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不孕不育、糖尿病、肥胖症与多囊症之迷

更新时间:2014-2-25 13:08:14 来源:华尔街日报中文网 作者:佚名

Infertility, Diabetes, Obesity and the Mystery of PCOS
不孕不育、糖尿病、肥胖症与多囊症之迷

Scientists know this much about polycystic ovary syndrome: It is one of the most common causes of infertility. It's linked to diabetes and several other troubling health problems. It affects as many as 5 million U.S. women.

But the condition, also known as PCOS, largely remains a mystery. Researchers are trying to better understand the disorder, which is generally defined by an excess production of the hormone testosterone, irregular ovulation and cysts-fluid-filled sacs-within the ovaries. Some teams are trying to improve its treatment to lessen its impact on women's reproductive health and metabolism, or how the body uses or makes energy.

'We really need better options,' says Esther Eisenberg, project scientist of the Reproductive Medicine Network, a research collaboration set up and funded through the Eunice Kennedy Shriver National Institute of Child Health and Human Development.

Even the diagnosis of PCOS can be tricky because the syndrome doesn't look the same in everyone. What is called PCOS is likely a number of different diseases that manifest similar symptoms, such as acne, excess facial- and body-hair growth in reproductive-aged females, insulin resistance and abnormal menstrual periods, according to experts.

Over 60% of women with PCOS are overweight or obese. Excess hair growth, called hirsutism, also can differ by ethnicity, as can body weight. Such demographic differences can cause doctors to have difficulty identifying PCOS in those patients. And since most girls have irregular periods when they first start menstruating, misdiagnosis may be more likely to occur with young adolescents.

Insulin resistance, an inability to properly process sugar, is common, regardless of body weight. This can greatly raise the risk in PCOS patients of developing diabetes. The uterine lining may build up excessively, which is related to the lack of ovulation, and endometrial cancer risk appears to be increased as well. And women with PCOS often have trouble conceiving because they may not ovulate regularly, and may be more likely to miscarry. There also are concerns about an increased risk of heart disease, although no definitive data support that notion.

Researchers fear a general rise in obesity is causing a spike in PCOS, too, though they don't have enough longitudinal data to say definitively.

PCOS appears to have a genetic component that may be triggered or influenced by environmental factors, like weight gain, later in life. But scientists are still trying to determine exactly what goes wrong. The symptoms of PCOS are at least in part due to excess androgens, the family of hormones to which testosterone belongs.

The womb environment also appears critical to its development. Daniel Dumesic, a professor of reproductive endocrinology and infertility at the University of California, Los Angeles, and his colleagues found that by exposing mother monkeys with high doses of testosterone, their female offspring developed PCOS-like features after birth, including higher testosterone levels.

They now are studying whether the bodies of women with PCOS, because of excess testosterone, store fat in tissues where it shouldn't be. Dr. Dumesic hypothesizes that this may impact the function of the ovary and perhaps fertility.

Christopher McCartney, a professor of medicine at the University of Virginia, is examining whether the high levels of testosterone could increase the body's secretion of another chemical, called luteinizing hormone, or LH, at puberty, contributing to the development of PCOS. LH, in turn, is needed for the ovaries to produce testosterone, so high levels of LH may be helping produce additional testosterone, leading to a vicious cycle, Dr. McCartney says.

Why the syndrome increases the risk of diabetes remains unclear. One possibility is that because the body doesn't respond well to insulin, it overcompensates to make more of it, which leads to increased levels of luteinizing hormone and lower levels of follicle-stimulating hormone, as well as increased ovarian production of androgens.

Together, these slow or prevent ovulation, according to Richard Legro, a professor of obstetrics and gynecology and public health sciences at Penn State University College of Medicine in Hershey, Pa.

'It's likely that the menstrual and reproductive dysfunction is a harbinger of later metabolic abnormalities like diabetes,' Dr. Legro says.

Treatments include hormonal contraceptives to prompt ovaries to stop producing testosterone and other hormones, plus anti-androgen medications like flutamide, usually used to treat prostate cancer, and insulin sensitizers for metabolic issues. Metformin, which isn't an insulin sensitizer but is used to treat high blood sugar, is given as well on a case-by-case basis. Some of these treatments carry risks and most, with the exception of metformin, can't be used when women are trying to get pregnant.

Lourdes Ibáñez, a professor of pediatrics at the University of Barcelona, has been studying combination treatments for PCOS. She found that metformin, an insulin sensitizer called pioglitazone and flutamide taken together performed better than oral contraceptives. Oral contraceptives appeared to actually worsen the girls' metabolic abnormalities.

Six months after the 18-month treatment, no one in the combination therapy group has relapsed but 50% of those in the oral contraceptive groups have, according to a paper Dr. Ibáñez published in 2013 in the Journal of Clinical Endocrinology & Metabolism.

She is also studying whether the symptoms of PCOS can be prevented in girls at high risk for the condition. She conducted a tiny pilot study of 38 girls who were born with a low birth weight and had precocious puberty, which are often precursors to PCOS.

She began treating them with metformin between ages 8 to 12. At 18 years old, the rate of detectable symptoms in the treated group was 5%, compared with 50% of those in the untreated group. She hopes to run a larger trial to further explore the possibility of prevention.

Scientists also have focused on improving fertility in women with PCOS. With clomiphene citrate, the most commonly used agent for ovulation induction in women with PCOS, only about half the women who ovulate end up having babies, according to NICHD's Dr. Eisenberg.

Dr. Eisenberg, Penn State's Dr. Legro and the Reproductive Medicine Network have been running a clinical trial to improve fertility. In a presentation to the American Society for Reproductive Medicine in October, they showed that early results indicate a medication called letrozole, a drug commonly used for in vitro fertilization, appears to result in more live births than clomiphene.

One of those success stories was Lindsey Maloney, from Fredericksburg, Va. She had so much facial hair she started waxing it off in the fifth grade and always struggled with her weight because of insulin resistance. She had her period only once in the seventh grade and was first diagnosed with PCOS at 15.

When Ms. Maloney, now a 29-year-old school counselor, got engaged to her now-husband, her fertility worried her. When the couple heard about Dr. Legro's study, Ms. Maloney enrolled and drove three hours to Hershey once a month for drugs to help her ovulate. She was randomly assigned to the letrozole group, she says.

They now have a 2-year-old girl, Briley. Ms. Maloney and her husband are trying for a second child on their own and haven't had any luck yet.
Ms. Maloney has been taking metformin since she was a teenager, sees an endocrinologist every three months and buys supplements and organic foods without hormones in them, but her symptoms have remained, she says.

'It's not just on your ovaries. It's a whole mess of endocrine problems that you have,' she says.

关于多囊卵巢综合症,科学家知道的也就是这些:它是不孕不育的最常见原因之一。它与糖尿病和另外多种恼人的健康问题有关。它影响着多达500万的美国女性。

但多囊症总体上还是一个迷。研究人员正在努力更好地理解这一病症。它大体上被定义为睾丸激素分泌过多、排卵不规律、卵巢内存在囊肿(积液囊)。有些团队希望改进治疗方案,减轻它对女性生殖健康和新陈代谢(身体使用或产生能量的过程)的影响。

尤尼斯·肯尼迪·施莱佛美国国家儿童健康与人类发育研究所(Eunice Kennedy Shriver National Institute of Child Health and Human Development)设立并资助的研究协作团体“生殖医学网络”(Reproductive Medicine Network)项目科学家埃丝特·艾森伯格(Esther Eisenberg)说:“我们真的需要更好的选择。”

多囊症的诊断有时候都很困难,因为这一综合症并不是在每个人身上都表现得一样。据专家说,所谓多囊症可能是一系列表现为相似症状的不同疾病,这些症状包括痤疮、育龄妇女面部和身体毛发过旺、胰岛素抵抗、月经不调等。

六成以上多囊症妇女都存在过重或肥胖的问题。毛发生长过旺(称为“多毛症”)的情况可能因为种族的不同而不同,体重问题也是如此。这些人口学差异可能导致医生在诊断这些病人的多囊症时发生困难。由于大多数女孩在刚开始来月经时都存在经期不正常的问题,在青少年身上或许更有可能发生误诊。

胰岛素抵抗(无法有效处理糖分)是常见病征,与体重无关。它可以极大地提高多囊症患者患上糖尿病的风险。子宫内膜可能会过度生长,而这与排卵缺乏有关。患子宫内膜癌的风险似乎也会增加。多囊症女性之所以存在生育困难,是因为她们的排卵可能不规律,流产的概率也可能更大。另外还有心脏病风险增加的担忧,不过没有确切数据支持这样一种说法。

研究人员担心,肥胖率的总体上升也在造成多囊症患病率的猛增。不过他们没有足够的纵向数据来得出确切的结论。

多囊症似乎含有一种遗传成分,这种成分可能会受到年龄增大时体重增加等环境因素的诱发或影响。但科学家仍在试图明确究竟是什么地方出了问题。多囊症的症状至少在一定程度上是因为雄激素(指包括睾丸激素在内的一系列激素)过多。

子宫环境似乎也是形成多囊症的关键。加州大学洛杉矶分校(University of California, Los Angeles)生殖内分泌与不孕不育教授丹尼尔·杜麦西克(Daniel Dumesic)及其同事发现,将母猴暴露于高剂量的睾丸激素,它们的雌性后代在出生之后出现了类似于多囊症的特征,比如更高的睾丸激素水平。

现在他们在研究多囊症患者的身体是否会因为睾丸激素而在本不应储存脂肪的组织中储存脂肪。杜麦西克假想,这一点可能会影响卵巢功能和生育能力。

弗吉尼亚大学(University of Virginia)医学教授克里斯托弗·麦卡特尼(Christopher McCartney)正在检验高水平的睾丸激素是否有可能增加体内另一种化学物质“促黄体生成素”在青春期的分泌,从而促进多囊症的形成。麦卡特尼说,促黄体生成素又是卵巢产生睾丸激素所需的物质,所以高水平的促黄体生成素可能是在帮助形成过多的睾丸激素,构成了一种恶性循环。

多囊症增加糖尿病风险的原因仍旧不明。有一种可能性是,因为身体对胰岛素的反应不敏感,作为补偿它便过多地生成胰岛素。过多的胰岛素会导致促黄体生成素水平提高、促卵泡生成素水平下降、卵巢雄激素分泌增加。

据宾州赫希市宾夕法尼亚州立大学医学院(Penn State University College of Medicine)妇产科与公共卫生学教授理查德·勒格罗(Richard Legro)说,这些因素会一起延缓或阻止排卵。

勒格罗说:“月经和生殖障碍可能是糖尿病之类后期代谢异常的先兆。”

治疗办法包括服用激素避孕药,促使卵巢停止产生睾丸激素和其他激素,服用通常用于治疗前列腺癌的氟他胺等抗雄激素药物,以及针对代谢问题服用胰岛素增敏剂。本身不是增敏剂但用于治疗高血糖的二甲双胍也可酌情让病人服用。这些治疗方法中的一部分存在风险,除了二甲双胍之外,大多数治疗方法都不能在妇女准备怀孕的时候使用。

巴塞罗纳大学(University of Barcelona)儿科教授洛德斯·伊瓦涅斯(Lourdes Ibanez)一直在研究多囊症的组合治疗。她发现,二甲双胍、胰岛素增敏剂“?格列酮”和氟他胺一起服用的效果好于口服避孕药。口服避孕药似乎还加重了女孩的代谢异常。

根据伊瓦涅斯2013年发表在《临床内分泌和代谢杂志》(Journal of Clinical Endocrinology & Metabolism)上的论文,经过18个月的治疗并观察六个月之后,组合治疗组里面无人复发,而口服避孕药组里面50%的人复发。

她也正在研究能不能阻止患多囊症风险较高的女孩出现多囊症症状。她对38名出生体重低、性早熟(常常是多囊症的先兆)的女孩展开了一项微型试点研究。

她在她们八岁到12岁的时候开始用二甲双胍治疗。在18岁的时候,治疗组出现可观测症状的比例为5%,未治疗组的比例为50%。她希望开展一场规模更大的试验,以进一步探索预防多囊症的可能性。

科学家也一直在集中精力改善多囊症妇女的生育能力。据艾森伯格说,在服用多囊症患者最常用的排卵诱导剂枸橼酸氯米芬(克洛米芬)的情况下,只有大约一半成功排卵的妇女最后生了孩子。

艾森伯格、宾大的列格罗以及生殖医学网络已经在做一次旨在提高生育率的临床试验。他们在2013年10月份向美国生殖医学会(American Society for Reproductive Medicine)做报告的时候表示,初步结果表明,常常用于体外授精的来曲唑产生的活胎数量似乎高于枸橼酸氯米芬。

弗吉尼亚州弗雷德里克斯堡的琳赛·马洛尼(Lindsey Maloney)便是成功例子之一。由于面部毛发过多,她在上五年级的时候便开始动手脱毛;而因为胰岛素抵抗,她又总是因为体重问题而烦恼。她只在上七年级的时候有过一次例假,15岁时第一次诊出多囊症。

马洛尼现年29岁,是一名中学辅导员。在跟现在的丈夫订婚时,她因为自己的生育能力而担忧。夫妻二人听说列格罗的研究时,马洛尼加入了研究,每个月开车三小时到赫希去服用帮助她排卵的药物。她说,她被随机分配到服用来曲唑的小组。

现在他们的女儿布里利(Briley)已经两岁了。马洛尼和丈夫正在尝试自行孕育第二个孩子,目前尚未成功。

马洛尼说,她从十几岁以来一直在服用二甲双胍,每三个月都要看一次内分泌科医生,她还购买补充剂和没有激素的有机食品,但症状依然没有消失。

她说:“不只是卵巢的问题,而是一大堆内分泌问题。”

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