来曲唑序贯治疗来曲唑促排卵失败多囊卵巢综合征的疗效观察

目的 探讨来曲唑序贯治疗来曲唑促排卵失败多囊卵巢综合征的临床疗效。方法 选取2016年12月-2018年3月在天津医科大学第二医院计划生育科就诊的来曲唑促排卵失败的178例多囊卵巢综合征患者为研究对象,共234个促排周期。按照随机数字表将发生来曲唑促排卵失败的178例多囊卵巢综合征患者随机分为来曲唑序贯来曲唑组（62例,共87个周期）、来曲唑序贯氯米芬组（59例,共75个周期）和来曲唑序贯尿促性素组（57例,共72个周期）。3组患者均在月经第5天口服来曲唑片5 mg/次,1次/d,停药第3天监测卵泡,卵泡直径≤ 10 mm的患者用药。来曲唑序贯来曲唑组患者口服来曲唑片,5 mg/次,1次/d,连续5 d,停药后第1天行阴道超声检查。来曲唑序贯氯米芬组患者口服枸橼酸氯米芬片,100 mg/d,连续5 d,停药后第1天行阴道超声检查。来曲唑序贯尿促性素组患者肌内注射注射用尿促性素,75 U/d,根据卵泡反应调整剂量,直到出现优势卵泡。比较3组患者的单卵泡率、排卵率、周期取消率和失败率;人绒毛膜促性腺激素日子宫内膜的厚度和类型;临床妊娠率、早期胚胎丢失率、多胎妊娠率和卵巢过度刺激综合征发生率;促排方案中序贯用药的时间、费用和患者对促排卵方案的满意度。结果 治疗后,来曲唑序贯来曲唑组、来曲唑序贯氯米芬组的单卵泡发育率显著高于来曲唑序贯尿促性素组,且来曲唑序贯来曲唑组的单卵泡发育率显著高于来曲唑序贯氯米芬组,3组间差异均有统计学意义（P<0.05）。治疗后,来曲唑序贯来曲唑组、来曲唑序贯尿促性素组的排卵率均高于来曲唑序贯氯米芬组,差异有统计学意义（P<0.05）。治疗后,来曲唑序贯来曲唑组、来曲唑序贯氯米芬组的周期取消率显著低于来曲唑序贯尿促性素组,且来曲唑序贯来曲唑组的周期取消率显著低于来曲唑序贯氯米芬组,3组间差异均有统计学意义（P<0.05）。治疗后,来曲唑序贯来曲唑组、来曲唑序贯尿促性素组子宫内膜厚度明显厚于来曲唑序贯氯米芬组（P<0.05）。治疗后,来曲唑序贯来曲唑组、来曲唑序贯氯米芬组的多胎妊娠率显著低于来曲唑序贯尿促性素组,且来曲唑序贯来曲唑组的多胎妊娠率显著低于来曲唑序贯氯米芬组,3组间差异均有统计学意义（P<0.05）。治疗后,来曲唑序贯来曲唑组、来曲唑序贯氯米芬组的卵巢过度刺激综合征发生率低于来曲唑序贯尿促性素组,差异有统计学意义（P<0.05）。来曲唑序贯来曲唑组、来曲唑序贯氯米芬组明显短于来曲唑序贯尿促性素组的用药时间（P<0.05）。来曲唑序贯尿促性素组的总费用显著高于来曲唑序贯氯米芬组、来曲唑序贯来曲唑组。患者对来曲唑序贯来曲唑组、来曲唑序贯氯米芬组的促排卵方案满意度高。结论 来曲唑序贯来曲唑方案具有较高的排卵率、妊娠率,同时多胎妊娠率、卵巢过度刺激综合征风险最低,不但减少了肌内注射尿促性素多卵泡发育的风险,而且方案更加简单方便,节省患者的时间和花费,是一种既经济有效又安全省时的促排卵方案,非常适合全科医生在基层医疗机构中推广应用。     

哺乳动物黄体生成素(LH)峰效应由颗粒细胞向卵母细胞传递的分子通路

血液中黄体生成素(luteinizing hormone,LH)在排卵前形成一个极大的峰值,LH与壁层颗粒细胞中的LH受体(LHR)结合诱导类表皮生长因子(EGF)的表达,通过自分泌和旁分泌的作用激活颗粒细胞与卵丘细胞中的EGF受体(EGFR)、大鼠肉瘤病毒致癌基因(KRAS)、细胞外信号调节激酶1/2(ERK1/2),激活的ERK1/2诱导表达前列腺素合成酶2(PTGS2)、类固醇合成快速调节蛋白(STAR)、透明质酸合成酶2(HAS2)、肿瘤坏死因子α诱导蛋白6(TNFAIP6)产生的前列腺素又和卵丘细胞上的PTGER2结合,激活p38MAPK,这一LH作用的信号转导通路最终刺激卵丘扩展卵母细胞成熟并最终排卵。     

Does adding endometrial scratching to diagnostic hysteroscopy improve pregnancy rates in women with recurrent in-vitro fertilization failure?

Objective: To investigate the effect of additional endometrial scratching procedure during hysteroscopy on assisted reproductive technology (ART) cycle outcomes in repeated implantation failure (RIF) patients without endometrial or uterine abnormalities on hysteroscopic evaluation.

Materials and methods: Three hundred and forty-five RIF patients who underwent ART at a university-based infertility clinic between January 2011 and June 2015 were recruited in this retrospective cohort study. Uterine cavities of all included patients were evaluated by diagnostic hysteroscopy 7–14 days prior to the subsequent ART cycle. Women without endometrial abnormalities were allocated into two groups; the scratching group was consisted of patients who underwent endometrial scratching by using monopolar electric energy with needle forceps during hysteroscopy, and the control group was consisted of patients who underwent only diagnostic hysteroscopy.

Results: The implantation rate was significantly higher in the scratching group than the control group (37.7% versus 24.5%; p?=?0.04). Clinical and ongoing pregnancy rates were also found to be significantly higher in the scratching group than the control group (37.7% versus 27.6%; p?=?0.03; and 33.3% versus 23%; p?=?0.03, respectively).

Conclusion: Endometrial scratching during diagnostic hysteroscopy seems to enhance implantation and as well pregnancy rates in comparison to diagnostic hysteroscopy alone.     

中医综合治疗排卵障碍性不孕症中促排卵效应的临床疗效研究

目的:观察中医综合治疗排卵障碍性不孕症中促排卵效应的临床疗效。方法:95例排卵障碍性不孕症患者随机分成中医综合组、中西医结合组及西医组,中医综合组采用中药人工周期、针灸及耳穴压豆促排卵,中西医结合组用中药人工周期及氯米芬促排卵,西医组用氯米芬促排卵。结果:中医综合组33例中,排卵29例,占87.88%,妊娠25例,占75.76%;中西医结合组30例中,排卵24例,占80.00%,妊娠15例,占50.00%;西医组32例中,排卵18例,占56.25%,妊娠8例,占25.00%;3组比较妊娠率有显著差异(P0.05);中医综合组、中西医结合组与西医组比较排卵率有显著差异(P0.05)。结论:中医综合治疗促排卵疗效好,可明显提高受孕率。     

吡格列酮联合他莫昔芬治疗多囊卵巢综合征的疗效观察

目的探讨盐酸吡格列酮片联合枸橼酸他莫昔芬片治疗多囊卵巢综合征的临床疗效。方法选取2014年9月—2017年10月江油市人民医院妇科收治的多囊卵巢综合征患者100例为研究对象,将所有患者随机分为对照组和治疗组,每组各50例。对照组患者于月经周期开始的第5天口服枸橼酸他莫昔芬片,20 mg/次,1次/d。治疗组患者在对照组治疗的基础上早餐后口服盐酸吡格列酮片,30 mg/次,1次/d。以21 d为1个疗程,两组患者均连续治疗3个疗程。比较两组治疗前后排卵情况、临床症状、卵巢情况、性激素水平、胰岛素抵抗指标和不良反应发生情况。结果治疗后,对照组患者成熟卵泡数为(1.6±0.5)个,排卵率为64.0%;治疗组患者成熟卵泡数为(2.2±0.5)个,排卵率为88.0%,两组排卵情况比较差异有统计学意义(P0.05)。治疗后,两组月经稀发、痤疮、多毛例数均显著降低,同组治疗前后比较差异有统计学意义(P0.05);且治疗后治疗组临床症状例数均显著少于对照组,两组比较差异具有统计学意义(P0.05)。治疗后,两组卵巢体积显著降低,子宫内膜厚度显著增加,同组治疗前后比较差异有统计学意义(P0.05);且治疗后治疗组卵巢情况显著优于对照组,两组比较差异具有统计学意义(P0.05)。治疗后,两组黄体生成素(LH)、睾酮(T)水平明显降低,促卵泡激素(FSH)、雌二醇(E2)水平明显升高,同组治疗前后比较差异有统计学意义(P0.05);且治疗后治疗组性激素水平改善显著优于对照组,两组比较差异具有统计学意义(P0.05)。治疗后,两组空腹血糖(FPG)、空腹胰岛素(FINS)、胰岛素抵抗指数(HOMA-IR)均显著降低,同组治疗前后比较差异有统计学意义(P0.05);且治疗后治疗组胰岛素抵抗指标显著低于对照组,两组比较差异具有统计学意义(P0.05)。治疗后,治疗组不良反应发生率为6.0%,明显低于对照组的16.0%,两组比较差异具有统计学意义(P0.05)结论盐酸吡格列酮片联合枸橼酸他莫昔芬片治疗多囊卵巢综合征疗效显著,可显著改善患者的临床症状,促进性激素紊乱和胰岛素抵抗情况的恢复,具有一定的临床推广应用价值。     

低促性腺激素性腺功能减退症患者的促排卵

低促性腺激素性腺功能减退症(hypogonadotropic hypogonadism,HH)是一种罕见的、以低促性腺激素为特征的、引起第二性征及生殖系统发育障碍的疾病。本文将对该疾病定义、病因、临床表现、诊断及治疗进行全面的介绍。由于HH主要影响育龄女性的生育力,因此诱发排卵以及恢复生育力是该疾病治疗中的关键。治疗HH促排卵的方法较正常人特殊而且复杂,本文将着重介绍HH促排卵的各种原理和方法,同时结合最新的国内外进展以及临床实践经验对各种方法的有效性进行探讨。     

有生育要求的多囊卵巢综合征患者的治疗

多囊卵巢综合征(polycystic ovary syndrome,PCOS)是无排卵性不孕常见的原因,有多种非药物性和药物性方法帮助有生育要求的PCOS患者排卵并怀孕。一线疗法包括改变生活方式和克罗米芬治疗。对于克罗米芬抵抗的PCOS患者可采用二线疗法:使用促性腺激素(Gonadotrophin,Gn)、腹腔镜下卵巢打孔术(laparoscopic ovarian drilling,LOD)或者胰岛素增敏剂。如果治疗无效或合并其他不孕因素,可采用三线疗法——辅助生殖技术(assisted reproductive technology,ART)。本文重点介绍每种疗法的特点和治疗进展,以便为PCOS患者制定更加个性化的治疗方案提供参考。     

In vivo imaging reveals an essential role of vasoconstriction in rupture of the ovarian follicle at ovulation

Rupture of the ovarian follicle releases the oocyte at ovulation, a timed event that is critical for fertilization. It is not understood how the protease activity required for rupture is directed with precise timing and localization to the outer surface, or apex, of the follicle. We hypothesized that vasoconstriction at the apex is essential for rupture. The diameter and blood flow of individual vessels and the thickness of the apical follicle wall were examined over time to expected ovulation using intravital multiphoton microscopy. Vasoconstriction of apical vessels occurred within hours preceding follicle rupture in wild-type mice, but vasoconstriction and rupture were absent in Amhr2^cre/+SmoM2 mice in which follicle vessels lack the normal association with vascular smooth muscle. Vasoconstriction is not simply a response to reduced thickness of the follicle wall; vasoconstriction persisted in wild-type mice when thinning of the follicle wall was prevented by infusion of protease inhibitors into the ovarian bursa. Ovulation was inhibited by preventing the periovulatory rise in the expression of the vasoconstrictor endothelin 2 by follicle cells of wild-type mice. In these mice, infusion of vasoconstrictors (either endothelin 2 or angiotensin 2) into the bursa restored the vasoconstriction of apical vessels and ovulation. Additionally, infusion of endothelin receptor antagonists into the bursa of wild-type mice prevented vasoconstriction and follicle rupture. Processing tissue to allow imaging at increased depth through the follicle and transabdominal ultrasonography in vivo showed that decreased blood flow is restricted to the apex. These results demonstrate that vasoconstriction at the apex of the follicle is essential for ovulation.During ovulation in typically mono-ovulatory species such as humans, as well as in poly-ovulatory species such as rodents, the oocyte is released from the preovulatory follicle by extrusion through a rupture site on the outer surface, or apex, of the follicle, which protrudes from the surface of the ovary (1). Precise timing and accurate spatial localization of rupture at the apex are essential to allow capture of the oocyte by a hormonally primed oviduct where fertilization occurs, but the mechanisms involved are not yet understood. The rupture site breaches multiple layers of cells and their associated extracellular matrix and basement membranes (2). These include the single layer of epithelial cells that covers the surface of the ovary, the basement membrane that supports it, and the multiple cell layers comprising the wall of the preovulatory follicle. The outer wall of the ovarian follicle contains androgen-secreting theca cells and extensive vasculature. This vasculature consists of an inner and an outer plexus of capillaries with associated arterioles and venules that supply nutrients to the entire follicle (3–5). Underlying the theca and separated from it by a basement membrane is the avascular granulosa cell layer that serves as the major source of estrogen. The oocyte resides in the center of the follicle surrounded by multiple layers of specialized granulosa cells known as “cumulus cells.” In a mature preovulatory follicle, formation of a fluid-filled antral cavity separates the oocyte–cumulus complex from the mural granulosa cells that form the wall of the follicle except at a region known as the “stalk,” which connects the oocyte–cumulus complex to the antral granulosa cells of the follicle wall. At ovulation the oocyte is released from the follicle in association with attached cumulus cells.The preovulatory release of surge levels of luteinizing hormone (LH) from the anterior pituitary acts on receptors in the follicle to trigger events critical for the rupture and remodeling of the follicle and differentiation of granulosa and theca cells into progesterone-producing cells of the corpus luteum. The cumulus cells are induced to secrete a mucoelastic extracellular matrix which causes loosening of contacts between granulosa cells and between granulosa cells and the oocyte, a process known as “cumulus expansion,” which is essential for ovulation (1). Expression of proteases belonging to several major families, including the matrix metalloproteinase, plasminogen activator/plasmin, and ADAMTS (a disintegrin and metalloproteinase with thrombospondin-like motifs) families, increases. Simultaneously, follicle cells express protease inhibitors such as tissue inhibitors of metalloproteinases (TIMPs 1–4) and plasminogen activator inhibitors (PAI 1–3) (6, 7). The increase in protease activity is essential for rupture of the follicle and for the breakdown of the basement membrane separating theca and granulosa cells to allow the ingrowth of blood vessels to establish the corpus luteum. The mechanisms that regulate the balance of protease and protease inhibitor activity in the follicle to allow precise rupture at the apex while protecting most of the follicle structure from protease activity are not understood (1, 6, 7).We postulated that vasoconstriction of vessels within the theca at the apex of the follicle is required to promote follicle rupture. Our first approach was to examine mice with conditional expression of a dominant active allele of smoothened (SMO), the transmembrane protein that relays signaling by the hedgehog (HH) pathway. In these Amhr2^cre/+SmoM2 mice, preovulatory follicles develop normally in many respects, including changes in the expression of critical genes in response to the preovulatory LH surge (8, 9). However, follicles fail to rupture, and oocytes remain trapped as the follicles luteinize. The major ovarian phenotype in these mice is a pronounced deficiency of vascular smooth muscle (VSM) surrounding vessels in the theca cell layer, whereas other vessels that are present throughout the stroma of the ovary have normal maturation with VSM. Because VSM is required for vasoconstriction, the mice provided a model to test whether failure of vasoconstriction contributes to anovulation. In additional experiments with wild-type mice, we blocked the increase in the expression of endothelin 2 (Edn2) by granulosa cells that normally occurs within hours before follicle rupture (10, 11). Because EDN2 is a potent vasoconstrictor, this approach allowed us to test the effect on follicle rupture of inhibiting vasoconstriction versus treatment with exogenous compounds to restore vasoconstriction. In addition, treatment of wild-type mice with EDN2 receptor antagonists was used to test the role of EDN2 in vasoconstriction and rupture. Vasoconstriction and changes in the follicle wall were monitored repeatedly relative to the time of ovulation using intravital multiphoton microscopy.     

Effect of oral administration of a continuous 18 day regimen of meloxicam on ovulation: experience of a randomized controlled trial

Background

Cyclooxygenase-2 (COX-2) is expressed in all female reproductive organs. Therefore, inhibitors of COX-2 may affect reproductive function. We evaluated the effect of extended administration of meloxicam on ovulation and the menstrual cycle. Our hypothesis was that meloxicam administered from menstrual cycle day 5- 22 could interfere with follicular rupture, without disrupting the menstrual cycle, and could be a potential non-hormonal contraceptive method.

Methods

The study was conducted in 56 healthy sterilized women. Before the onset of treatment and after the end of treatment, participants were observed during a control cycle to ensure that they had progesterone (P₄) serum levels (> 12 nmol/l) consistent with ovulation. Participants were treated for 18 days, during three consecutive cycles. They were randomized to 15 or 30 mg/day. The menstrual cycle was monitored with serial ultrasound and hormone assays in blood.

Results

Fifty-six volunteers completed the study. In 55% of cycles treated with 15 mg/day and in 78% of cycles treated with 30mg/day (p<0.001) we observed dysfunctional ovulation defined as follicular rupture not preceded 24–48 h earlier by an LH peak or preceded by a blunted LH peak (< 21 IU/l) or not followed by an elevated serum P₄ level > 12 nmol/l. Ovulation was observed in 44.6% and in 21.7% of women in the lower dose group and the higher dose group, respectively. There were no differences between the two doses in other parameters measured. There were no serious adverse events and adverse events were not different between doses or between control and treated cycles.

Conclusions

Although administration of meloxicam on menstrual cycle days 5- 22 resulted in a dose-dependent inhibition of ovulation, more than 20% of subjects had normal ovulation with the highest dose.

Implications

Previous studies have shown that oral meloxicam can delay follicle rupture. This study investigated daily oral meloxicam as a non-hormonal contraceptive. Since ovulation occurs in over 20% of cycles even with a high dose of 30 mg daily, it is not likely that the approach would be a highly effective contraceptive strategy.     

来曲唑对SD大鼠促排卵及致畸作用的研究

目的:评价来曲唑对SD大鼠促排卵作用及其对胎鼠可能的致畸影响。方法:58只清洁级SD雌性大鼠随机分为空白对照组、溶剂(CMC)对照组及来曲唑不同剂量组(0.26mg/kg、0.52mg/kg、0.78mg/kg),分别于动情前期灌胃相应试剂,次晚合笼,阴栓及阴道涂片阳性者为孕0d,观察孕鼠的摄食饮水等一般情况,定期测体质量,于孕20d剖腹取胎仔,记录黄体数、着床腺数、吸收胎数、活胎数、死胎数、胎鼠体质量、身长、尾长等参数;每孕鼠取一半存活胎鼠进行内脏形态学检查,另一半做骨骼形态学检查。结果:CMC对试验结果无影响。来曲唑各试验组均对大鼠有促排卵作用,但可引起部分孕鼠流产,其活胎数、着床腺数低于对照组;胎鼠的植入前和植入后死亡率均高于对照组;来曲唑0.26mg/kg、0.52mg/kg对胎鼠无致畸作用,来曲唑0.78mg/kg组胎鼠内脏畸形率高于对照组。结论:来曲唑可促进大鼠的卵泡发育,但增加胎鼠的植入前和植入后死亡率;在≥0.78mg/kg剂量时,可能增加胎鼠的内脏畸形率。