Polycystic ovary syndrome, androgen excess, and the risk of nonalcoholic fatty liver disease in women: A longitudinal study based on a United Kingdom primary care database.
Polycystic ovary syndrome, androgen excess, and the risk of nonalcoholic fatty liver disease in women: A longitudinal study based on a United Kingdom primary care database.
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DOI：
10.1371/journal.pmed.1002542
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发表时间：
2018-03
期刊：
影响因子：
15.8
通讯作者：
Nirantharakumar K
中科院分区：
文献类型：
--
作者：
Kumarendran B;O'Reilly MW;Manolopoulos KN;Toulis KA;Gokhale KM;Sitch AJ;Wijeyaratne CN;Coomarasamy A;Arlt W;Nirantharakumar K
雄激素过多是多囊卵巢综合征(PCOS)的一个明显特征，这种综合征影响10%的女性，代表着一种终生代谢紊乱，并增加了患2型糖尿病、高血压和心血管事件的风险。以前的研究表明，患有多囊卵巢综合征的人患非酒精性脂肪性肝病(NAFLD)的风险增加，并暗示雄激素过量是潜在的驱动因素。我们利用英国大型初级保健数据库进行了一项回溯性纵向队列研究，评估了2000年1月至2016年5月登记的63,120名患有多囊卵巢综合征的女性和121,064名年龄、体重指数(BMI)和位置匹配的对照组女性的NAFLD发生率。在两个独立的队列中，我们还通过测量血清睾酮(n=71,061)和性激素结合球蛋白(SHBG；n=49,625)来确定女性NAFLD的发生率。我们使用多变量COX模型估计非酒精性脂肪肝的风险比(HR)，发现在调整了体重指数或血糖异常后，多囊卵巢综合征妇女患非酒精性脂肪肝的比率增加(HR=2.23，95%可信区间1.86-2.66，p<；0.001)。血清睾酮3.0nmol/L与非酒精性脂肪肝升高相关(P=0.017，P=0.017；P=0.009)。与这一发现相一致的是，SHBG<；30nmol/L与非酒精性脂肪肝的风险增加有关(对于20-29.99nmol/L，HR=4.75，95%可信区间2.44-9.25，p<；0.001；对于<；20nmol/L，HR=4.98，95%CI 2.45-10.11，p<；0.001)。这项研究的局限性包括其回溯性，缺乏用于诊断PCOS和NAFLD的标准的详细信息，以及缺乏用于测量血清雄激素的实验室分析数据。我们发现，患有多囊卵巢综合征的女性患非酒精性脂肪肝的几率更高。除了体重指数增加和血糖异常外，雄激素过量还会导致多囊卵巢综合征女性NAFLD的发展。对于患有PCOS相关雄激素过剩的女性，应考虑进行系统的NAFLD筛查。Krishnarajah Nirantharakumar和他的同事指出，在患有多囊卵巢综合征的女性中，高水平的雄激素与非酒精性脂肪性肝病的发展之间存在联系。多囊卵巢综合征(PCOS)影响10%的女性，其定义是雄激素过多、慢性无排卵和超声下卵巢的多囊外观。多囊卵巢综合征不仅是一种生殖疾病，而且是一种终生代谢疾病，会增加2型糖尿病、高血压和心血管事件的发生率。最近的研究表明，患有PCOS的女性患非酒精性脂肪性肝病(NAFLD)的比例可能更高，雄激素可能在其发病机制中起到了致病作用。我们利用英国大型初级保健数据库进行了一项基于人群的回顾性队列研究，包括2000至2016年间登记的63,000多名患有多囊卵巢综合征的女性和121,000名匹配的对照组。我们发现，患有多囊卵巢综合征的女性NAFLD的发生率增加。我们发现，即使是患有多囊卵巢综合征的正常体重女性也有更高的NAFLD发生率。除了体重指数和血糖异常，我们发现雄激素过量是多囊卵巢综合征患者发生NAFLD的潜在额外危险因素。我们还研究了来自同一初级保健数据库的两个独立的队列，他们的血清睾酮(n=71,000)或性激素结合球蛋白(SHBG，n=49,000)被测量，发现具有雄激素过剩的生化证据(高睾酮，低SHBG)的妇女NAFLD的发生率增加。我们的发现表明，患有多囊卵巢综合征的女性患NAFLD的风险可能会增加，雄激素过剩是这种风险的一个潜在因素。应考虑对患有PCOS相关雄激素过剩的妇女进行NAFLD筛查。未来的研究将需要确定雄激素过量是否也会导致肝脏炎症和纤维化的进展，并确定抗雄激素药物是否可以降低NAFLD的风险。
Androgen excess is a defining feature of polycystic ovary syndrome (PCOS), which affects 10% of women and represents a lifelong metabolic disorder, with increased risk of type 2 diabetes, hypertension, and cardiovascular events. Previous studies have suggested an increased risk of nonalcoholic fatty liver disease (NAFLD) in individuals with PCOS and implicated androgen excess as a potential driver. We carried out a retrospective longitudinal cohort study utilizing a large primary care database in the United Kingdom, evaluating NAFLD rates in 63,120 women with PCOS and 121,064 age-, body mass index (BMI)-, and location-matched control women registered from January 2000 to May 2016. In 2 independent cohorts, we also determined the rate of NAFLD in women with a measurement of serum testosterone (n = 71,061) and sex hormone-binding globulin (SHBG; n = 49,625). We used multivariate Cox models to estimate the hazard ratio (HR) for NAFLD and found that women with PCOS had an increased rate of NAFLD (HR = 2.23, 95% CI 1.86–2.66, p < 0.001), also after adjusting for BMI or dysglycemia. Serum testosterone >3.0 nmol/L was associated with an increase in NAFLD (HR = 2.30, 95% CI 1.16–4.53, p = 0.017 for 3–3.49 nmol/L and HR = 2.40, 95% CI 1.24–4.66, p = 0.009 for >3.5 nmol/L). Mirroring this finding, SHBG <30 nmol/L was associated with increased NAFLD hazard (HR = 4.75, 95% CI 2.44–9.25, p < 0.001 for 20–29.99 nmol/L and HR = 4.98, 95% CI 2.45–10.11, p < 0.001 for <20 nmol/L). Limitations of this study include its retrospective nature, absence of detailed information on criteria used to diagnosis PCOS and NAFLD, and absence of data on laboratory assays used to measure serum androgens. We found that women with PCOS have an increased rate of NAFLD. In addition to increased BMI and dysglycemia, androgen excess contributes to the development of NAFLD in women with PCOS. In women with PCOS-related androgen excess, systematic NAFLD screening should be considered. Krishnarajah Nirantharakumar and colleagues indicate a link between high levels of androgen and the development of nonalcoholic fatty liver disease in women with polycystic ovary syndrome. Polycystic ovary syndrome (PCOS) affects 10% of women and is defined by androgen excess, chronic anovulation, and polycystic appearance of the ovaries on ultrasound. PCOS is not only a reproductive but also a lifelong metabolic disorder with increased rates of type 2 diabetes, hypertension, and cardiovascular events. Recent research has shown rates of nonalcoholic fatty liver disease (NAFLD) may be higher in women with PCOS and that androgens may play a causative role in its pathogenesis. We performed a population-based retrospective cohort study utilizing a large UK primary care database and included more than 63,000 women with PCOS and 121,000 matched controls registered between 2000 and 2016. We found that rates of NAFLD were increased in women with PCOS. We found that even normal-weight women with PCOS had an increased rate of NAFLD. In addition to body mass index and dysglycemia, we identified androgen excess as a potential additional contributing risk factor for NAFLD development in PCOS. We also studied 2 independent cohorts drawn from the same primary care database who had serum testosterone (n = 71,000) or sex hormone-binding globulin (SHBG, n = 49,000) measured and found that women with biochemical evidence of androgen excess (high testosterone, low SHBG) had an increased rate of NAFLD. Our findings indicate there may be an increased risk of NAFLD in women with PCOS and that androgen excess is a factor underlying that risk. Screening for NAFLD should be considered in women with PCOS-related androgen excess. Future studies will need to determine if androgen excess also drives progression to liver inflammation and fibrosis and to establish whether antiandrogen medication can reduce the risk of NAFLD.
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