来曲唑与克氯米芬用于多囊卵巢综合征促排卵疗效比较

目的探讨来曲唑与克氯米芬用于多囊卵巢综合征（PCOS）引起无排卵性不孕妇女的促排卵效果及其对生殖激素的影响。方法选择PCOS患者41例,随机分为2组,来曲唑组（试验组）在月经周期第3～7 d口服来曲唑（LE）2.5 mg/d,克氯米芬组（对照组）在月经周期第3～7 d口服克氯米芬50 mg/d,开始超声监测卵泡发育,当最大卵泡平均直径≥18 mm时,肌肉注射绒毛膜促性腺激素（hCG）10 000 IU诱发排卵,于hCG日取肘静脉血测定黄体生成素（LH）、雌二醇（E2）、睾酮（T）,并观察排卵率、妊娠率、子宫内膜厚度及生殖激素的变化。结果来曲唑组的排卵率和周期妊娠率与克氯米芬组相似（P〉0.05）,来曲唑组单个优势卵泡的发生率和在hCG日子宫内膜的厚度均高于克氯米芬组（P〈0.05）,来曲唑组在hCG日血清LH、T水平与克氯米芬组间差异无统计学意义。结论来曲唑用于多囊卵巢综合征引起无排卵性不孕妇女具有良好的排卵率和妊娠率。     

Harm or benefit of hormonal treatment in metastatic low-grade endometrial stromal sarcoma: single center experience with 10 cases and review of the literature

Endometrial stromal sarcoma (ESS) is a rare disease with probably less than 700 new cases in the US or EU per year. ESS usually expresses steroidal receptors and is regarded to be hormone-sensitive. A higher risk in women receiving estrogen replacement therapy (ERT) or tamoxifen has been suspected, and remissions following treatment with progestins have been reported in case studies. Aromatase inhibitors represent an interesting new treatment option. Due to the rarity of the tumor, only few case series and no prospective studies are published. We therefore conducted a retrospective study to evaluate the influence of hormonal treatment to ESS. METHODS: Our institutional sarcoma data bank was screened for cases of ESS since 1999. All corresponding files and radiographs were reviewed retrospectively. RESULTS: Ten patients with low-grade ESS were identified. Diagnosis was established before or by hysterectomy in 6 patients, by local recurrence after previous hysterectomy for nonmalignant disease in 3 patients or by pulmonary metastases with no primary tumor found so far in 1 patient. 5/10 patients were on ERT and 3/10 on tamoxifen at the time of diagnosis of metastatic disease. Treatment strategies consisted of stopping ERT and tamoxifen, respectively, or initiation of the progestin MPA or letrozole. Three patients achieved stable disease after stopping ERT. 2/3 patients responded to MPA as first-line treatment (1 CR; 50+ months, 1 PR; 9 months). 4/5 patients responded to letrozole as first-line therapy (3 PR;3+, 9+ and 10+ months) or second-line treatment after MPA (1 PR; 37+ months). 9/10 patients are alive 33 to 255 months after hysterectomy. Survival since diagnosis of metastatic disease is 4 to 164 months. CONCLUSIONS: Patients with a previous history of low-grade ESS should not be treated with estrogens or tamoxifen. If nevertheless present, withdrawal of ERT or tamoxifen is strongly advised, resulting in disease stabilization in some cases. MPA and letrozole, in particular, are highly effective and lead to sustained disease control in most cases.     

Overcoming acquired resistance to letrozole by targeting the PI3K/AKT/mTOR pathway in breast cancer cell clones

Development of resistance to endocrine therapy is a clinical issue in estrogen receptor (ER)-positive breast cancer. Here we show that persistent activation of AKT/mTOR signaling is crucial to the acquisition of letrozole resistance in cell clones generated from MCF-7/AROM-1 aromatase-expressing breast cancer cells after prolonged letrozole exposure. ERα plays a marginal role in this context. As a proof of concept, the association between PI3K/AKT/mTOR signaling and insensitivity to endocrine therapies was confirmed in breast cancer patients who developed early letrozole resistance in neoadjuvant setting. In addition our results suggest that, regardless of the mechanism mediating the activation of AKT/mTOR pathway, either RAD001 or NVP-BEZ235 treatment may represent a promising strategy to overcome acquired resistance to letrozole in breast cancers dependent on AKT/mTOR signaling.     

来曲唑联合促性腺素促排卵在IVF-ET中的临床应用

目的:研究来曲唑联合促性腺激素(Gn)促排卵在体外受精胚胎移植(IVF-ET)中的应用。方法:将237例不孕患者336个完整IVF-ET助孕周期随机分成GnRHa短方案组146周期和来曲唑促排卵组190周期,比较两组的促排卵参数和临床结局。结果:来曲唑促排组促排天数、Gn总量、诱导日E2、获卵数、MII卵的百分率显著低于短方案促排卵组(P<0.05),诱导日LH、P显著高于短方案组(P<0.05),而两组的受精率、卵裂率、优质胚胎率、移植胚胎数、种植率、临床妊娠率、流产率均无统计学差异(P>0.05)。结论:来曲唑联合Gn促排卵在不影响临床妊娠率的前提下能减少Gn使用剂量,降低治疗费用,是一种很有应用前景的IVF-ET促排卵方案。     

Functional Investigation on Aromatase in Endometrial Hyperplasia in Polycystic Ovary Syndrome Cases

Objective: To explore the possible significance of aromatase P450 in endometrial hyperplasia with abackground of polycystic ovary syndrome (PCOS). Methods: Immunohistochemistry was used to determine theexpression of aromatase P450 in endometrium of PCOS patients. Semiquantitative analysis of aromatase P450expression of mRNA and protein level wasalso carried out by real-time quantitative RT-PCR method. Afterendometrial cells were stimulated by testosterone and letrozole in vitro, the estradiol (E2) level was determined,and the expression of cell aromatase P450 mRNA was assessed. Results: The aromatase P450 mRNA level wasincreased in endometria of PCOS patients. When endometrial cells were cultured with 10-6 M testosterone, theE2 level in the culture medium increased. An inhibitory effect on E2 generation and expression of aromataseP450 mRNA was observed when the endometrial cells were treated with 10-5 M letrozole. Conclusions: There isan increased expression of aromatase P450 in PCOS patient endometrium. Androgen stimulation could enhancethe synthesis of aromatase P450 mRNA and the production of E2 in endometrial cells in vitro while letrozolecould do the reverse.     

来曲唑对子宫内膜异位症大鼠TNF-α、IL-6、NF-κB表达的影响

目的:研究不同剂量来曲唑对大鼠子宫内膜异位症(EMs)模型的治疗作用及其对异位病灶中肿瘤坏死因子-α(TNF-α)、白细胞介素-6(IL-6)、核转录因子-κB(NF-κB)表达的影响。方法:将建模成功的大鼠随机分为来曲唑组(低、中、高剂量组)、米非司酮组及生理盐水空白对照组。灌胃4周后采用自定义疼痛评分及阴道痛觉过敏实验评价大鼠疼痛情况;观察异位内膜生长情况;放射免疫法测定血清E2、P、T水平;应用免疫组化法检测TNF-α、IL-6、NF-κB蛋白表达;用逆转录聚合酶链反应(RT-PCR)技术检测TNF-α mRNA、IL-6 mRNA、NF-κB mRNA的含量。结果:来曲唑各组异位病灶体积明显缩小或萎缩,与空白对照组比较差异均有统计学意义(P<0.05);来曲唑中、高剂量组与低剂量组、米非司酮组相比较,异位病灶体积缩小更明显(P<0.05)。治疗后各组大鼠血清E2、P水平均无显著差异(P>0.05),但来曲唑组大鼠血清T水平升高,且呈剂量依赖性(P<0.05)。来曲唑治疗后模型鼠疼痛评分降低,与对照组比较差异有统计学意义(P<0.05),且高剂量来曲唑组较米非司酮组疼痛减轻更明显(P<0.05)。在20、30、40mmHg阴道压力的刺激下,米非司酮组和来曲唑组大鼠的逃避率较空白组显著降低(P<0.05),较少发生痛觉过敏,而在压力为5、10mmHg时,各组间逃避率的差异无统计学意义(P>0.05)。各治疗组异位内膜中TNF-α、IL-6、NF-κB蛋白和mRNA的表达,均较空白组显著降低(P<0.05),尤以高剂量来曲唑组蛋白表达最低。NF-κB与TNF-α、IL-6的表达均呈正相关(P<0.05)。结论:来曲唑对大鼠异位病灶体积影响明显,可缓解EMs引起的疼痛。这可能是通过降低异位病灶局部雌激素水平,降调TNF-α、IL-6、NF-κB在异位内膜组织中的表达而发挥治疗作用的。     

Systematic review and meta-analysis of letrozole and clomiphene citrate in polycystic ovary syndrome

This study aims to systematically evaluate the clinical efficacy and safety of both clomiphene citrate (CC) and letrozole, and to examine if the efficacy of letrozole is superior to CC in women with polycystic ovary syndrome (PCOS).Major databases were searched for eligible randomised controlled trials (RCTs). The methodological quality of the included studies was assessed by two independent reviewers. Meta-analysis was performed using random-effect model to account for the high levels of heterogeneity. Overall, ten eligible RCTs involving 1905 women were included. Letrozole was associated with significantly higher ovulation rate (relative risk (RR) 1.20; 95% CI 1.03–1.40; P?=?0.02); clinical pregnancy rate (RR 1.48; 95% Cl 1.12–1.94; P?=?0.005) and endometrial thickness (standardized mean difference (SMD) 2.31; 95% Cl 0.85–3.76; P?=?0.002). There was no evidence of a difference between the treatment groups in the rate of miscarriage, number of mature follicles and multiple pregnancy rates. The result suggests that letrozole is a superior ovulation induction agent for women with PCOS as it is associated with higher ovulation and clinical pregnancy rates with no obvious increased side effects. However, this conclusion should be considered with a slight caution in that the quality of the evidence could have improved if more recent studies on the subject were available to be included in the review.     

多囊卵巢综合征患者再次冻融胚胎移植内膜准备方案策略

目的:探讨来曲唑促排卵及移植前预处理对多囊卵巢综合征(PCOS)患者再次冻融胚胎移植内膜准备及妊娠成功率的影响。方法:对尚有冷冻胚胎的26例PCOS初次冻融胚胎移植妊娠失败患者,应用来曲唑促排卵法作为子宫内膜准备方法,并对宫腔异常者行宫腔镜检查及治疗,对移植困难者行扩宫治疗,再次移植前常规行宫腔刺激,观察冷冻复苏移植的效果。结果:诱发排卵日E2平均水平为(326±229)pg/ml,较前次激素替代周期E2值增加,差异有统计学意义(P<0.05)。前次10例E2<100 pg/ml者经促排卵后6例临床妊娠;子宫内膜厚度、移植胚胎数和胚胎复苏率与前次移植差异无统计学意义(P>0.05),其中宫腔息肉摘除者3例均妊娠成功,移植困难者经扩宫后2例妊娠,本次移植临床妊娠率为53.84%(14/26)。结论:对于PCOS行人工周期内膜准备冻胚移植失败的患者,再次移植时可采用来曲唑促排卵,联合移植前宫腔及宫颈预处理可提高再次冻胚移植的成功率。     

Ultrasonographic markers of endometrial receptivity of letrozole and clomiphene citrate in unexplained infertile women

ObjectiveTo compare endometrial receptivity of letrozole and clomiphene citrate.Study designA prospective comparative study.Subjects120 women with unexplained infertility undergoing superovulation.InterventionSixty patients underwent ovulation induction using 5 mg letrozole compared with another 60 patients using 100 mg clomiphene citrate.Main outcomeThe endometrial thickness, the endometrial volume, uterine artery and spiral artery Doppler indices at 7 days after HCG administration.ResultsThe mean age, parity and duration of infertility in both groups of patients were similar. There was a significant difference in the endometrial thickness, endometrial volume, and spiral artery Doppler indices between the two groups one week after HCG administration. No difference was found in the uterine artery Doppler indices in both groups. The pregnancy rate was higher in the letrozole group but it was statistically insignificant.ConclusionLetrozole (5 mg) showed a significantly better endometrial response than 100 mg of clomid.     

来曲唑微刺激方案和短方案对卵巢低反应助孕的临床研究

目的:探讨卵巢低反应助孕患者在进行体外受精/卵细胞浆内单精子注射-胚胎移植(IVF/ICSI-ET)治疗中来曲唑(LE)微刺激方案和短方案的应用.方法:回顾性分析进行IVF/ICSI-ET治疗的卵巢低反应患者共206个周期.按治疗方案分短方案组(97周期)和微刺激组(109周期),分别比较两组患者的一般情况、促排卵情况及妊娠结局等.结果:短方案组的促性腺激素(Gn)用量、Gn刺激天数、HCG注射日雌激素(E2)值、≥16 mm卵泡数等均高于微刺激组,差异有统计学意义(P＜0.05).而两组成熟率、正常受精率、卵裂率、周期取消率、生化妊娠率及临床妊娠率比较,差异无统计学意义(P＞0.05),但微刺激组的优质胚胎率显著高于短方案组(P＜0.01).结论:来曲唑微刺激方案是卵巢反应低下患者较理想的促排卵方案.