Influence of synthetic sex hormones on alcohol effects and consumption in women

项目总结/摘要 有充分的临床前证据表明，卵巢激素影响神经生物学系统， 介导药物和酒精奖励，这可能有助于增强女性对AUD的脆弱性;研究 表明雌激素促进而孕激素对抗酒精奖励。然而，几乎没有确凿的经验证据， 数据来自对自然骑自行车的女性进行的酒精影响和消费的对照人体研究。因此，委员会认为， 我们对如何预防和更好地治疗女性AUD的理解是妥协的，新的研究 需要采取一些办法。最近的研究结果表明，在月经周期中的高激素通量时期， 与酗酒的增加有关口服避孕药（OC）是含有合成卵巢激素的药物。 抑制与月经周期相关的内源性激素波动的激素。内源性雌激素 孕酮和外源性雌二醇在整个周期中保持较低水平，而合成孕激素则较高， 稳定研究酒精的影响和消费的妇女使用OC相比，自然循环 女性将促进我们对卵巢激素如何影响AUD的理解，因为有更大的力量， 检测卵巢激素对低变异性背景的影响，我们也可以比较相对 激素稳定性与变化。这项研究的长期目标是更好地了解卵巢激素是如何 影响女性的酒精使用、滥用和AUD病程。拟议研究的目的是 使用受控实验室程序确定OC如何影响酒精效果和消耗。工作 假设是口服避孕药中的合成孕激素模拟天然孕酮的作用， 削弱酒精和酒精消费的奖励和激励作用。基本原理是 确定合成卵巢激素（OC）对酒精效应的影响将提供一个强有力的框架 寻求以妇女为重点的新型预防和治疗方法。该假设将由两个 具体目标：1）确定口服避孕药对酒精剂量依赖效应的影响，以及酒精 使用受控的人类实验室程序进行自我给药，以及2）确定 循环水平的天然和合成卵巢激素和酒精的影响和消费。的这个计划 这项研究是创新的，因为它将转移研究卵巢激素对酒精影响的重点。 从内源性激素到外源性激素的反应和消耗。这也将是第一个对照研究 使用OC的女性中酒精的影响和消费。该项目意义重大，因为它将大大 推进我们对卵巢激素如何影响酒精效应和饮酒的理解，这是一个重要因素， 导致澳元的性别差异。这些发现将具有临床意义，因为它们适用于大型 目前使用激素避孕药的美国妇女的比例，并将强调被忽视的研究 合成激素和AUD的区域。最后，积极的发现，高稳定性的合成甜菜碱抑制 酒精奖励将为开发针对女性机制的疗法提供框架。

PROJECT SUMMARY/ABSTRACT There is ample preclinical evidence showing that ovarian hormones influence the neurobiological systems that mediate drug and alcohol reward which may contribute to the enhanced vulnerability of women to AUD; studies show that estrogen promotes and progesterone opposes alcohol reward. Yet, there is little conclusive empirical data from controlled human studies of alcohol effects and consumption in naturally-cycling women. Consequently, our understanding of how to prevent and better treat AUD among women is compromised, and new research approaches are needed. Recent findings suggest that periods of high hormonal flux during the menstrual cycle are associated with increased binge drinking. Oral contraceptives (OC) are medications containing synthetic ovarian hormones that suppress menstrual cycle-related fluctuations in endogenous hormones. So, endogenous estrogen and progesterone, and exogenous estradiol remain low across the cycle while synthetic progestins are high and stable. Studies of alcohol effects and consumption among women using OC in comparison to naturally cycling women will advance our understanding of how ovarian hormones influence AUD because there is greater power to detect effects of ovarian hormones against a background of low variability, and we can also compare relative hormone stability vs. variation. The long-term goal of this research is to better understand how ovarian hormones influence alcohol use, abuse, and the course of AUD among women. The objective of the proposed research is to determine how OC influence alcohol effects and consumption using controlled laboratory procedures. The working hypothesis is that synthetic progestins in oral contraceptives mimic the effects of natural progesterone thereby attenuating the rewarding and motivational effects of alcohol, and alcohol consumption. The rationale is that determining the influence of synthetic ovarian hormones (OC) on alcohol effects will provide a strong framework to pursue novel women-focused prevention and treatment approaches. The hypothesis will be tested by two specific aims; 1) Determine the influence of oral contraceptives on dose-dependent effects of alcohol, and alcohol self-administration using controlled human laboratory procedures, and 2) Determine the relationship between circulating levels of natural and synthetic ovarian hormones and alcohol effects and consumption. This plan of research is innovative because it will shift the focus of research on the effects of ovarian hormones on alcohol responses and consumption from endogenous to exogenous hormones. This will also be the first controlled study of alcohol effects and consumption among women using OC. The project is significant because it will substantially advance our understanding of how ovarian hormones influence alcohol effects and drinking, an important factor that contributes to sex differences in AUD. The findings will be clinically significant as they apply to a large proportion of US women who currently use hormonal contraceptives and will highlight the overlooked research area of synthetic hormones and AUD. Finally, positive findings that high stable synthetic progestin dampens alcohol reward will provide a framework for the development of therapies focused on female mechanisms.