养精胶囊治疗DAZ基因缺失所致无精子症的临床价值
|
摘要
[目的]探讨DAZ基因缺失所致无精子症药物治疗的可能性,研究养精胶囊对DAZ基因缺失所致无精子症的疗效,并进一步分析其作用机理。
[方法]将48例患者随机分为治疗组28例,对照组20例。治疗组给予养精胶囊,每次5粒,每日3次；对照组给予十一酸睾酮胶丸(安特尔),每次40mg,每日2次。观察指标：治疗6个月后疗效,随访ICSI/PGD结果,治疗前和治疗3个月后精液量、精浆α-糖苷酶(α-Glu)、精浆前列腺酸性磷酸酶(ACP)、精浆果糖(Fru),血清性激素指标(FSH、LH、T、E2、PRL)。
[结果]1.治疗组有效10例,无效18例,有效率35.7%；对照组有效2例,无效18例,有效率10.0%(P<0.05); ICSI/PGD后,治疗组正常受精数34,受精率44.7%,生化妊娠5例,生化妊娠率41.7%,临床妊娠3例,临床妊娠率33.3%,活产2例。对照组正常受精数5,受精率35.7%,生化妊娠1例,生化妊娠率50.0%,无临床妊娠。2.治疗组中有效患者和无效患者的平均年龄,双侧睾丸容积和血清FSH之间均存在显著性差异(P<0.05)。3.养精胶囊能升高血清FSH、LH及T水平,对E2及PRL无显著影响；十一酸睾酮能通过升高T水平,进而负反馈抑制LH的分泌。4.养精胶囊能增加精液量,促进附属性腺的分泌,升高精浆α-Glu、Fru及ACP水平。
[结论]1.临床上对于DAZ基因缺失患者中,年龄较轻、睾丸体积较大及血清FSH不是很高的无精子症患者,可以尝试给予药物治疗。反之,则不主张治疗。2.养精胶囊可以作为治疗DAZ基因缺失所致无精子症的候选药物之一。探讨养精胶囊有效的原因,可能是养精胶囊通过调节下丘脑-垂体-性腺轴功能,从而促进精子的生成。’3.养精胶囊还能促进附睾、精囊及前列腺的分泌功能。
Objective:To observe the effects of Yangjing Capsule treatment on azoospermia due to DAZ gene deletion, and discuss the mechanisms.
Methods:Forty-eight patients of azoospermia with DAZ gene deletion, were randomly divided into a treatment group(n=28) and a control(n=20). The former treated by Yangjing Capsule (5 pills, tid) and the latter with testosterone undecanoate (40mg, bid). The efficacy was observed after treatment for six months and the inedxes such as semen volume, seminal a-glucosidase enzyme(a-Glu), prostatic acid phosphatase(ACP), fructose in seminal plasma(Fru), gonadal hormone(FSH, LH, T, E2, PRL) were analyzed at 3 months before and after treatment.
Results:1. The totaleffective rate was 35.7%(10/28) in the treated group, which was significantly higher than that in the controlgroup,10.0%(2/20, P<0.05). After ICSI/PGD, in treatment group, fertilization number was 34, fertilization rate was 44.7%,5 cases got biochemical pregnancy, biochemical pregnancy rate was 41.7%,3 cases got clinical pregnancy, clinical pregnancy rate was 33.3% and two of live births. While in the control group, fertilization number was 5, the fertilization rate of 35.7%,1 case of biochemical pregnancy, biochemical pregnancy rate was 50.0%, no clinical pregnancy.2. There are significant differences on the average age, bilateral testicular volume and serum FSH values between the effectives and non-effectives in the treatment group(P<0.05).3. Yangjing capsule elevated serum FSH, LH and T levels, had no significant impact on the E2 and PRL, while testosterone undecanoate increased T levels, and suppressed LH levels by the way of the negative feedback.4. Yangjing capsule increased semen volume and the a-Glu, Fru and ACP level in seminal plasma.
Conclusion:1. It is treatable for the patients of lower age, larger testicular volume and not too high serum FSH.2. Yangjing capsule is an effective drug on azoospermia duo to DAZ gene deletion. The mechanisms which may act on the hypothalamus-pituitary-gonadal axis, thus promoting the generation of sperm.3.Yang Jing Capsule can also promote the secretory function of epididymis, seminal vesicle and prostate.
[方法]将48例患者随机分为治疗组28例,对照组20例。治疗组给予养精胶囊,每次5粒,每日3次；对照组给予十一酸睾酮胶丸(安特尔),每次40mg,每日2次。观察指标：治疗6个月后疗效,随访ICSI/PGD结果,治疗前和治疗3个月后精液量、精浆α-糖苷酶(α-Glu)、精浆前列腺酸性磷酸酶(ACP)、精浆果糖(Fru),血清性激素指标(FSH、LH、T、E2、PRL)。
[结果]1.治疗组有效10例,无效18例,有效率35.7%；对照组有效2例,无效18例,有效率10.0%(P<0.05); ICSI/PGD后,治疗组正常受精数34,受精率44.7%,生化妊娠5例,生化妊娠率41.7%,临床妊娠3例,临床妊娠率33.3%,活产2例。对照组正常受精数5,受精率35.7%,生化妊娠1例,生化妊娠率50.0%,无临床妊娠。2.治疗组中有效患者和无效患者的平均年龄,双侧睾丸容积和血清FSH之间均存在显著性差异(P<0.05)。3.养精胶囊能升高血清FSH、LH及T水平,对E2及PRL无显著影响；十一酸睾酮能通过升高T水平,进而负反馈抑制LH的分泌。4.养精胶囊能增加精液量,促进附属性腺的分泌,升高精浆α-Glu、Fru及ACP水平。
[结论]1.临床上对于DAZ基因缺失患者中,年龄较轻、睾丸体积较大及血清FSH不是很高的无精子症患者,可以尝试给予药物治疗。反之,则不主张治疗。2.养精胶囊可以作为治疗DAZ基因缺失所致无精子症的候选药物之一。探讨养精胶囊有效的原因,可能是养精胶囊通过调节下丘脑-垂体-性腺轴功能,从而促进精子的生成。’3.养精胶囊还能促进附睾、精囊及前列腺的分泌功能。
Objective:To observe the effects of Yangjing Capsule treatment on azoospermia due to DAZ gene deletion, and discuss the mechanisms.
Methods:Forty-eight patients of azoospermia with DAZ gene deletion, were randomly divided into a treatment group(n=28) and a control(n=20). The former treated by Yangjing Capsule (5 pills, tid) and the latter with testosterone undecanoate (40mg, bid). The efficacy was observed after treatment for six months and the inedxes such as semen volume, seminal a-glucosidase enzyme(a-Glu), prostatic acid phosphatase(ACP), fructose in seminal plasma(Fru), gonadal hormone(FSH, LH, T, E2, PRL) were analyzed at 3 months before and after treatment.
Results:1. The totaleffective rate was 35.7%(10/28) in the treated group, which was significantly higher than that in the controlgroup,10.0%(2/20, P<0.05). After ICSI/PGD, in treatment group, fertilization number was 34, fertilization rate was 44.7%,5 cases got biochemical pregnancy, biochemical pregnancy rate was 41.7%,3 cases got clinical pregnancy, clinical pregnancy rate was 33.3% and two of live births. While in the control group, fertilization number was 5, the fertilization rate of 35.7%,1 case of biochemical pregnancy, biochemical pregnancy rate was 50.0%, no clinical pregnancy.2. There are significant differences on the average age, bilateral testicular volume and serum FSH values between the effectives and non-effectives in the treatment group(P<0.05).3. Yangjing capsule elevated serum FSH, LH and T levels, had no significant impact on the E2 and PRL, while testosterone undecanoate increased T levels, and suppressed LH levels by the way of the negative feedback.4. Yangjing capsule increased semen volume and the a-Glu, Fru and ACP level in seminal plasma.
Conclusion:1. It is treatable for the patients of lower age, larger testicular volume and not too high serum FSH.2. Yangjing capsule is an effective drug on azoospermia duo to DAZ gene deletion. The mechanisms which may act on the hypothalamus-pituitary-gonadal axis, thus promoting the generation of sperm.3.Yang Jing Capsule can also promote the secretory function of epididymis, seminal vesicle and prostate.
引文
[1]徐福松主编.男科临证指要[M].北京：人民卫生出版社,2008：116-124.
[2]胡钢铮.辨证治疗男性无精子不育症32例[J].湖北中医杂志,1992,14(5)：14-15.
[3]曹继刚.周安方治疗不育症从精液微观辨证用药经验[J].湖北中医杂志,2009,31(3)：29-30.
[4]马卫国.贾金铭教授治疗男性不育症的经验[J].中医研究,2006,19(5)：53-55.
[5]陈建设.王琦教授治疗男性不育经验介绍[J].四川中医,2004,22(1)：7-8.
[6]王东坡.王琦教授治疗男科疾病经验介绍[J].新中医,2005,37(10)：12-13.
[7]韩晓峰.自拟四君生精汤治疗无精子症疗效观察[J].卫生职业教育,2005,23(8):57.
[8]訾红霞,朱庆国,刘湘芸.无精症的辨证论治体会[J].内蒙古中医药,2004,(6)：6-7.
[9]胡秉德.自拟生精汤治疗无精症36例[J].吉林中医药,2004,24(9)：35.
[10]宋红湘,胡彬,胡孝刚.种子金丹治疗无精子症82例[J].中医研究,2001,14(4)：54-55.
[11]徐焙.“健脾益肾生精汤”治疗无精子症[J].时珍国医国药,1992,3(1)：35.
[12]蔡玉国.二鹿生精丸治疗无精子症24例[J].北京中医,1995,2：32-33.
[13]叶光宇,文绪芬.生精通关汤治疗无精子症40例[J].河北中医,1994,16(4)：22-23.
[14]赵铁砚.冬蛤生精饮治疗无精子症60例[J].辽宁中医杂志,1990,14(5)：23.
[15]陈文伯.生精赞育丸治疗无精子症66例临床分析[J].江西中医药,1986,06：45.
[16]张玲楚.籽药治疗无精子症[J].湖北中医杂志,1996,18(04)：45.
[17]王旭初,刘文轩,王元松,等.中药治疗男性无精子症临床疗效观察[J].中华中医药学刊,2007,25(2)：308-309.
[18]金保方,杨晓玉,刘嘉茵,等.精原细胞瘤术后放疗致无精子症经综合治疗致孕1例[J].中华男科学杂志,2006,12(9)：836-838.
[19]王晓峰.重视无精子症的病因诊断[J].中华男科学杂志,2009,15(8)：675-678.
[20]Repping S, Skaletsky H, Brown L, et al. Polymorphism for a 1.6 Mb deletion of the human Y chromosome persists through balance between recurrent mutation and haploid selection[J]. Nat Genet,2003, 35 (3):247-251.
[21]Kuroda-Kawaguchi T, Skaletsky H, Brown L G, et al. The AZFc region of the Y chromosome features massive palindromes and uniform recurrent deletions in infertile men[J]. Nat Genet,2001,29 (3):279-286.
[22]Eddy EM. Male germ cell gene expression. Recent Prog Horm Res,2002,57(1):103-128.
[23]Pryor JL, Kent-First M, Muallem A, et al. Microdeletion in the Y chromosome of infertile men[J]. N Eng J Med,1997,336:534-539.
[24]Zhu XB, Guo AL, Cao XR, et al. Screening for Y chromosomal mircrodeletions in AZF region with modifiled multiplex PCR[J]. Chin J Androl,2006,12:199-201.
[25]Li H, Ding X, Zhao J, et al. Y chromosome microdeletions of 664 Chinese men with azoospermia or severe oligozoospermia[J]. Zhonghua Yi Xue Yi Chuan Xue Za Zhi,2008, 25 (3):252-255.
[26]Hargreave TB. Genetic basis of male fertility[J].British Medical Bulletin,2000,56 (3):650-671.
[27]Vogt PH, Edelmann A, Kirsch S, et al. Human Y chromosome azoospermia factors (AZF) mapped to different subregions in Yq11[J]. Hum Mol Genet,1996,5:933-943.
[28]Yang J, Zhang SZ, Smppia Libofio, et al.Microdeletions in interval 6 of Y chromosome detected in the patients with oligo or azoospermia[J]. Chin J Urol, December,2001,22 (12):712-715.
[29]Kent-First M, Muallem A, Shulz J, et al. Denfining regions of the Y chromosome responsible for male infertility and identification of a fourth AZF region (AZFd) by Y chromosome microdeletion detection[J]. Mol Reprod Dev,1999,53 (1):27-41.
[30]Yueh-Hsiang Yu, Yi-Wen Lin, Jane-Fang Yu, et al. Evolution of the DAZ gene and the AZFc region on primate Y chromosomes[J]. BMC Evolutionary Biology,2008,8 (96):1471-2148.
[31]Saxena R, de Vries J W, Repping S, et al. Four DAZ genes in two clusters found in the AZFc region of the human Y chromosome[J]. Genomics,2000,67 (3):256-267.
[32]Habermann B, Mi HF, Edelmann F, et al. DAZ gene encoding proteins located in human late spermatids and sperm tails[J]. Hum Reprod,1998,13:363-369.
[33]Saxena R, Brown LG, Hawkins T, et al. The DAZ gene cluster on thehuman Y chromosome arose from an autosomal gene that was transposed, repeatedly amp lified and p runed[J]. Nature Genet,1996,14(3): 292-299.
[34]Xu EY, Frederick LM, Renee A. A gene family required for human germ cell development evolved from an ancientmeiotic gene conserved in metazoans[J]. Proc Natl Acad Sci USA,2001,98 (13):7414-7419.
[35]阿周存,杨元,张思仲,等.严重寡精症ICSI精子供体的DAZ基因拷贝缺失研究[J].遗传,2006,28(9)：1057-1060.
[36]VogelT, Speed RM, RossA, et al. Partial rescue of the DAZL knockout mouse by the human DAZL gene[J]. Mol Hum Reprod,2002,8 (9):797-804.
[37]Reynolds N&Cooke HJ. Role of the DAZ genes in male fertility[J]. Reprod Biomed Online,2005,10 (1):72-80.
[38]Cauffman G, van de Velde H, Liebaers I, et al. DAZL expression in human oocytcs, preimplantation embryos and embryon ic Stem cells[J]. Mol Hum Reprod,2005,11 (6):405-411.
[39]Brian C, Barbara G, Carolyn L, et al. The DAZL familyproteins are PABP-binding proteins that regulate translation in germ cells[J]. EMBOJ,2005,24 (14):2656-2666.
[40]Simoni M, Tuttelmann F, Gromoll J, et al. Clinical consequences of microdeletions of the Y chromosome:the extended Munster experience [J]. Reprod Biomed Online,2008,16 (2):289-303.
[41]阿周存,杨元,张思仲,等.严重寡精症ICSI精子供体的DAZ基因拷贝缺失研究[J].遗传,2006,28(9)：1057-1060.
[42]马明义,钟一梅,韦小妮,等.AZFc区gr/gr及DAZ基因拷贝缺失与原发性男性生精障碍的相关性研究[J].中国优生与遗传杂志,2007,15(5)：20,21,98.
[43]Hucklenbroich K, Gromoll J, Heinrich M, et al. Partial deletions in the AZFc region of the Y chromosome Occur in men with impaired as well as norm al spermatogencsis[J]. Hum Reprod,2005,20 (1): 191-197.
[44]Giaehini C, Guarducei E, Longcpied G, et al.The gr/gr deletion(s):a new genetic test in male infertility[J]? J Med Genet,2005,42 (6):497-502.
[45]Lynch M, Cram DS, Reilly, et al. The Y chromosome subdeletion is associated with male infertility[J]. Mol Hum Reprod,2005,11 (7):507-512.
[46]Laila Imken, Brahim E1 Houate, Abdelaziz Chafik, et al. AZF microdeletions and partial deletions of AZFc region on the Y chromosome in Moroccan men[J]. Asian Journal of Androlog,2007,9(5):674-678.
[47]Ferlin A, Tessari A, Ganz F, et al. Association of partial AZFc region deletions with spermatogenic impairment and male infertility[J]. J Med Genet,2005,42 (3):209-213.
[48]Santos FR, Pan dya A, Metal K, et al.A polymorphic L1 retroposon insertion in the centeromere of the human Y chromosome[J]. Hum Mol Genet,2000,9 (3):421-430.
[49]Hargreave TB. Genetic basis of male fertility [J]. British Medical Bulletin,2000,56 (3):650-671.
[50]Sun C, Skaletsky H, Rozen S, et al. Deletion of asoospermia factor a (AZFa) region of human Y chromosome caused by recombination between HERV15 proviruses[J]. Hum Mol Genet,2000,9 (15): 2291-2296.
[51]Vogt PH. Molecular genetic of human male infertility:from genes to new therapeutic perspectives[J]. Curt Pharm Des,2004,10 (5):471-500.
[52]Vogt PH. Azoospermia factor (AZF) in Yq11:towards a molecular understanding of its function for human male fertility and spermatogenesis[J]. Reprod Biotaed Online,2005,10 (1):81-93.
[53]Vogt PH. Genomic heterogeneity and instability of the AZF locus on the human Y chromosome[J]. Mol Cell Endocrinal,2004,224 (1-2):1-9.
[54]Kunej T, Zorn B, Peterlin B. Y chromosome microdeletions in infertile men with cryptorchidism[J]. Fertil Steril,2003,79 (Suppl3):1559-1565.
[55]Dada R, Gupta NP, Kucheria K. AZF microdeletions associated with idiopathic and non-idiopathic cases with cryptorchidis and varicocele[J]. Asian J Androl,2002,4 (4):259-263.
[56]Martinez MC, Bemabe MJ, Gomez E, et al. Screening for AZF deletion in a large series of severely impaired spermatogenesis patients [J]. J Androl,2000,21 (5):651-655.
[57]Rima Dada, Kumar, M. B. Shamsi, et al.Azoospermia Factor Deletions in Varicocele Cases with Sever Oligozoospermia[J]. India J Med Sci,2007,61 (9):505-510.
[58]邱毅,杨丹彤,张爱东,等.Klinefelter综合征患者Y染色体AZF微缺失分析[J].中国优生与遗传杂志,2008,16(1)：41-43.
[59]Choe JH, Kim JW, Lee JS, Seo JT. Routine screening for classical azoospermia factor deletions of the Y chromosome in azoospermic patients with Klinefelter syndrome[J]. Asia J Androl,2007,9(6):815-820.
[60]李练兵,吕静,马明福,等.不育患者Y染色体AZF微缺失的分析[J].中国优生与遗传杂志,2008,16(6)：13,23.
[61]单桂芬,苏学今,郑贤红,等. 染色体核型异常男性不育患者Y染色体微缺失分析[J].中国优生与遗传杂志,2009,17(1)：49-50.
[62]Katherine LN, Peter AK, Rachel H, et al. The Y Deletion gr/gr and Susceptibility to Testicular Germ Cell Tumor[J]. Am J Hum Genet,2005,77 (6):1034-1043.
[63]Dewan S, Puscheck EE, Coulam CB, et al. Y-chromosome microdeletions and recurrent pregnancy loss[J]. Fertil Steril.2006,85 (2):441-445.
[64]夏欣一,崔英霞,潘连军,等.1个AZFc缺失自然遗传的家系分析[J].中华男科学杂志,2006,12(8)：720-722.
[65]朱晓斌,李铮,郭安亮,等.Y染色体微缺失父子间垂直遗传分析[J].中华医学遗传学杂志,2007,24(2)：203-205.
[66]Oates RD, Silber S, Brown LG, et al. Clinical characterization of 42 oligospermia or azoospermic men with microdeletion of the AZFc region of the Y chromosome, and of 18 children conceived via ICSI. Hum Rep rod,2002,17 (11):2813-2824.
[67]Mau Kai C, Juul A, Mc Elreavey K, et al. Sons conceived by assisted reproduction techniques inherit deletions in the azoospermia factor (AZF) region of the Y chromosome and the DAZ gene copy number[J]. Hum Reprod,2008,23 (7):1669-1678.
[68]戴黎华,翁兰英.Y染色体长臂无精子因子DAZ基因缺失与精子生成障碍[J].中国实用妇科与产科杂志,2008,24(7)：549-551.
[69]PalermoG, JorisH, DevroeyP, VanSteirteghemAC. Pregnancies after intraeyto-plasmic injection of a single spermatozoon into an oocyte[J].Lancet,1992,340 (8810):17-18.
[70]Michelmann HW, Gratz G, Hinney B. X-Y sperm selection:fact or fiction[J]? Hum Reprod Genet Ethics, 2000,6 (2):32-38.
[71]金保方,黄宇烽,杨晓玉,等.养精胶囊治疗弱精子症的临床观察[J].南京中医药大学学报,2006,22(5)：286-289.
[72]金保方,黄宇烽,夏欣一,等.养精胶囊联合锌硒宝对不育患者精子DNA完整性的影响[J].中国男科学杂志,2006,20(12)：45-48.
[73]金保方,黄宇烽,陆晓和.养精胶囊治疗男性性功能障碍的临床观察[J].中华男科学杂志,2006,12(3)：272-274,276.
[74]张晓文,宋清.从基因角度探讨“肾主生长发育”的本质[J].中医药研究,1996,3(3)：12.
[75]田进文,孙奉雷,石巧荣.中心法则与肾脏本质[J].山东中医学院学报,1996,20(1)：17.
[76]陈晓霞.论中医肾与垂体促性腺激素的关系[J].辽宁中医学院学报,2003,5(3)：226.
[77]司富春.从下丘脑-垂体-性腺轴研究中医肾的现状及对策[J].中医研究,1994,7(3)：2.
[78]张瑞兰,林日省.脾与肾的实质探秘[J].湖北中医杂志,2001,23(10)：8.
[79]张启明.中医肾与现代西医学组织器官的相关性研究[J].辽宁中医杂志,2003,30(8)：634.
[80]吴水生,邱山东,林求诚,等.中老年女性性激素水平与不同肾虚证关系的研究[J].福建中医药,2000,31(1)：3-4.
[81]吴水生,叶钦勇,林求诚,等.中老年男性性激素水平与不同肾虚证关系[J].福建中医药,2000,31(2)：3-4.
[82]丘瑞香,吴国珍,金明华.性激素对肾虚患者阴阳平衡的调节作用[J].中国中医基础医学杂志,1999,5(3)：46-47.
[83]田文艺,曾嵘,蒋传付.送子衍宗丸颗粒剂生精作用的研究[J].湖南中医学院学报,1993,13(4)：35.
[84]夏卫平,陈磊,蒋学洲,等.康宁口服液对肾虚不育症影响的实验研究[J].上海中医药杂志,1997,43(6)：45-46.
[85]李育浩,吴清和,李茹柳,等.五子衍宗丸对生殖系统的影响[J].中药药理与临床,1992,8(3)：4.
[86]王学美,谢竹藩,刘庚信,等.五子衍宗液对雄性大鼠下丘脑单胺类递质、性激素和生育能力的影响[J].中国中西医结合杂志,1993,13(6)：349.
[87]陈健安,高崎悦司,铃木辙.六味地黄汤对大鼠下丘脑-垂体-性腺轴组织器官形态和性激素的影响[J].江苏中医,1999,20(3)：46.
[88]许绍芬.神经生物学[M].第2版.上海：上海医科大学出版社,1999：279-287.
[89]BernardiF, Pluchino N, StomatiM, et al. CNS:sex steroids and SERMs[J]. Ann NY Acad Sci,2003, 997 (1):378-388.
[90]曹兴午.睾丸生精障碍的靶区、靶细胞和靶点[J].中国男科学杂志,2008,22(7)：58-60,63.
[91]鲁海鸥,丁晓萍,张宁,等.正常男性血清生殖内分泌激素与睾丸、精液的相关研究[J].中国优生与遗传杂志,2003,11(5)：129-130.
[92]Plant TM, Marshall GR. The functional Significance of FSH in spermatogenesis and the control of its secretion in male primates[J]. Endocrine RevieWS,2001,22 (6):764-786.
[93]Haywood M, SpaliViero J, JimemezM, et al. Sertoli and germ cell development in hypogonadal (hpg) mice expressing transgeenic follicle-stimulating hormone alone or in combination with testosterone[J]. Endocrinologyt,2003,144 (2):509-517.
[94]GroverA, Smith CE, Gregory M. Effects of FSH receptor deletionon epididymal tubules and sperm morphology, numbers, and motility[J]. MolReprod Dev,2005,72 (2):135-144.
[95]Ramaswamy S, Marshall GR, et al. Dynamics of the follicle-stimulating hormone (FSH)-inhibin B feedback loop and its role in regulating spermatogenesis in the adult male rhesus monkey (Macacamulatta) as revealed by unilateral or chidectomy[J]. Endocrinology,2000,141 (1):18-27.
[96]郭应禄,胡礼泉.男科学[M].北京：人民卫生出版社,2004：124-127.
[97]Johnston H, Baker PJ, Abel M, et al. Regulation of Sertoli cell number and activity by follicle-stimulating hormone and androgen during postnatal deveiopment in the mouse[J]. Endocrinology.2004,145(1):318-329.
[98]HenkelR, MaassG, SchuppeHC, et al. Seasonal changes of neutral alpha-glucosidase activity in human semen[J].J Androl,2006,27 (1):34-49.
[99]张新东,金保方.精囊功能评价及调控研究概况[J].现代泌尿外科杂志,2009,14(2)：155-156.
[100]杨桂芹,邹兴淮.胎盘及其提取物的化学成分、药理作用及临床应用研究进展[J].沈阳农业大学学报,2003,34(2)：150-154.
[101]李晶,宋敏,罗晓,等.淫羊藿应用研究进展[J].浙江中西医结合杂志,2009,19(8)：541-515,封三.
[102]马慧萍,贾正平,葛欣,等.淫羊藿总黄酮抗大鼠实验性骨质疏松作用研究[J].华西药学杂志,2002,17(3)：163-167.
[103]殷力,李月白,许建中,等.糖皮质激素对骨髓基质细胞增殖及分化的影响[J].中国临床康复,2002,6(3)：169.
[104]韩冰,杨峻山.淫羊藿药理作用研究概况[J].中草药,2000,31(11)：873-875.
[105]闫爱荣,李二军.淫羊藿的现代药理研究概述[J].中医药研究,1999,15(1)：62.
[106]洪定钢,时光达.淫羊藿影响骨折愈合的骨组织学及骨组织形态计量学研究[J].中医正骨,1999,11(2)：4-6.
[107]佘白蓉,秦达念,王周,等.淫羊藿总黄酮对雄性大鼠生殖功能影响的初步研究[J].中国男科学杂志,2003,17(5)：294-296.
[108]沈自尹,黄建华,吴斌,等.淫羊藿激活内源性干细胞及其机制研究[J].中国中西医结合杂志,2009,29(93)：251-254.
[109]吴建元,肖玉玲,丁虹,等.雷公藤片对小鼠睾丸组织的毒性作用及其分子机制研究[J].中药材,2005,28(3)：207-210.
[110]章振保,田生平,杨镜秋,等.淫羊藿苷与睾酮治疗亚急性衰老雄性大鼠的实验研究[J].中国男科学杂志,2006,20(8)：13-17.
[111]张长城,周安方,张茂林,等.补肾活血方对实验性精索静脉曲张大鼠睾丸Bcl-2、Fas、FasL表达的影响[J].中国男科学杂志,2005,19(1)：18-21.
[112]夏庆华,路千里.熟地黄药理研究进展[J].江西中医学院学报,2008,20(6)：96-97.
[113]胡敏,王琴,周晓东.黄精药理作用研究进展及其临床应用[J].广东药学,2005,15(5)：68-70.
[114]谢玲,杨凌红,李晓惠.当归药理作用研究进展[J].中医药研究,2000,16(6)：56-59.
[115]张端莲,王松山,余墨声,等.当归对辐射损伤后小鼠卵泡影响的定量研究[J].中草药,1997,28(3)：221-227.
[116]张瑞莲,张世明,戎诚兴.当归对60Co-射线损伤后小鼠卵巢恢复过程中超超微结构变化的研究[J].湖北医学院学报,1990,11(4)：322-325.
[117]徐福松,时永华,何映,等.聚精丸治疗精液异常所致男性不育症246例[J].江苏中医,1996,17(2)：21.
[118]Hogenesch JB, Ching KA, Batalov S, et al. A comparison of the Celera and Ensembl predicted gene sets reveals little overlap in novel genes[J].Cell,2001,106 (4):413-415.
[2]胡钢铮.辨证治疗男性无精子不育症32例[J].湖北中医杂志,1992,14(5)：14-15.
[3]曹继刚.周安方治疗不育症从精液微观辨证用药经验[J].湖北中医杂志,2009,31(3)：29-30.
[4]马卫国.贾金铭教授治疗男性不育症的经验[J].中医研究,2006,19(5)：53-55.
[5]陈建设.王琦教授治疗男性不育经验介绍[J].四川中医,2004,22(1)：7-8.
[6]王东坡.王琦教授治疗男科疾病经验介绍[J].新中医,2005,37(10)：12-13.
[7]韩晓峰.自拟四君生精汤治疗无精子症疗效观察[J].卫生职业教育,2005,23(8):57.
[8]訾红霞,朱庆国,刘湘芸.无精症的辨证论治体会[J].内蒙古中医药,2004,(6)：6-7.
[9]胡秉德.自拟生精汤治疗无精症36例[J].吉林中医药,2004,24(9)：35.
[10]宋红湘,胡彬,胡孝刚.种子金丹治疗无精子症82例[J].中医研究,2001,14(4)：54-55.
[11]徐焙.“健脾益肾生精汤”治疗无精子症[J].时珍国医国药,1992,3(1)：35.
[12]蔡玉国.二鹿生精丸治疗无精子症24例[J].北京中医,1995,2：32-33.
[13]叶光宇,文绪芬.生精通关汤治疗无精子症40例[J].河北中医,1994,16(4)：22-23.
[14]赵铁砚.冬蛤生精饮治疗无精子症60例[J].辽宁中医杂志,1990,14(5)：23.
[15]陈文伯.生精赞育丸治疗无精子症66例临床分析[J].江西中医药,1986,06：45.
[16]张玲楚.籽药治疗无精子症[J].湖北中医杂志,1996,18(04)：45.
[17]王旭初,刘文轩,王元松,等.中药治疗男性无精子症临床疗效观察[J].中华中医药学刊,2007,25(2)：308-309.
[18]金保方,杨晓玉,刘嘉茵,等.精原细胞瘤术后放疗致无精子症经综合治疗致孕1例[J].中华男科学杂志,2006,12(9)：836-838.
[19]王晓峰.重视无精子症的病因诊断[J].中华男科学杂志,2009,15(8)：675-678.
[20]Repping S, Skaletsky H, Brown L, et al. Polymorphism for a 1.6 Mb deletion of the human Y chromosome persists through balance between recurrent mutation and haploid selection[J]. Nat Genet,2003, 35 (3):247-251.
[21]Kuroda-Kawaguchi T, Skaletsky H, Brown L G, et al. The AZFc region of the Y chromosome features massive palindromes and uniform recurrent deletions in infertile men[J]. Nat Genet,2001,29 (3):279-286.
[22]Eddy EM. Male germ cell gene expression. Recent Prog Horm Res,2002,57(1):103-128.
[23]Pryor JL, Kent-First M, Muallem A, et al. Microdeletion in the Y chromosome of infertile men[J]. N Eng J Med,1997,336:534-539.
[24]Zhu XB, Guo AL, Cao XR, et al. Screening for Y chromosomal mircrodeletions in AZF region with modifiled multiplex PCR[J]. Chin J Androl,2006,12:199-201.
[25]Li H, Ding X, Zhao J, et al. Y chromosome microdeletions of 664 Chinese men with azoospermia or severe oligozoospermia[J]. Zhonghua Yi Xue Yi Chuan Xue Za Zhi,2008, 25 (3):252-255.
[26]Hargreave TB. Genetic basis of male fertility[J].British Medical Bulletin,2000,56 (3):650-671.
[27]Vogt PH, Edelmann A, Kirsch S, et al. Human Y chromosome azoospermia factors (AZF) mapped to different subregions in Yq11[J]. Hum Mol Genet,1996,5:933-943.
[28]Yang J, Zhang SZ, Smppia Libofio, et al.Microdeletions in interval 6 of Y chromosome detected in the patients with oligo or azoospermia[J]. Chin J Urol, December,2001,22 (12):712-715.
[29]Kent-First M, Muallem A, Shulz J, et al. Denfining regions of the Y chromosome responsible for male infertility and identification of a fourth AZF region (AZFd) by Y chromosome microdeletion detection[J]. Mol Reprod Dev,1999,53 (1):27-41.
[30]Yueh-Hsiang Yu, Yi-Wen Lin, Jane-Fang Yu, et al. Evolution of the DAZ gene and the AZFc region on primate Y chromosomes[J]. BMC Evolutionary Biology,2008,8 (96):1471-2148.
[31]Saxena R, de Vries J W, Repping S, et al. Four DAZ genes in two clusters found in the AZFc region of the human Y chromosome[J]. Genomics,2000,67 (3):256-267.
[32]Habermann B, Mi HF, Edelmann F, et al. DAZ gene encoding proteins located in human late spermatids and sperm tails[J]. Hum Reprod,1998,13:363-369.
[33]Saxena R, Brown LG, Hawkins T, et al. The DAZ gene cluster on thehuman Y chromosome arose from an autosomal gene that was transposed, repeatedly amp lified and p runed[J]. Nature Genet,1996,14(3): 292-299.
[34]Xu EY, Frederick LM, Renee A. A gene family required for human germ cell development evolved from an ancientmeiotic gene conserved in metazoans[J]. Proc Natl Acad Sci USA,2001,98 (13):7414-7419.
[35]阿周存,杨元,张思仲,等.严重寡精症ICSI精子供体的DAZ基因拷贝缺失研究[J].遗传,2006,28(9)：1057-1060.
[36]VogelT, Speed RM, RossA, et al. Partial rescue of the DAZL knockout mouse by the human DAZL gene[J]. Mol Hum Reprod,2002,8 (9):797-804.
[37]Reynolds N&Cooke HJ. Role of the DAZ genes in male fertility[J]. Reprod Biomed Online,2005,10 (1):72-80.
[38]Cauffman G, van de Velde H, Liebaers I, et al. DAZL expression in human oocytcs, preimplantation embryos and embryon ic Stem cells[J]. Mol Hum Reprod,2005,11 (6):405-411.
[39]Brian C, Barbara G, Carolyn L, et al. The DAZL familyproteins are PABP-binding proteins that regulate translation in germ cells[J]. EMBOJ,2005,24 (14):2656-2666.
[40]Simoni M, Tuttelmann F, Gromoll J, et al. Clinical consequences of microdeletions of the Y chromosome:the extended Munster experience [J]. Reprod Biomed Online,2008,16 (2):289-303.
[41]阿周存,杨元,张思仲,等.严重寡精症ICSI精子供体的DAZ基因拷贝缺失研究[J].遗传,2006,28(9)：1057-1060.
[42]马明义,钟一梅,韦小妮,等.AZFc区gr/gr及DAZ基因拷贝缺失与原发性男性生精障碍的相关性研究[J].中国优生与遗传杂志,2007,15(5)：20,21,98.
[43]Hucklenbroich K, Gromoll J, Heinrich M, et al. Partial deletions in the AZFc region of the Y chromosome Occur in men with impaired as well as norm al spermatogencsis[J]. Hum Reprod,2005,20 (1): 191-197.
[44]Giaehini C, Guarducei E, Longcpied G, et al.The gr/gr deletion(s):a new genetic test in male infertility[J]? J Med Genet,2005,42 (6):497-502.
[45]Lynch M, Cram DS, Reilly, et al. The Y chromosome subdeletion is associated with male infertility[J]. Mol Hum Reprod,2005,11 (7):507-512.
[46]Laila Imken, Brahim E1 Houate, Abdelaziz Chafik, et al. AZF microdeletions and partial deletions of AZFc region on the Y chromosome in Moroccan men[J]. Asian Journal of Androlog,2007,9(5):674-678.
[47]Ferlin A, Tessari A, Ganz F, et al. Association of partial AZFc region deletions with spermatogenic impairment and male infertility[J]. J Med Genet,2005,42 (3):209-213.
[48]Santos FR, Pan dya A, Metal K, et al.A polymorphic L1 retroposon insertion in the centeromere of the human Y chromosome[J]. Hum Mol Genet,2000,9 (3):421-430.
[49]Hargreave TB. Genetic basis of male fertility [J]. British Medical Bulletin,2000,56 (3):650-671.
[50]Sun C, Skaletsky H, Rozen S, et al. Deletion of asoospermia factor a (AZFa) region of human Y chromosome caused by recombination between HERV15 proviruses[J]. Hum Mol Genet,2000,9 (15): 2291-2296.
[51]Vogt PH. Molecular genetic of human male infertility:from genes to new therapeutic perspectives[J]. Curt Pharm Des,2004,10 (5):471-500.
[52]Vogt PH. Azoospermia factor (AZF) in Yq11:towards a molecular understanding of its function for human male fertility and spermatogenesis[J]. Reprod Biotaed Online,2005,10 (1):81-93.
[53]Vogt PH. Genomic heterogeneity and instability of the AZF locus on the human Y chromosome[J]. Mol Cell Endocrinal,2004,224 (1-2):1-9.
[54]Kunej T, Zorn B, Peterlin B. Y chromosome microdeletions in infertile men with cryptorchidism[J]. Fertil Steril,2003,79 (Suppl3):1559-1565.
[55]Dada R, Gupta NP, Kucheria K. AZF microdeletions associated with idiopathic and non-idiopathic cases with cryptorchidis and varicocele[J]. Asian J Androl,2002,4 (4):259-263.
[56]Martinez MC, Bemabe MJ, Gomez E, et al. Screening for AZF deletion in a large series of severely impaired spermatogenesis patients [J]. J Androl,2000,21 (5):651-655.
[57]Rima Dada, Kumar, M. B. Shamsi, et al.Azoospermia Factor Deletions in Varicocele Cases with Sever Oligozoospermia[J]. India J Med Sci,2007,61 (9):505-510.
[58]邱毅,杨丹彤,张爱东,等.Klinefelter综合征患者Y染色体AZF微缺失分析[J].中国优生与遗传杂志,2008,16(1)：41-43.
[59]Choe JH, Kim JW, Lee JS, Seo JT. Routine screening for classical azoospermia factor deletions of the Y chromosome in azoospermic patients with Klinefelter syndrome[J]. Asia J Androl,2007,9(6):815-820.
[60]李练兵,吕静,马明福,等.不育患者Y染色体AZF微缺失的分析[J].中国优生与遗传杂志,2008,16(6)：13,23.
[61]单桂芬,苏学今,郑贤红,等. 染色体核型异常男性不育患者Y染色体微缺失分析[J].中国优生与遗传杂志,2009,17(1)：49-50.
[62]Katherine LN, Peter AK, Rachel H, et al. The Y Deletion gr/gr and Susceptibility to Testicular Germ Cell Tumor[J]. Am J Hum Genet,2005,77 (6):1034-1043.
[63]Dewan S, Puscheck EE, Coulam CB, et al. Y-chromosome microdeletions and recurrent pregnancy loss[J]. Fertil Steril.2006,85 (2):441-445.
[64]夏欣一,崔英霞,潘连军,等.1个AZFc缺失自然遗传的家系分析[J].中华男科学杂志,2006,12(8)：720-722.
[65]朱晓斌,李铮,郭安亮,等.Y染色体微缺失父子间垂直遗传分析[J].中华医学遗传学杂志,2007,24(2)：203-205.
[66]Oates RD, Silber S, Brown LG, et al. Clinical characterization of 42 oligospermia or azoospermic men with microdeletion of the AZFc region of the Y chromosome, and of 18 children conceived via ICSI. Hum Rep rod,2002,17 (11):2813-2824.
[67]Mau Kai C, Juul A, Mc Elreavey K, et al. Sons conceived by assisted reproduction techniques inherit deletions in the azoospermia factor (AZF) region of the Y chromosome and the DAZ gene copy number[J]. Hum Reprod,2008,23 (7):1669-1678.
[68]戴黎华,翁兰英.Y染色体长臂无精子因子DAZ基因缺失与精子生成障碍[J].中国实用妇科与产科杂志,2008,24(7)：549-551.
[69]PalermoG, JorisH, DevroeyP, VanSteirteghemAC. Pregnancies after intraeyto-plasmic injection of a single spermatozoon into an oocyte[J].Lancet,1992,340 (8810):17-18.
[70]Michelmann HW, Gratz G, Hinney B. X-Y sperm selection:fact or fiction[J]? Hum Reprod Genet Ethics, 2000,6 (2):32-38.
[71]金保方,黄宇烽,杨晓玉,等.养精胶囊治疗弱精子症的临床观察[J].南京中医药大学学报,2006,22(5)：286-289.
[72]金保方,黄宇烽,夏欣一,等.养精胶囊联合锌硒宝对不育患者精子DNA完整性的影响[J].中国男科学杂志,2006,20(12)：45-48.
[73]金保方,黄宇烽,陆晓和.养精胶囊治疗男性性功能障碍的临床观察[J].中华男科学杂志,2006,12(3)：272-274,276.
[74]张晓文,宋清.从基因角度探讨“肾主生长发育”的本质[J].中医药研究,1996,3(3)：12.
[75]田进文,孙奉雷,石巧荣.中心法则与肾脏本质[J].山东中医学院学报,1996,20(1)：17.
[76]陈晓霞.论中医肾与垂体促性腺激素的关系[J].辽宁中医学院学报,2003,5(3)：226.
[77]司富春.从下丘脑-垂体-性腺轴研究中医肾的现状及对策[J].中医研究,1994,7(3)：2.
[78]张瑞兰,林日省.脾与肾的实质探秘[J].湖北中医杂志,2001,23(10)：8.
[79]张启明.中医肾与现代西医学组织器官的相关性研究[J].辽宁中医杂志,2003,30(8)：634.
[80]吴水生,邱山东,林求诚,等.中老年女性性激素水平与不同肾虚证关系的研究[J].福建中医药,2000,31(1)：3-4.
[81]吴水生,叶钦勇,林求诚,等.中老年男性性激素水平与不同肾虚证关系[J].福建中医药,2000,31(2)：3-4.
[82]丘瑞香,吴国珍,金明华.性激素对肾虚患者阴阳平衡的调节作用[J].中国中医基础医学杂志,1999,5(3)：46-47.
[83]田文艺,曾嵘,蒋传付.送子衍宗丸颗粒剂生精作用的研究[J].湖南中医学院学报,1993,13(4)：35.
[84]夏卫平,陈磊,蒋学洲,等.康宁口服液对肾虚不育症影响的实验研究[J].上海中医药杂志,1997,43(6)：45-46.
[85]李育浩,吴清和,李茹柳,等.五子衍宗丸对生殖系统的影响[J].中药药理与临床,1992,8(3)：4.
[86]王学美,谢竹藩,刘庚信,等.五子衍宗液对雄性大鼠下丘脑单胺类递质、性激素和生育能力的影响[J].中国中西医结合杂志,1993,13(6)：349.
[87]陈健安,高崎悦司,铃木辙.六味地黄汤对大鼠下丘脑-垂体-性腺轴组织器官形态和性激素的影响[J].江苏中医,1999,20(3)：46.
[88]许绍芬.神经生物学[M].第2版.上海：上海医科大学出版社,1999：279-287.
[89]BernardiF, Pluchino N, StomatiM, et al. CNS:sex steroids and SERMs[J]. Ann NY Acad Sci,2003, 997 (1):378-388.
[90]曹兴午.睾丸生精障碍的靶区、靶细胞和靶点[J].中国男科学杂志,2008,22(7)：58-60,63.
[91]鲁海鸥,丁晓萍,张宁,等.正常男性血清生殖内分泌激素与睾丸、精液的相关研究[J].中国优生与遗传杂志,2003,11(5)：129-130.
[92]Plant TM, Marshall GR. The functional Significance of FSH in spermatogenesis and the control of its secretion in male primates[J]. Endocrine RevieWS,2001,22 (6):764-786.
[93]Haywood M, SpaliViero J, JimemezM, et al. Sertoli and germ cell development in hypogonadal (hpg) mice expressing transgeenic follicle-stimulating hormone alone or in combination with testosterone[J]. Endocrinologyt,2003,144 (2):509-517.
[94]GroverA, Smith CE, Gregory M. Effects of FSH receptor deletionon epididymal tubules and sperm morphology, numbers, and motility[J]. MolReprod Dev,2005,72 (2):135-144.
[95]Ramaswamy S, Marshall GR, et al. Dynamics of the follicle-stimulating hormone (FSH)-inhibin B feedback loop and its role in regulating spermatogenesis in the adult male rhesus monkey (Macacamulatta) as revealed by unilateral or chidectomy[J]. Endocrinology,2000,141 (1):18-27.
[96]郭应禄,胡礼泉.男科学[M].北京：人民卫生出版社,2004：124-127.
[97]Johnston H, Baker PJ, Abel M, et al. Regulation of Sertoli cell number and activity by follicle-stimulating hormone and androgen during postnatal deveiopment in the mouse[J]. Endocrinology.2004,145(1):318-329.
[98]HenkelR, MaassG, SchuppeHC, et al. Seasonal changes of neutral alpha-glucosidase activity in human semen[J].J Androl,2006,27 (1):34-49.
[99]张新东,金保方.精囊功能评价及调控研究概况[J].现代泌尿外科杂志,2009,14(2)：155-156.
[100]杨桂芹,邹兴淮.胎盘及其提取物的化学成分、药理作用及临床应用研究进展[J].沈阳农业大学学报,2003,34(2)：150-154.
[101]李晶,宋敏,罗晓,等.淫羊藿应用研究进展[J].浙江中西医结合杂志,2009,19(8)：541-515,封三.
[102]马慧萍,贾正平,葛欣,等.淫羊藿总黄酮抗大鼠实验性骨质疏松作用研究[J].华西药学杂志,2002,17(3)：163-167.
[103]殷力,李月白,许建中,等.糖皮质激素对骨髓基质细胞增殖及分化的影响[J].中国临床康复,2002,6(3)：169.
[104]韩冰,杨峻山.淫羊藿药理作用研究概况[J].中草药,2000,31(11)：873-875.
[105]闫爱荣,李二军.淫羊藿的现代药理研究概述[J].中医药研究,1999,15(1)：62.
[106]洪定钢,时光达.淫羊藿影响骨折愈合的骨组织学及骨组织形态计量学研究[J].中医正骨,1999,11(2)：4-6.
[107]佘白蓉,秦达念,王周,等.淫羊藿总黄酮对雄性大鼠生殖功能影响的初步研究[J].中国男科学杂志,2003,17(5)：294-296.
[108]沈自尹,黄建华,吴斌,等.淫羊藿激活内源性干细胞及其机制研究[J].中国中西医结合杂志,2009,29(93)：251-254.
[109]吴建元,肖玉玲,丁虹,等.雷公藤片对小鼠睾丸组织的毒性作用及其分子机制研究[J].中药材,2005,28(3)：207-210.
[110]章振保,田生平,杨镜秋,等.淫羊藿苷与睾酮治疗亚急性衰老雄性大鼠的实验研究[J].中国男科学杂志,2006,20(8)：13-17.
[111]张长城,周安方,张茂林,等.补肾活血方对实验性精索静脉曲张大鼠睾丸Bcl-2、Fas、FasL表达的影响[J].中国男科学杂志,2005,19(1)：18-21.
[112]夏庆华,路千里.熟地黄药理研究进展[J].江西中医学院学报,2008,20(6)：96-97.
[113]胡敏,王琴,周晓东.黄精药理作用研究进展及其临床应用[J].广东药学,2005,15(5)：68-70.
[114]谢玲,杨凌红,李晓惠.当归药理作用研究进展[J].中医药研究,2000,16(6)：56-59.
[115]张端莲,王松山,余墨声,等.当归对辐射损伤后小鼠卵泡影响的定量研究[J].中草药,1997,28(3)：221-227.
[116]张瑞莲,张世明,戎诚兴.当归对60Co-射线损伤后小鼠卵巢恢复过程中超超微结构变化的研究[J].湖北医学院学报,1990,11(4)：322-325.
[117]徐福松,时永华,何映,等.聚精丸治疗精液异常所致男性不育症246例[J].江苏中医,1996,17(2)：21.
[118]Hogenesch JB, Ching KA, Batalov S, et al. A comparison of the Celera and Ensembl predicted gene sets reveals little overlap in novel genes[J].Cell,2001,106 (4):413-415.