低剂量棉酚男性避孕效果和副作用的临床观察

棉酚的男性避孕作用和副作用（如：不可逆性不育和低血钾症）均为男性学学者所熟悉，其副作用使棉酚至今不能成为广泛应用的男性避孕药。本文试图通过减低棉酚的起效量和维持量以减少或避免副作用的发生。结果发现：每天服用１０ｍｇ或１２．５ｍｇ，待精子密度降为≤４００万／ｍｌ时，改服维持量（隔天１０ｍｇ，或１２．５ｍｇ）均有避孕效果，但起效期较长。服药期间血清ＦＳＨ、ＬＨ和睾酮水平无明显变化，尿β－２ＭＧ和ＮＡＧ以及血钾也无明显异常，服药者更无低血钾症状出现。服药对象的女方无妊娠。     

醋酸棉酚服用者子代外周血淋巴细胞染色体畸变与SCE的观察

本文对服用醋酸棉酚停药恢复生精后所生子代30例及相应的对照组进行了外周血淋巴细胞染色体的观察。实验组的父代每日口服醋酸棉酚20mg,服至起效(一般服药后60～90天以每毫升精液中精子数在400万以下者定为起效指标)。起效后改为维持量,每周40mg。父代平均服药的时间为440天,平均服药总量为3382.34mg。停药后至受孕,时间平均为18个月。结果提示:30例服醋酸棉酚的子代与相应对照组儿童在染色体断裂、裂隙及SCE 均未见明显差异。     

棉酚对大鼠及豚鼠肾细胞膜Na-K-ATP酶影响的研究

本文对喂服不同剂量棉酚后大鼠和豚鼠肾皮质细胞膜组分中的Na-K-ATP 酶的活性变化进行了分析。大鼠及豚鼠喂服棉酚(5毫克/日×56,10毫克/日×28,15毫克/日×48)后,肾皮质细胞膜组分中与Na-K-ATP 酶特异结合的~3H-哇巴因的量随剂量增加而有减少趋势,但服药组与对照组之间的差别无显著意义。豚鼠喂服不同剂量棉酚和不同饲料(20毫克+低K 饲料,40及60毫克+常规饲料)后,肾细胞膜及匀浆的Na-K-ATP 酶活力随剂量的增加而相应下降,低K 饲料组较常规饲料组为明显,服药组与对照组之间的差异有显著意义。文中讨论了棉酚引起Na-K-ATP 酶活性降减与肾性失钾之间的关系。     

棉酚所致低血钾及其与棉酚剂量关系的可能机理

1974年以来,我室试用棉酚男子避孕药255例,发生低血钾性瘫痪24例,这些病例均发生在15mg和20mg的给药组,而当剂量减至12.5mg和10mg时,低血钾不再发生。低血钾性瘫痪病例,用补钾能迅速治愈。通过实验和临床研究表明,部分服醋酸棉酚20mg/天作为起效剂量的对象,服药2个月后开始出现尿NAG和/或β_2M增高以及同时发生肾性失钾。这表明棉酚可能引起近端肾小管损害。作者认为降低棉酚起效剂量或许是一个防止发生低血钾症的途径,而棉酚所致低血钾症是由于肾小管损害所致。     

棉酚抑精种属差异的原因初探

<正> 王月娥等报道,饲料中若含5%棉子粉,5周后大鼠附睾尾内均为死精子;然而给兔连续喂饲含10%棉子粉的饲料,历时9周,对精子活力仍无影响。张明觉等报道,雄兔服1.25—10毫克/公斤的醋酸棉酚,每周5次,历时5—14周,精子发生依然正常;但大鼠与仓鼠服棉酚5或10毫克/公斤,12周后,即出现死精和不正常的精子。本实验室曾以10毫克/公斤/天剂量的棉酚给大鼠灌服,每周6次,5周后附睾尾内全为死精;而以20毫克/公斤/天的棉酚灌服小鼠,历时60天,亦未见附睾尾内有死精子出现。Nieschlag认为,大鼠、仓鼠、猴和人对棉酚敏感,而小鼠、豚鼠、兔、猪、山羊、绵羊和牛则不然。棉酚抑精作用为何有如此明显的种属差异?为了探讨其     

醋酸棉酚在雌性大鼠的抗着床作用及其机理分析

本工作观察了醋酸棉酚对大鼠早期妊娠的影响。于大鼠妊娠的第1—5天,每鼠每天灌服一次醋酸棉酚混悬液(100毫克/公斤体重),对照组灌服等量蒸馏水。于妊娠第10天处死,处死前取血测定血清孕酮,处死后取卵巢测定⊿~5-3β-羟甾脱氢酶活性并记录妊娠动物数及正常着床胎数。结果表明,醋酸棉酚对大鼠具有明显的抗着床作用,抗着床率达85.7%,同时伴有血清孕酮水平下降。若同时皮下注射5毫克孕酮或是同时皮下注射50国际单位的hCG 均能有效地对抗醋酸棉酚的抗着床作用,而同时注射20微克的LH-RH 类似物并不能对抗醋酸棉酚的抗着床作用。在延缓着床的大鼠,醋酸棉酚不能对抗外源性雌二醇的致着床作用。以上结果提示,对抗LH 对黄体功能的支持有可能是醋酸棉酚抗着床作用的机理之一。     

棉酚对钾和前列腺素代谢的影响

本文概述了棉酚与钾代谢关系的文献,也报导了这方面的以及涉及前列腺素问题的一些新资料。从多数动物实验和临床药理研究来判断,棉酚与钾和前列腺素代谢的关系大致可归纳为:1.棉酚可以影响钾代谢。在人类,棉酚可通过肾失钾而引起体钾丧失和低血钾症;在大鼠,棉酚对钾代谢的影响主要表现在细胞内钾离子浓度下降。棉酚影响钾代谢的可能机理为干扰Na-K-LATP 酶活性及促进前列腺素的生物合成。初步的实验结果提示,前列腺素也可能参与棉酚的抑制生精机制。2.棉酚对钾代谢的影响是有条件的,在机体摄入钾量低下时,此影响较为明显,摄入钾量充分时则不显著。3.预防性使用钾盐,即补充钾摄入量的不足,可防止棉酚所引起的低血钾性麻痹。但作者认为,此问题的最终解决,将求助于增加食物钾量,甚或改变棉酚结构。     

已烯雌酚作为事后避孕药的研究

本文作者曾于1971年报道使用己烯雌酚作为事后避孕药的研究,在1000例中达到100%的避孕效果。本文为前一报道的继续。截止1972年7月已有1410名有生育能力的妇女,房事后服用己烯雌酚,除112名失去联系外,作者追访了1298名(92.1%)服药妇女,其中1217名按规定方法服药,即房事后72小时内服药,每天两次,每次25毫克,共服5天。结果100%有效,无1例失败。另外81名妇女未按指定方法服药。结果有6名怀孕,但都作了流产术。服用已烯雌酚的妇女未出现严重的副作用,仅有少数有胃刺激症状和呕吐,一般都在服药6—8小时后出     

棉酚抑制仓鼠精子顶体酶类活性及其与受精能力的关系

为了预防棉酚引起生育力不可逆的问题,我们研究了棉酚对精子顶体酶类活力与其受精能力之关系.结果表明棉酚对体外仓鼠精子穿透牛宫颈粘液及受精率有明显的抑制作用.喂服棉酚6周后,它可明显地抑制仓鼠精子的受精率,延缓睾丸提取物扩散颗粒细胞的能力,提示透明质酸酶和其他精子顶体酶类可能受到抑制.此外棉酚还可显著降低精子顶体酶和芳香基硫酸酯酶活力.这些结果表明:棉酚抑制仓鼠精子顶体酶活力与其受精率的下降相一致,其抑制作用是可逆的,并与所用棉酚剂量和服药时间呈相关性.据此可得出结论,精子顶体酶活力可用来作为监护棉酚引起不育的指标.     

男子停服棉酚后的精液、血液生化和激素水平随访观察

<正> 我国科学工作者首先发现棉酚的抗生育作用,对其避孕效果和副作用已有详述本文对长期服用棉酚者停药后的生精恢复、血液生化及激素水平进行了观察,现报告如下。对象和方法一、20名已服用棉酚2～9年(平均5年)的志愿者,年龄为29～48岁(平均40岁),服药总量为4.8～27.5克(平均12.1克)。二、停药后六个月内每月检查一次,以后每两个月检查一次,连续三次精子密度d≥20×10~5/ml即终止观察。三、检查指标均按WHO男性生育调节随访表格要求进行,包括(1)体检(含胸透,肝、胆脾超声波     

30例育龄男性服用棉酚期间的心电图追踪观察

为了解小剂量口服棉酚的安全性，对３０例育龄男性进行了口服小剂量棉酚（１５ｍｇ／ｄ×１２ｗ，继以７．５ｍｇ／ｄ或１０ｍｇ／ｄ×４０ｗ）期间的心电图（ＥＫＧ）随访观察。在整个服药期间有ＥＫＧ改变者中，多数（７７％）为ＰＲ间期延长，平均ＰＲ间期在第４周和第１２周为０．１６６±０．０１７ｓ，显著高于服药前的０．１５９±０．０１４ｓ，差异具统计学的显著性（Ｐ＜０．０５）。ＱＲＳ时限，ＱＴ间期则不见明显变化。本项结果提示小剂量棉酚对心肌和心内传导系统可能有着不同的影响。     

Effect of gossypol on the fertility of male rats.

Thirty male rats were grouped into 5 groups of 6 animals each. Animals in groups II-V were given gossypol at a dose of 5 mg/kg, 10 mg/kg, 20 mg/kg and 40 mg/kg body weight per day for 45 days respectively. Animals of group I served as control. A significant decrease in body weight after administration of 40 mg/kg body weight of gossypol was observed; low doses of gossypol, however did not affect the body weight. Testis, epididymis, prostate and seminal vesicles weights decreased gradually with the increasing doses of gossypol. With the increasing doses of gossypol, a marked decrease in the vas deferens sperm motility was observed. At 40 mg/kg dose there was a total inhibition of sperm motility. Histological studies after 5 mg/kg revealed no apparent sign of degeneration, while after 10 mg/kg dose the changes in the individual cell types were accompanied by overall disorganisation of the germinal epithelium involving displacement of the spermatocytes. The rats treated with 20-40 mg/kg gossypol showed a pronounced deleterious effect on the histological structure of the testis. The drug effect was dose dependent developing sequentially; from the uppermost layer of elongated spermatids affecting round spermatids and finally spermatocytes. Quantitatively the ratios of pachytene spermatocytes: resting spermatocytes, stage 7 spermatids: pachytene spermatocytes, and stage 19 spermatids: stage 7 spermatids and tubular diameter and germinal height decreased significantly. The activities of glucose-6-phosphatase, fructose 1, 6-diphosphatase, glucose-6-phosphate isomerase in testis decreased significantly at high dose (40 mg/kg), while the activity of amylase and glycogen content increased significantly with the increasing doses of gossypol.(ABSTRACT TRUNCATED AT 250 WORDS)     

棉酚引起雌鼠实验性子宫内膜异位症的快速消退

为研究棉酚对子宫内膜异位症的治疗作用及其机理，２４只经自体子宫内膜移植引起的实验性子宫内膜异位症雌鼠随机分成对照组和棉酚治疗组。对照组予以０．５％Ｔｗｅｅｎ８０皮下注射，棉酚组予以０．５％Ｔｗｅｅｎ８０溶释的棉酚混悬液以５ｍｇ／（ｋｇ·ｄ）皮下注射２～３周。结果表明，与对照组比较，经２～３周棉酚治疗的实验性子宫内膜异位症雌鼠卵巢重量和血浆雌二醇明显降低（Ｐ＜０．０１）；而子宫重量和子宫内膜移植病灶也明显减少（Ｐ＜０．０５），棉酚引起移植子宫内膜异位病灶消退率为６６．６％，研究证实：棉酚可有效地阻遏实验性子宫内膜异位病灶的生长发育并可使其快速消退，其作用部位在卵巢和子宫水平而非在下丘脑－垂体水平，实验进一步证实棉酚对子宫内膜异位症的治疗作用并可望开发成为新一代治疗药物。     

Studies on gossypol. I. Toxicity, antifertility, and endocrine analyses in male rats

Toxicity, antifertility, and endocrine effects of gossypol have been studied in male rats. The animals grew nearly normally when administered a daily dose of 7.5 mg/kg orally for 12 wk. At 15 and 30 mg/kg/d doses growth rates were significantly reduced. Infertility occurred at all dose levels, but mating behavior was maintained throughout the period of treatment. Examination of the cauda epididymis after 6 wk at the 30-mg/kg/d dose and after 12 wk at the lower doses showed reductions in sperm numbers as compared with controls. All of the sperm from the groups receiving the 15- and 30-mg/kg/d doses were immotile; and at the 7.5-mg/kg/d dose level most sperm were immotile. Many of nonmotile sperm showed sharply bent tails or lacked tails. There was no significant change in the serum levels of testosterone, LH, or FSH in animals receiving 7.5 and 15 mg/kg/d of gossypol for 12 wk. However, at a dose of 30 mg/kg/d for 6 wk, the serum testosterone and LH concentrations were significantly reduced. FSH concentrations remained normal in all groups. A group of 5 animals receiving 15 mg/kg/d were allowed a recovery period of 6 wk after 12 wk of therapy and they evidenced complete recovery of fertility.     

Response of hamster to the antifertility effect of gossypol.

One hundred and five sexually mature male hamsters were divided in different groups. In the first experiment hamsters were administered gossypol, 10 mg/kg and 20 mg/kg/body weight/day, for twenty and thirty days. In the second experiment hamsters were administered gossypol, 5, 10 and 20 mg/kg/body weight/day, for sixty days. In the third experiment, hamsters were administered gossypol 5 mg, 10 mg, 20 mg and 40 mg/kg body weight/day for 45 days. Animals in all the groups were given gossypol by oral intubation every day. No significant effect on the body weight of hamsters following gossypol treatment was observed. At low doses the weights of testis and accessory sex organs were not statistically different from those of the controls. A significant decrease in testis and epididymis weight was however observed following high doses of gossypol. Low doses of gossypol treatment did not affect the motility of the vas deferens spermatozoa. The vas deferens spermatozoa were however immotile after 40 mg/kg/day gossypol treatment. Gossypol treatment induced a series of histological changes in the seminiferous epithelium of the hamster testis. The earliest sign of drug effect was seen in spermatids and with the increase in doses the effects became more pronounced and extended to the spermatocytes. At 40 mg/kg dose an almost complete arrest of spermatogenesis was observed. Quantitatively, the ratio of pachytene spermatocytes: resting spermatocytes and step 7 spermatids: pachytene spermatocytes decreased significantly. The step 7 spermatids did not mature to step 19 spermatids at all. Histochemically activities of ATPase, SDH and LDH decreased with the increasing doses of gossypol, the activity of 3B hydroxysteroid dehydrogenase was not affected by gossypol treatment. In testis the glucose-6-phosphatase activity was not affected significantly but the activities of fructose 1, 6-diphosphatase and glucose-6-phosphate isomerase decreased significantly with the increasing doses of gossypol. Amylase activity rose significantly at higher doses. Marked changes in LDH and LDH-X were however observed with the increase in gossypol dose. In liver the activity of glucose-6-phosphatase increased significantly while the activities of fructose 1, 6-diphosphatase, glucose-6-phosphate isomerase and amylase were not affected following gossypol treatment. The glycogen contents however increased significantly following high doses of gossypol. No changes in testosterone production and plasma levels of testosterone were observed following gossypol treatment.     

Antifertility and ultrastructural effects of optical isomers of gossypol administered intratesticularly in rats

This study reports on the effects of optical isomers of gossypol administered intratesticularly on testicular ultrastructure and fertility in rats. Gossypool isomers were administered to adult male rats by daily intratesticular injections for up to two days at a dose of 1200 ugm/testis. The results of this study have demonstrated that the intratesticular injection of racemic and (-) gossypol at a dose of 1200 ugm for 1 or 2 days mimic the effect of gossypol on rat testis after oral administration of 20 to 30 mg dose for 5-7 weeks; (-)-gossypol was found to be 81% effective in inducing mitochondrial sheath damage in the late spermatids of stage VI, VII and VIII tubules compared to 67% for racemic and 7% for (+)-gossypol, the intratesticular injection of (+/-) and (-)-gossypol (1200 ugm/testis, daily for 1 or 2 days) induces complete infertility three weeks after the last injection.     

Response of mice testis to gossypol acetic acid

Male mice were administered gossypol (2.5, 5.0, 10.0 and 20.0 mg/kg body weight) by oral intubation, subcutaneous and intraperitoneal routes for 30 days. The drug treatment did not have any effect on body weight and organ weights. The motility of cauda epididymis and vas deferens spermatozoa was not affected by gossypol treatment nor there was any effect of gossypol on the histoarchitecture of the testis irrespective of the dose and route of administration. Maximum mortality was observed in mice when animals were given gossypol by intraperitoneal route.     

65Zn incorporation in the male reproductive organs following gossypol treatment

Male hamsters and rats were administered gossypol 10 mg/kg/day for 45 and 56 days respectively. Twenty four hours before the last dose, animals were administered 65Zn (specific activity 0.258 uci/mg) subcutaneously. A marked decrease in 65Zn incorporation was observed in testis, epididymis, seminal vesicles and prostate following drug administration. A significant increase in 65Zn uptake was however observed in vas deferens in both rat and hamster following drug administration. Our results suggest that whatever the mechanism of gossypol action on testis-epididymis complex may be, the marked decrease in 65Zn uptake by testis--epididymis complex following gossypol treatment may be related to the antispermatogenic effect of gossypol.