(2.86±0.03)上升,差异均有统计学意义(均P＜ 0.01).结论 加减知柏地黄丸可改变ICPP患儿骨相关指标N-MIDOCT、PⅢNP、Ghrelin的水平,抑制成骨细胞过度亢进活动.     

高效液相色谱-荧光检测法测定性早熟女童血浆中双酚A和4-壬基酚的含量

目的：建立高效液相色谱-荧光检测法测定性早熟女童血浆中双酚A和4-壬基酚含量的方法。方法：采用Shim-pack VP-ODS C18色谱柱（150 mm×4.6 mm，5 μm），流动相为乙腈∶水=70∶30，流速1 mL/min，柱温30 ℃，检测激发波长275 nm，发射波长315 nm，外标法定量检测血浆中双酚A和4-壬基酚含量。结果：双酚A和4-壬基酚分别在1.45~5 937.50 ng/mL （r2=0.999 9，n=7），1.53~6 250.00 ng/mL（r2=0.998 8，n=7）范围内线性关系良好；日内、日间RSD均<7.83%，方法回收率均>94.6%。结论：本法简便、快速、灵敏、准确，适用于同时测定性早熟女童血浆中双酚A和4-壬基酚的含量和临床血样常规检测。     

青春期前特发性矮身材儿童的生长激素应用剂量研究

目的 研究重组人生长激素(rhGH)的不同应用剂量对青春期前特发性矮身材(ISS)儿童的临床治疗疗效。方法 选取2014年3月-2016年6月于郑州市妇幼保健院接受治疗的68例ISS患儿为研究对象,在经郑州市妇幼保健院伦理委员会通过的情况下,将其按照随机数表分成两组,其中34例采用皮下注射rhGH 0.25 mg/(kg·每周)为低剂量组,34例采用皮下注射rhGH 0.40 mg/(kg·每周)为高剂量组,治疗疗程均为14个月,对比两组患儿治疗后生长速度(GV)、身高标准差积分(HtSDS)、骨龄以及不良反应的发生率。结果 研究发现,两组患儿在治疗前后的身高(cm)(107.4±6.85 vs. 126.7±7.15)、GV(7.45±1.09 vs. 11.68±1.37)以及HtSDS(-0.96±0.43 vs. -0.64±0.52)等存在明显差异,差异具有统计学意义(P<0.05),两组患儿的骨龄比较,差异无统计学意义(P>0.05);两组患儿出现注射部位红肿、疼痛的例数比较,差异无统计学意义(P>0.05),均可自行消退。结论 rhGH对治疗ISS有显著效果,高剂量rhGH的治疗效果优于低剂量rhGH。     

Association between Lead and Cadmium and Reproductive Hormones in Peripubertal U.S. Girls

Background

Lead (Pb) and cadmium (Cd) are known reproductive toxicants thought to disrupt hormone production throughout sensitive developmental windows, although this has not been previously examined in nationally representative peripubertal children.

Objectives

We examined the association between blood Pb and urinary Cd concentrations and the reproductive hormones inhibin B and luteinizing hormone (LH) in girls 6–11 years of age who participated in the cross-sectional Third National Health and Nutrition Examination Survey (NHANES III) (1988–1994).

Methods

Pb (micrograms per deciliter) was measured in whole blood, and Cd was measured in urine (nanograms per milliliter). Inhibin B (picograms per milliliter) and LH (milli–International units per milliliter) were measured in residual sera for 705 girls. Survey logistic regression was used to estimate associations with pubertal onset based on inhibin B concentration > 35 pg/mL or LH concentration > 0.4 mIU/mL, and multinomial logistic regression was used to estimate the association between Pb and increasing categories of hormone concentrations.

Results

High Pb (≥ 5 μg/dL) was inversely associated with inhibin B > 35 pg/mL [odds ratio (OR) = 0.26; 95% confidence interval (CI), 0.11–0.60; compared with Pb < 1 μg/dL]. At 10 and 11 years of age, girls with low Pb (< 1 μg/dL) had significantly higher inhibin B than did girls with moderate (1–4.99 μg/dL) or high Pb (≥ 5 μg/dL). In the subsample of 260 girls with levels of inhibin B above the level of detection and using survey regression modeling, inhibin B levels were lower among girls with both high Pb and high Cd (β = −0.52; 95% CI, −0.09 to −1.04) than among girls with high Pb alone (β = −0.35; 95% CI, −0.13 to −0.57), relative to girls with low Pb and low Cd.

Conclusions

Higher Pb was inversely associated with inhibin B, a marker of follicular development, and estimated effects suggestive of pubertal delays appeared to be stronger in the context of higher Cd concentrations. These data underscore the importance of Pb and Cd as reproductive toxicants for young girls.     

Reproductive and developmental effects of phthalate diesters in females

Abstract

Phthalate diesters, widely used in flexible plastics and consumer products, have become prevalent contaminants in the environment. Human exposure is ubiquitous and higher phthalate metabolite concentrations documented in patients using medications with phthalate-containing slow release capsules raises concerns for potential health effects. Furthermore, animal studies suggest that phthalate exposure can modulate circulating hormone concentrations and thus may be able to adversely affect reproductive physiology and the development of estrogen sensitive target tissues. Therefore, we conducted a systematic review of the epidemiological and experimental animal literature examining the relationship between phthalate exposure and adverse female reproductive health outcomes. The epidemiological literature is sparse for most outcomes studied and plagued by small sample size, methodological weaknesses, and thus fails to support a conclusion of an adverse effect of phthalate exposure. Despite a paucity of experimental animal studies for several phthalates, we conclude that there is sufficient evidence to suggest that phthalates are reproductive toxicants. However, we note that the concentrations needed to induce adverse health effects are high compared to the concentrations measured in contemporary human biomonitoring studies. We propose that the current patchwork of studies, potential for additive effects and evidence of adverse effects of phthalate exposure in subsequent generations and at lower concentrations than in the parental generation support the need for further study.     

Continuous exposure to dibromoacetic acid delays pubertal development and compromises sperm quality in the rat.

Previously our work on the haloacid by-products of drinking water disinfection focused on adult exposures. Herein we evaluate the consequence of continuous exposure to dibromoacetic acid (DBA) via drinking water through reproductive development into adulthood. An initial study in which offspring were exposed from gestation day (GD) 15 through adulthood revealed significant delays in preputial separation and vaginal opening, dose-related decreases in the fertility of cauda epididymal sperm, and dose-related diminutions in the sperm membrane protein SP22. Subsequent studies consisted of groups in which exposure ceased on postnatal day 21 (PND 21) versus adulthood. For each exposure, animals were evaluated after puberty (PND 56) as well as at adulthood (PND 120). Exposure to 4, 40, or 400 ppm DBA from GD 15 through PND 21 failed to result in any significant reproductive alterations. By contrast, continuous exposure until adulthood resulted in dose-related alterations consistent with those observed in the dose-finding study. Preputial separation and vaginal opening were delayed 4 and 3 days in males and females exposed to 400 ppm (76.3 mg/kg) DBA. This was associated with increased responsiveness of both the testis and ovary to hCG ex vivo; hCG-stimulated testosterone production by testicular parenchyma on PND 56 was increased at 4 ppm (0.6 mg/kg) DBA and higher. Finally, the quality of proximal cauda epididymal sperm was compromised by continuous exposure to DBA. The sperm membrane proteome was altered in a dose-related manner with SP22, and one of its charged variants, diminished at 40 ppm (3.6 mg/kg) DBA and higher. As more sensitive endpoints are evaluated, lower effect levels can be attributed to haloacid exposure. We are now extending our evaluations to epidemiology studies designed to evaluate sperm quality in men exposed to varying levels of disinfection by-products.     

特发性中枢性性早熟女童血浆kisspeptin、神经激肽B及强啡肽浓度的变化研究

目的 研究特发性中枢性性早熟(ICPP)女童血浆kisspeptin,神经激肽B(NKB)及强啡肽浓度的变化,探索其在ICPP发病中的作用。方法 选取2016年1月-2017年1月在山东大学齐鲁医院确诊为ICPP并未经治疗的女童50例,观察并比较ICPP女童与正常健康女童以及ICPP女童治疗前后性发育状况和血浆kisspeptin、神经激肽B、强啡肽浓度的变化。结果 未行治疗的ICPP女童的骨龄、骨龄/年龄、身高标准差单位(SDS)、黄体生成素基础值(B-LH)、卵泡刺激素基础值(B-FSH)、雌二醇(E2)、kisspeptin、NKB与健康对照组相比差异均有统计学意义(P<0.01),治疗6个月后,其B-LH、黄体生成素峰值(P-LH)、B-FSH、卵泡刺激素峰值(P-FSH)、P-LH/P-FSH、E2、kisspeptin、NKB较治疗之前均显著下降(P<0.01),治疗12个月后上述指标与治疗6个月时差异无统计学意义(P>0.05),强啡肽在各组之间差异无统计学意义(P>0.05)。ICPP女童接受促性腺激素释放激素类似物(GnRHa)治疗后,其性发育在3个月之内均得到明显控制,持续观察至12月,性发育均未再明显进展。Kisspeptin和NKB、P-LH、P-LH/P-FSH、E2均存在明显正相关关系(P<0.05),NKB和kisspeptin、P-LH、P-LH/P-FSH、E2也存在明显正相关关系(P<0.05)。结论 Kisspeptin和NKB在ICPP的发病过程中起重要作用,其有可能成为监测儿童性发育及评价ICPP治疗效果的有效指标。