子宫内膜异位症相关性低生育力机制的探讨
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摘要
【背景】子宫内膜异位症(内异症)是一种中青年妇女的常见病、多发病,它所引起的疼痛和不育严重影响其健康和生活质量。目前关于内异症所致不育的潜在机制研究甚少。动物和人体试验显示触珠蛋白(Hp)可能参与了内异灶的形成,并在不孕中发生作用,值得深入研究。
【目的】1)建立内异症大鼠模型并比较内异症组与对照组在排卵、受精、体外发育潜能方面的差异,探讨内异症相关性低生育力之可能的受损环节;2)定量比较内异症组和对照组血清和子宫触珠蛋白(Hp)的表达,探讨其与内异症大鼠妊娠结局的相关性。
【方法】随机选取8周龄SD大鼠采用自体子宫移植法建立内异症模型后,比较自然妊娠10天时的胚胎着床数,评价内异症对生育力的影响;随机选取5周龄SD大鼠建立内异症模型后进行PMSG-hCG超排卵,比较采卵数、受精率和胚胎的体外培养情况;运用ELISA检测血清Hp,实时定量RT-PCR检测子宫Hp mRNA,并且评价在内异症大鼠中Hp与妊娠的相关性。
【结果】大部分移植的子宫组织均可存活,并使着床数较对照组显著下降(-28.6%,P＜0.05)。内异症大鼠对超排方案的反应较差,表现为采卵数减少、受精率下降,在本研究的体外培养条件下,大部分胚胎均停滞于2-细胞胚。妊娠期内异症大鼠血清Hp显著高于对照组(P＜0.001),但与着床数无相关性;内异症组和对照组的子宫Hp表达无显著差异,但是Hp mRNA水平与着床数呈显著的正相关性(P＜0.01)。
【结论】
1、采用自体子宫移植法建立的大鼠内异症模型具有与人类子宫内膜异位症相似的病理、病生理特点。
2、内异症大鼠卵巢功能储备下降以及卵泡发育、受精障碍系导致卵/胚胎数量下降、引起生育力下降的重要原因。
3、特定亚型的血清触珠蛋白在内异症大鼠血清中有明显高表达,有望成为疾病诊断的一项特异性标志物。
4、妊娠期子宫Hp的表达量可能是一项反映内膜容受性的指标。
BACKGROUND Endometriosis(EM) is the most common pelvic pathologic process that occurs in women of childbearing potential,and is associated with pain and subfertility/infertility;unfortunately,the underlying mechanisms still remain poorly understood.Studies on animals and human both indicate the implication of haptoglobin(Hp) in the pathogenesis of EM;whereas,the role of Hp in EM-related subfertility/infertility has not yet been fully investigated.
OBJECTIVES To establish a rat model for endometriosis and compare ovulation and fertilization competence with sham-operated controls;to compare the expression of haptoglobin in serum and uterus of the endometriosis and control rats during gestation and determine its relation with pregnancy outcomes.
METHODS The rats were autotransplanted with uterine squares as previously described,and mated;fecundity was documented as the number of day 10 embryos.Superovulation with sequential PMSG-hCG was administered to rats to evaluate the effect of surgically induced endometriosis on ovulation,fertilization and developmental competence in vitro.Haptoglobin expression in serum and eutopic endometrium during pregnancy was determined by using ELISA and real-time RT-PCR,respectively.
RESULTS The autotransplanted uterine squares resulted in healthy implants with similar histological appearance with eutopic endometrium.The presence of ectopic endometrial tissue significantly reduced fecundity by 28.6% (P＜0.05).The rats with induced EM showed poor response to superovulation with fewer ova released and fertilized.Serum Hp in rats with EM was 2-fold up-regulated as compared to the controls(P＜0.001) whilst demonstrating no association with fecundity.Eutopic endometrial Hp mRNA in the rats with EM was comparable to the controls during pregnancy;whereas,a strong positive correlation was revealed between Hp mRNA level and the number of embryos implanted within the EM and the control group and in pooled population,too(P＜0.01).
CONCLUSIONS Surgically-induced enodmetriosis in rats with similar pathological and physiological features to those in human offers a valuable research model to study the aspects of EM that cannot be adequately evaluated in women. Dysfunctional ovarian reserve,folliculogenesis and fertilization may be an important root cause for subfertility observed in rats with EM.Serum Hp level of specific isoforms possesses the potential of developing a novel non-invasive biomarker for the diagnosis of EM;local expression of Hp within endometrium during pregnancy is first recognized as a candidate factor to assess uterine receptivity.
【目的】1)建立内异症大鼠模型并比较内异症组与对照组在排卵、受精、体外发育潜能方面的差异,探讨内异症相关性低生育力之可能的受损环节;2)定量比较内异症组和对照组血清和子宫触珠蛋白(Hp)的表达,探讨其与内异症大鼠妊娠结局的相关性。
【方法】随机选取8周龄SD大鼠采用自体子宫移植法建立内异症模型后,比较自然妊娠10天时的胚胎着床数,评价内异症对生育力的影响;随机选取5周龄SD大鼠建立内异症模型后进行PMSG-hCG超排卵,比较采卵数、受精率和胚胎的体外培养情况;运用ELISA检测血清Hp,实时定量RT-PCR检测子宫Hp mRNA,并且评价在内异症大鼠中Hp与妊娠的相关性。
【结果】大部分移植的子宫组织均可存活,并使着床数较对照组显著下降(-28.6%,P＜0.05)。内异症大鼠对超排方案的反应较差,表现为采卵数减少、受精率下降,在本研究的体外培养条件下,大部分胚胎均停滞于2-细胞胚。妊娠期内异症大鼠血清Hp显著高于对照组(P＜0.001),但与着床数无相关性;内异症组和对照组的子宫Hp表达无显著差异,但是Hp mRNA水平与着床数呈显著的正相关性(P＜0.01)。
【结论】
1、采用自体子宫移植法建立的大鼠内异症模型具有与人类子宫内膜异位症相似的病理、病生理特点。
2、内异症大鼠卵巢功能储备下降以及卵泡发育、受精障碍系导致卵/胚胎数量下降、引起生育力下降的重要原因。
3、特定亚型的血清触珠蛋白在内异症大鼠血清中有明显高表达,有望成为疾病诊断的一项特异性标志物。
4、妊娠期子宫Hp的表达量可能是一项反映内膜容受性的指标。
BACKGROUND Endometriosis(EM) is the most common pelvic pathologic process that occurs in women of childbearing potential,and is associated with pain and subfertility/infertility;unfortunately,the underlying mechanisms still remain poorly understood.Studies on animals and human both indicate the implication of haptoglobin(Hp) in the pathogenesis of EM;whereas,the role of Hp in EM-related subfertility/infertility has not yet been fully investigated.
OBJECTIVES To establish a rat model for endometriosis and compare ovulation and fertilization competence with sham-operated controls;to compare the expression of haptoglobin in serum and uterus of the endometriosis and control rats during gestation and determine its relation with pregnancy outcomes.
METHODS The rats were autotransplanted with uterine squares as previously described,and mated;fecundity was documented as the number of day 10 embryos.Superovulation with sequential PMSG-hCG was administered to rats to evaluate the effect of surgically induced endometriosis on ovulation,fertilization and developmental competence in vitro.Haptoglobin expression in serum and eutopic endometrium during pregnancy was determined by using ELISA and real-time RT-PCR,respectively.
RESULTS The autotransplanted uterine squares resulted in healthy implants with similar histological appearance with eutopic endometrium.The presence of ectopic endometrial tissue significantly reduced fecundity by 28.6% (P＜0.05).The rats with induced EM showed poor response to superovulation with fewer ova released and fertilized.Serum Hp in rats with EM was 2-fold up-regulated as compared to the controls(P＜0.001) whilst demonstrating no association with fecundity.Eutopic endometrial Hp mRNA in the rats with EM was comparable to the controls during pregnancy;whereas,a strong positive correlation was revealed between Hp mRNA level and the number of embryos implanted within the EM and the control group and in pooled population,too(P＜0.01).
CONCLUSIONS Surgically-induced enodmetriosis in rats with similar pathological and physiological features to those in human offers a valuable research model to study the aspects of EM that cannot be adequately evaluated in women. Dysfunctional ovarian reserve,folliculogenesis and fertilization may be an important root cause for subfertility observed in rats with EM.Serum Hp level of specific isoforms possesses the potential of developing a novel non-invasive biomarker for the diagnosis of EM;local expression of Hp within endometrium during pregnancy is first recognized as a candidate factor to assess uterine receptivity.
引文
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8 Croxato HB et al. Effect of 15(S)-15-methyl prostaglandin F2a on human ovdiuctal motility and ovum transport. Fertil Steril 1978;30:408-14.
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