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Researchers have identified a potential biological mechanism that could explain why oral contraceptives may be less effective at preventing pregnancy in obese women, as some epidemiological studies have indicated.
Although conventional oral contraceptives appear to eventually reach the effective blood concentrations needed in the body to prevent conception in obese women, it appears to take twice as long, leaving a "window of opportunity" every month where the contraceptive may not be at a high enough level to prevent a pregnancy.
The findings are of particular importance, researchers noted in their study, because about 30 percent of all adults in the U.S. are obese and the birth control pill is one of the most popular forms of contraception in the nation.
"We don't have enough data yet to recommend that physicians change their clinical practice for use of oral contraceptives with patients who are very overweight," said Ganesh Cherala, an assistant professor in the College of Pharmacy at Oregon State University. "However, until more studies are done, women may wish to consult with their physicians about this issue and consider a backup method of contraception at some times of the month."
The study was just published in the journal Contraception, by scientists from OSU, Oregon Health and Science University, University of Colorado at Denver, Oregon National Primate Research Center, and the University of Southern California. The research was supported by the National Institutes of Health.
The underlying problem, Cherala said, is that oral contraceptives, like most drugs, are initially tested in "healthy" people, which rarely includes people who are more than 130 percent of their ideal body weight.
"When we first test drugs for safety and efficacy, we generally do not include people with a high body mass index," Cherala said. "But body weight and amounts of fat can seriously change the pharmacokinetics, or way drugs act and are processed in the body. There's a growing awareness that we need to more carefully consider obesity and other factors that affect drug absorption, distribution, metabolism and other factors."
Conventional oral contraceptives, Cherala said, are thought to be relatively "lipophilic," or tend to concentrate in fat tissue. However, the researchers in this study said they were somewhat surprised to find that the affinity of these drugs for fat tissue was not significantly different between obese and normal body weight subjects.
Rather, the researchers found that contraceptive drug levels in both obese women and those of normal weight eventually were about the same, but it took longer to achieve that level in very overweight women.
The study showed it took an average of about five days for the drugs to achieve their maximum concentration in women of normal weight, an average of 10 days for obese women, and even longer than that for some individuals. One woman in the study took more than 20 days to reach a "steady state" drug concentration. Women of normal weight who follow their oral contraceptive directions should have appropriate protection against pregnancy. But the delay in reaching a steady state drug concentration raises questions about how well oral contraceptives may work for obese women.
Increasing the drug dosage might help address this issue, Cherala said, but also adds other health concerns.
In fact, the researchers noted in their report that many clinicians actually prescribe lower-dose oral contraceptives to obese patients in an effort to decrease their risk of venous thrombosis. These are blood clots in the legs or elsewhere that can increase the risk of stroke and heart attacks.
The study was done with 20 women of ages 18 to 35, all of them healthy and seeking contraception, 10 of whom were of normal weight and 10 with a "body mass index" of more than 30 – a common measure of obesity.
According to Dr. Alison Edelman, lead author of the study and assistant director of the Family Planning Fellowship at Oregon Health and Science University, the participants in this study were purposely selected for obesity in order to explore this issue. But several demographic studies have shown that even women just considered "overweight," with a body mass index of 25-30, may also be at increased risk of contraceptive failure.
"Although our research has found this interaction between obese women and oral contraceptives, we don't have enough information yet to recommend changes in clinical practice, other than choosing a contraceptive option that works better for both normal weight and obese women, like an intrauterine device," Edelman said.
For future work, she said, studies of contraception would be more useful if they included participants that reflect the general population, including women with different body mass indexes. The biological underpinnings of how oral contraceptives work, their effects on the hypothalamic-pituitary-ovarian axis, has only been studied in women of normal weight, the researchers noted in their study.
At present, Cherala said, there is no readily available test that would tell a woman how long it would take for her to reach an effective concentration level of a particular contraceptive, and this does vary with the individual. However, scientists are continuing research on that issue, and they may ultimately develop tests or methods that would improve drug efficacy for women who wish to use oral contraceptives.
研究人员发现了一种导致肥胖女性服用口服避孕药失效的生物机制，以解释流行病学研究发现的上述现象。
虽然传统的口服避孕药可以帮助肥胖女性达到有效的血液浓度以防止怀孕，其所需的时间却是一般人的两倍。因此每个月就存在一定的漏洞时期，肥胖女性体内的口服避孕药浓度不够而导致怀孕。
上述发现异常重要，研究者在其报告中表示，因为美国大约30%的成年人为肥胖症患者，而口服避孕药是最为普遍的避孕方法。
"现阶段我们还没有足够的数据支持来建议医生改变对其肥胖病人使用口服避孕药的临床实践，"Ganesh Cherala,俄勒冈州立大学药学院的副教授说。"然而，在我们取得更多数据以前，那些需要进行避孕的肥胖女性，可以咨询她们的医生在每个月的一些时候采取一些备份的避孕方法。"
这项研究结果刊登在避孕杂志中，由俄勒冈州立大学、美国俄勒冈保健科学大学、丹佛科罗拉多大学、俄勒冈国家灵长类动物研究中心和南加州大学的科学家共同发布，并由国家卫生院资助。
问题的根本在于，Cherala说，如其他药物一样，对口服避孕药的最初检测对象是健康人群，基本没有包括那些超重30%的人。
"在首次进行药物安全和有效性检测时，我们一般部考虑那些身体质量指数高的人群，"Cherala说，"但是体重和脂肪的数量会严重影响药代动力，也就是药物在体内的作用效果以及起效过程。人们越来越多的意识到，其应该认真研究肥胖以及其他因素对药物的吸收、分布、代谢和其他方面的影响。"
Cherala说，传统的口服避孕药相对而言具有嗜油脂性，也就是说会在脂肪处聚集。然而，令本次研究人员感到意外的是，这些药物的嗜油脂性在肥胖以及一般被试中没有明显区别。
相反，研究人员发现，口服避孕药的最终浓度在肥胖和正常体重的被试中是相同的，但是超重女性达到最终浓度的时间较长。
研究发现，正常体重的女性，口服避孕药发挥药效需要大概5天，超重女性大概是10天，而一些特殊人群则需要更长的时间。一个被试女性用了超过20天才达到避孕所需的稳定浓度。正常体重的女性使用口服避孕药就能够达到避孕效果，但这些药在肥胖女性体内达到稳定浓度所需的较长时间，让人们不得不考虑它们的有效性。
增加药量金额以解决这个问题，Cherala说，然而这将会产生其他健康问题。
事实上，根据研究报道，许多临床医生通常减少肥胖女性的口服避孕药剂量以降低静脉血栓（在大腿或其他部位的可以增加中风和心脏病发作风险的血块）形成的风险。
研究的被试由20名健康并需要希望采取避孕措施的女性组成，年龄为18~35岁。其中10人体重正常，另外10人的身体质量指数超过30（肥胖症的一般标准）.
Alison Edelman医生，本研究的骨干，俄勒冈保健科学大学计划生育协会的副主席表示，本次实验的被试是特别选定的。然而一些人口研究的结果显示，那些身体质量指数超过25,不到30的女性也存在不断增加的避孕风险。
"虽然，我们研究了肥胖女性和口服避孕药之间存在的关系，我们还没有足够的数据支持来做出临床医学改革建议。我们现在只能建议那些对于正常和超重女性都较为有效的避孕方法，比如子宫环，"Edelman说。
对于未来的研究工作，她说，最好是选取代表性好的样本，能够包括不同身体质量指数的女性。研究报告中显示，对于口服避孕药起作用的生物学基础以及其对下丘脑-垂体-卵巢的影响，我们只是针对正常体重的女性进行了研究。
目前为止，还没有现成的实验数据显示口服避孕药再女性体内起效的具体时间，而这个时间也因人而异。然而，科学家正在对此进行深入研究，希望有朝一日他们能发现改善口服避孕药效果的实验或方法，给那些希望使用者带来福音。
