DOES NESTORONE GEL HAVE GONADOTROPIN SUPPRESSIVE ACTIVITY AND DEMONSTRATE AN

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目及 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 我们的长期目标是开发一些方法，提供雄激素加孕激素男性避孕药的男子。 该提案将测试在大多数正常男性中，与单独使用睾酮（T）凝胶相比，在经皮应用的睾酮（T）凝胶中加入奈司酮是否更有效地将促性腺激素（研究1）和精子浓度（研究2）抑制至接近零水平（无精子症）。它还将研究Nestorone（一种合成孕激素）凝胶是否单独抑制促性腺激素。 我们中心和其他人最近的研究表明，睾酮凝胶，当应用于皮肤，达到剂量依赖性，稳态水平的血清T。 当10 g凝胶应用于部分雄激素缺乏的男性时，血清LH和FSH下降到基线值的90%以上，使得一些值无法检测到。 此外，自2000年在美国推出以来，经皮T凝胶被发现更用户友好，是许多雄激素缺乏男性的首选方法。 我们小组是T凝胶研究的主要中心，熟悉这种透皮制剂的药代动力学和药效学。 最后，Nestorone是一种合成的雌激素，预期不具有任何雄激素和雌激素活性，并且可能没有左炔诺孕酮或去氧孕烯的一些不良副作用。 它已经作为妇女的植入物和阴道环进行了临床试验，人口理事会正在开发作为阴道环和透皮凝胶。 这项研究将分为两个阶段。 具体目标是： 研究1是一项剂量探索研究，将评估单独使用T凝胶（10 g/天）、单独使用两种剂量的Nestorone凝胶（2或4 mg/天）以及T和Nestorone凝胶联合使用14天（各给药之间有14-21天的洗脱期）对促性腺激素分泌的抑制作用。 每剂药物将给予24名健康男性。 24名健康男性将在筛选检查（包括一般和生殖史的临床评价、详细的体格检查、血液和精液分析）后随机入组研究。 未完成研究的受试者将在研究1中被替换。 受试者的基线血液和精液检查应正常。 我们预计将有24名受试者完成研究1。 要求受试者在整个研究期间使用另一种避孕方法。 终点将是血清促性腺激素抑制的有效性。 只有12名受试者将在Harbor-UCLA入组。 只有当研究1显示T和Nestorone凝胶联合使用对促性腺激素有显著和深刻的抑制作用时，才进行研究2。 本研究将评估两组（每组22例受试者，n=44）的生精抑制疗效，根据研究1的结果，接受显示最大促性腺激素抑制的最低剂量组合或相同的T凝胶单独剂量。 这将是一项为期24周的研究，将精子计数抑制至严重少精子症（<100万/mL）作为主要终点。只有22名男子将在海港加州大学洛杉矶分校注册。 受试者无直接获益。 这项研究将有助于开发一种男性避孕药，该避孕药利用经皮给药系统产生持续、恒定水平的雄激素和孕激素。 这些风险都不可能引起任何临床问题，因为给予的睾酮的生理剂量，Nestorone的已知安全性，研究1中药物暴露的持续时间短，研究2的药物暴露时间为24周，严格的入选和排除标准，研究人员及其工作人员的经验，以及对所有可能的不良反应的仔细监测。 将向每例受试者提供并解释知情同意书。 只有研究者或其指定的具有医学资质的同事才能获得知情同意书。 研究者向受试者提供的信息将包括：研究者和资金来源的识别、研究和患者参与的描述、研究目的、研究对患者的益处、睾酮和宁芙凝胶的风险和可能的副作用以及随时退出而不受处罚的可能性。 这些信息将在知情同意书中详细说明，并由两个中心的IRB和人口理事会审查和批准。 受试者还将签署HIPAA同意书，以允许研究者根据HIPAA法规和机构IRB的法规访问受保护的健康信息。 受试者将有机会提问，研究者将有机会回答受试者的问题。 然后将要求受试者在见证人在场的情况下签署知情同意书。受试者还将获得一份实验受试者权利法案的副本。 洛杉矶和西雅图的受试者将通过公告栏、报纸、广播和电视广告招募。 将要求他们通过电话联系任一研究中心。 护士协调员将通过电话询问潜在受试者的年龄和病史来筛选他们。 通过电话筛选合格的潜在受试者将安排预约，与研究者就研究的进一步合格性要求进行咨询。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Our long-term goal is to develop a number of methods of delivering androgen plus progestogen male contraceptive agents for men. This proposal will test whether addition of Nestorone to testosterone (T) gel both applied transdermally will be more efficient in suppressing gonadotropins (Study 1) and sperm concentration (Study 2) to near zero levels (azoospermia) in most normal men when compared to T gel alone. It will also study whether Nestorone¿ (a synthetic progestogen) gel alone will suppress gonadotropins . Recent studies from our center and others demonstrated that testosterone gel, when applied to the skin, achieved dose-dependent, steady state levels of serum T. When 10 g gel was applied to men with partial androgen deficiency, serum LH and FSH dropped to more than 90% of baseline values, rendering some of the values undetectable. In addition, transdermal T gel was found to be more user friendly and the preferred method for many androgen deficient men since its introduction in the United States in 2000. Our group was the lead center for the T gel studies and is familiar with the pharmacokinetics and pharmacodynamics of this transdermal preparation. Lastly, Nestorone is a synthetic progestin that is not expected to have any androgenic and estrogenic activity and may not have some of the undesirable side effects of levonorgestrel or desogestrel. It has undergone clinical trials as an implant and vaginal ring in women and is being developed by the Population Council as a vaginal ring and transdermal gel. This study will be divided into two phases. The specific aims are: Study 1 is a dose finding study which will estimate the suppression of gonadotropin secretion by T gel alone (10 g/day), Nestorone gel alone at two doses (2 or 4 mg/day), and the combinations of T and Nestorone gel for 14 days each with a 14-21 day washout period between dosing. Each dose of medication will be administered to 24 healthy men. 24 healthy men will be randomized for the study after screening examinations, which include clinical evaluation of general and reproductive history, a detailed physical examination, analyses of blood and semen. Subjects who do not complete the study will be replaced in Study 1. Subjects should have normal baseline blood and semen tests. We anticipate that 24 subjects will complete Study 1. Subjects will be required to use another method of contraception throughout the study. The end point will be the efficacy of suppression of serum gonadotropins. Only 12 subjects well be enrolled at Harbor-UCLA. Study 2 will be done only if Study 1 showed significant and profound suppression of gonadotropins by the combination of T and Nestorone Gel. This study will assess the efficacy of spermatogenic suppression in two groups of 22 subjects each (n=44), receiving the lowest dose combinations that showed the most suppression of gonadotropins based on the results of Study 1 or the same T gel dose alone. This will be a 24-week study with suppression of sperm counts to severe oligozoospermia (< 1 million/mL) as the primary endpoint). Only 22 men will be enrolled at Harbor-UCLA. There is no direct benefit to the subjects. The study will help to develop a male contraceptive for men utilizing transdermal delivery systems producing sustained, constant levels of an androgen and a progestogen. None of the risks are likely to cause any clinical problem because of the physiological dose of testosterone administered, the known safety of Nestorone, the short duration of drug exposure in study 1 and 24 weeks for study 2, the strict inclusion and exclusion criteria, the experience of the investigators and their staff, and the careful monitoring of all possible adverse effects. The consent form will be given and explained to each subject. Only the investigators or their designated medically qualified associates will obtain informed consent. The information provided by the investigator to the subject will include: identification of the investigators and funding source, description of the research study and the patient's involvement, the purpose of the study, the benefit of the research to the patient, the risks and possible side effects of testosterone and Nesterone gels and the possibility of withdrawal at any time without penalty. This information will be clearly detailed in a Consent Form, which will be reviewed and approved by the IRB at both centers and the Population Council. The subjects will also sign a HIPAA consent form to allow the investigators access the protected health information according to HIPAA regulations and those of the Institution's IRB. The subjects will be given the opportunity to ask questions and the investigators to respond to the subject's questions. The subject will then be asked to sign the Consent Form in the presence of a witness. The subjects will also be given a copy of the Experimental Subject's Bill of Rights. The subjects in Los Angeles and Seattle will be recruited via advertisement in bulletin boards, newspapers, radio, and television. They will be asked to contact either one of the study sites by telephone. The nurse coordinator will screen potential subjects over the telephone by inquiring about their age and medical history. Potential subjects who qualify by phone screen will be scheduled for an appointment to consult with the investigator about further eligibility requirements for the study.