雄激素的临床应用

<正> 男性性功能低减是最重要的雄激素替代治疗的指征。婴儿小阴茎及青年体质性青春发育延缓也可短期用雄激素治疗。偶而高身材男孩也可用雄激素关闭骨骺。目前正在研究雄激素是否增加血睾酮水平低的老年人的骨骼及肌肉量,使其生活质量提高。在用激素为男性避孕的临床研究中,需给受试者雄激素替代治疗。雄激素也可用于某些血液疾患及虚弱-恶病质状态,但雄激素对其中的一些情况是否有效尚有争论。不推崇运动员用雄激素类固     

前列腺癌的新激素治疗

抗雄激素虽现许多药属抗雄激素范畴,但每一药物的作用机制不同,也许比单独阻滞雄激素更复杂。然而每一种化合物都可抑制男性激素的细胞代谢。甲地孕酮为一合成激素,用于转移性乳腺癌的保守治疗。本药的作用同于天然产生的孕激素,包括通过抑制垂体促性腺激素的释放抑制血清睾酮浓度,加之本药已显示它能通过竞争细胞     

雄激素受体在前列腺癌细胞系中作用的研究进展

前列腺癌是男性高发的恶性肿瘤之一,目前广泛运用的雄激素阻断治疗能抑制早期前列腺细胞生长,但最终多数肿瘤会复发并转变为侵袭能力更强的激素非依赖性前列腺癌.雄激素受体(AR)是前列腺上皮分化的调节因子,在调控前列腺癌进展的过程中发挥着重要作用.本文总结并比较了不同分化度的三种前列腺癌细胞LNcaP、PC3、DU145中AR...     

孕激素与男性生殖

孕激素对男性下丘脑 垂体 睾丸轴具有反馈抑制作用。垂体及生殖腺均检出明显的孕激素受体mRNA ,且呈不同分布特点。人生精细胞和精子中含有一定数量的孕酮 ,提示孕激素与精子产生的数量、精子胞膜完整性和染色体稳定性以及受精有关。孕、雄激素合用引起的可逆性抑制精子发生 ,其机制在于孕激素反馈抑制促性腺激素的分泌 ,近来还发现其可能直接作用于睾丸及附睾 ,在局部直接发生效应。生理剂量的孕激素可以促进雄激素依赖的雄性性行为 ;而药理浓度孕激素可以抑制雄性性行为 ,其机制不仅仅是通过降低睾酮水平 ,而且在中枢神经系统有直接的作用。孕烷衍生物具有部分选择性抑制Ⅱ型 5α 还原酶的作用 ,提示用于前列腺疾病有更多益处     

前列腺癌患者单个CTCs RNA测序揭示了抗雄激素治疗耐药后非经典Wnt信号转导机制

<正>前列腺癌进展受男性雄激素的驱动,其中最常见的雄激素来源是睾酮。雄激素阻断疗法对有转移但激素敏感性前列腺癌患者仍然是最有效的治疗方法。而临床上抑制雄激素的药物达到去势效果后,不久又会出现去势抵抗"激素不敏感"。目前治疗转移性激素不敏感前列腺癌患者的新型二线药物有阿比特龙(雄激素合成抑制剂)和恩杂鲁胺[雄激素受体(AR)拮抗剂]。但这种治疗靶点的疗效及激素敏感与否的具体机制不详。Miyamoto等通过收集前列腺癌患者外周血标本提取CTCs细胞,对单个     

男性甾体激素避孕的展望——雄/孕激素联合用药

男性避孕的迫切性　　来自许多国家的问卷调查发现65%～90%男性愿意计划生育[1]。近年来,随着经济的发展和社会的进步,特别是来自妇女界的呼声使更多的男子表示愿意与其配偶共同承担计划生育的义务。这样的社会大潮流为男性参与计划生育提供了一个广泛的群众基础;为男性避孕方法的发展提供了一个潜在的广阔市场。此外,更多的研究揭示可供选择的避孕措施与避孕使用率呈正相关,与生育率呈负相关。因此,开发安全、有效和可复的男性避孕方法是迫在眉睫的任务。在当前正在新研制的男性避孕药具中,男性激素避孕是最有可能过渡到临床应用阶段,并可…     

雄激素受体在前列腺癌中的抗凋亡效应研究进展

前列腺癌(PCa)是中老年男性多发癌症之一,目前针对晚期转移性患者的主要治疗手段是去雄激素治疗,但是绝大部分患者最终都进展为侵袭性更强的激素非依赖型PCa,而对此类患者尚无有效治疗方法。雄激素受体(AR)是前列腺上皮细胞分化与增生的基本调节因子,在调控PCa细胞存活机制方面具有非常重要作用。目前的研究结果已经表明在激素非依赖型PCa进展过程中,AR的非正常激活是关键性因素。现简要综述AR调控的PCa细胞存活机制以及针对它而设计的RNA干扰技术对PCa的治疗运用方面的进展。     

雄激素水平增龄变化对老年男性的影响

雄激素对机体的影响是多方面的。随着人体的衰老 ,雄激素水平会发生变化 ,这种变化对老年男性生理和心理会产生影响 ,如生殖功能、性功能、认知能力、情绪、骨骼肌肉等 ,老年男性雄激素水平的降低与临床表现之间的关系较为复杂 ,这方面的研究受很多因素的影响。对雄激素水平下降的老年男性可以给予激素替代治疗 ,但是也应对其副作用引起足够重视。     

雄激素受体基因CAG多态性对男性激素避孕有效性影响的研究

目的:分析应用肌注十一酸睾酮酯(TU)进行激素避孕的男性志愿者中起反应者与不起反应者雄激素受体(AR)基因(CAG)n微卫星多态性,并探讨该多态性对激素避孕效果的影响。方法:29例TU不起反应者和34例起反应者分别作为试验组和对照组,应用PCR和DNA测序技术对两组外周血标本进行CAG重复数测定,分析该微卫星多态性对激素避孕效果的影响。结果:试验组和对照组CAG重复数的均数分别为23.62和22.97,均数比较差异无显著性(P>0.05)。短组CAG(n≤22)在试验组和对照组的分布分别为51.7%、50.0%;长组CAG(n>22)在试验组和对照组分布分别为48.3%、50.0%,长短组分布相同。CAG重复数与精子密度之间未见相关性。在FSH浓度>0.2IU/L组中,CAG重复数>22的受试者达到无精子症的机会是其他受试者的1.5倍。结论:受试者AR基因(CAG)n重复数呈多态性,但不反应组与反应组之间不具有显著性差异,AR基因CAG重复数或其他因素与男性激素避孕效果之间的关系有待进一步探讨。     

WHO男性生育调节方法专题组的研究战略

<正> 男性专题组建立于1972年,受命发展新、安全、有效和可复的男性避孕方法。这是男性学领域内正在从事的广泛研究活动。他们当中的很多人是中国男性学家,他们在 WHO 人类生殖规划处资助下在国外受过训练在 WHO 支持的专门研究所工作。目前在9个国家15个中心(其中包括中国)参加的多中心研究课题旨在评估睾酮诱导的无精子症和严重少精子症进行评估。专题组支持的这一中心研究具有重要意义的发现是不同种族的男子对甾体激素避孕药的反应是不同的。例如,印尼的5个中心的研究发现雄、孕激素合用诱导的抑制精子发生率高达97%以上,     

Does ethnicity matter in male hormonal contraceptive efficacy？

The development of male hormonal contraception has progressed significantly during the last three decades. The ultimate goal is to produce an effective, safe and reversible male method of contraception that are within reach of and can be used by all men globally. This review aims to outline the recent developments in male hormonal contraception with special emphasis on how ethnicity influences acceptability, extent of sperm suppression, and rate of recovery of spermatogenesis. Baseline differences in testicular histomorphology and testosterone metabolism between East Asian and Caucasian men have been reported, but whether this contributes significantly to varying degrees of sperm suppression in response to exogenous testosterone therapy is less known. Testosterone alone male hormonal contraceptive regimens are effective and applicable for East Asian men, and less so for Caucasians. Combinations of progestins with androgens are sufficient to optimize effectiveness of suppression and applicability to all ethnicities. New compounds such as steroidal or non-steroidal selective androgen receptor modulators with dual androgenic and progestational activities are potential compounds for further development as male hormonal contraceptive methods. At the present time, combined androgen and progestin contraceptive regimens appear to be effective, safe, reversible and convenient to use for all men with ethnic, cultural and environmental differences. Further refinements on the hormonal agent, methods of delivery, and dose optimization of the androgen relative to the progestin are necessary. This goal mandates further investment and large clinical trials in multiethnic populations to better define safety and efficacy.     

Reversible, non-barrier male contraception: status and prospects

OBJECTIVE: Male, non-barrier, contraceptive options are limited to vasectomy and inadequate methods such as withdrawal and periodic abstinence. Herein we give an overview of current research on male contraception by pharmacological means. METHODS: Literature search of PubMed documented publications and abstracts from meetings. RESULTS: Cross-cultural surveys show men's willingness to carry contraceptive responsibility. Clinical trials substantiate that hormonal contraception involving suppression of gonadotropins holds the best promise to provide a male pharmacological contraceptive. Androgens have been demonstrated to induce reversible infertility particularly in combination with certain progestins and GnRH antagonists. Advances in non-endocrine contraception include intervention with triptolide derivatives, alkylated imino sugars, and immunization by eppin. CONCLUSION: The prospect of a pharmacological, male contraceptive has been considerably advanced in recent years. Long-term studies involving a greater number of subjects may result in a safe, reversible and effective means. Asia is likely to be the first market for male, hormonal contraceptive methods. The clinical evaluation of non-endocrine approaches may ultimately lead to an alternative to hormone-based male contraception.     

Male contraception: mechanical,hormonal and non-hormonal methods

There is a definite need for an effective and reversible form of male contraception, both for maintaining a stable population in industrial countries and for diminishing population growth in developing countries. It has been agreed upon that contraception is an essential component of reproductive health for men and women (the Weimar Manifesto on Male Contraception). The development of new, effective methods of male contraception has been identified as a high priority by the WHO Task Force on methods of regulation of male fertility. Hormonal male contraception is based on suppression of gondotrophins and substitution of testosterone in order to maintain male sexual function and bone mineralisation and to prevent muscle waist. For complete interruption of spermatogenesis, an adequate suppression of intratesticular testosterone production is needed. Various contraceptive regimens have been developed and tested, including testosterone monotherapy, androgen/progestin combinations, testosterone with GnRH analogs, and selective androgen and progestin receptor modulators. The combination of testosterone with progestogen is currently the most promising approach to hormonal male contraception. Also, several non-hormonal approaches to male contraception are promising and may offer the foundation for developing new male contraceptives.     

Suppression of spermatogenesis with desogestrel and testosterone pellets is not enhanced by addition of finasteride

Conversion of testosterone to dihydrotestosterone (DHT) by the action of 5alpha-reductase can amplify androgen action. This may be of particular importance in the presence of low testosterone concentrations and may contribute to maintenance of spermatogenesis in a proportion of men receiving male contraceptive regimens. We therefore investigated whether the addition of finasteride, a 5alpha-reductase inhibitor, to a prototype male hormonal contraceptive regimen consisting of desogestrel (150 microg orally daily) and repeated administration of testosterone pellets (2 x 200 mg per 12 weeks) would enhance suppression of spermatogenesis. Sixteen normal men were randomized to receive either the standard androgen/progestogen treatment alone (control group) or with finasteride (5 mg orally daily-FIN group) for 24 weeks. Both groups showed profound suppression of spermatogenesis with azoospermia being obtained in 6 of 8 subjects in the control group and in 5 of 7 in the FIN group. There were no significant differences between the groups with respect to sperm concentrations. Significant suppression of luteinizing hormone and follicle-stimulating hormone was achieved within 2 weeks of treatment in both groups, while testosterone concentrations were maintained in the normal physiological range. DHT concentrations fell in both groups but were significantly lower in the FIN group. Gonadotropin and testosterone concentrations were similar for both regimens throughout the study. This study demonstrates the potential for long-term suppression of spermatogenesis using a combination of an oral progestogen with repeated administration of a depot preparation of testosterone. However, these data do not support the involvement of 5alpha-reductase in maintaining residual spermatogenesis during gonadotropin suppression for hormonal male contraception.     

Constraints in the development of contraceptives for men

Considerable efforts have been made to develop a male contraceptive and the studies have provided very useful information in this field. At least five different strategies to develop a male contraceptive have been pursued, namely: inhibition of sperm production, interference with sperm function, interruption of sperm transport, prevention of sperm deposition, and prevention of sperm-egg interaction. Of all these approaches, inhibition of sperm production by using androgens either alone or in combination with progestins have given the most encouraging results. A number of clinical trials substantiate that it is indeed possible to have a reversible, effective and safe hormonal method of contraception. A postmeiotic and epididymal approach to interfere with sperm function or the secretory and metabolic processes of the epididymis is another attractive option of male contraceptive development. A number of chemical compounds have been identified which interfere with sperm function in the epididymis without affecting sperm production, however, the compounds evaluated so far were found to be toxic. Interruption of sperm transport through the vas either by vasectomy or percutaneous intravasal injection of liquids which form cure-in-place plugs is also an attractive option. However, reversibility of the methods is of concern in their wide scale use. The major constraint in developing a long-acting male contraceptive seems to be the need for greater investment for product development. The clinical trials for evaluating the efficacy and safety of the new products and formulations stretch over several years and require enormous financial commitment. Nevertheless, the long-term gain of having a long-acting reversible contraceptive for men is far greater than the financial commitments over few years. Male attitude towards using methods of family planning is much more favourable than originally believed. The pharmaceutical industry as well as the health care providers theretbre have a greater responsibility. For early development of a contraceptive for men, it is essential to increase investment and simplify the drug regulatory procedures. The advent of newer technologies coupled with the convergent efforts of scientists will certainly make it possible to have an effective, safe and reversible male contraceptive in the near future.     

Hormonal Contraception for Men

Between 1971 and 1977, a public-sector contraceptive development program organized 35 clinical studies to test whether progestins, alone or with androgens, could be used to develop a new contraceptive for men. This review presents the principal findings from these studies. The studies demonstrated that when high doses of progestins are administered to men. sperm production is suppressed to very low levels in the majority of cases. But full suppression of sperm production in all men could not be achieved even when high doses of progestins were administered alone or in combination with high doses of an androgen. All of the progestins tested were associated with weight gain and transient decreases in libido in some men. Some of the regimens tested caused additional side effects, including gynecomastia and impairment of liver function. It is concluded that none of the 25 regimens investigated to date is suited for further development as a male contraceptive. However, the finding that several of the regimens suppressed sperm production to very low levels – often to azoospermic levels – without producing substantial side effects is encouraging. Based on these findings, it is suggested that other combined regimens of more ***     

Intratesticular androgens and spermatogenesis during severe gonadotropin suppression induced by male hormonal contraceptive treatment

Male hormonal contraceptive regimens function by suppressing gonadotropin secretion, resulting in a dramatic decrease in testicular androgen biosynthesis and spermatogenesis. Animal studies suggest that persistent intratesticular (iT)-androgen production has a stimulatory effect on spermatogenesis in the setting of gonadotropin suppression. We hypothesized that men with incompletely suppressed spermatogenesis (>1,000,000 sperm/mL) during male hormonal contraceptive treatment would have higher iT-androgen concentrations than men who achieved severe oligospermia (相似文献   

中国男性十一酸睾酮酯注射避孕有效性多中心研究

目的评估十一酸睾酮酯（TU）注射避孕的安全性、有效性、可复性和可接受性。方法1,045名健康的有生育力的中国男性,每月一次TU500mg肌注共30个月,统计分析其配偶的妊娠率、精液参数、睾丸体积、生殖激素水平及安全性评估。结果在6个月的抑制期内有43名对象（4．8％）未达到无精子或严重少精子症;855名对象进入起效期,其中733名完成每月一次TU注射和恢复阶段。在避孕有效期的24个月,暴露1,554／人年中有9次妊娠,累计避孕失败率为1．1／100人;综合失败率6．1％,其中包括1．3％抑制不充分和4．8％短暂抑制后的精子反跳。本研究无严重不良事件报告。除了2名对象以外全部恢复生精功能,达到正常有生育力参考值范围。结论每月一次TU500mg肌注可以为健康有生育力的中国男性提供安全、有效、可逆的避孕。     

Elevated end-of-treatment serum INSL3 is associated with failure to completely suppress spermatogenesis in men receiving male hormonal contraception

The administration of testosterone plus a progestogen functions as a male contraceptive by inhibiting the release of pituitary gonadotropins. After 3 to 4 months of treatment, most men are azoospermic or severely oligospermic (< or =1 million sperm/mL). However, 10% to 20% of men have persistent sperm production despite profound gonadotropin suppression. Since insulin-like factor 3 (INSL3) has been shown to prevent germ cell apoptosis in mice, we hypothesized that INSL3 might be higher in men with persistent spermatogenesis during treatment with male hormonal contraceptives. In a retrospective analysis, we measured serum INSL3 in 107 men from 3 recent male hormonal contraceptive studies and determined the relationship between suppression of spermatogenesis and serum INSL3. At the end of treatment 63 men (59%) were azoospermic and 44 men (41%) had detectable sperm in their ejaculates. Baseline INSL3 did not predict azoospermia; however, end of treatment serum INSL3 was significantly higher in nonazoospermic men compared with those with azoospermia (median [interquartile range]: 95 [73-127] pg/mL vs 80 [67-101] pg/mL; P = .03). Furthermore, serum INSL3 was positively correlated with sperm concentration (r = .25; P = .009) at the end of treatment and was significantly associated with nonazoospermia by multivariate logistic regression (P = .03). After 6 months of treatment with a hormonal male contraceptive regimen, higher serum INSL3 concentrations were associated with persistent sperm production. INSL3 may play a role in preventing complete suppression of spermatogenesis in some men on hormonal contraceptive regimens. This finding suggests that INSL3 may be a potential target for male contraceptive development.     

Pharmacokinetics of testosterone undecanoate injected alone or in combination with norethisterone enanthate in healthy men

Long-acting injectable testosterone undecanoate (TU) is a promising androgen for male hormonal contraception. As a prerequisite for a planned multicenter male contraceptive efficacy study, we studied the pharmacokinetics of 2 doses of TU alone or in combination with norethisterone enanthate (NETE) in a prospective 2-center study, randomized for TU dose in each center. Twenty healthy male volunteers in each center were administered intramuscular injections of 750 or 1000 mg TU alone or in combination with 200 mg of NETE IM every 8 weeks for 3 injections. There were no significant differences in maximum concentration and area under the curve (AUC) for serum total and free testosterone (T) between the TU 750 and 1000 mg groups, irrespective of whether TU was administered with 200 mg of NETE. TU 1000 mg IM alone or with NETE at 8-weekly intervals resulted in linear increases in average concentration and AUC of serum total and free T with each injection. Accumulation ratios of serum total and free T levels (calculated as 8 weeks post- to preinjection levels) for each period showed significant increases in the TU+ NETE groups. Serum gonadotropins levels and sperm concentration were more consistently suppressed in the TU 1000 mg + NETE group. We conclude that despite some accumulation of T, TU 1000 mg + NETE 200 mg administered every 8 weeks may be preferable for the future contraceptive efficacy study because of more complete suppression of gonadotropins and spermatogenesis.