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.

    研究人員發(fā)現(xiàn)了一種導(dǎo)致肥胖女性服用口服避孕藥失效的生物機(jī)制，以解釋流行病學(xué)研究發(fā)現(xiàn)的上述現(xiàn)象。

    雖然傳統(tǒng)的口服避孕藥可以幫助肥胖女性達(dá)到有效的血液濃度以防止懷孕，其所需的時(shí)間卻是一般人的兩倍。因此每個(gè)月就存在一定的漏洞時(shí)期，肥胖女性體內(nèi)的口服避孕藥濃度不夠而導(dǎo)致懷孕。

    上述發(fā)現(xiàn)異常重要，研究者在其報(bào)告中表示，因?yàn)槊绹?guó)大約30%的成年人為肥胖癥患者，而口服避孕藥是最為普遍的避孕方法。

    "現(xiàn)階段我們還沒有足夠的數(shù)據(jù)支持來(lái)建議醫(yī)生改變對(duì)其肥胖病人使用口服避孕藥的臨床實(shí)踐，"Ganesh Cherala,俄勒岡州立大學(xué)藥學(xué)院的副教授說(shuō)。"然而，在我們?nèi)〉酶�多�?shù)據(jù)以前，那些需要進(jìn)行避孕的肥胖女性，可以咨詢她們的醫(yī)生在每個(gè)月的一些時(shí)候采取一些備份的避孕方法。"

    這項(xiàng)研究結(jié)果刊登在避孕雜志中，由俄勒岡州立大學(xué)、美國(guó)俄勒岡保健科學(xué)大學(xué)、丹佛科羅拉多大學(xué)、俄勒岡國(guó)家靈長(zhǎng)類動(dòng)物研究中心和南加州大學(xué)的科學(xué)家共同發(fā)布，并由國(guó)家衛(wèi)生院資助。

    問(wèn)題的根本在于，Cherala說(shuō)，如其他藥物一樣，對(duì)口服避孕藥的最初檢測(cè)對(duì)象是健康人群，基本沒有包括那些超重30%的人。

    "在首次進(jìn)行藥物安全和有效性檢測(cè)時(shí)，我們一般部考慮那些身體質(zhì)量指數(shù)高的人群，"Cherala說(shuō)，"但是體重和脂肪的數(shù)量會(huì)嚴(yán)重影響藥代動(dòng)力，也就是藥物在體內(nèi)的作用效果以及起效過(guò)程。人們?cè)絹?lái)越多的意識(shí)到，其應(yīng)該認(rèn)真研究肥胖以及其他因素對(duì)藥物的吸收、分布、代謝和其他方面的影響。"

    Cherala說(shuō)，傳統(tǒng)的口服避孕藥相對(duì)而言具有嗜油脂性，也就是說(shuō)會(huì)在脂肪處聚集。然而，令本次研究人員感到意外的是，這些藥物的嗜油脂性在肥胖以及一般被試中沒有明顯區(qū)別。

    相反，研究人員發(fā)現(xiàn)，口服避孕藥的最終濃度在肥胖和正常體重的被試中是相同的，但是超重女性達(dá)到最終濃度的時(shí)間較長(zhǎng)。

    研究發(fā)現(xiàn)，正常體重的女性，口服避孕藥發(fā)揮藥效需要大概5天，超重女性大概是10天，而一些特殊人群則需要更長(zhǎng)的時(shí)間。一個(gè)被試女性用了超過(guò)20天才達(dá)到避孕所需的穩(wěn)定濃度。正常體重的女性使用口服避孕藥就能夠達(dá)到避孕效果，但這些藥在肥胖女性體內(nèi)達(dá)到穩(wěn)定濃度所需的較長(zhǎng)時(shí)間，讓人們不得不考慮它們的有效性。

    增加藥量金額以解決這個(gè)問(wèn)題，Cherala說(shuō)，然而這將會(huì)產(chǎn)生其他健康問(wèn)題。

    事實(shí)上，根據(jù)研究報(bào)道，許多臨床醫(yī)生通常減少肥胖女性的口服避孕藥劑量以降低靜脈血栓（在大腿或其他部位的可以增加中風(fēng)和心臟病發(fā)作風(fēng)險(xiǎn)的血塊）形成的風(fēng)險(xiǎn)。

    研究的被試由20名健康并需要希望采取避孕措施的女性組成，年齡為18~35歲。其中10人體重正常，另外10人的身體質(zhì)量指數(shù)超過(guò)30（肥胖癥的一般標(biāo)準(zhǔn)）.

    Alison Edelman醫(yī)生，本研究的骨干，俄勒岡保健科學(xué)大學(xué)計(jì)劃生育協(xié)會(huì)的副主席表示，本次實(shí)驗(yàn)的被試是特別選定的。然而一些人口研究的結(jié)果顯示，那些身體質(zhì)量指數(shù)超過(guò)25,不到30的女性也存在不斷增加的避孕風(fēng)險(xiǎn)。

    "雖然，我們研究了肥胖女性和口服避孕藥之間存在的關(guān)系，我們還沒有足夠的數(shù)據(jù)支持來(lái)做出臨床醫(yī)學(xué)改革建議。我們現(xiàn)在只能建議那些對(duì)于正常和超重女性都較為有效的避孕方法，比如子宮環(huán)，"Edelman說(shuō)。

    對(duì)于未來(lái)的研究工作，她說(shuō)，最好是選取代表性好的樣本，能夠包括不同身體質(zhì)量指數(shù)的女性。研究報(bào)告中顯示，對(duì)于口服避孕藥起作用的生物學(xué)基礎(chǔ)以及其對(duì)下丘腦-垂體-卵巢的影響，我們只是針對(duì)正常體重的女性進(jìn)行了研究。

    目前為止，還沒有現(xiàn)成的實(shí)驗(yàn)數(shù)據(jù)顯示口服避孕藥再女性體內(nèi)起效的具體時(shí)間，而這個(gè)時(shí)間也因人而異。然而，科學(xué)家正在對(duì)此進(jìn)行深入研究，希望有朝一日他們能發(fā)現(xiàn)改善口服避孕藥效果的實(shí)驗(yàn)或方法，給那些希望使用者帶來(lái)福音。