甲氨蝶呤对小鼠抗早孕作用的研究

用小鼠抗早孕实验,观察甲氨蝶呤(MTX)单用和合并用药的抗早孕作用。小鼠于妊娠d7分别一次scMTX8,24和72mg·kg-1可引起胚胎死亡,妊娠d13死亡率分别为18.0%,55.5%和60.3%。给药后测定血清孕酮水平,妊娠d9未发现明显改变,妊娠d13其水平明显降低。小鼠于妊娠d7～9注射MTX24mg·kg^-1连续3d引起胚胎全部死亡。hCG和孕酮可拮抗MTX的抗早孕作用。RU486可增强MTX的抗早孕作用,提示两药合用抗早孕有协同作用。     

青蒿琥酯钠对大鼠抗孕作用的研究

目的:研究青蒿琥酯钠(SA)对大鼠的抗孕作用以及其对妊娠及假孕大鼠血清孕酮含量和蜕膜组织的影响,以探讨其终止妊娠的机理。方法:采用放射免疫分析法(RIA)测定血清孕酮含量;HE染色法观察SA对大鼠子宫内膜的影响;用人蜕膜细胞体外培养方法观察SA对蜕膜细胞的直接作用。结果:SA 40mg·kg^-1·5d可使妊娠和假孕大鼠血清孕酮水平显著下降(P<0.05) ,但假孕大鼠血清孕酮水平下降晚于妊娠大鼠;整体水平能损伤蜕膜组织乃至胎盘;对体外培养的人蜕膜细胞有直接杀伤作用,其LC₅₀为25.18±3.49ml·L^-1。结论:青蒿琥酯钠能使血清孕酮含量下降并损伤蜕膜和胎盘而使胚胎坏死、吸收而终止妊娠。     

抗孕唑对假孕大鼠的溶黄体作用

目的：测定抗孕唑对假孕大鼠黄体和蜕膜的作用,以探索抗孕唑抗早孕作用的机制。方法：用放射免疫法和紫外分光光度计等方法。结果：抗孕唑可缩短大鼠假孕期4.8 d;降低卵巢重量,蛋白含量和血清孕酮浓度;给药5 d后,3β-HSD活性显著低于对照组;20α-HSD的活性则在给药1 d后即非常显著上升;子宫PGF_2α含量也显著升高,而给药5　d后,子宫和血清中的PGF_2α分别为对照组的3.2倍和2.2倍。结论：抗孕唑的溶黄体作用是由于降低假孕大鼠血清孕酮水平和增加PGF_2α含量所致,似乎与胚胎坏死无关。     

酪氨酸单用及合并RU486对小鼠生殖功能的影响及作用机理

用小鼠抗早孕实验及体外大鼠黄体细胞培养的方法,研究酪氨酸单用及酪氨酸与已知抗生育药RU486合并用药对小鼠早期妊娠的影响及作用机制。结果表明,酪氨酸与RU486合用有协同抗早孕作用。进一步的机理研究发现,酪氨酸170mg·kg^-1·5d可使早孕小鼠血清孕酮水平显著降低;酪氨酸50μg·mL^-1与(+)PG05合用;对抑制大鼠黄体细胞孕酮的基础分泌有协同作用,并能显著抑制hCG诱导的大鼠黄体细胞孕酮的分泌。结果提示:降低孕酮分泌可能是酪氨酸抗生育作用的途径之一。     

醋酸棉酚与米索前列醇对大鼠和小鼠的抗早孕研究

用抗早孕实验和大鼠子宫离体实验,研究了醋酸棉酚与米索前列醇抗早孕的协同作用。结果表明,早孕小鼠单服米索,其终止早孕作用微弱;当与棉酚合用时,对小鼠的抗早孕作用增强。对离体大鼠子宫,米索有明显的增强宫缩作用,而棉酚则无影响,但早孕大鼠po棉酚80mg·kg^-1·d^-1,3d后其子宫对米索的敏感性较对照组有显著提高。大鼠于妊娠d 6～8 po棉酚或米索,或两药剂量的一半合并用药,可使子宫蜕膜组织损伤,而以两药合用组最为严重,但子宫孕酮受体含量和分布与对照组相似。结果提示,两药合用有协同抗早孕作用。     

米非司酮对大鼠的抗着床作用研究

研究了米非司酮对大鼠的抗着床作用。大鼠在妊娠d₁、d₂或d₃口服米非司酮10mg/kg,每天1次,连续3d,有显著的抗着床作用、大鼠妊娠d1单次给米非司酮40mg/ks无抗着床作用,妊娠d₂给40mg/ks,d₃给10mg/kg有显著的抗着床作用。给药组大鼠子宫内膜发育延迟,蜕膜不能形成,影响孕卵着床。     

(+),(-)和(±)棉酚在雌大鼠抗早孕作用的研究

妊娠第6～9天大鼠,分别ig(±)和(-)棉酚80mg·kg^-1·d^-1和40mg·kg^-1·d^-1,结果有明显的抗早孕作用。然而(+)棉酚40mg·kg^-1·d^-1对大鼠生育无明显影响。(-)棉酚30μg·ml^-1能抑制体外培养黄体细胞孕酮的分泌。(+)棉酚10μg·ml^-1能促进黄体细胞分泌孕酮。hCG1IU·ml^-1能明显刺激体外培养颗粒细胞孕酮的分泌。(±)棉酚10和30μg·ml^-1皆能明显降低颗粒细胞对hCG的反应性。     

二氢青蒿素与青蒿琥酯的抗孕作用

研究表明,二氢青蒿素与青蒿琥酯对小鼠、金黄地鼠、豚鼠及兔均有抗孕作用。在金黄地鼠和豚鼠表现为引致流产,在小鼠和兔表现为使胚胎吸收。小鼠妊娠d7、金黄地鼠妊娠d5单次sc二氢青蒿素的抗孕ED₅₀(95%可信限)分别为32.8(27.7～38.9)及6.1(5.6～6.7)mg·kg^-1,豚鼠妊娠d18单次im二氢青蒿素的抗孕ED₅₀为18.3(13.9～24.2)mg·kg^-1,。金黄地鼠妊娠d5单次sc青蒿琥酯的抗孕ED₅₀为12.2(10.3～14.4)mg.kg^-1.以金黄地鼠进行的观察表明二氢青蒿素对胚胎有较高的选择性作用,引起胚胎坏死的剂量对于母体子宫、卵巢和一般健康状况无明显损害。     

青蒿琥酯对大鼠孕酮、雌二醇和蜕膜组织的影响

目的研究青蒿琥酯对妊娠大鼠血清孕酮和雌二醇含量及蜕膜组织的影响,以探讨其终止妊娠机理。方法采用放射免疫分析法(RIA)、HE染色和人蜕膜细胞体外培养等方法。结果青蒿琥酯40mg·kg^-1*5d可使妊娠大鼠血清孕酮水平显著下降(P<0.05);雌二醇有下降趋势,肿瘤坏死因子水平则有上升趋势;整体水平能损伤蜕膜组织乃至胎盘;对体外培养的人蜕膜细胞有直接杀伤作用,其LC₅₀为(25±3)mg·L^-1。结论青蒿琥酯能使血清孕酮含量下降并损伤蜕膜和胎盘而使胚胎坏死、吸收而终止妊娠。     

青紫颗粒单次及重复给药毒性试验研究

目的 观察青紫颗粒单次给药以及重复给药13周对大鼠产生的毒性反应,评价临床前安全性。方法 单次给药毒性试验:SD大鼠随机分为溶媒对照组(去离子水),青紫颗粒组(18 g·kg^-1),给药体积为每次30 mL·kg^-1,24 h内灌胃给药2次(间隔至少4 h),给药后观察14 d,通过临床观察体质量变化和病理解剖等确定毒性反应。重复给药毒性试验:幼龄SD大鼠(4日龄)随机分为溶媒对照组(去离子水),低、中、高剂量青紫颗粒组(1,2,4 g·kg^-1),给药13周,给药体积每次10 mL·kg^-1,每天给药2次,恢复期4周。检查项目包括临床观察、体质量、摄食量、血液学、生物化学、免疫学和尿液分析检测、激素水平、幼鼠发育指标、组织病理学检查等。结果 单次给药毒性试验:青紫颗粒灌胃给予SD大鼠,无明显毒性,最大耐受量>18 g·kg^-1。重复给药毒性试验:幼龄SD大鼠灌胃给予青紫颗粒重复给药13周,最大无毒性反应剂量为2 g·kg^-1。潜在毒性靶器官为肝脏,主要毒性作用表现为肝细胞炎性坏死,没有剂量依赖关系。结论 青紫颗粒对受试动物在拟临床使用剂量范围内未见有明显的毒性作用。     

hCG和LHRH-A对人早孕和孕终末期胎盘绒毛分泌孕酮作用的体外研究

在妊娠的不同时期,胎盘中黄体生成素释放激素(LHRH)的含量不同。离体培养的绒毛组织实验也发现,相同剂量的外源性LHRH对妊娠中期和终末期胎盘绒毛组织分泌hCG和孕酮作用强度也不同。本实验室曾发现,LHRH类似物(LHRH-A)对体外培养孕早期(10～12周)和孕终末期(38～40周)绒毛组织分泌hCG均有兴奋作用,但对分泌孕酮的作用不同,即LHRH-A对早孕绒毛分泌孕酮有抑制作用,而对终末期分泌孕酮     

黄体生成素释放激素-A治疗子宫内膜异位症41例

近年来试用黄体生成素释放激素-A(LHRH-A)对卵巢功能可起到良好的药物切除作用。本文应用国产LHRH-A~1治疗子宫向膜异位症41例。按美国生育委员会(AFS)标准分类:有Ⅰ级者19例,Ⅱ级者17例,Ⅲ级者5例。按痛经症状分,有原发性痛经26例、继发性痛经8例、不规则阴道流血2例。自月经d2(第2天)开始肌注LHRH-A200μg(或500μg)qd,继续3-6mo。结果痛经消失者31例(91％)。实验室观察16例在治疗前、中、后的E_2与P水平发现,治疗前15例有排卵。排卵在治疗时受抑制的15例与治疗后的15例均可恢复排卵。本组在治疗3mo后妊娠的有5例,其中4例已分娩,1例流产。     

Antifertility effect of methoxychlor in female rats: dose- and time-dependent blockade of pregnancy

Long-term exposure to methoxychlor (MXC), an estrogenic pesticide, produces infertility in rats, and short-term exposure blocks the decidual cell response (DCR). To address the short-term effects of MXC on fertility, the differential effects of MXC dosage and timing of administration (relative to implantation) on several gestational parameters were investigated. When MXC was administered during early pregnancy (Days 1-8), a dose-dependent decline in implantations and uterine weight was seen with no effect on ovarian weight or corpora lutea; MXC reduced serum progesterone at all doses. Preimplantation administration of MXC (Days 1-3 of pregnancy) produced a decline in implantations and uterine weight, while postimplantation dosing (Days 4-8 of pregnancy) increased resorptions to 100%, decreased uterine weight, and reduced serum progesterone without affecting the number of implantations, ovarian weight, or number of corpora lutea. The DCR of pseudopregnancy was inhibited by 500 mg/kg/day MXC when administered either pre- or postimplantation, but 200 mg/kg/day was without effect in either regimen. When hormonally primed, long-term ovariectomized rats were exposed to doses of 500 mg/kg/day, MXC blocked the induced DCR seen in controls. The data show that short-term MXC dosing during early pregnancy produces a dose-related infertility. The bloickade of pregnancy by the preimplantation administration of MXC may be mediated by a direct effect on preimplantation uterine development. The fetal resorption seen following postimplantation dosing is considered a manifestation of both reduced serum progesterone and the direct disruption of normal decidual development by MXC.     

Protective effects of progesterone on implantation failure induced by dibutyltin dichloride in rats

We previously showed that dibutyltin dichloride (DBTCl) at 7.6 mg/kg and higher on days 0-3 of pregnancy caused implantation failure and a decline in serum progesterone levels in rats and hypothesized that the decline is responsible for the implantation failure. This study was conducted to determine the protective effects of progesterone on the DBTCl-induced implantation failure in rats. Rats were given oral DBTCl at 0, 7.6, or 15.2 mg/kg on days 0-3 of pregnancy and/or subcutaneous progesterone at 2 mg/rat on days 0-8 of pregnancy. The reproductive outcome was determined on day 9 of pregnancy. No effects of administration of progesterone alone on the pregnancy rate and number of implantations were found. The pregnancy rate and number of implantations were significantly decreased after administration of DBTCl alone. The pregnancy rate and number of implantations were higher in the groups given DBTCl and progesterone than the groups given DBTCl alone. The present data indicate that progesterone protects, at least in part, against the DBTCl-induced implantation failure and support our hypothesis that the decline in progesterone levels is a primary mechanism for the implantation failure due to DBTCl.     

天花粉抗早孕作用的药理研究

小鼠妊娠第4、5日皮下注射天花粉,其抗早孕ED₅₀为1.78±0.28 mg/kg。天花粉的抗早孕作用可被甲地孕酮和HCG所部分拮抗,而为15-甲-PGF_2α所增强。抗早孕剂量天花粉对假孕小鼠的蜕膜有明显抑制作用。其抗早孕作用及抑制蜕膜作用均随剂量增加而增强。外源性甲地孕酮可对抗其抗早孕作用和抑制蜕膜作用。提示天花粉的抗早孕作用与其抑制蜕膜反应有关。外源性甲地孕酮有对抗天花粉抑制蜕膜反应的作用,提示天花粉有可能通过对抗假孕小鼠体内黄体激素作用而发挥抑制蜕膜反应的作用。本文初步探讨了这种对抗作用。     

Serum hormone characterization and exogeneous hormone rescue of bromodichloromethane-induced pregnancy loss in the F344 rat.

Previously, we demonstrated that bromodichloromethane (BDCM), a drinking water disinfection by-product, causes pregnancy loss in F344 rats when given on gestational days (GD) 6-10, encompassing the luteinizing hormone (LH)-dependent period of pregnancy (GD 7-10). Pregnancy loss, i.e., full-litter resorption, was associated with reduced serum progesterone levels; however, we were unable to identify an effect on serum LH. Here, we reevaluated serum LH levels using the more sensitive technique, DELFIA(R). We further sought to better define the temporal pattern of endocrine disruption caused by BDCM during pregnancy with more frequent sampling. Lastly, we attempted to prevent BDCM-induced pregnancy loss using exogenous progesterone or human chorionic gonadotropin (hCG), an LH-agonist. BDCM, in 10% Alkamuls(R), was dosed at 75 mg/kg/day by gavage to F344 rats on GD 6-10 (plug day = GD 0). BDCM-induced pregnancy loss was associated with marked reductions in serum progesterone and LH on GD 10. The decrease in serum LH consistently preceded the decrease in progesterone. In the hormone replacement studies, BDCM and progesterone were administered on GD 6-10, hCG on GD 8-10. BDCM was delivered at 100 mg/kg/day, progesterone at 10 mg/kg twice daily, and hCG at 0.5 IU/0.2 ml/rat. Both progesterone and hCG prevented BDCM-induced pregnancy loss. Thus, BDCM-induced pregnancy loss was associated with marked GD-10 reductions in serum LH and corresponding decreases in progesterone. Furthermore, coadministration of an LH agonist prevented pregnancy loss, supporting the hypothesis that BDCM-induced pregnancy loss in the rat occurs via an LH-mediated mode of action.     

Suppression of decidual cell response induced by dibutyltin dichloride in pseudopregnant rats: as a cause of early embryonic loss

In our previous study, dibutyltin dichloride (DBTCl) caused preimplantation embryonic loss and postimplantation embryonic loss in rats following administration at 7.6 mg/kg and above on Days 0-3 and at 3.8 mg/kg and above on Days 4-7 of pregnancy, respectively. This study was designed to assess the effects of DBTCl on uterine function as a cause of early embryonic loss using pseudopregnant rats. DBTCl was given orally to pseudopregnant rats at 3.8, 7.6 or 15.2 mg/kg on pseudopregnant day (PPD) 0-3 or on PPD 4-7. The decidual cell response was induced by bilateral uterine scratch on PPD 4. The uterine weight on PPD 9 served as an index of uterine decidualization. Uterine weight and serum progesterone levels on PPD 9 were significantly decreased after administration of DBTCl at 7.6 mg/kg and above on PPD 0-3 and PPD 4-7. DBTCl had no effect on the serum estradiol levels and number of corpora lutea. Administration of progesterone reversed the suppression of uterine decidualization in rats given DBTCl on PPD 0-3. It can be concluded that DBTCl suppresses the uterine decidual cell response and decreases progesterone levels, and these effects are responsible for early embryonic loss due to DBTCl exposure.     

5位,6位,8位氨基酸残基对LHRH类似物生物活性的影响

采用假孕大鼠黄体细胞体外培养和孕酮放射免疫(RIA)测定法,比较通式为 pGlu~1-His~2-Trp-Ser~4-A~5-B~6-C~7-D~8-Pro~9-Gly~10-NH_2的七种不同结构的 LHRH 类似物抑制黄体细胞分泌孕酮作用的强弱,初步分析其构效关系。结果表明:(1)5位以 His 取代优于5位不取代者;(2)8位 Gln 取代优于 Leu 取代;(3)6位 D 型氨基酸取代提高活性的顺序是 D-Trp~6>D-Leu~6>D-Ala~6、D_2Nal~6。本文结果提示大鼠黄体细胞培养法可取代垂体细胞培养法作为 LHRH 类似物生物活性的初步定量。     

壮药香花护乳凝胶剂对大鼠乳腺增生模型的影响

目的 观察壮药香花护乳凝胶剂对乳腺增生大鼠血清雌激素、孕激素水平及病变乳腺组织的影响。方法 采用注射苯甲酸雌二醇、黄体酮建立大鼠乳腺增生模型,待造模成功后,给药25 d,测量大鼠第3对乳头直径,并取乳腺组织做病理切片;测定血清中孕酮（P）、雌二醇（E2）的含量。结果 香花护乳凝胶剂高剂量组与模型组大鼠比较,其血液中的E2浓度明显降低（P〈0.05）,P含量明显升高（P〈0.05）,大鼠第3对乳头直径明显缩小（P〈0.01）,此外,高剂量组大鼠乳腺组织病理表现与模型组相比改善明显。结论 壮药香花护乳凝胶剂具有缩小模型大鼠乳头直径,调节血清中E2、P激素水平和改善乳腺组织病理形态的作用。     

紫草抑制青春期雌性大鼠性腺轴功能的研究

目的:研究紫草对青春期♀大鼠下丘脑-垂体-性腺轴(HPGA)功能的影响。方法:将实验大鼠随机分为阴性对照组、阳性对照组和紫草组,其中紫草组在用药过程中同时给予促性腺激素(HMG)。在用药第21、32、42天及停药第21天时,分别处死大鼠,比较各组血清促卵泡生成素(FSH)、促黄体生成素(LH)、雌二醇(E2)水平和阴道细胞形态学变化情况。结果:紫草组的血清激素水平显著低于阴性对照组,与阳性对照组比较无显著不同。紫草组和阳性对照组在用药后阴道细胞学检查以底层细胞为主,而阴性对照组始终以表层细胞为主。紫草组在同时予以HMG后,LH、FSH水平显著增高,E2水平无显著变化,阴道脱落细胞以底层细胞为主;停药后激素水平恢复至干预前状态,阴道细胞学检查以表层细胞为主,与激素水平变化相一致。结论:紫草对大鼠的HPGA功能有抑制作用,可能既作用于下丘脑-垂体水平,又作用于卵巢水平。