Prostate and Cardiovascular Effects of Male Hormonal Contraceptive Regimens

男性激素避孕方案对前列腺和心血管的影响

基本信息

批准号：
8074940
负责人：
WILLIAM J BREMNER
金额：
$ 6.59万
依托单位：
UNIVERSITY OF WASHINGTON
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/8074940
关键词：
5a-Reductase Inhibition Acetates Adverse effects Affect Androgens Apoptosis Benefits and Risks Body Composition Body Weight decreased Body fat C-reactive protein Cardiovascular Diseases Cardiovascular system Cell Proliferation Cells Cellular biology Cervical Cessation of life Contraceptive Agents Contraceptive Usage Contraceptive methods Data Development Disease Dutasteride Endometrial Carcinoma Epidemiologic Studies Epithelial Epithelial Cells Epithelium Estrogens Fatty acid glycerol esters Fibrinogen Gel Gender Gene Expression General Anesthesia Genes Hand Health Health Care Costs Hepatic High Density Lipoproteins High Prevalence Hormonal Hormones Human Hypogonadism Incidence Inflammation Insulin Insulin Resistance Interleukin-6 Intramuscular Knowledge Label Lead Leptin Lipids Liver Maintenance Male Contraceptive Agents Malignant neoplasm of prostate Measures Medroxyprogesterone 17-Acetate Metabolic Molecular Nonesterified Fatty Acids Obesity Oral Oral Administration Organ Ovarian Oxidoreductase Pharmaceutical Preparations Phase II Clinical Trials Physiology Placebos Population Portal vein structure Prevalence Progestins Prostate Prostatic Prostatic Diseases Regimen Research Design Risk Risk Factors Route Safety Serum Serum amyloid A protein Severities Specimen Spermatogenesis Stanolone Stromal Cells Surveys System Technical Expertise Techniques Testing Testosterone Tissues Visceral Weight Weight Gain Woman absorption adiponectin base body system cardiovascular disorder risk cardiovascular risk factor caspase-3 complement C3a, des-Arg-(77)control trial hormonal contraception human subject hypothalamic pituitary gonadal axis indexing inflammatory marker inhibitor/antagonist insight insulin sensitivity male male health malignant breast neoplasm man men middle age older men prevent prostate cancer prevention protein expression randomized placebo controlled trial species difference sperm cell volunteer

项目摘要

World population continues to grow at an astonishing rate and surveys suggest that both genders desire more male contraceptive options. Male hormonal contraceptive regimens that consist of androgens plus a progestin are attractive options as they have high efficacy rates (over 95%) and are fully reversible. However, little is known about the extra-gonadal effects of exogenous hormone administration in men. We propose two randomized, placebo-controlled trials that will further our understanding of the potential benefits and risks of androgens and progestins on the prostate and cardiovascular system, organ systems with high disease prevalence in men that might be modulated by androgens and progestins. We have recently developed technical expertise performing molecular analyses on prostate tissue specimens obtained from normal volunteers after hormone manipulation. We propose in Study 1 to determine intraprostatic hormone levels, cell turnover, and cell-specific gene expression in men treated with 3 months of testosterone (T) gel, T + dutasteride, a drug that blocks the conversion of T to the more potent androgen dihydrotestosterone and may contribute to prostate cancer prevention, or T + intramuscular depomedroxyprogesterone (IM DMPA), a promising male hormonal contraceptive regimen. This study will provide significant insights into the impact of hormonal manipulation on the prostate at the molecular level in normal, healthy men. Exogenous testosterone and progestins suppress serum high density lipoprotein (HDL) and cause weight gain. These changes may be associated with increased visceral adiposity, systemic inflammation, insulin resistance and increased risk of cardiovascular disease. Because there have been no systematic studies done on the effects of androgens + progestins on these cardiovascular risk factors, we propose in Study 2 to compare the effects of 6 months of treatment with T gel alone vs. T + IM DMPA vs. T + oral MPA on serum HDL, body composition, inflammatory markers, insulin sensitivity, and spermatogenesis. In Study 2, we will determine how T alone and T + IM DMPA affect these measures, and whether oral administration of the progestin MPA impacts these cardiovascular risk factors, and spermatogenesis, differently, due to first-pass hepatic effects. Together these studies will significantly advance our knowledge of the potential risks and benefits of T-based contraceptive regimens and T + MPA, a promising male hormonal contraceptive regimen.

世界人口继续以惊人的速度增长，调查表明，男女都希望有更多的男性避孕选择。由雄激素加孕激素组成的男性激素避孕方案是很有吸引力的选择，因为它们具有高有效率（超过 95%）并且完全可逆。然而，人们对外源激素对男性的性腺外影响知之甚少。我们提出了两项随机、安慰剂对照试验，这将进一步了解雄激素和孕激素对前列腺和心血管系统以及男性疾病患病率高的器官系统的潜在益处和风险，这些系统可能受到雄激素和孕激素的调节。我们最近开发了技术专业知识，可以对从正常志愿者获得的前列腺组织标本进行激素操作后进行分子分析。我们在研究 1 中建议，测定接受 3 个月睾酮 (T) 凝胶、T + 度他雄胺治疗的男性的前列腺内激素水平、细胞更新和细胞特异性基因表达，T + 度他雄胺是一种阻止 T 转化为更有效的雄激素的药物。二氢睾酮，可能有助于预防前列腺癌，或 T + 肌内注射去甲羟黄体酮 (IM DMPA)，一种有前景的男性激素避孕方案。这项研究将从分子水平上揭示荷尔蒙控制对正常健康男性前列腺的影响。外源性睾酮和孕激素抑制血清高密度脂蛋白（HDL）并导致体重增加。这些变化可能与内脏肥胖增加、全身炎症、胰岛素抵抗和心血管疾病风险增加有关。由于尚未对雄激素+孕激素对这些心血管危险因素的影响进行系统研究，我们建议在研究 2 中比较单独使用 T gel 与 T + IM DMPA 与 T + 口服 MPA 治疗 6 个月对血清 HDL、身体成分、炎症标志物、胰岛素敏感性和精子发生的影响。在研究 2 中，我们将确定单独 T 和 T + IM DMPA 如何影响这些指标，以及口服孕激素 MPA 是否会因首过肝脏效应而不同地影响这些心血管危险因素和精子发生。这些研究将显着提高我们对基于 T 的避孕方案和 T + MPA（一种有前途的男性激素避孕方案）的潜在风险和益处的认识。