EFFECT OF NOVEL ANDROGENS ON ECTOPIC ENDOMETRIUM IN RHESUS MACAQUES

新型雄激素对恒河猴异位子宫内膜的影响

• 批准号: 8357807
• 负责人: OV D SLAYDEN
• 金额: $ 7.28万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-05-01 至 2012-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8357807
• 关键词: Adverse effects; Androgen Therapy; Androgens; Animals; Biological Models; Dose; Endometrial; Endometrium; Estrogens; Fatty acid glycerol esters; Female; Funding; Goals; Grant; Growth; Implant; Intra-abdominal; Liver; Macaca; Macaca mulatta; Methods; National Center for Research Resources; Pharmacotherapy; Preclinical Testing; Primates; Principal Investigator; Research; Research Infrastructure; Resources; Site; Source; Stanolone; Testing; Testosterone; Tissues; Transplantation; United States National Institutes of Health; Woman; analog; cost; endometriosis; novel; subcutaneous

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. The goal is to investigate new drug therapies for endometriosis. Macaque uterine endometrium can be auto-transplanted to ectopic intra-abdominal and subcutaneous sites. These endometrial grafts provide an excellent endometriosis-like model system for preclinical testing of novel anti-endometriotic therapies. Bayer Schering Pharma AG (BSP) is developing a testosterone analog (eF-MENT) that exerts higher androgenic activity than testosterone and is not converted to estrogens like testosterone by the liver and fat tissues. In this study we will test the effect of eF-MENT on estrogen-stimulated growth in endometrial grafts, and compare the effects of eF-MENT with the effects of dihydrotestosterone (DHT a natural androgen) as a positive control. This study had two aims: Aim 1 is to develop methods to identify nonreproductive "off-target" effects of androgens in female macaques that are analogous to the side effects of androgen therapy in women. Aim 2 is to determine if eF-MENT therapy will inhibit growth in ectopic endometrium in rhesus macaques. Dose finding studies, with eF-MENT administered by siclastic implant, are underway. We identified a implant dose that resulted in no off-target actions and compared it to doses that resulted in non-target effects. All doses of eF-MENT resulted in suppression of ectopic endometrium in the animals. In contrast only the high dose DHT implants suppress graft growth. We propose that eF-MENT can be developed as a therapy for endometriosis in women.

该子项目是利用资源的众多研究子项目之一 由 NIH/NCRR 资助的中心拨款提供。子项目的主要支持 并且子项目的主要研究者可能是由其他来源提供的， 包括其他 NIH 来源。 子项目可能列出的总成本 代表子项目使用的中心基础设施的估计数量， NCRR 赠款不直接向子项目或子项目工作人员提供资金。 目标是研究子宫内膜异位症的新药物疗法。 猕猴子宫内膜可以自体移植到异位腹腔内和皮下部位。 这些子宫内膜移植物为新型抗子宫内膜异位疗法的临床前测试提供了出色的子宫内膜异位症样模型系统。 拜耳先灵制药公司（BSP）正在开发一种睾酮类似物（eF-MENT），它比睾酮具有更高的雄激素活性，并且不会像睾酮那样被肝脏​​和脂肪组织转化为雌激素。 在这项研究中，我们将测试 eF-MENT 对雌激素刺激的子宫内膜移植物生长的影响，并将 eF-MENT 的效果与作为阳性对照的二氢睾酮（DHT 一种天然雄激素）的效果进行比较。 这项研究有两个目标：目标 1 是开发方法来识别雄激素对雌性猕猴的非生殖“脱靶”效应，类似于女性雄激素治疗的副作用。 目标 2 是确定 eF-MENT 疗法是否会抑制恒河猴异位子宫内膜的生长。通过 siclastic 植入物进行 eF-MENT 的剂量探索研究正在进行中。我们确定了不会导致脱靶作用的植入剂量，并将其与导致非靶标效应的剂量进行比较。 所有剂量的 eF-MENT 都会抑制动物的异位子宫内膜。 相比之下，只有高剂量的 DHT 植入物才能抑制移植物生长。 我们建议将 eF-MENT 开发为女性子宫内膜异位症的治疗方法。