Contraceptive efficacy and body weight: Does obesity affect the risk of failure?

描述(申请人提供)：肥胖症和意外怀孕在美国都处于流行水平。因此，肥胖和意外怀孕之间的联系将构成一个重大的公共卫生问题。最近的流行病学研究表明，肥胖可能会降低口服避孕药(OC)的效果，这可能对极低剂量的口服避孕药(即乙炔雌二醇[EE]=20微克])特别令人担忧。研究还没有确定什么机制可能会导致这种疗效下降。我们的长期目标是确定肥胖女性OCS失败的机制，以提高这些女性的避孕效果。我们的主要假设是体重指数(BMI)的增加改变了OC的利用率，导致肥胖女性在使用OC期间对下丘脑-垂体-卵巢(HPO)轴的抑制不足。在这项R03应用中，我们建议检测20名排卵生殖年龄妇女[10名正常体重和10名肥胖体重]的合成类固醇代谢和促性腺激素搏动性，以关注是否存在与我们的主要假设一致的趋势。我们的具体目标是：1.确定肥胖是否影响OCS的药代动力学。这一目标的目的将是测量在肥胖和正常体重指数队列中以标准循环方式给药的循环OC的峰值和稳态浓度；(1a)专注于一个治疗周期后EE和LNG稳态水平的差异；(1b)停止治疗(在无激素间隔开始时)的清除率；以及(1c)重新开始治疗(在无激素间隔结束时)达到稳定状态的时间；2.确定肥胖是否损害使用OC实现的HPO轴抑制。这一目标的目的将是测量肥胖和正常体重指数队列中促性腺激素的搏动性(脉冲幅度和频率)和卵巢反应(平均血清雌二醇[E_2]和孕酮[P]水平)；以及3.比较血点(自制指棒)和静脉穿刺法获得的FSH、LH、E_2和P水平，以确定血点分析是否可以作为生殖研究中血清分析的可靠替代方法，因为它们可以最大限度地减少更大规模研究中所需的侵袭性和血量。

DESCRIPTION (provided by applicant): Both obesity and unplanned pregnancies are at epidemic levels in the United States. An association between obesity and unplanned pregnancy would, therefore, constitute a significant public health concern. Recent epidemiological studies suggest that obesity may reduce oral contraceptive (OC) efficacy, and that this may be of particular concern with very low-dose OCs (i.e., ethinyl estradiol [EE] = 20 mcg]). Studies have not established what mechanisms might lead to this reduced efficacy. Our long-term goal is to identify the mechanisms leading to failure of OCs in obese women in order to improve contraceptive efficacy for these women. Our main hypothesis is that increased Body Mass Index (BMI) alters OC availability resulting in inadequate hypothalamic-pituitary-ovarian (HPO) axis suppression during OC use in obese women. In this R03 application, we propose to examine synthetic steroid metabolism and gonadotropin pulsatility in 20 ovulatory reproductive-age women [10 normal and 10 obese BMI] placed on a very low-dose OC [20 mcg EE/100 mcg levonorgestrel (LNG)], to focus on whether trends exist that are consistent with our main hypothesis. Our specific aims are: 1. to determine whether obesity affects the pharmacokinetics of OCs. The goal of this aim will be to measure peak and steady state concentrations of circulating OC dosed in a standard cyclic fashion in obese and normal BMI cohorts; (1a) focusing on the differences in EE and LNG steady state levels after one treatment cycle; (1b) the clearance rates with stopping treatment (at the start of the hormone free interval); and (1c) the time to steady state with restarting treatment (at the end of the hormone free interval); 2. To determine whether obesity impairs HPO axis suppression achieved with OC use. The goal of this aim will be to measure gonadotropin pulsatility (pulse amplitude and frequency) and ovarian response (average serum levels for estradiol [E2] and progesterone [P]) in obese and normal BMI cohorts; and 3. To compare FSH, LH, E2, and P levels obtained by blood spots (self-performed finger sticks) versus venipuncture to determine whether blood spot assays represent a reliable alternative to serum assays in reproductive research, as they would minimize the invasiveness and blood volume required in a larger study.