来曲唑和克罗米酚促排卵的比较研究
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摘要
随着人工助孕技术的广泛应用,促排卵治疗也成为是辅助生殖技术中首要而关键的一步。然而临床上常用的克罗米酚(clomiphene citrate, CC)和促性腺激素类等促排卵药物可带来一些副作用,如宫颈粘液质量差、子宫内膜薄、子宫内膜成熟延迟、卵巢过激、多胎妊娠等。近来国外许多研究报道,治疗雌激素依赖性疾病的芳香酶抑制剂—来曲唑可作为生育调节剂用于促进人和动物模型卵泡的发育。同时发现LE无类似CC的抗雌激素作用,对宫颈粘液、子宫内膜等影响小,妊娠率也较CC促排卵高。本课题从动物实验和临床研究两个方面对LE和CC促排卵后的影响和结局进行比较,旨在证实LE的促排卵作用和其促排卵优于CC,为LE这种新的促排卵药物的临床运用提供依据。
第一部分来曲唑和克罗米酚促排卵对小鼠子宫内膜容受性影响的比较研究
目的:比较来曲唑(Letrozole,LE)和克罗米酚(clomiphene citrate, CC)促排卵对小鼠排卵前期子宫内膜形态学和着床期子宫内膜容受性的影响。探讨LE促排卵较克罗米酚(CC)的优越性,为LE促排卵的临床运用提供一定的理论基础。
方法:将48只小鼠随机分为3组:来曲唑组(16只)、克罗米酚组(16只)及对照组(16只)。促排卵后于排卵前期和着床期(妊娠第4.5天)取小鼠血清、子宫和着床期的胚胎,利用多功能图像分析仪测定子宫内膜厚度、腺体的面积、周长和最大直径;采用化学发光法检测血清性激素水平;以及采用显微镜观察胚胎发育情况、扫描电镜观察3组子宫内膜胞饮突的变化和通过免疫组化技术检测子宫内膜白血病抑制因子(LIF)和雌、孕激素受体(ER、PR)的表达强弱。
结果:(1)排卵前期无论是E2水平还是子宫内膜的厚度,LE组均低于对照组和CC组。(2)着床期(D4.5)CC组E2和P水平高于对照组和LE组,而所测该组小鼠子宫内膜腺体的面积、周长、直径的结果均显著性低于对照组。LE组与对照组相似。同时发现,CC组小鼠子宫内膜发育不良。(3)在3组胚胎发育与妊娠天数一致的情况下,LE组中无论是子宫内膜胞饮突,还是子宫内膜上皮LIF和ER、PR的表达,均与对照组相似。而CC组的表达显著性弱于前两组。
结论:与CC促排卵相比,LE虽然于排卵前期对子宫内膜厚度的影响并不优于CC,但却不影响小鼠着床期子宫内膜的形态学变化、子宫内膜超微结构和相关基因LIF和雌、孕激素受体的表达,有利于子宫内膜容受性的建立。
第二部分来曲唑和克罗米酚对PCOS的促排卵及妊娠结局的比较研究
目的:比较来曲唑和克罗米酚对PCOS的促排卵及妊娠结局,旨在寻找一种新的促排卵药物。
方法:拟行促排卵治疗的多囊卵巢综合症(PCOS)患者(66例),分为来曲唑组(20例)和克罗米酚组(46例)。来曲唑组(LE)从月经第3天至第7天(D3-7)给与LE5.0mg/d口服,D7加用尿促性腺激素(HMG)至HCG日;克罗米酚组(CC)从D5-9给与CC100mg/d口服,D6加用HMG至HCG日。于HCG日观察≥14mm卵泡数、≥16mm卵泡数、子宫内膜厚度、形态和血清E 2、LH、T水平以及排卵后第7天血清E2、P水平。记录妊娠率、流产例数、异位妊娠例数和OHSS发生例数。
结果:尽管HCG日LE组E2水平显著性的低于CC组(P﹤0.01),但是子宫内膜的厚度和形态两组无差异。然而CC组中有13例患者HCG日子宫内膜厚度﹤7.0mm,LE组中无1例。与CC组相比,HCG日LE组≥14mm数明显减少(P﹤0.05),且无1例卵巢过度刺激综合症(OHSS)的发生。LE组妊娠率和继续妊娠率都高于CC组,但无统计学意义。
As the improvement of the artificial assisted technology, the treatment of ovulation induction has become a key and chief role in assisted reproductive techniques. However, Clomiphene Citrate (CC) and Gonadotropins used for inducing ovulation bring about some side effects, including leading to poor cervical mucus , thin endometrium, OHSS, the multiple pregnancy and so on. Recently many investigations were published to discover letrozole, an aromatase inhibitor that has been used widely in the treatment of diseases depended on estrogen, is able to achieve the pleasant results in inducing ovulation for human and animal model as a fertility regulator, and to acquire LE, meanwhile, is associated with less influence on the cervical mucus, the endometrium and higher pregnancy rates than CC for inducing ovulation without a peripheral antiestrogenic effect unlike CC. We carried out a comparative study of the effects and the outcome letrozole versus clomiphene citrate for ovulation induction through both animal experiment and clinical research, in order to prove that LE can be used to induce ovulation and its effect is better than CC, which was based on the clinical use of LE that was a new ovulation induction agent.
PartⅠA comparative study of the effects of letrozole versus clomiphene citrate for ovulation induction on endometrial receptivity in mouse
Objective: To investigate the effects of letrozole (LE) versus clomiphene citrate (CC) for induction of ovulation on mouse endometrial morphology during preovulatory and on mouse endometrium of endometrial receptivity during implantation. And compared with CC, the superiority of LE for induction of ovulation would be evaluated, which offer theoretical foundation for the clinical use of LE for inducing ovulation.
Methods: The 48 mice were divided into three groups of 16 mice each including the LE group, the CC group and the control group. The serum and uterus of mice in preovulatory phase and implantation phase (on the 4.5 day of pregnancy) and Embryos in implantation phase after ovulation were obtained. The thickness of endometrium and the average area, perimeter and maximal diameter of single gland were determined by computerized multi-functional image analyzer. The concentration of serum sex hormone was measured by the method of chemiluminescence. Embryo development were observed by microscope, the detection of pinopode were examined by scanning electron microscopy and the expression of LIF, ER and PR implantation endometrium of mouse, was examined by immunohistochemistry technique.
Result: (1) not only the concentration of serum estradiol( E2) but also the endometrial thickness in the LE group were lower than those in both the CC group and the control group in preovulatory phase. (2) With the level of both serum E2 and progesterone (P) in the CC group being higher than those in other two groups, the thickness of endometrium and the average area, perimeter and maximal diameter of single gland in this group were significantly lower those in the control group. However, these in the LE group were similar to those seen in the control group. Meanwhile the endometrial underdevelopment was found in the CC group. (3) With embryo development of the three groups synchronized with pregnancy day, the expression of not only pinopode but also LIF , ER and PR in mice endometrium of the LE group were similar to that seen in the control group. However, their expression in the CC group was significantly lower than the former two groups.
Conclusion:, LE has no effect on and expression in the mouse implantation endometrium. Conclusion: Compared with CC for ovulation induction , the impact of the endometrial thickness that using LE for treatment result in is not better than CC , but it has no effectiveness on the change of endometrial morphology and the expression ultrastructure, pinopode formation, and LIF, ER and PR in mouse during implantation phase, and is beneficial to establish endometrial receptivity.
PartⅡA comparison of the effects and pregnancy outcome of letrozole versus clomiphene citrate for ovulation induction in women with polycystic ovarian syndrome.
Object: To search for a new drug for ovulation induction through a comparison of the effects and pregnancy outcome of letrozole (LE) versus clomiphene citrate (CC) for induction of ovulation. Methods: The patients with polycystic ovarian syndrome(PCOS)undergoing ovarian stimulation were divided into LE group and CC group. All subjects received either LE at a dosage of 5.0mg daily from cycle day 3 to 7 plus HMG injection staring on day 7 or CC (100mg/day) from day 5 to day 9 plus HMG injection on day 6 until the day of HCG. The number of follicle≥14mm and follicle≥16mm, endometrial thickenss and pattern were observed on the day of HCG. Some samples were analyzed including serum E2, testosterone and LH on the day of HCG and E2 and P on day +7 after follicular rupture. Meanwhile, pregnancy rate were recorded as well as the case of miscarriage, ectopic and ovarian hyperstimulation syndrome (OHSS).
Result: Despite there being significantly (P﹤0.01) lower E2 level in the letrozole group, no significant differences between two groups were found in terms of endometrial thickenss and endometrial pattern on the day of HCG. However, endometrial thickenss was thinner 7mm in 13 patients from the CC group at the time of HCG administration, without anyone in the LE group. Compared with the CC group, letrozole was associated with a statistically significantly fewer follicles≥14mm and no one patient with OHSS. The pregnancy rate and ongoing pregnancy rate were higher in the LE group, but a marked difference wasn’t found between the two groups. Conclusion: Letrozole results in stimulation of ovarian folliculogenesis and the pregnancy rate similar to that seen with CC.
第一部分来曲唑和克罗米酚促排卵对小鼠子宫内膜容受性影响的比较研究
目的:比较来曲唑(Letrozole,LE)和克罗米酚(clomiphene citrate, CC)促排卵对小鼠排卵前期子宫内膜形态学和着床期子宫内膜容受性的影响。探讨LE促排卵较克罗米酚(CC)的优越性,为LE促排卵的临床运用提供一定的理论基础。
方法:将48只小鼠随机分为3组:来曲唑组(16只)、克罗米酚组(16只)及对照组(16只)。促排卵后于排卵前期和着床期(妊娠第4.5天)取小鼠血清、子宫和着床期的胚胎,利用多功能图像分析仪测定子宫内膜厚度、腺体的面积、周长和最大直径;采用化学发光法检测血清性激素水平;以及采用显微镜观察胚胎发育情况、扫描电镜观察3组子宫内膜胞饮突的变化和通过免疫组化技术检测子宫内膜白血病抑制因子(LIF)和雌、孕激素受体(ER、PR)的表达强弱。
结果:(1)排卵前期无论是E2水平还是子宫内膜的厚度,LE组均低于对照组和CC组。(2)着床期(D4.5)CC组E2和P水平高于对照组和LE组,而所测该组小鼠子宫内膜腺体的面积、周长、直径的结果均显著性低于对照组。LE组与对照组相似。同时发现,CC组小鼠子宫内膜发育不良。(3)在3组胚胎发育与妊娠天数一致的情况下,LE组中无论是子宫内膜胞饮突,还是子宫内膜上皮LIF和ER、PR的表达,均与对照组相似。而CC组的表达显著性弱于前两组。
结论:与CC促排卵相比,LE虽然于排卵前期对子宫内膜厚度的影响并不优于CC,但却不影响小鼠着床期子宫内膜的形态学变化、子宫内膜超微结构和相关基因LIF和雌、孕激素受体的表达,有利于子宫内膜容受性的建立。
第二部分来曲唑和克罗米酚对PCOS的促排卵及妊娠结局的比较研究
目的:比较来曲唑和克罗米酚对PCOS的促排卵及妊娠结局,旨在寻找一种新的促排卵药物。
方法:拟行促排卵治疗的多囊卵巢综合症(PCOS)患者(66例),分为来曲唑组(20例)和克罗米酚组(46例)。来曲唑组(LE)从月经第3天至第7天(D3-7)给与LE5.0mg/d口服,D7加用尿促性腺激素(HMG)至HCG日;克罗米酚组(CC)从D5-9给与CC100mg/d口服,D6加用HMG至HCG日。于HCG日观察≥14mm卵泡数、≥16mm卵泡数、子宫内膜厚度、形态和血清E 2、LH、T水平以及排卵后第7天血清E2、P水平。记录妊娠率、流产例数、异位妊娠例数和OHSS发生例数。
结果:尽管HCG日LE组E2水平显著性的低于CC组(P﹤0.01),但是子宫内膜的厚度和形态两组无差异。然而CC组中有13例患者HCG日子宫内膜厚度﹤7.0mm,LE组中无1例。与CC组相比,HCG日LE组≥14mm数明显减少(P﹤0.05),且无1例卵巢过度刺激综合症(OHSS)的发生。LE组妊娠率和继续妊娠率都高于CC组,但无统计学意义。
As the improvement of the artificial assisted technology, the treatment of ovulation induction has become a key and chief role in assisted reproductive techniques. However, Clomiphene Citrate (CC) and Gonadotropins used for inducing ovulation bring about some side effects, including leading to poor cervical mucus , thin endometrium, OHSS, the multiple pregnancy and so on. Recently many investigations were published to discover letrozole, an aromatase inhibitor that has been used widely in the treatment of diseases depended on estrogen, is able to achieve the pleasant results in inducing ovulation for human and animal model as a fertility regulator, and to acquire LE, meanwhile, is associated with less influence on the cervical mucus, the endometrium and higher pregnancy rates than CC for inducing ovulation without a peripheral antiestrogenic effect unlike CC. We carried out a comparative study of the effects and the outcome letrozole versus clomiphene citrate for ovulation induction through both animal experiment and clinical research, in order to prove that LE can be used to induce ovulation and its effect is better than CC, which was based on the clinical use of LE that was a new ovulation induction agent.
PartⅠA comparative study of the effects of letrozole versus clomiphene citrate for ovulation induction on endometrial receptivity in mouse
Objective: To investigate the effects of letrozole (LE) versus clomiphene citrate (CC) for induction of ovulation on mouse endometrial morphology during preovulatory and on mouse endometrium of endometrial receptivity during implantation. And compared with CC, the superiority of LE for induction of ovulation would be evaluated, which offer theoretical foundation for the clinical use of LE for inducing ovulation.
Methods: The 48 mice were divided into three groups of 16 mice each including the LE group, the CC group and the control group. The serum and uterus of mice in preovulatory phase and implantation phase (on the 4.5 day of pregnancy) and Embryos in implantation phase after ovulation were obtained. The thickness of endometrium and the average area, perimeter and maximal diameter of single gland were determined by computerized multi-functional image analyzer. The concentration of serum sex hormone was measured by the method of chemiluminescence. Embryo development were observed by microscope, the detection of pinopode were examined by scanning electron microscopy and the expression of LIF, ER and PR implantation endometrium of mouse, was examined by immunohistochemistry technique.
Result: (1) not only the concentration of serum estradiol( E2) but also the endometrial thickness in the LE group were lower than those in both the CC group and the control group in preovulatory phase. (2) With the level of both serum E2 and progesterone (P) in the CC group being higher than those in other two groups, the thickness of endometrium and the average area, perimeter and maximal diameter of single gland in this group were significantly lower those in the control group. However, these in the LE group were similar to those seen in the control group. Meanwhile the endometrial underdevelopment was found in the CC group. (3) With embryo development of the three groups synchronized with pregnancy day, the expression of not only pinopode but also LIF , ER and PR in mice endometrium of the LE group were similar to that seen in the control group. However, their expression in the CC group was significantly lower than the former two groups.
Conclusion:, LE has no effect on and expression in the mouse implantation endometrium. Conclusion: Compared with CC for ovulation induction , the impact of the endometrial thickness that using LE for treatment result in is not better than CC , but it has no effectiveness on the change of endometrial morphology and the expression ultrastructure, pinopode formation, and LIF, ER and PR in mouse during implantation phase, and is beneficial to establish endometrial receptivity.
PartⅡA comparison of the effects and pregnancy outcome of letrozole versus clomiphene citrate for ovulation induction in women with polycystic ovarian syndrome.
Object: To search for a new drug for ovulation induction through a comparison of the effects and pregnancy outcome of letrozole (LE) versus clomiphene citrate (CC) for induction of ovulation. Methods: The patients with polycystic ovarian syndrome(PCOS)undergoing ovarian stimulation were divided into LE group and CC group. All subjects received either LE at a dosage of 5.0mg daily from cycle day 3 to 7 plus HMG injection staring on day 7 or CC (100mg/day) from day 5 to day 9 plus HMG injection on day 6 until the day of HCG. The number of follicle≥14mm and follicle≥16mm, endometrial thickenss and pattern were observed on the day of HCG. Some samples were analyzed including serum E2, testosterone and LH on the day of HCG and E2 and P on day +7 after follicular rupture. Meanwhile, pregnancy rate were recorded as well as the case of miscarriage, ectopic and ovarian hyperstimulation syndrome (OHSS).
Result: Despite there being significantly (P﹤0.01) lower E2 level in the letrozole group, no significant differences between two groups were found in terms of endometrial thickenss and endometrial pattern on the day of HCG. However, endometrial thickenss was thinner 7mm in 13 patients from the CC group at the time of HCG administration, without anyone in the LE group. Compared with the CC group, letrozole was associated with a statistically significantly fewer follicles≥14mm and no one patient with OHSS. The pregnancy rate and ongoing pregnancy rate were higher in the LE group, but a marked difference wasn’t found between the two groups. Conclusion: Letrozole results in stimulation of ovarian folliculogenesis and the pregnancy rate similar to that seen with CC.
引文
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24. Sammour A, Biljan MM, Tan SL, Tulandi T. Prospective randomized trial comparing the effects of letrozole (LE) and clomiphene citrate (CC) on follicular development, endometrial thickness and pregnancy rate in patients undergoing super-ovulation prior to intrauterine insemination (IUI). Fertil Steril, 2001;76(3):S110.
1. Atay V, Cam C & Muhcu M, et al. Comparion of letrozole and clomiphene citrate in women with polycystic ovaries undergoing stimulation. J Int med Res, 2006;34(1):73-76.
2. Hananel Holzer & Robert Casper, et al. A new era in ovulation induction. Fertil Steril. 2006;85(2):277-284.
3. Mitwally MF, Casper RF. Use of aromatase inhibitor for ovulation induction in patients with an inadequate response to clomiphene citrate. Fertil Steril, 2001;75(2):305–309.
4. Sammour A, Biljan MM, Tan SL, Tulandi T. Prospective randomized trial comparing the effects of letrozole (LE) and clomiphene citrate (CC) on follicular development, endometrial thickness and pregnancy rate in patients undergoing super-ovulation prior to intrauterine insemination (IUI) [abstract]. Fertil Steril 2001;76(3):S110.
5. Al-Fozan H, Al-Khadouri M & Tan SL, et al. A randomized trial of letrozole versus clomiphene citrate in women undergoing superovulation. Fertil Steril. 2004;82(6):1561-1563.
6.李艳萍,张琼.来曲唑治疗克罗米酚促排卵无效三例分析.生殖医学杂志.2005,14(4):239-241.
7. UlküBayar, Alper Tanr?verdi, et.al. Letrozole vs. clomiphene citrate in patients with ovulatory infertility. Fertil Steril. 2006;85(4):1045-1048.
8. Mitwally M & Casper R. Using aromatase inhibitors to induce ovulation in breast Ca survivors. Contemporary Ob/Gyn. 2004;49(1):73-83.
9. Vendola KA, Zhou J & Adesanya OO, et al. Androgens stimulate early stages of follicular growth in the primate ovary. J Clin Invest. 1998;101(12):2622-2629.
10. Mitwally, Casper.R.F. LH surge is associated with higher LH levels and more physiogic estradiol levels in aromatase inhibitor ovarian stimulstion cycles. Fertil Steril. ;2004;82(suppl 2):S144.
11. AL-Fadhli R & Sylvestre C, et al. A randomized trail of superovulation with two different doses of letrozole. Fertil Steril, 2006;85(1):161-164.
1、Shetty G, Krishnamurthy H & Krishnamurthy HN, et al. Effect of estrogen deprivation on the reproductive physiology of male and female primates. J Steroid Biochem Mol Biol, 1997;61(3-6):157–166.
2、Robert F.Casper. Letrozole: ovulation or superovulation ? Fertil Steril, 2003; 80(6): 1335-1337.
3、Mitwally M & Casper R. The aromatase inhibitor, letrozole: a promising alternative for clomiphene citrate for induction of ovulation.Fertil Steril, 2000; 4(Suppl1): S35.
4、Healey S, Tan SL & Tulandi T, et al. Effects of letrozole on superovulation with gonadotropins in women undergoing intrauterine insemination. Fertil Steril, 2003;80(6);1325–1329.
5、Fisher SA, Reicl RL & Vuget DA, et al. A randomized double-blind comparison of the effects of clomiphene citrate and the aromatase inhibitor letrozole on ovulatory function in normal women. Fertil Steril, 2002;78(2):280-285.
6、张琼,李艳萍.来曲唑治疗克罗米酚促排卵无效三例分析.生殖医学杂志, 2005, 14(4):239-241.
7、Mitwally MF & Casper RF. Aromatase inhibiton improves ovarian response to follicle-stimulation hormone in poor responders. Fertil Steril, 2002;77(4):776-780.
8、Mitwally MF& Casper RF. Aromatase inhibiton reduces gonadotrophin dose required for controlledovarian stimulation in women with unexplained infertility. Hum Reprod, 2003;18(8):1588-1597.
9、Dickey RP& Holtkamp DE. Development, pharmacology and clinical experience with clomiphene citrate.[J] Hum Reprod Update, 1996;2(6):483– 506.
10、Dehba shi. S , Parasanezhad. M.E & Alborzi. s , et al. Effect of clomipphene citrate on endometrium thickness and echogenic patterns. Int J Gynecol Obstet, 2003; 80(1):49-53.
11、Gonen Y, Caper RF. Prediction of implantation by the sonographic appearance of the endometrium during controlled ovarian stimulation for IVF. J In Vitro Fertil Embryo Transfer, 1990;7(3):146-152.
12、Mitwally MF, Casper RF. Use of aromatase inhibitor for ovulation induction in patients with an inadequate response to clomiphene citrate. Fertil Steril, 2001;75(2):305–309.
13、Kilic-Okman T, Kucuk M & Altaner S. Comparison of the effects of letrozole and clomiphene citrate on ovarian follicle, endometrium, and hormone levels in the rat. Fertil Steril, 2003;80(6):1330-1332.
14、AL-fozan H, AL-Khadouri M & Tan SL,et al. A randomized trial of letrozole versus clomiphene citrate in women undergoing superovulation. Fertil Steril, 2004;82(6):1561-1563.
15、Cortinez A, De Carvalho I & Vantman D, et al. Hormonal profile and endometrial morphology in letrozole-controlled ovarian hyperstimulation in ovulatory infertile patients. Fertil Steril, 2005;83(1):110-115.
16、王颖,陈咏建,李美芝等.促排卵周期PCOS妇女子宫内膜纤维粘连蛋白及层粘连蛋白的表达.生殖与避孕,2005;25(12):724-731.
17、Albert Palomino.W, Ariel Fuentes & Ruben Rene Gonzalez, et al. Differential expression of endometrial integrins and progesterone receptor during the window of implantation in normo-ovnlatory women treated with clomiphene citrate. Fertil Steril, 2005; 80(3): 587-593.
18、Krusche CA, Herrler A & Classen-Linke I, et al. The progesterone antagonist onapristone retards the advanced endometrial transformation after gonadotropin stimulation in rabbits. Steroids, 2000;65(10-11):773-782.
19、Mitwally MF & Casper RF. LH surge is associated with higher LH levels and more physiologic estradiol levels in aromatase inhibitor ovarian stimulation cycles. Fertil Steril, 2004;82(suppl 2):S144.
20、Kettel LM, Roseff SJ & Berga SL, et al. Hypothalamicpituitary- ovarian response to clomiphene citrate in women with polycystic ovary syndrome. Fertil Steril, 1993;59(3):532– 538.
21、Mohamed Farouk Mitwally & Casper RF. Pregnancy outcome after the use of an aromatase inhibitor for ovarian stimulation. Fertil Steril, 2002;78(Suppl1):S277-S278.
22、Mitwally MF, Biljan MM & Casper RF. Pregnancy outcome after the use of an aromatase inhibitor for ovarian stimulation. Am J Obstet Gynecol, 2005;192(2):381-386.
23、Mohamed F. M. Mitwally & Casper RF. Aromatase inhibiton reduces the dose of gonadotropin required for controlled ovarian hyperstimulation. J Soc Gynecol Investing, 2004;11(6):406-415.
24、Mitwally MFM & Casper RF. The use of an aromatase inhibitor for induction of ovulation in cases of clomiphene citrate failure. In: Program and abstracts of the 16th Annual Meeting of the European Society for Human Reproduction and Embryology (ESHRE), Bologna, Italy, 2000. (Abstract no. O-178)
25、Bhatnagar AS, Bat?l C, Hausler A, Nogues V. The role of estrogen in the feedback regulation of follicle-stimulating hormone. J Steroid Biochem Mol Biol 1993;47(1-6):161–166.
26、Sinha S, Kaseta J, Santner SJ, Demers LM. Effect of CGS 20267 on ovarian aromatase and gonadotropin levels in the rat. Breast Cancer Res Treat 1998;48(1):45–51.
27、Raedah AL-Fadhli, Camille Sylvestre & William Buckett. A randomized trial of superovulation with two different doses of letrozole. Fertil Steril, 2006; 85(1): 161-164.
28、Mohamed F.M. Mitwally & Robert F. Casper. Single-dose administration of an aromatase inhibitor for ovarian stimulation. Fertil Steril, 2005; 83(1): 229-231.
29、Juan A Garcia-Velasco,Luis Moreno,& Albert Pacheco. The aromatase inhibitor letrozole increases the concentration of intraovarian androgens and improves in vitro fertilization outcome in low responder patients: a pilot study. Fertil Steril, 2005; 84(1): 82-87.
30、Sammour A, Biljan MM & Tan SL, et al. Prospective randomized trial comparing theeffects of letrazole LE and clomiphene citrate (CC) on follicular development, endometrial thickness and pregnancy rate in patients undergoing super-ovulation prior to intrauterine insemination (IUI). Fertil Steril, 2001;76(3):S110.
31、Weil S, Vendola K & Zhou J, et al. Androgen and follicle-stimulating hormone interactions in primate ovarian follicle development. J Clin Endocrinol Metab, 1999;84(80):2951-2956.
32、Yang MY & Rajamahendran R. morphological and biochemical identification of apoptosis in small, medium, and large bovine follicle and the effects of follicle-stimulating hormone and insulin-like growth factor-Ⅰon spontaneous apoptosis in cultured bovine granulose cell. Biol Reprod, 2000; 62(5); 1209-1217.
33、Mazerbourg S, Bondy CA & Zhou J, et al. The insulin-like growth factor system; a key determinant role in the growth and selection of ovarian follicles ? a comparative species study. Reprod Domest Anim, 2003; 38(4); 247-258.
34、Gian Mario Tiboni. Aromatase inhibitors and teratogenesis. Fertil Steril, 2004; 81(4): 1158-1159.
35、Mitwally MF & Casper RF. Aromatase inhibitors for ovulation induction. J clin Endocrinol Metab, 2006; 91(3): 760-771..
2.李莉,章汉旺Mitwally.芳香酶抑制剂——来曲唑促排卵作用的研究进展.生殖与避孕,2006,26(8):486-490.
3. Kilic-Okman T, Kucuk M, Altaner S. Comparison of the effects of letrozole and clomiphene citrate on ovarian follicles, endometrium, and hormone levels in the rat. Fertil Steril. 2003, 80(6):1 130-2.
4. Weil S, Vendola K, Zhou J, et al. Androgen and follicle-stimulating hormone interactions in primate ovarian follicle development. J Clin Endocrinol Metab, 1999;84:2951-2956.
5. Vendola KA, Zhou J, Adesanya OO, et al. Androgens stimulate early stages of follicular growth in the primate ovary. J Clin Invest,. 1998;101:2622-2629.
6. Adashi E. Intraovarian regulation: the proposed role of insulin-like growth factors. Ann NY Acad Sci, 1993;687:10–12.
7. Giudice LC. Insulin-like growth factors and ovarian follicular development. Endocr Rev, 1992;13:641–669.
8. Yen SSC, Laughlin GA, Morales AJ. Interface between extra- and intra-ovarian factors in polycystic ovary syndrome (PCOS). Ann NY Acad Sci, 1993;687:98–111.
9. Al-Fozan H, Al-Khadouri M & Tan SL, et al. A randomized trial of letrozole versus clomiphene citrate in women undergoing superovulation. Fertil Steril. 2004;82(6):1561-1563.
10. Hananel Holzer & Robert Casper, et al. A new era in ovulation induction. Fertil Steril. 2006;85(2):277-284.
11. Mitwally M & Casper R. Using aromatase inhibitors to induce ovulation in breast Ca survivors. Contemporary Ob/Gyn. 2004;49(1):73-83.
12. Mitwally MF& Casper RF. Use of aromatase inhibitor for ovulation induction in patients with an inadequate response to clomiphene citrate. Fertil Steril, 2001;75(2):305–309.
13. Fisher SA, Reicl RL, Vuget DA, et al. A randomized double-blind comparison of the effects of clomiphene citrate and the aromatase inhibitor letrozole on ovulatory function in normal women. Fertil Steril, 2002, 78(2):280-285.
14. Pierson RA. Imaging the endometrium: are there predictors uterine receptivity? J Gynaecol Can, 2003, 25(5): 360-368.
15. Creus M, Ordi J & Fabregues F, et al. The effect of different hormone therapies on integrin expression and pinopode formation in the human endometrium: a controlled study. Hum Reprod, 2003, 18(4):683-693.
16. Cortinez A, De Carvalho I & Vantman D, et al. Hormonal profile and endometrial morphology in letrozole-controlled ovarian hyperstimulation in ovulatory infertile patients. Fertil Steril, 2005;83(1):110-115.
17.翁亚光,王应雄,刘学庆等.妊娠小鼠子宫内膜LIF基因表达的研究[J].遗传,2000,22(2):73—74.
18. Cullinan EB, Abbondanzo SJ & Anderson PS. Leukemia inhibitory factor (LIF) and LIF receptor expression in human endometrium suggests a potential autocrine /paracrin function in regulation embryo implantation [ J ]. Proc Natl Acad Sci USA, 1996, 93(7): 3115 - 3120.
19. Bhatt H, et al. Uterine expression of leukemia inhibitory factor concides with the onset of blastocyst implantation. Proceedings of the National Academy of Science of the USA, 1991, (88):11408-11412.
20. Hambartsoumia E , et al . Leuhemia inhibitory factor (LIF) production by human decidua and its relationship with pregnancy hormones[J] Gynecal Endocrinol ,1998 ,12 :17～22.
21.夏雅仙,周馥贞,黄荷凤等.克罗米酚对子宫内膜雌、孕激素受体的影响.中华妇产科杂志, 1996 , 31(10): 606-609.
22.陈丹青,周馥贞.克罗米酚对分泌期子宫内膜组织形态影响的研究.中国实用妇科与产科杂志, 1998 ,14 (2):97-99.
23. Molina R, Castilla JA & Vergara F, et al. Luteal cytoplasmic estrodiol and progesterone receptors in human endometrium: in vitro fertilization and normal cycles. Fertil Steril, 1989, 51(6): 976-979.
24. Sammour A, Biljan MM, Tan SL, Tulandi T. Prospective randomized trial comparing the effects of letrozole (LE) and clomiphene citrate (CC) on follicular development, endometrial thickness and pregnancy rate in patients undergoing super-ovulation prior to intrauterine insemination (IUI). Fertil Steril, 2001;76(3):S110.
1. Atay V, Cam C & Muhcu M, et al. Comparion of letrozole and clomiphene citrate in women with polycystic ovaries undergoing stimulation. J Int med Res, 2006;34(1):73-76.
2. Hananel Holzer & Robert Casper, et al. A new era in ovulation induction. Fertil Steril. 2006;85(2):277-284.
3. Mitwally MF, Casper RF. Use of aromatase inhibitor for ovulation induction in patients with an inadequate response to clomiphene citrate. Fertil Steril, 2001;75(2):305–309.
4. Sammour A, Biljan MM, Tan SL, Tulandi T. Prospective randomized trial comparing the effects of letrozole (LE) and clomiphene citrate (CC) on follicular development, endometrial thickness and pregnancy rate in patients undergoing super-ovulation prior to intrauterine insemination (IUI) [abstract]. Fertil Steril 2001;76(3):S110.
5. Al-Fozan H, Al-Khadouri M & Tan SL, et al. A randomized trial of letrozole versus clomiphene citrate in women undergoing superovulation. Fertil Steril. 2004;82(6):1561-1563.
6.李艳萍,张琼.来曲唑治疗克罗米酚促排卵无效三例分析.生殖医学杂志.2005,14(4):239-241.
7. UlküBayar, Alper Tanr?verdi, et.al. Letrozole vs. clomiphene citrate in patients with ovulatory infertility. Fertil Steril. 2006;85(4):1045-1048.
8. Mitwally M & Casper R. Using aromatase inhibitors to induce ovulation in breast Ca survivors. Contemporary Ob/Gyn. 2004;49(1):73-83.
9. Vendola KA, Zhou J & Adesanya OO, et al. Androgens stimulate early stages of follicular growth in the primate ovary. J Clin Invest. 1998;101(12):2622-2629.
10. Mitwally, Casper.R.F. LH surge is associated with higher LH levels and more physiogic estradiol levels in aromatase inhibitor ovarian stimulstion cycles. Fertil Steril. ;2004;82(suppl 2):S144.
11. AL-Fadhli R & Sylvestre C, et al. A randomized trail of superovulation with two different doses of letrozole. Fertil Steril, 2006;85(1):161-164.
1、Shetty G, Krishnamurthy H & Krishnamurthy HN, et al. Effect of estrogen deprivation on the reproductive physiology of male and female primates. J Steroid Biochem Mol Biol, 1997;61(3-6):157–166.
2、Robert F.Casper. Letrozole: ovulation or superovulation ? Fertil Steril, 2003; 80(6): 1335-1337.
3、Mitwally M & Casper R. The aromatase inhibitor, letrozole: a promising alternative for clomiphene citrate for induction of ovulation.Fertil Steril, 2000; 4(Suppl1): S35.
4、Healey S, Tan SL & Tulandi T, et al. Effects of letrozole on superovulation with gonadotropins in women undergoing intrauterine insemination. Fertil Steril, 2003;80(6);1325–1329.
5、Fisher SA, Reicl RL & Vuget DA, et al. A randomized double-blind comparison of the effects of clomiphene citrate and the aromatase inhibitor letrozole on ovulatory function in normal women. Fertil Steril, 2002;78(2):280-285.
6、张琼,李艳萍.来曲唑治疗克罗米酚促排卵无效三例分析.生殖医学杂志, 2005, 14(4):239-241.
7、Mitwally MF & Casper RF. Aromatase inhibiton improves ovarian response to follicle-stimulation hormone in poor responders. Fertil Steril, 2002;77(4):776-780.
8、Mitwally MF& Casper RF. Aromatase inhibiton reduces gonadotrophin dose required for controlledovarian stimulation in women with unexplained infertility. Hum Reprod, 2003;18(8):1588-1597.
9、Dickey RP& Holtkamp DE. Development, pharmacology and clinical experience with clomiphene citrate.[J] Hum Reprod Update, 1996;2(6):483– 506.
10、Dehba shi. S , Parasanezhad. M.E & Alborzi. s , et al. Effect of clomipphene citrate on endometrium thickness and echogenic patterns. Int J Gynecol Obstet, 2003; 80(1):49-53.
11、Gonen Y, Caper RF. Prediction of implantation by the sonographic appearance of the endometrium during controlled ovarian stimulation for IVF. J In Vitro Fertil Embryo Transfer, 1990;7(3):146-152.
12、Mitwally MF, Casper RF. Use of aromatase inhibitor for ovulation induction in patients with an inadequate response to clomiphene citrate. Fertil Steril, 2001;75(2):305–309.
13、Kilic-Okman T, Kucuk M & Altaner S. Comparison of the effects of letrozole and clomiphene citrate on ovarian follicle, endometrium, and hormone levels in the rat. Fertil Steril, 2003;80(6):1330-1332.
14、AL-fozan H, AL-Khadouri M & Tan SL,et al. A randomized trial of letrozole versus clomiphene citrate in women undergoing superovulation. Fertil Steril, 2004;82(6):1561-1563.
15、Cortinez A, De Carvalho I & Vantman D, et al. Hormonal profile and endometrial morphology in letrozole-controlled ovarian hyperstimulation in ovulatory infertile patients. Fertil Steril, 2005;83(1):110-115.
16、王颖,陈咏建,李美芝等.促排卵周期PCOS妇女子宫内膜纤维粘连蛋白及层粘连蛋白的表达.生殖与避孕,2005;25(12):724-731.
17、Albert Palomino.W, Ariel Fuentes & Ruben Rene Gonzalez, et al. Differential expression of endometrial integrins and progesterone receptor during the window of implantation in normo-ovnlatory women treated with clomiphene citrate. Fertil Steril, 2005; 80(3): 587-593.
18、Krusche CA, Herrler A & Classen-Linke I, et al. The progesterone antagonist onapristone retards the advanced endometrial transformation after gonadotropin stimulation in rabbits. Steroids, 2000;65(10-11):773-782.
19、Mitwally MF & Casper RF. LH surge is associated with higher LH levels and more physiologic estradiol levels in aromatase inhibitor ovarian stimulation cycles. Fertil Steril, 2004;82(suppl 2):S144.
20、Kettel LM, Roseff SJ & Berga SL, et al. Hypothalamicpituitary- ovarian response to clomiphene citrate in women with polycystic ovary syndrome. Fertil Steril, 1993;59(3):532– 538.
21、Mohamed Farouk Mitwally & Casper RF. Pregnancy outcome after the use of an aromatase inhibitor for ovarian stimulation. Fertil Steril, 2002;78(Suppl1):S277-S278.
22、Mitwally MF, Biljan MM & Casper RF. Pregnancy outcome after the use of an aromatase inhibitor for ovarian stimulation. Am J Obstet Gynecol, 2005;192(2):381-386.
23、Mohamed F. M. Mitwally & Casper RF. Aromatase inhibiton reduces the dose of gonadotropin required for controlled ovarian hyperstimulation. J Soc Gynecol Investing, 2004;11(6):406-415.
24、Mitwally MFM & Casper RF. The use of an aromatase inhibitor for induction of ovulation in cases of clomiphene citrate failure. In: Program and abstracts of the 16th Annual Meeting of the European Society for Human Reproduction and Embryology (ESHRE), Bologna, Italy, 2000. (Abstract no. O-178)
25、Bhatnagar AS, Bat?l C, Hausler A, Nogues V. The role of estrogen in the feedback regulation of follicle-stimulating hormone. J Steroid Biochem Mol Biol 1993;47(1-6):161–166.
26、Sinha S, Kaseta J, Santner SJ, Demers LM. Effect of CGS 20267 on ovarian aromatase and gonadotropin levels in the rat. Breast Cancer Res Treat 1998;48(1):45–51.
27、Raedah AL-Fadhli, Camille Sylvestre & William Buckett. A randomized trial of superovulation with two different doses of letrozole. Fertil Steril, 2006; 85(1): 161-164.
28、Mohamed F.M. Mitwally & Robert F. Casper. Single-dose administration of an aromatase inhibitor for ovarian stimulation. Fertil Steril, 2005; 83(1): 229-231.
29、Juan A Garcia-Velasco,Luis Moreno,& Albert Pacheco. The aromatase inhibitor letrozole increases the concentration of intraovarian androgens and improves in vitro fertilization outcome in low responder patients: a pilot study. Fertil Steril, 2005; 84(1): 82-87.
30、Sammour A, Biljan MM & Tan SL, et al. Prospective randomized trial comparing theeffects of letrazole LE and clomiphene citrate (CC) on follicular development, endometrial thickness and pregnancy rate in patients undergoing super-ovulation prior to intrauterine insemination (IUI). Fertil Steril, 2001;76(3):S110.
31、Weil S, Vendola K & Zhou J, et al. Androgen and follicle-stimulating hormone interactions in primate ovarian follicle development. J Clin Endocrinol Metab, 1999;84(80):2951-2956.
32、Yang MY & Rajamahendran R. morphological and biochemical identification of apoptosis in small, medium, and large bovine follicle and the effects of follicle-stimulating hormone and insulin-like growth factor-Ⅰon spontaneous apoptosis in cultured bovine granulose cell. Biol Reprod, 2000; 62(5); 1209-1217.
33、Mazerbourg S, Bondy CA & Zhou J, et al. The insulin-like growth factor system; a key determinant role in the growth and selection of ovarian follicles ? a comparative species study. Reprod Domest Anim, 2003; 38(4); 247-258.
34、Gian Mario Tiboni. Aromatase inhibitors and teratogenesis. Fertil Steril, 2004; 81(4): 1158-1159.
35、Mitwally MF & Casper RF. Aromatase inhibitors for ovulation induction. J clin Endocrinol Metab, 2006; 91(3): 760-771..