电针对正常大鼠性发育前后下丘脑GnRH释放调控的影响

目的 观察电针(EA)对不同发育阶段大鼠下丘脑促性腺激素释放激素(GnRH)的影响.方法 218只SD大鼠分为幼年段(JG)、青春发育早期段(EPG)、青春发育后期段(LPG)和成年段(AG);每个年龄段随机分为穴位组(EWA)、非穴位组(ENA)、非特异刺激组(IC)和自然对照组(NC).EWA组选取百会、太溪、命门、肾俞穴.3 Hz的EA分别刺激EWA组与ENA组大鼠10 d,每天20 min.10 d后测定所有大鼠下丘脑GnRH mRNA的表达.结果 EPG与LPG中的EWA组大鼠在持续电针后GnRH mRNA的表达明显受到抑制(P＜0.01).结论 持续EA刺激可降低青春发育早期与成熟期大鼠下丘脑GnRH的释放.     

子宫肌瘤药物治疗研究进展

子宫肌瘤是女性生殖器官最常见的良性肿瘤 ,是卵巢依赖性肿瘤。月经过多是子宫肌瘤的主要症状 ,约占 3 0 % ,常导致贫血 ,其次有压迫症状、下腹痛、不育等症状。过去均以手术治疗有症状的子宫肌瘤 ,近年来研究认为子宫能产生多种生物活性物质 ,并有内分泌功能 ,参与体内生殖、生理及病理过程。绝经前切除子宫者即使保留卵巢 ,也常引起更年期综合征、冠心病及骨质疏松的提早出现 ,故采用药物治疗子宫肌瘤越来越引起人们的重视。随着分子生物学技术的发展 ,对子宫肌瘤的发生机制进行了深入研究 ,提高了对该疾患的认识水平 ,子宫肌瘤是受性激素…     

促性腺激素释放激素类似物化学合成研究进展

促性腺激素释放激素是由下丘脑分泌的一种肽类物质,主要作用于生殖系统.经过人工合成改性、置换或者去除部分氨基酸得到了药效更优的促性腺激素释放激素类似物.该类化合物依据对垂体促性腺激素释放激素受体的作用被分为激动剂及拮抗剂.目前被广泛用于前列腺癌的临床治疗.本文综述了上市的七种用于治疗前列腺癌的促性腺激素释放激素类似物的化...     

低剂量促性腺激素释放激素类似物在人工授精周期的应用

在人工授精周期 ,为了提高妊娠率 ,往往要对卵巢进行刺激 ,促使多个卵泡发育。传统的卵巢刺激方案是克罗米芬/促性腺激素 (h MG)。但应用该方案时 ,有时会发生自发性黄体生成素 (LH)峰 ,使卵子的质量下降。低剂量促性腺激素释放激素类似物 (Gn RHa)可使垂体功能下调 ,从而防止自发性 LH峰。近年来 ,广泛应用于体外受精——胚胎宫腔内移植周期。但目前 Gn RHa的剂量很不统一。而 Gn RHa剂量过大可造成垂体功能过度抑制 ,增加 h MG的用量 ,加重患者的经济负担。在本研究中 ,我们在人工授精周期应用低剂量 Gn RHa/h MG方案 ,并与传统…     

Biological characterization of a novel and potent gonadotropin releasing hormone （GnRH） antagonist LXT-101

AIM The biological characterization of LXT-101 was investigated in vivo using intact male rats and nude mice bearing xenografts of LNCaP prostate cancer. The effect of LXT-101 on the proliferation of androgen -sensitive prostate cancer cell LNCaP and androgen-insensitive DU145 and PC-3M in vitro was also determined. METHODS Rats were injected subcutaneously with LXT-101 while control animals received only vehicle (5% mannitol). Blood samples were collected at different time after adminis-tration of LXT-101. The androgen-dependent LNCaP prostate cancer cells were grown, mixed with Matrigel and injected subcutaneously into nude mice. Experimental group received LXT-101 injectionfor up to 4 weeks. At the end point, blood samples were drawn and the excised tumors and sex organswere weighted. The serum testosterone was determined by specific immunochemiluminescence assay using kits produced by Beckman-Counter Co. The mRNA expressions of the genes of hormone receptor related to the gonadal axis were investigated by real-time RT-PCR technique. Cell viability was determined by MTT method.     

性早熟女孩促性腺激素释放激素类似物激发试验结果分析

目的对促性腺激素释放激素类似物（GnRHa）激发试验不同时相的结果分析,探讨单时相GnRHa激发试验对性早熟的诊断价值。方法应用GnRHa激发试验4个时相促性腺激素的值、B超检查、骨龄评估等方法对60例性早熟女孩进行诊断。结果GnRHa激发试验0、30、60、120min的LH,FSH浓度相比差异有统计学意义。30、60、120min的LH浓度相比差异无统计学意义,与LH峰值相比差异无统计学意义,60min的LH浓度最接近峰值。结论LH基值对性早熟性质无诊断价值,GnRHa激发试验被证实能鉴别性早熟性质,简化的60minGnRHa激发试验具有可信性。     

促性腺激素释放激素类似物在妇科疾病治疗中的应用

促性腺激素释放激素类似物广泛用于妇科疾病治疗,掌握其作用特点和使用方法可取得较好的效果。本文简要介绍促性腺激素释放激素类似物在妇科疾病治疗中的应用。     

促性腺激素释放激素激动剂对子宫内膜异位症术后复发和生活质量的影响

目的：探讨促性腺激素释放激素激动剂（GnRHa）对子宫内膜异位症术后复发和生活质量的影响。方法：将2010年1月至2012年1月期间我院收治的子宫内膜异位症患者82例按数字随机法分为观察组和对照组,每组患者41例。对照组接受常规的子宫内膜异位手术及术后抗感染治疗,观察组在对照组的基础上于术后月经来潮第2天皮下注射曲普瑞林（3.75 mg,每28天1次,共治疗3次）。比较两组疗效、复发情况以及生活质量。结果：观察组疗效显著的患者比例和治疗有效率分别为58.54%和97.56%,均显著高于对照组。观察组治疗后6个月、1年和2年的复发率分别为2.44%、2.44%和4.88%,均显著低于对照组。两组治疗后躯体功能和社会功能2个维度和11个因子的生活质量评分得分均提高,且观察组得分较对照组提高。差异都有统计学意义。结论：GnRHa用于子宫内膜异位症术后辅助治疗疗效显著,可有效减少术后复发,并提高患者的生活质量,值得临床推广使用。     

Detection of gonadotropin-releasing hormone and its analogues in equine and canine urine by high-resolution data-independent acquisition

Gonadotropin-releasing hormone (GnRH) and its synthetic analogues are considered banned substances by the racing industry. GnRH is used as a pharmaceutical to regulate the female oestrous cycle, but the hormone is also thought to increase the production of testosterone in male animals. Using liquid chromatography in conjunction with high-resolution mass spectrometry (LC–HRMS) and data-independent acquisition (DIA), a method is presented for the detection of intact and truncated peptides of GnRH and its analogues down to the low picogram level in equine urine. The study of the catabolism of GnRH and analogues in plasma, combined with the analysis of urine from administration studies, reveals a common pattern of peptide catabolites that can be used to guide the design of MS-based screens for this class of drugs. This culminated in the successful detection of the peptide in two out-of-competition canine urine samples.     

Interaction of gonadotropin-releasing hormone and its agonist analogs with Ca2+ in a nonpolar milieu. Correlation with biopotencies

Extracellular Ca²⁺ is necessary for the action of gonadotropin-releasing hormone (GnRH). Assuming that this partly because of the interaction of the hormone with the relatively abundant extracellular Ca²⁺ in the low dielectric milieu of the bilayer plasma membrane, we studied the interaction of GnRH and five of its agonist analogs with Ca²⁺ under membrane-mimetic conditions. The peptides used, in increasing order of their reported gonadotropin-releasing activities, were: des-amide GnRH (or GnRH-OH); [Ala⁶]GnRH; [d -Ala⁶]GnRH; des-Gly¹⁰[d -Ala⁶,Pro⁹-NHEt]GnRH and, des-Gly¹⁰[d -Trp⁶,Pro⁹-NHEt]GnRH. Changes in the far-UV CD and fluorescence spectra of these peptides in trifluoroethanol were used to monitor conformational changes and obtain the Ca²⁺-binding isotherms. The data show that GnRH and its active analogs contain two Ca²⁺ binding sites, whereas the inactive analogs have only one. The extent of Ca²⁺ binding by the agonist peptides paralleled their biological potency ranking. The superactive analog des-Gly¹⁰[d -Trp⁶,Pro⁹-NHEt]GnRH exhibited the ability to transport Ca²⁺ ions across large unilamellar vesicles of dimyristoylphosphatidylcholine. Our study shows that significant differences among the GnRH and its analog peptides, suggestive of differences in their conformations, are manifested only in the presence of Ca²⁺. This observation would provide a basis for understanding GnRH action in terms of the hormone's interaction with Ca²⁺ in the lipid milieu.     

GnRH类似物在乳腺癌治疗中的应用和卵巢功能保护

促性腺激素释放激素（gonadotropin—releasing hormone,GnRH）类似物治疗绝经前乳腺癌具有疗效好、停药后卵巢功能可恢复的特点,已取代手术和放疗成为治疗绝经前乳腺癌的一种主要治疗手段,现主要介绍GnRH类似物在乳腺癌内分泌治疗中的应用及其卵巢功能保护作用。     

促性腺激素释放激素拮抗剂elagolix

促性腺激素释放激素(Gn RH)拮抗剂是在促性腺激素释放激素的基础上经过人工改造,使其在体内不易被酶裂解,稳定性增强,半衰期延长的一种药物,临床应用更安全。其主要通过快速竞争性地与GnRH受体结合阻断信号的传递,从而达到临床治疗目的。艾伯维公司与Neurocrine Biosciences公司共同开发的elagolix是一种口服GnRH拮抗剂,通过抑制脑垂体促性腺释放激素受体,最终降低血循环中的性腺激素水平来治疗子宫内膜异位症,目前处于临床Ⅲ期,计划在2017年提交其治疗子宫内膜异位症的新药申请。     

Mechanisms of interaction of endocrine-disrupting chemicals with glutamate-evoked secretion of gonadotropin-releasing hormone.

In previous studies, we detected a dichlorodiphenyltrichloroethane (DDT) derivative in the serum of children with sexual precocity after migration from developing countries. Recently, we reported that DDT stimulated pulsatile gonadotropin-releasing hormone (GnRH) secretion and sexual maturation in the female rat. The aim of this study was to delineate the mechanisms of interaction of endocrine-disrupting chemicals including DDT with GnRH secretion evoked by glutamate in vitro. Using hypothalamic explants obtained from 15-day-old female rats, estradiol (E2) and DDT caused a concentration-related increase in glutamate-evoked GnRH release while p,p'-dichlorodiphenyldichloroethene and methoxychlor had no effect. The effective DDT concentrations in vitro were consistent with the serum concentrations measured in vivo 5 days after exposure of immature rats to 10 mg/kg/day of o,p'-DDT. Bisphenol A induced some stimulatory effect, whereas no change was observed with 4-nonylphenol. The o,p'-DDT effects in vitro were prevented partially by a selective antagonist of the alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) subtype of glutamate receptors. A complete prevention of o,p'-DDT effects was caused by an estrogen receptor (ER) antagonist as well as an aryl hydrocarbon receptor (AHR) antagonist and inhibitors of protein kinases A and C and mitogen-activated kinases. While an intermittent incubation with E2 caused no change in amplification of the glutamate-evoked GnRH release for 4 h, continuous incubation with E2 or o,p'-DDT caused an increase of this amplification after 3.5 h of incubation. In summary, DDT amplifies the glutamate-evoked GnRH secretion in vitro through rapid and slow effects involving ER, AHR, and AMPA receptor mediation.     

A randomized controlled trial of gonadotropin-releasing hormone agonist versus gonadotropin-releasing hormone antagonist in Iranian infertile couples: oocyte gene expression

Background

The main objective of the present work was to compare the effects of the gonadotropin-releasing hormone agonist (GnRH-a) and GnRH antagonist (GnRH-ant) on the gene expression profiles of oocytes obtained from Iranian infertile couples undergoing in vitro fertilization (IVF).

Methods

Fifty infertile couples who underwent IVF between June 2012 and November 2013 at the Infertility Center of Tehran Women General Hospital, Tehran University of Medical Sciences, were included in this study. We included women that had undergone IVF treatment because of male factor, tubal factor, or unexplained infertility. The women randomly underwent controlled ovarian stimulation (COS) with either the GnRH-a (n = 26) or the GnRH-ant (n = 24). We obtained 50 germinal vesicle (GV) oocytes donated by women in each group. After the sampling, pool of 50 GV oocytes for each group was separately analyzed by quantitative polymerase chain reaction (qPCR).

Result

The expression levels of Adenosine triphosphatase 6 (ATPase 6), Bone morphogenetic protein 15 (BMP15), and Neuronal apoptosis inhibitory protein (NAIP) genes were significantly upregulated in the GnRH-ant group compared to the GnRH-a group, with the fold change of 3.990 (SD ± 1.325), 6.274 (SD ± 1.542), and 2.156 (SD ± 1.443), respectively, (P < 0.001). Growth differentiation factor 9 (GDF9) mRNA did not have any expression in the GnRH-a group; however, GDF9 mRNA was expressed in the GnRH-ant group. Finally, it was found that the genes involved in the DNA repairing and cell cycle checkpoint did not have any expression in either group.

Conclusion

The present study showed, for the first time, the expression levels of genes involved in the cytoplasmic maturity (BMP15, GDF9), adenosine triphosphate production (ATPase 6), and antiapoptotic process (NAIP), in human GV oocytes were significantly higher in the GnRH-anta group than in the GnRH-a group in COS. Higher expression level of these genes when GnRH-ant protocol is applied, this protocol seems to be a more appropriate choice for women with poly cystic ovarian syndrome, because it can probably improve the expression of the aforementioned genes.

Trial registration

Current Controlled Trials: IRCT 2014031112307 N3.     

New developments in the use of peptide gonadotropin-releasing hormone antagonists versus agonists

Gonadotropin-releasing hormone (GnRH) stimulates the pituitary secretion of both luteinising hormone (LH) and follicle-stimulating hormone (FSH), and thus controls the hormonal and reproductive functions of the gonads. The blockade of the effects of GnRH may be sought for a variety of reasons; for example, to control premature LH surges and to reduce the cancellation rate with the aim of improving the pregnancy rate per treatment cycle or in the treatment of sex hormone-dependent disorders. Selective blockade of LH/FSH secretion and subsequent chemical castration have previously been achieved by desensitising the pituitary to continuously administered GnRH or by giving long-acting GnRH agonists. GnRH analogues are indicated for clinical situations in which the suppression of endogenous gonadotropins (precocious puberty, contraception and controlled ovarian hyperstimulation) or sexual steroids (endometriosis, prostate hyperplasia, cancer and uterine fibroids) is desired. The immediate suppression of the pituitary that is achieved by GnRH antagonists without an initial stimulatory effect is the main advantage of these compounds over the agonists. GnRH antagonists have been developed for clinical use with acceptable pharmacokinetic, safety and commercial profiles. In assisted reproduction, these compounds seem to be as effective as established therapy, but with shorter treatment times, less use of gonadotropic hormones, improved patient acceptance, and fewer follicles and oocytes. All of the current indications for GnRH agonist desensitisation may prove to be indications for a GnRH antagonist, including endometriosis, leiomyoma and breast cancer in women, benign prostatic hypertrophy and prostatic carcinoma in men, and central precocious puberty in children. However, the best clinical evidence has been in assisted reproduction and prostate cancer.