醋酸棉酚在大鼠的抗甾体激素和抗促性腺激素作用

给去卵巢后一周的大鼠皮下注射雌二醇,同时喂以醋酸棉酚40mg/kg,连续8天,可抑制雌二醇的促子宫作用。此外,醋酸棉酚40mg/kg能抑制黄体酮致蜕膜瘤的增长。醋酸棉酚尚能抑制hCG引起的未成熟雄大鼠血清睾丸酮水平的升高。醋酸棉酚能直接抑制体外培养的间质细胞分泌睾丸酮;又能对抗hCG对间质细胞的刺激作用。     

宫内一次给予醋酸棉酚对大鼠的抗早孕作用

于大鼠妊娠第7天,每侧子宫角内注入1.5mg醋酸棉酚混悬液(0.15ml),对照组注入等量溶剂。于妊娠第16天处死大鼠。处死前取血测定血清孕酮,处死后取卵巢,称重及测△~5-3β-羟甾脱氢酶的活性,同时记录妊娠动物数及正常胚胎数。结果表明,醋酸棉酚对大鼠具有明显的抗早孕作用,止孕率达84.6%。对血清孕酮水平及△~5-3β-羟甾脱氢酶的活性均无显著影响。以上结果提示,宫内用醋酸棉酚抗早孕的作用有可能是局部性的。     

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。     

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。     

棉酚合并卡前列甲酯(PG05)抗早孕作用研究

观察棉酚合并 PG0 5对小鼠的抗早孕作用。结果显示 :单用棉酚 75mg/( kg·d) ,3d无抗早孕作用 ,而同样剂量棉酚与 PG0 50 .2 mg/( kg·d) ,合用 2 d可显著增强抗早孕作用 ,使小鼠活胎数进一步减少 ;棉酚 30 μg/ml和 ( - )棉酚 1 5μg/ml对大鼠黄体细胞 3β- HSD活性均有显著抑制作用 ,( + )棉酚 1 5μg/ml和PG0 51 0 μg/ml对此酶活性无影响 ;( - )棉酚 1 5μg/ml还能抑制大鼠颗粒细胞雌二醇的分泌 ,提示棉酚增强 PG0 5抗早孕作用可能是从多环节影响胚胎正常发育。     

盐酸苯乙哌啶和dl-15甲基PGF_(2α)甲酯对大鼠卵巢黄体细胞的影响

盐酸苯乙哌啶(R1132)10μg/ml或dl-15甲基PGF_(2α)甲酯(PG05)5或10μg/ml在体外能明显抑制黄体细胞对hCG的反应性,使孕酮分泌下降。假孕大鼠po R1132 10 mg/kg或Sc PG 05 5.1 mg/kg不影响卵巢孕酮分泌,合并给药后却能使其降低。R1132无抗孕酮作用。卵巢分泌孕酮减少可能是抗早孕的主要原因.假孕大鼠po R1132 50 mg/kg或sc PG050.5 mg/kg可抑制卵巢腺苷环化酶的活性.该酶可能是R1132或PG05在大鼠抗早孕作用的重要靶酶。     

醋酸棉酚对hCG促进大鼠分散黄体细胞产生孕酮的影响

本文在体外研究了醋酸棉酚对分散大鼠黄体细胞产生孕酮的影响及其作用机制。当棉酚浓度在20μg/ml、作用时间1h,hCG刺激黄体细胞孕酮的生成量显著下降,但对基础孕酮的产生无明显影响;上述剂量的棉酚在作用4h后时细胞存活率无明显影响。经棉酚作用过的黄体细胞,经2h再孵育,不能恢复其对hCG的反应性。同时棉酚显著降低黄体细胞cAMP产生。结果提示,棉酚可能通过降低cAMP产生而抑制hCG的生孕酮作用。     

盐酸苯乙哌啶和dl-15甲基PGF2α甲酯对大鼠卵巢黄体细胞的影响

盐酸苯乙哌啶(R1132)10μg/ml或dl-15甲基PGF_2α甲酯(PG05)5或10μg/ml在体外能明显抑制黄体细胞对hCG的反应性,使孕酮分泌下降。假孕大鼠po R1132 10 mg/kg或Sc PG 05 5.1 mg/kg不影响卵巢孕酮分泌,合并给药后却能使其降低。R1132无抗孕酮作用。卵巢分泌孕酮减少可能是抗早孕的主要原因.假孕大鼠po R1132 50 mg/kg或sc PG050.5 mg/kg可抑制卵巢腺苷环化酶的活性.该酶可能是R1132或PG05在大鼠抗早孕作用的重要靶酶。     

醋酸棉酚对hCG促进大鼠分散黄体细胞产生孕酮的影响

本文在体外研究了醋酸棉酚对分散大鼠黄体细胞产生孕酮的影响及其作用机制。当棉酚浓度在20μg/ml、作用时间1h,hCG刺激黄体细胞孕酮的生成量显著下降,但对基础孕酮的产生无明显影响;上述剂量的棉酚在作用4h后时细胞存活率无明显影响。经棉酚作用过的黄体细胞,经2h再孵育,不能恢复其对hCG的反应性。同时棉酚显著降低黄体细胞cAMP产生。结果提示,棉酚可能通过降低cAMP产生而抑制hCG的生孕酮作用。     

醋酸棉酚对大鼠睾网液中K~+、Na~+及睾酮水平的影响

成年雄鼠给予15mg/kg/d醋酸棉酚,连续50d灌服,导致不育,精子生成与附睾精子活力都受到明显影响。但血清与睾网液中K~+、Na~+、睾酮水平与对照组相比无明显变化。因此认为给予较低剂量的醋酸棉酚灌服大鼠,可以阻断生精作用而达到抗生育效果,但并不影响K~+、Na~+与睾酮在睾丸中分泌与转运。     

(+),(-)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。     

(-)和(+)棉酚对雄大鼠生育力的影响

Racemic, (-) and (+) gossypol, provided by the Department of Organic Chemistry of our institute, was suspended in 2.5% tween 80 solution. Adult male Wistar rats 190～220 g in weight were allotted to 5 groups. Animals in group 1 received 2.5% tween 80 solution as control. Rats in group 2 were treated with racemic gossypol at the dosage of 30 mg/kg for 2 weeks. Animals in group 3 and 4 were given 15 mg/kg of (-) gossypol for 2 weeks and 30 mg/kg of (-) gossypol for 1 week respectively. Rats in group 5 were treated with (+) gossypol at the dosage of 30 mg/kg for 2 weeks.Four weeks from the beginning of gossypol treatment the rats were cohabited with adult females for 7 days. Then the motility of the sperms in the cauda epididymides was estimated The female rats were examined for pregnancy 7 days later.Treatment with (-) gossypol at 30 mg/kg caused significant decreases in body weight of the rats (P<0.05). One of the five rats died 7 days after the last administration, while (+) gossypol and racemic gossypol at the dosage employed had no effect on the body weight. (+) Gossypol at 30 mg/kg for 2 weeks had no effect on the motility of the sperms in the cauda epididymides and no effect on the fertility of the animals: nor was there any effect on the weights of the testis, epididymis, prostate and seminal vesicle. The sperms of the cauda epididymides were found to be dead in the groups treated with 15 and 30 mg/kg of (-)gossypol. Raccmic gossypol given for 2 weeks at 30 mg/kg caused loss of fertility of the male rats which confirmed our previous findings.(?)t may be postulated that (+) gossypol has no antifertility effect nor toxicity at the dosage employed. (-) Gossypol is the active stereoisomer of racemic gossypol.     

Teratogenic effects of carboplatin, an oncostatic drug, administered during the early organogenetic period in rats

In the preceding study, no teratological effects against rat fetuses were observed when carboplatin, an oncostatic platinum coordination complex, was dosed to their dams from days 7 to 17 of gestation at a dose level of 4 mg/kg/day. However, there are a few reports which show the teratogenic action of carboplatin injected from days 6 to 15 of pregnancy at a dose level of 6 mg/kg/day. In the present study, carboplatin was administered intravenously to pregnant female Crj: CD (Sprague-Dawley) rats from days 6 to 9 or 7 to 10 of gestation at a dose level of 6 mg/kg/day in order to know the teratogenicity of this drug. Carboplatin were highly embryolethal in dams when dosed from days 6 to 9 of gestation, but not in animals when injected from days 7 to 10 of pregnancy. Carboplatin also produced external, internal and skeletal anomalies in fetuses such as gastroschisis, dilatation of cerebral ventricles, cleft sternum, fused ribs, malformed thoracic vertebra when administered from days 6 to 9 of gestation, but not in conceptuses when dosed from days 7 to 10 of pregnancy. However, the delayed ossification which was ascribed to the fetal growth retardation was observed in rats treated with this drug during both administration periods. These results suggest that carboplatin is embryotoxic, inducing intrauterine death and congenital malformations in rats, when injected during the early stages of gestation including day 6 of pregnancy.     

醋酸棉酚对幼龄大鼠睾丸间质细胞分泌活性及细胞膜表面LH/hCG受体发育的影响

醋酸棉酚有抗雄性生育作用,但对睾丸间质细胞的作用尚未取得一致意见。部分研究者观察到醋酸棉酚对睾丸间质细胞有抑制作用。本室也曾证明,服醋酸棉酚后,青春前期大鼠,睾丸间质细胞的生长发育及其类固醇激素合成酶的活性均受抑制。已有报告,睾丸间质细胞表面具有分子量为20万的LH/hCG受体,该受体的数量及活性决定了间质细胞睾酮分泌活性及对促激素的反应。此受体在大鼠五周龄前逐步发育完善,而在4周龄时已表现出对外源性LH/hCG敏感的反应性。本实验以幼龄大鼠为对象,用放射免疫测定及放射受体分析法研究了醋酸棉酚对睾丸间质细胞的影响。     

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.     

Fetal development in alloxan-treated rats

The effect of alloxan on embryo and fetal development in rats was evaluated. Alloxan was injected intraperitoneally (ip) in pregnant rats at doses of 80 to 150 mg/kg at Day 0 (day of fertilization), and 110 mg/kg at Day 4 of pregnancy. Hyperglycemia was rarely produced at alloxan doses from 80 to 100 mg/kg, and the frequency of malformations observed was low. Higher doses (110 to 150 mg/kg) caused severe hyperglycemia, and maternal or embryonic death. When 110 mg/kg was administered on Day 4 of gestation (the day before embryo implantation), all rats had resorption nodules and litters with embryos with delayed growth. We recommend the induction of diabetes mellitus on Day 4 of pregnancy for studies of diabetes–gestation interaction.     

左旋18-甲基炔诺酮肟与左旋18-甲基炔诺酮的抗生育作用比较

本文比较了LNGO和LNG对大鼠的抗生育作用,结果表明,LNGO在剂量为10mg/kg·d时可以完全抑制大鼠着床,剂量为40,60mg/kg·d时有明显抗早孕作用。光电镜观察提示,剂量为10mg/kg·d时,对大鼠子宫内膜间质细胞和上皮细胞均有影响。组织培养研究发现,对体外人胎盘滋养层细胞有直接损伤作用。LNG对大鼠未见抗着床及抗早孕作用,对大鼠子宫内膜和体外人胎盘滋养层细胞也均未见明显作用。