维普资讯 http://www.cqvip.com Vo1.6,No.9 Sep,2006 Contraception and HRT 15 indicate a willingness to use such a contraceptive. and 98%Of women surveyed were willing to trust their male partner to use a Male hormonaI C0ntraCepti0n:th e futu re of male contraception? John KAmory William J Bremner hormonal method of contraception.。 When administered to a norma1 male,testosterone functions as a contraceptive by suppressing secretion of the pituitary gonadotrophins luteinizing hormone(LH)and follicle—stimulating hormone(FSH).Low 1evels of LH and FSH deprive the testis of the signals required for normal spermatogenesis,leading to markedly decreased sperm counts and reversible infertility in most,but not all,men(Figure 1 j.Hormona1 contraceptives do not incapacitate existing sperm;they hinder sperm production.Because sperm take an average of 72 days to reach maturity,contraceptives based on Because of the shortcomings of existing methods of male contraception,efforts have been made to develop a hormonal contraceptive for men analogous to the estr0gen—prOgestOgen pill used by women.Such a hormonal contraceptive has the potential tO be safe,effective and easy to use.When surveyed.most men manipulation of the hormona1 axis are associated with a 2-3 month delay in the onset of the ful1 contraceptive effect rcomparable with vasectomyj.In addition,sperm counts do not fully recover unti1 severa1 months after discOntinuatiOn of the hormonesA male 《 hormonal contraceptive would be unlikely to provide protection against the transmission of sexually transmitted infections. Iohn KAmory『5 Associate Professor ofMedicine at the University of Washington,SeattlB USA.Conflicts ofinterest:none declared. In normal men,sperm counts are 2O一200 million/m1 ejaculate. The absence of spermatozoa in the ejaculate fazoospermia]renders fertilization impossible and iS the ultimate aim of hormona1 male cOntraceptives.However,most studies have shown that,though William J Bremner is Professor and Chairman ofthe Department of Medicine at the Universiy tof Washington,Seattle,USA.Conflicts of interest:none declared. most men exhibit azoospermia.some men experience only partia1 reduction of their sperm count(oligozoospermia).There is good ; 和≯, evidence from a tria1 of couples using bi—weekly testosterone injec— # 、●●●● Endocrinology of spermatOgenesis and male hormonal contraception Cortex ̄ { 。 ~ { ~ 啦 GnRH Progestogens,一一一 哮Pituitary《~一 antagonists GnRH 镕/ j FSH LH | Serc0li cell●-Leydig , , , 一 Mature sperm restosterone Solid arrows,promotes spermatOgenesis; dotted arrows,inhibits spermatOgenesis; FSH,follicle—stimulating hormone; GnRH,gOnadOtrOphin-releasing hormone; LH,luteinizing hormone MEDICINE INTERNAT10NAL @2006 The Medicine Publishing Company Ltd 维普资讯 http://www.cqvip.com 16 Contraception and H RT Vo1.6,No.9 Sep,2006 Male hormonal contraceptive efficacy trials Study Number of couples Azoospermic Oligozoospermic Failure to reduce Pregnancy rate 1_0taI failures Overall contraceptive WHO(1996) Gu eta1.(2003) Tu rne r et a1.(2003) Total 357 3O5 53 (%) 268(75) 130(43) 49(93) 447(62) (%) 81(23) 166(54) 2(3.6) 249(35) sperm count(%) 8(2.2) 9(2.9) 2(3.6) 19(2.6) (%) 11(3.1) 1(o.3) o(o.o) 12(1.7) (%) 19(5.3) 1O(3.3) 2(3.6) 31(4.4) efifcacy(95%C1) 94.7(92—97) 96.7(95-98) 96.4(91—1O0) 95.7(94-97) 71 5 Defined as pregnancy and/or failure to reduce sperm count to enrolment level in the efficacy phase 2 tions as a contraceptive that sperm counts below 3 inillion/inl ejaculate are associated with substantially reduced pregnancy rates. Severe oligozoosperinia(<1 inillion/in1)appears to reduce the likelihood of conception even further and is therefore considered a reasonable short—term aim for male contraceptive research. It is unknown why,i11 S0111e nlen.sperm counts do not decline to zero despite the extremely low levels of serum gOnadOtrOphins. There are no apparent differences in gonadotrophin levels in nlen who exhibit azoosperlnia and those who do not. Further inves— tigation will be needed to elucidate the innate differences in the intratesticular environnlent that account for this contrast. Because androgens alone are not uniformly effective in male contraception,investigators have combined then1 with second agents such as progestogens and gonadotrophin。‘releasing hor’。 nlone antagonists,which synergistically suppress FSH and LH release from the pituitary gland and increase the contraceptive effect of androgens alone.Most recently published male horlnonal contraceptive trials have use combinations of long—acting androgens (e.g.testosterone undecanoate—Nebido)or testosterone pellets with long—acting progestogens.Promising androgen—progestogen combinations have been tested in Europe and China,with azoosperlnia rates of ahnost 9O%5 The side—effects in these trials have been mostly mild and predictable,and include- ●acne 。weight gain 。reversible reduction in testicular volume and high—density lipoprotein cholestero1. In most trials.there have been no reported serious adverse events, and no adverse changes in prostate function,sexual desire or per— forinance have been attributed to these regimens.Full reversibility of sperm production was seen in all subjects,and quality of life appears to be well maintained on these contraceptive regimens.。 The true test of the usefulness of a male contraceptive is whether the method is effective in couples for whom it is the sole means of contraception.Four large‘efficacy’trials have been published. ・The first was conducted by the WHO in the late 1 980s and showed that horlnonal cOntraceDtiOn was effective in preventing pregnancy in men who exhibited azoosperinia 7 ・Three trials subsequently examined the efficacy of male hor一 1110nal cOntraceDtiOn in men whose sperm counts declined below a threshold thought to significantly reduce the likelihood of con— ception.Sununary analysis of these trials(Figure 2)reveals low pregnancy rates and a high overall efficacy of about 95%.These results include a small proportion of men(about 3%)who did MEDICINE INTERNATIONAL not achieve the reduction in sperm count required to enter into the study. It is to be hoped that refinements in drug delivery will allow such horlnonal combinations to reach the colnlnercial market within the next decade.Once the drugs are approved,large—scale follow—up will be required to ensure that there are no harlnful long—term side—effects on reproductive or overall health. New guidelines for the regulatory approval of hormonal contra— ceptives were recently agreed by most of the investigators working in male contraceptive development. These guidelines recommend that,before approval,two contraceptive efficacy trials involving 200 couples for at least 1 year should be conducted and achieve a rate of pregnancy prevention of more than 90—95%.Such rates would compare favourably with the effectiveness of alternative methods of male contraceDtion such as the condom. ◆ REFERENCES 1 Ma rtin C W,Anderson R A,Cheng L et a1.Potential impact of hormonaI maIe contraception:cross—culturaIimPlications fo r development of noveI maIe P repa rations.Hum Reprod 2000;15:637-45. 2 GlasierA F,Anakwe R,Everington D eta1.Would womentrustthei r pa rtners to use a maIe pill?Hum Reprod 2000;15:646—9. 3 WHO Task Fo rce on Methods for the Regulation of Male Fe rtility. Contraceptive efficacy of testosterone—induced azoospermia and oligozoospermia in no rmaI men.Fertil 5teril 1996;65:821-9. 4 Robertson D M,Pruysers E,Stephenson T eta1.Sensitive LH and FSH assays fo r monito ring low serum levels in men unde rgoing steroidaI contraception.Clin Endocrinof(Oxt)2001:55:331-9. 5 Anderson R A。Bai rd D Male contraception.EndocrRev 2002;23: 735—62. 6 Sjogren B,Gottlieb C.Testosterone fo r male contraception du ring one yea r:attitudes,well—being and quality of sex life.Contraception 2001:64:59—65. 7 WHO.Contraceptive efficacy of testosterone—induced azoospe rmia in no rmaI men.Lancet 1990;336:995-9. 8 Sixth summit meeting consensus:recOmmendatiOns fo r regulatory app roval fo r ho rmonaI maIe contraception.IntJAndrof 2002:25: 375. FURTHER READING Gu Y-Q。Wang X—H,Xu D ef a1.A multicenter contraceptive efficacy study of iniectable testosterone undecanoate in hea[thy Chinese men./Clin Endoerinof Metab 2003:88:562—8. Tu rner L,Conway A J,Jimenez M et a1.Contraceptive efficacy of a depot p rogestin and androgen combination in men.JClin EndocrinolMetab 2003:88:4659—67. 誊2006 The Medicine Publishing Company Ltd 维普资讯 http://www.cqvip.com 42 避孕和HRT 国际内科双语杂志2006,Vo1.6,No.9 这也是男性激素避孕的目的所在。然而,大多数研究 显示,尽管大部分男性已经表现为无精症,但仍有部 雄性激素避孕发展前景 如何 John K Am0 nr① William J Bremner ̄' 分男性只是精子数量部分下降(少精症)。一项夫妇 采用双周注射睾酮避孕的试验提供了很好的证据,试 验发现,每次射精精子计数低于3xl0 ̄ml使受孕率明 显降低。重度少精症(<1 06/m1)看来更能减少妊娠的 可能性,因此被当作一个合理的男性避孕研究的短效 目标。 MEDICINE,2006,34(1):25~26 目前还不了解,为什么有些男性的血清促性腺激 素水平已经非常低,但精子计数仍不能降低为0。而 促性腺激素水平在达到无精和未达到无精的男性中却 鉴于男性避孕措施的不足,人们在努力开发一种 没有明显差别。要解释这些现象尚需进一步研究睾丸 内微环境的内在差别。 与女用雌孕激素避孕药类似的男用激素避孕方法。这 种方法要安全、有效并且使用方便。在调查中,大部 分男性自愿使用这种避孕方法,同时98%的女性也愿 由于单方雄激素用于男性避孕不总是有效,研究 者们联合使用第二种制剂如孕激素类和促性腺激素释 放激素抑制剂类,以协同抑制垂体释放FSH和LH, 增加单方雄激素的避孕效果。在最近发表的雄激素避 意并信赖她们的性伴侣使用这种方法。 对于一个正常的男性,睾酮是通过抑制脑垂体分 泌黄体生成素(LH)和卵泡刺激素(FSH)来起到避 孕研究中已经使用长效雄激素(如十一酸睾酮—— Nebido)或睾丸酮片结合长效孕激素的复方制剂。复 方雄孕激素制剂已在欧洲和中国做过试验,无精症的 比率几乎达到90%。副作用绝大部分可预料并且轻 微,包括: 孕作用的。低水平的LH和FSH使睾丸不能产生正常 精子形成所需要的信号,从而导致精子数量显著下 降,使大部分但不是所有的男性发生可逆性不孕(图 1)。激素避孕方法并不能使已经生成的精子失去能 力,它只是阻碍精子的产生。由于精子平均需要72 天达到成熟,以激素轴调节为依据的避孕方法(与输 ・痤疮 ・体重增加 精管切除术相比)要延迟2~3个月后才能发挥避孕作 用。而且停用激素数月后,精子计数才能完全恢复。 男性激素避孕法不能防止经性传播的感染。 一・可逆转的睾丸体积缩小和高密度脂蛋白降低。 在大多数试验中,没有严重的不良事件报告,对 前列腺和性功能也没有不利影响。所有受试者的精子 生成都可完全恢复,并保持良好的生活质量。 真正测试男性避孕是看它对只用这种办法避孕的 个正常男性一次射精的精子数量为20~2xlO ̄ ml。如果射精时没有精子(无精症)就不可能怀孕, 表1男性激素避孕的有效性试验 @John K Amory是美国西雅图华盛顿大学内科学副教授。利益冲 突:未声明。 ②William J Bremner是美国西雅图华盛顿大学内科学系教授和主 席。利益冲突:未声明。 MEDICINE INTERNAT10NAL ⑥2OO6 The Medicine Publishing Company Ltd 维普资讯 http://www.cqvip.com 国际内科双语杂志2006,Vo1.6,No.9 壁 塑 1O年内上市。一旦这类药物被批准上市,就需要做大 规模的随访以确认其对人类生殖和健康没有长期有害 的副作用。 近期通过的新的激素避孕指导原则得到了大多数 从事男性避孕开发工作者的同意。指导原则建议,在 新的激素避孕药物被批准前,需做两项包含200对夫 妇并持续至少1年的避孕有效性试验,有效率应大于 90%~95%,并且比其他男性避孕方法如避孕套等的效 果好。 夫妇是否有效。目前已经有四个大型“有效性”试验 报告: ・第一个试验是2O世纪8O年代后期由世界卫 生组织指导的,结果显示激素避孕在用药后达到无精 症的男性中,可有效防止配偶怀孕。 ・另外3个试验证明,男性激素避孕方法对于 那些精子数量低于一定数值的男性是有效的,当精子 数低于这个数值时妊娠可明显减少。这些试验的总结 (表1)显示低妊娠率和总体有效率大约为95%。其 中还包括一小部分男性(大约3%),他们没有达到进 入试验要求的精子数减少的标准。 (刘 清泽刘欣燕校) 人们希望给药方法的改进将使复方激素类药物在 MED1ClNE lNTERNATl0NAL ⑥2006 The Medicine Publishing Company Ltd